Klaus & Fanaroff's Care of The High-Risk Neonate

Avroy A.
Fanaroff, MD, FRCP, FRCPCH

Professor Emeritus
Department of Pediatrics and Neonatology in Reproductive Biology
Case Western Reserve University School of Medicine;
Eliza Henry Barnes Chair in Neonatology
Department of Pediatrics
Rainbow Babies and Children’s Hospital
Cleveland, Ohio
Jonathan M. Fanaroff, MD, JD

Associate Professor
Case Western Reserve University School of Medicine;
Director, Rainbow Center for Pediatric Ethics
Co-Director, Neonatal Intensive Care Unit
Rainbow Babies and Children’s Hospital/University
Hospitals Case Medical Center
Cleveland, Ohio
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KLAUS & FANAROFF’S CARE OF THE HIGH-RISK NEONATE ISBN: 978-1-4160-4001-9

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Library of Congress Cataloging-in-Publication Data

Klaus & Fanaroff’s care of the high-risk neonate / [edited by] Avroy A. Fanaroff,
Jonathan M. Fanaroff. — 6th ed.
p. ; cm.
Care of the high-risk neonate
Rev. ed. of: Care of the high-risk neonate / [edited by] Marshall H. Klaus, Avroy A. Fanaroff.
5th ed. c2001.
Includes index.
ISBN 978-1-4160-4001-9 (hardcover : alk. paper)
I. Fanaroff, Avroy A. II. Fanaroff, Jonathan M. III. Klaus, Marshall H., 1927- IV. Care of the
high-risk neonate. V. Title: Care of the high-risk neonate.
[DNLM: 1. Infant, Newborn. 2. Infant Care. 3. Infant, Newborn, Diseases—therapy.
4. Intensive Care, Neonatal. WS 420]
618.92’01—dc23 2012028210
Senior Content Strategist: Stefanie Jewell-Thomas

Content Development Specialist: Rachel Miller
Publishing Services Manager: Anne Altepeter
Senior Project Manager: Cheryl A. Abbott
Design Direction: Steven Stave
Cover image courtesy Bella Baby Photography
Printed in the United States
Last digit is the print number: 9 8 7 6 5 4 3 2 1

To all students of perinatology; our patients and their parents;
Roslyn and Kristy Fanaroff; Peter, Jodi, Austin, and Morgan Tucker;
and Amanda, Jason, Jackson, and Raya Lily Hirsh
Contributors
David H. Adamkin, MD Waldemar A. Carlo, MD

Professor of Pediatrics Edwin M. Dixon Professor of Pediatrics
Director of Neonatal Medicine Department of Pediatrics
Director of Neonatal Research Director, Division of Neonatology
Co-Director of Neonatal Fellowship University of Alabama at Birmingham
Program Birmingham, Alabama
University of Louisville;
Attending Physician, Neonatal Intensive Moira A. Crowley, MD
Care Unit Assistant Professor
Kosair Children’s Hospital; Department of Pediatrics
Attending Physician, Neonatal Intensive Case Western Reserve University School
Care Unit of Medicine;
University of Louisville Hospital Attending Physician
Louisville, Kentucky Division of Neonatology
Sanjay P. Ahuja, MD, MSc Cleveland, Ohio
Associate Professor
Department of Pediatrics Clifford L. Cua, MD
Case Western Reserve University School Associate Professor of Pediatrics, Heart
of Medicine Center
Director, Hemostasis and Thrombosis Department of Pediatrics
Center Nationwide Children’s Hospital
Rainbow Babies and Children’s Hospital The Ohio State University, College
Cleveland, Ohio of Medicine
Columbus, Ohio
Namasivayam Ambalavanan, MD
Professor Arthur E. D’Harlingue, MD
Department of Pediatrics Medical Director, Neonatal Intensive
University of Alabama at Birmingham Care Unit
Birmingham, Alabama Division of Neonatology
Children’s Hospital and Research Center,
Jill E. Baley, MD Oakland
Professor Oakland, California
Case Western Reserve University School Avroy A. Fanaroff, MD, FRCP,
of Medicine; FRCPCH
Medical Director, Neonatal Transitional Professor Emeritus
Care Unit Department of Pediatrics and Neonatology
Department of Pediatrics in Reproductive Biology
Rainbow Babies and Children’s Hospital Case Western Reserve University School
Cleveland, Ohio of Medicine;
Eliza Henry Barnes Chair in Neonatology
Sheila C. Berlin, MD Department of Pediatrics
Assistant Professor of Radiology Rainbow Babies and Children’s Hospital
Department of Radiology Cleveland, Ohio
Case Western Reserve University School
of Medicine;
Pediatric Radiologist
Department of Diagnostic Radiology
Cleveland, Ohio
v
vi CONTRIBUTORS
Jonathan M. Fanaroff, MD, JD David N. Kenagy, MD

Associate Professor Assistant Professor
Department of Pediatrics Department of Pediatrics
Case Western Reserve University School Case Western Reserve University School
of Medicine; of Medicine
Director, Rainbow Center for Pediatric Ethics Cleveland, Ohio
Co-Director, Neonatal Intensive Care Unit
Rainbow Babies and Children’s Hospital/ John H. Kennell, MD
University Hospitals Case Medical Center Professor Emeritus
Cleveland, Ohio Department of Pediatrics
Neil N. Finer, MD of Medicine
Professor Cleveland, Ohio
University of California, San Diego School Marshall H. Klaus, MD
of Medicine; Professor Emeritus
Director, Division of Neonatology Department of Pediatrics
Department of Pediatrics University of California, San Francisco
University of California, San Diego San Francisco, California
Medical Center
San Diego, California Robert M. Kliegman, MD
Professor and Chair
Kimberly S. Gecsi, MD Department of Pediatrics
Assistant Professor Medical College of Wisconsin;
Department of Reproductive Biology Pediatrician-in-Chief
Case Western Reserve University School Pamela and Leslie Muma Chair in Pediatrics
of Medicine; Children’s Hospital of Wisconsin
Director, Obstetrics and Gynecology Milwaukee, Wisconsin
Clerkship
Department of Obstetrics and Gynecology Justin R. Lappen, MD
MacDonald Women’s Hospital Assistant Professor
University Hospitals Case Medical Center Department of Reproductive Biology
Cleveland, Ohio (Obstetrics and Gynecology)
Maureen Hack, MBChB of Medicine;
Professor Assistant Director, Residency Program
Department of Pediatrics Department of Obstetrics and Gynecology
Case Western Reserve University School Director, Fellowship in Advanced Obstetrics
of Medicine; Department of Family Medicine
Co-Director, High-Risk Follow-Up Clinic University Hospitals Case Medical Center
Department of Pediatrics Cleveland, Ohio
Cleveland, Ohio Linda Lefrak, RN, MS
Neonatal Clinical Nurse Specialist
Leta Houston Hickey, RN, MSN, Benioff Children’s Hospital
NNP-BC University of California, San Francisco
Neonatal Nurse Practitioner II San Francisco, California
Division of Neonatology
Rainbow Babies and Children’s Hospital/ Ethan G. Leonard, MD
University Hospitals Case Medical Center Associate Professor
Rosemary D. Higgins, MD of Medicine;
Program Scientist and Medical Officer Vice Chair for Quality
Pregnancy and Perinatology Branch Department of Pediatric Infectious Disease
National Institute of Child Health Rainbow Babies and Children’s Hospital
and Human Development Cleveland, Ohio
National Institutes of Health
Bethesda, Maryland
CONTRIBUTORS vii
Tina A. Leone, MD M. Jeffrey Maisels, MB, BCh, DSc

Associate Clinical Professor and Director, Professor and Chair
Neonatal-Perinatal Medicine Training Department of Pediatrics
Program Oakland University William Beaumont
Department of Pediatrics, Division of School of Medicine;
Neonatology Physician in Chief
University of California, San Diego School Beaumont Children’s Hospital
of Medicine; Royal Oak, Michigan
Attending Physician
Department of Pediatrics, Division of Richard J. Martin, MD
Neonatology Professor
University of California, San Diego Department of Pediatrics, Reproductive
Medical Center Biology, and Physiology & Biophysics
San Diego, California Case Western Reserve University School
of Medicine;
John Letterio, MD Drusinsky/Fanaroff Professor
Professor Department of Pediatrics
Department of Pediatrics, Division of Rainbow Babies and Children’s Hospital
Pediatric Hematology/Oncology Cleveland, Ohio
of Medicine Jacquelyn McClary, PharmD, BCPS
Cleveland, Ohio Clinical Pharmacist Specialist
Neonatal Intensive Care Unit
Jennifer Levy, MD Department of Pharmacy
Attending Neonatologist Rainbow Babies and Children’s Hospital
Division of Neonatology Cleveland, Ohio
Children’s Hospital and Research Center,
Oakland Lawrence J. Nelson, PhD, JD
Oakland, California Associate Professor
Department of Philosophy
Salisa Lewis, MS, RD Santa Clara University
Neonatal Nutritionist Santa Clara, California
Kosair Children’s Hospital
Louisville, Kentucky Mary Elaine Patrinos, MD
Assistant Professor
Tom Lissauer, MB BChir, FRCPCH Department of Pediatrics
Honorary Consultant Pediatrician Case Western Reserve University School
Consultant Pediatric Program Director of Medicine;
in Global Health Attending Neonatologist
Imperial College London Department of Pediatrics
London, United Kingdom Rainbow Babies and Children’s Hospital
Cleveland, Ohio
Carolyn Houska Lund, MS, RN, FAAN
Associate Clinical Professor Agne Petrosiute, MD
Department of Family Health Care Clinical Instructor
Nursing Department of Pediatrics
University of California, San Francisco University Hospitals Case Medical Center
San Francisco, California; Rainbow Babies and Children’s Hospital
Neonatal Clinical Nurse Specialist Cleveland, Ohio
Neonatal Intensive Care Unit
Children’s Hospital and Research Center, Christina M. Phelps, MD
Oakland Assistant Professor of Pediatrics, Heart
Oakland, California Center
Nationwide Children’s Hospital
Ohio State University, College of Medicine
Columbus, Ohio
viii CONTRIBUTORS
Paula G. Radmacher, MSPH, PhD Philip T. Thrush, MD

Assistant Professor Fellow, Heart Center
Department of Pediatrics, Division Department of Pediatrics
of Neonatal Medicine Nationwide Children’s Hospital
Neonatal Nutrition Research Laboratory The Ohio State University, College
University of Louisville School of Medicine of Medicine
Louisville, Kentucky Columbus, Ohio
Roya L. Rezaee, MD, FACOG Michael R. Uhing

Assistant Professor Professor
Department of Reproductive Biology Department of Pediatrics
Case Western Reserve University School Medical College of Wisconsin;
of Medicine; Medical Director
Medical Director, Women’s Health Center Neonatal Intensive Care Unit
Co-Director, Division of Sexual and Children’s Hospital of Wisconsin
Vulvovaginal Health Milwaukee, Wisconsin
Department of Obstetrics and Gynecology
MacDonald Women’s Hospital Beth A. Vogt, MD
University Hospitals Case Medical Center Associate Professor
Ricardo J. Rodriguez, MD of Medicine;
Associate Professor Attending Pediatric Nephrologist
Department of Pediatrics Department of Pediatric Nephrology
Cleveland Clinic Lerner College Rainbow Babies and Children’s Hospital
of Medicine, Case Western Reserve Cleveland, Ohio
University School of Medicine;
Chairman, Department of Neonatology Michele C. Walsh, MD, MS Epi
Pediatric Institute Professor
Cleveland Clinic Children’s Hospital Department of Pediatrics
Cleveland, Ohio Case Western Reserve University School
of Medicine;
Mark S. Scher, MD Chief, Division of Neonatology
Professor William and Lois Briggs Chair
Departments of Pediatrics and Neurology in Neonatology
Case Western Reserve University School Rainbow Babies and Children’s Hospital
of Medicine; Cleveland, Ohio
Division Chief, Pediatric Neurology
Director, Rainbow Neurological Center Jon F. Watchko, MD
Neurological Institute of University Professor of Pediatrics, Obstetrics,
Hospitals; Gynecology, and Reproductive Sciences
Director, Pediatric Neurointensive Care Division of Newborn Medicine
Program/Fetal Neurology Program Department of Pediatrics
Department of Pediatric Neurology University of Pittsburgh School of Medicine;
Rainbow Babies and Children’s Hospital/ Senior Scientist
University Hospitals Case Medical Center Magee-Women’s Research Institute
Cleveland, Ohio Pittsburgh, Pennsylvania
Phil Steer, Bsc, MD, FRCOG Deanne Wilson-Costello, MD

Emeritus Professor of Obstetrics Professor
and Gynecology Department of Pediatrics
Imperial College, London; Case Western Reserve University School
Consultant Obstetrician and Gynecologist of Medicine;
Chelsea and Westminster Hospital Director, High Risk Follow-Up Program
London, United Kingdom Department of Pediatrics
Division of Neonatology
Cleveland, Ohio
CONTRIBUTORS ix
COMMENTERS
Michael Caplan, MD Jonathan Hellmann, MBBCh,

Clinical Professor of Pediatrics FCP(SA), FRCP(C), MHSc
University of Chicago, Pritzker School Professor of Paediatrics
of Medicine University of Toronto
Chicago, Illinois; The Hospital for Sick Children
Chairman, Department of Pediatrics Toronto, Ontario, Canada
NorthShore University HealthSystem
Evanston, Illinois John Kattwinkel, MD
Charles Fuller Professor of Neonatology
Waldemar A. Carlo, MD Department of Pediatrics
Edwin M. Dixon Professor of Pediatrics University of Virginia
Department of Pediatrics Charlottesville, Virginia
Director, Division of Neonatology
University of Alabama at Birmingham
Birmingham, Alabama
Preface
It is with a great deal of humility, as well as practices and the accumulation of exten-
satisfaction, that we present the sixth edition sive data in randomized trials. To update
of Klaus & Fanaroff’s Care of the High-Risk Neo- this volume, each chapter has undergone
nate. There have been incredible advances comprehensive revision. To present fresh
in the field of neonatal-perinatal medicine perspectives and ideas, once again one
in the 40 years since the book was first pub- third of the chapters have been assigned to
lished. These include better understanding of new authors. However, we have adhered to
the pathophysiology of neonatal disorders, the basic format, utilizing text, case prob-
as well as sophisticated technologic advances lems, and critical comments. To emphasize
that permit monitoring, imaging, and sup- the importance of quality improvement
port of even the tiniest, least mature infant. and evidence-based medicine, we have
Over the same period, we have witnessed inserted a new lead chapter on this topic,
the development of therapeutic agents and which includes the role and impact of the
strategies to enable maximal survival with neonatal networks on modern neonatal
the least morbidity for many complicated intensive care.
neonatal structural and metabolic disor- Marshall H. Klaus, MD, has become an
ders. Although these advances are gratifying, emeritus author of this book. However,
many challenges remain. Prematurity, birth his wisdom, philosophy, and yearning
defects, neonatal infections, birth asphyxia, to provide quality, compassionate, and
and brain injury remain major causes of neo- minimally invasive care with emphasis on
natal mortality and morbidity. human milk feeding, alleviation of pain,
The dawning of the subspecialty in the and psychosocial support for the family,
late 1950s and the introduction of neonatal strongly pervades the book. We thank him
intensive care in the 1960s are often referred for his continuing support and inspiration.
to as the era of anecdotal medicine, accom- It has been a uniquely gratifying experi-
panied by many disasters. The first edition ence to have Jonathan M. Fanaroff, my
of Klaus & Fanaroff’s Care of the High-Risk son, assume the role of co-editor. We are all
Neonate, published toward the end of this grateful that this book continues to serve as
era in 1973, addressed the uncertainties in a companion and source of information for
knowledge by offering multiple choices and healthcare providers in many parts of the
approaches to management. Many of the world. Bonnie Siner, RN, has once again
gaps in knowledge have been filled, and there served as in-house editor extraordinaire.
is now sufficient data to practice a more uni- Without her we could never have com-
fied evidence-based neonatology. However, pleted this edition, and we are most grate-
evidence-based medicine predicts what hap- ful to have had her skillful assistance. We
pens to the masses but not the individual. thank, too, Rachel Miller and Judy Fletcher
The next era, individualized medicine, will at Elsevier for their support and assistance.
require the knowledge of the unique genetic We thank the authors and commenters
makeup of the individual and the applica- who gave of their time and knowledge. We
tion of therapeutics based on predictable also thank Bella Baby Photographers for
responses to pharmacologic agents. use of the cover image.
The 10-year interval between the fifth
and sixth editions of this book has been Avroy A. Fanaroff, MD, FRCP, FRCPCH
characterized by many changes in care Jonathan M. Fanaroff, MD, JD
xi
Evidence-Based
Medicine and the
Role of Networks in
Generating Evidence
Michele C. Walsh and Rosemary D. Higgins
1
The explosion of clinical research has led to of EBM within the reach of most practitio-
a conundrum in practice: Never before has ners.3 Neonatologists are indeed fortunate
so much evidence been generated to guide that the Eunice Kennedy Shriver National
practice, but the sheer volume generated Institute of Child Health and Human Devel-
makes it difficult for practitioners to keep opment (NICHD) has funded online publi-
pace with the knowledge, and new knowl- cation of the Neonatal Cochrane reviews for
edge rapidly eclipses existing practice. In more than a decade. This has contributed
2009, it is estimated that more than 120 ran- to the rapid uptake of EBM among neona-
domized clinical trials in neonatology were tal practitioners. The next innovation in
published.1 This dilemma has made it imper- EBM will incorporate rigorous assessments
ative that every physician become skilled at of quality improvement methods to aid us
evidence-based medicine (EBM), which, at in determining which methods most rapidly
its core as defined by Sackett in 1997 is “…a lead to the incorporation of evidence-based
process of life-long, self-directed learning treatments into practice. Many authors have
in which caring for our patients creates the documented that on average it takes more
need for clinically important information than 7 years for a new practice that has
about diagnosis, prognosis, therapy, and strong evidence of efficacy to achieve high
other clinical and health issues…”.2 This penetration at the bedside.4-6 Methods are
chapter will review the components of EBM needed to enhance the dissemination and
and the contribution of neonatal research uptake of these innovations. Physicians who
networks to the generation of high-quality are skilled in EBM are more likely to recog-
evidence. nize and incorporate these advances.
THE EVOLUTION OF EVIDENCE- A PRESCRIPTION FOR EVIDENCE-

BASED MEDICINE BASED MEDICINE FOCUSED
When first conceptualized in 1992 by Guyatt, PRACTICE
the fundamental principle of EBM was real Sackett and colleagues synthesized the steps
time application of the best available clini- needed to ask and answer a relevant ques-
cal evidence at the bedside. The chief barri- tion using EBM (Box 1-1). To these steps we
ers to such application in neonatology were have added a first step using the phrase by
the absence of high quality evidence and the Horbar, “developing the habit for using evi-
tedious search for, and synthesis of, avail- dence and implementing change,” which
able evidence. The development of large has been disseminated among neonatolo-
research collaboratives has led to the gen- gists by the Vermont Oxford Collaborative.7
eration of high-quality evidence. Advances
in computer technology and information DEVELOPING THE HABIT
management have made evidence avail- FOR EVIDENCE USE
able on the desktop of every clinician. The Medical students and residents who are
Cochrane Collaboration in 1990 developed educated in a culture that values, teaches,
standard approaches to literature review and models the use of EBM are more likely
and analyses that have placed the practice to apply the method themselves in later
1
2 CHAPTER 1 EVIDENCE-BASED MEDICINE AND THE ROLE OF NETWORKS
Steps in the Practice of Evidence- superior to ampicillin in the treatment of

Box 1-1. necrotizing enterocolitis?” Other questions
Based Medicine
that may be explored may relate to prognos-
1. Develop the habit for the use of evidence. tic factors or to risk factors.
2. Frame the question in a manner that can be
answered. Comparison
3. Search for evidence with maximum effi- What is the main alternative to compare
ciency from the most reliable sources. with the intervention (e.g., when compared
4. Critically appraise the evidence for its valid- with supportive therapy alone).
ity (closeness to the truth) and usefulness
(clinical application). Outcome
5. Apply the results of this appraisal in prac- State the outcome of interest in as specific
tice. terms as possible including a time horizon.
6. Evaluate the performance of the treatment. For example: “Will adding clindamycin to
ampicillin in a VLBW infant with stage 2
Adapted from Strauss SE, Richardson WS, necrotizing enterocolitis reduce mortality
Glasziou P, et al: Evidence-based medicine: how to
prior to hospital discharge?”
practice and teach EBM, ed 4, Churchill Livingstone,
2011.
A busy clinician will generate more ques-
tions than they have time to address. To
avoid frustration, the questions may be
prioritized by how critical the patient is, or
practice.8 Nevertheless, all physicians which question is of most interest to the cli-
can learn and practice the steps needed. nician. Other questions can be added to a
Research has shown that physicians who list, which can be used when off-service time
use EBM are more likely to be current in can be directed to self-education. Through
practice 15 years out of training than those this process the clinician will be actively
who are not practicing EBM.9 Today, the practicing lifelong learning.
American Board of Medical Specialties has
mandated continuous maintenance of cer- SEARCHING FOR EVIDENCE
tification, rather than permanent or inter- Searching for evidence to answer clinically
mittent recertification, as the best practice relevant questions is the most time con-
for documenting physician competency.10 suming aspect of practicing evidence-based
EBM will facilitate self-directed lifelong medicine. Strauss and others have sug-
learning and support maintenance of cer- gested that this is the major barrier to effec-
tification. tive implementation.11,12 Nordenstrom has
recommended that clinicians search for
FRAMING THE QUESTION evidence using online sources that contain
To be easily answered, the exact question critically reviewed data directed at clinical
must be carefully framed. Strauss and col- questions.13 By prioritizing sources, the cli-
leagues have summarized the four elements nicians’ time is used most efficiently. Nor-
of a good question as “PICO”: Patient pop- denstrom recommends that the first source
ulation, Intervention, Comparison, Out- should be the Cochrane Collaboration, fol-
come.2 lowed by meta search engines including
Google Scholar. The next step is to search
Patient Population secondary sources focused on clinical ques-
Describe precisely the patient population tions such as the United Kingdom’s National
under consideration; for example, “infants Institute for Health and Clinical Excel-
born at <28 weeks’ gestation,” OR “inborn lence (www.nice.org.uk), the United States
infants <28 weeks’ gestation,” OR “very low- Agency for Healthcare Research and Qual-
birth-weight (VLBW) neonates who remain ity Effective Health Care Program (http://
intubated and mechanically ventilated at 14 effectivehealthcare.ahrq.gov) or Up To
days of age.” The more precisely the popula- Date (www.uptodate.com), a commercial
tion is defined, the more targeted the search online source generated by content experts.
for evidence will be. Perhaps surprisingly, Nordenstrom rec-
ommends that PubMed be searched last,
Intervention because 75% of the PubMed content deals
Describe the main intervention in which you with basic science research topics versus
are interested. For example: “Is clindamycin clinically relevant questions. Thus, for a
CHAPTER 1 EVIDENCE-BASED MEDICINE AND THE ROLE OF NETWORKS 3
Table 1-1. The GRADE System
Study Design Quality of Evidence Lower/Higher Level of Quality if:

Randomized trial • High (further research is very unlikely to • Risk of bias (serious [−1]; very serious [−2])
change our confidence in the estimate • Inconsistency (serious [−1]; very serious [−2])
of effect) • Indirectness (serious [−1]; very serious [−2])
• Moderate (further research is likely • Imprecision (serious [−1]; very serious [−2])
to have an important impact on our • Publication bias (likely [−1]; very likely [−2])
confidence in the estimate of effect • Large effect (large [+1]; very large [+2])
and may change the estimate) • Evidence of a dose-response gradient (+1)
Observational trial • Low (further research is very likely • All plausible confounding: would reduce a dem-
to have an important impact on our onstrated effect (+1); would suggest a spurious
confidence in the estimate of effect effect when results show no effect (+1)
and is likely to change the estimate)
• Very low (any estimate of effect is very
uncertain)
Adapted from Scott IA, Guyatt GH: Clinical practice guidelines: the need for greater transparency in
formulating recommendations, Med J Aust 195(1):29, 2011.
busy clinician other sources are likely to of clinical epidemiologists have proposed
yield a better answer faster. a system that combines many of the ele-
ments of other systems and termed this
CRITICALLY APPRAISE THE EVIDENCE the GRADE (Grading of Recommendations
FOR VALIDITY, APPLICABILITY AND Assessment, Development, and Evalua-
IMPORTANCE tion) system.14 The British Journal of Medi-
In this discussion, we will focus on the cine has required a GRADE assessment of
appraisal of evidence regarding treatments. recommendations since 2006, and now
The highest hierarchy of evidence for these more than 25 groups who generate system-
are results from a randomized controlled atic reviews, including the World Health
trial. The following critical questions to ask Organization, the American College of
when assessing the validity of a trial are: Physicians, the American Thoracic Soci-
1. Were patients randomly assigned to the ety, UpToDate (www.uptodate.com), and
treatment? the Cochrane Collaboration have adopted
2. Were all patients who were randomized the GRADE standard (Table 1-1). The Grade
accounted for in the analysis? Were they system synthesizes the evidence into a rec-
analyzed in the group to which they were ommendation based first on the quality of
assigned (intent-to-treat analysis)? the evidence and second on the magnitude
3. Were patients, the clinicians caring for of effects, thereby yielding a recommenda-
them, and those assessing the outcome tion which is either “strong” or “weak.” The
kept masked to the treatment assign- GRADE system classifies quality of evidence
ment? into four levels: high, moderate, low, or very
4. Were the groups similar at the beginning low. Evidence from randomized controlled
of the trial? trials (RCTs) begins as high quality, but may
Randomized trials provide the most non- be rated down if trials demonstrate one of
biased assessment of the effect of a treat- five categories of limitations. Observational
ment. If the trial is not randomized, it may studies begin as low-quality evidence, but
be best to stop reading and search for other may be rated up if associated with one of
sources. If the only evidence available is three categories of special strengths.
from a nonrandomized study, one must The GRADE system suggests that when
view the stated effects with some skepticism the desirable effects of a treatment clearly
because the odds ratios from randomized outweigh the undesirable effects, or the
trials are generally smaller than those from contrary, that guideline offers strong rec-
nonrandomized studies. ommendations. When the data are less
There are a number of different sys- clear, such as when the quality of existing
tems proposed for grading the quality of evidence is low or when undesirable effects
evidence. The proliferation of systems outweigh desireable effects, the recom-
has made it difficult to adopt and under- mendations should be rated as weak, or
stand any one method. Recently, a group equivocal. Such a standardized approach
to rating the evidence would clearly ben- for evidence-based care for newborns. Several
efit clinicians. groups, including the NICHD the Neonatal
Research Network, the Canadian Neonatal
Applying the Evidence in Daily Practice Network, the Vermont Oxford Network, as
The Institute of Medicine (IOM) focuses on well as international networks, have been
the promise of evidence-based medicine to established and maintained to investigate
improve the quality and effectiveness of evidence-based strategies, including observa-
health care, and has also highlighted barri- tional studies, interventional clinical trials,
ers in the current system. The IOM cites “an and quality improvement initiatives. These
irony of the information-rich environment networks have made significant contribu-
is that information important to clinical tions to patient care and quality improve-
decision making is often not available, or is ment. This chapter will discuss advantages,
provided in forms that are not relevant to opportunities, and challenges for research
the broad spectrum of patients—with differ- networks as well as selected highlights from
ing levels of health, socioeconomic circum- the various networks.
stances, and preferences—and the issues Clinical networks can offer large num-
encountered in clinical practice.”15 In the bers of patients for study. For uncommon
IOM view, these limitations are driven by or rare conditions, networks can provide the
a paucity of clinical effectiveness research, numbers of patients needed to study dis-
poor dissemination of the evidence that is eases in an observational or interventional
available, and too few incentives and deci- study. Generally, networks are set up to look
sion supports for evidence-based care. Glen- at specific disease categories. The neonatal
ton and colleagues described several factors networks and collaborations concentrate on
hindering the effective use of systematic diseases of the newborn, particularly those
reviews for clinical decision making.15 They affecting preterm infants and critically ill,
found that reviews often lacked details about late preterm and term infants. Many of
interventions and did not provide adequate the neonatal networks have access to high-
information on the risks of adverse events, risk obstetrics or maternal-fetal medicine
the availability of interventions, and the consultants at their institutions. In addi-
context in which the interventions may or tion, most have level III newborn intensive
may not work. care units (NICUs) for care of patients and
recruitment of patients for clinical studies.
Evaluate the Performance Well-developed and established networks
of the Treatment have provisions for follow-up of the infants
The final step in EBM is to assess the out- and children after hospital discharge.
come of the treatment. Did the patient (or The NICHD Neonatal Research Network
their parents) judge their condition to be (NRN) was established in 1986 to form a set
improved? Was the treatment cost-effective? of academic centers to conduct common
Did the treatment fit within the context of protocols for observational and interven-
the unique circumstances and biology of tional studies of newborns.19,20 The goal
the family? If a similar scenario was encoun- of the NRN is to provide the research evi-
tered again, what would the clinician do dif- dence to facilitate advancement of neonatal
ferently? This habit for critical self-appraisal care by providing infrastructure for a net-
and unremitting learning is at the heart of work of academic centers to study required
EBM. Only by widespread implementation numbers of patients to provide data more
of the principals of EBM is healthcare qual- rapidly than individual center studies. The
ity and value likely to improve.16,17 perceived advantages of a network of cen-
ters included large patient numbers to pro-
CRITICAL PROGRESS IN vide evidence more rapidly than individual
GENERATING THE EVIDENCE: study sites, availability of patients with rare
THE ROLE OF NEONATAL or rarer diseases (such as hypoxic-ischemic
RESEARCH NETWORKS encephalopathy), and available infrastruc-
Neonatal-perinatal medicine was recognized ture for clinical studies (Table 1-2). Fur-
as a subspecialty by the American Board of ther, specialized needs including high-risk
Pediatrics in 1975.18 In the past 2 to 3 decades, pregnancy study subjects, preterm infants,
it has become increasingly apparent that neo- capability of short-term outcome ascertain-
natal research requires observational studies ment, and longer term follow-up can be
and interventional trials to provide the basis mandated in a request for application (RFA).
Table 1-2. Impact of Interventional Randomized Trials of the Eunice Kennedy Shriver NICHD Neonatal Research Network*
Study Patient Enrollment Outcome Impact
A Controlled Trial of Intravenous 2416 infants 501-1500 grams IVIG failed to significantly reduce Routine use of IVIG not recommended for
Immune Globulin to Reduce randomized by 72 hours of life to nosocomial infections (17% IVIG prevention of infection in VLBW infants.
Nosocomial Infections in Very Low IVIG or placebo (phase I)/no infusion vs 19% control). Increased NEC in
CHAPTER 1 EVIDENCE-BASED MEDICINE AND THE ROLE OF NETWORKS

Birth Weight Infants (phase II). infused groups.
N Engl J Med 330:1107, 1994
The Effect of Antenatal 610 women with gestation ≥24 and Antenatal administration of Prophylactic use of antenatal
Phenobarbital Therapy on Neonatal <33 weeks anticipated to deliver phenobarbital did not reduce the phenobarbital to prevent intracranial
Intracranial Hemorrhage in Preterm within 24 hours randomized to receive incidence of intracranial hemorrhage hemorrhage in preterm infants not
Infants phenobarbital or placebo daily until or early death (24% vs 23%) in infants recommended.
N Engl J Med 337:466, 1997 delivery or 34 weeks. born <34 weeks.
Vitamin A Supplementation for 807 infants ≤1000 grams randomized Vitamin A supplementation Routine use of vitamin A supplementation
Extremely Low Birth Weight Infants to receive IM injection of vitamin A or significantly reduced risk of CLD or recommended for infants ≤1000 grams in
N Engl J Med 340:1962, 1999 control (sham injection) 3 times per death (55% vs 62%). the first month of life.
week for 4 weeks.
Effects of Early Erythropoietin 290 infants 401-1250 grams birth Combination of erythropoietin and Early use of erythropoietin and iron
Therapy on the Transfusion weight randomized to erythropoietin iron-stimulated erythropoiesis but did to reduce transfusion number and
Requirements of Preterm Infants or placebo until 35 weeks’ post not affect transfusion requirements exposure of infants to the risks of multiple
Below 1250 Grams Birth Weight: A menstrual age. (4.3 vs 5.2 transfusions) in treated vs. transfusions not warranted.
Multicenter, Randomized Controlled control preterm infants ≤1250 grams.
Trial
Pediatrics 108(4):934, 2001
Parenteral Glutamine 1433 infants 401-1000 grams Parenteral glutamine supplementation Routine use of parenteral glutamine
Supplementation Does Not Reduce randomized to parenteral nutrition did not decrease rate of mortality or supplementation to reduce the risk of
the Risk of Mortality or Late-Onset with glutamine supplementation or late-onset sepsis (51% vs. 48%) in death or late-onset sepsis in ELBW
Sepsis in Extremely Low Birth control (standard parenteral nutrition). infants ≤1000 grams. infants not recommended. Importance of
Weight Infants early protein administration recognized,
Pediatrics 113(5):1209, 2004 changing practice.
Randomized Clinical Trial of 371 infants 501-1500 grams treated No clear pulmonary benefit starting Awareness of harmful effects of
Dexamethasone Therapy in Very DOL 14-42 with dexamethasone/ dexamethasone at 2 weeks vs. dexamethasone therapy for ventilator-
Low Birth Weight (VLBW) Infants placebo or placebo/dexamethasone. 4 weeks of age (39% vs. 42%). dependent premature infants. Decreased
at Risk for Chronic Lung Disease Dexamethasone increased GI use of postnatal steroids.
(CLD) perforation, hypertension, and
N Engl J Med 338:1112, 1998 hyperglycemia.
Inhaled Nitric Oxide for Premature 420 infants <34 weeks’ gestation No difference in incidence of BPD or No benefit to the early use of inhaled
Infants with Severe Respiratory with BW 401-1500 grams with severe death in the inhaled nitric oxide and nitric oxide in premature infants with
Failure respiratory failure randomized to placebo groups (80% vs. 82%). severe respiratory failure.
N Engl J Med 353:13, 2005 receive inhaled nitric oxide or placebo.
Whole-Body Hypothermia for 208 term infants with moderate or Whole-body cooling safe and Whole-body cooling instituted as
Neonates with Hypoxic-Ischemic severe HIE randomized by 6 hours effective in reducing the risk of death standard of care for term infants with
Encephalopathy of age to whole-body cooling for 72 or moderate or severe disability (44% moderate or severe hypoxic-ischemic
N Engl J Med 353:1571, 2005 hours or usual care (normothermia). vs. 62%) among infants with HIE. encephalopathy.
5
Continued
6
Table 1-2. Impact of Interventional Randomized Trials of the Eunice Kennedy Shriver NICHD Neonatal Research Network*—cont’d
Study Patient Enrollment Outcome Impact
Aggressive vs Conservative 1974 infants with BW 501-1000 No significant effect of aggressive vs Treatment still not standardized.
Phototherapy for Infants with grams randomized to aggressive or conservative phototherapy on death
Extremely Low Birth Weight conservative phototherapy by 12-36 or NDI. Aggressive phototherapy
CHAPTER 1 EVIDENCE-BASED MEDICINE AND THE ROLE OF NETWORKS

N Engl J Med 359:1885, 2008 hours of age. significantly reduced overall rate of NDI,
but showed trend toward increased
mortality in infants 501-750 grams.
Target Ranges of Oxygen 1316 infants 240 to 276 weeks’ No significant difference in the Caution for the use of low saturation
Saturation in Extremely Preterm gestation randomized at birth to combined primary outcome of severe ranges due to the increased risk of
Infants targeted oxygen saturation ranges of ROP or death between the low and mortality among preterm infants. Current
N Engl J Med 362:1959, 2010 low (85%-89%) vs. high (91%-95%) high saturation groups (28% vs. 32%) practice to keep saturation ranges of
until 36 weeks’ postmenstrual age or no but with increased risk of in-hospital 90%-94%.
longer receiving oxygen or respiratory death and reduced risk of severe ROP
support. (9% vs. 18%) in the low saturation
ranges.
Early CPAP versus Surfactant in 1316 infants 240 to 276 weeks No significant difference in Consideration for the use of CPAP as an
Extremely Preterm Infants randomized at birth to begin combined outcome of death or alternative to intubation and surfactant
N Engl J Med 362:1970, 2010 treatment with CPAP and limited bronchopulmonary dysplasia when administration in preterm infants.
ventilation or intubation and early defining BPD by the physiological
surfactant followed by conventional definition (48% vs. 51%) or the need
ventilation. for supplemental oxygen at 36 weeks
(49% vs. 54%).
Table prepared by N. Newman BA, RN, from data at neonatal.rti.org/studies.cfm.

BPD, Bronchopulmonary dysplasia; BW, birth weight; CLD, chronic lung disease; CPAP, continuous positive airway pressure; DOL, day of life; ELBW, extremely low
birth weight; GI, gastrointestinal; HIE, hypoxic-ischemic encephalopathy; IM, intramuscular; IVIG, intravenous immunoglobulin; IVH, intraventricular hemorrhage; NDI,
neurodevelopmental impairment; NEC, necrotizing enterocolitis; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; VLBW, very low birth weight.
The network is subject to open competition the intensive care nursery, including phy-
on 5-year cycles and undergoes peer review sicians, nurses, therapists, and consultants
and a second level of review by the NICHD to participate in the studies can be chal-
advisory council. The collective knowledge lenging. Education and in-service training
of the principal investigators, follow-up are performed on a routine basis. Time to
investigators, and coinvestigators at the study start can be highly variable depend-
individual study sites, are a clear advantage ing on staff, institutional review board lead
in determining appropriate studies, feasibil- time for submission, review and approval,
ity, and experimental design. Policies and and appropriate training at individual sites
procedures that are explicitly formulated and centers. Studies or trials that require
are allowed to change over time, depending recruitment in a short time window or at
on NICHD programmatic needs and input the time of delivery can pose significant
from the Steering Committee. challenges with research staff coverage on
The NICHD also has issued RFAs on 5-year nights, weekends, and holidays. Many suc-
cycles for a data coordinating center (DCC). cessful clinical research sites participate in
The DCC provides critical assistance with multiple projects at any one time, so the
study development and implementation. issue of conflicting trials must be addressed
Statistical expertise, as well as staff for data for each study.
collection, programming, study logistics The Canadian NICU Network was estab-
and training, data analysis, and manuscript lished in 1995 and funded by the Medical
writing is required. The DCC also assumes Research Council of Canada. The primary
responsibility for study monitoring, includ- objectives of the network were to establish a
ing activities required for data safety and standardized database of practices and out-
monitoring committee functions. The DCC comes, to examine variations in outcomes,
tracks patient enrollment and assists the and for improving efficiency and efficacy of
clinical sites with day-to-day activities nec- treatment in the NICU.21 Currently, there
essary for the conduct of studies. are members from 30 hospitals and 17 uni-
The NICHD NRN has been successful with versities in Canada. The network maintains
respect to recruiting and retaining patients. a standardized neonatal intensive care unit
Figure 1-1 shows a graphic representation of (NICU) database and conducts collabora-
NRN studies over time. Further, follow-up tive projects with the goal to improve neo-
rates at 18 to 22 months’ corrected age gen- natal health. The Canadian NICU Network
erally exceed 90% for clinical studies. The has provided multiple publications in the
clinical sites have various measures in place areas of practice variation and neonatal
to achieve optimum compliance, including outcomes, including mortality as well as
early identification of infants for follow-up, morbidity.
maintaining contact with families, schedul- The Vermont Oxford Network (VON)
ing and procedures for rescheduling missed consists of more than 800 institutions and
visits, and home visits for follow-up in spe- has worldwide representation.22 The VON
cific cases. is invested in quality and safety of medi-
The NICHD NRN has challenges in con- cal care for the newborn.23 The Network
ducting multicenter research. Center dif- provides an infrastructure for research,
ferences are a large challenge: populations education, and quality improvement. The
may be different, practice styles vary, and VON database is the largest data collection
equipment varies. Many units have written of infants weighing less than 1500 grams
policies or guidelines for specific manage- accruing over 56,000 births annually. It
ment such as nutrition, respiratory care, includes information on baseline character-
monitors, and so forth. Developing a clini- istics, interventions in the NICU serial, and
cal study oftentimes requires compromise acute hospital outcome information. The
as opposed to consensus. Simple defini- network provides a confidential Nightin-
tions can be a challenge if there is variation gale Internet Reporting System for centers
across sites. Determination of primary and to compare their data with data from other
secondary outcomes can be an area of lively VON hospitals. The VON also established a
debate. Further, determination of equipoise neonatal encephalopathy registry (NER) in
at any site may be a challenge, particularly if 2006 with the advent of cooling therapy
there are passionate views on management for hypoxic-ischemic encephalopathy (HIE)
strategies or entrenched systems of belief in with the primary objective of characterizing
patient care. Agreement from the staff in infants with neonatal encephalopathy.24
'85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 '10 '11 '12 '13 '14 '15
GDB
IVIG
Surfactant 1
Jaundice 1
Dexamethasone
Maternal lifestyles study

PPHN
STOP ROP
TIPP
Ballard
Growth
NINOS
Vitamin A
MgSO4
EPO
SAVE
Early iNO
Glutamine
Whole-body cooling
Cytokines
Delayed cord clamping
Surfactant 2
Benchmarking
Preemie iNO
NEC surgery
Delivery room CPAP
Phototherapy
Candida
PCV-7
Physiologic definition
SUPPORT
New aEEG
Early onset sepsis
Inositol single-dose pilot
Late hypothermia
IPGE1 pilot
Term hypotension
Early blood pressure pilot
Preemie aEEG pilot
Inositol multi-dose pilot
NEC laparotomy vs. drain
Observational trial Ongoing

Interventional trial Upcoming observational trial
Follow-up, 18-24 months Upcoming interventional trial
Follow-up, 30 months Upcoming follow-up
Follow-up, 6-7 years Summary
Figure 1-1. Neonatal Research Network Trial Timeline, 1987 to present. aEEG, Amplitude integrated electroencephalogram;
CPAP, continuous positive airway pressure; EPO, erythropoietin; GDB, generic database; iNO, inhaled nitric oxide; IPGE1,
inhaled prostaglandin E1; IVIG, intravenous immune globulin; NEC, necrotizing enterocolitis; NINOS, neonatal inhaled nitric
oxide study; PPHN, persistent pulmonary hypertension; ROP, retinopathy of prematurity; SAVE, steroids and ventilation;
STOP ROP, supplemental therapeutic oxygen for prethreshold ROP; TIPP, Trial of indomethacin prophylaxis.
Monitoring the introduction and dissemi- Regional initiatives are rapidly growing
nation of hypothermic therapy was a sec- in the United States. The California Peri-
ondary objective for the NER. The VON natal Quality Care Collaborative (CPQCC)
provides various tools and resources with was established as a regional collaboration
emphasis on high quality and safe care for to improve perinatal care.30 This entity is
newborns and their families. largely focused on quality improvement,
The Australian and New Zealand Neo- and has research and collaboration as vital
natal Network (ANZNN) was established components. There are now additional
in 1994 following a recommendation from statewide neonatal improvement collabora-
the National Health and Medical Research tive centers active in Ohio, New York, North
Council’s (NHMRC) Expert Panel on Peri- Carolina, and Tennessee.
natal Medicine. The goal is to improve the Various neonatal networks have been
care of high-risk newborn infants and their established over the past 25 years with
families through collaborative audits and common goals, including improvement of
research.25 The network’s achievements patient care and outcome, as well as quality
are in areas including follow-up outcome, improvement. Well-designed observational
mortality, retinopathy of prematurity, and studies and interventional trials have pro-
chronic lung disease. vided evidence for practice recommenda-
Various other networks and individual tions from the various networks. Care and
study groups have been organized in neona- management of high-risk newborns con-
tology. The international perspective, as well tinues to be advanced by existence of these
as an international perspective devoted to networks to provide the evidence to guide
sepsis in very low-birth-weight infants, has optimum medical treatment.
recently been reviewed.26,27 Region-specific
networks including China and the Middle REFERENCES
East have been developed to investigate neo- The reference list for this chapter can be found
natal-perinatal medicine and genetics.28,29 online at www.expertconsult.com.
2
Antenatal and
Intrapartum Care of
the High-Risk Infant
Roya L. Rezaee, Justin R. Lappen, and Kimberly S. Gecsi
Everything ought to be done to ensure that an infant be born at term, well developed,
and in a healthy condition. But in spite of every care, infants are born prematurely.
Pierre Budin, The Nursling
Preparations can be made for certain medi-

IDENTIFICATION OF THE PREGNANCY cal and obstetrical conditions long before
AT RISK untoward effects have occurred. There-
The goal of prenatal care is to ensure optimal fore, any such assessment should include
outcomes for both baby and mother. Prena- a detailed history that involves elements
tal care involves a series of assessments over of personal and demographic information,
time as well as education and counseling personal and family medical, psychiatric
that help guide the interventions that may and genetic histories, past obstetrical, gyne-
be offered. A significant part of the process cological, menstrual and surgical histories,
involves identifying a pregnancy as high current pregnancy history, domestic vio-
risk. Early and accurate establishment of lence history, and drug and tobacco use his-
gestational age, identification of the patient tory. The care provider should also assess for
at risk for complications, anticipation of any barriers to care and whether the patient
complications, and the timely implementa- has any social concerns that would be better
tion of screening, diagnosis, and treatment evaluated and managed by someone with
help to achieve these goals. The distinction social services expertise.2
between a high-risk versus a low-risk preg- Accurate estimation of date of delivery
nancy and/or mother gives the provider the (EDD) is crucial to the timing of interven-
opportunity to potentially intervene prior tions, monitoring fetal growth and timing
to the advent of adverse outcomes. This of delivery, as well as for overall manage-
chapter will discuss the identification of the ment. This is usually calculated from the
high-risk pregnancy focusing on some of date of a known last menstrual period (LMP)
the more commonly encountered fetal and and can be confirmed by ultrasound if dat-
maternal conditions. ing is uncertain due to irregular menses or
Many of the principal determinants of if conception occurred on hormonal contra-
perinatal morbidity and mortality have been ception. A standard panel of tests is ordered
delineated. Included among these are mater- for all pregnant women at their first pre-
nal age, race, socioeconomic status, nutri- natal visit. This work-up is modified based
tional status, past obstetric history, family on the woman’s risk profile. What consti-
history, associated medical illness, and cur- tutes optimal prenatal care and performed
rent pregnancy problems. Ideally, the pro- by whom and how often may still be up for
cess of risk identification is established prior debate.3 Screening and treatment of asymp-
to conception because it is the time when tomatic bacteriuria, group B beta-hemolytic
counseling for and against certain behaviors, Streptococcus (GBS), and sexually transmit-
foods and nutritional supplements, medi- ted diseases for at-risk women to prevent
cations, work and environmental risks is the consequences of horizontal and vertical
likely to have the most beneficial outcome.1 transmission is indicated. Screening should
10
CHAPTER 2 Antenatal and Intrapartum Care of the High-Risk Infant 11
also be offered for fetal structural and chro- factors existing before pregnancy as well as
mosomal abnormalities and women who factors and events associated directly with
are Rh (D)-negative should receive anti pregnancy. Historically, an attempt was
(D)-immune globulin to prevent alloimmu- made to put these together into some type
nization and reduce the risk of hemolytic of assessment technique capable of distin-
disease of the newborn. Screening for mal- guishing most of the high-risk patients from
presentation of the fetus, as well as develop- the low-risk patients before delivery (Table
ment of preeclampsia in the mother, is also 2-1). Unfortunately, when these scoring
likely to have a great impact on pregnancy systems have been applied to a large popu-
outcomes. lation base, they have not resulted in sig-
In the United States, about 12% to 13% of nificant changes in the prematurity rates.
all live births are premature and about 2% are Still, the grouping of risk factors may be of
born at less than 32 weeks.4 Approximately some use to the obstetrical provider because
50% of these births are the result of sponta- it allows for the identification of the woman
neous preterm labor, 30% from preterm rup- who might need additional surveillance,
ture of membranes, and 20% from induced counseling, referral, and resources.
delivery secondary to maternal or fetal indi-
cations. Prematurity remains a significant BIRTH DEFECTS AND CONGENITAL
perinatal problem, because prematurity along DISORDERS
with the associated low birth weight is the Birth defects affect approximately 2% to 4%
most significant contributor to infant mortal- of liveborn infants. Contributing factors
ity. Mortality increases with both decreasing include genetic and environmental influ-
gestational age and birth weight. Additional ences such as maternal age, illness, industrial
causes of mortality include congenital anom- agents, intrauterine environment, infection,
alies, as well as delivering in a hospital with and drug exposure. The frequency of the var-
a lower level of resources and experience ious etiologies of birth defects can be broken
in providing such complex neonatal care. down as follows: unknown and multifacto-
Improvements in obstetric and neonatal care, rial origin, about 65% to 75%; genetic origin,
including surfactant, antenatal steroids, and about 25%; and environmental exposures,
maternal transport to an appropriate deliv- about 10% (Table 2-2).
ery facility capable of caring for high-risk The terminology used to describe these
neonates have decreased the mortality rates anomalies is based on their underlying
except in those at the limit of viability. cause: malformation, deformation, disrup-
The goal remains to identify at-risk tion, and dysplasia. Dysmorphology is the
women as soon as possible. Careful analy- study of individuals with abnormal features,
sis indicates that determinants of morbid- and increased scholarship in this area has
ity and mortality are composed of historical led to specialists who study birth defects
Table 2-1. Scoring System* for Risk of Preterm Delivery
Socioeconomic Status Past History Daily Habits

1 Two children at home One abortion <1 year since last birth Works outside home
Low socioeconomic status
2 <20 years Two abortions >10 cigarettes/day
>40 years
Single parent
3 Very low socioeconomic status Three abortions Heavy work
Height <150 cm Long, tiring trip
Weight <45 kg
4 <18 years Pyelonephritis
5 Uterine anomaly
Second-trimester abortion
Diethylstilbestrol exposure
10 Premature delivery
Repeated second-trimester abortion
Adapted from Creasy R, Gummer B, Liggins G: System for predicting spontaneous preterm birth, Obstet
Gynecol 55:692, 1980.
*Score is computed by addition of number of points given any item. 0-5 = Low risk; 6-9 = medium risk;
≥10 = high risk.
12 CHAPTER 2 Antenatal and Intrapartum Care of the High-Risk Infant
and establish patterns. The result has been Deformations are defects in the position of
a better understanding of many conditions, body parts arising from some intrauterine
which has improved the quality of coun- mechanical force that interferes with the
seling for families including possible recur- normal formation of the organ or structure.
rence rates in future pregnancies. Such uterine forces could include oligohy-
Malformations are considered major if dramnios, uterine malformations or tumors,
they have medical or social implications and fetal crowding from multiple gestations.
and many times they require surgical repair. Disruptions refer to defects that result from
Defects are considered to be minor if they the destruction of or interference with nor-
have only cosmetic relevance. They can mal development. These are typically single
arise from genetic or environmental factors. events that may involve infection, vascular
compromise, or mechanical factors. Amni-
otic band syndrome is the most common
Leading Categories of Birth example of a disruption and the timing
Table 2-2.
Defects
occurs from 28 days’ postconception to 18
Estimated weeks’ gestation. Dysplasias are defects that
Birth Defect Incidence (births) result from the abnormal organization of
cells into tissues. There are recognizable pat-
STRUCTURAL/METABOLIC terns in many congenital defects. The termi-
Heart and circulation 1 in 115 nology to describe these patterns includes
Muscles and skeleton 1 in 130
syndrome, sequence, association, and devel-
Genital and urinary tract 1 in 135
Nervous system and eye 1 in 235
opmental field defect.
Chromosomal syndromes 1 in 600 The study of congenital malformations
Club foot 1 in 735 caused by environmental or drug exposure
Down syndrome (trisomy 21) 1 in 900 is called teratology. An agent that causes an
Respiratory tract 1 in 900 abnormality in the function or structure of a
Cleft lip/palate 1 in 930 fetus is called a teratogen (Table 2-3). About
Spina bifida 1 in 2000 4% to 6% of birth defects are caused by
Metabolic disorders 1 in 3500 teratogens and include maternal illnesses,
Anencephaly 1 in 8000 infectious agents, physical agents and drugs,
Phenylketonuria (PKU) 1 in 12,000 and chemical agents. Timing of exposure to
CONGENITAL INFECTIONS the agent plays a great role in the resulting
Congenital syphilis 1 in 2000 malformation. Exposure during the first 10
Congenital HIV infection 1 in 2700
to 14 days postconception can result in cell
Congenital rubella syndrome 1 in 100,000
death and spontaneous miscarriage. The all-
OTHER
or-none theory refers to the possibility that
Rh disease 1 in 1400
Fetal alcohol syndrome 1 in 1000
if only a few cells are damaged, then the
other cells may compensate for their loss
Table 2-3. Common Teratogens
Type of Teratogen Agent Defect

Chemical Retinoic Acid Hydrocephalus, CNS migrations
Thalidomide Limb reduction
Valproic acid Neural tube defects
Phenytoin Heart defects, nail hypoplasia, dysmorphic features
Lithium Ebstein anomaly
ACE inhibitors Renal and skull defects
Misoprostol Fetal death, vascular disruptions
DES (diethylstilbestrol) Cervical cancer in daughters, genital anomalies in males and females
Physical Ionizing radiation Fetal death, growth restriction, leukemia
Hyperthermia Microcephaly, mental retardation, seizures
Biological Cytomegalovirus Microcephaly, mental retardation, deafness
Toxoplasmosis Hydrocephalus, mental retardation, chorioretinitis
Maternal Diabetes Congenital heart anomalies, neural tube defects, sacral anomalies
Phenylketonuria (PKU) Microcephaly, mental retardation
Adapted from Reece EA, Hobbins JC: Developmental toxicology, drugs and fetal teratogenesis. In Reece
EA, Hobbins JC, editors: Clinical obstetrics: the fetus and mother, ed 3, Malden, Mass., 2008, Blackwell,
p 215.
and result in no abnormality. Most effects and Drug Administration. Maternal expo-
are seen after fertilization, but exposure prior sure to numerous physical and environmen-
to conception can cause genetic mutations. tal agents has also been implicated as a cause
Mechanisms of teratogenesis are varied and of birth defects. High plasma levels of lead,
include cell death, altered cell growth, pro- mercury, and other heavy metals have been
liferation, migration, and interaction. The associated with central nervous system dam-
embryo is most vulnerable during the period age and negative neurobehavioral effects in
of organogenesis and this occurs up to the infants and children.6 More controversial are
eighth week postconception, but certain the recent concerns over maternal exposure
organ systems including the eye, central ner- to so-called endocrine disruptors, bisphenol
vous system (CNS), genitalia, and hemato- A (BPA), and phthalates, and airborne poly-
poietic systems continue to develop through cyclic aromatic hydrocarbons. These entities
the fetal stage and remain susceptible. are chemicals that mimic the action of natu-
Maternal illness that can present a tera- rally occurring hormones such as estrogen.
togenic risk involves conditions in which a These chemicals can be found in pesticides,
metabolite or antibody travels across the pla- leaching from plastics found in water and
centa and affects the fetus. Maternal illness infant bottles, medical devices, personal
can include pregestational diabetes, phe- care products, tobacco smoke, and other
nylketonuria, androgen-producing tumors, materials. Exposure to them is widespread,
maternal obesity, and systemic lupus ery- and a large portion of the population has
thematosus. The mother may be infected measurable levels.7 The chemicals have been
but asymptomatic. Ultrasonic findings sug- associated with adverse changes in behavior,
gestive of fetal infection include microceph- the brain, male and female reproductive sys-
aly, cerebral and/or hepatic calcifications, tems, and mammary glands.
intrauterine growth restriction, hepato- Our knowledge of the effects of ionizing
splenomegaly, cardiac malformations, limb radiation on the fetus has been based on
hypoplasia, hydrocephalus, and hydrops. case reports and extrapolation of data from
Maternal fever or hyperthermia has also survivors of atomic bombs and nuclear reac-
been associated with teratogenesis when it tor accidents. Radiation exposure during
occurs in the first trimester and may be asso- pregnancy is a clinical issue when diagnostic
ciated with miscarriage and/or neural tube imaging in a pregnant woman is required.
defects (Table 2-4).5 Possible hazards of radiation exposure
Maternal ingestion of certain drugs can include: pregnancy loss, congenital mal-
cause birth defects or adverse fetal out- formation, disturbances of growth and/or
comes. It is important that nonpregnant development, and carcinogenic effects.8 The
women are counseled about the need for U.S. Nuclear Regulatory Commission rec-
contraception when using a medication that ommends that occupational radiation expo-
is classified as category X by the U.S. Food sure of pregnant women not exceed 5 mGy
Table 2-4. Viral-Induced Teratogenesis and Selected Fetal Infections
Agent Observed Effects Exposure Risk

Cytomegalovirus (CMV) Birth defects, low birth weight, Health care workers, childcare workers
developmental disorders
Hepatitis B virus Low birth weight Health care workers, household
members, sexual activity
Human immunodeficiency Low birth weight, childhood cancers, lifelong Health care workers, sexual partners
virus (HIV) disease
Human parvovirus B19 Miscarriage, fetal heart failure Health care workers, childcare workers
Rubella (German measles) Birth defects, low birth weight Health care workers, childcare workers
Toxoplasmosis Miscarriage, birth defects, developmental Animal care workers, veterinarians
disorders
Varicella-zoster virus Birth defects, low birth weight Health care workers, childcare workers
(chicken pox)
Herpes simplex virus Late transmission, skin lesions, convulsions, Sexual activity
systemic disease
Adapted from Reese EA, Hobbins JC, editors: Teratogenic infections. In Reece EA, Hobbins JC, editors:
Clinical obstetrics: the fetus and mother, ed 3, Malden, Mass., 2008, Blackwell, p 248.
(500 mrad) to the fetus during the entire fibrosis, fragile X syndrome, and a variety of
pregnancy. Diagnostic procedures typically disorders seen most commonly in the Ash-
expose the fetus to less than 0.05 Gy (5 rad) kenazi Jewish population.
and there is no evidence of an increased risk
of fetal anomalies or adverse neurologic out- Prenatal Genetic Testing for Trisomy 21
come. Caring for a special needs child or adult has
Diagnostic x-rays of the head, neck, chest, a significant impact on a couple and fam-
and limbs do not result in any measurable ily. Down syndrome is the most common
exposure to the embryo/fetus, but it is advised chromosomal abnormality causing mental
that the pregnant woman wear a shield for disability in the United States. In addition
such studies. Fetal exposure from nonab- to cognitive deficits, these children are also
dominal pelvic computed tomography (CT) at risk for congenital heart disease, duode-
scans is minimal, but again, the pregnant nal atresia, urinary tract malformations,
woman should have her abdomen shielded. epilepsy, and leukemia. Prenatal testing for
Ultrasound (US) imaging has demonstrated chromosomal abnormalities is a matter of
no untoward biologic effects on the fetus weighing the risks of the genetic condition
or mother because the acoustic output does in question with the ultimate risks of the
not generate harmful levels of heat. US has tests available to identify that abnormal-
been used extensively over the last 3 decades. ity. This should include the risks of a false-
Magnetic resonance imaging (MRI) also has negative result in an affected pregnancy and
not demonstrated any negative effects. the false-positive result in the unaffected
pregnancy and the possible riskier diagnos-
Genetic Origins tic tests that may follow. Over the last 2 to
Chromosomal abnormalities affect about 3 decades, the ability to more effectively
1 of 140 live births. In addition, approxi- and safely diagnose Down syndrome has
mately 50% of spontaneous abortions have improved.
an abnormal chromosomal pattern. More Prenatal testing for Down syndrome has
than 90% of fetuses with chromosomal moved away from the traditional invasive
abnormalities do not survive to term. In diagnostic testing based on age alone. Pres-
fetuses with congenital anomalies, the ently, a combination of maternal blood tests
prevalence of chromosomal abnormalities and ultrasound screening provide women
ranges from 2% to 35%.9 A comprehensive, with choices beyond routine chorionic vil-
three-generation family history and ethnic lus sampling or amniocentesis. Optimally,
origin assessment should be taken, whether this prenatal screening should minimize
evaluating preconceptionally or after birth. the number of women identified as screen-
Congenital anomalies of a genetic ori- positive while maximizing the overall detec-
gin can be sporadic or heritable and have tion rate. These screening tests, therefore,
a number of etiologies. They can involve require a high sensitivity and a low false-
nondisjunction, nonallelic homologous positive rate. The improvements in testing
recombination, inversions, deletions and have achieved this and ultimately reduced
duplications, and translocations. Infants the number of invasive tests performed and,
are also at a risk for having birth defects if in turn, decreased the rate of procedure-
their parents are carriers of genetic muta- related losses. Historically, the first screen-
tions. This single gene transmission pattern ing tests used maternal age as a cut-off for
in humans follows three typical patterns: risk assessment because the prevalence of
autosomal dominant, autosomal reces- trisomy 21 rises with age. Women age 35
sive, and x-linked conditions. These typi- and above were eligible for screening based
cally follow traditional mendelian genetics. on a cost-benefit analysis and an attempt to
Nonmendelian patterns of transmission match the risk of an affected fetus with a
include unstable DNA and fragile X syn- procedure-related loss. Screening based on
drome, imprinting, mitochondrial inheri- this parameter of advanced maternal age
tance, germline or gonadal mosaicism, and alone had a detection rate of about 30%
multifactorial inheritance. The most com- with a false-positive rate of 5% when imple-
mon genetic disorders for which prenatal mented in the 1970s.
screening may be offered are trisomy 21, From 1974 to 2002, the mean age of
trisomy 18, hemoglobinopathies (such as women giving birth in the United States
hemoglobin C disease, hemoglobin S-C dis- has increased from 24.4 to 27.4 years, and
ease, sickle cell anemia, thalassemia), cystic the percentage of women aged 35 years and
older at birth increased from 4.7% to 13.8%. Over the last 3 decades, the addition of
Using advanced maternal age (AMA) as the ultrasonography to the practice of obstetrics
main parameter became less efficacious.10 has allowed for the detection of significant
In 1984, the association between aneu- fetal abnormalities prior to delivery (Fig.
ploidy and low levels of maternal serum 2-1). About 20% to 27% of second trimester
alpha-fetoprotein (MS-AFP) was reported. fetuses with Down syndrome have a major
In 1987, the association between high anatomic abnormality.11 Over time, sono-
maternal serum human chorionic gonado- graphic markers were identified that, when
tropin (hCG) value and a low conjugated present, increase the likelihood that a chro-
estriol level in Down syndrome pregnan- mosomal abnormality may exist. The risk
cies was reported. In 1988, this information increases as the number of markers increases.
was first integrated and called the “Triple Sonographic markers are seen in 50% to
Screen Test.” Combining MS-AFP, hCG, and 80% of fetuses with Down syndrome. The
unconjugated estriol values with maternal most common markers are cardiac defects,
age risk and performing it between 15 and increased nuchal-fold thickness, hyper-
22 weeks, doubled the age-related detection echoic bowel, shortened extremities, and
rate to 60% and maintained the false-posi- renal pyelectasis. When a second trimester
tive rate at 5%. The test is considered posi- ultrasound is performed to search for these
tive when the result, stated as an estimate markers, it is called a “genetic sonogram.”
of risk, is above the set cut-off range. This The overall sensitivity of this ultrasound is
is usually about 1:270 and based on the sec- 70% to 85%.
ond trimester age-related risk of a 35-year- Nuchal translucency is a standard ultra-
old woman. In 1996, the “Quad Screen” sound technique and is most accurately mea-
was created when the level of inhibin-A was sured in skilled hands between 10 to 14 weeks
added to the Triple Screen. This test has a (Figs. 2-2 and 2-3). There is a direct correla-
detection rate of 76% and a false-positive tion between an increased measurement and
rate that remains at 5%. a risk for Down syndrome, other aneuploidy,
A B
C
Figure 2-1. Omphalocele at 12 weeks (A), 26 weeks (B), and 3D image at 22 weeks (C).
and major structural malformations.12 In This next phase of screening became the
fact, a very large nuchal translucency sug- “first-trimester screening” protocol. The
gests a very high risk for aneuploidy. Down ultrasound component involves the sono-
syndrome, trisomy 18, and Turner syndrome graphic measurement of the nuchal trans-
are the most likely chromosomal abnormali- lucency. If this measurement is increased
ties and cardiac defects are the most likely for the gestational age, it can indicate an
malformations. affected fetus. This is an operator-dependent
Serum genetic screening and genetic measurement, but has demonstrated a 62%
sonography evolved into a combined testing to 92% detection rate. The serum mark-
approach. With this method, the sensitiv- ers that are measured are maternal serum
ity of Down syndrome screening increased beta-hCG and maternal serum pregnancy-
whereas the false-positive rate decreased. associated plasma protein A (PAPP-A). In
The rationale involves modifying the a priori the first trimester, pregnancies in which the
maternal age risk up or down. If the pattern fetus has Down syndrome have higher levels
seen is similar to the pattern in a Down syn- of hCG and lower levels of PAPP-A than do
drome pregnancy, then the risk is increased; unaffected pregnancies. This combination
if it is the opposite, then it is decreased. The of maternal age, nuchal translucency, hCG,
magnitude of this difference is expressed in and PAPP-A is now the standard first trimes-
multiples of the median and it determines ter screening and is called the “first trimes-
how much the risk is modified. For sono- ter combined test.” It has a detection rate of
graphic markers, the magnitude of these 85% and a false-positive rate of 5%. This is
differences is measured by a likelihood ratio better than the quadruple screen detection
(LR = sensitivity/false-positive rate) that is rate of 80% and a false-positive rate of 5%
then multiplied by the a priori risk. and, therefore, it became the recommended
screen for women who presented early in
pregnancy.
It makes sense to offer Down syndrome
screening as early in pregnancy as possible.
NASAL Performed between 11 and 13 weeks, the
first trimester screening combined test pro-
vides for as early an evaluation and diag-
nosis as possible for fetal abnormalities. It
also provides for maximum decision mak-
ing time and adjustment, privacy, and safer
termination options if desired. One of the
issues with such sophisticated screening
NT protocols is the timing and availability of
such methods. The American College of
AMNION Obstetricians and Gynecologists (ACOG)
Figure 2-2. Normal nuchal translucency width at 11 recommends that all women be offered
weeks, 6 days. screening before 20 weeks and all women
should have an option of invasive testing
regardless of age.13 They also recommend
that prenatal fetal karyotyping should be
offered to women of any age with a history
of another pregnancy with trisomy 21 or
other aneuploidy, at least one major or two
minor anomalies in the present pregnancy,
or a personal or partner history of transloca-
NT tion, inversion, or aneuploidy.
amnion
The impact of prenatal screening is sig-
nificant. During this age of first trimester
screening, the number of amniocentesis
and chorionic villus sampling procedures
performed has dropped. In areas where
NT 4.85mm
Cine 985 17 sec Down syndrome screening tests have been
Figure 2-3. Abnormally thickened nuchal translucency at implemented, there has been an increase in
10 weeks, 5 days. the detection of affected fetuses and a drop
in the number of live births with Down there are two affected siblings.16 There is
syndrome. also some evidence that NTDs are associated
with the genetic variance seen in the homo-
Trisomy 18 cysteine pathways (MTHFR gene) and the
Trisomy 18 is also called Edwards syndrome VANGL1 gene.17 There is also a high preva-
and is the second most common autosomal lence of other karyotypic abnormalities and
trisomy, occurring in 1 in 8000 births. Many trisomy 18 is typically the most common
fetuses with trisomy 18 die in utero and so aneuploidy found.
the prevalence of this abnormality is three In the 1970s through the 1980s, maternal
to five times higher in the first and second serum screening programs were instituted
trimesters than at birth. Prenatal screening and combined with preconception supple-
for trisomy 18 is included with screening mentation with folic acid. In the 1990s,
for Down syndrome. The analyte pattern of folic acid food fortification was imple-
the first trimester test is a very low beta-hCG mented. During this time, screening proto-
and a very low PAPP-A with an increased cols were also instituted and initially they
nuchal translucency.14 Advanced maternal involved just the MS-AFP and amniocente-
age increases the risk of having a pregnancy sis for abnormal results and then went on to
affected with trisomy 18. These fetuses have include sonography. Where these methods
an extensive clinical spectrum disorder and were employed, a decrease in the prevalence
many organ systems can be affected. Fifty of NTDs was seen—largely due to the pre-
percent of these infants die within the first vention of folic acid-deficient women pre-
week of life and only 5% to 10% survive the conceptually.18
first year of life. The combined and inte- Screening for open NTDs typically involves
grated tests are especially effective at detect- the MS-AFP, which is most optimally drawn
ing these affected pregnancies. The earliest between 16 and 18 weeks’ gestation. It is
detection provides for the most comprehen- made by the fetal yolk sac, gastrointestinal
sive counseling and earliest intervention, if tract, and liver and is a specific fetal-specific
desired. globulin. It is similar to albumin and can
be found in the maternal serum, amniotic
Prenatal Screening for Neural Tube Defects fluid (from fetal urine), and fetal plasma. It is
The incidence of neural tube defects (NTDs) found in much lower concentrations in the
in the United States is considered to be maternal serum than in the amniotic fluid or
highly variable because it depends on geo- fetal plasma. The primary intent is to detect
graphic factors and ethnic background. Typ- open spina bifida and anencephaly, but
ically seen in 1 in 1000 pregnancies, they are when concentrations are abnormal, it can
considered to be the second most prevalent also suggest the presence of other nonneural
congenital anomaly in the United States, abnormalities such as ventral wall defects.
with only cardiac anomalies being seen more For each gestational week, these results
often. It has been recommended by ACOG are expressed as multiples of the median
that screening for NTDs should be offered (MoM). A value above 2.0 to 2.5 MoM is
to all pregnant women. The American Col- considered abnormal. Some characteristics
lege of Medical Genetics also recommends can significantly affect the interpretation
screening using the MS-AFP and/or ultraso- of the results. A screen performed before 15
nography between 15 and 20 weeks.15 weeks and after 20 weeks will falsely raise or
The majority of NTDs are isolated malfor- lower the MoM. Maternal weight affects the
mations caused by multiple factors such as results because the AFP is diluted in the larger
folic acid deficiency, drug exposure, exces- blood volume of obese women.19 Women
sive vitamin A intake, maternal diabetes with diabetes mellitus have an increased risk
mellitus, maternal hyperthermia, and obe- of NTDs and so their threshold value has to
sity. A genetic origin is also suggested by the be adjusted to have a more accurate sensi-
fact that a high concordance rate is found tivity. The presence of other fetal anomalies
in monozygotic twins. NTDs are also more increases the level of the MS-AFP. The MoM
common in first-degree relatives and are level also has to be adjusted in pregnancies
more often seen in females versus males. with multiple gestations because the MS-
Family history also supports a genetic mode AFP level is proportional to the number of
of transmission. The recurrence risk for fetuses. Race can affect the results of the MS-
NTDs is about 2% to 4% when there is one AFP because African-American women have
affected sibling and as high as 10% when a baseline level that is 10% higher than that
of non–African-American women. Finally, seen with prenatal surgery. A composite

MS-AFP cannot be interpreted in the face of outcome of fetal or neonatal death or the
fetal death; therefore, it cannot be used as a need for placement of cerebrospinal fluid
screening method when there is a nonviable shunt by the age of 12 months was seen in
fetus present in a multiple gestation. 98% of the postnatal-surgery group versus
Ultrasound can potentially detect more 68% of the infants in the prenatal surgery
NTDs than MS-AFP.20 Detection rates group. Prenatal surgery, however, was asso-
depend on the type of anomaly and the tri- ciated with more preterm delivery as well as
mester during which it is used. Anenceph- uterine dehiscence at delivery.
aly and encephalocele have detection rates
between 80% and 90% in the first trimester, MULTIPLE GESTATION
whereas detection rates of >90% for spina Multiple gestation has been increasing in
bifida are not seen until the second trimes- the United States. In the most recent data
ter.21 Although the vast majority of NTDs for 2008, the twin birth rate rose 1% to
can be seen on ultrasound and the sensitiv- 32.6 per 1000 births.24 This rate has now
ity of the ultrasound evaluation is high, the remained essentially stable between 2004
ultimate diagnosis depends on the position and 2008 after rising almost 80% between
of the fetus, the size and location of the 1980 and 2004. The natural occurring rate
defect, the maternal body habitus, and the of twins and triplets in the Unites States
skill of the ultrasonographer. is 1 in 80 and 1 in 8000, respectively. The
Women who have a screen-positive preg- likely reason for the increasing numbers of
nancy will be counseled to undergo an ultra- multiple births has to do with the increas-
sound to document accurate gestational ing maternal age at childbirth and the use
age, fetal viability, and possible presence of of assisted reproductive technology (ART).
multiple gestation. A detailed anatomic sur- Maternal age, ART, parity, race, geographic
vey of the fetus will also be performed. The origin, family history, maternal weight and
use of amniocentesis may also be employed height have all been associated with an
if there is some discrepancy found on ultra- increased risk of twins.
sound that does not explain the abnormal Zygosity is an important concept for mul-
MS-AFP. Elevations in both amniotic fluid tiple gestation. Twins are most commonly
AFP and amniotic fluid acetylcholinesterase referred to as either di- or monozygotic.
(AChE) suggests an open NTD with almost Dizygotic twins result from ovulation and
96% accuracy. There is some conflict today fertilization of two separate oocytes. Mono-
regarding the use of amniocentesis, and zygotic twins result from the ovulation and
some experts believe that ultrasound alone fertilization of one oocyte then followed by
should be used given its high detection rate, division of the zygote. The timing of the egg
absent procedure loss rate, and cost savings division determines placentation. Diam-
advantage. After reviewing the data, ACOG niotic, dichorionic (DA/DC) placentation
still recommends that the most sensitive occurs with division prior to the morula
approach to prenatal diagnosis of NTDs is stage. Diamniotic, monochorionic (DA/MC)
the MS-AFP screening followed by ultra- placentation occurs with division between
sound examination when elevated, and then days 4 and 8 postfertilization. Monoamni-
amniocentesis if there are discrepant find- otic, monochorionic (MA/MC) placenta-
ings or the patient desires more information tion occurs with division between days 8
to help formulate a management decision. and 12 postfertilization. Division after day
Magnetic resonance imaging (MRI) of the 12 results in conjoined twins. Placentation
fetus can also be used when there is some is typically dichorionic for dizygotic twins
factor that is interfering with ultrasound and can be mono- or dichorionic for mono-
diagnosis of the defect.22 This additional zygotic twins. Sixty-nine percent of natu-
modality can be of great significance when rally occurring twins are dizygotic, whereas
planning for potential fetal or neonatal sur- 31% are monozygotic. Dizygotic twins are
gery, route of delivery, and overall counsel- also more common with ART pregnancies
ing of the parents. and account for 95% of all twins conceived
Fetal surgery for myelomeningocele was with ART.
recently compared in a randomized trial Chorionicity is also an important con-
comparing outcomes of in utero repair to cept because the presence of monocho-
standard postnatal repair.23 The trial was rionicity places those monzygotic twins
stopped early because of the improvements at an increased risk for complications:
twin-to-twin transfusion syndrome (TTTS), acardiac twins. Acardia is lethal in the

twin anemia-polycythemia sequence (TAPS), affected twin, but also can result in a mor-
twin reversed arterial perfusion sequence tality rate of 50% to 75% in the donor twin.
(TRAP), and selective intrauterine growth This condition occurs in about 1% of mono-
restriction.25 The risk of neurologic morbid- zygotic twins.
ity and perinatal mortality in these twins is Growth restriction and premature birth
higher than that of dichorionic twins. are major causes of the higher morbidity
Early ultrasound assessment is a reliable and mortality in twins compared to single-
way to not only diagnose multiple gesta- tons. The growth curve of twins deviates
tion, but to also establish amnionicity and from that of singletons after 32 weeks’ ges-
chorionicity. It provides accurate assess- tation and, 15% to 30% of twin gestations
ment of gestational age, which can be of may have growth abnormalities. This is
vital importance given the risk of preterm more likely to be seen in monochorionic
birth and intrauterine growth abnormali- twins, but discordant growth can be seen
ties in multiple gestation. The optimal time in dichorionic twins depending on the pla-
for this ultrasound would be in the first and cental surface area available to each. Twin
early second trimester. Offering early ultra- growth should be monitored with serial
sound can also include screening for Down ultrasound, and if there is evidence of dis-
syndrome because each fetus is at the same cordance, then additional evaluation is
risk for having a chromosomal abnormality needed. Starting in the second trimester,
based on maternal age and family history monochorionic pregnancies are followed
and all women should be offered options every 2 to 3 weeks, whereas dichorionic
for risk assessment. Maternal serum ana- pregnancies are followed every 4 to 6 weeks.
lyte interpretation can be difficult in mul- There is no consensus on the optimal defi-
tiple gestation because all fetuses, living nition of discordance because a difference
or not, contribute to the concentration. of 15% to 40% has been found to be pre-
Measurement of the nuchal translucency dictive of a poor outcome.27 Presently, an
can improve the detection rate by helping estimated fetal weight below the tenth per-
to identify the affected fetus. The first tri- centile using singleton growth curves or a
mester combined test can be offered to the 20% discordance in estimated fetal weight
woman carrying multiples when chorionic between the twins is the working definition
villus sampling is available. of abnormal growth. Doppler velocimetry
Although twins are not predisposed of the umbilical artery can be added to the
to any one type of congenital anomaly, ultrasound evaluation and may improve
monozygotic twins are two to three times the detection rate of growth restriction.
more likely to have structural defects than The risk of preterm birth is higher for
singletons and dizygotic twins. Anenceph- multiple gestations than for singletons and
aly, holoprosencephaly, bladder exstro- represents the most serious risk to these
phy, VATER association (vertebral defects, pregnancies. When compared to singletons,
imperforate anus, tracheoesophageal fistula, the risk of preterm birth for twins and trip-
radial and renal dysplasia), sacrococcygeal lets was five and nine times higher. As the
teratoma, and sirenomelia are the anoma- number of fetuses increases, the gestational
lies seen with increasing frequency. Most age at the time of birth decreases. In 2008,
often the co-twin is structurally normal. the average gestational ages were 35.3, 32,
The diagnosis of an anomalous twin is espe- 30.7, and 28.5 weeks for twins, triplets,
cially problematic if management might quadruplets, quintuplets, and higher order
require early delivery or therapy that ulti- multiples, respectively. The rate of preterm
mately affects both twins. In the setting of birth for twins in the United States in 2008
conjoined twins, this process is even more was 59% before 37 weeks and 12% before
complicated. The incidence ranges from 32 weeks. Additionally, 57% of these twins
1 in 50,000 to 1 in 100,000 live births.26 were of low birth weight (<2500 g) and 10%
Additional causes for concern in monozy- were of very low birth weight (<1500 g).
gotic twins are monochorionic placentas Interestingly, the outcomes after delivery
that have vascular connections. The con- are similar between twins and singletons
nections occur frequently and can lead to born prematurely.28 Preterm premature rup-
artery-to-artery shunts and, ultimately, the ture of membranes is also a cause of preterm
TRAP sequence with reversed arterial perfu- birth in multiple gestations and most often
sion. This results in the fetal malformation, occurs in the presenting sac, but can occur
in the nonpresenting twin. It seems that optimal management is unclear. As with

multiple gestations have a shorter period of twins, the risk is associated with monocho-
latency before delivery when compared to rionicity and mortality is worse when this
singleton gestations. fetal demise occurs later in pregnancy.
A majority of triplets are born prematurely
Triplet Gestation and 95% of them weigh less than 2500 g (low
The incidence of natural spontaneous triplet birth weight) and 35% are less than 1500 g
births is about 1 in 8000. Triplet pregnancy (very low birth weight). The primary cause
has a higher risk of maternal, fetal, and neo- of these preterm births is premature labor.
natal morbidity than does twin pregnancy. Multiple protocols have been tried to reduce
As the number of fetuses increases to that the risk of preterm birth including decreased
of the higher order multiples, these risks activity, bed rest hospitalization, home
increase even more significantly. Some con- uterine activity monitoring, and tocolysis.
sequences found more often in these preg- Unfortunately, elective cerclage, progester-
nancies include growth restriction, fetal one supplementation, and sonographic cer-
death, preterm labor, premature preterm vical assessment also do not seem to have
rupture of membranes, preterm birth, neo- reduced the spontaneous preterm birth rate.
natal neurologic impairment, pregnancy- Although great strides have been made in
related hypertension, eclampsia, abruption, the management of the neonate, the goal
placenta previa, and cesarean delivery.29 remains to reduce the risk and numbers of
Diagnosis of a triplet or higher order preterm birth or at least uncover a reliable
multiple gestation is done by ultrasound method to predict women at the highest
and most instances are found in the first risk of developing preterm labor or prema-
trimester because the vast majority of these ture rupture of membranes. This will be dis-
pregnancies are conceived via ART. As with cussed in more detail in a separate section.
twin pregnancy, chorionicity identification
is important. Monozygotic gestations can ANTEPARTUM ASSESSMENT
occur even though most of these pregnan- OF THE FETAL CONDITION
cies originate from three or more separate Improved physiologic understanding and
oocytes, especially in those that are spontane- multiple technologic advancements pro-
ously conceived. Spontaneous loss is common vide the obstetrician with tools for objective
and it occurs in 53% of triplet pregnancies. evaluation of the fetus. In particular, specific
Given the inherent increased maternal and information can be sought and obtained
fetal risks involved with these pregnancies, relative to maternal health and risk, fetal
historically, fetal reduction has been offered anatomy, growth, well-being, and func-
in hopes that fewer fetuses would translate tional maturity, and these data are used
into a reduced risk. For triplet gestation, this to provide a rational approach to clinical
presumption may be changing. management of the high-risk infant before
The risk of premature delivery or fetal birth. It is important to emphasize that no
death in utero of one fetus is specific to procedure or laboratory result can supplant
multiple gestation. The surviving fetus(es) the data obtained from a careful history
is affected by the chorionicity and the and physical examination and these have
number of fetuses. There is an ethical to be interpreted in light of the true or pre-
dilemma not seen in singleton pregnan- sumed gestational age of the fetus. The ini-
cies because one must weigh the benefits tial prenatal examination and subsequent
for the affected fetus against the risks of physical examinations are approached with
the potential interventions to the remain- these facts in mind to ascertain whether
ing fetus(es). Typically, delivery before 26 the uterine size and growth are consistent
weeks is not considered because the risk with the supposed length of gestation. In
of mortality is significant for all fetuses. the era prior to routine ultrasound dat-
After 32 weeks, it is appropriate to move to ing, the milestones of quickening (16 to 18
deliver all if one is at risk because the mor- weeks) and fetal heart tone auscultation by
bidity is considered low. Between 26 and 32 Doppler ultrasound (12 to 14 weeks) were
weeks is a more difficult period and remains important and needed to be systematically
a time when parental preference is taken recorded. Although most of this informa-
into great consideration after counseling tion is gathered early in pregnancy, the sig-
has occurred. Chorionicity helps to guide nificance may not be appreciated until later
delivery when fetal death occurs because in gestation when decisions regarding the
appropriateness of fetal size and the timing ultrasound is performed to comply with the
of delivery are contemplated. mother’s request only.
As noted earlier, gestational age is most
Ultrasonography accurately determined the earlier it is perfor
A clear role for antenatal ultrasound has been med during pregnancy. In the first trimester,
established in dating pregnancies, diagnosing the gestational age of the fetus is assessed by
multiple gestations, monitoring intrauterine a crown-to-rump measurement and this is
growth, and detecting congenital malfor- the most accurate means for ultrasound dat-
mations. It is also integral to locating the ing.30 After the thirteenth week of gestation,
placental site and documenting any pelvic measurement of the fetal biparietal diameter
organ abnormalities. Ultrasound is valuable (BPD) or cephalometry is the most commonly
when performing chorionic villus sampling used technique. Before 20 weeks’ gestation,
or amniocentesis. Ultrasound may be used this measurement provides a good estima-
during labor to detect problems related to tion of gestational age within a range of plus
vaginal bleeding, size or date discrepancies, or minus 10 days. After 20 weeks’ gestation,
suspected abnormal presentation, amniotic the predictability of the measurement is less
fluid levels, loss of fetal heart tones, delivery reliable, so an initial examination should be
of a twin, attempted version of a breech pre- obtained before this time whenever possible.
sentation, and diagnosis of fetal anomalies. Such early examination also assists in inter-
Ultrasound is a technique by which short pretation of prenatal genetic screening as
pulses (2 µsec) of high-frequency (approxi- well as in detection of major malformations.
mately 2.5 MHz), low-intensity sound waves Follow-up examinations can then be done
are transmitted from a piezoelectric crystal to ascertain whether fetal growth in utero is
(transducer) through the maternal abdo- proceeding at a normal rate.
men to the uterus and the fetus. The echo
signals reflected back from tissue interfaces EDITORIAL COMMENT: In countries with great ac-
provide a two-dimensional picture of the cess to prenatal care, the problem of attending a de-
uterine wall, placenta, amniotic fluid, and livery with uncertain gestational age occurs much less
fetus. Some indications for ultrasound are frequently.3
contained in Box 2-1. In certain instances,
When fetal growth is restricted, however,

Box 2-1. Uses of Ultrasound brain sparing may result in an abnormal
ratio of growth between the head and the
Confirmation of pregnancy rest of the body. Because the BPD may then
Determination of be within normal limits, other measure-
Gestational age ments are needed to detect the true restric-
Fetal number, chorionicity, presentation tion of growth. The measurement of the
Placental location, placentation ratio between the circumferences of head
Fetal anatomy (previous malformations) and abdomen is particularly valuable under
Assessment of these circumstances.31
Size/date discrepancy Femur length (FL), which may be less
Fetal well-being (biophysical profile, Doppler affected by alterations in growth than the
measurements of umbilical vessels, middle head or abdomen, is used to aid in deter-
cerebral artery) mining gestational age and to identify the
Volume of amniotic fluid (suspected oligohy- fetus with abnormal growth. Serial assess-
dramnios or polyhydramnios) ment of growth and deviations from nor-
Fetal arrhythmias mal, including both macrosomia and
Fetal anatomy (abnormal alpha-fetoprotein) growth restriction, helps to identify the
Assist with procedures fetus at risk during the perinatal period.
CVS, amniocentesis, PUBS, intrauterine trans- Calculation of estimated fetal weight (EFW)
fusion, external version based on various fetal biometric parameters
(BPD, head circumference [HC], abdominal
Amniocentesis circumference [AC], and FL) plotted against
Intrauterine transfusion gestational age using various sonographic
nomograms is an extremely useful method
CVS, chorionic villus sampling; PUBS, percutaneous
umbilical blood sampling.
for serial assessment of fetal growth. Sophis-
ticated computer software to serially plot
EFW and provide percentile ranking of a an inactive fetus is not necessarily an omi-
given fetus is commonly used. nous finding and may merely reflect fetal
Three-dimensional and four-dimensional state (fetal activity is reduced during quiet
ultrasonography have added technological sleep, by certain drugs including alcohol
advancement to the imaging possibilities. and barbiturates, and by cigarette smok-
Using these modalities, the volume of the ing). Three commonly used methods for
targeted anatomic area can be acquired and fetal kick counts include perception of at
displayed. When the vectors have been for- least 10 fetal movements during 12 hours of
matted, the anatomy can be demonstrated normal maternal activity, perception of at
topographically. This has been a promising least 10 fetal movements over 2 hours when
technique for delineating malformations of the mother is at rest and concentrating on
the fetal face, neural tube, and skeletal sys- counting and perception of at least 4 fetal
tems, but proof of clinical advantage over movements in 1 hour when the mother is at
two-dimensional sonography is still lacking. rest and focused on counting. Fetal move-
ment does decrease with hypoxemia, but
Antepartum Surveillance there are conflicting data regarding its use to
Early identification of any risk for neuro- prevent stillbirth.32 Nonetheless, maternal
logic injury or fetal death is the primary perceived fetal inactivity requires prompt
goal of any fetal assessment technique. The reassessment including real-time ultrasound
process of antenatal assessment was intro- or electronic FHR monitoring.
duced to help pursue this underlying risk of
fetal jeopardy and thereby prevent adverse EDITORIAL COMMENT: Just as pediatricians are
outcomes. It is based on the rationale that taught to “listen to the parents,” prudent obstetricians
fetal hypoxia and acidosis create the final pay attention when a pregnant woman thinks some-
common pathway to fetal injury and death thing is different about the pregnancy.
and that prior to their development, there is
a sequence of events that can be identified.
There is a general pattern of fetal response Antepartum Fetal Heart Rate Monitoring
to an intrauterine challenge or chronic Antepartum electronic monitoring of the
stress. The most widely used tests to evalu- FHR has provided a useful approach to fetal
ate the function and reserve of the fetopla- evaluation (Table 2-5). It essentially involves
cental unit and the well-being of the fetus the identification of two fetal heart rate pat-
before labor are maternal monitoring of terns: nonreassuring (associated with adverse
fetal activity, contraction stress test (CST) outcomes) and reassuring (associated with
and nonstress test (NST) monitoring of the fetal well-being). These patterns are inter-
fetal heart rate (FHR), fetal biophysical pro- preted in the context of gestational age,
file (BPP), and Doppler velocimetry. maternal conditions, and fetal conditions,
and compared to any prior evaluations. Elec-
Formal Maternal Monitoring of Fetal Activity tronic fetal monitors use a small Doppler
Fetal movement perception is routinely ultrasound device that is placed on the mater-
taught in obstetrical practice as an expres- nal abdomen. It focuses a small beam on the
sion of fetal well-being in utero and its fetal heart and the monitor interprets these
counting is purported to be a simple method signals of the heart beat wave and reflects
of fetal oxygenation monitoring. With a its peak in a continuously recording graphic
goal of decreasing the stillbirth rate near form. This pattern is then evaluated for the
term, there has been an increased tendency presence and absence of certain components
to use fetal movements as an indicator of that help to identify fetal well-being.
fetal well-being. It is monitored by mater- Antepartum testing is performed to
nal recording of perceived activity or using observe pregnancies with an increased risk
pressure-sensitive electromechanical devices of fetal death or neurologic consequences
and real-time ultrasound. A diagnosis of (Box 2-2). The nonstress test (NST) is the
decreased fetal movement is a qualitative most commonly used method. It is per-
maternal perception of reduced normally formed at daily or weekly intervals, but there
perceived fetal movement. There is no con- are no high-quality data regarding the opti-
sensus regarding a perfect definition nor is mal interval of testing. Frequency is based
there consensus regarding the most accurate on clinical judgment and the presence of a
method for counting. Whereas evidence of reassuring test only indicates that there is no
an active or vigorous fetus is reassuring, fetal hypoxemia at that time. It is commonly
Table 2-5. Criteria for Interpreting Nonstress Test and Acoustic Stimulation Test
Reactivity Terms Criteria

Reactive NST Two fetal heart rate (FHR) accelerations of at least 15 beats per minute (bpm), lasting a total
of 15 sec, in 10-min period
Nonreactive NST No 10-min window containing two acceptable (as defined by reactive NST) accelerations
for maximum of 40 min
Reactive AST Two FHR accelerations of at least 15 bpm, lasting a total of 15 sec, within 5 min after
application of acoustic stimulus or one acceleration of at least 15 bpm above baseline
lasting 120 sec
Nonreactive AST After three applications of acoustic stimulation at 5-min intervals, no acceptable accelera-
tions (as defined by reactive AST) for 5 min after third stimulus
AST, Acoustic stimulation test; NST, nonstress test.
jeopardy. The CST evaluates uteroplacental

Indications for Antepartum Fetal
Box 2-2.
Surveillance
function and was traditionally performed
by initiating uterine contractions with oxy-
Maternal antiphospholipid syndrome tocin (Pitocin). Because continuous supervi-
Poorly controlled hyperthyroidism sion and an electronic pump is required for
Hemoglobinopathies regulated oxytocin infusion, and because of
Cyanotic heart diseases the invasiveness of intravenous infusion,
Systemic lupus erythematosus attempts have been made to induce uterine
Chronic renal disease contractions with nipple stimulation either
Type 1 diabetes mellitus by automanipulation or with warm com-
Hypertensive disorders presses. Nipple stimulation has a variable
Pregnancy complications success rate and, because of inability to reg-
Preeclampsia ulate the contractions, as well as concerns
Decreased fetal movement raised by the observation of uterine hyper-
Oligohydramnios stimulation accompanied by FHR decelera-
Polyhydramnios tions, it has not gained wide acceptance.
Intrauterine growth restriction Nonetheless, breast stimulation provides
Postterm pregnancy an alternative, cheap technique for initiat-
Isoimmunization ing uterine contractions and evaluating pla-
Previous unexplained fetal demise cental reserve. Similar information may be
Multiple gestation obtained by evaluating the response of the
FHR to spontaneous uterine contractions
Adapted from the American College of Obstetricians and perhaps also from the resting heart rate
and Gynecologists: Antepartum fetal surveillance. patterns without contractions. Because the
Practice Bulletin No. 9, October 1999. CST requires the presence of contractions
and has the major drawback of a high false-
positive rate, its use has diminished with
understood that a reactive NST assures fetal the better understanding of the NST and the
well being for 7 days, but this is not proven. use of the BPP and Doppler velocimetry.
The management of a nonreactive NST As understanding of the NST evolved, it
depends on the gestational age and clinical was noted that the absence of accelerations
context. The false-positive rate of an NST on the fetal heart rate tracing was associated
may be as high as 50% to 60%, so additional with poor fetal outcomes and the presence
testing such as vibroacoustic stimulation, of two or more accelerations on a CST was
BPP, and possibly CST are useful adjuncts. associated with a negative CST. Although
The oxytocin challenge test or contraction the false-negative and false-positive rates are
stress test (CST) records the responsiveness higher for an NST than a CST, it is more eas-
of the FHR to the stress of induced uterine ily used and, therefore, the initial method of
contractions and thereby attempts to assess choice for first line antenatal testing.
the functional reserve of the placenta. A neg- The modified NST has become the initial
ative CST (no FHR decelerations in response testing scheme of choice. The modified NST
to adequate uterine contractions) gives reas- comprises vibroacoustic stimulation, initiated
surance that the fetus is not in immediate if no acceleration is noted within 5 minutes
Table 2-6. Technique of Biophysical Profile Scoring
Biophysical Variable Normal (score = 2) Abnormal (score = 0)

Fetal breathing At least one episode of at least 30 sec in Absent or no episode of ≥30 sec in
movements 30-min observation 30 min
Gross body movement At least three discrete body/limb movements Two or fewer episodes of body/limb
in 30 min (episodes of active continuous movements in 30 min
movement considered as single movement)
Fetal tone At least one episode of active extension Either slow extension with return
with return to flexion of fetal limb(s) or trunk; to partial flexion or movement of
opening and closing of hand considered limb in full extension or absent fetal
normal tone movement
Reactive fetal heart rate At least two episodes of acceleration of ≥15 Less than two accelerations or
beats per minute (bpm) and at least 15 sec accelerations <15 bpm in 30 min
associated with fetal movement in 30 min
Qualitative amniotic fluid At least one pocket of amniotic fluid that Either no amniotic fluid pockets or a
volume measures at least 1 cm in two perpendicular pocket <1 cm in two perpendicular
planes planes
From Manning F, Morrison I, Lange I, et al: Antepartum determination of fetal health: composite
biophysical profile scoring, Clin Perinatol 9:285, 1982.
during the standard NST. Because reactivity is Fetal Biophysical Profile

defined by two accelerations within 10 min- Five components—the NST, fetal move-
utes, the sound is repeated if 9 minutes have ments of flexion and extension, fetal breath-
elapsed since the first acceleration. Vibro- ing movements, fetal tone, and amniotic
acoustic stimulation, using devices emitting fluid volume—constitute the fetal biophysi-
sound levels of approximately 80 dB at a cal profile (Table 2-6). It is performed over
frequency of 80 Hz, results in FHR accelera- a 30-minute period and the presence of
tion and reduces the rate of falsely worrisome each component is assigned a score of 2
NSTs. Thus, the specificity of the NST may be points for a maximum of 10 of 10. A nor-
improved by adding sound stimulation. mal score is considered to be 8 of 10 with a
nonreactive NST or 8 of 8 without the NST.
Amniotic Fluid Volume Equivocal is 6 of 10 and abnormal is ≤4 of
The amniotic fluid volume (AFV) is mea- 10. This test assesses the presence of acute
sured via ultrasound using the value of the hypoxia (changes in the NST, fetal breath-
amniotic fluid index (AFI). This is the sum of ing, body movements) and chronic hypoxia
the measured vertical amniotic fluid pock- (decreased AFV). A modified biophysical
ets in each quadrant of the uterus that does profile refers to an NST and an AFI. The risk
not contain umbilical cord. The value can of developing fetal asphyxia within the next
be associated with a number of potential 7 days is about 1 in 1000 with a score of 8 to
complications depending on whether it is 10 of 10 (when the amniotic fluid index is
too high (polyhydramnios) or too low (oli- normal). The false-negative rate is 0.4 to 0.6
gohydramnios), although set recommenda- per 1000. A normal fetal biophysical profile
tions for monitoring are not established.33 appears to indicate intact central nervous
When found, alterations in amniotic fluid system (CNS) mechanisms, whereas factors
volume can suggest the presence of prema- depressing the fetal CNS reduce or abolish
ture rupture of membranes, fetal congenital fetal activities. Thus, hypoxemia decreases
and chromosomal anomalies, fetal growth fetal breathing and, with acidemia, reduces
restriction, and the potential for adverse body movements. The biophysical profile
perinatal outcomes such as intrauterine offers a broader approach to fetal well-being
fetal demise. Pregnancies that are at risk than does the NST, but still allows for a
for AFV abnormalities where surveillance noninvasive, easily learned and performed
may be indicated include those with such method for predicting fetal jeopardy. Guide-
conditions as preterm premature rupture of lines for implementation parallel that for
membranes, hypertension, certain fetal con- other antenatal fetal assessment techniques
genital abnormalities, maternal infection and so the BPP is usually initiated at 32 to
conditions, diabetes, intrauterine growth 34 weeks’ gestation for most pregnancies at
restriction, and postterm pregnancies. risk for stillbirth.
Doppler Velocimetry the heritable disorders of the fetus, diagno-

Doppler velocimetry has been used to assess sis of fetal infection, and determination and
the fetoplacental circulation since 1978, but treatment of fetal Rh(D) disease and severe
still has a limited role in fetal evaluation. anemia. Historically, PUBS, or cordocente-
Because the placental bed is characterized sis, provided direct access to the fetal circu-
by low resistance and high flow, the umbili- lation for both diagnostic and therapeutic
cal artery maintains flow throughout dias- purposes. Presently, the procedures of cho-
tole. Diastolic flow steadily increases from rionic villus sampling and amniocentesis
16 weeks’ gestation to term. A decrease in allow for the acquisition of the same infor-
diastolic flow, indicated by an elevated sys- mation at an earlier time and with lower risk
tolic-to-diastolic ratio, reflects an increase in to the fetus. Fetal diagnostic tests for karyo-
downstream placental resistance. A normal type can be performed on the amniocytes or
waveform is considered reassuring and pre- chorionic villi. Fetal involvement in mater-
sumes normal fetal oxygenation. Elevated nal infections, such as parvovirus B19, can
systolic-to-diastolic ratios are best interpreted also be determined through identification
in conjunction with NSTs and the fetal bio- of infection in amniotic fluid, fetal ascites
physical profile. The information gathered or pleural fluid, and Doppler of the middle
from the study of Doppler waveform patterns cerebral artery is used to evaluate and follow
depends on the vessel being studied. Mea- subsequent fetal anemia. Inherited coagu-
surement of these velocities in the mater- lopathies, hemoglobinopathies, and plate-
nal and fetal vessels suggests information let disorders can also be identified through
about blood flow through the placenta and chorionic villus sampling and amniocente-
the fetal response to any negative changes, sis, but the immunologic platelet disorders
and so, any challenge to the fetoplacental such as idiopathic thrombocytopenia pur-
circulation can ultimately result over time pura (ITP) and alloimmune thrombocytope-
in a compromise of the vascular tree. These nia may benefit from fetal blood sampling
indices in the umbilical artery will rise when with antepartum PUBS and during labor
60% to 70% of the vascular tree has been through fetal scalp sampling. Preparations
altered. The ultimate development of absent for and ability to transfuse must be avail-
or reversed diastolic flow (defined as the able. Suspected fetal thyroid dysfunction
absence or reversal of end-diastolic frequen- remains an area where fetal blood sampling
cies before the next systolic upstroke) in the by PUBS may be necessary and plays a criti-
umbilical artery is regarded as an ominous cal role in the diagnosis and management of
finding and is associated with fetal hypoxia the disease.36
and fetal acidosis with subsequent adverse
perinatal outcome.34 Umbilical artery Dop- Chorionic Villus Sampling
pler evaluation is most useful in monitoring and Amniocentesis
the pregnancy that is associated with mater- Chorionic villus sampling (CVS) is a method
nal disease (hypertension or diabetes), utero- of prenatal diagnosis of genetic abnormali-
placental insufficiency, and fetal intrauterine ties that can be used during the first trimes-
growth restriction, and it is not supported in ter of pregnancy. Small samples of placenta
the routine surveillance in other settings. are obtained for genetic analysis. It can be
When a fetus is compromised, the systemic performed either transcervically or transab-
blood flow is redistributed to the brain.35 dominally. The major indication for chori-
Doppler assessment of the fetal middle cere- onic villus sampling is an increased risk for
bral artery is presently the best tool for evalu- fetal aneuploidies owing to advanced mater-
ating for the presence of fetal anemia in the nal age, family history, and abnormal first
at-risk pregnancy. It has all but replaced the trimester screening for Down syndrome. It
use of percutaneous fetal umbilical blood can also be used to detect hemoglobinopa-
sampling (cordocentesis or PUBS) in the eval- thies. Amniocentesis is a transabdominal
uation of pregnancies involving Rh isoim- technique by which amniotic fluid is with-
munization and other causes of severe fetal drawn so it may be assessed. The most com-
anemia such as parvovirus-induced hydrops mon indications include prenatal genetic
fetalis or hemolytic anemia. analysis and assessment for intrauterine
infection and fetal lung maturity. It may
Fetal Blood Sampling also be used to evaluate for other fetal con-
In the past, fetal blood sampling was indi- ditions associated with hemoglobinopa-
cated for rapid karyotyping and diagnosis of thies, blood and platelet disorders, neural
tube defects, twin-to-twin transfusion, and a good correlation with fetal size and gesta-
polyhydramnios. It is usually performed tional age. They were, however, inadequate
under ultrasound guidance and has a low predictors of fetal pulmonary maturity.
rate of direct fetal injury from placement of Amniocentesis to assess fetal pulmonary
the needle. maturity is the currently accepted technique.
Procedure-related loss rates for CVS have Fetal lung secretions can be found in amni-
been identified as 0.7% and 1.3% within 14 otic fluid. Evaluation of the amniotic fluid
and 30 days, respectively, after a transab- either tests for the components of the fetal
dominal procedure. It has been found that pulmonary surfactant (biochemical tests)
the loss rate may be higher with a trans- or the surface-active effects of these phos-
cervical approach. The pregnancy loss rate pholipids (biophysical tests). The lecithin
associated with amniocentesis has been to sphingomyelin ratio, and the presence of
reported to be 1 in 300 to 1 in 500. Although phosphatidylglycerol are biochemical tests,
the safety and efficacy of both procedures whereas the fluorescence polarization or the
has been established, CVS is considered to surfactant to albumin ratio (TDx-FLM II) is
be the method of choice for first trimester a biophysical test. Lamellar body counts can
evaluation because it has a lower risk of also be used. No test has been shown to be
pregnancy-related loss than does amnio- more superior to the other at predicting RDS
centesis before 15 weeks. Second trimester and each has its own defined level of risk.
amniocentesis is associated with the lowest The predictive values of RDS vary with ges-
risk of pregnancy loss. tational age and with the population.37
The risk of respiratory distress syndrome
Assessing Fetal Maturity is least when the ratio of lecithin to sphin-
Because respiratory distress syndrome (RDS) gomyelin (L:S) is greater than 2.0. However,
is a frequent consequence of premature this does not preclude the development of
birth, both spontaneous and iatrogenic, RDS in certain circumstances (e.g., infant of
and is also a major component of neona- a diabetic mother or erythroblastosis). Given
tal morbidity and mortality in many high- the physiology of fetal lung maturity, the
risk situations, it is critical that an antenatal presence of phosphatidylglycerol is a good
assessment of pulmonary status be per- indication of advanced maturity and, there-
formed when indicated. The main value fore, a correlated lessened risk of RDS with
of fetal lung maturity testing is predicting fewer false-negative results. Phosphatidyl
the absence of RDS. It is not typically per- glycerol can be measured by rapid tests and
formed prior to 32 weeks because physi- is not influenced by blood or vaginal secre-
ologically the fetus is likely to have not yet tion, and can be sampled from a vaginal
matured. Fetal pulmonary maturity should pool of fluid. The surfactant to albumin ratio
be confirmed in pregnancies scheduled for is a true direct measurement of surfactant
delivery before 39 weeks unless the follow- concentration. Levels greater than 55 mg
ing criteria can be satisfied: ultrasound mea- of surfactant per gram of albumin correlate
surement at less than 20 weeks of gestation well with maturity, whereas those less than
that supports gestational age of 39 weeks or 40 mg are considered immature. Lamellar
greater; fetal heart tones (FHT) by Doppler body count, with a size similar to platelets,
ultrasonography have been present for 30 is a direct measurement of surfactant pro-
weeks; or it has been 36 weeks since a posi- duction by type I pneumocytes. Given their
tive serum or urine pregnancy test. If any of size, a standard hematology counter can
these confirm a gestational age of 39 weeks, be used for their measurement; values of
amniocentesis can be waived for delivery. greater than 50,000/µL indicate maturity.38
Lung maturity does not need to be per- The negative predictive value of these tests
formed when delivery is mandated for fetal is high so that when one result is positive,
or maternal indications. the development of RDS is unlikely.
Historically, the introduction of amnio-
centesis for study of amniotic fluid and
Rh-immunized women paved the way for INTRAPARTUM FETAL SURVEILLANCE
development of the battery of tests cur- The ultimate goal of fetal heart rate (FHR)
rently available to assess fetal maturity. The monitoring is to identify the fetus that
initial methods developed were based on may suffer neurologic injury or death, and
amniotic fluid levels of creatinine, biliru- to intervene prior to the development of
bin, and fetal fat cells, and these provided these events. The rationale behind this goal
is that FHR patterns reflect states of hypox- presence of decelerations.42 Complications

emia and subsequent acidosis. It is the of fetal scalp blood sampling and fetal scalp
relationship between the condition of the electrode monitoring may include significant
mother, fetus, placenta, and labor course fetal blood loss and infections in the new-
that can result in a poor neonatal outcome. born, although these occur rarely. Fetal scalp
Although one can identify risk factors such pH sampling has largely been abandoned
as maternal hypertension and diabetes, fetal due to its problematic collection and poor
growth restriction, and preterm birth, these sensitivity and positive predictive value. An
conditions account for only a small number alternative to fetal scalp pH determination
of the neonates with asphyxia at birth.39 is digital stimulation of the fetal scalp in the
The two most common approaches are absence of uterine contractions and when
intermittent auscultation and continuous the FHR is at the baseline. A positive test
electronic FHR monitoring. There are no (i.e., an acceleration [15 bpm for 15 seconds]
studies comparing the efficacy of electronic response to such stimulation) is considered
fetal monitoring (EFM) to no fetal moni- fairly reliable evidence of the absence of fetal
toring to decrease complications such as acidosis and a pH of 7.2 or greater, and clini-
neonatal seizures, cerebral palsy, or intra- cal investigation supports its use.
partum fetal death.40 A recent metaanaly-
sis compared intermittent auscultation to Principles Related to FHR Monitoring
continuous EFM found as follows: the use Despite the frequency of its use, the EFM has
of EFM increased the risk of both operative poor inter- and intraobserver reproducibil-
vaginal delivery and cesarean delivery, did ity and a high false-positive rate.43 Almost
not reduce cerebral palsy or perinatal mor- 99% of nonreassuring FHR abnormalities
tality, and did not change Apgar scores or are not associated with the development
neonatal unit admission rates, although of cerebral palsy. For this reason, in 2008,
it did reduce the risk of neonatal seizures. the National Institutes of Child Health and
The reason for this is unknown, although Human Development convened a workshop
it is suspected that 70% of cases of cerebral with experts from the American College of
palsy occur before the onset of labor.41 Also, Obstetricians and Gynecologists and the
the use of EFM instead of intermittent aus- Society for Maternal-Fetal Medicine to try
cultation has not resulted in a decrease of to reach a consensus on the definitions of
the overall risk of perinatal death. Given FHR patterns. This is a standard that has
these findings, the American College of been adopted and endorsed by ACOG (Table
Obstetricians and Gynecologists stated that 2-7). Two major assumptions that have been
high-risk pregnancies should be monitored made is that these definitions are primarily
continuously during labor and that either for visual interpretation of FHR patterns,
EFM or intermittent auscultation is accept- and that they should be applied to intrapar-
able in uncomplicated patients. tum patterns, but are applicable to antepar-
At present, continuous EFM is the pre- tum testing as well.
ferred method of identifying the FHR pat- Terminology used to describe uterine
tern. This is typically performed externally activity has been revised to include44 the
through a Doppler ultrasound device belted following:
to the maternal abdomen. The device plots Normal: five contractions or less in 10 min-
the continuous FHR while another pressure utes averaged over a 30-minute period.
transducer attached to the maternal abdo- Tachysystole: more than five contractions in
men simultaneously plots the frequency 10 minutes, averaged over a 20-minute
and duration of uterine contractions. These window.
patterns can also be obtained from internal The terms hyperstimulation and hypercon-
measurement of the FHR and uterine tone tractility are not defined and should be
by a fetal scalp electrode and intrauterine abandoned.
pressure catheter. The scalp electrode yields Tachysystole should always be qualified as
a fetal electrocardiogram (ECG) and calcu- to the presence or absence of associated
lates the FHR based on the interval between FHR decelerations. The term tachysystole
the R waves. External monitoring is usually applies to both spontaneous and stimu-
as reliable as internal and is the preferred lated labor.
method as long as it remains interpretable. The FHR pattern is usually identified as
A fetal scalp pH can be measured when the either reassuring or nonreassuring in
FHR record is difficult to interpret or in the order to guide clinical management.
Table 2-7. 2008 Electronic Fetal Monitoring Definitions
Pattern Definition
Baseline Bradycardia = below 100 beats per minute (bpm)
Normal = 110 to 160 bpm
Tachycardia = over 160 bpm
The baseline must be for a minimum of 2 min in any 10 min period or the baseline for
that time is indeterminate. May refer to prior 10 minute segment to exclude periodic
changes, areas of marked variability.
Variability Fluctuations in the baseline that are irregular in amplitude and frequency
Absent = amplitude undetectable
Minimal = amplitude is 0-5 bpm
Moderate = amplitude is 6-25 bpm
Marked = amplitude greater than 25 bpm
Measured in a 10 min window, peak to trough. There is no longer a distinction between
short- and long-term variability.
Acceleration A visually abrupt increase in the fetal heart rate (FHR) (onset to peak is less than 20 sec)
Before 32 wk, 10 beats above the baseline for 10 sec
After 32 wk, 15 beats above the baseline for 15 sec
A prolonged acceleration lasts 2 min or more, but less than 10 min
If it lasts longer than 10 min, then it is a baseline change.
Early Deceleration A gradual, usually symmetrical decrease from the baseline of the FHR with a contraction
The nadir occurs at the same time as the peak of the contraction.
Late Deceleration A gradual, usually symmetrical decrease from the baseline of the FHR with a uterine
contraction.
The deceleration is delayed in timing, with the nadir occurring after the peak of the
contraction.
Variable Deceleration An abrupt decrease in the FHR below the baseline
The decrease is ≥15 bpm, lasting ≥15 sec and <2 min from the onset to return to baseline.
The onset, depth, and duration of the variable commonly vary with successive contractions.
Prolonged Deceleration A decrease in FHR below the baseline of more than 15 bpm lasting at least 2 min but
<10 min from the onset to return to baseline
A prolonged deceleration of 10 min or more is considered a change in baseline.
Adapted from Macones GA, Hankins GD, Spong CY, et al: The 2008 National Institute of Child Health
and Human Development workshop report on electronic fetal monitoring: update on definitions,
interpretation, and research guidelines, Obstet Gynecol 112:661, 2008.
The presence of a reassuring tracing suggests Serial evaluation of the tracing is necessary
that there is no fetal acidemia at that point because the FHR pattern represents only a
in time. To be considered reassuring, a trac- risk of acidosis at that point in time and
ing must have the following components: does not predict future status because the
a baseline fetal heart rate of 110 to 160 pattern can change in response to labor
beats per minute (bpm), absence of late or and maternal and fetal predisposing con-
variable FHR decelerations, moderate FHR ditions. Transient tachycardia with heart
variability, and age-appropriate FHR accel- rates of more than 160 beats per minute
erations (2 accelerations in 20 minutes of (Fig. 2-4, A) may be an isolated finding.
15 beats above the baseline for 15 seconds It frequently precedes a variable deceler-
for 32 weeks’ gestation and above, and 2 of ation pattern as a brief episode (see Fig.
10 beats above the baseline for 10 seconds 2-4, B and C), which may reflect umbilical
for less than 32 weeks’ gestation). cord venous compression.
Nonreassuring tracings are associated with A late deceleration pattern (Fig. 2-5) is com-
an altered fetal acid-base status and monly associated with uteroplacental
require immediate attention and inter- insufficiency. Either of these patterns may
vention. In addition to the new defini- be compatible with fetal stress (Box 2-4).
tions, a three-tiered interpretation system Some additional principles include39,44 the
was established to help facilitate manage- following:
ment (Box 2-3). • The presence of FHR accelerations with
A category I tracing represents a normal FHR moderate variability almost always indi-
pattern, category II represents an indeter- cates a fetus that is not acidotic.
minate tracing, and category III represents • In the presence of normal FHR variability,
an abnormal tracing. a fetus without accelerations is unlikely to
Three-Tiered Fetal Heart Rate FHR 180

Box 2-3.
Interpretation System
(beats/min) 100
Category I
All of the following criteria must be present
and, when present, are predictive of normal Pressure 50
acid-base status at that time:
• Baseline rate: 110-160 beats per minute
A (mm Hg) 0
(bpm) 180
FHR
• Moderate variability
(beats/min) 100
• Absent late or variable decelerations
• Present or absent early decelerations
• Present or absent accelerations
Pressure 50
Category II
Includes all fetal heart rates (FHRs) that are B (mm Hg) 0
neither Category I nor Category III. They are
considered indeterminate. FHR 180
Category III (beats/min) 100

These tracings are predictive of abnormal fetal
acid-base status at the time of observation
and need to be promptly evaluated. Pressure 50
FHR tracings include either: C (mm Hg) 0
• Absent baseline FHR variability and any
Figure 2-4. Changes in fetal heart rate (FHR) during
of the following:
uterine contractions as reflection of fetal distress. Arrows
Recurrent late decelerations indicated transient tachycardia (A), variable deceleration
Recurrent variable decelerations (B), and variable deceleration with slow recovery after
Bradycardia uterine relaxation (C). Pressure is uterine pressure. (See
Sinusoidal pattern text for explanation.)
Adapted from Macones GA, Hankins GD, Spong CY,

et al: The 2008 National Institute of Child Health and FHR 180
Human Development workshop report on electronic (beats/min)100
fetal monitoring: update of definitions, interpretation,
and research guidelines, Obstet Gynecol 112:661, 2008.
Pressure 50
(mmHg) 0
be acidotic because moderate variability is Figure 2-5. Changes in fetal heart rate (FHR) during
strongly associated with an umbilical cord uterine relaxation as reflection of fetal distress. Arrows
pH of greater than 7.15. An attempt can indicate late deceleration pattern with slow recovery after
be made via vibroacoustic stimulation or uterine relaxation. Pressure is uterine pressure. (See text for
explanation.)
scalp stimulation to elicit an acceleration.
• Neither baseline bradycardia (FHR <120
bpm) nor tachycardia (FHR >160 bpm) of fetal acidosis, especially when com-
alone is predictive of acidosis. bined with recurrent late decelerations.
• Baseline tachycardia may be due to early Normal baseline variability and accel-
asphyxia but is more frequently the result erations occurring spontaneously or after
of maternal fever, fetal infection, mater- stimulation indicate intact fetal reserves.
nal drugs, or prematurity. • Recurrent variable decelerations may be
• Persistent fetal bradycardia with good relieved with intrauterine amnioinfusion
variability is generally not associated with of saline to relieve cord compression.
acidosis. It is more likely to be the result • A sinusoidal pattern is no longer con-
of drugs (medications) or fetal arrhyth- sidered a preterminal condition in all
mias. Persistent bradycardia below 100, cases and may not be due to acidosis. An
even with variability present, is nonreas- attempt should be made to identify the
suring because this level of FHR may not cause. Fetal scalp stimulation may pro-
be able to perfuse tissue adequately. vide some reassurance.
• Variability is a measure of fetal reserve. • With any FHR tracing, if there is an
Absent or minimal variability is suggestive increase in FHR at the time of digital
Fetal Heart Rate Patterns and can be used for tachysystole that is unre-
Box 2-4. lenting; these agents contribute to intra-
Underlying Mechanisms
uterine resuscitation. These are just a few
Reflecting fetal reserve of the measures that can be taken to correct
Normal baseline heart rate and fetal heart rate the nonreassuring FHR pattern changes. If
(FHR) the FHR tracing continues to indicate fetal
Tachycardia (>160 beats per minute [bpm]) compromise and it remains unresolved by
Diminished variability (<6 bpm variation) interventions, a prompt delivery may be
Bradycardia (<120 bpm) indicated. The method of delivery, operative
Sinusoidal pattern vaginal or cesarean section, will depend on
Reflecting acute environmental change cervical dilation, station, position of the
Early deceleration fetal head, maternal obstetrical history, and
Variable deceleration urgency of the situation.
Late deceleration Adequate preparation is desirable for
Acceleration prompt effective resuscitation of the new-
Head compression born. The pediatrician should be alerted
Cord compression, acute hemorrhage when a decision is being made to intervene
Contraction-induced hypoxia operatively for a fetus in distress (Box 2-5;
Intact autonomic response to intrinsic or also see Chapter 3). A nonreassuring FHR
extrinsic stimuli tracing may or may not be associated with
Underlying mechanisms birth asphyxia because only 30% to 40% of
Intact autonomic cardiovascular reflexes newborns who have low Apgar scores at birth
Prematurity, maternal fever, acidosis (depressed) are actually acidotic as well. His-
“Sleep cycle,” drug effects, acidosis, congeni- torically, low 1- and 5-minute Apgar scores
tal anomaly were used to define birth asphyxia. In our
Normal variant, congenital heart block, cardiac modern understanding of the development
anomaly, maternal hypothermia of cerebral palsy and neurologic impairment,
Anemia, hypoxia, drug effect this is considered a misuse of the Apgar
score. In general, because measurement of
Modified from Clark SL, Miller FC: Scalp blood sam- the process that leads to birth asphyxia is
pling—fetal heart rate patterns tell you when to do it, almost impossible in the fetus, asphyxia is
Contemp Obstet Gynecol 21:47, 1984. described as the presence of hypoxia and
metabolic acidosis that is severe enough to
result in hypoxic encephalopathy.45
stimulation of the fetal scalp, then the pH Neonatal encephalopathy is the present
is likely to be greater than 7.15. preferred terminology to describe central
• Transient episodes of hypoxemia due to nervous system abnormalities during the
contraction or temporary cord occlu- newborn period of a neonate who was born
sion are generally well tolerated, but pro- after 36 weeks’ gestation.46 Birth asphyxia,
longed or repeated episodes, especially if now called hypoxic-ischemic (anoxic)
severe and/or associated with decreased encephalopathy (HIE), is a subset of neona-
variability, can lead to acidosis. tal encephalopathy. The underlying cause
of brain injury in the neonate is oftentimes
Treatment of the Category II and III poorly understood, so the criteria for diag-
Tracings nosing HIE have not been completely estab-
Most category II and III tracings require lished. The task force that was convened by
expeditious intervention. Administration ACOG and the AAP determined that four
of a high concentration of oxygen to the criteria must be met in order to define an
mother of a fetus under stress is one of the intrapartum event as the cause of neonatal
few methods of treating acute fetal hypox- encephalopathy that would lead to cere-
emia. Maternal position changes are made bral palsy47: profound metabolic acidosis
to displace the gravid uterus or an occult (pH <7.0 and base deficit >12 mmol/L) on
cord. Treatment of maternal hypotension umbilical cord arterial sample; early onset
with intravenous crystalloid fluid bolus or of severe or moderate neonatal encepha-
ephedrine is given if hypotension is related lopathy in infants past 34 weeks’ gestation;
to neuraxial anesthesia. Medications such cerebral palsy of the spastic quadriplegic or
as pitocin are discontinued if tachysystole is dyskinetic type; and exclusion of other iden-
present. Beta-adrenergics such as terbutaline tifiable etiologies. Additional supportive
Planning Care of the High-Risk findings of an intrapartum origin that are

Box 2-5. discussed also include a sentinel hypoxic
Infant
event in labor, electronic FHR abnormali-
Fetal disorders (suspected or confirmed) ties, Apgar score of 0 to 5 after 5 minutes,
Size for date discrepancy onset of multiorgan involvement within 72
Abnormal karyotype hours, and early neuroimaging studies that
Polyhydramnios or oligohydramnios show evidence of an acute nonfocal abnor-
Hydrops fetalis mality.
Fetal anomalies There are a number of antenatal risk
Abnormal alpha-fetoprotein determination factors that are associated with neonatal
Abnormal stress or nonstress contraction test encephalopathy and cerebral palsy and it
Reduced biophysical profile score is not surprising that they include maternal
Reduced fetal movement medical conditions, placental abnormali-
Immature L:S ratio ties, postterm gestation, preeclampsia, pre-
Cardiac dysrhythmias maturity, maternal fever and infection, and
Maternal problems intrauterine growth restriction. Further dis-
Pregnancy-associated hypertension cussion of the etiologies, diagnostic options,
Diabetes and management strategies of this condition
Previous stillbirth or neonatal death will be discussed in subsequent chapters.
Maternal age <18 or >34 years
Anemia or abnormal hemoglobin FETAL TREATMENT
Rh sensitization A combination of medical and surgical
Maternal infection therapies is available for the prevention and
Prematurity or postmaturity treatment of fetal disorders. As noted in
Malnutrition or poor weight gain (Box 2-6), these range from simple dietary
Premature rupture of membranes supplements (which prevent birth defects)
Antepartum hemorrhage to complex surgical procedures, usually
Collagen vascular disorders mandated by severe fetal compromise with
Drug therapy hydrops fetalis or gross disturbances in the
Maternal drug or alcohol abuse volume of amniotic fluid. The development
Multiple gestation of invasive fetal therapy can be attributed
Intrapartum factors associated with to advances in prenatal ultrasonography.
Maternal/fetal compromise Ultrasonography has been critical in follow-
Extreme prematurity or postmaturity ing the natural history of many of the birth
Placenta previa or abruptio placentae defects and disorders. It has also permitted
Abnormal presentation early identification of structural anomalies
Prolapsed cord and served as a guide for the minimally
Prolonged rupture of membranes >24 h invasive prenatal therapy as well as intra-
Maternal fever or chorioamnionitis operative monitoring during open fetal sur-
Abnormal labor pattern gery. MRI can now be used when ultrasound
Prolonged labor >24 h is limited or its evaluation is incomplete.
Prolonged second stage of labor >2 h Direct or indirect treatment of the fetus
Persistent fetal tachycardia continues to evolve slowly. These treat-
Persistent abnormal fetal heart rate (FHR) ments include short-term oxygen therapy
pattern for IUGR, blood transfusions for fetal ane-
Loss of beat-to-beat variability in FHR mia, antibiotics and antiretrovirals for toxo-
Meconium-stained amniotic fluid plasmosis and HIV, steroid replacement for
Fetal acidosis congenital adrenal hyperplasia, stem cell
General anesthesia therapy for immune deficiency disorders,
Narcotic administered to mother within 4 h of therapy for fetal arrhythmias, and thyrox-
delivery ine instillation for severe hypothyroidism.
Cesarean delivery The field of fetal surgery has continued to
Difficult delivery grow and even diaphragmatic hernias, cyst-
adenomatous malformations of the lung,
neural tube defects, hydrocephalus, and
hydronephrosis, are conditions that may be
managed with in utero interventions and
surgery.
Box 2-6. An Overview of Fetal Therapy Criteria for the Diagnosis

Box 2-7.
of Severe Preeclampsia
Prevention of birth defects
Folic acid Blood pressure of 160 mm Hg systolic or
Periconceptual glucose control in diabetes higher or 110 mm Hg diastolic or higher on
Hormonal therapy two occasions at least 6 hours apart while
Thyroid hormone the patient is on bed rest
Antenatal corticosteroids for acceleration of Proteinuria of 5 g or higher in a 24-hour urine
pulmonary maturation specimen or 3+ or greater on two random
Corticosteroids for congenital adrenal urine samples collected at least 4 hours
hyperplasia apart
Oliguria of less than 500 mL in 24 hours
Prevention and treatment of anemia/ Cerebral or visual disturbances
jaundice Pulmonary edema or cyanosis
Anti-d globulin (Rhogam) at 28 weeks to Epigastric or right upper quadrant pain
prevent erythroblastosis Impaired liver function
Direct transfusions for severe anemia/hydrops Thrombocytopenia
Treatment and prevention of infection Fetal growth restriction
Spiramycin for toxoplasmosis
Zidovudine or other agents for human immu-
nodeficiency virus gestation and accompanied by proteinuria
Antibiotics for premature rupture of membranes (>300 mg in 24-hour specimen) is defined
Intrapartum penicillin for group B streptococ- as preeclampsia. Preeclampsia can be fur-
cal disease ther divided into mild and severe categories
Treatment of cardiac arrhythmias based on the presence of at least one of the
Agents administered to mother, injected into criteria in Box 2-7. When seizure activity is
amniotic fluid or directly into the fetus present, the diagnosis of eclampsia is made.
Fetal surgery: highly selected cases Preeclampsia superimposed on chronic
Usually with hydrops fetalis or gross altera- hypertension can have a worse prognosis
tions in amniotic fluid volume for mother and fetus than either condition
Congenital diaphragmatic hernia alone. The diagnosis of superimposed pre-
Congenital cystic adenomatoid malformation eclampsia can be difficult, and should be
Fetal hydrothorax suspected when worsening hypertension
Sacrococcygeal teratoma and new onset or worsening proteinuria is
Obstructive uropathy noted. A woman who is noted to have new
Fetal airway obstruction due to giant neck onset hypertension without proteinuria
masses after 20 weeks’ gestation can be classified
Neural tube defects as having gestational hypertension. Many
of these women will go on to develop pre-
eclampsia or be diagnosed post pregnancy
with chronic hypertension.
Preeclampsia occurs in about 4% of preg-
SELECTED DISORDERS OF THE nancies and two thirds of cases occur in nul-
MATERNAL-FETAL INTERFACE liparous women.49 Other risk factors include
PREGNANCY-RELATED HYPERTENSION advanced maternal age, chronic hyperten-
Hypertensive disorders in pregnancy can sion, chronic renal insufficiency, obesity,
be grouped into four main classes: chronic diabetes, systemic lupus erythematosus, and
hypertension, preeclampsia and eclamp- multiple gestation. Numerous tests have
sia, preeclampsia superimposed on chronic been proposed for the prediction or early
hypertension, and gestational hyperten- detection of preeclampsia. At present, there
sion. This system was prepared by the is no single screening test that is considered
National Institutes of Health (NIH) Work- reliable and cost-effective for predicting pre-
ing Group on Hypertension in Pregnancy.48 eclampsia.50 Concurrently, numerous trials
Chronic hypertension is defined as per- have described the use of various methods to
sistent blood pressure greater than 140/90 reduce the rate or severity of preeclampsia.
mm Hg observed prior to pregnancy or in Magnesium, zinc, vitamin C, vitamin E, fish
the first 20 weeks of gestation. Hyperten- oil, calcium, and low-dose aspirin have all
sion that is diagnosed after the 20th week of been proposed. Many of these studies show
minimal to no benefit or conflicting results hemorrhage, neonatal infection, and neo-

and at present none are recommended. natal death.
Maternal and neonatal outcomes in pre- Mild preeclampsia can be expectantly
eclampsia depend on the severity of the managed until 37 weeks’ gestation, when
disease and the gestational age affected, as delivery is recommended. At gestational ages
well as presence of other comorbidities. In less than 37 weeks, inpatient or outpatient
a study that examined 10,614,679 single- management is acceptable depending on
ton pregnancies in the United States from patient compliance with home blood pres-
1995 to 1997 after 24 weeks’ gestation, the sure and symptom monitoring, resources
relative risk for fetal death was 1.4 for any available to return to the hospital if needed,
hypertensive disorder and 2.7 for those and ability to maintain modified bed rest.
born to women with chronic hypertensive These women need to have twice weekly
disorders compared to low-risk controls.51 testing including NST and ultrasound evalu-
Causes of perinatal death in preeclampsia ation. Women with gestational hyperten-
include abruption, placental insufficiency, sion at term with a favorable cervix should
and prematurity. The perinatal mortality be considered for induction of labor.54
rate is greatest for women with preeclamp- Intrapartum management of preeclamp-
sia superimposed on preexisting vascular sia centers on prevention of seizures, detec-
disease. Maternal morbidity and mortality is tion of fetal heart rate abnormalities, and
also increased with preeclampsia. Seizures, detection and treatment of worsening
pulmonary edema, acute renal or liver fail- maternal disease. Magnesium sulfate is the
ure, liver hemorrhage, disseminated intra- drug of choice to prevent seizures in women
vascular coagulopathy, and stroke can be with preeclampsia. The efficacy of magne-
seen in severe preeclampsia and are more sium for seizure prevention in severe disease
common in women who develop the dis- is well established; however, the benefit for
ease before 32 weeks’ gestation or in those women with mild disease remains unclear.55
with preexisting medical conditions.52 The Most U.S. investigators recommend prophy-
currently used combination of magnesium lactic anticonvulsant therapy for all women
sulfate and antihypertensive drugs, fol- with the diagnosis of preeclampsia, regard-
lowed by timely delivery, has reduced the less of severity. Control of severe hyperten-
maternal mortality rate to almost zero. sion is imperative to prevent cardiovascular
Given the progressive deteriorating course and cerebrovascular complications. Recom-
of severe preeclampsia and the increased mended agents include hydralazine, labet-
risk of maternal and neonatal morbidity alol and nifedipine. The mode of delivery is
and mortality, prompt delivery after 34 based on obstetric considerations, and a vag-
weeks’ gestation is recommended. However, inal delivery should be attempted in most
in women with severe persistent symptoms, women. Continuous fetal heart rate moni-
eclampsia, multiorgan dysfunction, severe toring and evaluation for vaginal bleeding
fetal growth restriction, abruptio placentae, is essential during the labor process. Moni-
or nonreassuring fetal testing, the recom- toring for signs of worsening disease with
mendation is to undergo prompt delivery laboratory evaluation is also recommended
regardless of gestational age.53 There is dis- for some patients. Women with HELLP syn-
agreement about the treatment of severe drome—intravascular hemolysis, elevated
preeclampsia before 34 weeks’ gestation in liver function test results, and low platelets
which the maternal condition is stable and (thrombocytopenia)—require more intense
fetal status is reassuring. Although deliv- monitoring and evaluation.
ery is always appropriate for the mother, it
may not be optimal for the premature fetus. OBESITY IN PREGNANCY
Several studies have shown that with close Obesity is an epidemic in the United States
monitoring, pregnancies with severe pre- and worldwide. The NIH and the World
eclampsia can be expectantly managed with Health Organization define normal weight
good maternal and neonatal outcomes. and obesity according to body mass index
Continuing a pregnancy long enough to (BMI) as shown in Table 2-8. The Centers
administer corticosteroids has been shown for Disease Control and Prevention (CDC)
to be beneficial for infants born before 34 reports that in women of reproductive age
weeks’ gestation in the setting of severe pre- in the United States, the prevalence of obe-
eclampsia to reduce the rate of respiratory sity was 30.2% and the prevalence of over-
distress syndrome, neonatal intraventricular weight was 56.7%. Obesity is a risk factor
Normal Weight and Obesity macrosomia, defined as weight greater than

Table 2-8. 4000 g, is increased in the obese population
According to Body Mass Index
from 8.3% in nonobese women to 13.3% in
Weight BMI the obese, and 14.6% in the morbidly obese.
Normal 18.5-24.9
Although the risk of macrosomia is greater
Overweight 25-29.9 in women with gestational diabetes (OR
Obesity class I 30-34.9 4.4 versus 1.6), the high prevalence of obe-
Obesity class II 35-39.9 sity correlates to a fourfold higher number
Obesity class III >40 of large-for-gestational age and macroso-
mic infants than is seen as a result of dia-
Adapted from World Health Organization: Obesity: preventing betes. Being born macrosomic or large for
and managing a global epidemic, World Health Organ Tech
Rep Ser 894:1, 2000. gestational age correlates with an increased
BMI, Body mass index. risk of obesity in the adolescent and adult
years.60 Macrosomia also contributes to
the increased risk for cesarean section in
for a number of pregnancy complications. obese gravidas and decreased success when
Therefore, as recommended by ACOG in attempting vaginal birth after cesarean sec-
Committee Opinion No. 315, obese women tion. Increased difficulties with regional and
should be encouraged to decrease weight general anesthesia are also concerns and
before considering pregnancy.56 Given the should prompt consideration for antepar-
high number of unplanned pregnancies, tum anesthesia consultation.
this goal is often not achieved. In 2009, the
Institute of Medicine revised the recom- DIABETIC PREGNANCY
mendations for weight gain in pregnancy Major advances in the knowledge of carbo-
to account for the increasing prevalence of hydrate metabolism provide the opportunity
obesity and the resultant complications.57 for improved screening and identification
Miscarriage and recurrent miscarriage of the gestational diabetic woman.61 Physi-
are increased in obese women compared ologic studies currently offer a better ratio-
to normal weight controls. Fetal malforma- nale for management of the chemical and
tions, specifically neural tube defects, heart the overt diabetic pregnant woman and
defects, and omphalocele are increased in her fetus. The increased risks for stillbirth,
obesity. Obese gravidas have an increased prematurity, and neonatal morbidity asso-
incidence of gestational diabetes above ciated with diabetes pose a direct challenge
that in the general obstetrical population to the efficacy of antenatal surveillance and
(6% to 12% vs. 2% to 4%), and the magni- neonatal intensive care.
tude of this risk is positively correlated with Pregnancy increases the risks of adverse
increases in maternal weight. An association outcomes for mother and infant in women
between obesity and hypertensive disorders with type 1 diabetes. Reducing the risk of
during pregnancy also exists. A review of 13 adverse outcomes in diabetic pregnancies to
cohort studies comprising nearly 1.4 million the level of risk in nondiabetic pregnancies
women found that the risk of preeclampsia is a major goal in diabetes care. Tight gly-
doubled with each 5 to 7 kg/m2 increase in cemic control before and during pregnancy
prepregnancy BMI. Because of the underly- is crucial. Preconception care is effective
ing medical issues and pregnancy complica- with an approximately threefold reduction
tions present in morbidly obese women, an in the risk of malformations. Supplementa-
increased risk of preterm delivery (OR, 1.5; tion with folic acid may also reduce the risk
95% CI, 1.1 to 2.1) is observed compared to of malformations.62,63 Rapid-acting insulin
normal weight controls.58 analogs are regarded as safe to use in preg-
Obesity is also associated with an increased nancy, and studies on long-acting insulin
risk of unexplained stillbirth. Data from the analogs are in the pipeline. It is imperative
Danish National Birth Cohort noted an to minimize episodes of severe hypogly-
increased hazard rate of stillbirth in obese cemia during pregnancy to optimize out-
women from 37 to 39 weeks of 3.5 (95% comes. Screening for diabetic retinopathy,
CI, 1.9 to 6.4) and at 40 weeks of 4.6 (95% diabetic nephropathy, and thyroid dys-
CI, 1.6 to 13.4).59 Furthermore, a Canadian function is important, and indications for
study revealed that the factor most strongly antihypertensive treatment and treatment
associated with unexplained fetal death of thyroid dysfunction need to be in focus
was increased prepregnancy weight. Fetal before and during pregnancy. Pregnancy
in women with pregestational diabetes is However, universal consensus on the diag-

associated with high perinatal morbidity nostic methods and thresholds has long
and mortality. Stillbirth accounts for the been lacking. Published guidelines from
majority of cases of perinatal death. Mater- major societies differ considerably from one
nal smoking, hypertension (preeclampsia), another, ranging in recommendations from
and substandard utilization of antenatal aggressive screening to no routine screen-
care are significantly associated with still- ing at all. As a result, real-world practice
births in diabetic women. Intrauterine is equally varied. The recently published
growth restriction, fetal hypoxia, and con- Hyperglycemia and Adverse Pregnancy
genital malformations may be additional Outcomes (HAPO) Study,66 and two ran-
contributing factors, but more than 50% of domized controlled trials evaluating treat-
stillbirths remain unexplained. The major- ment of mild maternal hyperglycemia,
ity of stillbirths are characterized by subop- have confirmed the findings of smaller,
timal glycemic control during pregnancy. nonrandomized studies solidifying the
Better glycemic control together with regu- link between maternal hyperglycemia and
larly scheduled antenatal surveillance tests, adverse perinatal outcomes. In response to
including ultrasound examinations of the these studies, the International Association
fetal growth rate, kick counting, and non- of Diabetes and Pregnancy Study Groups
stress testing of fetal cardiac function are (IADPSG) have formulated new guidelines
necessary but do not ensure a favorable for screening and diagnosis of diabetes in
outcome. In summary, all known diabetic pregnancy. Key components of the IADPSG
women should plan their pregnancies and guidelines include the recommendation to
optimize glycemic control preconceptually screen high-risk women at the first encoun-
and throughout pregnancy to reduce the fre- ter for pregestational diabetes, to screen uni-
quency of congenital abnormalities, obstet- versally at 24 to 28 weeks’ gestation, and to
ric complications, and perinatal mortality. screen with the 75-g oral glucose tolerance
Because of the increasing incidence of type test interpreting abnormal fasting, 1-hour,
1 diabetes, the recent emergence of type 2 and 2-hour plasma glucose concentrations
diabetes as a condition that can begin during as individually sufficient for the diagnosis
childhood, and the increasing prevalence of of gestational diabetes. The diagnosis of ges-
gestational diabetes mellitus, the number of tational diabetes is made when any of the
women who have some form of diabetes dur- following three 75-g, 2-hour oral glucose tol-
ing their pregnancies is increasing. Together erance test thresholds are met or exceeded:
diabetes and obesity are the most common • Fasting—92 mg/dL
and important metabolic disorders. These • 1 hour—180 mg/dL
women and their babies are at increased risk • 2 hours—153 mg/dL
of morbidity, not just during pregnancy and Increases in each of the three values on the
birth but for the long term as well. Between 75-g, 2-hour oral glucose tolerance test are
1989 and 2004, the prevalence of gestational associated with graded increases in the like-
diabetes mellitus (GDM) in the United States lihood of pregnancy outcomes such as large
increased by 122%. Glycosylated hemoglo- for gestational age, cesarean section, fetal
bin, as measured by hemoglobin A1C (A1C), insulin levels, and neonatal fat content. Fur-
can potentially identify pregnant women thermore, to translate the continuous associ-
at high risk for adverse outcomes association between maternal glucose and adverse
ated with GDM, including macrosomia and outcomes demonstrated in the HAPO cohort,
postpartum glucose intolerance. An elevated they recommend thresholds for positive
hemoglobin A1C at GDM diagnosis was pos- screening tests at which the odds of elevated
itively associated with postpartum abnormal birth weight, cord C-peptide, and fetal body
glucose tolerance. A 1% increase in A1C at fat percent are 1.75 relative to odds of those
GDM diagnosis was associated with 2.36 outcomes at mean glucose values.65
times higher odds of postpartum abnormal Despite insulin therapy, the perinatal
glucose 6 weeks after delivery.64 Women mortality rate among offspring of diabetic
with pregnancies complicated by preeclamp- mothers remains higher than the general
sia or GDM had an increased risk of later dia- population. Note that the infant survival
betes, especially those having GDM. rate at the Joslin Clinic from 1922 to 1938
Leary and associates wrote “The impact was only 54%. From 1938 to 1958, the sur-
of gestational diabetes on maternal and fetal vival rate improved to 86%, and from 1958
health has been increasingly recognized.”65 to 1974, a 90% survival was achieved. Thus,
the combined toll from stillbirth and neona- to be lower than in women in the nongravid
tal death may persist at five times the rate of state. The continuous siphoning of glucose
nondiabetic women, even at major medical by the fetus profoundly affects maternal car-
centers. Where care is less intensive, peri- bohydrate metabolism and, as a result, fast-
natal mortality rate for diabetics of 20% to ing glucose levels are 15 to 20 mg/dL lower
30% still exists. Congenital malformations during pregnancy than postpartum. Physi-
are responsible for 30% to 50% of perinatal ologic studies describing diurnal profiles
deaths in diabetics compared with 20% to for blood glucose concentrations in normal
30% in nondiabetics. pregnancies have shown a remarkable con-
Based on the increased risk of stillbirth stancy of these concentrations throughout
during the last month of pregnancy, pre- the day. The fetus is thus, under normal cir-
term delivery at 36 to 37 weeks’ gestation cumstances, provided with a constant glu-
was the generally accepted recommenda- cose environment.
tion for many years. Möller was one of the These physiologic principles have pro-
first to strive for an avoidance of premature vided a rational basis for the care of preg-
deliveries.67 In 1970, she reported from Swe- nant diabetic women, and the importance
den a series of diabetic women carried closer of rigid blood glucose control has been illus-
to term when blood sugar regulation com- trated by several clinical studies. The marked
parable to the nondiabetic pregnancy had improvement in perinatal mortality rates
been achieved and when evidence of fetal and morbidity obtained by Möller and Gyves
jeopardy or pregnancy complications such and colleagues was with a mean preprandial
as toxemia did not appear. The perinatal blood glucose concentration kept close to
mortality rate in her series of 47 patients was 100 mg/dL, particularly during the third tri-
2.1% as compared with a 21% mortality rate mester.67,68 The latter series also described a
in a prior series from the same obstetric unit. significant reduction in macrosomia among
Similar favorable results have been the infants of such well-controlled diabetic
reported from other institutions in Europe mothers. Karlsson and Kjellmer reported that
and in the United States.68-70 Gyves and their perinatal mortality rate could be directly
coworkers described a reduction in perina- correlated with maternal mean blood glucose
tal mortality rate from 13.5% to 4.1% in a concentrations.72 When mean concentrations
group of 96 diabetic patients in whom the were greater than 150 mg/dL, the mortality
modern technology was applied and pre- rate was 23.6%. At concentrations between
term delivery was not routinely employed.68 100 and 150 mg/dL, the rate declined to
These statistics continue to improve. 15.3%, and at less than 100 mg/dL, mortal-
ity of 3.8% was achieved. The King’s College
EDITORIAL COMMENT: On the basis of a literature group in London reported on deliveries of 100
review, Syed and colleagues concluded that optimal diabetic pregnant women in whom the mean
control of serum blood glucose versus suboptimal preprandial blood glucose concentrations
control was associated with a significant reduction were maintained at approximately 100 mg/
in the risk of perinatal mortality but not stillbirths.71 dL. There was no perinatal loss in this series.
Preconception care of diabetes (information about Because improvements in obstetric and
need for optimization of glycemic control before neonatal management have evolved over the
pregnancy, assessment of diabetes complications, same time span as these studies of intensive
review of dietary habits, intensification of capillary blood sugar control, it is difficult to attribute
blood glucose self-monitoring, and optimization of marked improvements in outcome to only
insulin therapy) versus none was associated with a one variable. Nevertheless, it seems prudent
reduction in perinatal mortality. They estimate that the that the therapeutic objective in pregnant
stillbirth rate can be reduced by 10%. diabetic patients be an effort at normalization
of plasma glucose throughout the day. This
approach should apply to the woman with
For many years, good control of maternal gestational diabetes as well as to the woman
blood sugar concentration has been con- who was diabetic before pregnancy.73
sidered important for the well-being of the
fetus of the diabetic mother. However, wide Principles of Management of Diabetes
differences of opinion exist as to what con- in Pregnancy
stitutes good control. The fasting plasma 1. Metabolic derangements are the major
glucose concentration in pregnancy, in nor- abnormality affecting individuals with
mal and diabetic mothers, has been shown diabetes mellitus.
Table 2-9. Clinical Status of Diabetes: Timing of Assessments
Insulin-Dependent, Insulin-Dependent,
Assessment Noninsulin-Dependent No Vasculopathy with Vasculopathy
MATERNAL
History/physical examination Preconceptual/initial visit Preconceptual/initial visit Preconceptual/initial visit
Ophthalmologic evaluation*
No known abnormality Preconceptual/initial visit Preconceptual/early first Preconceptual/early first
trimester trimester
Known abnormality Each trimester Each trimester Each trimester as indicated
Electrocardiogram† NI Preconceptual/initial visit‡ Preconceptual/initial visit†
Prenatal screen panel and Preconceptual/initial visit Preconceptual/initial visit Preconceptual/initial visit
bacteriuria screen
Glycosylated proteins‡ NI Initial visit/delivery‡ Initial visit/delivery‡
Thyroid panel screen NI Preconceptual/initial visit Preconceptual/initial visit
(repeat monthly until normal) (repeat monthly until normal)
Creatinine clearance NI Preconceptual/initial visit Preconceptual/initial visit
(if abnormal, each trimester) (if abnormal, each trimester)
Urine protein
Dipstick Serially Serially Serially
24 h NI ≥1 + by dipstick ≥1 + by dipstick
Lipid profile NI Preconceptual/initial visit Preconceptual/initial visit
FETAL Weeks’ Gestation
Alpha-fetoprotein (maternal 16-18 16-18 16-18
serum)
Ultrasonography
Dating/anomaly screen 18-22 18-23 18-22
Echocardiography NI 20-24 20-24
Fetal growth/development 37-39§ 30-32; 37-39 30-32; 37-39
Fetal movement§ 36 to intervention§ 34 to intervention§ 30 to intervention§
CST/NST (biophysical NI 32-34 to intervention§ 32-34 to intervention§
profile: backup)§
Lung maturity If intervention <38 wk If intervention <39 wk If intervention <39 wk
documentation
From Guidelines for care: California diabetes and pregnancy program, Maternal and Child Health
Branch, Department of Health Services, 1986.
NI, Not routinely indicated.
*Implies pupillary dilation.
†Advised with diabetes >10 yr duration or known cardiovascular disease or abnormal lipid profile.
‡More frequently if used as compliance evaluator.
§Earlier or more frequent assessment dependent on clinical status (e.g., evidence of intrauterine growth
restriction or multiple gestation).
2. Pregnant women with diabetes should be pregnancy outcome for the woman and her
managed by suitably trained individuals offspring. Optimal care of gravidas with
and teams who comprehensively moni- prepregnancy diabetes must begin before
tor mother and fetus throughout preg- conception. A well-disciplined, well-coordi-
nancy (Table 2-9). nated, and well-organized multidisciplinary
3. Optimal care of women with diabetes team and a compliant patient are the prime
must begin before conception because it ingredients for a successful pregnancy
has been demonstrated that careful pre- outcome. The team comprises internists,
conception control of diabetes reduces perinatologists, and selected other medi-
the incidence of major anomalies. cal subspecialists; a nutritionist, a social
4. All pregnancies should be screened so worker, and other perinatal nurse special-
that women with gestational diabetes can ists who coordinate the dietary needs; and
be identified and appropriately managed. specialists in ongoing education, exercise,
and blood glucose regulation. The goal is to
Management of Diabetic Women Before achieve a mean fasting glucose of less than
Conception 92 mg/dL and a 2-hour postprandial level
The rationale of the preconception pro- around 120 mg/dL. Glycosylated hemo-
gram for diabetic women is to optimize the globin should be maintained within the
normal range. The objective is to achieve EDITORIAL COMMENT: Despite technological ad-
glycemic control before conception and vances in the field, testing for fetal lung maturity at a
throughout embryogenesis and then con- more advanced gestational age (>36 weeks) is neither
tinue throughout gestation. In this way, reliable nor cost effective. Data mandate reconsidera-
major abnormalities may be averted. In tion of our current recommendation of amniocentesis
addition, prophylactic folate supplemen- to confirm fetal lung maturity prior to elective delivery
tation is advocated during the pericon- at 36 to 39 weeks’ gestation in well-dated pregnancies.
ceptual period to reduce the risk of neural
tube defects. Strict glucose control may also
diminish other perinatal complications Congenital malformations have assumed
including intrauterine demise, macroso- a major role in diabetic pregnancies. In a pro-
mia, and neonatal disorders such as hypo- spective study, Simpson et al76 documented
glycemia and polycythemia in addition to a 6.6% incidence of major anomalies among
a cardiomyopathy. Ongoing surveillance, offspring of diabetic mothers as compared
continued education, and careful monitor- with a 2.4% incidence in control mothers.
ing throughout the pregnancy are necessary (Other centers report even higher rates.)
to achieve optimal maternal and perinatal Because the anomaly rate in those patients
outcome. whose diabetes was aggressively managed
Outpatient management of the dia- was similar to that observed by others in
betic pregnancy has replaced the obliga- patients whose diabetes was less vigorously
tory period of hospitalization. However, in managed, the researchers hypothesized that
the face of deteriorating glycemic control, abnormal development had occurred before
maternal complications including hyper- the patients entered the study. There is a
tensive disorders, infection, preterm labor, major emphasis on carefully managing dia-
or evidence of fetal compromise, hospital- betes before conception and even in the first
ization is mandated. A comprehensive pro- trimester to reduce the high anomaly rate
gram devised by the California Maternal associated with diabetic pregnancies.
and Child Health Division is outlined in Patients with high hemoglobin (Hb)
Table 2-9. A1C (variably defined as greater than 7.99
A critical determinant of the outcome of or greater than 9.0) have extremely high
diabetic pregnancy is the timing of delivery. (22.5% to 40%) risk of congenital malforma-
The risk of intrauterine death increases as tion compared with women whose HbA1C is
term approaches. Alternatively, the infant less than that level (5%). This is supported by
delivered preterm is exposed to the risks data generated by Ylinen et al,77 who mea-
of prematurity, particularly that of respira- sured maternal HbA1C as an indication of
tory distress, which may result in neonatal maternal hyperglycemia during pregnancy
loss. The risk of RDS is higher in diabetic to determine its relationship to fetal mal-
pregnancies compared with nondiabetic formations. Maternal HbA1C was measured
pregnancies. Over the past 35 years, the fea- at least once before the end of the fifteenth
sibility of extending the gestational period week of gestation in 139 insulin-dependent
and of individualizing delivery timing for patients who delivered after 24 weeks’ gesta-
the diabetic mother has been enhanced by tion. The mean initial HbA1C was 9.5% of
the availability of objective tests for fetal the total hemoglobin concentration in the
surveillance. 17 pregnancies complicated by malforma-
Because the major consequence of pre- tions, which was significantly higher than in
mature birth is respiratory distress, fetal pregnancies without malformations (8.0%).
pulmonary functional maturity is the most Fetal anomalies occurred in 6 of 17 cases
critical objective of current care. Biochemi- (35%) with values initially of 8% to 9.9%,
cal estimations of this maturity can be and only 3 of 63 (5%) anomalies occurred
obtained from the amniotic fluid with either in babies of patients who had an initial level
the L:S ratio or the foam stability test.74,75 less than 8%. These data support the notion
These determinations provide an important that there is an increased risk of malforma-
dimension in the management of the preg- tion associated with poor glucose control.
nant diabetic woman, particularly when Unplanned pregnancies should be avoided
maternal blood sugar control has been good in diabetic women, and determination of
and a normal physiologic milieu has been HbA1C before conception may assist in plan-
approximated. ning the optimal time for conception.
EDITORIAL COMMENT: Many studies confirm the

is associated with a higher risk of emergency
extensive work of Fuhrman et al that strict diabetic
cesarean section, longer maternal hospital
control before conception significantly reduces the
stay of >3 days, and a four times higher risk
incidence of congenital malformations.78 To have a
of shoulder dystocia, together with a greater
meaningful effect, this information must be widely dis-
need for neonatal resuscitation and inten-
seminated. It is unfortunate that these results have not
sive care admission of the babies.
been achieved because appropriate preconceptional
PRETERM LABOR AND PRETERM
control was not attempted. The reasons for this remain
DELIVERY
undefined but are probably shared. Examples are (1)
unplanned nature of pregnancies (i.e., lack of planned,
Preterm birth, defined as birth before 37
or recommendation for, contraception by internist); (2)
weeks’ gestation, remains an unsolved prob-
noncompliance by the patient; and (3) lack of effort by
lem of paramount importance in perinatal
health care provider (generally internist) to attempt to
medicine. The rate of preterm delivery in
achieve good control because of lack of consideration
the United States has increased over 33%
of the possibility of pregnancy.
in the past 25 years from 9.4% in 1981 to
approximately 12.8% in 2006 (one in eight
births).79 Although advances in neonatal
intensive care have improved outcomes
The application of current technology for preterm infants, the complications of
provides the clinical team with the means prematurity remain the most common
of minimizing both fetal death in utero underlying cause of perinatal and infant
and preventable neonatal morbidity and morbidity and mortality. Approximately
mortality from the hazards of prematurity. 75% of preterm births occur between 34
Together with intensive control of maternal and 36 weeks’ gestation, and although these
blood glucose, the technology of fetal sur- infants experience morbidity, the majority
veillance offers the possibility of normaliz- of perinatal mortality and serious morbidity
ing perinatal outcomes in large numbers of occurs among the 15% of preterm infants
diabetic pregnancies. who are born before 32 weeks’ gestation.
Preterm birth may fall into two broad cat-
EDITORIAL COMMENT: Infants of diabetic mothers
egories: spontaneous preterm birth or indi-
are at risk for many physiologic, metabolic, and con-
cated preterm birth. Spontaneous preterm
genital complications that include, but are not limited
birth includes preterm labor with intact
to, malformations, macrosomia, asphyxia, birth injury,
membranes, preterm premature rupture of
respiratory distress, hypoglycemia, hypocalcemia,
membranes (PPROM) prior to the onset of
hyperbilirubinemia, polycythemia and hyperviscosity,
labor, and cervical insufficiency. Indicated
cardiomegaly, cardiomyopathy, and central nervous
preterm births are those that occur second-
system disruption. (See also Chapter 12). Interestingly,
ary to an underlying fetal or maternal medi-
macrosomia is common, but serious perinatal compli-
cal conditions or compromise. Seventy-five
cations specifically associated with gestational diabe-
percent of all preterm births are spontane-
tes are rare. Maternal obesity is an additional risk factor
ous, whereas the remaining 25% are indi-
for complications, regardless of diabetes status.
cated. Although a distinction between
indicated and spontaneous preterm birth
may not always be clear or clinically evident,
The definition of macrosomia may be the distinction provides a conceptual frame-
a birth weight more than 4000 or 4500 or work for evaluating etiologies and trends
5000 g or, if you are a stickler for taking gen- of preterm birth. Notably, the overall rise
der and gestational age into consideration, in preterm birth rate in the United States is
a birth weight above the 90th percentile for largely attributed to indicated preterm birth.
gestation, or, if you are a statistical purist, This rise in preterm birth has been accom-
above the 97.75th percentile of a reference panied by an overall decline in fetal mortal-
population corrected for gestational age ity, which suggests that this rise may reflect
and sex have been proposed. Whatever you improved perinatal care (Fig. 2-6).
select, these are large babies with consider- Spontaneous preterm birth represents
able risk for morbidity before, during, and a multifactorial disorder in which mul-
after birth. Because the number of adverse tiple modifiable and nonmodifiable risk
outcomes increases substantially above factors interact, predispose, and cause dis-
4500 g, this is widely accepted. Macrosomia ease. Maternal characteristics and behavior,
12
Preterm birth <37 weeks (%)

10
0
1989 1991 1993 1995 1997 1999 2001
A Year
Medically indicated Spontaneous preterm birth

All preterm births Ruptured membranes
36
50
32
Stillbirth rate (per 1000 births)
40
Change in preterm birth rate
28
30
relative to 1989 (%)
20 24
10
20
0
–10
16
–20
–30
–40 12
1989 1991 1993 1995 1997 1999 2001 1989 1991 1993 1995 1997 1999 2001
B Year C Year of birth
Medically indicated Spontaneous preterm birth Medically indicated Spontaneous preterm birth
All preterm births Ruptured membranes All preterm births Ruptured membranes
Figure 2-6. Temporal change in singleton preterm births < 37 weeks: overall, medically indicated, from spontaneous
preterm labor, from ruptured membranes, and from stillbirth. A, Rates in each group by year. B, Change (%) in rates relative
to 1989. C, Trend of stillbirth by year. (Adapted from Ananth CVP, Joseph KSM, Oyelese YM, et al: Trends in preterm
birth and perinatal mortality among singletons: United States, 1989 through 2000, Obstet Gynecol 105:1084, 2005.)
maternal reproductive history, and charac- unpredictable, and no threshold of contrac-

teristics of the index pregnancy all affect the tion frequency has been shown to correlate
risk of preterm delivery (Box 2-8). Although with the risk of preterm delivery. Traditional
risk factors may identify patients at risk for diagnostic criteria—persistent uterine con-
preterm birth, many preterm deliveries occur tractions accompanied by dilation and/or
in women without risk factors. effacement of the cervix—demonstrate rea-
The diagnosis and treatment of preterm sonable accuracy if contraction frequency is
labor remains a challenging, inexact process greater than 6 per hour and cervical dilation
for a multitude of reasons: the signs and is greater than or equal to 3 cm and efface-
symptoms of early preterm labor are often ment is 80% or greater. However, many
noted in normal pregnancy (menstrual-like symptomatic women present with lower
cramping, low back or abdominal pain, thresholds of cervical dilation or progression,
nausea), the progression from subclinical and therefore, over-diagnosis remains preva-
to overt preterm labor may be gradual and lent. Initial evaluation includes a detailed
Risk Factors that Increase Risk highly useful in the initial triage of patients
Box 2-8. presenting with symptoms of preterm labor
of Spontaneous Preterm Delivery
because patients with negative tests may
Nonmodifiable reliably be discharged home.
Familial Risk After diagnosis of acute preterm labor and
Low socioeconomic status prior to the initiation of treatment, contrain-
Low education status dications must be excluded and gestational
Low or high maternal age (<18 or >40 years) age must be established. Contraindications
African-American race to tocolysis include placental abruption, cho-
Uterine anomalies rioamnionitis, fetal demise, and acute fetal or
Prior spontaneous PTD maternal compromise, among others. Regard-
Multiple gestation ing gestational age, the lower limit at which
ART (singleton or multiple gestation) therapy should be offered is controversial
Uterine volume and no definitive data from randomized trials
Cervical length (“short cervix”) exist to support a recommendation. However,
Modifiable greater consensus regarding an upper gesta-
Maternal smoking tional age limit exists. At 34 weeks’ gestation,
Substance abuse the perinatal morbidity and mortality are
Nutritional status (low BMI) too low to justify the potential maternal and
Genital tract infection/colonization fetal complications or cost associated with
Prior pelvic surgery inhibition of labor. Treatment of preterm
?Antenatal stress or depression labor consists of administration of GBS pro-
phylaxis, magnesium sulfate for neuropro-
ART, Assisted reproductive technology; PTD, preterm tection if appropriate (see later discussion),
delivery. and the administration of tocolytic therapy
to inhibit uterine contractions and antenatal
corticosteroids.
obstetric and medical history, physical The goal of tocolysis is to reduce neona-
examination, establishment of gestational tal morbidity and mortality long enough to
age, evaluation of fetal status (monitoring allow for the administration of antenatal
or ultrasound), and a consideration of other corticosteroids and maternal transport to an
etiologies (PPROM, cervical insufficiency, appropriately equipped hospital. Metaanal-
abruption), and an evaluation for underly- yses have demonstrated the utility of toco-
ing infection. Transvaginal ultrasound and/ lytic therapy for preterm labor in that all
or fetal fibronectin (fFN) testing in cervico- agents were more effective than no therapy
vaginal fluid may improve diagnostic accu- or placebo at delaying delivery for 48 hours
racy and decrease false-positive diagnoses. to 7 days. However, this prolongation was
Women with a cervical length of 30 mm not associated with a statistically significant
by transvaginal ultrasound are at a very low decrease in respiratory distress or neonatal
risk for preterm delivery.80 These women death.82 Tocolytic therapy includes many
may be discharged home after a period of classes of drugs: calcium channel block-
observation with confirmation of fetal well ers, cyclooxygenase inhibitors, magnesium
being, lack of cervical change, and exclusion sulfate, oxytocin antagonists, nitric oxide
of a precipitating event. Fetal fibronectin, donors, and beta-mimetics. However, no
a glycoprotein thought to promote cellular tocolytic drug is currently FDA-approved for
adhesion at the fetal-maternal interface, is the indication of arresting labor. Selection
released into cervicovaginal secretions when of appropriate tocolytic therapy requires
the chorionic/decidual interface is disrupted. consideration of the maternal and fetal risk,
Although this is a likely candidate to predict efficacy, and side effects. A detailed dis-
preterm labor and preterm delivery if pres- cussion of the numerous trials comparing
ent, numerous studies have demonstrated tocolytic agents is beyond the scope of this
that the principal utility of fFN testing rests discussion. However, recent evidence shows
in the very high negative predictive value the following:83
(>99% for prediction of preterm labor and • Nifedipine and indomethacin are suggested
preterm delivery in the next 14 days). The first-line agents, with some authorities
positive predictive value (less than 30% in suggesting indomethacin as the first-line
most populations) limits the utility of a posi- agent in patients less than 32 weeks who
tive test.81 Therefore, negative tests remain are also receiving magnesium sulfate for
Table 2-10. Impact of 17-OHP on Spontaneous Preterm Delivery
N* <37 wk (%) <35 wk (%) <32 wk (%)

Placebo 153 54.9 30.7 19.6
17OHP 306 36.3 20.6 11.4
Adapted from Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm delivery by
17α-hydroxyprogesterone caproate, N Engl J Med 348:2379, 2003.
17-OHP, 17α-hydroxyprogesterone.
neuroprotection (potential for increased Box 2-9. Factors and Etiologies of PPROM
maternal adverse events with simultane-
ous use of magnesium sulfate and a cal- Amniocentesis
cium channel blocker). Cerclage
• Magnesium sulfate should be used with Cervical insufficiency
caution as a primary tocolytic, given that Cigarette smoking
data support less efficacy and increased Collagen defect or degradation
side effects or adverse events. Low socioeconomic status
• The use of multiple tocolytic agents History of cervical conization
(“double tocolysis”) should be performed History of preterm delivery
with caution because the propensity for History of PPROM
adverse events increases and no evidence Sexually transmitted infection
supports increased efficacy. Other choriodecidual infection or inflammation
• Data from poorly designed studies do not Uterine overdistention (polyhydramnios, multi-
support maintenance or repeat tocolysis fetal gestation)
after initial inhibition of preterm labor. Vaginal bleeding in pregnancy (subchorionic
Although the identification and inhi- hemorrhage, abruption, abnormal placenta-
bition of acute preterm labor remains an tion)
important strategy aimed at reducing neo-
natal morbidity and mortality, primary pre- PPROM, Prolonged premature rupture of membranes.
vention strategies have remained slow to
develop owing to the multifactorial, com-
plex pathophysiology of preterm labor and approximately 3% of pregnancies and affects
delivery. However, over the past 10 years, more than 120,000 pregnancies annually in
secondary prevention has made a marked the United States. PPROM is responsible for
impact on recurrent preterm delivery. Meis more than one third of all preterm births
et al published a landmark trial in 2003 and remains an important cause of maternal,
demonstrating a decrease in recurrent,84 fetal, and neonatal morbidity and mortal-
spontaneous preterm delivery for women ity. The etiology of PPROM is multifacto-
receiving weekly intramuscular (IM) injec- rial, and many patients will have multiple
tions of 17α-hydroxyprogesterone caproate risk and etiologic factors (Box 2-9). Many
(17-OHP) from 16 to 36 weeks (Table 2-10). of these factors are involved with pathways
Notably, the risk reduction increased with that result in accelerated membrane weak-
earlier gestational age of the index preterm ening such as increased stretch or degrada-
delivery. Subsequent studies confirmed that tion from local inflammation or ascending
supplementation in multiple gestation does infection. A history of early preterm birth
not provide any benefit. With primary pre- (23 to 27 weeks) after PPROM is the strong
ventive strategies still in development, sec- est risk factor for PPROM, which carries a
ondary prevention with 17-OHP has been three-fold increase in risk of recurrence. In
estimated to save in excess of $2 billion the majority of cases, an exact etiology of
annually in the United States alone.85 PPROM remains unknown after diagnosis.
The frequency and severity of neonatal
PRETERM PREMATURE RUPTURE complications after PPROM vary with ges-
OF THE MEMBRANES tational age at which membrane rupture
Preterm premature rupture of the mem- and delivery occur. Additional factors that
branes (PPROM), defined as spontane- increase perinatal morbidity and mortality
ous membrane rupture before labor and are perinatal infection, placental abruption,
before 37 weeks’ gestational age, occurs in and umbilical cord compression. The most
notable morbidities include respiratory distress, which are indications for delivery
distress syndrome, necrotizing enterocoli- independent of gestational age.
tis, intraventricular hemorrhage, and sep- • A patient must be admitted to a facility
sis, which are common with early preterm that is appropriately equipped to provide
birth. However, the risk of sepsis is twofold emergent obstetric services as well as neo-
higher in the context of PPROM relative to natal intensive care, and therefore trans-
preterm labor without PPROM. With conser- fer may be appropriate.
vative management after PPROM, the risk of A large National Institute of Child Health
intrauterine fetal demise is approximately and Human Development Maternal-Fetal
1% to 2%. Additionally, with expectant or Medicine Units Network (NICHD-MFMU)
conservative management of PPROM in the study demonstrated the safety and efficacy
early midtrimester, the risk of pulmonary of intravenous erythromycin and ampicil-
hypoplasia increases with estimated risks of lin followed by oral therapy to complete
0% to 26% of births after PPROM at 16 to a 1-week course. In this trial, antibiotics
26 weeks’ gestation and approximately 50% improved neonatal outcomes by reducing
when PPROM occurs before 20 weeks. the risk of death, RDS, early neonatal sepsis,
In the majority of cases, PPROM can be severe intraventricular hemorrhage, severe
diagnosed clinically by a combination of necrotizing enterocolitis, patent ductus
clinical suspicion, patient history, and physi- arteriosus, and bronchopulmonary dyspla-
cal examination. Notably, patient history has sia (from 53% to 44%; p < .05). A decrease
90% accuracy for diagnosis of PPROM. Physi- in amnionitis and increase in latency of at
cal examination should include a sterile spec- least 1 week was also demonstrated.86
ulum investigation with collection of fluid Several studies have evaluated other anti-
from the posterior vaginal fornix to evalu- biotic regimens. The use of oral amoxicillin-
ate by the nitrazine and ferning tests. Both clavulanic acid has been associated with
of these tests are highly sensitive and specific an increased risk of necrotizing enteroco-
for the diagnosis of PPROM, with nitrazine litis and should be avoided. The algorithm
being more susceptible to contamination. in Figure 2-7 outlines the management of
In rare cases where history and examination PPROM by gestational age.
remain equivocal, a dye test by amniocente-
sis (intrauterine injection of indigo carmine CERVICAL INSUFFICIENCY
followed by observation for passage of blue Cervical insufficiency describes a presumed
fluid onto a perineal pad) may be performed physical or structural weakness that causes
to confirm PPROM. Notably, digital cervi- or contributes to the loss of an otherwise
cal examination should be avoided because healthy pregnancy. Classically, cervical
multiple trials have demonstrated decreased insufficiency manifests in the midtrimester
latency periods with one to two cervical with painless cervical dilation. Although
examinations in patients with PPROM. anatomic, biochemical, and clinical evidence
Given that gestational age at membrane supports structural weakness as an underly-
rupture and delivery substantially affects the ing cause of midtrimester birth, cervical
risk of perinatal morbidity and mortality, a integrity or competence represents only one
gestational-age based model guides manage- variable of a multifactorial problem. Other
ment in the context of PPROM. This model factors such as uterine overdistention, hem-
balances the risks of fetal and neonatal com- orrhage, decidual infection, or inflammation
plications with immediate delivery compared may trigger the parturition process leading
with the potential risks and benefits of con- to changes that ripen, shorten, or weaken
servative management to prolong pregnancy. the cervix. When this occurs, the clini-
Although practice variation exists, a few gen- cal presentation may be indistinguishable
eral principles and trials deserve attention: from so-called “weakness”-mediated cervi-
• Gestational age must be established cal insufficiency. Therefore, in the absence
based on clinical history and ultrasound of definitive tests to discriminate between
evaluation. underlying etiologies or mechanisms, cer-
• Ultrasound should be performed to evalu- vical insufficiency may be defined when
ate fetal growth, position, amniotic fluid other variables (labor, intrauterine infec-
volume, and anatomy. tion, hemorrhage, etc.) that may precipitate
• Women with PPROM must undergo clini- midtrimester loss are not clinically evident.
cal evaluation for preterm labor, chorio- Many patients who present with cervi-
amnionitis, placental abruption, or fetal cal insufficiency do not have underlying
Diagnosis confirmed
Fluid per cervical os or
vaginal pool with positive nitrazine/ferning test or
indigo carmine amino infusion
Ultrasound for gestational age, growth, anomalies as appropriate

Cervical cultures: Chlamydia, gonorrhea
Anovaginal culture: Group B Streptococcus
Urine culture: Group B Streptococcus
Initial and continuous monitoring for labor, fetal distress
Intrapartum group B
streptococcus prophylaxis,
Amnionitis,
based on risk factors if no
abruptio placentae, Yes
Deliver recent negative
fetal death,
anovaginal culture
nonreassuring testing,
or advanced labor
Broad-spectrum antibiotics
No if amnionitis
Previable PROM Early Preterm PROM Preterm PROM Late preterm PROM Term PROM
<23 weeks 23–31 weeks 32–33 weeks 34–36 weeks >37 weeks
Documented fetal Yes

Initial pulmonary maturity
monitoring
No
for infection,
labor, abruptio Conservative Immature testing
placentae management or
Modified bed rest/ fluid unavailable
Initial bed rest pelvic rest to
to encourage encourage
resealing resealing, reduce Consider
infection conservative
management
Evaluate for Serial evaluation for corticosteroid
persistent for amnionitis, labor, benefit with
oligohydramnios abruption, fetal concurrent
and pulmonary well-being, growth antibiotic
hypoplasia with therapy,
serial ultrasound Administer or
corticosteroids expeditious
and antibiotics delivery if
Re- (NICHD protocol) + previous
counsel short-term antenatal steroids
tocolysis and attempted
latency >1 week
Induction If discharged Deliver for not planned
with before viability amnionitis,
oxytocin, and remains non-reassuring
PGE2 or pregnant, fetal testing,
misoprostol readmit at abruption, 33
or fetal viability advanced labor 32 weeks
dilatation for weeks Deliver
and conservative Deliver at 34 weeks Deliver at after Expeditious Expeditious
evacuation management if stable until then 34 weeks steroids delivery delivery
Intrapartum group B streptococcus prophylaxis based on

risk factors if no recent negative anovaginal culture
Broad-spectrum antibiotics if amnionitis

Figure 2-7. An algorithm for evaluation and management of preterm premature rupture of the membranes (PPROM). PGE2;
Prostaglandin E2; NICHD, National Institute of Child Health and Human Development (Maternal-Fetal Medicine Units Network).
(From Mercer BM: Treatment of preterm premature rupture of the membranes, Obstet Gynecol 101(1):178, 2003.)
800
14
700
Relative risk of premature delivery

12 Relative No. of women
risk 600
10
500
No. of women
8
400
6
300
4 200
2 100
0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
Length of cervix (mm)
1 5 10 25 50 75
Percentile
Figure 2-8. Distribution of subjects among percentiles for cervical length measured by transvaginal ultrasonography at 24
weeks of gestation (solid line) and relative risk of spontaneous preterm delivery before 35 weeks of gestation according to
percentiles for cervical length (bars). (From Creasy RK, Resnik R: Preterm labor and delivery. In Creasy RK, Resnik R,
editors: Maternal-fetal medicine, ed 4, Philadelphia, 1999, WB Saunders.)
risk factors. However, some patients may or in combination with other sonographic
have congenital or acquired forms of cervi- characteristics to predict cervical insuffi-
cal insufficiency that include those with a ciency have been unsuccessful.
history of collagen disorders (e.g., Ehlers- Therefore, cervical insufficiency remains
Danlos syndrome), uterine anomalies, dieth- a clinical diagnosis informed by history,
ylstilbestrol (DES) exposure, prior cervical physical examination, and ultrasound eval-
trauma, or surgery. Notably, the cervix is a uation. Notable historical factors include the
dynamic organ and it undergoes various bio- following: history of cervical trauma; repeat
logical changes during normal pregnancy, midtrimester pregnancy loss; absence of
parturition, and postpartum, which include painful contractions, bleeding or infection;
softening, ripening, dilation, and repair.87 advanced cervical dilation or effacement on
In normal pregnancies, the cervix begins to presentation; and ultrasound findings of a
efface at 32 to 34 weeks’ gestation in prepa- cervical length less than the tenth percen-
ration for term birth. Over the past 15 years, tile before 24 weeks’ gestation. Notable ele-
cervical length (measured by transvaginal ments of a physical exam include a speculum
ultrasound) has emerged as a notable risk evaluation for prolapsing or “hourglassing”
factor for preterm delivery. A landmark study membranes, which are always abnormal,
by Iams and coworkers, published in 1996, and a sterile vaginal exam to evaluate for
demonstrated a few important principles: (1) advanced dilation or effacement. A compre-
cervical length is normally distributed in the hensive physical evaluation for symptoms
population (Fig. 2-8); (2) the risk of spontane- of intrauterine infection (tachycardia, uter-
ous preterm birth before 35 weeks’ gestation ine tenderness) should also be completed.
increases as cervical length shortens, particu- Laboratory evaluation includes a white
larly for those in the lowest quartile of the blood count to exclude leukocytosis. Some
distribution. Although ultrasound may iden- authorities recommend amniocentesis to
tify women at risk for preterm delivery due exclude intrauterine infection (glucose >20
to a “short” cervix, ultrasound cannot distin- mg/dL) prior to offering treatment with an
guish the diagnosis of cervical insufficiency emergent cerclage. The treatment of cervical
compared to other causes of premature cervi- insufficiency may vary based on gestational
cal effacement. Attempts to characterize the age at presentation and on the history and
cervix with percentile cervical length alone clinical scenario.
Presentation with Unanticipated Advanced and normal obstetric histories do not ben-
Cervical Dilation or Effacement efit from cerclage.90 Preliminary evidence
Management of cervical insufficiency in the for treatment with vaginal progesterone
emergent setting (when advanced dilation to decrease the risk of preterm delivery in
or effacement is discovered <24 weeks’ gesta- asymptomatic women with an incidentally
tion in the absence of infection, hemorrhage, discovered short cervix exists, and an ongo-
or labor) remains controversial. Very lim- ing multicenter randomized control trial of
ited data exist to guide management; how- 17-OHP in nulliparous women with inciden-
ever, data from one small randomized trial tally discovered short cervix is ongoing.91
and a larger observational trial suggest that
increased gestational time can be gained by Women with a History of Spontaneous
placement of an emergent cerclage compared Preterm Delivery
with expectant management.88 The benefits Data from a recent randomized controlled
of this increased latency remain unclear trial supports a role for cerclage placement
because many patients deliver children at for women with a history of preterm birth
the threshold of viability who suffer from (defined between 16 and 34 weeks). As a part
the complications and sequelae of extreme of this trial, 301 women with a history of
prematurity. A retrospective study of 116 preterm birth were screened with serial cervi-
patients with emergent cerclage placement cal length assessment beginning at 16 weeks,
concluded that nulliparity, the presence of and those with a cervical length below
prolapsing membranes beyond the exter- 25 mm were randomly assigned to cerclage
nal cervical os, and gestational age less than or no cerclage. Cerclage did not result in a
22 weeks at the time of cerclage placement significant reduction in the primary outcome
are associated with a decreased likelihood of preterm birth before 35 weeks for the
of delivery at or after 28 weeks’ gestation.89 study cohort (OR 0.67, 95% CI 0.42 to 1.07)
Additionally, the risks of cerclage placement, except in the women with cervical length
particularly membrane rupture, increase less than 15 mm (OR 0.23, 95% CI 0.08 to
with the degree of cervical dilation and 0.66). Additionally, the cerclage group was
effacement as well as the gestational age at noted to have improvement in the follow-
the time of placement. These factors should ing secondary outcomes: perinatal death
inform counseling regarding emergent cer- (8.8% vs. 16%), birth before 24 weeks (6.1%
clage and the decision should be individual- vs. 14%), and birth before 37 weeks (45%
ized to the clinical scenario at hand. vs. 60%).92 This benefit was also reaffirmed
by an individual, patient-level metaanalysis
Documented History of Cervical that demonstrated a reduction in composite
Insufficiency perinatal morbidity and mortality as well as
Patients with a history of cervical insuf- preterm birth at <24, 28, 32, and 37 weeks’
ficiency in a previous pregnancy may be gestation.93
followed by either serial ultrasound surveil-
lance of cervical length or with prophylactic INTRAUTERINE GROWTH
cerclage, which is generally placed between RESTRICTION (IUGR)
12 to 15 weeks’ gestation. Recommenda- Identifying a fetus at risk for or with growth
tions may include history-indicated prophy- restriction remains a major focus of prena-
lactic cerclage over ultrasound surveillance tal care. The classification of newborns by
when history is confirmed. Prophylactic cer- birth weight percentile cannot be under-
clage is an accepted treatment in this subset stated because there is an inverse relation-
of patients with success rates reported to be ship between birth weight and adverse
as high as 75% to 90%. perinatal outcomes: newborns in the lowest
percentiles are at increased risk of immedi-
Incidental Observation of Short Cervix ate perinatal morbidity and mortality (Fig.
by Ultrasound 2-9) as well as subsequent adult cardiovas-
This increasingly common scenario has cular disease (hypertension, hyperlipidemia,
no evidence-based recommendation for coronary artery disease, diabetes mellitus) as
management. Many of these women are described in the Barker hypothesis. In the
asymptomatic and short cervix is discovered 1960s, Lubchenco and colleagues published
incidentally by a midtrimester ultrasound to a series of classic papers with detailed graphs
assess fetal anatomy. Women with single- depicting birth weight as a function of ges-
ton pregnancies with cervical shortening tational age and adverse outcomes. Since
100 175
Factors and Disorders Associated
Box 2-10.
90 Morbidity with Intrauterine Growth Rate
Perinatal morbidity (cumulative)
Mortality 150
Perinatal mortality (per 1000)

80 Maternal factors
70 Hypertensive disease, chronic or preeclampsia
100 Renal disease
60
Diabetes mellitus
50 75 Antiphospholipid syndrome
40 Hemoglobinopathy
50 Collagen vascular disease
30 Severe nutrition deficiency (inflammatory
20 bowel disease, poor weight gain, low
25
pregnancy BMI)
10
Smoking and substance abuse
0 Maternal hypoxia (cyanotic heart disease, lung
>10 10 9 8 7 6 5 4 3 2 1 <1 disease, high altitude)
Birth weight centile Medications
Figure 2-9. Relationship between birth weight percentiles Fetal factors
and adverse perinatal outcomes in infants with intrauterine Multiple gestation
growth restriction. (From Creasy RK, Resnik R: Placental abnormalities
Intrauterine growth restriction. In Creasy RK, Resnik R, Infection (viral, protozoal)
editors: Maternal-fetal medicine, ed 4, Philadelphia, 1999,
Congenital anomalies
WB Saunders.)
Chromosomal abnormalities
that time, various classification schemes and BMI, Body mass index.
terminology have been adapted to describe
infants that fail to reach their growth
potential, such as “premature,” “low birth
weight,” “small for gestational age,” “small appropriate counseling and management
for dates,” or “growth restricted.” The evolu- plans. Additionally, the underlying etiology
tion of these differing terms highlights the may have implications for future pregnan-
complexity of this problem as well as the cies. Therefore, when IUGR is identified,
difficulty of establishing uniform diagnostic additional testing such as a detailed ana-
criteria. The most common definition for tomic ultrasound evaluation, karyotype, or
IUGR today is an estimated fetal weight less evaluation for viral infections may be war-
than the 10% for gestational age by ultra- ranted—depending on the clinical scenario.
sound evaluation. However, this criteriun Typically, the fundal height measure-
remains controversial given that it relies ment in centimeters should approximate the
on a population-based reference standard weeks of gestational age. Therefore, a fundal
and does not provide a means to distin- height measurement significantly less than
guish fetuses that are constitutionally small, the estimated gestational age may suggest
growth restricted and small, and growth an IUGR fetus. However, clinical diagnosis
restricted but not small. Studies evaluating of IUGR is inaccurate. In fact, studies dem-
customized, individual fetal growth curves onstrate that with the use of physical exam
have been published in Spain, France, and alone, IUGR remains undetected or is incor-
New Zealand and demonstrate improved rectly diagnosed in about 50% of cases. Cur-
accuracy in detecting fetuses at risk for rently, ultrasound is the preferred modality
adverse outcome but are not currently for the diagnosis of IUGR. Therefore, one
employed in the United States.94-97 essential principle of the antenatal recogni-
Numerous maternal and fetal factors tion of IUGR is identification of the mater-
have been associated with IUGR and these nal and fetal risk factors that may prompt
etiologies are listed in Box 2-10. Often, the ultrasound surveillance.
underlying etiology is clinically apparent Ultrasound measurements of the bipari-
and in such cases a diagnosis and manage- etal diameter, head circumference, abdomi-
ment plan can be established. In other cases, nal circumference, and femur length are
the underlying cause may be more elusive. four standard measurements used to esti-
Importantly, an attempt should be made to mate fetal weight and allow for the determi-
determine the cause antenatally to provide nation of the pattern of growth aberration.
Symmetrical IUGR, which accounts for delivery timing (median delay 4.9 days). The
approximately 20% to 30% of cases, occurs primary finding was that delayed delivery
after an insult early in pregnancy (infec- results in more stillbirths than immediate
tion, drug or environmental exposure, chro- delivery; however, the number of stillbirths
mosomal abnormality) affects fetal growth was equal to the increase in neonatal deaths
equally at all morphologic parameters. Con- observed in the immediate delivery arm.
versely, asymmetrical IUGR occurs more The long-term outcomes failed to demon-
frequently and results from placental insuf- strate any neurodevelopmental differences
ficiency later in pregnancy. In asymmetrical in either group among survivors.98
IUGR, the femur length and head circum- Therefore, timing of delivery should be
ference are preserved but the abdominal individualized and based on gestational age
circumference is decreased secondary to the and fetal condition. The following princi-
redistribution of blood flow to vital organs ples may guide management of pregnancies
(heart, brain, placenta) at the expense of less complicated by IUGR:
vital organs (lungs, abdominal viscera, skin). • Remote from term, conservative man-
Notably, the finding of a normal abdominal agement to prolong pregnancy may be
circumference reliably excludes IUGR with a performed safely with serial antepartum
false-negative rate of less than 10%. surveillance as described earlier to achieve
An optimal or standard management of further fetal maturity.
pregnancies complicated by IUGR has not • The term or late preterm (>34 weeks) IUGR
been established. The cornerstones of man- fetus should be delivered when there is
agement for a fetus with IUGR include ante- evidence of maternal hypertension, poor
natal testing with serial NSTs or BPPs; serial interval growth (over 2- to 4-week inter-
ultrasound surveillance of fetal growth, vals), nonreassuring antenatal testing
amniotic fluid volume, and umbilical artery (NST, BPP), and/or umbilical artery Dop-
Doppler velocimetry; and the administra- pler testing to demonstrate absence or
tion of antenatal corticosteroids if preterm reversal of flow.
delivery is anticipated. Notably, the weekly • When growth restriction is mild, no com-
monitoring of umbilical artery Doppler plicating maternal or fetal factors are pres-
velocimetry is the recommended primary ent, and the umbilical artery Doppler and
surveillance tool for the fetus with IUGR. fetal testing are reassuring, delivery can be
Numerous studies and metaanalyses have delayed until at least 37 weeks to mini-
demonstrated a reduction in perinatal mor- mize the risks of prematurity.
tality and iatrogenic prematurity (prema- • Each specific clinical scenario requires
ture or unnecessary induction of labor) for close consideration and an individualiza-
a preterm infant with IUGR when umbilical tion of management plans.
artery Doppler is utilized in decisions regard-
ing timing of delivery. Normal or decreased MAGNESIUM FOR NEUROPROTECTION
umbilical artery flow is rarely associated Cerebral palsy (CP) comprises a heteroge-
with significant morbidity whereas absence neous group of chronic, nonprogressive
or reversal of end-diastolic flow suggests disabilities of the central nervous system,
poor fetal condition. primarily of movement and/or posture. CP
The optimal timing of delivery for the represents the most common cause of child-
IUGR fetus remains controversial and with- hood motor disability and the prevalence
out consensus. However, although opinions has remained stable over time at approxi-
vary, experts generally agree that the growth- mately 1 to 2 per 1000 live births. Prematu-
restricted infants should be delivered close rity is one of the most powerful risk factors
to term, assuming that growth continues for CP, and in one study the prevalence of
and antenatal testing remains reassuring. CP rose from 0.1% in term infants to 0.7%
The Growth Restriction Intervention Trial at 32 to 36 weeks, 6% at 28 to 31 weeks, and
highlighted the difficulty in selecting the to 14% at 22 to 27 weeks.99 Observational
appropriate timing of delivery. This trial studies, primarily secondary analyses of tri-
randomized 548 preterm IUGR pregnan- als involving very low-birth-weight infants
cies for which both fetal compromise and whose mothers received magnesium sulfate
uncertainty regarding delivery were identi- either for tocolysis or eclampsia prophylaxis,
fied to immediate or delayed delivery. In the emerged in the 1980s-1990s, describing
delayed group delivery occurred when the an association between magnesium sulfate
primary obstetrician felt certainty regarding exposure and neurologic outcomes. Many of
these studies noted that exposure conferred inclusion criteria in accordance with trials
a protective effect against the development that have demonstrated benefit.
of CP. Importantly, animal models have sup-
ported the biological plausibility for a neu- ANTENATAL CORTICOSTEROIDS
roprotective effect, which may involve the In a landmark paper published in 1972, Lig-
inhibition of N-methyl-d-aspartate (NMDA) gins and Howie demonstrated a decrease
excitotoxic neuronal damage, promotion of in respiratory distress syndrome and neo-
cerebral vasodilation, scavenging of free radi- natal mortality in the offspring of women
cals, or reduction of inflammatory cytokines. treated with antenatal corticosteroids. Sub-
Subsequently, multiple randomized consequently, the efficacy of antenatal gluco-
trolled trials were conducted to evaluate the corticoid therapy has been confirmed by
efficacy of magnesium sulfate specifically for more than 12 randomized controlled trials
neuroprotection in women at risk for pre- and multiple metaanalyses. In 1994, the
term delivery.100-102 Notably, all trials dem- NIH held a consensus conference to address
onstrated a decrease in the risk of moderate antenatal corticosteroids use, which resulted
or severe CP in the magnesium-exposed in the recommendation for the administra-
trial arms. In the largest trial, the Benefits of tion of a single course of corticosteroids to all
Antenatal Magnesium (BEAM) by Rouse and pregnant women between 24 and 34 weeks’
associates,102 magnesium reduced the risk of gestation at risk for preterm delivery within
moderate to severe CP from 7.3% to 4.2% 7 days, including patients with PPROM prior
(P<.004). Although there was no statistically to 32 weeks’ gestational age. A recent com-
significant difference noted in the primary mittee opinion notes that although data
composite outcome (death or cerebral palsy) remain inconclusive, steroid administration
in the larger two trials, the published analy- for women with PPROM between 32 0/7 and
sis included data demonstrating that there 33 6/7 may be beneficial, particularly if pul-
was no impact of magnesium on the risk of monary immaturity is documented.105 See
death, thereby eliminating the possibility Figure 2-7 recommendations for steroids in
that the lower rate of CP in the treatment the context of PPROM.
arm was caused by increased death with Corticosteroid therapy is thought to
magnesium. No increase in serious mater- improve neonatal lung function through
nal adverse events was reported in any trial. multiple mechanisms: accelerating the mor-
Additionally, multiple metaanalyses have phologic development and maturation of
been performed that confirm the findings both type I and type II alveolar pneumo-
of the individual trials (reduction in moder- cytes, stimulating surfactant production
ate to severe CP, no impact on death alone) from type II pneumocytes, and increasing
and also demonstrate a statistically signifi- the synthesis of surfactant-binding pro-
cant reduction in the primary outcome of teins and lung antioxidant enzymes. The
death or CP (summary RR 0.85, 95% CI 0.74 cumulative effect is a maturation of the
to 0.98.103) lung architecture and the biochemical path-
Therefore, the weight of the available ways that improve the mechanical function
evidence supports the use of magnesium of the lungs and gas exchange. Regarding
for neuroprotection, and ACOG published clinical respiratory morbidity and mortal-
a Committee Opinion in March 2010 sup- ity outcomes, a Cochrane systematic review
porting its use.104 Notably, the number of concluded that treatment with antenatal
women who must be treated to prevent one corticosteroids was associated with an over-
case of CP decreases with decreasing gesta- all reduction in RDS as well as severe RDS
tional age: at less than 32 weeks’ gestation (relative risk reduction of approximately
63 women must receive magnesium to pre- 40% to 50%), thereby decreasing require-
vent one case of moderate-to-severe cere- ments for respiratory support. Importantly,
bral palsy; at less than 28 weeks, 29 women numerous studies and systematic reviews
must be treated. If magnesium sulfate were have demonstrated that antenatal cortico-
administered uniformly to women at risk steroid administration decreases the risk of
of preterm delivery before 32 weeks in the other severe morbidities related to prematu-
United States more than 1000 cases of hand- rity. The aforementioned Cochrane review
icapping CP would be prevented yearly. also concluded that corticosteroid treat-
Institutions adopting the use of magnesium ment decreases the risk of intraventricular
sulfate for neuroprotection should develop hemorrhage (RR 0.54, 95% CI 0.43 to 0.69),
specific treatment protocols, guidelines, and necrotizing enterocolitis (RR 0.46, 95% CI
0.29 to 0.74), neonatal mortality (RR 0.69, short-term neonatal respiratory morbidity.
95% CI 0.58 to 0.81), and systemic infection A recent multicenter randomized control
within the first 48 hours of life (RR 0.56, trial of a single rescue course was conducted
0.38 to 0.85). in 437 patients without PPROM who had
Betamethasone and dexamethasone are completed a course of antenatal corticoste-
the preferred corticosteroids for antenatal roids before 30 weeks of gestation. Other
treatment and have been the most widely inclusion criteria included completion of a
studied agents. Both drugs cross the placenta course of corticosteroids more than 14 days
in their active form and have similar bio- before randomization and a recurring threat
logical activity. Although comparative trials of preterm delivery before 33 weeks’ gesta-
between betamethasone and dexamethasone tion. The study demonstrated a significant
exist, results have been inconsistent and con- reduction in respiratory distress syndrome,
flicting, and there is insufficient evidence to surfactant use, and composite morbidity
recommend one steroid over the other. The in those delivering before 34 weeks’ gesta-
most commonly used regimens that consti- tion and for the overall cohort without any
tute a single course include the following: increase in other fetal, neonatal, or mater-
• Betamethasone—12 mg intramuscularly nal outcomes.108 Long-term data have not
every 24 hours for two doses yet been published. Since publication of this
• Dexamethasone—6 mg intramuscularly trial, ACOG has released a committee opin-
every 12 hours for four doses ion stating that in the appropriate candi-
There is no evidence to support the effi- dates a single rescue course of steroids “may
cacy or safety of increasing the quantity of be considered.”105
the dose or accelerating a dosing regimen Little evidence supports the use of ante-
should prompt delivery be expected. natal corticosteroids for the previable fetus.
The initial data of Liggins and Howie sug- Administration prior to 24 weeks’ gestation
gested that the benefits of antenatal corti- will unlikely have a significant impact on
costeroid administration decreased beyond the improvement of lung function, given
7 days after administration, which was also that lungs are still in the canalicular phase of
evident in the aforementioned Cochrane development with few primitive alveoli avail-
analysis. However, other retrospective stud- able on which steroids can exert an effect.
ies have challenged this view and, subse- Few studies regarding neonatal outcomes
quently, various trials have examined the role after steroid administration prior to 24 weeks
for repeat courses of corticosteroids.105,106 In have been conducted, and the available data
2000, the NIH reconvened another consensus are limited to case series and observational
panel to update the 1994 recommendations studies. The largest study conducted to date
with regard to repeat courses of antenatal evaluated 181 neonates born between 23
corticosteroids. The panel concluded that 0/7 and 23 6/7 weeks’ gestation and noted
although existing evidence suggested a pos- that neonates exposed to a complete course
sible benefit in respiratory outcomes, animal of corticosteroids had a decreased mortality
and human studies demonstrated evidence risk (OR 0.18, 95% CI 0.06 to 0.54). However,
of adverse fetal effects on fetal growth (head exposure to corticosteroids had no impact on
circumference), lung growth and organiza- the risk of severe intraventricular hemorrhage
tion, retinal development, insulin resistance, or necrotizing enterocolitis.109 Although a
renal glomerular number, and maturation detailed discussion of the management of
and myelination of the central nervous sys- the periviable fetus is beyond the scope of
tem. Two studies with long-term follow-up this chapter, the authors believe that the
of children exposed to multiple courses of administration of antenatal corticosteroids
steroids to 2 years of age did not demonstrate prior to 24 weeks may be considered in select
any significant difference in neurocognitive circumstances. This decision should be indi-
outcomes.100,107 However, a large random- vidualized after a careful consideration of the
ized controlled trial demonstrated a trend, clinical scenario, prognostic factors (weight,
albeit statistically insignificant, toward an fetal gender, presence of intraamniotic infec-
increased incidence of cerebral palsy with tion, etc.), and parental wishes regarding
repeat courses of corticosteroids.107 Both the neonatal resuscitation.
NIH and ACOG do not recommend repeat
courses of corticosteroids.105 NORMAL AND ABNORMAL LABOR
However, a single rescue course of antena- Labor and delivery is dependent on the
tal corticosteroids may significantly improve complex interaction of three variables: the
powers, the passenger, and the passage. States, either by continuous electronic or
The powers refer to the forces generated by manual auscultation.
the uterus. Uterine activity is characterized Assessment of contractions and cervical
by the intensity, frequency, and duration change are also done at regular intervals to
of contractions. The passenger is the fetus: follow the progress of labor and guide the
the absolute size, lie, position, presentation, need for intervention. There is no standard
attitude, and number. The passage refers to interval for cervical assessment and many
the pelvis and its ability to allow for delivery practitioners weigh the risk of chorioamnio-
of the fetus. The bony limits of the pelvis nitis with frequent cervical exams versus the
can be assessed using clinical pelvimetry or, prolongation of labor due to lack of prog-
rarely, radiography and CT. ress. Contraction frequency and duration
Labor occurs in three distinct stages. First can be monitored using simple observation
stage is the interval between the onset of and palpation of the fundus or with inter-
labor and full cervical dilation. This stage nal or external tocodynamometry. How-
has been further subdivided into three ever, only internal tocodynamometry with
phases: latent, active, and deceleration. The an intrauterine pressure catheter (IUPC)
second stage is the interval between full cer- can measure the strength of contractions.
vical dilation and delivery of the infant. The Contractions or cervical change that is not
mother assists in this stage with active push- deemed adequate for labor, a lack of pow-
ing, although this is not a requirement. The ers, can be augmented using oxytocin. The
third stage is the interval between delivery use of oxytocin in most institutions is given
of the infant and delivery of the placenta under a standard protocol to ensure safe
and fetal membranes. Each of these stages administration and low incidence of hyper-
has an expected length, although recent stimulation that can lead to fetal heart rate
research has questioned this older data.110 abnormalities and acidemia.
Abnormalities of the labor process can occur Abnormalities in labor progression that
at any of these stages. lead to arrest or protraction disorders can
Intrapartum management depends on occur in the first or second stages. Typically
assessment of risk and evaluation for current first stage arrest that is not amenable to oxy-
or pending complications. Complications tocin administration is treated with cesar-
can arise rapidly during labor. Approxi- ean delivery. Second stage arrest can also be
mately 20% to 25% of all perinatal morbid- treated by cesarean delivery if an operative
ity and mortality occurs in pregnancies with vaginal delivery cannot be safely completed.
no underlying risk factors.111 The presence In the United States, 4.5% of births are com-
of medical comorbidities such as diabetes, pleted by operative vaginal delivery and the
hypertension, asthma, HIV, and obesity, success rate is high.112 Choice of instrument
will affect management. Labor will also be is determined by level of training with either
affected by complications of pregnancy; pre- forceps or vacuum. Other considerations
eclampsia, macrosomia, chorioamnionitis, include the degree of maternal anesthesia,
preterm premature rupture of membranes gestational age of the fetus, and anticipated
preterm labor, and fetal anomalies. When difficulty of the procedure. Maternal and
possible, the assessment and management of fetal complications rates depend on a num-
these complications and comorbidities ante- ber of factors and may be more related to
natally is essential for the proper care of the abnormal labor than to the devices them-
patient during her labor course. selves. A metaanalysis of 10 trials compar-
During labor, all pregnant women require ing vacuum with forceps delivery found
surveillance of vital signs and fetal heart rate. vacuum deliveries were associated with less
The value of routine continuous electronic maternal soft tissue trauma and required
fetal monitoring during labor is controver- less anesthesia, but were less likely to result
sial. The United States Preventive Services in successful vaginal delivery. Neonates
Task Force states that: “routine electronic delivered by vacuum extraction had more
fetal monitoring for low-risk women in cephalohematoma and retinal hemorrhages
labor is not mandatory and there is insuffi- than those delivered by forceps. Sequential
cient evidence to recommend for or against attempts at operative vaginal delivery using
intrapartum electronic fetal monitoring for different instruments should be avoided due
high-risk pregnant women.” Regardless, to an increased risk of fetal injury.
some form of FHR monitoring has become a Reducing infectious complications in
standard of care for all women in the United the mother and the neonate are important
in the management of labor. In the United no difference or improvement in neonatal

States, a universal screening program for neurobehavior after epidural compared to
Group B Streptococcus (GBS) has been imple- systemic opioid analgesia or no medication.
mented. This screening program combined The effect of neuraxial analgesia in labor on
with the chemoprophylaxis of screen- breast feeding is controversial and studies to
positive patients has dramatically reduced date are inconclusive. ACOG concluded that
the incidence of early onset GBS infections breast feeding is not affected by choice of
in neonates.113 The diagnosis of chorio- anesthetic; thus anesthetic choice should be
amnionitis can contribute to significant based on other considerations. Local injec-
morbidity for the mother and infant. Risk tions of anesthesia in the area of the puden-
factors for intrauterine infection include dal nerve (pudendal block) can be used in
nulliparity, spontaneous labor, prolonged the second or third stage of labor without
rupture of membranes (>18 hours), multiple any effect on the neonate.
digital vaginal examinations, meconium-
stained fluid, internal fetal or uterine moni- HUMAN IMMUNODEFICIENCY VIRUS
toring, and the presence of genital tract Pregnant women with HIV require com-
pathogens. Maternal fever and two of the prehensive medical care to achieve good
following symptoms contribute to the diag- maternal outcomes and low rates of perina-
nosis: maternal or fetal tachycardia, uterine tal HIV transmission. Antiretroviral therapy
fundal tenderness, foul-smelling amniotic is recommended to reduce perinatal trans-
fluid, or elevated maternal white blood mission. Transmission can occur during
cell count. Prompt treatment with broad pregnancy, labor and delivery, or the breast-
spectrum intravenous antibiotics is recom- feeding period. The risk has been reduced to
mended to improve maternal and neonatal less than 2% in the United States with the
outcomes. Typically ampicillin, gentamy- administration of antiretroviral prophylaxis
cin, and clindamycin or metronidazole is and viral suppression.115 The first study in
used. Alternative regimens include ampicil- 1994 showed the benefit of administering a
lin-sulbactam or cefoxitin. single agent, zidovudine, intrapartum and
Labor is a painful process and women use to the infant after delivery. It was effec-
different methods to relieve this discom- tive in significantly decreasing transmis-
fort. While some prefer nonpharmacologic sion from 25% to 8%. Since that time, other
methods, ACOG supports the concept that studies have shown benefit of multiple
maternal request alone is a sufficient medi- agents and administration earlier in preg-
cal indication for labor analgesia. Pharmaco- nancy.116 The current recommendation is
logic approaches can be classified as systemic, to start antiretroviral therapy immediately if
regional, or local. Systemic methods involve the patient requires it for her own health, or
intravenous or intramuscular administra- otherwise after the first trimester. Delaying
tion of typically opioid agents or opioid ago- treatment until after 28 weeks may result in
nist-antagonists. These agents provide only an increased risk of transmission. Treatment
minimal relief unless high dosages are used. regimens for pregnant patients with HIV are
When used in higher dosages, opioid anal- the topic of guidelines produced and regu-
gesics can cause respiratory depression and larly updated by the U.S. Department of
an increased risk of aspiration in the mother Health and Human Services.117
as well as neonatal respiratory depression. In addition to standard screening, preg-
Regional techniques include epidurals, spi- nant women with HIV should be screened
nals, and combined spinal-epidurals. The for other infectious diseases including hep-
methods typically use a mixture of a local atitis B and C, toxoplasmosis, tuberculo-
anesthetic and opioid agent. Neuraxial anes- sis, and cytomegalovirus. For women with
thesia is very widely used in the United States CD4 counts <200 cells/mm3, pneumocystis
with approximately 70% of patients receiv- pneumonia prophylaxis is recommended.
ing this type of labor pain relief.114 Maternal Counseling on sexually transmitted disease
risks of neuraxial anesthesia are rare, includ- prevention and reduction of other risk fac-
ing systemic toxicity, high spinal, hypoten- tors should be performed. Women should
sion resulting in fetal bradycardia, postdural be informed that in resource-rich areas,
puncture headache, infection, hematoma, such as the United States, breast feeding is
and urinary retention. The effects on the not recommended because of the increased
neonate have been studied and show either risk of transmission to the infant.
tus (GDM). This recommendation is based

QUESTION on well-designed studies that have found
these agents are as efficacious as insulin for
True or False all severities of gestational diabetes. Also
Insulin is the first line of treatment for gestational there is no association between these agents
diabetics with elevated glucose levels. and congenital malformations.118 There-
fore, the answer is false.
When pharmacologic therapy is required,
oral antidiabetic agents have been almost REFERENCES
universally endorsed as first-line drugs in The reference list for this chapter can be found
the treatment of gestational diabetes melli- online at www.expertconsult.com.
Resuscitation at Birth
Tina A. Leone and Neil N. Finer
The transition from fetal to neonatal life

is a dramatic and complex process involv-
3
of the American Heart Association and the
American Academy of Pediatrics, the Neona-
ing extensive physiologic changes that are tal Resuscitation Program (NRP) was initiated
most obvious at the time of birth. Individu- in 1987 and was designed to address the spe-
als who care for newly born infants during cific needs of the newly born infant. Since
these first few minutes of neonatal life must the origination of the NRP, on-going evalua-
monitor the progress of the transition and tion of the program has resulted in changes
be prepared to intervene when necessary. In when new evidence becomes available. The
the majority of births, this transition occurs most recent edition of the NRP textbook
without a requirement for any significant published in 2011 made several revisions
assistance. However, when the need for including specific recommendations for the
intervention arises, the presence of providers preterm infant.4 Various groups throughout
who are skilled in neonatal resuscitation can the world also provide resuscitation recom-
be life saving. Each year approximately 4 mil- mendations that may be more specific to the
lion children are born in the United States practices in certain regions. An international
and more than 30 times as many are born group of scientists, the International Liaison
worldwide.1,2 It is estimated that approxi- Committee on Resuscitation (ILCOR), meets
mately 5% to 10% of all births will require on a regular basis to review available resusci-
some form of resuscitation beyond basic care, tation evidence for all the different areas of
thereby making neonatal resuscitation the resuscitation and puts forth a summary of
most frequently practiced form of resuscita- its review.5
tion in medical care. Throughout the world, The overall goal of the NRP is similar to
approximately 1 million newborn deaths are other resuscitation programs in that it intends
associated with birth asphyxia. Although it to teach large groups of individuals of varying
cannot be expected that neonatal resuscita- backgrounds the principles of resuscitation
tion will eliminate all early neonatal mortal- and to provide an action plan for providers.
ity, it has the potential for helping save many Similarly, a satisfactory end-result of resus-
lives and for significantly reducing associated citation would be common to all forms of
morbidities. resuscitation, namely to provide adequate
Attempts at reviving nonbreathing infants tissue oxygenation to prevent tissue injury
immediately after birth have occurred and restore spontaneous cardiopulmonary
throughout recorded time with references function. When comparing neonatal resusci-
in literature, religion, and early medicine. tation with other forms of resuscitation, sev-
Although the organization and sophistica- eral distinctions can be noted. First, the birth
tion has changed, the basic principle and of an infant is a more predictable occurrence
goal of initiating breathing has remained than most events that require resuscitation in
constant throughout time. It has just been an adult, such as an arrhythmia or a myocar-
over the last 20 years that the process of dial infarction. Although not every birth will
neonatal resuscitation has been more offi- require “resuscitation,” it is more reasonable
cially regimented. Resuscitation programs to expect that skilled individuals can be pres-
in other areas of medicine were initiated in ent when the need for neonatal resuscitation
the 1970s in an effort to improve knowledge arises. It is possible to anticipate with some
about effective resuscitation and provide an accuracy which neonates will more likely
action plan for early responders. The first of require resuscitation based on perinatal fac-
such programs was focused on adult cardio- tors and thus allow time for preparation. The
pulmonary resuscitation.3 These programs second distinction of neonatal resuscitation
then began increasing in complexity and compared with other forms of resuscitation
becoming more specific to different types of involves the unique physiology involved in
resuscitation needs. With the collaboration the normal fetal transition to neonatal life.
54
CHAPTER 3 Resuscitation at Birth 55
The fetus exists in the protected environ- a negative intrathoracic pressure of approxi-
ment of the uterus where temperature is mately 50 cm H2O is generated.12,13 The alve-
closely controlled, continuous fetal breath- oli become filled with air, and with the help
ing is not essential to provide gas exchange, of pulmonary surfactant, the lungs retain a
the lungs are filled with fluid, and the gas small amount of air at the end of exhalation
exchange organ is the placenta. The transi- known as the functional residual capacity
tion that occurs at birth requires the neonate (FRC). Although the fetus makes breathing
to increase heat production, initiate continu- movements in utero, these efforts are inter-
ous breathing, replace the lung fluid with mittent and are not required for gas exchange.
air/oxygen, and significantly increase pul- Continuous spontaneous breathing is main-
monary blood flow so that gas exchange can tained after birth by several mechanisms
occur in the lungs. The expectations for this including the activation of chemoreceptors,
transitional process and knowledge of how the decrease in placental hormones, which
to effectively assist the process help guide the inhibit respirations, and the presence of nat-
current practice of neonatal resuscitation. ural environmental stimulation. Spontane-
ous breathing can be suppressed at birth for
FETAL TRANSITION TO several reasons, most critical of which is the
EXTRAUTERINE LIFE presence of acidosis secondary to compro-
The key elements necessary for a success- mised fetal circulation. The natural history of
ful transition to extrauterine life involve the physiologic responses to acidosis has been
changes in thermoregulation, respiration, described by researchers creating such con-
and circulation. In utero, the fetal core tem- ditions in animal models. Dawes described
perature is approximately 0.5° C greater than the breathing response to acidosis in differ-
the mother’s temperature.6 Heat is produced ent animal species.14 He noted that when
by metabolic processes and is lost over this pH was decreased, animals typically have a
small temperature gradient through the pla- relatively short period of apnea followed by
centa and skin.7 After birth, the tempera- gasping. The gasping pattern then increases
ture gradient between the infant and the in rate until breathing ceases again for a sec-
environment becomes much greater and ond period of apnea. Dawes also noted that
heat is lost through the skin by radiation, the first period of apnea or primary apnea
convection, conduction, and evaporation. could be reversed with stimulation, whereas
The newly born infant must begin produc- the second period of apnea, secondary or ter-
ing heat through other mechanisms such minal apnea, required assisted ventilation to
as lipolysis of brown adipose tissue.8 If heat establish spontaneous breathing. In the clini-
is lost at a pace greater than it is produced, cal situation, the exact timing of onset of aci-
the infant will become hypothermic. Pre- dosis is generally unknown and, therefore,
term infants are at particular risk because of any observed apnea may be either primary
increased heat loss through immature skin, a or secondary. This is the basis of the resus-
greater surface area to body weight ratio, and citation recommendation that stimulation
decreased brown adipose tissue stores. Pre- may be attempted in the presence of apnea,
term hypothermic infants who are admitted but if not quickly successful, assisted venti-
to the nursery have decreased chances of lation should be initiated promptly. With-
survival.9 Routine measures during neona- out the presence of acidosis, a newborn may
tal resuscitation, such as the use of radiant also develop apnea because of recent expo-
warmers and drying the infant are aimed at sure to respiratory-suppressing medications
preventing heat loss. For the preterm infant, such as narcotics, anesthetics, and magne-
special measures for temperature manage- sium. These medications, when given to the
ment, such as the use of plastic wrap as a mother, cross the placenta, and depending
barrier to evaporative heat loss, are necessary on the time of administration and dose, may
to ensure adequate thermoregulation. act on the newborn.
The fetus lives in a fluid-filled environ- Fetal circulation is unique because gas
ment and as lung development occurs, the exchange takes place in the placenta. In the
developing alveolar spaces are filled with fetal heart, oxygenated blood returning via
lung fluid. Lung fluid production decreases the umbilical vein is mixed with deoxygen-
in the days prior to delivery and the remain- ated blood from the superior and inferior
der of lung fluid is resorbed into the pulmo- vena cava and is differentially distributed
nary interstitial spaces after delivery.10,11 As throughout the body. The most oxygenated
the infant takes the first breaths after birth, blood is directed toward the brain, while the
56 CHAPTER 3 Resuscitation at Birth
most deoxygenated blood is directed toward prepare for resuscitation. For example, some
the placenta. Thus, blood returning from the hospitals may have a separate room desig-
placenta to the right atrium is preferentially nated for resuscitation where the infant
streamed via the foramen ovale to the left will be taken after birth, others bring all the
atrium and ventricle, and then to the ascend- necessary equipment into the delivery room
ing aorta, providing the brain with the most when resuscitation is expected, and some
oxygenated blood. Fetal channels, includ- have every delivery room already equipped
ing the ductus arteriosus and foramen ovale, for any resuscitation. Wherever the resus-
allow blood flow to mostly bypass the lungs citation will take place, a few key elements
with their intrinsically high vascular resis- should be ensured. The room should be
tance, which will receive only approximately warm enough to prevent excessive new-
8% of the total cardiac output. Thus, the born heat loss, bright enough to assess the
fetal circulation is unique in that the pulmo- infant’s clinical status, and large enough to
nary and systemic circulations are not equal accommodate the necessary personnel and
as occurs after these channels close. In the equipment to care for the baby.
mature postnatal circulation, the lungs must When no added risks to the newborn are
receive 100% of the cardiac output. When identified, the term birth frequently may
the low resistance placental circulation is occur without the attendance of a specific
removed after birth, the infant’s systemic neonatal resuscitation team. However, it is
vascular resistance increases while the pul- frequently recommended that one individ-
monary vascular resistance begins to fall as ual be present who is only responsible for
a result of pulmonary expansion, increased the infant and can quickly alert a neonatal
arterial oxygen tension, and local vasodi- resuscitation team if necessary. Even the best
lators. These changes result in a dramatic neonatal resuscitation triage systems will not
increase in pulmonary blood flow. The aver- anticipate the need for resuscitation in all
age fetal oxyhemoglobin saturation as mea- cases. Using a retrospective risk assessment
sured in fetal lambs is approximately 50%,15 scoring system, Smith and colleagues found
but ranges in different sites within the fetal that 6% of newborns requiring resuscita-
circulation between values of 20% to 80%.16 tion would not be identified based on risk
The oxyhemoglobin saturation rises gradu- factors.17 Antenatal determination of neo-
ally over the first 5 to 15 minutes of life to natal risk allows the neonatal resuscitation
90% or greater as the air spaces are cleared of team to be present for the delivery and to be
fluid. In the face of poor transition secondary more thoroughly prepared for the situation.
to asphyxia, meconium aspiration, pneumo- Preterm infants require resuscitation more
nia, or extreme prematurity, the lungs may frequently than term infants and, therefore,
not be able to develop efficient gas exchange, require the presence of a prepared neonatal
and the oxygen saturation may not increase resuscitation team at the delivery. Any situ-
as expected. In addition, in some situations ation in which the infant’s respirations may
the normal reduction in pulmonary vascu- be suppressed or the fetus is showing signs of
lar resistance may not fully occur, resulting distress should signal the need for a neonatal
in persisting pulmonary hypertension and resuscitation team. A list of factors that may
decreased effective pulmonary blood flow be associated with an increased risk of need
with continued right to left shunting through for resuscitation can be found in Box 3-1.
the aforementioned fetal channels. Although Hospitals may vary to some extent about
the complete transition from fetal to extra- which conditions require presence of the
uterine life is complex and much more intri- neonatal resuscitation team at delivery.
cate than can be discussed in these few short The composition of the neonatal resus-
paragraphs, a basic knowledge of these pro- citation team will also vary tremendously
cesses will contribute to the understanding among institutions. Probably the most
of the rationale for resuscitation practices. important factor in how well a team func-
tions is how well the group has prepared for
ENVIRONMENTAL PREPARATION the delivery. When there is a high index of
The environment in which the infant is suspicion that the newborn infant will be
born should facilitate the transition to neo- born in a compromised state, the minimally
natal life as much as possible and should effective team should have at least three
readily accommodate the needs of a resusci- members, including one member with sig-
tation team when necessary. Hospitals may nificant previous experience leading neona-
vary in the approach to the details of how to tal resuscitations. Preparation involves both
Box 3-1. Risk Factors Related to Resuscitation at Birth

Maternal factors Fetal factors Placental factors
Diabetes mellitus Preterm birth Placenta previa
Preeclampsia Known fetal anomalies Placenta accreta
Chronic illness Multiple gestation Vasa previa
Poor prenatal care Hydrops fetalis Placental abruption
Substance abuse Oligohydramnios Premature rupture of membranes
Uterine rupture Polyhydramnios
General anesthesia Intrauterine growth restriction
Chorioamnionitis Signs of fetal distress
Decreased fetal movement
the immediate tasks of readying equipment all team members to perform other tasks.
and personnel, as well as the more broad In addition, the pulse oximeter can be used
institutional preparation of training team as a more accurate measure of oxygenation
members and providing appropriate space than the evaluation of color alone. It has
and equipment. Teams that regularly work been well established that color alone is
together and divide tasks in a routine man- an unreliable measure to accurately assess
ner will have a better chance of function- the infant’s oxygen saturation, especially
ing smoothly during a critical situation. where the room lighting is suboptimal.
Although much attention has been raised in Whenever interventions beyond brief mask
the literature regarding teamwork and team positive pressure ventilation are required,
and leadership training, minimal evidence a pulse oximeter should be considered for
is available to recommend a specific team additional monitoring of the infant.
composition or training approach. The overall assessment of a newborn was
quantified by Virginia Apgar in the 1950s
ASSESSMENT with the Apgar score.18 The score describes
Immediately after birth, the infant’s condi- the infant’s condition at the time it is
tion is evaluated by general observation as assigned and consists of a 10-point scale with
well as measurement of specific parameters. a maximum of 2 points assigned for each of
Typically after birth, a healthy newborn the following categories: respirations, heart
will cry vigorously and maintain adequate rate, color, tone, and reflex irritability. The
respirations. The color will transition from score was initially intended to provide a uni-
blue to pink over the first 2 to 5 minutes, form, objective assessment of the infant’s
the heart rate will remain in the 140s to condition and was used as a tool to com-
160s, and the infant will demonstrate ade- pare different practices, especially obstetri-
quate muscle tone with some flexion of cal anesthetic practices. Despite the intent
the extremities. The overall assessment of of objectivity, there is often disagreement in
an infant who is having difficulty with the score assignment among various practition
transition to extrauterine life will often ers.19,20 Low scores have been consistently
reveal apnea, bradycardia, cyanosis, and associated with increased risk of neonatal
hypotonia. Resuscitation interventions are mortality,21,22 but have not been predictive
based mainly on the evaluation of respira- of neurodevelopmental outcome.23 Inter-
tory effort and heart rate. These parameters preting the score when interventions are
need to be continually assessed throughout being provided may be difficult and current
the resuscitation. Heart rate can be moni- recommendations suggest that clinicians
tored by auscultation or by palpation of the should document the utilized interventions
cord pulsations with auscultation being a at the time the score is assigned.24
more reliable method. In many situations,
the use of a device for more extensive moni- INITIAL STEPS: TEMPERATURE
toring such as a pulse oximeter can be help- MANAGEMENT AND MAINTAINING
ful during resuscitation. A pulse oximeter THE AIRWAY
can provide the resuscitation team with a In the first few seconds after birth, all
continuous audible and visual indication infants are evaluated for signs of life and a
of the newborn’s heart rate throughout the determination of the need for further assis-
various steps of resuscitation while allowing tance is made. This is done both formally,
as described in the NRP, and informally as the neonatal intensive care unit (NICU) with
the initial care providers observe the infant core temperatures well below 37o C, and in a
in the first few moments of life. When the population-based analysis of all infants less
determination that further assistance and than 26 weeks’ gestation, greater than one
formal resuscitation is necessary, the infant third of these preterm infants had admission
is then placed on a radiant warmer and temperatures less than 35o C. More disturb-
positioned appropriately for resuscitation to ing is the fact that infants with such admis-
proceed. Appropriate positioning includes sion temperatures survived less often than
placing the infant supine on the warmer those with admission temperatures greater
in such a way that care providers have easy than 35o C.10 Vohra and colleagues have
access, traditionally with the baby’s head shown that admission temperatures may be
toward the open end of the warmer. In improved in infants less than 28 weeks’ ges-
addition, the head should be in a neutral or tation by immediately covering the infant’s
“sniffing” position to facilitate maintenance body with polyethylene wrap prior to dry-
of an open airway. Frequently, the orophar- ing the infant.28,29 With this approach, the
ynx contains large amounts of fluid which infant’s head is left out of the wrap and is
can be removed by suctioning with a stan- dried, but the body is not dried prior to wrap
dard bulb syringe. application. Other measures for maintain-
An infant born through meconium- ing infant temperatures include perform-
stained amniotic fluid is at risk for aspirating resuscitation in a room that is kept at
ing meconium and developing significant an ambient temperature of approximately
pulmonary disease known as meconium aspi- 25o C to 26o C (77o F to 79o F), using mod-
ration syndrome, which may also be accompa- ern radiant warmers with servo controlled
nied by persistent pulmonary hypertension. temperature probes placed on the infant
For many years, routine management of all within minutes of delivery, and the use of
infants with meconium-stained amniotic accessory prewarmed mattress/heating pads
fluid included endotracheal intubation and for the tiniest of such infants. It is important
tracheal suctioning in an attempt to remove to note that as a required safety feature, radi-
any meconium from the trachea and pre- ant warmers will substantially decrease their
vent the development of meconium aspira- power output after 15 minutes of continuous
tion syndrome. Recognizing that intubation operation in full power mode. If this decrease
may not be necessary for all infants, while in power is unrecognized, the infant will be
the procedure may be associated with com- exposed to a much cooler radiant tempera-
plications, a more selective approach was ture. By applying the temperature probe and
proposed and evaluated.25,26 A metaanalysis using the warmer in servo mode, the temper-
of studies that have evaluated this question ature output will adjust as needed and the
supported the notion that universal endotra- power will not automatically decrease.
cheal suctioning does not result in a lower
incidence of meconium aspiration syndrome ASSISTING VENTILATION
when compared with selective endotracheal As the newborn infant begins breathing and
suctioning.27 The likelihood that an infant replaces the lung fluid with air, the lung
with meconium-stained amniotic fluid will becomes inflated and a functional residual
develop meconium aspiration syndrome is capacity is developed and maintained. With
increased in the presence of fetal distress. The inadequate development of FRC, the infant
selective approach to endotracheal suction- will not adequately oxygenate, and if pro-
ing requires a quick evaluation of the infant longed, the infant will develop bradycardia.
after delivery. If the infant is vigorous with The steps involved in performing resusci-
good respiratory effort, normal heart rate tation include providing assisted positive
and tone, the steps of resuscitation should pressure ventilation when the infant shows
proceed as usual. However, if the infant is signs of inadequate lung inflation. The indi-
not vigorous, has poor respiratory effort, a cations for provision of positive pressure
heart rate less than 100 beats per minute ventilation include apnea or inadequate
(bpm) and/or decreased tone, endotracheal respiratory effort, poor color, and heart
intubation and tracheal suctioning are per- rate less than 100 bpm. Positive pressure
formed as quickly as possible. ventilation can be delivered noninvasively
The provision of warmth is particularly with a pressure delivery device and a face
important for the extremely preterm infant. mask or invasively with the same pressure
Preterm infants are commonly admitted to delivery device and an endotracheal tube.
Pressure delivery devices can include self- pulmonary blood flow, as occurs with inad-
inflating bags, flow-inflating or anesthesia equate cardiac output. At times, multiple
bags, and T-piece resuscitators, each with its maneuvers are required to achieve a patent
own advantages and disadvantages. A self- airway, such as readjusting the head and
inflating bag requires a reservoir to provide mask positions, choosing a mask of more
nearly 100% oxygen, may deliver very high appropriate size, and further suctioning
pressure if not used carefully, but is easy to of the pharynx. Alternate methods of pro-
use for inexperienced personnel and will viding a patent airway include the use of
work in the absence of a gas source. These a nasopharyngeal tube,35 a laryngeal mask
devices have pressure blow-off valves, but airway device,36 or an endotracheal tube.
these valves do not always open at the target The amount of pressure provided with
blow-off pressures.30 An anesthesia bag or each breath during assisted ventilation is
flow-inflating bag requires a gas source for critical to the establishment of lung infla-
use, allows the operator to “instinctively” tion and therefore adequate oxygenation.
vary delivery pressures, but requires signifi- Although it is important to provide adequate
cant practice to develop expertise with use. pressure for ventilation, excessive pressure
A T-piece resuscitator is easy to use, requires can contribute to lung injury. Achieving the
a gas source for use, delivers the most con- correct balance of these goals is not simple
sistent levels of pressure, but requires inten- and is an area of resuscitation that requires
tional effort to vary pressure levels.31 The more study. A specific level of inspiratory
flow-inflating bag and T-piece resuscitator pressure will never be appropriate for every
allow the operator to deliver continuous baby. Initial inflation pressures of 25 to
positive airway pressure (CPAP) or positive 30 mm Hg are probably adequate for most
end expiratory pressure (PEEP) relatively term babies. The current NRP textbook rec-
easily.32,33 ommends initial pressures of 20 to 25 mm Hg
A level of experience is required to perfor preterm infants.5 The first few breaths
form assisted ventilation using a face mask may require increased pressure if lung fluid
and resuscitation device, especially for an has not been cleared, as occurs when the
extremely low-birth-weight infant. It is infant does not initiate spontaneous breath-
important to maintain a patent airway for ing, and infants with specific pulmonary
the air to reach the lungs. The procedure disorders, such as pneumonia or pulmonary
of obtaining and maintaining a patent air- hypoplasia, also frequently require increased
way includes, at minimum, clearing of fluid inspiratory pressure. It has been shown that
with a suction device, holding the head in a using enough pressure to produce visible
neutral position, and sometimes lifting the chest rise may be associated with hypocar-
jaw slightly anteriorly. The face mask must bia on blood gas evaluation and excessive
make an adequate seal with the face for air pressure may decrease the effectiveness of
to pass to the lungs effectively. No device surfactant therapy.37,38 It may be possible
will adequately inflate the lungs if there is to establish FRC without increasing peak
a large leak between the mask and the face. inspiratory pressures by providing a few
Until recently, there were no masks that prolonged inflations (3 to 5 seconds inspi-
were small enough to provide an adequate ration)37, although the use of prolonged
seal over the mouth and nose for the tiniest inflations has not been associated with bet-
infants. Such masks are now readily avail- ter outcomes than has conventional breaths
able and facilitate bag and mask resuscita- during resuscitation.39 Choosing the actual
tion of very small infants. Signs that the initial inspiratory pressure is less important
airway is patent and air is being delivered to than continuously assessing the progress of
the lungs include visual inspection of chest the intervention.
rise with each breath and improvement in
the clinical condition, including heart rate EDITORIAL COMMENT: Current neonatal resuscita-
and color. The use of a colorimetric carbon tion guidelines recommend using visual assessment of
dioxide detector during bagging will allow chest wall movements to guide the choice of inflating
confirmation that gas exchange is occurring pressure during positive pressure ventilation (PPV) in
by the observed color change of the device the delivery room. The accuracy of this assessment has
or alerting the operator of an obstructed air- not been tested. Poulton et al compared the assess-
way with lack of such color change.34 It is ment of chest rise made by observers standing at the
important to remember that these devices infant’s head and at the infant’s side with measurements
will not change color in the absence of
of tidal volume. Airway pressures and expiratory tidal

in death or bronchopulmonary dysplasia
volume (V[Te]) were measured during neonatal resusci-
between infants randomly assigned CPAP
tation using a respiratory function monitor. After 60 sec-
beginning in the delivery room versus
onds of PPV, resuscitators standing at the infant’s head
those who received intubation and early
(head view) and at the side of the infant (side view) were
surfactant.43
asked to assess chest rise and estimate V(Te). These
If assisted ventilation is necessary for a
estimates were compared with V(Te) measurements
prolonged period of time or if other resus-
taken during the previous 30 seconds. Agreement be-
citative measures have been unsuccessful,
tween clinical assessment and measured V(Te) was
ventilation should be provided via an endo-
generally poor. During mask ventilation, resuscitators
tracheal tube. If it has been difficult to main-
were unable to accurately assess chest wall movement
tain a patent airway by ventilating with a
visually from either head or side view.
face mask, the appropriately placed endo-
tracheal tube will provide a stable airway.
Poulton DA, Schmölzer GM, Morley CJ, et al: Assessment of This will allow more consistent delivery of
chest rise during mask ventilation of preterm infants in the gas to the lungs and, therefore, provide for
delivery room, Resuscitation 82:175, 2011.
the ability to establish and maintain FRC. At
this time, intubation is required for admin-
istering surfactant and may be used to
A manometer in the circuit during assisted administer other medications necessary for
ventilation provides the clinician with an resuscitation. Finally, for depressed infants
indication of the actual administered pres- born through meconium-stained amniotic
sure, although if the airway is blocked, fluid, intubation is performed for suction-
this pressure is not delivered to the lungs. ing of the airway.
The most critical component of continued
assessment is evaluation of the infant’s
response to the intervention. If after initiat- EDITORIAL COMMENT: Videotaping resuscitations
ing ventilation, the condition of the infant to review in detail, techniques, timing, and so on are
does not improve (specifically improved extremely helpful. The debriefing is a valuable lesson
heart rate, breathing, and color), then the for all involved, and it helps prepare the team for all
ventilation is most likely inadequate. Two emergencies. Furthermore, simulation provides a
most common reasons for inadequate ven- unique opportunity to test the team, establish team
tilation are a blocked airway or insufficient leadership, and test the techniques. For example,
inspiratory pressure. The blocked airway Schilleman et al established that mask ventilation dur-
frequently can be corrected with changes in ing simulated neonatal resuscitation was often ham-
position or suctioning, whereas inadequate pered by large leaks at the face mask. Moderate air-
pressure is corrected by adjusting the venti- way obstruction occurred frequently when effort was
lating device. taken to minimize the leaks. Training in mask venti-
In addition to consideration of inspira- lation reduced mask leaks, but should also focus on
tory pressure, use of continuous pressure preventing airway obstruction. In the delivery room, it
throughout the breathing cycle seems to be is neither possible for the observers to accurately de-
beneficial for the establishment of FRC and termine tidal volume nor to determine degree of leak
improvement in surfactant function.40,41 (Schmölzer et al).
This is accomplished during assisted ven- Schilleman K, Witlox RS, Lopriore E, et al: Leak and
tilation with the use of PEEP or CPAP obstruction with mask ventilation during simulated
when additional inspiratory pressure is neonatal resuscitation, Arch Dis Child Fetal Neonatal
not needed. In the absence of PEEP, a lung Ed 95:F398, 2010.
Schmölzer GM, Kamlin OC, O’Donnell CP, et al: Assessment
that has been inflated with assisted inspira- of tidal volume and gas leak during mask ventilation of
tory pressure will lose on expiration most preterm infants in the delivery room. Arch Dis Child Fetal
of the volume that had been delivered on Neonatal Ed 95:F393, 2010.
inspiration. This pattern of repeated infla-
tion and deflation is frequently thought to
be associated with lung injury. In preterm The intubation procedure, although poten-
infants, a general approach of using CPAP tially critical for successful resuscitation,
as a primary mode of respiratory support requires a significant amount of skill and
in neonatal intensive care units has been experience to perform reliably and may
associated with a low incidence of chronic be associated with serious complications.
lung disease.42 The recently published SUP- The procedure entails using a laryngoscope
PORT trial found no significant difference to visualize the vocal cords and passing
the endotracheal tube between the vocal oxygen.51-53 The latest NRP guidelines advo-
cords. The placement of the laryngoscope cate starting resuscitation of term babies
in the pharynx often produces vagal nerve with room air (21% oxygen).
stimulation, which leads to bradycardia. The preterm infant may be more sus-
Assisted ventilation must be paused for the ceptible to any harmful effects of exces-
procedure, which if prolonged, will lead sive oxygen delivery because of decreased
to hypoxia and bradycardia. Intubation antioxidant enzyme capacity. Some of
has been shown to increase blood pressure the infants in the previous oxygen trials
and intracranial pressure.44 Trauma to the were preterm, but few were less than 1000
mouth, pharynx, vocal cords, and trachea grams. Neonatal intensive care units gen-
are all possible complications of intubation. erally attempt to reduce oxygen toxicity
Performing the intubation procedure when by limiting the amount of oxygen deliv-
the infant already has bradycardia and is ered to neonates using an upper limit for
hypoxic can lead to further decline in heart oxygen saturation and adjusting delivered
rate and oxygenation.45 Therefore, it seems oxygen levels to maintain oxygen satura-
most appropriate to make an attempt to tion levels within that limit. The unlim-
stabilize the infant with noninvasive ven- ited use of oxygen during resuscitation will
tilation prior to performing the procedure, expose the preterm infant to higher oxy-
limit each attempt to 30 seconds or less, gen saturation levels than would routinely
and stabilize the infant between attempts. be accepted in the neonatal intensive care
If misplacement of the endotracheal tube unit. When initiating resuscitation of very
into the esophagus goes unrecognized, preterm infants with room air, desired
the infant may experience further clinical oxygen saturation targets may be achieved
deterioration. Clinical signs that the endo- without providing supplemental oxygen.54
tracheal tube has been correctly placed in The most recent NRP guidelines recom-
the trachea include the following: auscul- mend resuscitating preterm babies using a
tation of breath sounds over the anterolat- pulse oximeter and an oxygen blender so
eral aspects of the lungs (near the axilla); that the amount of oxygen can be adjusted
mist visible on the endotracheal tube; chest based on the needs of the infant. The use
rise; and clinical improvement in heart rate of oxygen concentrations between 21%
and color or oxygen saturation. The use of and 100% requires compressed air and a
a colorimetric carbon dioxide detector to blender. When choosing oxygen saturation
confirm intubation decreases the amount of targets, it is important to remember that the
time necessary to determine correct place- neonate transitioning from fetal life begins
ment of the endotracheal tube,46 and is now with an oxygen saturation of approxi-
recommended by the NRP as one of the pri- mately 50% and gradually increases to 90%
mary methods of determining endotracheal over the first 5 to 10 minutes of life. The
tube placement. most recent NRP guidelines recommend
that supplemental oxygen be delivered via
Oxygen Use a blender and that an oximeter probe be
The use of pure oxygen for ventilation placed on the newborn, with the amount
became routine practice in resuscitation of oxygen titrated to maintain SpO2 within
because it seemed logical that oxygen would the ranges shown in Table 3-1. Clearly, tar-
be beneficial. However, the recognition geted oxygen delivery requires the early
that oxygen could also be toxic led many use of pulse oximeters and blended oxygen
investigators to question this previously in the resuscitation area.
well-accepted practice. Several worldwide
trials have compared the use of pure (100%)
oxygen with room air (21% oxygen) for Table 3-1. Target Oxygen Saturation
newborn resuscitation. These trials found According to Time after Birth
that room air was as successful as oxygen in Time After Birth (min) Target SpO2 (%)
achieving resuscitation, and infants resusci-
tated with room air had a shorter time to 1 60-65
initiate spontaneous breathing and less evi- 2 65-70
dence of oxidative stress.47-50 Metaanalyses 3 70-75
4 75-80
of several of the trials indicated that infants
5 80-85
resuscitated with room air had less risk of
10 85-95
mortality than those resuscitated with pure
Assisting Circulation administration. If there is any prenatal indi-

In newly born infants, the need for resusci- cation that substantial resuscitation will
tative measures beyond assisted ventilation be required, the necessary equipment for
is extremely rare. Additional circulatory umbilical venous catheter placement should
assistance can include chest compressions, be prepared before delivery as completely as
administration of epinephrine, and volume possible. It is probably advisable to initiate
infusion. In a large urban delivery center the process of umbilical venous catheter
with a resuscitation registry, 0.12% of all placement when the need for chest com-
infants delivered received chest compres- pressions arises. Epinephrine may be given
sions and/or epinephrine from 1991 to 1993 by endotracheal tube but the delivery is not
and 0.06% of all infants delivered received as certain and, therefore, an increased dose
epinephrine from 1999 to 2004.55,56 of 0.05 to 0.1 mL/kg of a 1:10,000 solution is
The importance of chest compressions in currently recommended. Epinephrine doses
resuscitation is currently being emphasized may be repeated every 3 minutes if heart rate
in adult resuscitation programs.57 Although does not increase. Excessive epinephrine
neonatal resuscitation is clearly distinct administration may result in hypertension,
from adult resuscitation as previously dis- which in preterm infants may be a factor in
cussed, any situation in which circulation the development of intraventricular hemor-
has been sufficiently compromised will rhage. However, the risks are balanced by
require support with chest compressions the benefit of successful resuscitation in an
until spontaneous circulation is initiated. infant who might not otherwise survive.
Ventilation remains the most critical prior- If the infant has not responded to all
ity in neonatal resuscitation. However, if an of the prior measures, a trial of increasing
airway is established (either with a face mask intravascular volume should be consid-
and good positioning or an endotracheal ered by the administration of crystalloid or
tube), adequate ventilation is provided for blood. Situations associated with fetal blood
30 seconds, and bradycardia of <60 bpm loss are also frequently associated with the
persists, chest compressions are initiated. need for resuscitation. These include pla-
Further attention to ventilation with the cental abruption, cord prolapse, and fetal
use of increased pressures and/or intubation maternal transfusion. Some of these clinical
may be required. Chest compressions may circumstances will have an obvious history
be provided with either two fingers of one associated with blood loss, whereas others
hand or two thumbs. The preferred method may not be readily evident at the time of
according to current guidelines is the two- birth. Signs of hypovolemia in the newly
thumb method which involves encircling born infant are nonspecific but include pal-
the chest with both hands and placing the lor and weak pulses. Volume replacement
thumbs on the sternum. During placement requires intravenous access for which emer-
of an umbilical catheter, the two-finger tech- gent placement of an umbilical venous cath-
nique may be necessary to allow access to eter is essential. Any infant who has signs
the umbilical cord. With either method, the of hypovolemia and has not responded to
chest is then compressed in a 3:1 ratio coor- other resuscitative measures should have an
dinated with ventilation breaths to provide umbilical venous line placed and a volume
90 compressions to 30 breaths per minute. infusion administered. The most common
Further circulatory support may be neces- volume replacement (and currently rec-
sary if adequate chest compressions do not ommended fluid) is isotonic saline. A trial
result in an increase in heart rate after 30 sec- volume of 10 mL/kg is given initially and
onds. Epinephrine is then indicated as a repeated if necessary. If a substantial blood
vasoactive substance, which increases blood loss has occurred, the infant may require
pressure by alpha-receptor agonist effects, infusion of red blood cells to provide ade-
improves coronary perfusion pressure, and quate oxygen-carrying capacity. This can
increases heart rate by beta-receptor agonist be accomplished emergently with uncross-
effects. The strongly recommended method matched O-negative blood, with blood
of epinephrine administration is intrave- collected from the placenta, or with blood
nous in a dose of 0.01 to 0.03 mg/kg (0.1 drawn from the mother who will usually
to 0.3 mL/kg of a 1:10,000 solution). There- have a compatible antibody profile with her
fore, early placement of an umbilical venous infant at the time of birth. Because not all
catheter during a difficult resuscitation is blood loss is obvious, and resuscitation algo-
important for both volume and epinephrine rithms usually discuss volume replacement
as a last resort of a difficult resuscitation, problems may be modifiable with interven-

the clinician needs to keep an index of sus- tions that could improve the course of the
picion for significant hypovolemia so that resuscitation. For example, an unrecognized
action may be taken to correct the problem pneumothorax could prevent adequate
as promptly as possible. Therefore, in situa- pulmonary inflation, and if under ten-
tions where the possibility for hypovolemia sion, could impair cardiac function. If the
is known prior to birth, it would be wise pneumothorax is recognized and drained,
to prepare an umbilical catheter, an initial both gas exchange and circulation can
syringe of isotonic saline, and discuss with be improved. Some congenital anomalies
the blood bank the possibility that uncross- that were not diagnosed antenatally make
matched blood may be required. resuscitation more difficult. Congenital dia-
phragmatic hernia is one such anomaly that
Specific Problems Encountered During is difficult to recognize on initial inspec-
Resuscitation tion of the infant but can cause significant
Neonatal Response to Maternal Anesthesia/ problems with resuscitation. The abdominal
Analgesia organs are displaced into one hemithorax
Medications administered to the mother and the lungs are unable to develop nor-
during labor can affect the fetus by transfer mally, causing ventilation to be quite diffi-
across the placenta and acting on the fetus cult. If the intestines are displaced into the
or by adversely affecting the mother’s con- thorax and mask ventilation is provided, the
dition, thereby altering uteroplacental cir- intestines will become inflated making ven-
culation and placental oxygen delivery. The tilation even more difficult. If the congenital
most commonly discussed complication of diaphragmatic hernia is known before deliv-
intrapartum medication exposure is peri- ery or a presumptive diagnosis is made in
natal respiratory depression after maternal the delivery room, the baby should be intu-
opiate administration. Because opiates can bated early to prevent intestinal inflation. A
cross the placenta, the fetus may develop large (10 F) orogastric suction tube should
respiratory depression from the direct effect also be placed to decompress the inflated
of the drug. Naloxone has been used during intestines. Many other congenital anomalies
neonatal resuscitation as an opiate receptor that can lead to a difficult resuscitation will
antagonist to reverse the effects of fetal opi- be more visibly obvious when the baby is
ate exposure. Despite a lack of evidence of born. For example, hydrops fetalis occurring
beneficial effect, naloxone hydrochloride for any reason can be associated with very
in a dose of 0.1 mg/kg (intravenous route difficult resuscitation. Although most cases
preferred, intramuscular route acceptable, are diagnosed on fetal ultrasound before
endotracheal administration NOT recom- delivery, severe hydrops would be visible on
mended) may be given if the newborn does examination with skin edema and abdomi-
not develop spontaneous respirations after nal distention. Frequently, peritoneal and/
adequate resuscitation and the mother has or pleural fluid will need to be drained to
received an opiate analgesic during labor. achieve adequate ventilation.
Do not give this medication to a newborn A situation which may create a particularly
when the mother has either been on meth- difficult resuscitation is an airway obstruc-
adone maintenance or is suspected of being tion, especially if not diagnosed prior to
addicted to narcotics, because seizures may delivery. If a significant airway obstruction
occur. It is also critical that assisted venti- is diagnosed antenatally, an EXIT procedure
lation be provided as long as spontaneous (EX-utero Intrapartum Treatment) can be
respirations are inadequate. It should be planned. This allows for establishment of a
noted that the administration of a narcotic stable airway prior to clamping of the umbili-
antagonist is never an acutely required cal cord, which maintains placental function
intervention during neonatal resuscitation until the airway is secure. The therapy will
because such infants can be adequately vary depending on the cause of obstruction.
ventilated with a bag and mask. An alternate airway (oral or nasopharyngeal)
can be helpful if endotracheal intubation is
Conditions Complicating Resuscitation not possible as can occur with micrognathia.
When resuscitation has proceeded through Tracheal suctioning can be attempted if a
the described steps without improvement in tracheal plug is suspected. In extreme situ-
the infant’s clinical condition, other prob- ations of airway obstruction, an emergency
lems should be considered. Some of these cricothyroidotomy may be attempted.
After Resuscitation
What Apgar score do you assign him at
In infants born without a heart rate or
5 minutes of life?
any respiratory effort, if resuscitation is
performed to the full extent without any By 5 minutes of life, the baby has a heart rate greater
response, discontinuation may be appropri- than 100 bpm (2 points), adequate regular spontane-
ate after 10 minutes. This recommendation ous respirations (2 points), good tone (2 points), good
is based on the high incidence of mortality reflex irritability (2 points), and is centrally pink (1 point).
and morbidity among infants born without Therefore, the Apgar score at 5 minutes of life is 9.
any signs of life and poor response to resus-
citation.58,59 The new NRP guidelines do Once the initial stabilization has been
recognize that the decision of when to dis- completed, what do you look for in this
continue resuscitation is complicated and infant whose mother had no prenatal care?
influenced by a number of factors. Among the most important observations to make is
Infants who do survive a significant resus- an approximation of gestational age. In addition to
citation may require special attention in the evaluating the size of the baby, a quick physical ex-
hours to days that follow. Frequent compli- amination with attention to physical maturity findings
cations immediately following resuscitation will indicate an approximate gestational age which
include hypoglycemia, hypotension, and will be important in determining the further care nec-
persistent metabolic acidosis. In addition, essary for this newborn. A brief physical examination
infants with evidence of hypoxic-ischemic will also be important as a preliminary screen for con-
encephalopathy may benefit from mild genital anomalies. Further evaluation and observa-
therapeutic hypothermia.60 This therapy is tion will be necessary because of the lack of prenatal
most beneficial when initiated as quickly screening. Some of these routine prenatal screens
as possible after an insult and is not avail- may be completed by testing the mother at the time
able at every center. Institutions that do not of admission. The pediatrician needs to be aware
provide this therapy should coordinate in of these screens to treat the baby properly. Urgent
advance with centers that do to ensure that considerations for the baby include rapid HIV test-
treatment is started in a timely manner. ing, hepatitis B screening, syphilis screening, blood
type assessment, and a sepsis risk assessment as
group B Streptococcus carrier status is unknown. An
CASE 1
urgent or early therapy for each of these conditions
A woman presents to labor and delivery in can be life altering. Further evaluation may also be
active labor after having had no prenatal indicated but is not necessarily as urgent.
care. She precipitously delivers the baby
and you are called urgently to the room.
Who will go with you to the delivery room?
Each institution must decide the composition of CASE 2
their delivery resuscitation team. The individuals in- A woman with a twin gestation at 25 weeks
tended to participate on any given day should be is admitted to labor and delivery with
identified prior to the start of the day. A team that has preterm labor. Fetal monitoring is initiated,
worked well together consistently would be expected a dose of betamethasone is administered,
to work well together in difficult situations. and a course of antibiotics is begun. You
have a chance to talk with the parents; in
The baby is handed to you; you place the addition to discussing general issues of
baby on a radiant warmer and begin to prematurity at 25 weeks, what do you tell
evaluate the baby. You suction the mouth them to expect in the delivery room?
and remove the wet linens. The baby is To begin the discussion, it would be helpful to in-
making intermittent respiratory effort and form the parents who will be caring for the babies at
the heart rate is over 100 bpm. the delivery and where they will be cared for immedi-
ately after delivery. When multiples are delivered, it is
As you are drying the baby, you are best to have a separate resuscitation team planned
stimulating him and his breathing becomes for each infant. This may take extra preparation to en-
more regular by one minute of life. His sure that enough resources are available at the time
heart rate always remains greater than of delivery. It would be appropriate to inform the par-
100 bpm, his color transitions from blue to ents that preterm babies at 25 weeks have a higher
pink centrally by 2 minutes of life. You note chance of requiring resuscitation, including the need
that his extremities are flexed and he cries for intubation, but that currently survival for such in-
when you examine him. fants is 70% or greater in most institutions.
Later that evening her labor is progressing displays a heart rate of 85 bpm and an
and late decelerations develop on fetal oxygen saturation of 30%. The baby has
heart rate monitoring. Your team is called made some attempts at breathing but
to the delivery and a cesarean section is does not have sustained spontaneous
performed. The first baby is handed to you respirations. Why do you think the baby
and does not have any apparent respiratory is not making further improvements and
effort. Describe what you expect to occur what is your next step?
in the first 1 minute of life. The most likely cause of the continued bradycar-
The infant will be brought to a radiant warmer and dia is lack of development of an adequate functional
wet linens will be removed. On the warmer there will residual capacity. Because attempts to stabilize the
be a plastic wrap/bag waiting which will cover the in- baby with noninvasive ventilation have failed, it is
fant’s body as soon as the wet linens are removed. necessary to intubate the baby to provide a more
While one team member assesses the heart rate by direct and secure method of providing positive pres-
auscultation and providing a visual display for the ensure. One may try a further increase in the inspiratory
tire team, a second team member will bulb suction pressure because inadequate ventilation is the most
the infant’s mouth, position the baby on the bed in a frequent cause for continuing bradycardia and de-
straight fashion with the neck neutral. After suctioning saturation, and add 5 cm H2O end-expiratory pres-
the mouth, the second team member will place a face sure to assist in establishing and maintaining FRC. It
mask and initiate assisted ventilation. The third per- would also be appropriate at this time to increase the
son will place a pulse oximeter and adjust the deliv- delivered oxygen concentration if an amount <100%
ered oxygen concentration to meet the saturation tar- is being administered.
gets recommended by NRP, which is 60% to 65% at The equipment necessary for intubation had been
1 minute of life, and 65% to 70% at 2 minutes of life. prepared and inspected prior to delivery and is waiting
at the bedside. An appropriately sized endotracheal
You begin positive pressure ventilation tube is available. The designated operator performs
because the baby’s spontaneous the procedure with the assistance of a second team
respiratory effort was inadequate. The member. Because the pulse oximeter is functioning,
nurse auscultates the heart rate and finds the baby will be monitored throughout the procedure.
it to be approximately 80 bpm and not yet An additional team member will track the time and
increasing. How do you proceed? notify the operator if 30 seconds has elapsed prior
Because you are already giving positive pressure to passing the endotracheal tube. If the attempt is
ventilation, you need to assess whether the breaths unsuccessful, the laryngoscope will be removed from
are being delivered adequately—in other words, the baby’s mouth and the positive pressure ventila-
whether the airway is open. The first step would be tion will be reinstituted to allow the baby to recover
to readjust the head position ensuring that there is a prior to another attempt. Once the endotracheal tube
good seal with the face mask and the neck is neutral. is positioned, a carbon dioxide detector will be used
It can be helpful to gently hold upward pressure on to ensure placement in the trachea. Breath sounds
the corners of the mandible while stabilizing the face will be auscultated and the depth of the tube will be
mask. Observe the chest for movement with breaths, adjusted as necessary.
although this is sometimes difficult to see in very small
babies. An additional indication of an open airway is When the endotracheal tube is inserted
detection of carbon dioxide on a disposable device and positive pressure is restarted, the
placed in line with the face mask and breathing de- heart rate increases to 150 bpm and
vice. If the heart rate does not improve with these the baby becomes pink with an oxygen
initial measures, the positive inspiratory pressure saturation that increases to 95%. How
of the delivered breaths should be increased (done would you care for the baby until you are
differently depending on the device used) or the in- able to arrive in the neonatal intensive care
spiratory time of each breath should be increased. A unit?
prolonged breath with an inspiratory time of approxi- Attention will be paid to the infant’s temperature,
mately 5 seconds may be attempted for one or two breathing, and heart rate throughout the entire time in
breaths as well. These measures may be attempted the delivery room and through transport to the NICU.
and frequently lead to improvement but should not A temperature probe will be placed and the radiant
be prolonged and delay more definitive therapy. warmer switched to servo mode. The pulse oxime-
ter will be kept in place throughout the time in the
At this point (it is now approximately 1.5 delivery room and transport to the NICU. The deliv-
minutes of life), the baby has a functioning ered oxygen concentration will be adjusted to main-
pulse oximeter on the right hand which tain the oxygen saturation appropriate for the time of
life. Continued positive pressure ventilation with end and positive pressure ventilation is initiated. At the
expiratory pressure will be provided with delivered same time, a second team member is evaluating the
pressures adjusted as needed for the infant. In this heart rate.
case, the pressure was increased prior to intubation.
If a T-piece resuscitator is being used for ventilation, The heart rate is not appreciable by
the pressure will need to be manually adjusted to auscultation or palpation. What is your
obtain desired levels and should be decreased once next step?
the intubation is performed and the heart rate and The effectiveness of ventilation is evaluated look-
oxygen saturation have improved. The most consis ing for evidence of a patent airway. The head posi-
tent methods of providing continued ventilation with tion is adjusted and the level of positive pressure
consistent levels of pressure would be either with a delivered is increased. If these actions have made no
T-piece resuscitator or a ventilator. The use of ei- difference in heart rate, chest compressions are initi-
ther the self-inflating bag or flow-inflating bag for ated. At this point, a third team member is placing a
prolonged periods of time will likely lead to inconsis pulse oximeter, while the team member who had been
tent pressure delivery with the potential for delivery evaluating the heart rate begins chest compressions.
of excess peak inspiratory pressure or inadequate Chest compressions and breaths are coordinated in
positive end expiratory pressure levels, both of which a three compressions to one breath rhythm with the
may contribute to lung injury. Some institutions deter- team member performing chest compressions count-
mine the level of pressure provided by measuring the ing the actions out loud. The pace will be such that in
tidal volume delivered, targeting an exhaled volume 1 minute there will be approximately 90 compressions
of 5 to 6 mL/kg. Additional care for an infant of this and 30 breaths.
gestational age who has required intubation would
be administration of exogenous surfactant. Although The heart rate is reevaluated after 30
the provision of surfactant early, particularly within the seconds of assisted ventilation and
first 15 minutes of life, is a proven intervention that chest compressions and continues to be
will reduce the severity and mortality from respiratory undetectable. What do you do now?
distress syndrome, later administration up to 2 hours At this point, endotracheal intubation is neces-
of age is also beneficial. Administration of surfactant sary. This is performed by the team member who was
may vary in preferred location (delivery room versus providing positive pressure ventilation previously, with
NICU) and timing. assistance from the team member who had placed
the pulse oximeter. Chest compressions are paused
during the intubation. If the intubation attempt is un-
successful within 30 seconds, chest compressions
CASE 3 and mask ventilation are reinitiated for at least 10
A 27-year-old gravida 2 para 0 woman seconds before another intubation attempt is made.
presents to labor and delivery at 30 weeks’ Depending on the number of individuals present at
gestation with rupture of membranes. She the resuscitation, more help should be called at this
is admitted to the hospital, betamethasone point, if necessary. Because the baby is being intu-
is administered, and fetal monitoring is bated with a low (absent) heart rate, it will most likely
initiated. After she has been hospitalized be necessary to give epinephrine. Therefore, an addi-
for 4 days, the fetal heart rate is noted to tional (fourth) individual could be preparing the epine-
increase to the 170s. On examination, it is phrine dose, and if a fifth skilled individual is available,
noted that the umbilical cord is palpable an umbilical line should be prepared for placement.
in the vagina. The mother is rushed to When the intubation is complete, if the heart rate is
the operating room and an emergency still low, the dose of epinephrine could be given in
cesarean section is performed. The the endotracheal tube. Ensure that this dose is ad-
pediatric team is called to the delivery equately flushed through the ETT so that it reaches
room and is handed the baby who is limp, the lung. At the same time that this is being done, the
pale, and has no respiratory effort. How do umbilical venous catheter is being placed so that a
you proceed? dose of epinephrine can be given intravenously.
The baby is positioned on a radiant warmer,
quickly dried, wet linens are removed, and the mouth Can you do anything else to help the baby
is bulb suctioned. If these simple measures, which at this point?
also act to stimulate the baby, do not cause the infant A dose of intravenous epinephrine should be given
to begin breathing spontaneously, then assisted ven- as soon as the umbilical venous catheter is placed
tilation must be initiated without delay. The face mask because the effectiveness of intravenous epinephrine
and ventilating device are then immediately applied is more consistent than endotracheal epinephrine.
Because the baby appeared pale from the start and The baby is delivered and is limp and
there was a history of cord prolapse, it may be help- apneic. After he is handed to you, you
ful to provide intravenous fluid volume. A bolus of place him on the radiant warmer with his
10 mL/kg of normal saline can be given initially and head to you. What do you do next?
repeated if necessary. If suspicion of blood loss is This infant’s tone and respiratory effort are poor. He
high, a transfusion of emergency blood may be pro- is, therefore, not vigorous and immediate intervention
vided. In addition, repeat doses of epinephrine can is indicated. Before any other action is taken, a direct
be administered every 3 minutes. An evaluation for laryngoscopy is performed. The pharynx is suctioned
other causes of cardiopulmonary insufficiency should to clear any fluid that is obstructing the view of the
be done. A pneumothorax may cause circulatory larynx, and you then pass the endotracheal tube
compromise and may be evaluated by auscultation through the glottis. As you continue to hold the en-
of breath sounds and transillumination of the chest. dotracheal tube in place, another team member con-
A brief survey for congenital anomalies might dis- nects the suction tubing directly to the endotracheal
close a cause for difficulty with resuscitation. tube by the meconium aspirator and applies suction
as you remove the endotracheal tube. As you are do-
After you have given one dose of ing this, a third team member is continuously assess-
intravenous epinephrine and one bolus ing the heart rate.
of normal saline, the baby’s heart rate
becomes detectable and steadily increases As you were suctioning, you saw a small
to greater than 100 bpm. How long would amount of meconium in the tubing before
you have continued resuscitation if there the endotracheal tube was pulled back to
had been no improvement? the pharynx. At this point, the baby has
In a situation where there are no signs of life (no made weak respiratory effort, the heart
heart rate or respiratory effort), and full resuscitative rate is approximately 100 bpm and the
efforts are continued for 10 minutes with no effect, it tone is still poor. What is your next step?
is considered appropriate to stop the resuscitation. If meconium is suctioned from the trachea and the
Each team may vary the time frame based on when baby’s heart rate is not decreasing, another endotra-
resuscitative efforts were felt to be truly adequate, and cheal intubation and suctioning could be performed.
whether there is any clinical evidence of signs of life. Frequently at this time, the infant has either begun
crying or has a decreasing heart rate because there
has been inadequate breathing. In this case, there
CASE 4 may be benefit to attempting a second suctioning
You are called to the delivery room since there is an indication that the baby did aspirate
emergently because a woman at 40 weeks’ and he seemed to tolerate the first procedure well.
gestation is delivering an infant vaginally.
She has just ruptured her membranes and As you place the laryngoscope into the
thick meconium is noted. You arrive at the pharynx, the heart rate begins to drop
delivery room as the baby’s head is being which you note by the indication of slower
delivered. How do you quickly prepare tapping from your fellow team member.
your equipment? How do you proceed?
A glance at the power display on the radiant At this point, you abandon the second effort to suc-
warmer will determine whether the device is in the tion the trachea, remove the laryngoscope, and begin
full power mode. If not, this can be done quickly. A positive pressure ventilation. As you initiate positive
laryngoscope with blade is prepared and the function pressure ventilation, you note the heart rate being
of light bulb is tested. The blade is then left in place in tapped out begins increasing. You continue providing
the off position and the laryngoscope is placed on the assisted breaths and the baby develops a stronger
bed. An endotracheal tube with meconium aspirator regular respiratory effort. You stop providing assisted
is opened and placed on the bed in the packaging. breaths when the respiratory effort is adequate and
Confirmation that a source of suction is available and the heart rate is about 140 bpm. You do, however,
functioning properly is made. The flow of air and oxy- continue to provide supplemental oxygen and place
gen to a ventilating device is initiated and function of a pulse oximeter.
the ventilating device is tested. If additional time is
available, extra warm blankets can be prepared and The baby is now vigorous and crying with
any other usual preparations can be made. Informa- good muscle tone. You note, however,
tion about the prenatal history can also be solicited that he has developed severe intercostal
at this time. retractions and grunting. The oxygen
saturation level on the right hand is 95% to 90 bpm when ventilation was initiated.
while blow-by oxygen is being delivered. You note that there appears to be chest
What is your plan for the baby at this point? rise and you have used a carbon dioxide
You know that the baby is at risk for developing a detector between the mask and ventilating
severe respiratory illness and persistent pulmonary device which is changing color indicating
hypertension of the newborn. You want to monitor that you have an open airway. The baby
the baby closely and begin any necessary therapy in continues to be apneic and the heart rate
a timely manner. You decide to transport the baby to remains at approximately 90 bpm. What
the NICU while providing oxygen. When in the NICU, would you do next?
you will place an intravenous catheter, obtain a blood Ventilation was somewhat effective, but did not im-
gas level, a glucose level, and a chest x-ray. You will prove the heart rate to normal and spontaneous
place pre- and postductal oxygen saturation moni- respirations have not yet begun. An increase in the
tors, and start intravenous fluids and antibiotics. It is amount of positive pressure may help to develop
likely that you will need to intubate the baby to as- the functional residual capacity and improve the
sist ventilation and place umbilical venous and arterial heart rate. After increasing the pressure for several
lines for medication delivery and closer monitoring. breaths, if there is no further improvement, the next
One might choose to perform intubation in the deliv- step would be to intubate the baby.
ery room based on the description of the infant that
was given. However, the choice to return to the NICU You now have a functioning pulse oximeter
allows you to obtain intravenous access and provide which indicates that the heart rate is 95
medications for intubation which may be particularly bpm and the oxygen saturation on the right
beneficial in an infant who is now vigorous and will hand is 35%. The baby is now 2 minutes
likely fight the procedure. old and you proceed with the intubation.
Describe the procedure.
The baby is positioned on the bed with the body
CASE 5 straight, neck in the neutral position, and back flat
against the bed. You obtain the correctly-sized
A 30-year-old gravida 2 para 1 woman
endotracheal tube (a 3.5 mm for this infant of
presents to labor and delivery at 35 weeks’
35 weeks’ gestational age) and you insert a stylet to
gestation with spontaneous rupture of
the appropriate depth above the side hole if so de-
membranes and early labor. She develops
sired. You ensure that the pharynx is suctioned and
a fever and is started on antibiotics
you quickly test the function of the light bulb before
for presumed chorioamnionitis. Labor
inserting the laryngoscope into the mouth. Because
is progressing slowly but ultimately a
the pulse oximeter is functioning, you are comfort-
cesarean section is performed. You are
able that the baby is being monitored while you are
called to the cesarean section and your
performing the procedure and you ask another team
team of three individuals attends the
member to watch the time while you are performing
delivery. The baby is handed to you and
the procedure. You move the laryngoscope blade to
you place her on the radiant warmer. She
the locked and functioning position. You open the
is dried and the wet blankets are removed.
baby’s mouth with your right hand, insert the laryn-
You suction her mouth and note that she is
goscope blade into the mouth with your left hand
not breathing. How do you proceed?
and advance it toward the base of the tongue. The
The drying and suctioning that you previously per- laryngoscope handle should be along the baby’s
formed would be adequate to stimulate breathing if midline making an approximate 45 degree angle
breathing could have been stimulated. It is, therefore, with the baby’s chin. You then lift the tongue with the
necessary to initiate positive pressure ventilation. You laryngoscope blade using a straight upward motion,
do this while a second team member auscultates the but maintaining the same angle of the laryngoscope
heart rate and taps out the beats. You ensure that handle with the chin. The tendency when lifting the
the assisted breaths that you are providing are be- tongue is to make a rocking motion with the laryngo-
ing adequately delivered to the lungs by looking for scope handle which will increase the angle that the
chest rise and continuously monitoring the heart rate laryngoscope handle makes with the chin and will
to determine the occurrence and direction of change. obscure the view of the larynx. After you have insert-
Throughout these initial steps, the third team mem- ed the blade and have lifted the tongue, you identify
ber is placing a pulse oximeter. the normal airway landmarks including the epiglottis
and vocal cords. When you see the vocal cords, a
The heart rate prior to starting ventilation second team member places the endotracheal tube
was 70 bpm and it has increased slightly in your right hand and you pass it through the glottis.
heart rate (HR) is less than 100 beats per min

You then remove the laryngoscope while holding the
(bpm) and giving cardiac compressions when
endotracheal tube with your right hand and a second
the HR is less than 60 bpm. How soon does the
team member helps remove the stylet and attach a
heart rate rise with positive pressure ventilation
carbon dioxide detector and ventilating device. You
in babies born at less than 32 weeks’ gestation?
look for cyclical color change on the carbon dioxide
detector and mist on the tube. You listen for breath
It takes more than a minute for newly born
sounds bilaterally. You can also palpate the tip of
infants less than 30 weeks’ gestation with a
the tube in the suprasternal notch to ensure that the
HR less than 100 bpm to achieve a HR above
tube is not placed too far distally, which could poten-
100 bpm. In these infants, HR does not sta-
tially result in a right main stem bronchus intubation.
bilize until it reaches 120 bpm (Yam et al).
When you have confirmed tube placement, you tape
Also, there was no significant difference in
the tube in place.
arterial oxygen saturation (SpO2) at 5 min-
utes after birth in infants less than 29 weeks’
After you successfully intubate the baby,
gestation given PPV with a T-piece or a self-
the heart rate increases to approximately
inflating bag (Dawson et al).
100 to 110 bpm, the baby begins to make
gasping respirations and the oxygen Yam CH, Dawson JA, Schmölzer GM, et al: Heart rate
saturation is 40%. Despite continued changes during resuscitation of newly born infants
assisted ventilation, the heart rate and <30 weeks’ gestation: an observational study. Arch Dis
Child Fetal Neonatal Ed 96:F102, 2011.
oxygen saturation do not increase beyond
Dawson JA, Schmölzer GM, Kamlin CO, et al: Oxygenation
these levels. How do you proceed at this
with T-piece versus self-inflating bag for ventilation
point? of extremely preterm infants at birth: a randomized
This baby has not followed the usual pattern of controlled trial, J Pediatr 158:912, 2011.
improvement after provision of what seems to be
adequate ventilation. It is, therefore, necessary to
evaluate for other problems that might be hinder- True or False
ing resuscitation. You have a second team member The majority of extremely preterm infants are ap-
providing ventilation and the third team member is neic at birth?
ensuring adequate temperature control. You do a
quick survey of the baby for any obvious anomalies. O’Donnell et al reviewed the videos of 61
You note that the face appears normally formed; extremely preterm infants taken immedi-
there is no evidence of compression deforma- ately after birth. The majority cried (69%)
tions which would be associated with longstand- and breathed (80%) without intervention.
ing oligohydramnios and could lead to pulmonary Most preterm infants are not apneic at birth.
hypoplasia. There is no obvious edema to suggest Therefore, the answer is false.
hydrops fetalis or ascites, which could lead to com-
pression of the thoracic cavity and respiratory com- O’Donnell CP, Kamlin CO, Davis PG, et al: Crying and
breathing by extremely preterm infants immediately after
promise. You auscultate the chest on both sides
birth, J Pediatr 156:846, 2010.
and hear breath sounds louder on the right, and
note that the abdomen appears scaphoid. Transil-
lumination of the chest is unremarkable. You, there- True or False
fore, suspect a congenital diaphragmatic hernia on Some neonatologists state that at the deliv-
the left and insert an orogastric tube. You aspirate ery of extremely premature infants they rely on
the syringe and obtain 10 mL of air. The heart rate “how the baby looks” when deciding whether to
slowly increases and the oxygen saturation has in- initiate resuscitation. This is a reliable and pre-
creased slowly to 55%. You now consider admin- cise method to determine whether to initiate re-
istering surfactant and move the infant to the NICU suscitation.
for further management.
Previous studies have reported poor correla-
tion between early clinical signs and prog-
nosis. To determine if neonatologists can
accurately predict survival to discharge of
QUESTIONS extremely premature infants on the basis of
observations in the first minutes after birth,
The International Liaison Committee on Resus- Manley et al showed videos of the resuscita-
citation recommends starting positive pressure tion of 10 extremely premature infants (<26
ventilation (PPV) in the delivery room when the weeks’ gestation) to 17 attending neonatol-
ogists and 17 fellows from the three major CONCLUSION: Neonatologists’ reliance on
perinatal centers in Melbourne, Australia. initial appearance and early response to
Antenatal information was available to the resuscitation in predicting survival for
observers. A monitor visible in each video extremely premature infants is misplaced.
displayed the heart rate and oxygen satura- Therefore, the answer is false.
tion of the infant. Observers were asked to Manley BJ, Dawson JA, Kamlin CO, et al: Clinical assessment
estimate the likelihood of survival to dis- of extremely premature infants in the delivery room is a
charge for each infant at three time points: poor predictor of survival, Pediatrics 125:e559, 2010.
20 seconds, 2 minutes, and 5 minutes after
birth. Observers’ ability to predict survival
was poor and not influenced by their level REFERENCES
of experience. The reference list for this chapter can be found
online at www.expertconsult.com.
Recognition,
4
Stabilization, and
Transport of the
High-Risk Newborn
Jennifer Levy and Arthur E. D’Harlingue
At delivery, the newborn infant makes a factors may continue to have effects on the
complicated transition from intrauterine to postnatal course of the newborn. Intrapar-
extrauterine life. Although most newborns tum factors, including obstetric compli-
adapt without difficulty, the first few hours cations, maternal therapy, and mode of
of life can be a precarious time for the high- delivery may also affect the condition of the
risk infant. Health care professionals who newborn infant.
provide care to newborns must anticipate It is essential to obtain a complete mater-
potential problems for the high-risk infant nal history to anticipate and prepare for a
before delivery. Early recognition of high- high-risk newborn. The physician should
risk factors in the maternal history and of obtain this information before the delivery
significant findings in the newborn allows of the infant whenever possible. The mater-
for timely and appropriate monitoring and nal record should be reviewed, including
treatment. The goal of this approach of the current hospital chart and, as available,
active anticipation and intervention is to the prenatal care record. Particular atten-
prevent the development or progression of tion should be paid to the results of mater-
more serious illness and to minimize the nal prenatal laboratory studies, peripartum
risk of morbidity and mortality in the high- cultures, underlying maternal illnesses, and
risk newborn. A newborn infant should peripartum complications (Box 4-1). Mater-
receive a level of care specific to his or her nal illnesses and medical problems have
unique needs. If an infant is critically ill, it an important impact on the well-being of
is essential to intervene rapidly and effec- the fetus and the newborn (Table 4-1). Dis-
tively to stabilize the infant. In contrast, cussions with the obstetrician and nursing
some infants with perinatal risk factors may staff are essential to clarify the status of the
do quite well postnatally. After an initial mother and infant. When high-risk fac-
assessment and careful observation, such an tors are identified, the physician and nurs-
infant might be advanced to well newborn ery staff are then prepared to deal with the
care. This chapter outlines an approach to anticipated problems of the newborn during
the preparation for, and management of, delivery and subsequent hospital course.
the high-risk infant in the first hours of life,
including initial stabilization and transport. MATERNAL DISEASES
Maternal diabetes mellitus affects the fetus
MATERNAL HISTORY before conception and throughout the
During fetal growth the infant is somewhat entire pregnancy. Uncontrolled diabetes
protected in the intrauterine environment. during the periconceptional period and
However, in the course of a pregnancy the during early embryogenesis increases the
health of the mother affects the well-being risk for fetal malformations, including con-
of the fetus.1 Both acute and chronic mater- genital heart disease, limb abnormalities,
nal illnesses can adversely affect embryo- and central nervous system anomalies.2
genesis and fetal growth and maturation. Small left colon syndrome, femoral hypo-
Maternal nutrition, medications, smoking, plasia–unusual facies syndrome, and caudal
and drug use all affect the growth and devel- regression syndrome are particularly associ-
opment of the fetus. Such prenatal maternal ated with maternal diabetes. Poor diabetic
71
72 CHAPTER 4 Recognition, Stabilization, and Transport of the High-Risk Newborn
Box 4-1. Review of Obstetric and Perinatal History

Routine prenatal care Marijuana
Last menstrual period Cocaine
Estimated date of conception (by dates and Amphetamines
ultrasound) Heroin or methadone
Onset of prenatal care Phencyclidine (PCP)
Previous pregnancies Fetal laboratory studies
Number Amniotic fluid lung maturity studies
Outcome of each Fetal karyotype and other genetic tests
Previous prenatal, intrapartum, neonatal compli- Amniotic fluid delta 450 to assess fetal bilirubin
cations Cordocentesis labs (complete blood count, platelet
Maternal laboratory studies count)
Blood type and Rh Scalp pH
Antibody screen Fetal status
Rapid plasma regain (syphilis) Singleton, twins, higher multiples
Hepatitis B surface antigen Ultrasound findings (weight, gestational age,
Rubella immunity anomalies, intrauterine growth restriction)
Human immunodeficiency virus antibody Amniotic fluid (polyhydramnios, oligohydram-
Alpha-fetoprotein and other prenatal markers nios, meconium staining)
Results of cultures or antibody titers Time of rupture of membranes
Maternal illnesses and infections Cord injuries or prolapse
Diabetes Results of fetal heart rate monitoring
Hypertension Maternal bleeding; placenta previa, abruptio
Thyroid disease placentae
Seizure disorder Delivery
Infections (gonorrhea, syphilis, chlamydia, her- Method of delivery: vaginal or cesarean section
pes simplex, HIV) (indication)
Pregnancy-related and perinatal conditions Instrumentation at delivery: forceps, vacuum
Pregnancy-induced hypertension, eclampsia Presentation and position
Chorioamnionitis, maternal fever Prolonged second stage
Premature labor (use of tocolytics) Shoulder dystocia
Cord complications: nuchal cord, true knot, lacera-
Maternal medications and drug use
tion, avulsion
Steroids
Tocolytics Social factors
Antibiotics Maternal support system
Psychotropics History of family violence, neglect, or abuse
Analgesics Previous childen in foster care
Anesthetics Stable living situation, homelessness
Tobacco History of depression, psychosis
Alcohol
control with resulting chronic hypergly- on the combined effects of maternal trans-
cemia during the third trimester leads to placental antithyroid antibodies and thy-
fetal macrosomia, which increases the risk roid medications. The neonate born to a
for birth trauma and the need for cesar- mother with Graves disease can be hypo-
ean delivery. Fetal lung maturation is also thyroid, euthyroid, or hyperthyroid at birth.
delayed by maternal diabetes, increasing When the mother’s Graves disease is well
the risk for respiratory distress syndrome controlled with medications (e.g., propyl-
even in near-term infants. The infant of the thiouracil) during the pregnancy, then the
diabetic mother is at risk for hypoglycemia, infant is usually euthyroid at birth. However,
hypocalcemia, hypomagnesemia, polycy- as the effects of maternal antithyroid medi-
themia, and hyperbilirubinemia. cation wear off, persistent maternal antithy-
Maternal thyroid disease can have a wide roid antibodies may stimulate the neonatal
variety of effects on the newborn, depending thyroid gland and cause thyrotoxicosis.
CHAPTER 4 Recognition, Stabilization, and Transport of the High-Risk Newborn 73
Table 4-1. Maternal Medical Conditions and the Newborn
Maternal Condition Potential Effects on the Fetus or Newborn

ENDOCRINE, METABOLIC
Diabetes mellitus Hypoglycemia, macrosomia, hyperbilirubinemia, polycythemia,
increased risk for birth defects, birth trauma, small left colon syndrome,
cardiomyopathy, and respiratory distress syndrome
Hypoparathyroidism Fetal hypocalcemia, neonatal hyperparathyroidism
Hyperparathyroidism Neonatal hypocalcemia and hypoparathyroidism
Graves’ disease Fetal and neonatal hyperthyroidism, intrauterine growth restriction,
prematurity
Obesity Macrosomia, birth trauma, hypoglycemia
Phenylketonuria (poorly controlled) Mental restriction, microcephaly, congenital heart disease
Vitamin D deficiency Neonatal hypocalcemia, rickets
CARDIOPULMONARY
Asthma Increased rates of prematurity, toxemia, and perinatal loss
Congenital heart disease Effects of cardiovascular drugs; risk of maternal mortality
Pregnancy-induced hypertension Premature delivery due to uncontrolled hypertension or eclampsia.
Uteroplacental insufficiency, abruptio placentae, fetal loss, growth
restriction, thrombocytopenia, neutropenia
HEMATOLOGIC
Severe anemia (hemoglobin <6 mg/dL) Impaired oxygen delivery, fetal loss
Iron deficiency anemia Reduced iron stores, lower mental and developmental scores in follow-up
Idiopathic thrombocytopenic purpura Thrombocytopenia, central nervous system (CNS) hemorrhage
Fetal platelet antigen sensitization Thrombocytopenia, CNS hemorrhage
Rh or ABO sensitization Jaundice, anemia, hydrops fetalis
Sickle cell anemia Increased prematurity and intrauterine growth restriction
INFECTIOUS
Chorioamnionitis Increased risk for neonatal sepsis, prematurity
Gonorrhea Ophthalmia neonatorum
Hepatitis A Perinatal transmission
Hepatitis B and C Perinatal transmission, chronic hepatitis, hepatic carcinoma
Herpes simplex Encephalitis, disseminated herpes (risk of neonatal disease is much
higher with primary versus recurrent maternal infection)
Human immunodeficiency virus Risk of transmission to the fetus or newborn
Syphilis Congenital syphilis, intrauterine growth restriction
Tuberculosis Perinatal and postnatal transmission
INFLAMMATORY, IMMUNOLOGIC
Systemic lupus erythematosus Fetal death, spontaneous abortions, heart block, neonatal lupus,
t hrombocytopenia, neutropenia, hemolytic anemia
Inflammatory bowel disease Increase in prematurity, fetal loss, and growth restriction
RENAL, UROLOGIC
Urinary tract infection Prematurity, intrauterine growth restriction
Chronic renal failure Prematurity, intrauterine growth restriction
Transplant recipients Prematurity, intrauterine growth restriction, possible effects of maternal
immunosuppressive therapy and mineral disorders
Maternal preeclampsia has a number of well as any maternal treatment for syphilis,
adverse effects on the fetus and the new- should be recorded in the neonatal record.
born. When preeclampsia occurs early in In communities with a high prevalence of
the pregnancy, it may have severe effects syphilis or in high-risk patients, repeat test-
on fetal growth. Fetal distress caused by pre- ing (despite negative prenatal results) of the
eclampsia may necessitate premature deliv- mother for syphilis at the time of delivery
ery of the infant before maturation of the should be considered. All women should be
lungs. Preeclampsia also causes neonatal tested for hepatitis B surface antigen during
neutropenia and thrombocytopenia. pregnancy, and all neonates born to posi-
Particular attention must be paid to tive mothers should receive both hepatitis
infectious illnesses during the pregnancy B immunoglobulin and hepatitis B vaccine.
and in the perinatal period. The results of Maternal testing for antibody to the human
the prenatal RPR (rapid plasma reagin), as immunodeficiency virus (HIV) should be
recommended for all women prenatally. with use of medications (both prescribed
Treatment of the HIV-positive mother dur- and over the counter) and illicit drugs
ing the pregnancy and through the intra- before conception and embryogenesis.
partum course, combined with postnatal Besides their teratogenic potential, medica-
treatment of the infant, greatly reduces the tion used by the mother can have a variety
risk of transmission of HIV to the infant. of other effects on the fetus and newborn.
Any infant born to a mother who tests posi- Fetal growth can be impaired by antineo-
tive for HIV antibody or other evidence of plastic agents, heroin, cocaine, irradiation,
HIV infection should be referred, when and some anticonvulsants. Drugs used for
possible, to an infectious disease special- tocolysis of labor can cause symptoms in the
ist for appropriate evaluation and possible neonate. Beta-sympathomimetics are asso-
treatment. ciated with neonatal hypoglycemia result-
Active maternal genital infection with ing from the mobilization of glycogen from
herpes simplex virus (HSV) in a woman the fetal liver. Magnesium sulfate, which is
with ruptured membranes or who delivers used for treatment of preterm labor and pre-
vaginally puts the infant at risk for neonatal eclampsia, depresses respiratory effort and
herpes disease. The risk for vertical transmis- can lead to respiratory failure in the new-
sion of HSV is particularly high when the born. In contrast, prenatal steroids for fetal
mother has active primary infection at the lung maturation are generally safe and with-
time of delivery or the infant is born prema- out adverse effects on the newborn.
turely. In contrast, with recurrent maternal Psychotropic drugs used during preg-
herpes, the risk for vertical transmission of nancy have the potential for effects on the
HSV is about 2%.3 fetus and newborn. Fluoxetine, a selective
Maternal chorioamnionitis increases the serotonin reuptake inhibitor (SSRI), has been
risk for bacterial sepsis in the newborn, reported to increase the risk for neonatal
particularly in the premature infant. It is problems and may have some neurobehav-
strongly encouraged to follow the recom- ioral effects.7 SSRIs in general may put the
mendations of the Centers for Disease Con- neonate at risk for pulmonary artery hyper-
trol and Prevention (CDC) regarding the use tension.8 Benzodiazepines may increase the
of intrapartum prophylactic antibiotics for risk for oral clefts. Lithium is associated with
mothers at risk to transmit group B STREP- a small increased risk for Ebstein anomaly.
TOCOCCUS to their infants.4 When clinical Illicit and recreational drug use among
chorioamnionitis is diagnosed in a mother, pregnant women remains a major problem
the risk for sepsis in the newborn is greatly that affects both the fetus and the newborn.
increased. Such infants should have a sepsis Maternal heroin and methadone use cause
screen—a blood culture obtained and the neonatal abstinence syndrome, which is
infant started on broad spectrum antibiotics characterized by irritability, hypertonia,
(e.g., ampicillin and gentamicin) pending jitteriness, seizures, sneezing, tachycardia,
culture results. diarrhea, and difficulties with feedings.9,10
Withdrawal symptoms can be prolonged,
MATERNAL MEDICATIONS particularly with methadone exposure.
Medications given to the mother may have Intrauterine opiate exposure is also associ-
adverse effects on the fetus (Table 4-2).5,6 ated with intrauterine growth restriction,
One area of great concern has been the risk poor postnatal growth, and abnormal neuro-
for fetal malformations caused by mater- developmental outcome. Maternal cocaine
nal drug use. Because organogenesis occurs exposure has also been reported to be asso-
primarily in the first 12 weeks of gestation, ciated with neurobehavioral disturbances
the fetus can easily be exposed to a variety in the newborn, although true withdrawal
of potentially teratogenic toxins and drugs symptoms are less pronounced than with
before a woman knows that she is pregnant heroin or methadone.11 In utero cocaine
or before the first prenatal visit. Appropriate exposure affects fetal growth, and such
counseling about the dangers of maternal infants tend to have a lower birth weight
drug use on the fetus is further complicated and smaller head circumference. Cocaine
if prenatal care is delayed or lacking. Hence, use in pregnancy is associated with neonatal
the issue of medications and drugs during cerebral hemorrhage, premature delivery,
pregnancy is truly a public health issue. abruptio placentae, and stillbirth. There are
Women of childbearing age need to be edu- conflicting data about the role of prenatal
cated about the potential risks associated cocaine exposure and the risk for congenital
Table 4-2. Maternal Medications and Toxins: Possible Effects on the Fetus and Newborn
Medication Effect on Fetus and Newborn

ANALGESICS AND ANTI-INFLAMMATORIES
Acetaminophen Generally safe except with maternal overdose
Aspirin Hemorrhage, premature closure of ductus arteriosus, pulmonary artery hypertension
(effects not seen at ≤100 mg/day)
Opiates Neonatal abstinence syndrome with chronic use
Ibuprofen Reduced amniotic fluid volume when used in tocolysis; risk for premature ductus
arteriosus closure and pulmonary hypertension
Indomethacin Closure of fetal ductus arteriosus and pulmonary artery hypertension
Meperidine Respiratory depression peaks 2 to 3 hours after maternal dose
ANESTHETICS
General anesthesia Respiratory depression of infant at delivery with prolonged anesthesia just before
delivery
Lidocaine High serum levels cause central nervous system (CNS) depression; accidental direct
injection into the fetal head causes seizures
ANTIBIOTICS
Aminoglycosides Ototoxicity reported after use of kanamycin and streptomycin
Cephalosporins Some drugs in this group displace bilirubin from albumin
Isoniazid Risk for folate deficiency
Metronidazole Potential teratogen and carcinogen, but not proven in humans
Penicillins Generally no adverse effect
Tetracyclines Yellow-brown staining of infant’s teeth (when given at ≥5 months’ gestation); stillbirth
and prematurity due to maternal hepatotoxicity
Sulfonamides Some drugs in this group displace bilirubin from albumin; can cause kernicterus
Trimethoprim Folate antagonism
Vancomycin Potential for ototoxicity
ANTICONVULSANTS
Carbamazepine Neural tube defects; midfacial hypoplasia
Phenobarbital Withdrawal symptoms, hemorrhagic disease; midfacial hypoplasia
Phenytoin Hemorrhagic disease; fetal hydantoin syndrome: growth and mental deficiency,
midfacial hypoplasia, hypoplasia of distal phalanges
Trimethadione Fetal trimethadione syndrome: growth and mental deficiency, abnormal facies
(including synophrys with upslanting eyebrows), cleft lip and palate, cardiac and
genital anomalies
Valproic acid Neural tube defects, midfacial hypoplasia
ANTICOAGULANTS
Warfarin (Coumadin) Warfarin embryopathy: stippled epiphyses, growth and mental deficiencies, seizures,
hypoplastic nose, eye defects, CNS anomalies including Dandy-Walker syndrome
Heparin No direct adverse effects on the fetus
ANTINEOPLASTICS
Aminopterin Cleft palate, hydrocephalus, meningomyelocele, intrauterine growth restriction
Cyclophosphamide Intrauterine growth restriction, cardiovascular and digital anomalies
Methotrexate Absent digits, CNS malformation
ANTITHYROID DRUGS
Iodide-containing drugs Hypothyroidism
Methimazole Hypothyroidism, cutis aplasia
Potassium iodide Hypothyroidism and goiter, especially with chronic use
Propylthiouracil Hypothyroidism
Iodine 131 Hypothyroidism, partial to complete ablation of thyroid gland
ANTIVIRALS
Acyclovir No definite adverse effects
Ribavirin Teratogenic and embryolethal in animals
Zidovudine Potential for fetal bone marrow suppression; combined maternal and neonatal
treatment reduces perinatal transmission of human immunodeficiency virus
CARDIOVASCULAR DRUGS AND ANTIHYPERTENSIVES
Angiotensin-converting Fetal hypocalvaria, oligohydramnios and fetal compression, oliguria, renal failure
enzyme inhibitors
β-Blockers (propranolol) Neonatal bradycardia, hypoglycemia
Calcium channel blockers If maternal hypotension occurs, this could affect placental blood flow
Diazoxide Hyperglycemia; decreased placental perfusion with maternal hypotension
Continued
Table 4-2. Maternal Medications and Toxins: Possible Effects on the Fetus and Newborn—cont’d

Digoxin Fetal toxicity with maternal overdose
Hydralazine If maternal hypotension occurs, this could affect placental blood flow
Methyldopa Mild, clinically insignificant decrease in neonatal blood pressure
DIURETICS
Furosemide Increases fetal urinary sodium and potassium levels
Thiazides Thrombocytopenia, hypoglycemia, hyponatremia, hypokalemia
HORMONES AND RELATED DRUGS
Androgenics (danazol) Masculinization of female fetuses
Corticosteroids Cleft lip/palate
Diethylstilbestrol (DES) DES daughters: vaginal adenosis, genital tract anomalies, increased incidence of clear
cell adenocarcinoma, increased rate of premature delivery in future pregnancy
DES sons: possible increase in genitourinary anomalies
Estrogens, progestins Risk for virilization of female fetuses reported with progestins; small, if any, risk for
other anomalies
Insulin No apparent direct adverse effects, uncertain risk related to maternal hypoglycemia
Tamoxifen Animal studies suggest potential for DES-like effect
SEDATIVES, TRANQUILIZERS, AND PSYCHIATRIC DRUGS
Barbiturates Risk for hemorrhage and drug withdrawal
Benzodiazepines Drug withdrawal; possible increase in cleft lip/palate
Selective serotonin Pulmonary artery hypertension, jitteriness, irritability
reuptake inhibitors (SSRIs)
Lithium Ebstein anomaly, diabetes insipidus, thyroid depression, cardiovascular dysfunction
Thalidomide Limb deficiency, cardiac defects, ear malformations
Tricyclic antidepressants Jitteriness, irritability
SOCIAL AND ILLICIT DRUGS
Alcohol Fetal alcohol syndrome, renal and cardiac anomalies
Amphetamines Withdrawal, prematurity, decreased birth weight and head circumference, cerebral
injury
Cocaine Decreased birth weight, microcephaly, prematurity, abruptio placentae, stillbirth,
cerebral hemorrhage; possible teratogen: genitourinary, cardiac, facial, limb, intestinal
atresia/infarction
Heroin Increased incidence of low birth weight and small for gestational age, drug withdrawal,
postnatal growth and behavioral disturbances; decreased incidence of respiratory
distress syndrome
Marijuana Elevated blood carboxyhemoglobin; possible cause of shorter gestation, dysfunctional
labor, intrauterine growth restriction, and anomalies
Methadone Increased birth weight as compared to heroin, drug withdrawal (worse than with heroin
alone)
Phencyclidine (PCP) Irritability, jitteriness, hypertonia, poor feeding
Tobacco smoking Elevated blood carboxyhemoglobin; decreased birth weight, increased prematurity
rate, increased premature rupture of membranes, placental abruption and previa,
increased fetal death, possible oral clefts
TOCOLYTICS
Magnesium sulfate Respiratory depression, hypotonia, bone demineralization with prolonged (weeks) use
for tocolysis
Ritodrine Neonatal hypoglycemia
Terbutaline Neonatal hypoglycemia
VITAMINS AND RELATED DRUGS
A (preformed, not carotene) Excessive doses (≥50,000 IU/day) may be teratogenic
Acitretin Activated form of etretinate (see later)
D Megadoses may cause hypercalcemia, craniosynostosis
Etretinate Limb deficiency, neural tube defect; ear, cardiac, and CNS anomalies
Folate deficiency Neural tube defects
Isotretinoin (13-cis-retinoic Ear, cardiac, CNS, and thymic anomalies
acid)
Menadione (vitamin K3) Hyperbilirubinemia and kernicterus
Phytonadione (vitamin K1) No adverse effect
Table 4-2. Maternal Medications and Toxins: Possible Effects on the Fetus and Newborn—cont’d

MISCELLANEOUS
Anticholinergics Neonatal meconium ileus
Antiemetics Doxylamine succinate and/or dicyclomine HCl with pyridoxine reported to be
teratogens, but bulk of evidence is clearly negative
Aspartame Contains phenylalanine; potential risk to fetus of a mother with phenylketonuria
Chorionic villus sampling Limb deficiency with early CVS
(CVS)
Irradiation Adverse effects primarily associated with therapeutic, not diagnostic doses, and is
dose dependent: fetal death, microcephaly, intrauterine growth restriction
Lead Decreased IQ (dose related)
Methylene blue Hemolytic anemia, hyperbilirubinemia, methemoglobinemia; intraamniotic injection in
early pregnancy associated with intestinal atresia
Methylmercury CNS injury, neurodevelopmental abnormalities, microcephaly
Misoprostol Möebius sequence
Oral hypoglycemics Neonatal hypoglycemia
Polychlorinated biphenyls Cola skin coloration, minor skeletal anomalies, neurodevelopmental deficits
malformations (including intestinal atresia, problems, and low IQ scores. Many infants
urogenital anomalies, and limb reduction exposed to alcohol in utero do not have
anomalies), and necrotizing enterocolitis.12 sufficient physical features or anomalies
Prenatal opiate and cocaine exposure is required to make the diagnosis of fetal alco-
associated with an increased incidence of hol syndrome. However, these same infants
sudden infant death syndrome.13 Persistent may still demonstrate neurobehavioral and
illicit drug activity in the mother or other motor problems, which have been referred
family members can continue to affect the to as fetal alcohol effects.
care of the high-risk infant throughout hos- Maternal smoking increases blood levels
pitalization and at the time of discharge, of carboxyhemoglobin and impairs oxygen
especially if the infant requires any type delivery to the fetus. Smoking is associated
of special treatment at home. The manage- with a decrease in birth weight of 175 to
ment of the dysfunctional drug-exposed 250 grams. Several studies have suggested
family can complicate the care of the sick that nonsmoking mothers who are exposed
newborn. to environmental tobacco smoke are more
Prenatal alcohol use has serious adverse likely to have low-birth-weight infants than
effects on the fetus that can manifest mothers with minimal tobacco exposure.
as problems in the neonatal period and Maternal smoking has also been implicated
beyond. The greatest risk to the fetus seems in placental abruption, preterm delivery,
to be associated with heavy chronic drink- and postnatal respiratory illnesses. Whether
ing during the pregnancy (four to six drinks prenatal exposure to tobacco causes an
per day). However, with even more modest increased incidence of congenital malfor-
alcohol consumption (e.g., two drinks per mations is unclear.16,17
day), effects have been noted in some stud-
ies. The most extreme result of maternal PREPARATIONS FOR DELIVERY
alcohol use is fetal alcohol syndrome.14,15 After the maternal record has been reviewed,
Signs of this syndrome at birth may include the physician should meet with the parents
symmetrical intrauterine growth restric- before the delivery of a high-risk infant.
tion, central nervous system problems Important information regarding the pre-
(microcephaly, irritability, tremulousness), natal course is not always reflected in the
facial dysmorphic features, congenital heart hospital obstetric record, particularly if pre-
disease, and ear, eye, and limb (joint con- natal care was lacking or fragmented, and
tractures, nail hypoplasia) anomalies. The this information may be available from the
facial dysmorphic features include short mother. This is particularly relevant regard-
palpebral fissures, thin upper lip, smooth ing familial and genetic disorders. If the
philtrum, maxillary hypoplasia, and a short delivery of a premature infant is expected,
nose. Later in life, these infants may have it is appropriate to explain the role of the
continued poor growth, neurobehavioral pediatrician, neonatal nurse practitioner,
neonatologist, or other health care pro- cardiology team, including cardiothoracic

fessionals in the delivery room, as well as surgery, should be informed of impending
resuscitation and subsequent management deliveries of infants with known cardiac
procedures (Box 4-2). Aspects of the antici- defects.
pated hospital course for a sick premature The pediatrician can also play an impor-
infant should be discussed. Preparing par- tant role in the appropriate prepartum
ents for the prolonged hospitalization of a management of a high-risk mother. Aggres-
premature infant begins to build the founda- sive tocolysis and use of prenatal steroids
tions of trust and communication that will to induce fetal lung maturity should be
be needed between the family and the medi- strongly encouraged for the mother in pre-
cal team. If time is limited because of the term labor. Despite the multiple postnatal
imminent delivery of the infant, the physi- benefits for premature infants who were
cian should, at the least, introduce himself given prenatal steroids (Box 4-3)18, mater-
or herself to the parents and briefly explain nal steroids are sometimes withheld in the
how the infant will initially be managed. presence of ruptured membranes, extreme
Depending on the type and severity of prematurity, or an anticipated interval of
anticipated problems, specific equipment less than 24 hours before delivery. Assessing
or extra personnel may be needed in the the gestational age of the fetus can be very
delivery room. For example, if an infant important in extremely premature infants.
is known to have hydrops with pleural The discussion with the parents regarding
effusions and ascites, then the resuscita- outcomes will be markedly different for a
tion team should have equipment fully 23-week as opposed to a 26-week fetus or
prepared before the delivery for needle newborn. Unless there are clear contraindi-
thoracentesis, chest tube drainage, intuba- cations to steroid treatment or proven fetal
tion, ventilation, and umbilical catheter- lung maturity, in the setting of anticipated
ization. For such a high-risk delivery, the premature delivery, the mother should be
presence of two physicians to care for the given steroids.19 The pediatrician should
infant may be indicated. Neonatal nursing also advocate for delivery of high-risk moth-
personnel should be kept informed regard- ers in the most appropriate setting. The
ing the admission of high-risk mothers and needs of the mother, the fetus, and the new-
possible pending deliveries. The pediatric born infant must all be recognized, and the
surgeon should be notified of the antici- personnel, equipment, and expertise must
pated delivery of any infants with abdomi- be available to meet these needs. Certain
nal wall defects, possible gastrointestinal high-risk mothers, if stable for transport,
anomalies or obstruction, diaphragmatic should be transferred to a perinatal center.
hernia, or tracheoesophageal fistula. The In particular, if premature delivery is antici-
pated before 32 weeks’ gestation or if there
are known major fetal congenital anomalies
Subjects to Discuss with Parents
Box 4-2. Before Delivery of a Premature
Newborn Effects of Prenatal Steroids on the
Box 4-3.
Premature Newborn
Anticipated birth weight and gestational age
Approximate risk of death and major morbidi- Increased tissue and alveolar surfactant
ties Maturational effects on the lung: structural and
Anticipated length of hospitalization biochemical
Respiratory distress syndrome, oxygen, venti- Possible maturational effects on brain, gastro-
lation, surfactant intestinal tract, and other organs
Procedures: intubation, intravenous catheters, Decreased mortality rate
umbilical catheterization, lumbar puncture Decreased incidence and severity of respira-
Blood transfusion: risks, benefits, alternatives, tory distress syndrome
use of designated donor Decreased incidence of necrotizing enterocolitis
Potential problems: patent ductus arteriosus, Decreased incidence of intraventricular hemor-
intraventricular hemorrhage, jaundice rhage
Possible need for transport (if not delivered in a Decreased incidence of significant patent duc-
tertiary center) tus arteriosus
Role of the parents in the intensive care nursery Decreased length of stay and costs of hospi-
Importance of providing breast milk talization
that would affect the stabilization of the of retinopathy of prematurity. In addition,

newborn, then maternal transfer to a peri- oxygen may have an adverse affect on cere-
natal center with an intensive care nursery bral circulation and breathing physiology.22
is most appropriate.20 Most extremely low-birth-weight (ELBW)
infants will need some supplemental oxy-
LABOR AND DELIVERY gen in the delivery room, and it is suggested
Appropriate supplies and a well-trained staff to begin with about 30% O2 in such infants
are essential in the delivery room. Whether who require resuscitation and then adjust
the birth occurs in a birthing room or in Fio2 as needed, guided by pulse oximetry.
the operating room, the equipment and
procedures need to be the same—an infant TRANSITION
warming table with working lights, Apgar Transition is a term used to describe a series of
timer, air and oxygen supply, and an oxy- events that are centered around birth itself,
gen blender. A person needs to be delegated beginning in utero and continuing into the
to ensure that the infant table is adequately postnatal period. The fetus is well adapted
prepared. There needs to be mechanical suc- to the intrauterine environment. However,
tion and a device to deliver positive pressure during this intricate symbiotic relationship
ventilation. Endotracheal tubes of different with the mother, the fetus must also prepare
sizes, meconium aspirators, and a laryngo- for transition to extrauterine life. This tran-
scope must be readily available. If a mul- sition requires striking adaptive changes
tiple delivery is anticipated, there must be in multiple organ systems of the newborn.
a stocked infant table for each infant. An Some of these dynamic changes are largely
emergency crash cart designated specifi- completed in the first minutes to hours after
cally for neonates must be close by and well birth. Others are initiated at birth, but con-
stocked in case of emergency. tinue to evolve over the first weeks of life.
The value of a staff that is well trained The ability of the newborn to make this
and prepared cannot be overstated. Health transition safely and expeditiously affects
care workers who attend deliveries should the health and survival of the infant. Rec-
have appropriate training in NRP (neonatal ognition of the factors that may adversely
resuscitation program). Additionally, emer- affect the transitional period allows the
gency procedures for alerting more sub- health professional to act promptly and
specialized health care professionals (e.g., judiciously for the benefit of the infant.
neonatologists or pediatricians) must be in The most dramatic changes during transi-
place in the event of an acutely ill infant. tion involve the cardiovascular and respira-
There are additional special consider- tory systems. During fetal life, gas exchange
ations in the delivery room when antici- is accomplished by the placenta, whereas the
pating the delivery of a preterm infant. fetal lungs are gasless and filled with fluid.
Preterm infants are especially prone to cold In the several days before delivery, fetal lung
stress and hypothermia. Infants less than 29 water begins to decrease and is accelerated by
weeks should be placed in a polyurethane labor. Various hormones, including epineph-
bag up to the neck to minimize heat loss.21 rine and vasopressin, decrease fluid secre-
Most premature infants should have a pulse tion into the pulmonary intraluminal space.
oximeter applied shortly after birth in the Plasma protein levels increase with labor,
delivery room. A proportion of infants and this augmented oncotic pressure likely
born at 32 weeks or less will develop respi- increases pulmonary intraluminal water reab-
ratory distress syndrome from surfactant sorption. Intraluminal fluid is transported to
deficiency. Preparations to support such the interstitium and is removed primarily
an infant should include the potential to by augmented postnatal pulmonary blood
provide nasal continuous positive airway flow as pulmonary artery pressure decreases.
pressure (CPAP), intubation, and surfac- Some intraluminal fluid is transported by the
tant administration as needed. If available, lymphatics through the mediastinal tissues
a neonatal respiratory therapist should or across the pleural space. Previously, it has
be present to facilitate the stabilization of been suggested that thoracic compression
these infants. There has been increasing evi- during vaginal birth played a prominent role
dence that infants resuscitated in the deliv- in the expulsion of lung fluid through the
ery room with room air, rather than 100% oropharynx, but such a mechanism does not
oxygen, have lower levels of oxygen-free seem to have a major role in the reduction of
radicals, which may affect the incidence lung water in the newborn.
Fetal breathing is episodic and occurs venosus closes within 1 to 2 days (contrib-
primarily during periods of low-voltage uting to the technical difficulty of passing
electrocortical activity. It likely plays a role an umbilical venous catheter to the right
in the conditioning of respiratory muscles atrium beyond the first day of life). Pulmo-
and may have other effects on chest wall, nary artery pressure continues to decline
lung, and muscle growth. A variety of phe- through the first weeks of life. During these
nomena contribute to the onset of continu- dramatic changes in the cardiovascular sys-
ous breathing, which occurs shortly after tem, the sick newborn may demonstrate
birth in relatively healthy nonasphyxiated difficulties in making these transitions.
infants. Aspects of the physical environ- Because of the parallel pumping systems of
ment may play a role, such as light, sound, the fetal cardiovascular system, most infants
cutaneous stimulation, and heat loss. Cord with complex congenital heart disease are
occlusion and an increase in blood oxygen well adapted to the in utero state. However,
appear to be potent stimulants of continu- these infants often do poorly in the tran-
ous breathing by the newborn. The fetus sition to extrauterine life. In infants with
prepares for air breathing by the synthesis ductal dependent cyanotic congenital heart
and release of surfactant into the alveo- disease, progressive cyanosis develops as the
lar space. The process can be accelerated ductus arteriosus closes. In those infants
by premature rupture of fetal membranes, with left-sided obstructive lesions (e.g.,
β-mimetic tocolysis, and the administration hypoplastic left heart), acidosis and shock
of steroids to the mother. Delivery of a term develop as the ductus arteriosus closes and
infant by elective cesarean section with- distal aortic blood flow is lost. Infants with
out labor may prevent maturation of this pulmonary artery hypertension shunt right
late process of surfactant production and to left at the foramen ovale or patent ductus
release, resulting in an infant with respira- arteriosus. Recognition of infants at risk for
tory distress syndrome. If an infant is sched- pulmonary artery hypertension (e.g., meco-
uled to be delivered via elective cesarean nium aspiration) may lead the physician to
section before 39 weeks, fetal lung maturity earlier interventions (e.g., endotracheal suc-
should be checked to avoid the sequelae of tioning, oxygen, ventilation) to reverse or
surfactant deficiency.23 prevent this problem.
The transitional changes in the cardio- The uterine environment is relatively
vascular system are primarily an adaptation quiet, very dark, and rather unchanging
to the elimination of the placental circula- until labor and passage through the birth
tion and an adaptation to pulmonary gas canal. At birth, the newborn is bombarded
exchange. As the lungs expand at birth, pul- with stimuli, including exposure to light,
monary artery pressure declines, and there different sounds, and tactile stimuli. In addi-
is a dramatic increase in pulmonary blood tion, the newborn must begin to defend its
flow. Systemic arterial resistance increases core temperature against heat loss, despite
with cord occlusion and elimination of the being born both wet and into a much cooler
low resistance placental circulation. These environment. These multiple stresses result
factors combine to favor an increase in in a surge of sympathetic nervous system
pulmonary blood flow rather than the pas- activity. Catecholamines increase dramati-
sage of blood via the ductus arteriosus into cally at birth. Brown fat (nonshivering)
the distal aorta. Because of the increase in thermogenesis causes the hydrolysis of
pulmonary blood flow, left atrial pressure stored triglycerides and the release of fatty
increases and functionally closes the fora- acids. Box 4-4 summarizes these and other
men ovale, thereby eliminating this source events during transition.
of previous right-to-left shunting. The right Specific physical and behavioral changes,
and left ventricles now function primarily which occur in the healthy newborn in the
in series versus pumping in parallel as in the hours after birth, have been described (Fig.
fetal state. The ductus arteriosus remains 4-1). The healthy newborn may have some
open for a variable period, but it begins initial bradycardia or tachycardia, and cuta-
to close in response to exposure to highly neous perfusion may be mottled or pale. Res-
oxygenated blood. It generally functionally pirations may be initially somewhat irregular
closes by 1 to 2 days in a term infant, but but should improve steadily and become reg-
frequently remains open in the premature ular and vigorous. There may be some mild
or the seriously ill term newborn with pul- transient grunting and flaring, but true respi-
monary artery hypertension. The ductus ratory distress with retractions should not
Box 4-4. Summary of Transitional Events in the Newborn

Pulmonary Decline in serum calcium with nadir at 24 hours
Reabsorption of intraluminal fluid and subsequent elevation
Onset of continuous breathing Increase in parathyroid hormone, 1,25 OH
Expansion of pulmonary air spaces vitamin D, and calcitonin
Pulmonary gas exchange replaces placental Increase in glycerol and free fatty acids
circulation Nervous system
Surfactant synthesis and release Adaptive interaction with parents and environ-
Cardiovascular ment
Removal of the placental circulation Movement between states
Decline in pulmonary artery pressure and Increase in motor activity
increase in pulmonary blood flow Renal
Closure of ductus arteriosus, foramen ovale, Increase in renin production
and ductus venosus Increase in sodium reabsorption
Glucose homeostasis Onset of long-term maturational changes with
Loss of transplacental glucose transport with improving glomerular filtration rate
decline in serum glucose Reduction of extracellular fluid compartment
Increase in glucagon and decrease in insulin (diuresis)
levels Hematologic
Thermogenesis Marked reduction in erythropoietin and erythro-
Sympathetic nervous system activation caused genesis
by cold stress Postnatal increase in blood leukocyte and neu-
Nonshivering thermogenesis (brown fat) trophil count
Hormonal and metabolic Improved vitamin K-dependent carboxylation of
Shift from primarily glucose metabolism (RQ = coagulation factors
1) to glucose and fat (RQ = 0.8-0.85) Gastrointestinal
Increase in oxygen consumption Evacuation of meconium
Increase in levels of epinephrine and norepi- Induction of intestinal enzymes with feeding
nephrine Establishment of effective coordinated suck,
Acute increase in TSH with subsequent decline swallow, breathing
Peak increase in T4, free T4, and T3 at 48 hours
Decrease in reverse T3
be present. If the infant has made a stable over the infant and the room is not too
transition, these parameters stabilize within cold.26 Early contact with the mother has
the first hour of life. After birth, the healthy been shown to increase the success of breast
newborn often undergoes a quiet alert phase, feeding, and it is an important first step in
which has been referred to as the first phase the bonding process. Most hospital staff in
of reactivity. When placed skin-to-skin on birthing centers recognize the importance of
the mother’s chest shortly after birth, the this early contact between the mother and
infant often becomes quiet or exploring.24 infant. Sometimes mothers are encouraged
Rhythmic, pushing movements of the lower to promptly attempt to nurse their infant
extremities have been described as the infant immediately after birth. It may be more
searches for the mother’s breast. If left undis- appropriate to quickly dry the infant and to
turbed, the infant crawls and searches for rapidly determine that the infant is healthy
the areola in an attempt to attach and suckle and requires no immediate interventions.
(Fig. 4-2). Suckling causes release of oxytocin Then the infant can be placed on the moth-
in the mother, stimulating milk production er’s chest, skin to skin, and allowed to have a
and uterine contractions. Sucking move- private quiet time with the parents.
ments in the infant stimulate the release of
multiple gastrointestinal hormones, which PHYSICAL EXAMINATION
prepare the infant to digest enteral nutri- OF THE NEWBORN
ents.25 The warmth provided by the moth- The first 24 hours of life are particularly
er’s chest maintains a stable temperature in precarious as the infant makes the transi-
the infant, as long as a blanket is also placed tion from intrauterine to extrauterine life.
SD 1084
APGAR 9
Brief Birth weight: 3586
Flushing Swift color
cyanosis with cry changes 100
breaths/min
Resp. rate -
or
ol
C
Rales 80
Flaring Barrelling
60
n
of
tio
Grunting
ra
Retractions chest 40
pi
es
200
R
180
Loud
beats/min
Heart rate -
Forceful Regular Labile 160
ds t
un ar
So He
Irregular 140
120
100
First period Second period
80
Figure 4-1. A summary of of reactivity of reactivity
the physical findings in normal Alerting Sleep Variable
w ucu tivi tor
transition (the first 10 hours of (gagging - arching)

ty
Ac Mo
extrauterine life in a representative Present Absent Present

s
high-Apgar-score infant delivered

Sound absent Sound present Meconium passage
39
M
under spinal anesthesia without
Temp.°C
el
premedication). (From Desmond 37

Bo
M, Rudolph A, Phitaksphraiwan 35
P: The transitional care nursery.
Pediatr Clin North Am 13:651, Birth 5 10 15 30 1 2 4 6 8 10
1966.) Minutes after birth Hours after birth
During this critical period, a thorough Such a quick examination of an apparently

physical examination is essential to iden- healthy infant in the delivery room can usu-
tify problems and institute early interven- ally be performed in 1 to 2 minutes. Any
tion. Physicians should continually strive major abnormalities should be discussed
to improve their observational skills and with the parents as soon as feasible.
the quality of their newborn examinations. In a stable, healthy, term or near-term
Nothing can replace years of clinical experi- newborn, a more detailed examination by
ence with the many normal variations and the physician may be deferred. However,
abnormal findings with which a newborn admitting nursing personnel should perform
may present.27,28 a thorough assessment of the infant within
After initial resuscitation and stabiliza- 2 hours of birth. This allows the infant to be
tion in the delivery room, the newborn with the parents and to start breast feeding.
should receive an initial examination to The nursing personnel should evaluate the
identify any significant problems or anoma- infant for high-risk factors, review the perti-
lies. The infant’s respiratory effort and air nent maternal history (usually included on
exchange should be observed closely. An the labor and delivery record), and examine
infant with persistently shallow and irregu- the infant. The physician should be noti-
lar respirations needs further resuscitation fied of any high-risk factors in the history
and appropriate monitoring. Symptoms of or significant findings on examination. This
respiratory distress such as grunting, flaring, nursing assessment should be recorded in a
retractions, and cyanosis should be identi- standardized format. It should include mea-
fied promptly. Particular attention should surement of weight, length, head circumfer-
be paid to the adequacy of the infant’s heart ence, estimate of gestational age, and vital
rate and clinical indicators of cardiovascu- signs. The physician should perform a com-
lar function. Pallor and poor perfusion need plete physical examination no later than
immediate further evaluation and possible 24 hours after birth, but preferably within
intervention. It should be established that 12 hours of birth. The normal newborn
the infant is appropriately responsive and should also be examined by the physician
has good muscle tone. The extremities, within the 24 hours before discharge. High-
facies, genitalia, abdomen, and back should risk infants, including those with respiratory
be quickly inspected for any anomalies. distress, poor cardiac output, gestational age
VITAL SIGNS, BODY MEASUREMENTS,

AND GESTATIONAL AGE ASSESSMENT
The admitting nursing personnel should
measure the temperature, respiratory rate,
and heart rate of all newborn infants within
the first hour of life. In the past, the ini-
tial measurement of temperature was com-
monly performed rectally to additionally
determine patency of the anus. This prac-
tice of an initial rectal temperature has been
largely abandoned by birth centers because
of the small but real risk of bowel perfora-
tion with rectal measurement. The nurse
A
should not only record the respiratory rate,
but also should observe for any signs of
respiratory distress, irregularities in respi-
ratory pattern (e.g., apnea), and the degree
of work of breathing. In the first day of life
most newborns have a respiratory rate of 40
to 60 breaths per minute. However, in tran-
sition, some newborns have a respiratory
rate as high as 80 to 100 breaths per minute
with little or no signs of distress. Heart rate
should be checked by auscultation and any
irregularities in rhythm should be noted.
Healthy term newborns do not require rou-
tine blood pressure determination on admis-
B sion. Any sick newborn and any premature
infant (less than 35 weeks’ gestational age)
should have at least an initial blood pressure
measurement, which is easily performed by
an oscillometric technique.
Every newborn should have assessment
of gestational age performed.29 In some
nurseries, the gestational age examination
is performed by the nursing staff on admis-
sion of all newborns. We encourage physi-
cians to continue to perform a gestational
age assessment as part of their evaluation
of a premature infant. The results of this
examination should then be compared with
C
the maternal estimated date of confinement
Figure 4-2. A, Infant about 15 minutes after birth, (by ultrasound and last menstrual period).
sucking on the unwashed hand and possibly looking at The nursing staff should record the weight
mother’s left nipple. B, An arm push-up, which helps the (in kilograms), and the length and head cir-
infant to move to mother’s right side. C, At 45 minutes cumference (in centimeters) of the infant
of age, the infant moved to the right breast without
on admission. These measurements should
assistance and began sucking on the areola of the breast.
The infant has been looking at the mother’s face for
be plotted on the appropriate intrauterine
5 to 8 minutes. (Photographed by Elaine Siegel. From growth curves. This facilitates the identifi-
Klaus PH: Your amazing newborn, Cambridge, Mass., cation of infants who are small or large for
1998, Perseus, pp 13, 16, and 17.) gestational age, or who are microcephalic or
macrocephalic.
of less than 35 weeks, congenital anomalies, GENERAL EXAMINATION

infants of a diabetic mother, or clinical signs It is useful to observe the overall condition
of asphyxia or sepsis should be assessed of the infant, including major anomalies,
immediately by the nursing staff and exam- respiratory effort, color, perfusion, activ-
ined by the physician. ity, and responsiveness. In infants with
respiratory distress, it is important to note meconium has been present in the amni-
the presence of grunting, flaring, and retrac- otic fluid for a number of hours. The post-
tions and to assess the work of breathing. mature infant has parchment-like skin with
The quality and the strength of the infant’s deep cracks on the trunk and extremities.
cry and overall motor activity are especially Fingernails may be elongated, and peeling
useful indicators of the infant’s general con- of the distal extremities is often evident in
dition. Such general observations are useful the postmature infant.
to quickly categorize an infant and to focus Erythema toxicum neonatorum is a ben
one’s attention on a critically ill newborn. ign rash seen generally in term infants begin-
A vigorous, screaming, pink infant clearly ning on the second or third day of life. It is
does not demand the same immediate inter- characterized by 1- to 2-mm white papules,
vention required by the infant who is pale which may become vesicular, on an ery-
and hypotonic with labored or irregular thematous base. Wright or Giemsa stain of
breathing. the lesions demonstrates large numbers of
Edema is readily noted in any initial eosinophils. Milia, which are 1- to 2-mm
examination. The presenting part at birth whitish papules, are frequently found on
may be edematous, bruised, and covered the face of newborns. Transient neonatal
with petechiae. Edema of the dorsum of the pustular melanosis, which is seen predomi-
feet may be seen as a focal finding in Turner nantly in black infants, is a benign general-
syndrome, or it may be part of a more gen- ized eruption with a mixture of superficial
eralized picture of edema. Infants with pustules that progress to hyperpigmented
hydrops, whether immune or nonimmune, macules. Congenital dermal melanocytosis
often have generalized edema, which can (Mongolian spot) is a gray-blue nonraised
include the trunk, extremities, scalp, and area of hyperpigmentation seen predomi-
face. In critically ill infants who require fluid nantly over the buttocks or trunk and is
volume resuscitation, generalized edema seen most commonly in black, Asian, and
may develop over the course of their illness. Hispanic infants.
Such edema often localizes to the face and The newborn infant can have a variety of
trunk, and especially the flanks. color changes in the first day of life, some
The initial examination should also of which are due to cardiovascular labil-
include a quick survey for dysmorphic fea- ity during transition. The harlequin sign
tures, whether malformations or deforma- is a benign transient finding in which the
tions. The presence of a major congenital infant is pale on one side and flushed on
anomaly or multiple minor anomalies may the contralateral side with a distinct border
indicate the need for an aggressive investi- in the midline. Mottling of the skin is com-
gation of other major organ defects. mon in the first days to weeks of life in some
infants. The color and perfusion of the skin
SKIN can provide information regarding cardiac
In the extremely premature infant (23 to 28 output and oxygenation. Acrocyanosis is a
weeks’ gestation) the skin can be translu- common finding in the first 6 to 24 hours
cent with little subcutaneous fat and super- of life, but is usually of little significance by
ficial veins that are easily visualized. Because itself. Central cyanosis persisting beyond
the stratum corneum is quite thin, the skin the first few minutes of life may indicate
of the extremely premature infant is easily inadequate oxygen delivery and demands
injured by seemingly innocuous procedures further evaluation. Infants can have cya-
or manipulation that results in denudation nosis over just the lower half of the body
of the stratum corneum and a raw weeping in the presence of right-to-left shunting
surface. With advancing gestational age, the across a patent ductus arteriosus. Capillary
fetal skin matures as the stratum corneum refill time can be sluggish in the first hours
thickens, subcutaneous fat increases, and of life as the infant adapts to extrauterine
the skin loses its translucent appearance. By life. Persistent pallor and poor perfusion
term, the fetal skin is relatively opaque with may reflect inadequate cardiac output as a
considerable subcutaneous fat. result of perinatal hypoxia and ischemia,
By 35 to 36 weeks’ gestational age, the congenital heart disease, or sepsis. Infants
infant is covered with vernix. The vernix with anemia may have pallor, but this is an
thins by term and is usually absent in the inconsistent finding even in the presence of
postterm infant. Meconium staining of severe anemia. Marked plethora may occur
the skin, nails, and cord is evident when with polycythemia, but this finding is also
inconsistent. Hence, the physician must and fluctuant on palpation and can give
have a high index of suspicion for those a sensation of absence of the bony skull
infants at risk for either anemia or polycy- beneath the hematoma. In contrast, sub-
themia. Jaundice at birth is abnormal and galeal hematomas are not limited by suture
requires immediate investigation. Physi- margins and usually cross the midline. A
ologic jaundice is generally not seen before rapidly expanding subgaleal hematoma can
24 hours of age. Petechiae and bruising are be life threatening because of the blood loss
very common on the presenting fetal parts. into the hematoma. Such patients require
However, in the presence of thrombocyto- close monitoring and aggressive volume
penia or platelet dysfunction, petechiae are replacement.
more likely to be generalized. The skull sutures should be checked to
A careful examination of the newborn’s note whether they are widened or overrid-
skin should be made to identify congenital ing. A widely open full anterior fontanelle
nevi, hemangiomas, areas of abnormal pig- with split sutures suggests increased intra-
mentation, tags, and pits. A port wine stain cranial pressure, which may be caused by
of the face should alert the physician to the intracranial hemorrhage, cerebral edema, or
possibility of Sturge-Weber syndrome. Con- hydrocephalus. Unusual scalp hair patterns
genital strawberry hemangiomas should be can be an indication of underlying brain
identified and their progression monitored. dysmorphogenesis, particularly if the infant
Large hemangiomas of the face and neck has other dysmorphic features. A midline
can potentially cause airway obstruction. mass protruding from the skull may be an
Massive hemangiomas of the extremities encephalocele and requires thorough evalu-
or trunk can result in large systemic shunts ation.
and high-output cardiac failure. Congeni-
tal defects in the skin are important in the EYES, EARS, MOUTH, AND FACIAL
identification of underlying structural prob- FEATURES
lems or systemic disorders. Localized scalp The overall configuration of the face should
defects are associated with trisomy 13. Mid- be inspected including the profile, which
line posterior defects of the skin are particu- helps in the detection of micrognathia.
larly important to identify. Sacral dimples Such overview reveals areas of maxillary or
should be carefully examined to ensure that mandibular hypoplasia, any distortion, or
the base is clearly visualized and the possi- hemifacial hypoplasia. The eyes should be
bility of a sinus tract to the spinal cord is inspected for abnormalities in the size of the
excluded. Such dermal sinuses can com- globes or orbits, and for any malposition
municate with the cerebrospinal fluid and (e.g., proptosis as in neonatal hyperthyroid-
result in meningitis. ism). Abnormalities of the eyebrows may be
a clue to specific syndromes, such as syno-
HEAD AND SCALP phrosis in Cornelia de Lange syndrome. The
The occipital-frontal head circumference eyelids of the newborn may be edematous
should be measured and recorded for all or may display ecchymosis from the deliv-
newborns. Ideally, three careful measure- ery process. Nevus flammeus is commonly
ments should be taken at various positions noted on the upper eyelids. After vaginal
over the occipital-frontal area, and the larg- delivery, the conjunctivae are often injected
est measurement is then recorded. The head and scleral hemorrhages may be present.
should be palpated carefully and visually The parents may need reassurance regarding
inspected to detect any unusual distortions, these generally benign features.
hematomas, or caput. Because the fetal skull Abnormal slanting of the palpebral fis-
is molded by the delivery process, abnormal sures is associated with a number of syn-
skull shapes may need to be reevaluated in dromes. Notably, an upward slant is seen
1 to 2 days. Caput succedaneum is a com- in trisomy 21, whereas down-slanting eyes
mon and expected finding after vaginal ver- are a feature of Treacher Collins, Apert,
tex delivery. Bruising and edema caused by and DiGeorge syndromes. Short palpe-
caput is usually soft, crosses suture lines, and bral fissures with a smooth philtrum and
does not significantly expand in size postna- thin upper lip suggest fetal alcohol syn-
tally. Subperiosteal hematomas, which are drome. Hypertelorism or inner epicanthal
common, are easily identified by their dis- folds are associated with a large number
tinct margins which stop at the suture lines. of syndromes (most notably trisomy 21).
Subperiosteal hematomas are generally soft Marked hypotelorism is associated with
holoprosencephaly and trisomy 13. The NECK AND THORAX

eyes should be examined with an ophthal- The neck should be supple and easily turned
moscope to check for the red reflex and from side to side, and the trachea should
the presence of cataracts. Leukocoria, or a be in the midline. Gentle extension of the
white pupil, mandates a thorough ophthal- neck is performed looking for any mass,
mologic examination. Cloudiness of the cystic hygroma, or goiter. Large masses in
cornea may be seen at birth, especially in the neck require urgent evaluation because
the premature infant. The pupils should be of their potential for airway obstruction. A
round and equal in size. Pupillary reactiv- webbed neck or redundant skin is associated
ity to light is minimal beginning at 30 to with trisomy 21, Turner, Noonan, or Zell-
32 weeks’ gestation and increases with ges- weger syndromes. The clavicles should be
tational age. The lenticular pattern can be palpated to check for deformities. A clavicu-
useful in gestational age assessment. lar fracture often results in crepitance and
The oral cavity should be inspected using swelling, and an asymmetrical Moro reflex.
a tongue blade and a light source. Impor- The thorax may appear to be small or
tant findings to note include the presence malformed in a number of neuromuscu-
of neonatal teeth, the arch of the palate, the lar disorders, or in lung hypoplasia. With
integrity of both the hard and soft palate, congenital disorders of generalized muscle
the shape and movement of the tongue, and weakness, the thorax assumes a bell-shaped
the presence of any oropharyngeal masses appearance. In term infants, the areolae of
or mucosal lesions. Although cleft lip and the nipples are raised and there is an under-
palate are frequently isolated anomalies, lying breast bud with a diameter of 0.5 to 1
the infant with these anomalies should be cm. The nipples may be enlarged secondary
carefully examined for any other associated to the effects of maternal hormones, and a
anomalies. Abnormal masses (e.g., tumors, milky discharge (so-called “witch’s milk”)
hemangiomas) in the area of the mouth and is not uncommon in both male and female
pharynx demand prompt attention in view infants. Mastitis, which is usually unilateral,
of their potential to cause airway obstruc- causes swelling, erythema, warmth, and
tion. Neonatal teeth are generally a benign tenderness. In extremely premature infants,
finding, but may be associated with several the areola may be quite small, flat, and dif-
syndromes (Ellis-van Creveld, Hallermann- ficult to identify. Abnormal displacement of
Streiff, and Sotos syndromes). Protrusion of the nipple or supernumerary nipples should
the tongue from the mouth is seen in tri- be noted. The nipples are widely spaced in
somy 21, or it may be due to macroglossia, Turner syndrome, Noonan syndrome, and
which may be associated with storage dis- trisomy 18.
eases, Beckwith-Wiedemann syndrome, or
hypothyroidism. RESPIRATORY SYSTEM
The position, rotation, and shape of the When breathing at rest, the healthy new-
ears should be noted. In very premature born should move air easily and com-
infants, the pinna is soft, flat, and easily fortably at a rate of 40 to 60 breaths per
folded back on itself. In term infants, the minute. Because most air exchange in new-
outer helix of the pinna should be well borns is accomplished by the effects of dia-
formed with a definite curvature. Infants of phragmatic excursion, there is considerable
diabetic mothers may have unusually hairy abdominal wall motion with breathing.
ears. The presence of abnormally shaped Respiratory distress, whether because of
or malformed (e.g., microtia) ears should lung disease or airway obstruction, is evi-
prompt a careful examination of the infant dent by the presence of subcostal or sternal
for other potential dysmorphic features. In retractions. Suprasternal retractions may
particular, low set and posteriorly rotated be evident in the presence of severe respi-
ears are associated with a number of syn- ratory distress. Audible grunting occurs as
dromes. The ears are carefully inspected the infant expires against a partially closed
to ensure patency of the external auditory glottis and is an extremely reliable indica-
canal. Otoscopy is not routinely needed in tor of any process causing alveolar collapse
the newborn infant with normal external or atelectasis. Asymmetrical movement of
ear anatomy. Amniotic fluid debris and the chest wall with respirations occurs with
secretions often prevent easy viewing of a variety of unilateral lesions of the dia-
the tympanic membrane in the first days phragms or pleural space (e.g., pneumotho-
of life. rax, diaphragmatic hernia, diaphragmatic
paralysis, pleural effusion). The quality of with good air entry during the inspira-
the infant’s cry should be noted. A high- tory phase of positive-pressure ventilation.
pitched shrill cry may suggest a central Diminished breath sounds on the left may
nervous system disorder. A weak cry may indicate that the endotracheal tube has
occur in the presence of respiratory distress passed into the right mainstem bronchus.
or a depressed central nervous system. A In such a situation, the tube should be grad-
hoarse or muffled cry may occur with vocal ually withdrawn until the breath sounds are
cord swelling, intratracheal narrowing, or equal. The depth of the endotracheal tube
a mass. (in centimeters from the tip) is an impor-
The lungs should be auscultated ante- tant part of the physical examination of an
riorly, posteriorly, and at the sides of the intubated infant. Small movements of the
chest. Comparison should be made between endotracheal tube in a newborn can result
the two sides. The breath sounds should in inadvertent right mainstem placement
be checked for the amount of air exchange or accidental extubation. However, auscul-
(whether with spontaneous or with assisted tation of breath sounds alone for confirma-
ventilation). Asymmetrical breath sounds tion of intubation is not always adequate.
may be caused by pneumothorax (Box 4-5), The small size of the neonatal chest allows
an improperly placed endotracheal tube, dia- for wide transmission of breath sounds. The
phragmatic hernia, or any other space-occu- sounds created by ventilation through an
pying lesion in the hemithorax. Crepitant endotracheal tube inadvertently misplaced
breath sounds or crackles are often heard in into the esophagus can transmit through
the initial transitional period. These sounds the newborn’s chest. Even with a properly
generally clear as the newborn expands the placed endotracheal tube, chest movement
lungs and clears fluid from the pulmonary and air entry may be inconsistent with posi-
airspaces. However, crackles may be heard tive pressure breaths if the infant is fighting
with respiratory distress syndrome, pneu- the ventilator. If lung compliance is very
monia, and various types of aspiration syn- poor, chest movement may also be dimin-
dromes. Stridor occurs with a variety of ished except with high pressures. Devices
causes of airway obstruction, but may be that detect exhaled CO2 are widely used to
absent or difficult to appreciate in the infant confirm intubation, and their routine use is
who is moving little air. An audible leak dur- highly recommended.
ing the inspiratory phase of a ventilator may During high-frequency ventilation, whet
be heard around the endotracheal tube of her by oscillation or jet, the lungs are not
intubated infants and may obscure the qual- capable of being auscultated. The ampli-
ity of the breath sounds. The sounds caused tude of the “chest wiggle” in such infants
by air leak are often transmitted through the (by visual inspection or palpation) can be a
mouth and are audible by the unassisted ear. useful guide to the effectiveness of the high-
These sounds, when auscultated by a stetho- frequency pulsations. Such infants should
scope, are sometimes mistakenly attributed routinely be removed from high-frequency
to wheezing caused by bronchoconstriction. ventilation for a brief time in order to aus-
Coarse breath sounds or rhonchi may suggest cultate the chest while the infant is given
the need for suctioning to clear secretions in positive-pressure tidal breathing by bagging.
the upper airway or in an endotracheal tube.
For ventilated infants, auscultation of the CARDIOVASCULAR SYSTEM
lungs is routinely used to confirm appropri- The apical cardiac impulse can be appreci-
ate position of the endotracheal tube. The ated by visual inspection and palpation. A
breath sounds should be symmetrical and hyperdynamic precordium may occur with
there should be adequate chest excursion a large left-to-right shunt or with marked
cardiomegaly. The cardiac impulse in a nor-
mally positioned heart is most prominent at
Box 4-5. Signs of Tension Pneumothorax the lower left sternal border. Prominence of
Shift of cardiac apical impulse
the apical cardiac impulse at the lower right
Decreased breath sounds on the affected side
sternal border suggests dextrorotation or
Asymmetrical subcostal retractions and chest
dextroposition of the heart. A shift of the
wall movement
apical impulse is a useful sign to detect ten-
Ballooning of the chest on the affected side
sion pneumothorax.
Increased halo of light with transillumination
Auscultation of the heart should include
right and left second intercostal space, right
and left fourth intercostal space, the cardiac is best heard at the cardiac base and radiates
apex, and the axillae. Both the diaphragm widely to the axillae and the back. Hemody-
and bell (with a good seal) of the stetho- namically significant patent ductus arterio-
scope should be used. The infant should be sus (PDA) in a premature infant usually has
as quiet as possible. It is sometimes neces- a systolic murmur best heard along the left
sary to briefly disconnect the ventilator for sternal border. It is rarely a continuous mur-
intubated infants who can tolerate this pro- mur in the neonatal period and it may be
cedure. The quality of the heart tones (S1 silent. PDA with a large left-to-right shunt
and S2) and any clicks, murmurs, or addi- may further be associated with a hyperdy-
tional heart tones (S3, S4) should be noted. namic precordium, bounding pulses, low
The heart rate in the first day of life is gener- diastolic pressure, and wide pulse pressure.
ally between 120 and 160 beats per minute The femoral and brachial pulses should
while the infant is at rest. During quiet sleep, be palpated and compared. Pulses may be
some term infants have a resting heart rate diminished as a result of hypovolemia,
as low as 90 to 100 beats per minute. Nor- depressed myocardial contractility, sep-
mal sinus arrhythmia with breathing can be sis, or left-sided obstructive heart lesions.
more difficult to discern because of the rela- In left-sided obstructive heart lesions (e.g.,
tively rapid neonatal heart rate. S1 is rela- coarctation of the aorta and hypoplastic
tively loud in the newborn and is best heard left heart syndrome), the femoral pulses
at the apex. S2 is loudest at the left upper are usually diminished, but may be read-
sternal border. Because of the relatively fast ily palpable if distal flow is maintained by
heart rate of the newborn, it may be diffi- right-to-left shunting at the ductus arterio-
cult to appreciate the splitting of S2. With sus. While the normal newborn does not
the normal postnatal decline in pulmonary routinely require blood pressure measure-
artery pressure, splitting of S2 may be eas- ment, blood pressure should be checked by
ier to appreciate. A loud S2 that is narrowly palpation or by an automated technique
split may suggest pulmonary artery hyper- (e.g., oscillometric) in any unstable infant,
tension. Absence of a split S2 may occur including those infants with respiratory dis-
with various anomalies of the great vessels: tress, poor perfusion, presence of a cardiac
aortic atresia, pulmonary atresia, transposi- murmur, or depressed neurologic status.
tion, and truncus arteriosus. Any murmurs All premature infants admitted to an inten-
should be noted with regard to timing, sive care nursery should also have blood
intensity, and location. A soft systolic mur- pressure monitored. The blood pressure of
mur in a term infant during the first day of critically ill infants is optimally monitored
life may be due to a closing ductus arterio- continuously by a transducer connected to
sus or to flow across the pulmonary valve an indwelling umbilical or peripheral arte-
as pulmonary resistance declines. Harsh or rial catheter. Reference can be made to nor-
loud murmurs, particularly in the presence mal values of blood pressure by both birth
of other cardiovascular symptoms or respi- weight and postnatal age (see Appendix C).
ratory distress, require further evaluation. However, a normal blood pressure does not
The absence of a cardiac murmur does not ensure adequate cardiac output. The qual-
exclude the possibility of congenital heart ity of the pulses, skin perfusion, capillary
disease. Infants with persistent cyanosis or refill time, and color are further indirect
hypoxemia despite oxygen administration measures of cardiac output. The presence or
may have cyanotic congenital heart disease, absence of acidosis, measurement of mixed
primary lung disease, or pulmonary artery venous saturation, and the monitoring of
hypertension. Intubation and positive-pres- urine output can be further useful indices of
sure ventilation can sometimes distinguish tissue perfusion.
an infant with pulmonary artery hyperten- Infants with congestive heart failure may
sion and lung disease from an infant with have left-to-right shunting from congeni-
cyanotic congenital heart disease. Echocar- tal heart disease. Symptoms may include
diography should be promptly obtained tachycardia, tachypnea, respiratory dis-
in any critically ill infant with hypoxemia tress, poor feeding, and hepatomegaly. The
despite oxygen administration and ventila- cause of such symptoms may be obvious
tion. Peripheral pulmonary stenosis, which from echocardiography. However, more
is common in premature infants during the subtle etiologies of congestive heart failure
first weeks of life, usually manifests as a high- may escape easy detection. The skull and
pitched soft systolic murmur. This murmur abdomen (especially over the liver) should
be auscultated for bruits resulting from an by a combination of percussion and palpa-

arteriovenous malformation. Large hem- tion, but palpation is primarily used in the
angiomas or sacrococcygeal teratomas can newborn. The liver may normally extend
also cause high output failure. An enlarged 1 to 2 cm below the right costal margin. A
thyroid gland suggests hyperthyroidism, midline or left-sided liver should initiate
but specific laboratory studies are needed to a careful search for other anomalies and
confirm this diagnosis. appropriate imaging studies. Hepatomeg-
aly may be due to heart failure, congeni-
ABDOMEN tal infection, congenital anemia, hydrops,
The abdominal shape, size, and color intrahepatic tumors, hemangiomas, or
should be noted. Abdominal wall defects hematomas. Pulmonary hyperinflation
(e.g., gastroschisis, omphalocele) are readily causes the liver to extend deeper into the
apparent at birth and demand immediate abdomen and can give a false impression of
attention. Most newborns have a slightly hepatomegaly. The spleen is generally not
protuberant abdomen, which becomes more palpable in the healthy newborn, but may
evident as air is swallowed after birth. Bowel be appreciated at the costal margin. Sple-
obstruction caused by distal atresias, steno- nomegaly may occur with congenital infec-
sis, meconium plug, and Hirschsprung dis- tion, immune hemolytic disorders, and
ease usually manifests within the first 1 to portal venous hypertension. The kidneys
2 days of life with distention, visible loops should be carefully palpated bilaterally with
of bowel, and emesis. In duodenal atresia, the infant relaxed. Bimanual examination
there may be only mild distention in the can be helpful to evaluate kidney size and
epigastric area resulting from an enlarged shape. Common causes of an enlarged kid-
stomach. Distention is usually apparent at ney in the newborn include hydronephro-
birth when there is massive ascites, meco- sis, renal vein thrombosis, and multicystic
nium ileus, and peritonitis, or intrauter- renal dysplasia. Enlargement of the adrenal
ine midgut volvulus. Intestinal perforation gland is difficult to discern from a renal
usually gives the abdomen a bluish-gray mass by palpation. Causes of adrenal masses
tint, but frank abdominal wall erythema include hemorrhage and tumors (e.g., neu-
develops with the onset of peritonitis. Dia- roblastoma). The urinary bladder is palpable
phragmatic hernia may result in a scaphoid only if it is distended with urine. The sick
abdomen resulting from the herniation of newborn can have transient urinary reten-
abdominal contents into the thorax. Visible tion and bladder distention in the presence
loops of bowel suggest intestinal obstruc- of a critical illness and the use of sedative
tion, particularly in the presence of bilious drugs, particularly morphine. Reduction
emesis or gastric aspirates. Bilious emesis of an enlarged bladder by Credé’s method
should always be considered abnormal and (manual pressure) is discouraged, because
requires further evaluation. In extremely it may cause ureteral reflux or bladder per-
premature infants, some loops of bowel foration. Infants with pathologic urinary
may be seen through a thin abdominal wall bladder retention should undergo sterile
without clinical signs of overt obstruction. bladder catheterization as initial manage-
In prune belly (Eagle-Barrett) syndrome, ment. Palpable intraabdominal masses
the abdominal musculature is lax and the should be described by their location, size,
abdominal wall is quite thin, resulting in shape, mobility, and consistency. It should
visible loops of bowel. be noted whether the mass adheres to or is
Abdominal palpation should be per- contiguous with other internal organs.
formed with warm hands, patience, and a
quiet infant. Under such conditions, the UMBILICUS, CORD, AND PLACENTA
infant’s abdominal muscles generally relax The number of arteries and veins in the
after some initial resistance, thus permit- cord should be noted. The presence of a
ting a careful palpation of the internal single umbilical artery is associated with
organs. However, if the abdomen is tense an increased incidence of renal anomalies.
and distended, palpation may only reveal The base of the cord and umbilicus should
the absence or presence of tenderness. be inspected for any herniation of intestinal
Abdominal tenderness may be obscured if contents. A short umbilical cord has been
the infant is obtunded, sedated with medi- associated with an increased risk for psycho-
cations, or extremely premature. The size motor abnormalities,30 cord injuries, and
and position of the liver can be determined abruptio placentae. About 1% of singleton
and about 5% of multiple pregancies (twins, are more prominent than the labia minora
triplets, or more) have an umbilical cord and generally cover the latter. The female
that contains a single umbilical artery. The urethra may be difficult to visualize, but is
cause is unknown, but it is associated with found just anterior to the vaginal opening.
an increased risk of birth defects, includ- Outpouching of the vaginal mucosa (vagi-
ing heart, central nervous system, and renal nal tags) is common because of the effect
structures, in addition to chromosomal of maternal hormones on the fetus. In
abnormalities. The consensus is that it is contrast, the premature female infant may
unnecessary to do a renal ultrasound in all have more prominent labia minora and
babies with single umbilical artery because relative protrusion of the clitoris beyond
the yield is very low. A moist cord raises the the labial folds. Such findings are part of
spectrum of a persistent urachus which con- the normal morphogenesis of the growing
nects from the cord to the dome of the blad- fetus, but parents often need reassurance
der. Persistent omphalo mesenteric cysts are that the anatomy is normal. The groin and
another set of anomalies. There may also labia majora should be palpated for masses
be massive cord cysts or even herniation of (gonads or herniae). Female infants often
bowel into the cord. Major anomalies are have a whitish mucous vaginal discharge.
gastroschisis, which always occurs to the As the effects of maternal hormones subside
right of the cord and omphaloceles, which in the first week, female infants may have
may be small or very large containing liver a small amount of vaginal bleeding. Clito-
and bowel. romegaly, increased pigmentation, genital
Placental pathology, which may read- hair, and labioscrotal fusion are signs of vir-
ily explain an infant’s problems, is often ilization. Causes include congenital adrenal
overlooked. Abruption and infarcts of the hyperplasia, virilizing tumors, and mater-
placenta can lead to inadequate blood and nal androgenic medications. In females,
oxygen delivery to the fetus. Vasa previa obstructive lesions of the genital tract, such
may lead to acute fetal blood loss. Histo- as imperforate hymen and vaginal atresia,
pathologic examination of the placenta cause retention of secretions or blood in the
should be performed after any complicated uterine cavity. This condition manifests as
delivery, including multiple gestation preg- an abdominal mass or with symptoms of
nancies, premature delivery, cases of abrup- urinary tract obstruction.
tion or other acute blood loss, and stillbirth. The male infant’s genitalia are also first
evaluated by visual inspection. The size,
GENITALIA AND INGUINAL AREA color, and surface texture of the scrotum
The physician should become familiar with should be noted. In the term male infant,
the normal variations of newborn genitalia the scrotum is thin-skinned, rugated, and
and be able to recognize those abnormali- pendulous. In the premature infant, the
ties that require evaluation. The genitalia scrotum is thicker, smoother, and less pen-
may be abnormal as a result of primary dulous. Superficial abrasions, ecchymosis,
errors in morphogenesis, but other abnor- and swelling of the scrotum may occur
malities may result from secondary hor- after breech birth. The length and girth of
monal effects. Clues to underlying systemic the phallus are noted visually. Sometimes
hormonal disorders or dysmorphic syn- the phallus may appear to be small, but its
dromes may be obtained by careful exami- true size is merely hidden by the depth of
nation of the genitalia. Gender assignment the surrounding tissues. If there is a ques-
should never be made for the infant with tion of micropenis, then the phallus should
ambiguous genitalia until a full assessment be palpated and stretched, so its length can
has been performed. The parents should be be measured. Micropenis may be associated
reassured that gender assignment will be with hypothalamic dysfunction and hypo-
made as soon as feasible. pituitarism. The phallus should be observed
To fully examine the female genitalia, for any unusual angulation, ventral chordee,
the infant should be examined with the or web, and the completeness of the fore-
hips abducted while lying supine. The labia skin. If the foreskin is complete, then there
majora, labia minora, and clitoris should be is no need to retract it in order to identify
inspected for size and surface characteris- the urethral opening. The urethra should
tics. The labia majora may have some mild be slitlike and open on the glans penis. An
wrinkling, but should not have frank rugae. incomplete ventral foreskin should alert the
In the term female infant, the labia majora examiner for the possibility of hypospadias.
If there is hypospadias, the site of the ure- teratomas may distort the perianal anat-
thral orifice(s) should be determined by omy, displace the anal orifice, and cause
inspection and, if possible, by observation intestinal obstruction. These lesions, which
of the urinary stream. Infants with hypospa- can be very large and highly vascular, may
dias should not be circumcised because the rapidly enlarge after birth as a result of inter-
foreskin is often used in the repair. Hypo- nal hemorrhage, causing anemia and shock.
spadias may also be associated with bifid In infants with meningomyelocele or other
scrotum. disorders that may affect anal function, the
The scrotal sacs should be palpated anus should be checked for sphincter tone.
to determine the presence of a testis on An anal wink can be elicited by gently strok-
each side. The size of the testes should be ing the perianal area.
noted. If the testes are undescended, then
the inguinal area should be carefully pal- BACK AND EXTREMITIES
pated for incomplete descent of the testis. The back should be inspected for symme-
In the neonatal period, the testes may be try or any abnormal postures. The vertebral
very mobile between the inguinal canal and column should be palpated along its length
the scrotum. Torsion of a testis results in a with the fingertips. This combination is
swollen hard scrotal mass and bluish dis- usually sufficient to detect any moderate to
coloration of the scrotum. Viability of the severe scoliosis. Vertebral anomalies may
testis is established by ultrasound detection be difficult to appreciate by palpation on
of blood flow. The groin should be checked a routine examination. If there are clinical
for the presence of an inguinal hernia. In reasons to suspect vertebral anomalies (e.g.,
male infants, it is useful to hold the testes in VATER [vertebral defects, imperforate anus,
the scrotum while palpating the ipsilateral tracheoesophageal fistula, radial and renal
inguinal area in order to avoid confusing an dysplasia] syndrome), then radiographs
undescended testis with a hernia. Hydro- should be obtained. If a meningomyelocele
cele, a common cause of scrotal swelling, is noted, it should be carefully inspected
is nontender, often obscures the testis, and and minimally manipulated. The size and
causes the scrotum to brightly transillumi- location of a meningomyelocele should be
nate. If no gonads are palpable in an appar- noted, and then it should be covered with
ent male, then it is particularly important an appropriate saline-soaked sterile dress-
to examine the genitalia for other abnor- ing. When an infant is identified to have
malities and to exclude the possibility that a meningomyelocele, the child should be
the infant is a masculinized female. Obser- kept in a prone or decubitus position to
vation of the urinary stream can be useful. keep pressure off the defect. This creates a
Infants with neurogenic bladders typically significant challenge to thoroughly perform
“dribble” urine in small volumes with some the remainder of the physical examination.
frequency. Males with posterior urethral The midline of the back and sacrum should
valves typically have a poor stream during be carefully inspected for any unusual tufts
spontaneous micturition. of hair, dimples, or pits. Any midline pal-
Exstrophy of the bladder is evident in the pable masses, however small, need further
suprapubic region. It is associated with a evaluation. Ultrasound of the spine can be
widening of the pubic symphysis, and there very helpful in the evaluation of any verte-
is epispadias or a rudimentary penis. There bral or spinal cord anomaly.
are often associated gastrointestinal anoma- Careful inspection alone usually deter-
lies (imperforate anus and intestinal atresia). mines whether the extremities are well
formed. If there are any deformities, then
ANUS careful palpation, measurements of length,
Determination of patency of the anus by and testing for range of motion may pro-
inspection alone is usually sufficient. If vide further information. For example, limb
there is a question of anal patency, then a shortening may be visually evident in an
small catheter should be carefully passed infant with osteogenesis imperfecta. How-
through the orifice. The position of the ever, the bony swelling and tenderness of
anal orifice in relation to the genitalia and multiple fractures may only be evident by
the presence of fistulas or rectal prolapse palpation. Fractures of long bones of the
should be noted. Infants with imperforate extremities are associated with swelling, dis-
anus may pass meconium through a fistula tortion of shape, tenderness, and discolor-
to the genitourinary tract. Sacrococcygeal ation. There is often decreased spontaneous
movement of the affected extremity owing be performed until the findings are clari-
to pain. Humerus fractures may occur with fied. If there is frank dislocation or suspi-
birth trauma. Fractures of the femur and cious findings, then hip ultrasound should
humerus occur spontaneously in infants be obtained. If there is any evidence of
with severe osteopenia of prematurity. hip dysplasia, then orthopedic consulta-
Direct comparisons between any aspect tion should be obtained in a timely man-
of the right and left extremities can be ner. Specific testing for range of motion
very helpful to discern any abnormali- for joints other than the hips is generally
ties in size, shape, or function. The hands not indicated unless there are contractures
and feet of every newborn should be care- or gross anomalies noted. Many aspects
fully inspected. Abnormalities of the digits, of joint function and range of motion are
including reduction, tapering, syndactyly, indirectly tested during the neurologic
polydactyly, duplication, and nail hypopla- examination by passive range of motion.
sia, can be important clues to dysmorphic
syndromes. Postaxial polydactyly, which NEUROLOGIC EXAMINATION
can be inherited as an autosomal dominant The neurologic examination of a healthy
trait, is relatively common and is often an newborn is based on a combination of
isolated finding. In contrast, preaxial poly- observations of behavior and specific test-
dactyly is more commonly associated with ing on examination. The normal newborn
other anomalies. Transverse amputations or certainly does not require a lengthy com-
limb reductions may be a clue to amniotic plete neurologic examination; however,
band syndrome. certain aspects of neurologic function
Circumferential girth of the extremities should be assessed. A more detailed neu-
can be an initial clue to muscle mass, and rologic examination should be performed
this can be further assessed by palpation. in any infant with known neurologic dis-
However, marked edema (as in a hydropic orders (seizures, intracranial hemorrhage,
infant) or increased adipose tissue (as in an encephalopathy) or who is at high risk for
infant of a diabetic mother) can make mus- neurologic injury.
cle palpation more difficult. Extremely pre- A number of behaviors provide informa-
mature infants have relatively little muscle tion about global brain function. Observa-
mass. Observation of motor activity and tions of an infant’s overall responsiveness,
muscle tone is often sufficient in a healthy quality of the cry, interaction with the
term newborn. Neuromuscular disorders mother, and general motor activity pro-
may be associated with a decrease in muscle vide a broad useful perspective on cortical
mass and contractures caused by the lack of function. Although newborns sleep a great
fetal movement. Infants with a high myelo- deal (18 to 20 hours per day), they do have
meningocele can have marked muscle wast- periods of awake activity. The newborn
ing of the lower extremities with flexion infant goes through several states of alert-
contractions of the hips and knees and club- ness throughout each day. The neurologic
foot bilaterally. examination of the newborn is significantly
The hips should be examined for range of affected by the state of the infant. Tone
motion, and they should be fully abducted and motor activity are decreased during
to check for hip clicks or dislocation. Useful active or rapid eye movement (REM) sleep.
techniques for dislocated hip are the Bar- Examination of an infant in this state alone
low maneuver (hip is flexed and abducted; may give an incomplete impression of the
the femoral head is pushed downward; infant’s neurologic status. Important obser-
if dislocatable, the femoral head will be vations can be made as to whether an infant
pushed posteriorly out of the acetabulum) responds to comforting or withdraws from
and Ortolani test (hip is abducted with noxious stimuli.
upward leverage of femur; a dislocated Tone should be assessed by observa-
hip will return with a palpable clunk into tion of posture and by passive movement
the acetabulum). Additional useful find- of the extremities. Term infants have pri-
ings are discrepancies in length and asym- marily a flexion posture at the knees and
metrical creases of the lower extremities. elbows with the fingers generally closed.
Maternal hormones and abnormal fetal However, the term newborn spontaneously
positions (e.g., breech) can cause laxity in opens the hands and periodically extends
the newborn’s hips. If findings are uncer- the arms and legs. A term infant with tight
tain, then repeated examinations should persistent flexion of the extremities, tightly
clenched fists with adducted thumbs, and the eyes. Pupillary response to light may be
hypertonia suggests that there has been a absent in the premature infant because of
previous cortical injury. Premature infants, immaturity and cloudiness of the cornea.
in contrast, have relatively more extension, However, the pupils of the term or near-
especially with decreasing gestational age. term infant should constrict in response to
At 23 to 24 weeks’ gestation, the premature light. Eye movements should be observed
infant likely has fully extended extremi- for any abnormal deviation or sustained
ties, relatively decreased tone, and irregu- nystagmus. Conjugate gaze is often incon-
lar, twitchy, spontaneous motor activity sistent in the newborn. Facial nerve palsy
as normal findings. Head control and may be apparent by the observation of
neck tone may be tested by gently lifting asymmetry during crying. The gag reflex
the infant by the arms slightly off the bed can be checked at the same time the mouth
and assessing for head lag. Head control and tongue are being evaluated as part of
is generally poor in the premature infant, the general physical examination. Ineffec-
but some neck muscle tone is present in tive sucking, swallowing, and handling of
healthy term infants. oral secretions may be an indicator of cra-
Motor activity of the infant should be nial nerve dysfunction or central nervous
observed to detect any asymmetry or abnor- system depression. Hearing may be crudely
mality in movement. Motor strength is assessed by the response to the mother’s
assessed by the degree of resistance to pas- voice or sudden sounds. Universal hearing
sive range of motion, spontaneous move- testing of all newborns is recommended
ment, and active effort against restraint by prior to discharge to home.
the examiner. Jitteriness is very common
in the newborn. In otherwise apparently ROUTINE EVALUATION DURING
healthy term infants, such jitteriness is gen- TRANSITION
erally benign unless the movements are The first hours of life are a period during
particularly coarse or of a large amplitude. which the newborn should be carefully
Occasionally, such jitteriness can be due to monitored and evaluated. It is during this
hypoglycemia or hypocalcemia. In an irri- transition period that many of the problems
table, hypertonic infant, jitteriness may be of the high-risk infant manifest themselves.
due to drug withdrawal or neurologic injury. Because this is also an important period for
For most infants, testing of deep tendon the mother and family to bond with the
reflexes can be limited to the biceps and infant, most of the monitoring and evalu-
knee jerk. The ability to elicit deep tendon ating can be done by skilled obstetric and
reflexes is dependent on the infant’s activ- nursery nurses. Fortunately, most infants
ity and state, the patience of the examiner, are healthy and require little intervention
and the effects of medications. There are other than observation.
a large number of elicitable reflexes in the Where the infant is observed during the
newborn, but the physician rarely needs to first few hours depends on the parents, the
test more than a few of these responses in infant, and the hospital. Reasonable alter-
most routine examinations. The Moro reflex natives range from close observation of the
is particularly useful to detect Erb palsy. The mother and infant together in the mother’s
palmar reflex and asymmetrical tonic neck room to temporary admission to a transi-
response may reveal asymmetries in motor tional or intermediate nursery. Regardless of
function or strength. Sucking can be evoked the setting for this transitional period, the
even in extremely premature infants as early emphasis must always be on careful obser-
as 28 weeks. Rooting is easily demonstrated vation with the ability to intervene in time
in term infants by stroking the side of the to prevent significant problems.
mouth. For the high-risk infant, a number of
Cranial nerve function should be thor- problems may manifest themselves within
oughly and specifically evaluated in the the first hour. A systematic approach to
comatose infant or as part of an assess- these infants is important so that prob-
ment for brain death. However, a less lems can be identified and responded to
formal assessment of the cranial nerves suf- in a timely fashion, without overtreatment
fices in most infants. The term newborn is of infants. The most important evaluation
capable of following an object from 30 to of the infant within the first several hours
60 degrees. Shining a bright light into the is repeated physical examinations. These
eyes should cause the term infant to close “mini-exams” require little intervention
with the infant, but they can identify evolv- ductus arteriosus, a murmur in the presence
ing problems. of cyanosis, poor perfusion, or poor pulses is
often associated with cardiac disease.
RESPIRATORY
Is there any evidence of increasing respira- NEUROLOGIC
tory distress? Many newborns have some Is the infant lethargic and hypotonic, or,
mild grunting during the first few minutes conversely, is the infant jittery? The for-
of life. This grunting, often audible only mer can be due to sepsis, hypoxic-ischemic
with a stethoscope, decreases over the first insult, metabolic disorders, or neuromuscu-
30 minutes in a healthy infant. The infant lar disorders. The latter may indicate early
with increasing grunting at 15 to 30 minutes drug withdrawal or hypoglycemia. Coarse
of age, particularly if it is associated with high-amplitude jitteriness is sometimes seen
other signs of respiratory distress, should be in infants with hypoxic-ischemic encepha-
considered abnormal. In the preterm infant, lopathy.
respiratory distress syndrome is, by far, the
most common cause of respiratory distress TEMPERATURE
that increases during the first hour of life— Temperature must be followed closely in
although other processes, such as pneumo- the preterm infant who, because of a larger
nia or pneumothorax, may present a similar surface-to-volume ratio, is more likely to
picture. In the term infant, continued grunt- quickly become hypothermic. See Chapter
ing is most often associated with pneumonia, 6 for a more detailed discussion of tempera-
aspiration syndrome, or retained lung fluid. ture regulation.
Is there tachypnea without grunting?
This is most often either a benign finding LABORATORY EVALUATION
or it represents transient tachypnea of the The two laboratory tests most commonly
newborn. The differentiation between these performed during the transition period are
two entities depends on whether the infant an assessment of blood glucose and hema-
requires supplemental oxygen. tocrit (or hemoglobin). Some nurseries rou-
Is the infant pink and well saturated? All tinely check blood glucose on all newborns.
infants with any signs of respiratory dis- Although healthy newborns without any
tress should be placed on a pulse oximeter risk factors probably do not need routine
to more accurately assess oxygen saturation. blood glucose monitoring, infants with risk
Immediately after delivery, even without factors do require glucose monitoring. Any
any need for resuscitation, oxygen satura- sick newborn, in particular those with respi-
tion values for preterm infants increase more ratory distress or cardiovascular problems,
slowly than those for term infants. It takes need glucose monitoring. Other at-risk
about 4 minutes for term infants and nearly groups for hypoglycemia include prema-
8 minutes in preterm infants to reach a ture infants, small or large for gestational
median saturation of greater than 90%.31 age infants, infants of diabetic mothers, and
those who had hypoxic-ischemic perinatal
CARDIOVASCULAR insults. Signs of hypoglycemia include jit-
Is the infant well perfused? Hypoperfusion teriness, lethargy, or seizures (newborns
often accompanies sepsis or significant rarely sweat with hypoglycemia). However,
asphyxia. Does the infant have a murmur? many hypoglycemic infants are asympto
Cardiac murmurs are detected on routine matic. The frequency and duration of glu-
examination in 1% to 2% of normal infants. cose monitoring depends on whether an
Many are transient flow murmurs related infant has hypo- or hyperglycemia and the
to circulatory changes following birth, rate at which it resolves.
including tricuspid flow as pulmonary Either hematocrit or hemoglobin (or
hypertension resolves. Pulmonary artery CBC) should be checked in newborns who
branch stenosis is a common cause of a car- fall into a high-risk group. In particular,
diac murmur as is congenital heart disease. such testing should be done in the setting
Four extremity blood pressures should be of discordant twins, an infant of a diabetic
measured in newborns with murmurs, and mother, signs of plethora or hyperviscos-
the definitive diagnosis is made with ultra- ity, hypovolemia or hypotension, history of
sound. Although murmurs are present in a maternal bleeding (abruption, previa), fetal
large percentage of healthy newborns during or neonatal blood loss, suspected sepsis, or
the first day of life secondary to the closing pathologic jaundice.
In addition to these tests, routine new- of blood glucose and hematocrit, can be
born screening is widely performed. The deferred until the infant is at least 1 hour
scope of testing ranges regionally. Typi- old and the mother has been able to spend
cally, the newborn screen includes tests for some private time with her infant.
hypothyroidism, phenylketonuria (PKU),
galactosemia, congenital adrenal hyperpla- MANAGEMENT OF THE HIGH-RISK
sia, hemoglobinopathies, and a variety of INFANT DURING TRANSITION
tests for genetic metabolic disorders is also The areas that most often need to be
available. These tests are run in batches addressed in the high-risk infant are moni-
at reference laboratories and are usually toring, vascular access, oxygen and ventila-
not available for at least several days or tory support, and evaluation of suspected
weeks. Newborn screening tests should be sepsis. As with most other areas of newborn
obtained before discharge from the hospi- care, anticipation of potential problems
tal; however, the PKU test may not be valid leads to a practical and successful plan for
if it is performed before 12 hours of age. In the care of these infants.
most states, the hypothyroidism screen is
designed to detect only primary hypothy- MONITORING
roidism by measuring thyroid-stimulating Sick infants should be placed on a cardiores
hormone (TSH). Hypothyroidism, which is piratory monitor. Blood pressure should be
caused by hypopituitarism, is not detected evaluated in all infants who are not having
by TSH screening alone. Infants with sus- a normal transition after birth. Blood pres-
pected secondary hypothyroidism need sure is easily measured with automated cuff
specific testing of free thyroxine (T4) to eval- devices, which are noninvasive and simple
uate thyroid status. Prior transfusion invali- to use. In any infant with an arterial catheter
dates the results of hemoglobinopathy and in place, arterial pressure should be continu-
galactosemia screening tests. The hormone ously monitored, and the arterial waveform
17-hydroxy progesterone is measured to test displayed on the cardiorespiratory monitor.
for congenital adrenal hyperplasia. Estab- Not only does this provide important infor-
lishing normal refernce values for premature mation about the infant’s cardiovascular
infants, however, is under investigation. status, but it provides important alarms in
This leads to frequent false-positive val- case the arterial catheter becomes discon-
ues in premature infants. Many areas have nected. An arterial catheter that is not con-
begun testing for cystic fibrosis by measur- nected to a pressure transducer and that is
ing immunoreactive trypsinogen (IRT). If an not displayed with appropriate alarms could
infant has a positive IRT, then further muta- potentially cause massive undetected hem-
tion analyses are done on the sample. orrhage.
ROUTINE TREATMENT VASCULAR ACCESS

All newborns should receive vitamin K and The first question about vascular access
ophthalmic treatment to prevent ophthal- is whether the infant will need ongoing
mia neonatorum resulting from gonococcal blood gas monitoring. Because of the less
infection. We recommend the use of erythro- than ideal nature of capillary blood gas
mycin, rather than silver nitrate treatment, and arterial puncture blood gas monitor-
because of the efficacy of erythromycin in ing, we recommend the placement of an
treating chlamydial conjunctivitis. umbilical or peripheral arterial catheter in
Vitamin K is given as a single intramuscu- any newborn requiring frequent blood gas
lar dose, 1.0 mg to infants who weigh more monitoring.
than 2.5 kg and 0.5 mg to infants who weigh The next question that needs to be
less than 2.5 kg. Whereas some studies have answered is whether the infant will need
evaluated routine use of oral vitamin K,32 vascular access for fluid support. In general,
this is not recommended for routine use infants with a birth weight less than 1.8 kg
at this time. Failure to provide vitamin K do not tolerate immediate institution of
places the newborn (especially if breast fed) entirely enteral nutrition and should be
at risk for the development of hemorrhage given intravenous fluids. Hypoglycemia,
in the first weeks of life because of vitamin which is relatively common in premature
K deficiency. and stressed infants, often requires ongo-
In most healthy infants, these routine ing intravenous glucose infusion until
treatments, like the routine monitoring feedings can be established. Infants of
diabetic mothers, who have either severe be considered an indication for mechani-
or recurrent hypoglycemia, need intrave- cal ventilation.
nous dextrose. Any infant with significant
respiratory distress, gastrointestinal anom- EVALUATION AND TREATMENT
aly or obstruction, or suspected serious OF SUSPECTED SEPSIS
congenital heart disease needs intravenous Because of the potentially lethal nature of
access. neonatal sepsis, and because it may be diffi-
cult to detect early in its course, one should
SUPPLEMENTAL OXYGEN, NASAL always err in the direction of overevaluat-
CPAP, AND VENTILATORY SUPPORT ing and overtreating potential sepsis. Pneu-
Decisions about the correct amount of monia in the neonate has a wide range of
supplemental oxygen to deliver are usually clinical and radiographic appearances, often
straightforward. Patients should receive an mimicking either hyaline membrane disease
Fio2 that is adequate to prevent hypoxia (respiratory distress syndrome) or aspiration
and hyperoxia. Usually, maintaining arte- syndrome. For this reason, all infants with
rial saturation by pulse oximetry (SpO2) any significant degree of respiratory distress,
between 88% and 95% is a safe range. A whether from surfactant deficiency, aspi-
lower range of SpO2 (85% to 89%) in VLBW ration syndrome, or an idiopathic cause,
infants reduces retinopathy, but increases should be considered potentially septic.
mortality.33 No single screening test for sepsis is both
Infants with respiratory distress (oxygen sufficiently sensitive and specific. Leuko-
need, retractions, tachypnea, grunting) in cytosis and a high immature-to-mature
the delivery room or soon thereafter, often white blood cell count may indicate sep-
benefit from a trial of nasal continuous sis, but these elements are often seen in
positive airway pressure (NCPAP). Even the normal newborns. Leukopenia is more
smallest and most immature infants may specific for sepsis than is leukocytosis, but
benefit from NCPAP rather than immediate it is also often seen in newborns without
intubation and ventilation.34,35 Decisions sepsis, especially after maternal pregnancy-
about institution of mechanical ventila- induced hypertension. Thrombocytopenia
tion are more complex. The assessment of is a late finding that may be seen in infants
approaching respiratory failure depends with overwhelming sepsis and disseminated
on the infant’s gestational age, postnatal intravascular coagulopathy, but it should
age, pulmonary disease, physical examina- not be seen as a screening tool for sepsis.
tion, and blood gas measurements. Gen- C-reactive protein may be increased (≥1
eral rules for instituting ventilation are as mg/dL) in cases of proven bacterial sepsis
follows: at the time of initial evaluation. However,
1. Inability to achieve adequate oxygen- there is a significant false-negative rate at
ation, despite a trial of NCPAP, requires the time of presentation. C-reactive protein
positive pressure. In most cases, the pre- may be more useful to determine whether
mature infant on NCPAP who requires an to discontinue antibiotic therapy at 48 to
Fio2 above 0.50 to 0.60 should be intu- 72 hours after the start of treatment. It has
bated and ventilated. Some premature been shown that bacterial infection is very
infants may benefit from a trial of nasal unlikely if two sequential (24 hours apart)
ventilation. Term infants who require an C-reactive protein levels are less than 1 mg/
Fio2 above 0.70 to 0.80 often need to be dL in the 8 to 48 hours after presentation.36
intubated and ventilated. The minimum evaluation for sepsis
2. Inability to spontaneously provide ade- includes a complete blood count with dif-
quate CO2 exchange requires ventila- ferential, platelet count, and blood culture.
tion. In most cases, infants with a Paco2 C-reactive protein may also be a useful test
between 50 and 65 mm Hg should be fol- to determine the length of treatment, but its
lowed up closely for potential need for utility in the decision whether to start anti-
ventilation. Most newborns with a Paco2 biotics remains unclear. The infant who is
that remains above 60 to 70 mm Hg dur- at more than minimal risk of sepsis should
ing the first hours of life need mechani- also have a lumbar puncture for cell count,
cal ventilation. glucose, protein, Gram stain, and culture.
3. Respiratory fatigue, usually manifested However, there is considerable controversy
by poor air exchange, a markedly abnor- regarding selective use of lumbar puncture
mal respiratory pattern or apnea, should in the evaluation of neonatal sepsis.37-40
Because early onset sepsis rarely manifests maternal milk, suggesting that breast feed-
with urinary tract infection, a urinalysis ing should be withheld in young infants
or urine culture is not part of the routine during an episode of acute primary mater-
evaluation of early onset sepsis. A number nal herpes infection or if there are her-
of factors are associated with an increased pes lesions on the breasts. Mothers with
risk of neonatal infection including preterm recurrent cervical or oral herpes are gener-
delivery, rupture of membranes after 18 or ally allowed to breast feed, provided good
more hours, maternal fever or chorioam- hygiene is used to prevent transmission, and
nionitis, and positive maternal cultures for the infant is not directly exposed to lesions.
Group B S treptococcus. If there are lesions on the mother’s breast,
Useful algorithms have also been proposed the mother should not feed the infant from
for the newborn at risk for group B strep- the affected breast until lesions are resolved.
tococcal infection.4 An infant with symp- Although hepatitis B virus is transmitted via
toms strongly suggestive of sepsis should human milk in mothers who are positive
be cultured and started on antibiotics, usu- for hepatitis B surface antigen, these moth-
ally ampicillin and gentamicin, even in the ers are usually allowed to breast feed. Their
absence of risk factors. If the infant’s blood infants should be protected if they are given
and cerebrospinal fluid cultures are negative hepatitis B vaccine and hepatitis B immu-
and if the patient is clinically well, antibiot- noglobulin at birth, and the infant then
ics can be stopped at 48 hours. For further completes the hepatitis B vaccine series
discussion of antibiotics and their dosage, thereafter. Mothers who are seropositive for
see Chapter 14 and Appendix A. cytomegalovirus (CMV) also secrete virus
into human milk, but this does not appear
BREAST FEEDING: EFFECT OF to pose any risk to the healthy term infant.
MATERNAL ILLNESS AND DRUGS Many infants born to seropositive mothers
Mothers should be encouraged and sup- begin to excrete CMV postnatally, whether
ported in their efforts to establish breast or not they are breast fed. For the premature
feeding. Human milk is the preferred infant, postnatal acquisition of CMV (via
source of nutrition for healthy newborn blood transfusion) has been associated with
infants.41,42 Breast feeding not only provides respiratory morbidity. Pasteurization, a pro-
nourishment to the infant, but it also process used at breast milk banks, has had good
motes the process of bonding. Human milk success with eliminating CMV transmis-
contains factors that support intestinal cell sion. However, the efficacy of freezing breast
proliferation and bowel mucosal mass. A milk to eliminate CMV is still under debate.
number of factors, including secretory IgA, Human T-lymphotropic virus (HTLV) type 1
lysozyme, lactoferrin, C3, C4, and maternal is likely transmitted from mother to infant
leukocytes, influence neonatal bacterial flora through breast feeding. The AAP’s Redbook
and the incidence of gastrointestinal infec- recommends that women in the United
tions. However, maternal illnesses or drugs States who are HTLV-1 seropositive should
can have adverse effects on lactation, which be advised not to breast feed.43
may preclude the use of maternal milk or Almost all maternal medications are
may require special precautions in its use. secreted to some extent into human
Viral agents can be transmitted into milk.5,42,45 Factors that affect the degree of
human milk and result in infection in the secretion are the pKa of the drug, its lipid
infant. HIV is secreted into human milk and solubility, molecular size, and protein bind-
transmission to the breast-fed infant has ing. Drugs that are small in molecular size
been reported.43 The American Academy of or that are lipid soluble pass more readily
Pediatrics (AAP) and the CDC recommend into the breast milk. Drugs with a more
that infants born to mothers with human alkaline pKa are in the nonionized form in
immunodeficiency virus (HIV) infection the plasma, permitting easier passage across
should be fed infant formula and not be membranes and into the milk. Drugs that
breast fed.44 However, in underdeveloped are poorly bound to plasma proteins are
countries where a safe water supply and suf- more readily secreted into human milk than
ficient resources for infant formula are lack- drugs that are tightly bound. The time of
ing, as per the World Health Organization collection or feeding of human milk affects
recommendation, mothers with HIV should the level of the drug in the milk. Less drug
continue to breast feed. Herpes simplex virus is delivered to the infant if breast feeding is
has also been reported to be transmitted via performed just before the mother’s dose of
drug. Although the concentration of a drug both high-risk perinatal care to the mother
in human milk provides an estimate of how and intensive care to the newborn, this is
much maternal drug to which an infant often not possible. Because of the unpredict-
is exposed, the bioavailability of the drug able nature of preterm labor and of the often
may be limited by intestinal absorption. For unexpected pathology of an infant following
example, although phenytoin is excreted a normal pregnancy, high-risk infants are
into human milk, its intestinal absorption is often born at centers that are not equipped
quite poor in the newborn. to provide total support and therapy for
In counseling a mother regarding breast them. In these situations, it is necessary to
feeding, it should be emphasized that vir- transfer the infant to a higher level center.
tually all drugs are excreted into human Nurseries are commonly classified as level
milk and that caution should be taken with I, level II, and level III.46 Level I nurseries
regard to any drug. The lactating woman are those that provide routine well newborn
should always make her physician aware care and should be able to stabilize high-risk
that she is breast feeding when medications infants before transfer to a higher level cen-
are prescribed for her. Although with most ter. Level II nurseries provide all of the ser-
maternal medications, breast feeding can vices of a level I nursery, plus some support
be maintained, the data regarding adverse for smaller and sicker infants. Typically,
effects of drugs in infants are incomplete. healthy growing preterm infants, infants
Most reports about breast feeding and mater- needing intravenous support, or infants
nal medications involve small numbers of needing hood oxygen but not prolonged
infants; hence, adverse effects that occur mechanical ventilation, can be cared for in
infrequently are not easily recognized. The level II nurseries. Level III nurseries provide
physician is often forced to make a judg- complete neonatal intensive care, including
ment regarding the use of a drug in a lactat- access to pediatric surgical support, multiple
ing woman based on incomplete data. The pediatric subspecialists, and all of the sup-
mother should be informed of these uncer- port services that are required to care for the
tainties when appropriate. Medications for smallest and sickest newborns.
use in a lactating woman should be chosen A subgroup of level III nurseries, some-
in such a way as to minimize any risk to the times referred to as level IIID nurseries, pro-
infant and yet provide a therapeutic effect for vide therapies that are new or so specialized
the mother. Very few maternal medications that they are not needed at all level III nurs-
are an absolute contraindication to breast eries. Previously, therapies such as extra-
feeding.45 Because lactose is the predomi- corporeal membrane oxygenation (ECMO),
nant carbohydrate in breast milk, infants high-frequency ventilation, and nitric oxide
with galactosemia should not breast feed. were available only at a level IIID or regional
Maternal cocaine use during breast feed- intensive care nursery. Although ECMO will
ing may cause hypertension, seizures, and likely continue to be limited to a small num-
other toxic effects in the infant. Maternal ber of centers, high-frequency ventilation
heroin use or other illicit intravenous drug is becoming increasingly available at most
use puts both the mother and infant at risk level III nurseries. Surgical repair of serious
for HIV infection. Although breast feed- congenital heart anomalies is also reserved
ing by mothers on methadone has been for level IIID nurseries. Inhaled nitric oxide
reported to facilitate the control of neona- (iNO), which was approved by the U.S. Food
tal abstinence syndrome, this may not be and Drug Administration in 1999, is now
a sufficient reason to continue to expose widely available in the United States. How-
the infant to such a long-acting opiate and ever, wide availability of iNO does not nec-
infectious risks (e.g., HIV infection). essarily correlate with expertise in its use.
Infants are transported from lower level
TRANSPORT to higher level nurseries if conditions that
One of the major developments in modern cannot be treated at the lower level nursery
neonatal care was the concept of regionaliza- develop or if the infant is at risk for develop-
tion of perinatal care. Central to this concept ment of such conditions. The exact indica-
is transport, both of high-risk mothers and of tions for transferring an infant often depend
high-risk infants, to centers that specialize in on multiple factors other than the degree of
the care of these high-risk patients. Although pathology in the infant. The skill and com-
the ideal situation is to transfer the prepar- fort of the physicians caring for the infant,
tum mother to a center that can provide the skill and comfort of the nursing staff, the
availability of adequate numbers of skilled The entire transport process should in
nurses, and the availability of ancillary ser- volve the referring physician and nursing
vices all must be considered when deciding staff, the neonatal staff at the accepting
whether to continue treating an infant at a institution, the staff of the transport team,
level I or II nursery. Only if all members of and the parents. Clearly, communication
the nursery team are comfortable with their before, during, and after the transport are of
ability to provide optimal care for the infant paramount importance.
should a high-risk infant remain at a lower
level center. Because the high-risk infant RECOMMENDATIONS FOR CARE
is often a rapidly changing patient, deci- Although the care of the newborn should be
sions about transferring or not transferring individualized to the needs of each infant, the
a given infant must be flexible. These deci- perinatal service of each hospital must estab-
sions should be made in conjunction with lish and maintain policies that ensure high
neonatologists at the regional level III cen- quality of care for all newborns within each
ter who remain in close telephone contact institution. However, current practices in
with the team treating the infant. perinatal and neonatal care are being driven
All level III nurseries and some level II by a variety of forces. Parents, as consumers,
nurseries have neonatal transport teams. are demanding a more comfortable, almost
Whereas the composition of these teams homelike, environment for labor and delivery
varies widely, they should all have similar of their infant. Payors are carefully scrutiniz-
skills for stabilizing and transporting a sick ing costs and will continue to pressure hospi-
newborn. The goal of a transport team is to tals to reduce both costs and patient length of
provide total support of the newborn from stay. Health care professionals must respond
the time the team arrives at the referring to these forces of change in a careful man-
hospital to the time the infant is delivered ner so that the medical needs of the mother
to the accepting hospital. The transport and infant are thoroughly met. The following
team should be an extension of the inten- general recommendations are made:
sive care nursery, minimizing the risks of 1. Every delivery of a newborn, whether
transport as much as possible. anticipated to be routine or high risk,
Transport teams should have the ability should be attended by a person skilled
to rapidly and accurately assess the infant in neonatal resuscitation. This person,
and to immediately institute appropriate whether a nurse, nurse anesthetist, neo-
therapy. This includes the ability to intu- natal nurse practitioner, or physician,
bate and ventilate, gain venous and arterial should be skilled in bag-and-mask ventila-
access, treat pneumothoraces, treat shock, tion, endotracheal intubation, and neona-
institute pharmacologic therapy for cya- tal cardiopulmonary resuscitation (CPR).
notic congenital heart disease, and support This person cannot be available just on call
the infant with congenital or surgical anom- or standby, but should be there to imme-
alies. In addition, the team must be able to diately attend to the infant after delivery.
lucidly explain the infant’s condition, prog- The principles of neonatal delivery room
nosis, and treatment plans to the parents. resuscitation as outlined by the American
Indications for instituting therapies before Academy of Pediatrics and the American
transport are only slightly different than Heart Association’s Neonatal Resusciation
the indications for instituting those thera- Program (NRP) should be followed. Health
pies in an intensive care nursery. In general, care professionals who are responsible
because of the difficulty of instituting thera- for delivery room resuscitation should
pies when an infant is in an ambulance, the be trained in these principles. However,
transport team should provide early, rather completion of NRP training alone is inad-
than late, intervention. For the infant who equate by itself. There is no substitute for
is at high risk for needing ventilation, con- practical experience to achieve expertise
sideration should be given whether to intu- in newborn resuscitation.
bate the infant prior to transport, rather 2. For higher-risk deliveries, a physician, a neo-
than risking the need to intubate and begin natal nurse practitioner, or a neonatologist
ventilation during the transport. Similarly, may need to be present in order to imme-
one should decide whether to place a chest diately evaluate and, if needed, to resusci-
tube to evacuate a pneumothorax, which is tate the newborn. Each perinatal-neonatal
not yet large or under tension, prior to leav- service should establish its own criteria for
ing the referral hospital. when a physician, or more specifically a
neonatologist, should be called to attend poor perfusion, poor capillary refill, cya-
a high-risk delivery. Physicians who attend nosis, or respiratory distress should have
high-risk deliveries and care for seriously measurement of blood pressure. Ges-
ill newborns must be skilled in neonatal tational age is assessed using standard
resuscitation and certain technical proce- techniques such as the Dubowitz or Bal-
dures, including endotracheal intubation, lard examination. Weight, length, and
umbilical catheterization, needle thoracen- occipital frontal head circumference are
tesis, and chest tube placement. measured and plotted on an appropri-
3. After delivery, a sick or premature infant ate growth chart. The physician should
should be placed on a warming table, be promptly notified of any significant
dried, evaluated, and resuscitated as findings or abnormalities. For stable
appropriate. Apgar scores are assigned at healthy newborns, the physician should
1 and 5 minutes of age. If the 5-minute examine the infant by 12 to 18 hours of
Apgar score is less than 7, then Apgar age. Infants with significant respiratory
scores should continue to be assigned distress, major anomalies, signs of sepsis,
every 5 minutes up to 20 minutes. There or prematurity should be examined and
should be the capability, if needed, to per- evaluated promptly by the physician.
form intubation, provide positive pressure The initial assessment of the apparently
ventilation via the endotracheal tube, healthy newborn infant need not occur
needle thoracentesis, and umbilical cath- in the “transitional nursery” or “well
eterization within the delivery room. If an newborn” nursery. When possible, the
infant is critically ill and further person- healthy infant should be evaluated in the
nel are needed, assistance should be called mother’s room, rather than separating
for promptly. The sick newborn is moved her from her infant. This is particularly
from the delivery room to the intensive appropriate as labor and delivery services
care nursery when the infant is initially move to combine the care of the mother
stabilized with a patent airway, adequate and well newborn infant, the so-called
ventilation, and stable heart rate. model of a “mother-infant” dyad. It is
4. The apparently stable healthy newborn essential, however, that the nursing staff
can be readily evaluated in several minutes caring for such mother-infant dyads con-
in the delivery room with careful attention tinue to have the training and resources
to respiratory effort, heart rate, color, per- they need to fully evaluate the newborn
fusion, and tone. The infant should then infant and to be able to expeditiously
be dried and a quick physical examination provide for the infant’s needs. The new-
should be performed to ensure that there born infant should be regularly observed
are no significant anomalies or cardiopul- with frequent measurement of the heart
monary compromise before being allowed rate, respirations, and temperature in
to return to the mother. The infant can be the first 6 hours of life to ensure that the
placed skin to skin on the mother’s chest. infant has made a stable transition to
This time shortly after birth is especially extrauterine life.
important to allow the parents to be close 6. For the sick newborn, a full assessment
to their infant. Such a time for private should be performed immediately. If an
bonding between the parents and the infant has respiratory distress, poor per-
infant should not preclude close observa- fusion or hypotension, signs of asphyxia,
tion of the infant. Administration of eye or other significant problems that require
prophylaxis and vitamin K to the healthy close monitoring or intervention, the
newborn can generally be delayed until 1 child should be moved to the intensive
to 2 hours of age. care nursery. Infants who require intuba-
5. Within the first 1 to 2 hours of life, the tion and ventilation for more than several
healthy newborn should have a full hours should be transferred to an intensive
assessment performed by the nursing care nursery that regularly ventilates new-
staff. This should include measurement borns. Every effort should be made before
of temperature, heart rate, respiratory transport to stabilize the infant to ensure
rate, and a full physical examination. a safe and expeditious transfer. A physi-
The nursing staff should pay particular cian, neonatal nurse practitioner, or other
attention to adequacy of the respiratory individual with the training and ability to
effort and observe for any signs of respi- manage an intubated and ventilated new-
ratory distress. Infants with persistent born should remain in attendance during
the stabilization, transport, and ongo- actation counseling needs to be available

L
ing care of ventilated infants. Complex for all breast-feeding mothers as needed.
neonatal intensive care should remain 8. Newborn infants and their mothers
regionalized at tertiary centers that main- should be allowed to stay in the hospital
tain a well-organized program of services for at least 48 hours after birth to ensure
to provide the specialized care needed by a stable transition of the infant and a
critically ill newborns. Health care profes- safe postpartum course for the mother.47
sionals should advocate for the best care A 48-hour stay also provides a more
of the newborn and not allow themselves ample opportunity to support the moth-
to be forced to provide a lower quality of er’s efforts at breast feeding, to ensure
care in response to economic and social adequate oral intake by the infant,
pressures. and to evaluate the infant for signifi-
7. Mothers should be encouraged and sup- cant jaundice before discharge. Outpa-
ported in their efforts to breast feed. Nurses tient follow-up plans for the infant and
and physicians should be knowledge- mother should be clearly defined before
able regarding issues of lactation support. discharge.
CASE 1 190. UAC and UVC have been placed. Chest radio-
At 41 weeks’ gestation, a mother is about to deliver graph shows the catheters and ETT in good position,
vaginally through thick meconium-stained amniotic and the lungs have fluffy dense infiltrates bilaterally.
fluid. There have been late fetal heart rate decelera-
tions. In the past 2 minutes, the heart rate decreased The patient is in a community level I
to 80 bpm. Vacuum extraction is being performed to nursery. What measures might be taken
facilitate delivery. immediately to help stabilize the patient
for transport?
What considerations should be taken in Give volume expander 10 mL/kg (normal saline or
preparing for the delivery of the infant? lactated Ringer’s solution) in repeated boluses as
What general principles should guide needed to correct hypovolemia and hypotension.
the delivery room resuscitation? Are After volume repletion, consider starting dopamine
there any special risk factors for vacuum at 5 µg/kg/min. Previously, for such patients, most
extraction? practitioners would have given NaHCO3 to cor-
Those meconium stained infants, who are delivered rect metabolic acidosis, especially if it persists after
through thin meconium, who have uncomplicated deliv- a volume expander has been given. However, the
eries and are vigorous at birth, do not require intubation use of NaHCO3 to correct metabolic acidosis is now
and tracheal suctioning. Intubation and suctioning for controversial.48 In patients with hypoxic respiratory
meconium should be performed in this case, however, failure and pulmonary hypertension, past treatments
because of two factors: thick meconium and a compli- have included intentional hyperventilation, hyperoxia,
cated delivery. As for the method of tracheal suctioning, and NaHCO3 infusions to cause intentional metabolic
the use of a meconium aspirator attached to the en- alkalosis in an attempt to reverse pulmonary hyper-
dotracheal tube (ETT) and wall suction is preferred. The tension. These therapies are no longer considered ef-
ETT is withdrawn as the suction is applied. The direct fective. Moderate ventilation is advised to maintain a
insertion of a suction catheter alone into the trachea is normal Pco2 and to avoid prolonged hyperoxia.
not recommended. The patient should be repeatedly
reintubated and suctioned as needed to remove thick To what type of intensive care nursery
or particulate meconium. However, in an infant with should such a patient be ideally
respiratory depression and a low heart rate, apnea, or transferred?
poor respiratory effort, it may be necessary to proceed This patient likely has pulmonary artery hypertension
with resuscitation after the first suctioning of the ETT for and myocardial dysfunction in addition to meco-
meconium. With respect to vacuum extraction, if not nium aspiration syndrome. The patient may need
applied properly, this procedure may increase the risk high-frequency ventilation, surfactant administration,
for intracranial and subgaleal hemorrhage. inhaled nitric oxide (iNO), and possibly ECMO. The
This particular infant is critically ill with meconium patient will need an echocardiogram and cranial ul-
aspiration syndrome, and is intubated and ventilated. trasound before the initiation of ECMO. The patient
The first blood gas has a pH of 7.15, Pco2 of 40 mm should go to a level III nursery, preferably an ECMO
Hg, Pao2 of 40 mm Hg in 100% O2, and mean airway center, that is capable of applying these treatments
pressure of 16. Blood pressure is 40/20; heart rate is and evaluations expeditiously. Critically ill infants who
are near or at ECMO criteria can be managed with prepared for emergent placement. O negative blood
high-frequency ventilation and iNO in an attempt to or crystalloid volume bolus can be given when access
avoid ECMO. However, application of such therapies is established. Apgar scores need to be recorded. If
in a non-ECMO center must allow sufficient time to the infant has an Apgar score of 0 at 10 minutes of life,
transfer the patient to an ECMO center in case the despite adequate resuscitation, cessation of further re-
patient’s clinical course deteriorates. suscitative efforts should be considered.
The infant is stabilized in the operating

room and has Apgar scores of 1 at 1
CASE 2 minute, 4 at 5 minutes, and 5 at 10 minutes.
A mother presents to labor and delivery emergently He is comatose, without spontaneous
with profuse vaginal bleeding of 2 hours’ duration. respirations, and is seizing. What steps
She is 38 weeks pregnant and has had a benign should be done next in treatment and
pregnancy before this. She is 41 years old and this evaluation of this infant?
is her third child. When placed on an external fetal The infant has a hypoxic injury as a result of the
monitor, a sinusoidal heart tracing is appreciated and abruption. This has resulted in decreased oxygen
she is taken to the operating room immediately for a delivery to all major organ systems. The rules of air-
cesarean section. way, breathing, and circulation still apply here. Es-
tablishing venous and arterial access is paramount.
What arrangements need to be made for A blood gas and glucose should also be checked
preparation for this delivery? Which staff quickly. There is increasing evidence that moder-
needs to be present for the resuscitation ately encephalopathic infants have an improved
of this infant? neurodevelopmental outcome if given cerebral or
With the history of vaginal bleeding and the abnor- whole body cooling. The cooling must begin within
mal heart tracing, an acute hemorrhage is high on the first 6 hours of life. Identifying a NICU that is
the differential diagnosis list. Staff well versed in neo- equipped to transport, evaluate, and treat these in-
natal resuscitation need to be present. At minimum, fants is vital.
three caregivers need to be ready because this infant
may need intubation, CPR, and blood or volume ad- What is the definition of hypoxic-ischemic
ministration. A neonatologist needs to be notified of encephalopathy (HIE)?
the delivery as soon as possible. Equipment must be Profound acidemia with a pH of less than 7, an Apgar
available, including a crash cart stocked with medi- score of less than 6 for 5 minutes, neurologic seque-
cations necessary for resuscitation. The blood bank lae (seizures, hypotonia, coma), and multiple organ
should be notified immediately and O negative blood dysfunction.
should be sent to the operating room emergently.
What is the pathophysiology of HIE?
The infant is delivered pale, blue, and An acute asphyxia event elicits a diving reflex. This
apneic. The obstetrician notes a complete results in preferred blood flow to the brain, heart,
placental abruption. A cord arterial blood and adrenal glands with vasoconstriction to other
gas revealed a pH 6.96, Pco2 of 45, Po2 organs. Initially, there is an increase in cerebral blood
38, and base excess (BE)-20. What are the flow and glucose influx to the brain. There is also an
next necessary steps in resuscitation of increase in glycogenolysis, glycolysis, lactate and
this infant? hydrogen ions. Soon after, there is a decrease in oxi-
The infant should be warmed, dried, and assessed. dative phosphorylation, a decrease in brain glucose,
Each person of the neonatal resuscitation team should and a decrease in adenosine triphosphate (ATP).
be assigned a job (i.e., one for the airway, one for the These changes seem to be more pronounced in the
heart rate, etc.) The neonatal resuscitation guidelines white matter.
should be followed with assessment of airway, breath-
ing, and circulation. This infant likely has severe birth What is the best way to manage the
depression secondary to a profound hemorrhage. If the infant’s seizures?
infant continues to be apneic, intubation is necessary. It’s imperative to correct metabolic abnormalities, es-
The heart rate needs to be evaluated and CPR begun pecially hypoglycemia. Phenobarbital continues to be
if the heart rate is 60 per minute or lower. The infant will the first-line drug to manage seizures. Fosphenytion
need venous access. The most efficient method is via and lorazepam should also be considered.
the umbilical vein, so umbilical catheters need to be
CASE 3 recovery room. It should be emphasized that the di-

You are called to attend a delivery of a 27-year-old agnosis is suspected, and not confirmed. Establish-
gravida 2, para 1 female with good prenatal care. She ing a trustful and honest relationship with the parents
is scheduled to have a repeat cesarean section. Her immediately is important.
first child was breech. She had an uncomplicated preg-
nancy aside from a low alpha-fetoprotein (aFP) at 16 The karyotype comes back 47, XX, trisomy
weeks’ gestation. She refused an amniocentesis. Her 21. The parents are in shock. What do you
20-week anatomy scan was reported as normal. The say to them?
infant is delivered with clear amniotic fluid. The infant Although the risk of having an infant with Down syn-
cries spontaneously and is assigned Apgars of 9 at 1 drome is increased in women older than 35 years, the
minute and 9 at 5 minutes. She is taken to the warmer majority of children born with trisomy 21 have mothers
and you note facial features consistent with trisomy 21. younger than 35 years. This is due to the higher repro-
ductive rate of this age group. It is important to em-
What is your next step? phasize to the mother that she did not do something in
The infant requires a complete physical examination her pregnancy to cause this. The parents must under-
in the operating room. Whenever a caregiver has a stand the spectrum of medical problems associated
high suspicion of an anomaly, the parents should be with the diagnosis (i.e., cardiac, neurologic, endocrine,
notified as soon as possible. In this situation, it is fair etc.). A social work referral should be made to inform
to wait until the mother is awake and stable in the the family of the support services available to them.
MATCHING
Match the maternal medications on the left that might cause the listed neonatal problems on the right.
Maternal Medication or Drug Neonatal Condition or Disorder

1. Beta-blockers a. CNS, ear, cardiac and thymus anomalies
2. Diethylstilbestrol (DES) b. Neural tube defect, midfacial hypoplasia
3. Carbamazepine c. Neonatal abstinence syndrome
4. Cyclophosphamide d. Prematurity, lower birth weight
5. Oral hypoglycemics e. Hypoglycemia
6. Isotretinoin f. Bradycardia, hypoglycemia
7. Tobacco/smoking g. Vaginal adenosis, genital tract anomalies
8. Cocaine h. Growth restriction, cardiovascular and digital anomalies
9. Phenytoin i. Hypoplastic nails, midfacial hypoplasia, hemorrhagic disease
10. Methadone j. Abruptio placentae, preterm labor
Answers: 1 (f); 2 (g); 3 (b); 4 (h); 5 (e); 6 (a); 7 (d); 8 (j); 9 (i); 10 (c)
Match the birth trauma on the left with the symptom on the right.
Birth Trauma Symptom

1. Erb-Duchenne palsy a. Asymmetrical cry
2. Spinal cord injury b. Tachypnea and decreased respirations on one side
3. Facial nerve palsy c. Swelling on one side of the head, not crossing suture lines
4. Clavicular fracture d. Paralyzed abdominal muscles with rounded, distended appearance
5. Pneumothorax e. Tachycardia, pallor, and bluish discoloration along the neck and
6. Cephalohematoma behind the ears
7. Subgaleal hemorrhage f. Abrasion on crown of the head with minimal bleeding
8. Fetal scalp electrode placement g. No Moro reflex on left side
h. Arm adducted and internally rotated, extension of elbow, pronation
of forearm
Answers: 1 (h); 2 (d); 3 (a); 4 (g); 5 (b); 6 (c); 7 (e); 8 (f)

Match the genetic abnormality with the common clinical finding.
Genetic Abnormality Common Clinical Finding

1. Cystic fibrosis a. Meconium ileus
2. DiGeorge syndrome b. Macroglossia
3. Williams syndrome c. E.coli infection
4. Down syndrome d. Aplastic thymus
5. Hemophilia A e. Micrognathia
6. Osteogenesis imperfecta f. Supravalvular aortic stenosis
7. Galactosemia g. Excessive bleeding after a circumcision
8. Fanconi pancytopenia syndrome h. Congenital lymphedema
9. Pierre Robin sequence i. Blue sclera
10. Turner syndrome j. Radial hypoplasia
Answers: 1 (a); 2 (d); 3 (f); 4 (b); 5 (g); 6 (i); 7 (c); 8 (j); 9 (e); 10 (h)
REFERENCES
The reference list for this chapter can be found online at www.expertconsult.com.
5
Size and Physical
Examination of the
Newborn Infant
Tom Lissauer and Phil Steer
There are tiny, puny infants with great vitality. Their movements are untiring and
their crying lusty, for their organs are quite capable of performing their allotted
functions. These infants will live, for although their weight is inferior … their
sojourn in the womb was longer.
As indicated in the above quotation, a new- potential. The limitations and complexity
born infant’s problems and prognosis are of these concepts are considered further in
determined by birth weight and gestational this chapter.
age. The designation low birth weight (LBW)
is applied to all infants weighing less than DETERMINANTS OF FETAL GROWTH
2500 g at birth, regardless of the duration of Normal fetal growth requires contributions
gestation. Subsequently, the terms very low from the mother, the placenta, and the fetus.
birth weight (VLBW) and extremely low birth Numerous maternal metabolic adjustments
weight (ELBW) have been used to categorize are made during pregnancy, the unifying
those infants with birth weights less than goal of which appears to be provision of
1500 g and 1000 g, respectively. The clas- an uninterrupted supply of nutrients to the
sification of infants as preterm is reserved for developing fetus. Foremost among these are
those having completed less than 37 weeks adjustments in carbohydrate metabolism.
of pregnancy, whereas term gestation refers Mild fasting hypoglycemia and postprandial
to those infants delivered between 37 and hyperglycemia associated with an increased
41 completed weeks of pregnancy, and basal insulin level and relative insulin resis-
postterm indicates birth after or equal to 42 tance characterize the normal pregnancy.
completed weeks of pregnancy. The pro- Maternal glucose use is attenuated, with
portion of LBW infants who are preterm ketones and free fatty acids increasingly serv-
versus those with abnormal intrauterine ing as fuels for maternal tissues. The mecha-
growth varies around the world. In devel- nisms for these alterations are not entirely
oped countries, the majority of LBW babies clear. However, the effect is the provision of
are premature, whereas in developing coun- a continuous supply of glucose, the primary
tries, the major contributor to the LBW rate source of fetal oxidative metabolism, to the
is growth-restricted term infants. As the fetus, particularly during periods of maternal
standard of living improves in developing fasting. During relatively extended periods
countries, there is a shift toward the pattern of fasting, the fetus uses ketones to serve his
of developed nations with regard to LBW or her energy and synthetic needs as well.
infants. Maternal serum levels of lipids increase dur-
Infants are classified as small for ges- ing gestation. In midpregnancy, fat is stored
tational age (SGA) if their birth weight is for fetal use during late pregnancy when
below the 10th percentile and large for ges- demands increase. These, and a variety of
tational age (LGA) if their birth weight is other adjustments, are so effective in sup-
above the 90th percentile (Fig. 5-1)1. Intra- plying the fetus with required nutrients that
uterine growth restriction (IUGR) describes only with severe maternal malnutrition (e.g.,
failure of a fetus to reach its genetic growth wartime famine), and only then if starvation
105
106 CHAPTER 5 Size and Physical Examination of the Newborn Infant
5000 clinical significance of serum levels of the

4750
various growth factors and binding proteins
4500
4250
in the fetus and newborn is an area of active
ge research.
al a
4000 90th %
3750
tation
3500 ge
s THE CONCEPT OF INTRAUTERINE
or GROWTH RESTRICTION
al age
3250
tion
f
e
3000 t a The growth trajectory of any individual
rg es
GRAMS
La 10th %
2750 rg fetus results from the combined effects of its
2500 fo
te e genetic programming and the growth sup-
al ag
ria
2250
a tion port it receives from its mother. Clearly, the
op
2000 t
es genetic growth potential of a fetus is deter-
pr
rg
Ap
1750
mined by the contribution of the mother
o
lf
1500
al
and the father and how they interact. This

Sm
1250
1000 does not happen on the basis of equality of
750
parental contribution. For example, approx-
500
imately 30 genes are known to be active
24252627282930 31323334353637383940414243444546 only if they are acquired from the mother,
Weeks of gestation
Preterm Term Postterm or from the father. This phenomenon is
known as “genomic imprinting.” Paternal
Figure 5-1. Birth weights of liveborn singleton white
imprinting tends to encourage fetal growth,
infants at gestational ages from 24 to 42 weeks. (From
Battaglia F, Lubchenco L: A practical classification
whereas maternal imprinting tends to
of newborn infants by weight and gestational age, restrict fetal growth. Although maternal and
J Pediatr 7:159, 1967.) paternal genes have an approximately equal
contribution to adult height and weight,
the height and weight of the mother con-
occurs during the third trimester, is birth- tribute more than 90% of the influence on
weight reduced. If starvation occurs in the birth weight compared with the father. This
first trimester, the placenta grows larger to was dramatically illustrated in the 1930s by
compensate for the reduced energy supply Walton and Hammond who crossed very
to the fetus, and if nutrition is restored in large Shire horses with very small Shet-
the second and third trimester, birth weight land ponies,2 and demonstrated that birth
is actually increased. The human placenta, weight was appropriate to the mother’s
in addition to its role of transmitting nutri- size, whereas adult size was intermediate
ents from mother to fetus, functions as an (although foals born to the small mothers
incredibly active endocrine organ, produc- never quite reached the same size as those
ing an array of hormones unsurpassed in born to large mothers, showing that severe
the animal kingdom. Among those products intrauterine growth restriction can result in
with direct growth-promoting action are reduced adult size). A similar phenomenon
growth factors and human placental lacto- has been demonstrated in humans, such
gen (HPL), also known as chorionic somato- that the birth weight of babies born from
mammotropin. HPL is produced by the ovum donation is appropriate to the size
syncytiotrophoblast cells of the placenta. Its of the birth mother rather than that of the
growth-promoting effects are mediated by genetic mother.3 Although a convenient
the stimulation of fetal insulin-like growth definition of intrauterine growth restriction
factor (IGF) production and increasing is failure of the fetus to reach its genetic
nutrient availability. The previously men- growth potential, in practice this simple
tioned elevation of maternal serum lipids definition is not comprehensive because
plays a role here as well. The expression of the genetic potential is not invariable, but
the HPL gene is regulated, in part, by apo- is modifiable according to nutrient supply.
protein A1, the major protein component of In addition, some babies’ genetic growth
high-density lipoprotein. The fetus plays a potential is abnormal in the first place, for
role in his own growth by producing a vari- example, a high proportion of babies with
ety of polypeptide IGF molecules and mod- Down syndrome exhibit many of the char-
ulating binding proteins. These substances acteristics of intrauterine growth restriction.
are produced by a spectrum of fetal tissues, So how should we decide whether a fetus is
with site, timing, and control of expression growth restricted? Ideally, we should base our
varying with each IGF. The biologic and classification on functional measures,4 the
CHAPTER 5 Size and Physical Examination of the Newborn Infant 107
most obvious of which is the risk of stillbirth using serial ultrasound measurements of
or neonatal death. Other typical indicators of fetal size. Scans from 22 weeks’ gestation
inadequate growth status include an inabil- onward can be used to establish the “nor-
ity to cope with the hypoxia of labor, result- mal” growth velocity for an individual fetus,
ing in fetal acidosis and neonatal depression, and a subsequent decline in this growth
the passage of meconium during labor, and trajectory clearly fulfills the requirements
neonatal dysfunction such as hypoglycemia for the definition of growth restriction.
and hypothermia. In the longer term, catch Prospective studies have shown that such
up growth may be incomplete, resulting in measurements are at least as good a predic-
reduced adult size. Alternatively, catch-up tor of intrapartum dysfunction as percen-
growth can be excessive, leading to adult tile birth weight (and the latter cannot be
obesity, hypertension, and insulin resistance known accurately before birth anyway).13
with an increased risk of diabetes. The con- Some babies initially growing on the 90th
cept of intrauterine growth restriction lead- percentile show slowing of growth typical
ing to long-term sequelae has led to the “fetal of growth restriction, and sustain perina-
origins of adult disease” hypothesis proposed tal problems despite having a birth weight
by Barker and his colleagues.5,6 within the “normal” range. This phenom-
Intrauterine growth restriction does not enon is sometimes called normal weight
relate directly to percentile birth weight. growth restriction.
Although babies that are small for gesta-
tional age are at increased risk of the dys- PATTERN OF FETAL GROWTH
function typical of intrauterine growth With the use of anthropometric measure-
restriction, many of them will be normal ments, including fetal weight, length, and
small babies. There is no clear threshold of head circumference, fetal growth standards
percentile birth weight below which the risk have been determined for different reference
of dysfunction increases; instead the risk populations from various locations.14-16
rises steadily as the percentile birth weight From these data, it is apparent that there are
falls.7 One approach that can improve the variations in “normal” weight at any given
correlation of percentile birth weight with gestational age from one locale to another.
function is that of using “customized birth This variation is related to a number of fac-
weight percentiles,” in which the percentile tors including sex, race, socioeconomic
birth weight of a particular baby is adjusted class, and even altitude. Of course, the key
to take into account the mother’s height, issue here is what is meant by “normal.” For
weight, racial origin, and other relevant example, babies born at high altitude are,
factors.8 However, these variations can be on average, smaller than those born at sea
pathologic as well as physiologic. For exam- level. Thus, when percentile birth weights
ple, severely underweight or overweight for babies born at altitude are constructed,
mothers are more likely to have babies that the 10th percentile (commonly used as the
are born preterm or become macrosomic boundary between “normal” and “abnor-
(with all its attendant problems), and it mal”) will be at a lower birth weight than
would be inappropriate to correct percen- that for babies born at sea level. For exam-
tiles to this extent.9 Mothers from some ple, babies that are on the 11th percentile
racial groups are more likely to have small for altitude might be on the 8th percentile
babies that are twice as likely to be still- for sea level and would be categorized as
born,10 and again, correction for this would “normal weight” for altitude but as “below
clearly be inappropriate. It has also been normal weight” for sea level. However,
argued that using percentile charts based we also know that babies born at altitude
on estimated fetal weights of fetuses grow- have a higher stillbirth rate. Should we also
ing normally instead of percentiles based regard it as “normal” for more babies to be
on actual birth weights may give a better stillborn? It is vital to remember that, ide-
indication of the incidence and role of fetal ally, the purpose of customized percentiles
growth restriction on neonatal disease.11 is to correct for variations in birth weight
However, this approach is limited by the due to physiologic variations in the mother
difficulty to obtain accurate measurements and her environment that are associated
to establish growth charts based on esti- with variations in birth weight but not asso-
mated fetal weights.12 ciated with a worse outcome.
Perhaps the most appropriate way of For example, the Colorado data, pre-
defining intrauterine growth restriction is sented by Lubchenco et al. in the 1960s,15
summarized standards of intrauterine age of the fetus. Knowledge of the gesta-

growth for white (55%), black (15%), and tional age is important for interpretation
Hispanic (30%) newborns born between of common tests (e.g., nuchal translucency
1948 and 1961 in the vicinity of Denver. screening for Down syndrome), scheduling
The graphic display of this relationship pro- invasive procedures (e.g., amniocentesis),
vides a useful and simple method for deter- planning the delivery of high-risk fetuses
mining the appropriateness of growth with (e.g., assessing the risk of respiratory distress
respect to gestational age and with respect to syndrome [RDS]), and assessing fetal size
the local population. What such standards for gestational age. Determination of the
cannot do, however, is indicate whether expected date of delivery (due date) can be
the population as a whole (e.g., Hispanics made with varying degrees of certainty by
compared with whites) is disadvantaged. history of menstrual cycles, physical exami-
This can only be determined by looking nation of the pregnant woman, and a vari-
at perinatal mortality and morbidity rates. ety of clinical obstetrical milestones. Regular
Ideally, to be most useful, equivalent mea- ultrasound examination of the developing
sures of weight for gestational age between fetus is the most accurate (unless of course
two different populations should be based the date of conception is precisely known,
on equivalent risk of poor outcome, rather as with in vitro fertilization and associated
than simply the population distribution of techniques).
birth weight. The average duration of pregnancy is 280
Ten years after the Colorado data were days from the first day of the last menstrual
published, Brenner et al. presented fetal period in white mothers. Because concep-
weight curves based on more than 30,000 tion occurs on average on day 14 of the
pregnancies, including terminations of preg- menstrual cycle, the true duration of preg-
nancy and miscarriages as well as sponta- nancy is 266 days. There is now good evi-
neous births,17 with correction factors for dence that gestational age varies in different
parity, race, and sex. Although these and racial groups, being 5 to 7 days shorter, for
other such curves differ in details, all dem- example, in South Asians and black Afri-
onstrate nearly linear growth between 20 cans.18 Between 22 and 34 weeks’ gestation,
and 38 weeks of gestation, with slowing there is a reasonable correlation between
thereafter. Using such nomograms, one can the age of the normally growing, single
plot fetal growth and detect a decline in fetus in weeks and the height of the uterine
growth velocity, indicating growth restric- fundus in centimeters when measured as
tion. Although the use of customized ref- the distance over the abdominal wall from
erence ranges for normal fetal growth can the upper border of the symphysis pubis to
highlight intrauterine growth restriction by the top of the fundus. This can be used for
making a decline in growth more obvious, it screening, but it is very unreliable in the
must be emphasized that failing growth indi- 30% or more of western populations who
cates increased risk to the fetus—irrespective are obese. For this reason, the efficiency
of the percentile birth weight that the baby of screening for growth restriction is par-
is currently on. So, for example, a fall in ticularly poor in obese women (obesity also
relative intrauterine size from the 80th per- makes ultrasound measurements more dif-
centile to the 40th percentile can be as sig- ficult and therefore less reliable). The size of
nificant as a fall from the 10th percentile to the uterus changes more slowly in late preg-
the 5th percentile. Thus, many workers con- nancy because as the fetus grows, the rela-
sider that the best descriptor of intrauterine tive proportion of amniotic fluid decreases.
growth restriction is “a fall in growth veloc- Although physical examination estimates of
ity,” rather than being on, or falling below, a gestational age have a standard deviation of
particular percentile. plus or minus 2 weeks in the first trimester,
this extends to 4 weeks in the second tri-
ANTENATAL ASSESSMENT OF mester, and 6 weeks in the third trimester.
INTRAUTERINE GROWTH
ASSESSMENT OF GESTATIONAL AGE
CLINICAL ASSESSMENT OF Forty percent of pregnant women have an
GESTATIONAL AGE uncertain last menstrual period (20% have
Optimal management of the pregnant no idea of the date), making accurate esti-
woman and her fetus is highly dependent mation of gestational age by history dif-
on an accurate knowledge of the gestational ficult at best. Since the 1970s, antenatal
determination of gestational age using serial the accuracy of the assessment, a compos-
ultrasound studies of the fetus has become ite fetal size based on the average of these
universal in developed countries. The type four measurements is used and incorporated
of ultrasound, the parameters measured, into the software of the ultrasound machine
and the accuracy of the study vary with the for instantaneous calculations. Estimates of
progression of pregnancy. In the first trimes- fetal weight and growth patterns are most
ter, although it is possible to visualize the accurately assessed by measuring the fetal
early gestational sac as early as 5 weeks, the abdominal circumference.
optimal time for scanning is between 7 and
9 weeks, with measurement of the crown- INTRAUTERINE GROWTH
rump length using a high-resolution vaginal Substandard growth rates, intrauterine growth
probe. Routine ultrasound screens for dat- restriction (IUGR), can result from a multitude
ing, however, are usually carried out during of pathologic and nonpathologic processes
the second trimester, typically between 11 (see later discussion). The original term
and 14 weeks’ gestation, which is when the “intrauterine growth retardation” is no lon-
nuchal translucency assessment of Down ger used, because the use of the word “retar-
syndrome risk is most accurate. It is also dation” often alarmed parents who took it to
usual to perform a further scan at 20 to 22 mean that their baby would be “retarded” or
weeks’ gestational age, for comprehensive mentally deficient.
fetal anomaly screening. Measurements at At times, the existence of two terms that
this stage of pregnancy are less reliable for describe less-than-desired growth (IUGR)
assessing gestational age, because to esti- and small for gestational age (SGA) can cause
mate gestational age from the size of the confusion. Perhaps the easiest way to think
fetus, one has to assume that the fetus is about these terms is that IUGR is a term
of average size. Some babies will be small used to describe a pattern of fetal growth
and some will be large for any particular over a period, whereas SGA is the term used
gestational age. When the baby is growing by pediatricians to describe a baby’s weight
rapidly in the first trimester, the change in compared with its contemporaries born at
size from 1 week to the next is substantial; the same gestational age. The significance of
therefore, the standard deviation of likely the label “small for gestational age” depends
gestational age is small. Typically, 2 stan- on the cut-off percentile used to define small.
dard deviations are only 3 to 4 days different It is common to use the 10th percentile in
from the mean. It can be assumed that the population studies, because this gives a sub-
fetus is likely to be of the average gestational stantial number of babies to study while
age for a particular size, plus or minus 3 to 4 including probably 70% of babies that are
days. Fetuses smaller than 2 standard devia- genuinely growth restricted. However, most
tions below the average size for gestational babies less than the 10th percentile will be
age are likely to be heading for demise. How- “small normal,” and will therefore function
ever, the normal range of size increases as normally. If a 3rd or 2nd percentile cut-off is
gestation advances, and accuracy of dating used (approximately 2 standard deviations
in the second trimester is generally no bet- below the mean), a much higher proportion
ter than plus or minus 7 days. Ultrasound of babies will actually show dysfunction
measures size and not gestational age. A very secondary to growth restriction. The term
small baby on ultrasound examination may small for gestational age, despite its lack of
be just that, rather than having an incorrect specificity in relation to growth restriction,
gestational age assignment and, similarly, is still widely used, and is useful because it
a very large baby may be macrosomic. The can be defined for all babies, whereas the
most commonly used parameters for deter- growth trajectories of most babies remains
mining estimated gestational age during the unknown.
second trimester are head circumference,
biparietal diameter, abdominal circum- EPIDEMIOLOGY AND ETIOLOGY
ference, and femur length. Each of these OF FETAL GROWTH RESTRICTION
measurements has its own advantages and As previously discussed, normal fetal growth
disadvantages, but all have in common a is dependent on the contributions of the
decreasing level of accuracy with increasing mother, the placenta, and the fetus. The
gestational age, particularly after 20 weeks, corollary to this is that aberrant fetal growth
because of increasing normal biological vari- may result from disturbances in any of these
ation with advancing gestation. To enhance same areas.
RACE PRIOR OBSTETRIC AND FAMILY HISTORY

Almost without exception, studies in the Women who are younger than 15 years of
United States have demonstrated a signifi- age, older than 45 years of age, have a his-
cantly higher rate of LBW and its subcompo- tory of miscarriages or unexplained still-
nents, IUGR, and preterm birth, in African births after 20 weeks’ gestation, or have
Americans when compared with their white prior preterm deliveries, are at increased risk
contemporaries. However, the differences for delivering a growth-restricted baby.26
between the patterns of birth weight and Familial factors also appear to play a role
mortality in the different races are not sim- in the birth weight of babies. Mothers of
ple. First, studies in Europe have shown that LBW infants were frequently LBW infants
black African mothers have an average ges- themselves and are more likely to have sub-
tational length that is about five days shorter sequent LBW babies than other mothers, as
than that of white mothers.18 This is com- are their siblings.27,28 However, the patho-
pensated for by accelerated maturity in black logical implications of being small depend
Africans.19 An important study was carried on the context. Being small in an otherwise
out in South Carolina over a 20-year period, large family cohort is likely to be pathologic,
which showed that between 1975 and whereas being small in a family that is usu-
1979,20 African-American babies younger ally small is likely to be less of a problem.
than 37 weeks consistently had a lower peri-
natal mortality for gestational age than did ALTITUDE
white babies. However, this relationship When comparing growth curves, most
reversed at term, a particular problem for authors note that Lubchenco’s data were
African American babies being obstructed generated in Denver, the “mile-high city,”
labor and meconium aspiration. Analysis of and that the 10th percentile thus generated
data between 1990 and 1994 showed that is lower than the 10th percentile of data col-
although gestation-specific perinatal mor- lected from centers closer to sea level. Yip
tality had reduced in both groups, the same was able to demonstrate a “dose-dependent”
pattern of lower mortality before 37 weeks, effect of altitude on the LBW rate,29 with a
and higher mortality after 37 weeks in the two- to threefold greater rate of LBW seen
black babies, persisted. A more recent study at altitudes greater than 2000 meters than
on 22 million births in the United States of at sea level.
mortality from 1989 to 1991, and then from
1999 to 2001, gave a similar result.21 In con- MATERNAL FACTORS CONTRIBUTING
trast to the findings with African Americans TO INTRAUTERINE GROWTH
in the United States, European studies have RESTRICTION
shown that babies of South Asian origin In developed countries, a handful of mater-
have a raised perinatal mortality at all gesta- nal characteristics and behaviors have con-
tions compared with white babies.10 This is sistently been associated with an increased
likely to be due to the fact that South Asian risk of growth restriction. In addition to race
babies have a lower birth weight across the and prior obstetric history, the list includes
gestational age range. Babies born in India maternal nutritional status (prepregnancy
are on average approximately 600 g lighter weight and weight gain during pregnancy),
than those born in Europe. However, stud- short stature, smoking, preeclampsia/hyper-
ies of babies of South Asian racial origin tension, multiple gestation, and female sex
born in developed countries shows that of the infant. In developing nations, malaria
the deficit reduces to 300 g, but it persists. is a significant factor.
This highlights one of the potential pitfalls
in correcting for racial origin in relation to Maternal Nutritional Status
birth weight by using “customized birth- Prepregnancy weight and weight gain during
weight percentile.” The reason there should pregnancy, although indicators of maternal
be a systematically lower birth weight in nutritional status, are independent vari-
South Asian babies remains conjectural, ables. There is some evidence of the poten-
but it seems likely that it is an adaptation tial benefits of nutritional intervention in
to the average smaller maternal size, thus the mother who is poorly nourished before
minimizing deaths from obstructed labor.22 pregnancy but this remains controversial.30
However, the long-term sequelae in this Nutritional supplements provided to well-
population include a very high incidence of nourished women do not provide addi-
diabetes and cardiovascular disease.23-25 tional benefit. An obese mother is unlikely
to deliver a growth-restricted baby, even if Effect of Chronic Hypertension

her pregnancy weight gain is low. Table 5-1. on the Risk of Small for
Gestational Age by Maternal Age
Smoking
Cigarette smoking, a habit practiced by 20% SGA Births (%)
of pregnant Americans, has consistently Chronic
been identified as a dose-dependent contrib- Maternal Age Normotensive Hypertension
utor to abruptio placentae, late fetal death,
LBW, and IUGR. In developed nations, it is <26 years 10 6
by far the single most important contribu- 26-30 years 7 14
tor to LBW. Rates of IUGR in smokers are 3 >30 years 5 18
to 4.5 times that of nonsmokers, with aver- SGA, Small for gestational age.
age birth weights decreasing by 70 to 400 g.
These adverse effects are particularly pro-
nounced in babies born to older mothers. outcome in hypertensive pregnancies is seen
Elimination of smoking would diminish in those complicated by the superimposition
SGA rates by 20% to 30%. Multiple mech- of preeclampsia. Preeclampsia is not only a
anisms may contribute to the detrimental contributor to fetal growth restriction, but it
effect of smoking during pregnancy. Nico- also carries the most unfavorable prognosis
tine and subsequent catecholamine release in terms of severity of growth deficit. Both
along with reduced synthesis of prostacy- of these vascular-based problems are likely
cline result in placental vasoconstriction to produce their effects through a common
and elevated vascular resistance, decreasing placental disorder.
delivery of nutrients and oxygen across the
placenta. Levels of fetal carboxyhemoglo- MULTIPLE GESTATIONS
bin are increased, further interfering with The presence of more than one fetus in the
delivery of oxygen to the developing fetal uterus often results in SGA offspring. The
tissues. Indirect effects by way of subopti- onset of the growth restriction is determined
mal nutritional status both before and dur- by the number of fetuses: the more fetuses,
ing pregnancy have been suggested and are the earlier growth restriction is likely to be
likely due to an increased rate of maternal observed.
metabolism rather than decreased mater-
nal caloric intake. Smoking mothers con- OTHER
sume more calories than their nonsmoking Finally, a variety of other maternally related
counterparts, and supplementing the diet factors have been proposed to play a role in
of smoking mothers is ineffective in offset- the development of an SGA infant. Chronic
ting the detrimental effects on the fetus. If medical conditions that interfere with
smoking mothers can be convinced to stop maternal nutrition (inflammatory bowel
smoking before the third trimester, their disease, short gut syndrome), fetal oxy-
infant’s birth weight will be indistinguish- genation caused by decreased amounts of
able from those babies whose mothers did saturated hemoglobin (sickle cell disease,
not smoke at all. cyanotic heart disease), or oxygen and
A variety of other recreational drugs, nutrient delivery caused by vasculopathies
including alcohol, marijuana, cocaine, and (advanced diabetes mellitus, chronic renal
amphetamines, have likewise been associ- failure) can result in IUGR. The role of psy-
ated with adverse fetal effects. With the chosocial stressors in IUGR is unclear.31,32
exception of the fetal alcohol syndrome, the A summary of the relative contributions of
effect of these agents is not as well estab- the various factors with direct causal impact
lished or as pervasive as is tobacco. Certain is provided in Figure 5-2.
prescription drugs, particularly the anticon-
vulsants, can result in fetal growth restric- PLACENTAL CONTRIBUTIONS
tion and specific malformation syndromes. Placental tissue is fetal tissue. It follows that
if circumstances exist that ultimately result
Preeclampsia/Hypertension in abnormal fetal growth, then the placenta
Maternal chronic hypertension is an inde- will likewise be similarly affected. This has
pendent risk factor for SGA infants. Infants certainly been observed, with a significant
born to older mothers are at increased risk of correlation between birth weight and both
being SGA (Table 5-1). The worst perinatal placental weight and villus surface area.
Fetal factors
• Infection
• Heart disease
• Malformations
• Chromosomal abnormalities
• Osteogenesis imperfecta
Maternal factors Placental factors

• Cardiorespiratory disease • Abruptio placentae, placenta previa
• Renal disease, acidosis • Thrombosis, infarction (fibrin deposition)
FETAL GROWTH
• Anemia, fever • Deciduitis
DEFICIENCY
• Drugs (diethylstilbestrol, • Placentitis, vasculitis, edema
anticancer agents, narcotics) • Chorioamnionitis
• Smoking, alcohol • Placental cysts, chorioangioma
Uterine factors
• Decreased uteroplacental
blood flow
• Atheromatosis, arteriosclerosis
of decidual spiral arteries
• Connective tissue disorders
• Chronic hypertension
• Preeclampsia
• Diabetes mellitus
• Fibromyoma
• Morphologic abnormalities
Figure 5-2. Causes of growth restriction by compartment. (From James D, Steer P, Weiner C, Gonik B, editors: High risk
pregnancy, ed 4, Philadelphia, 2010, Saunders.)
Likewise, there are placental pathologic cor-

relates of known causes of IUGR (intrauterine Findings in the Placenta in Fetal
Box 5-1.
Growth Restriction
infections, chromosomal anomalies, hyper-
tensive disorders, twins) and gross placental Uteroplacental blood flow
and cord abnormalities (chronic abruptio Diminished blood flow
placentae, choriohemangioma, extensive Increased vascular resistance
infarction, and abnormal cord insertions), Absent spiral artery remodeling
which are likely to result in restricted fetal Atherosis of vessels of parietal decidua
growth. On the other hand, the majority of Fetoplacental blood flow
cases of IUGR are idiopathic, with the epide- Increased irregularity of luminal size
miologic risk factors discussed earlier (e.g., Abnormal umbilical Doppler flow studies
previous fetal losses, extremes of maternal Decreased number of placental arterial vessels
age, previous preterm or SGA infant, sub- Decreased size of placental vessels
stance abuse) as the only clue. The cause of Decreased artery to villus ratio
growth failure in these infants is presumed
Interface of maternal and fetal circulations
to be the result of the ill-defined uteroplacen-
Cytotrophoblastic hyperplasia
tal insufficiency. Human and animal in vivo
Thickened basement membrane
studies, Doppler ultrasound investigations,
Chronic villitis
and pathologic evaluations have identified
an array of placental abnormalities that may
well shed a unifying light on these appar-
ently disparate groups of mother-infant which is subsequently modulated by envi-
dyads26,33 (Box 5-1). As a result of these ronmental factors. IUGR can also result
investigations, the central role of the pla- from a variety of conditions (e.g., congenital
centa in the development of the growth- infections) in which an otherwise normal
restricted baby is coming to the forefront. fetus is prohibited from growing normally
or if there is a genetic aberration that pre-
DIMINISHED POTENTIAL: FETAL cludes the fetus from growing normally.
CONTRIBUTIONS
As described earlier, the genetic potential for CONGENITAL INFECTIONS
growth is inherited from both parents and is During the rubella pandemic of 1962 to
the major determinant of early fetal growth, 1964, IUGR was found to be the most
consistent characteristic of congenitally intrauterine growth restriction in low-risk

infected infants. In this episode, 60% of the populations using a single assessment at 32
affected infants were less than the 10th per- to 34 weeks’ gestation; however, these have
centile for weight at birth and 90% were less proved to be inefficient because a single
than the 50th percentile.34 Cytomegalovirus measurement cannot indicate growth trajec-
(CMV) is the infective organism most com- tory as opposed to size. Indeed, a Cochrane
monly associated with IUGR, although 90% review showed that the harm from false-
of infants congenitally infected with CMV positive ultrasound diagnoses exceeds the
are asymptomatic. Hepatosplenomegaly and benefit when screening is done in this way.38
microcephaly with paraventricular calcifica- Regular growth velocity profiling for every
tions are common findings in the symptom- baby would be prohibitively expensive.
atic infant. Diagnosis is made most reliably Currently, usual policy is to measure the
with viral cultures of the urine obtained after fetuses thought to be at risk of growth restric-
birth. Human immunodeficiency virus has tion from maternal (e.g., hypertension)
not been consistently associated with IUGR and epidemiologic factors (e.g., a previous
because other confounding variables have growth-restricted baby) every 2 weeks. Mea-
been difficult to separate. Although numer- surements at more frequent intervals are not
ous other bacterial, protozoal, and viral reliable indicators of poor growth because
pathogens are known to invade the devel- the change in fetal size is within the error of
oping fetus, most of these infants develop the measurement. If growth slows, then the
appropriately. next step is to measure umbilical artery blood
flow velocity waveforms.39 A raised pulsatil-
GENETIC FACTORS ity index (ratio of systolic velocity to diastolic
About 8% of all SGA infants have a major velocity), or even worse, absent or reversed
congenital anomaly.35 Conversely, the inci- end-diastolic flow, indicates increased resis-
dence of growth restriction in infants with tance to perfusion of the placenta, putting
significant congenital anomalies is 22%, the baby at risk of hypoxia. This investiga-
nearly three times that of the general popu- tion is well established as valuable and is part
lation, and a correlation exists between the of routine surveillance in most tertiary cen-
number of malformations and frequency ters; it can be carried out reliably by trained
of IUGR.36 A wide array of chromosomal ultrasonographers. More expert fetal medi-
aberrations (aneuploidy, deletions, translo- cine specialists can move on to assessing fetal
cations) are associated with IUGR. The like- vascular redistribution as a response to early
lihood of finding a chromosomal disorder hypoxia. This redistribution can be detected
in an SGA infant with a congenital anomaly by Doppler studies of key fetal organs,
is approximately 6%.37 Chromosomal dis- including the brain (by study of the middle
order, uniparental disomy, wherein a pair cerebral artery), to detect the maintenance of
of homologous chromosomes are inher- the oxygen supply to them, thereby protect-
ited from the same parent, has been associ- ing their vital functions. At the same time,
ated with IUGR. Single-gene disorders and flow to less vital organs is reduced. Impaired
inborn errors of metabolism (maternal and cardiac function in the fetus can be demon-
fetal phenylketonuria) are likewise repre- strated using venous Doppler examination of
sented in this population. In addition there the precordial veins (ductus venosus, inferior
are well over 100 nonchromosomal syn- vena cava, or superior vena cava), hepatic
dromes associated with IUGR. veins, and head and neck veins. Combining
the umbilical artery, middle cerebral artery,
IDENTIFICATION AND MANAGEMENT and venous Doppler examinations provides
OF GROWTH RESTRICTION information about the degree of placental
A major problem is knowing which babies disease, the level of redistribution, and the
are at risk of growth restriction and should, degree of cardiac compromise respectively.
therefore, have their growth monitored. Changes in the venous Doppler usually pre-
Using classic risk factors, and even includ- cede abnormalities of the fetal heart rate
ing regular fundal height measurements of pattern.40 However, at present, the use of
the uterus, at best two thirds of babies with venous Doppler remains largely a research
growth restriction can be detected antena- tool, and data from prospective trials of its
tally, and in routine clinical practice the pro- utility in preventing unexpected intrauter-
portion is often much lower, typically about ine demise are required before it is widely
30%. Attempts have been made to detect adopted.
There is no currently known effective has been thoughtfully challenged by Chard

treatment to improve the growth pattern et al., who point out that not only is there
of a fetus. If it is likely, because of failing no statistical evidence of a subpopulation
growth, that delivery will be necessary at of growth-restricted babies at term,43 but
<34 weeks’ gestation, antenatal steroids also, by using the 10th percentile, many
should be given to improve pulmonary cases of IUGR (defined as a failure to achieve
maturity before elective delivery. Prenatal growth potential) will be missed. Although
management is aimed at determining the these may be seen as interesting, if some-
best time and mode of delivery. Gestational what arcane academic issues, the practical
age is a critical factor in this decision. Decid- importance becomes apparent when one is
ing on the appropriate time of delivery is responsible for making decisions regarding
particularly difficult before 30 weeks’ gesta- expensive and painful laboratory evalua-
tion, when the risks to the neonate are sub- tions; when there is the need to monitor the
stantial. Early delivery of growth-restricted infant in a more costly special care nursery;
fetuses with an abnormal umbilical artery and when there are future referrals for formal
waveform results in a high liveborn rate but developmental evaluations.
at the cost of a high neonatal mortality and Excluding SGA infants who have signifi-
morbidity. Alternatively, delaying delivery cant congenital anomalies and infections,
until the fetal heart rate pattern is abnormal there is a group of SGA infants with a rela-
has been reported to result in a nearly five- tively characteristic physical appearance.
fold increase in stillbirths; neonatal deaths Their heads are often disproportionately large
before discharge fall by more than one third; for their trunks, and their extremities typi-
overall, the total mortality is unchanged; cally appear wasted. The nails are long. The
and there is some evidence that long-term facial appearance has been likened to that of
outcome may be improved.41 Therefore, if a a “wizened old man.” The anterior fontanelle
fetus with growth restriction has an abnor- is often larger than expected, and the cra-
mal umbilical artery waveform, twice daily nial sutures may be widened or overlapping.
monitoring of the fetal heart rate pattern The umbilical cord is typically thin with lit-
is recommended, and delivery should be tle Wharton’s jelly and may be meconium
undertaken as soon as the heart rate pattern stained; the abdomen is scaphoid, which
becomes abnormal. may mislead the examiner into considering a
congenital diaphragmatic hernia. Subcutane-
SMALL FOR GESTATIONAL AGE ous fat and tissue are diminished, resulting in
INFANTS loose skin on the arms, legs, back, abdomen,
Lubchenco et al. defined SGA as being birth and buttocks. Like the umbilical cord, the
weight less than the 10th percentile. By skin may be stained from meconium passed
definition then, 10% of all newborns in a in utero and be unusually dry and flaky with
given population are too small. Others have little protective vernix caseosa present.
proposed or have indeed used other cut-off It is often suggested that measuring
values (e.g., the 25th, 15th, 5th, or 3rd per- the weight, length, and head circumfer-
centile) or 2 standard deviations from the ence allows further classification of the
mean, which would correspond to approxi- SGA infant as either symmetrically growth
mately 2.5% of the population. No matter restricted (those infants with decreased
what cutoff is used, there may be multiple length and head circumference) or asym-
factors that result in a large discrepancy in metrically growth restricted (relatively nor-
absolute weights seen at the lowest “normal” mal length with relative “head sparing”).
percentile. Goldenberg reviewed several Such a distinction has been proposed as both
reports wherein the 10th percentile was used a diagnostic tool and prognostic marker.
as the definition of IUGR.42 More than a The symmetrically growth-restricted new-
500-g difference was noted across these stud- born, historically representing 20% of all
ies. This observation, however, may have SGA infants, is thought to result from an
been a reflection of the disparate methodo- injury or process (congenital infection,
logic approaches among the studies. Golden- genetic disorders) that occurred or began
berg’s plea for a concerted effort by a variety in the early stages of the pregnancy, during
of national professional academies and fed- the phase of growth primarily character-
eral agencies to endorse a national standard ized by cellular hyperplasia. The prognosis
has, so far, gone unheeded. The approach of for eventual growth and development of
using any percentile as an absolute criteria these infants is somewhat guarded, in large
part because of the underlying etiology. CLINICAL PROBLEMS

The asymmetrical (“wasted”) SGA baby,
on the other hand, has been proposed to PERINATAL AND NEONATAL MORBIDITY
result from a third trimester insult interfer- AND MORTALITY
ing with delivery of oxygen and nutrients The growth-restricted fetus and newborn have
(the effect of maternal hypertensive disor- a higher perinatal mortality at each gestation
ders, maternal starvation, advanced diabe- compared with those of appropriate weight
tes) during the cellular hypertrophy phase for gestation infants, whether preterm, term,
of fetal growth. This latter group has been or postterm (Fig. 5-3). They also have a vari-
projected to expect a much brighter future ety of other adverse outcomes, reflecting the
than their symmetrical brethren. Various underlying plethora of diagnoses and chronic
indices such as the Ponderal Index (PI = and acute deprivations of oxygen and nutri-
Birth weight × 100/Length44) have been ents. Overall, the perinatal mortality among
used to further describe or quantify the growth-restricted infants is eight to ten times
relationship between length and weight greater than for infants who have grown nor-
and identify these subgroups. mally. The risk of perinatal morbidity and
Whereas such an outline may appeal to mortality increases markedly with the degree
one’s sense of logic, recent data have necessi- of growth restriction49 (Fig. 5-4).
tated a reevaluation of this approach. Chard
et al. demonstrated that there is a continu- ACUTE NEONATAL PROBLEMS
ous relationship between the PI and weight
throughout the entire range of normal birth Asphyxia
weight.45 Infants in the lower half of the Perinatal asphyxia is the most significant
population have a lower PI than those in the risk for the growth-restricted fetus and new-
upper half. In other words, smaller infants born, who is often marginally oxygenated
tend to be thinner, and larger infants tend and who has limited carbohydrate reserves.
to be fatter. Kramer et al.46 when excluding With the stresses associated with labor and
infants with evidence of major malforma- delivery, fetal death or hypoxic-ischemic
tions and congenital infections, likewise encephalopathy may ensue.
found a direct relationship between sever-
ity of growth restriction and a decreasing Respiratory Difficulties
PI, arguing against distinct subgroups of In association with the relative intolerance
proportional and disproportional infants. of the stresses of labor and delivery, passage
Similarly, a normal frequency distribution of meconium and subsequent in utero or
of head-to-abdominal circumference ratio postpartum aspiration of this material poses
is seen in antenatal ultrasound assessments
of growth-restricted fetuses, with increased
severity of growth restriction being associ- 5000
ated with increased asymmetry.47 Even the 4500
relative frequency of the two groups has 4000 90%
come under question; in some populations, 3500
symmetrical SGA infants are found more 0.2%
Grams
3000
frequently than asymmetrical infants.48 The 10%
concept of asymmetry serving as a diagnos- 2500
2%
tic tool has been further challenged by Sala- 2000 1%
fia,33 who found that IUGR preterm infants 1500 20% 6%
born to mothers suffering from preeclamp- 1000 90% 39%
sia were far more likely to be symmetrical 63%
500
than asymmetrical, and David,47 who found
24 26 28 30 32 34 36 38 40 42 44 46
an equal distribution of a small number of
Preterm | Term | Postterm
chromosomal abnormalities between the
Weeks of gestation
symmetrical and asymmetrical populations.
Figure 5-3. Mortality risk according to birth weight/
In summary, although it may be premature
gestational age relationship. Based on 14,413 live births
to completely discard the framework of at University of Colorado Health Sciences Center (1974 to
symmetry and asymmetry in intrauterine 1980). IUGR, Intrauterine growth restriction. (From Koops B,
growth restriction, one should feel uncom- Morgan LJ, Battaglia FC: Neonatal mortality risk in relation
fortable with a dogmatic approach to its use to birth weight and gestational age: update, J Pediatr
in the SGA infant. 101:969, 1982.)
Relative Risk adipose tissue is not consistently depleted

0 1 2 4 6 8 10
in these infants, but, in some, this may
Stillbirth P<.0001
diminish the infant’s ability to respond to
27.5
Abnormal EFH P<.0001 hypothermia. The range of thermoneutral
environmental temperatures for SGA infants
Hypoglycemia P<.0001
is narrowed when contrasted with appropri-
17.4
Hypocalcemia P<.001 ate for gestational age (AGA) infants of the
same gestational age.
Polycythemia P<.0001
Depression P<.0001 Hematologic Issues

Spun, central venous hematocrit values
Meconium P<.05
greater than 65% occur in as many as 40%
1-min/Apgar ≤6 P<.0001 of term or near-term SGA babies. Poor pla-
5-min/Apgar ≤6 P<.0001
cental function with resultant relative fetal
hypoxia and subsequently elevated levels of
1-min/Apgar ≤3 P<.0001 erythropoietin is thought to be the cause.
In-hospital death P<.001
Elevated levels of fetal hemoglobin and
nucleated red blood cells have both been
observed in SGA newborns. Polycythemia
IUGR
has been associated with a myriad of car-
None Mild Moderate Severe diopulmonary, metabolic, and neurologic
Figure 5-4. Morbidity and mortality varies with degree of effects. The need to reduce the level of red
growth restriction. EFH, Electronic fetal heart pattern. (From cell mass, the benefits derived, and at what
Kramer MS, Olivier M, McLean FH, et al: Impact of level of hematocrit to intervene have been
intrauterine growth retardation and body proportionality a matter of debate. The following elements
on fetal and neonatal outcome, Pediatrics 86:707, 1990.) are certain: (1) the value should be checked
before any corrective action is taken (some
nurseries routinely perform a heel stick to
a risk to the term or near-term growth- determine the hematocrit; if this is high, a
restricted infant. Because of concerns free-flowing venous sample must be obtained
regarding risk of in utero fetal demise, SGA and a spun hematocrit must be determined);
infants are more likely to be electively deliv- (2) if a partial exchange transfusion is to be
ered prematurely, with the attendant risks carried out, saline is the diluent of choice;
of prematurity, including RDS. it is as effective and less hazardous and less
expensive than any blood-derived products;
Hypoglycemia and Hypocalcemia (3) immunologic function of the growth-
The SGA infant is at risk of hypoglycemia restricted infant may be compromised; (4)
during the first 48 to 72 hours of life. Hypo- serum IgG concentrations are depressed
glycemia can result from inadequate glyco- in term SGA infants when compared with
gen stores, diminished gluconeogenesis, a their AGA peers; (5) deficiencies in lympho-
reduction in alternative energy substrates cyte function have been observed; (6) neu-
(e.g., free fatty acids, hyperinsulinemia and/ tropenia and thrombocytopenia are seen in
or increased sensitivity to insulin and, in some SGA infants. Infants with congenital
some, asphyxia, polycythemia/hyperviscos- infections and those infants delivered to
ity, or hypothermia). Severe hypoglycemia mothers with systemic hypertension/pre-
can result in adverse long-term neurologic eclampsia are particularly at risk for these
morbidity and, therefore, must be consis- latter problems.
tently sought and appropriately managed.
Hypocalcemia is seen less frequently, but THE PRETERM GROWTH-RESTRICTED
must be considered as a possible complica- INFANT
tion in these babies (see Chapter 12). Animal data, as well as clinical research
and experience, have led many to conclude
Thermoregulation that the growth-restricted preterm infant
SGA babies often have difficulty with main- has a more favorable respiratory progno-
taining body temperature in the normal sis than the equally premature AGA infant
range. This may stem from a diminished because of in utero stress-induced accelera-
supply of glucose, diminished insulating fat, tion of lung maturation. Several investiga-
and impaired lipid metabolism. The brown tions make a cogent argument against this
Incidence of Respiratory fetal growth restriction in infants >32 weeks’

Distress in Small for Gestational gestation appears to be associated with an
Table 5-2. Age and Appropriate for increased incidence of cerebral palsy, cog-
Gestational Age Infants nitive deficits, and behavior problems.52,53
According to Gestational Age Poor prenatal head growth is associated
with worse cognitive outcome, but impaired
Infants with RDS (%) cognitive development is also seen in those
Gestation (wk) SGA AGA with appropriate head growth. However,
a comparison of health-related quality of
27-28 50 37 life indices in 50-year-old adults who were
29-30 43 23 born at term did not find an adverse effect
31-32 39 13
of being born SGA.54 In infants <32 weeks’
33-34 16 2.5
35-36 6 0
gestation, the problems associated with
37-38 1.5 0.1 prematurity overwhelm those of growth
restriction.55
AGA, Appropriate for gestational age; RDS, respiratory
distress syndrome; SGA, small for gestational age; wk, LARGE FOR GESTATIONAL AGE
weeks.
Like SGA infants, babies whose birth weight
exceeds the 90th percentile for gestational
age (LGA) represent a heterogeneous group.
hypothesis. Age-matched preterm growth- Maternal risk factors associated with fetal
restricted neonates, in fact, appear to be at macrosomia include multiparity, weight of
a significant disadvantage when compared 70 kg or more at the end of pregnancy, a
with other premature infants (Table 5-2). prolonged or postterm pregnancy, abnormal
Another study and analysis of a very large glucose tolerance, and previous history of a
number of VLBW infants without major macrosomic infant. In one study, the over-
birth defects and between 25 to 30 weeks’ all prevalence of macrosomic infants subse-
gestation showed that SGA infants were at quent to a previous macrosomic birth was
increased risk of neonatal death (odds ratio 22%, a proportion that did not vary notably
2.77), necrotizing enterocolitis (odds ratio with parity or when paternity changed
1.27), and RDS (odds ratio 1.19).50 between successive births.56
One of the more commonly recognized
GROWTH AND LONG-TERM clinical associations with LGA infants is their
OUTCOME increased likelihood of being delivered to
diabetic mothers. Even in expert centers, the
GROWTH rates of fetal macrosomia are between 20%
Most small for gestation infants show some and 40% for offspring of women with insulin-
catch-up growth in the first year of life. In dependent diabetes, noninsulin-dependent
general, they remain somewhat shorter and diabetes, and gestational diabetes.57
lighter and have a smaller head circumfer- Because the delivery of an excessively
ence than those with birth weights appro- large baby is potentially associated with sig-
priate for gestational age. As many as 44% nificant perinatal morbidity and increased
of preterm and 29% of term SGA infants mortality rate, efforts are made to predict
remain below the 5th percentile.51 Some do and confirm the presence of fetal macroso-
not have catch-up growth; about one half mia in an affected pregnancy before labor
of them remain short as adults. Infants with to facilitate appropriate management of the
poor prenatal and postnatal head growth mother and infant. The neonatal morbid-
are at most risk of growth problems and ity anticipated among LGA infants includes
poor developmental outcomes. The pres- birth trauma, hypoglycemia, polycythemia,
ence or absence of symmetry does not reli- and, more infrequently, congenital heart
ably predict poor or good growth in early disease (in particular, transposition of the
childhood.51 great vessels), and Beckwith-Wiedemann
syndrome, all of which, when anticipated,
NEURODEVELOPMENTAL OUTCOME are more likely to be detected and treated
In light of the varied causes of growth quickly. However, although antenatal pre-
impairment, it is not surprising that the lit- diction of fetal macrosomia is associated
erature regarding long-term neurodevelop- with a marked increase in cesarean deliver-
mental outcome is contradictory. Overall, ies, there has been no significant reduction
documented in the incidence of shoulder The initial examination may be carried

dystocia or fetal injury secondary to the sur- out by the labor and delivery nurse, the new-
gical delivery of macrosomic infants, chal- born nursery nurse assigned to the delivery
lenging its cost effectiveness.58-60 area, or the physician or nurse practitioner
attending the infant, depending on the cir-
PHYSICAL EXAMINATION cumstances surrounding the birth. The pur-
OF THE NEWBORN INFANT pose of this initial examination is twofold:
(1) to ensure that there is no evidence of
PREPARATION significant cardiopulmonary instability that
Before embarking on the physical examina- requires intervention; and (2) to identify
tion of the infant, the clinician must review significant congenital anomalies. For the
the mother’s medical and pregnancy history high-risk neonate, it may be advantageous
to help focus the examination and to ensure to use this setting to perform as complete
that no pertinent findings are overlooked. an examination as possible to forgo a sub-
For example, a history of maternal insulin- sequent examination and thereby avoid an
dependent diabetes should alert the exam- unnecessary disturbance of the baby in the
iner to the risk of a variety of congenital intensive care nursery.
anomalies as well as aberrant growth. A his- The assessment of cardiopulmonary adap-
tory of polyhydramnios raises the suspicion tation begins as soon as the infant is deliv-
of a proximal gastrointestinal obstruction or ered, and this initial evaluation is, in part,
underlying neurologic problem. A history of quantified by the Apgar score. Assessment
oligohydramnios may raise the question of of the presence, regularity, and effective-
structural renal anomalies. Knowing that a ness of respiratory effort is the first step in
fetus presented in breech position should evaluating any newborn. The presence of
lead the examiner to focus on examination apnea or signs of respiratory distress must
of the hips. As noted in the previous sec- be noted to determine the need for inter-
tions of this chapter, the presence of IUGR vention. It is not unusual for a healthy new-
should alert the examiner to search for the born to require a few minutes to establish
stigmata of intrauterine infections and vari- a regular respiratory pattern, and unlabored
ous syndromes. respiratory rates of 60 to 80 breaths per min-
Transfer of pathogenic microbes from the ute may be seen for the first 1 to 2 hours in
examiner to the baby must be prevented some normal infants.
by thorough hand hygiene, and the stetho- Cardiovascular adaptation is simultane-
scope to be used should be cleaned with ously assessed with the pulmonary adjust-
alcohol. For all newborns, but in particular ment to extrauterine life. The normal heart
the premature or sick neonate, the thermal rate of a baby in the delivery area is greater
environment must be appropriate. Attention than 100 beats per minute and may exceed
must also be given to the lighting and noise 160 beats per minute for brief periods. Sus-
in the examination area. Lighting needs to tained tachycardia is not a normal finding
be adequate but must avoid very bright light and may indicate hypovolemia, inadequate
because it interferes with the processes of oxygen delivery to the tissues, or, rarely,
stabilization and transition. Finally, a thor- an arrhythmia. Autonomic instability may
ough examination of the newborn should cause an asymptomatic irregular heart beat
take no more than 5 to 10 minutes. in the first few hours of life, which is not
uncommon.
VARYING PURPOSE It is important to assess color of the infant
OF THE EXAMINATION centrally (gums and inner lips); acrocya-
The extent and focus of the examination nosis (blue discoloration of the hands and
varies with circumstances. There are typi- feet and perioral area) is often present in
cally three distinct periods during which the normal infant during the first 24 hours
the infant is examined: (1) a brief exami- of life. Pallor and poor perfusion require
nation immediately after birth; (2) a com- further evaluation.
plete examination in the newborn nursery As soon as the initial cardiopulmonary
or mother’s room within 24 hours after assessment is complete, evaluation of respon-
birth; and (3) a focused examination within siveness and muscle tone is carried out as a
24 hours before discharge, which may be further indicator of the success of transition
accomplished with a single examination for and well-being of the infant. Normal tone
shortened hospital stay. varies considerably with gestational age, but
the finding of flaccidity, hypertonicity, or POSTNATAL ASSESSMENT

asymmetry of tone is always abnormal. OF GESTATIONAL AGE
When these initial steps are taken, an effi- A variety of methods for assessing the ges-
cient survey of the face, mouth, abdomen, tational age of the newborn infant have
back, extremities, genitalia, and perineum been developed. However, even in the most
is carried out. Major congenital anomalies experienced hands, one can expect up to a
must be sought while the infant is in the 2-week variance in the postnatal assessment
delivery area, and their presence and signifi- from well-established antenatal dating.
cance, and preliminary plans for their eval- Currently, the most widely used system
uation are discussed with the family. Even for the postnatal assessment of gestational
relatively minor anomalies can precipitate age in the United States is the New Ballard
strong reactions from anxious parents. Score (NBS) (Box 5-2 and Fig. 5-5).61 This sys-
After this initial assessment, assuming tem, like many others, including the Dubow-
the condition of the baby and mother per- itz Score from which the Ballard system is
mits, baby and parents should be provided derived, includes both physical and neuro-
with some private time. The baby is usu- logic characteristics.62 The advantages of the
ally in a state of quiet alertness, facilitating NBS are the relative ease with which it can
parent-infant bonding. This state of quiet be carried out, even in the newborn requir-
alertness will allow the mother to suckle ing ventilatory assistance, and the improved
her infant, which increases the likelihood of accuracy (within 1 week) for the extremely
breast-feeding success. The infant should be premature infant.
briefly assessed at least once every 30 min-
utes until there has been continued stability THE COMPLETE EXAMINATION
for 2 hours.44 The complete examination of the healthy
newborn can be carried out in the nursery
TRANSITION PERIOD or in the mother’s room. In the latter loca-
During the initial 15 to 30 minutes of life, tion, the family is more able to express any
the first period of reactivity, the observed concerns about the baby’s physical features
changes reflect a state of sympathetic dis- and the physician is better able to observe
charge. In addition to the irregular respi- parent-infant interactions.
ratory efforts and relative tachycardia, the The purpose of the complete examina-
normal infant is alert and responsive, and tion is to
exhibits spontaneous startle reactions, • Detect any physical abnormalities—A sig-
tremors, bursts of crying, side-to-side move- nificant congenital anomaly is present at
ments of the head, smacking of the lips, and birth in 10 to 20 per 1000 live births.
tremors of the extremities. Bowel sounds, • Confirm and/or consider the further man-
passage of meconium, and saliva produc- agement of any abnormalities detected
tion become evident as a reflection of para- antenatally.
sympathetic discharge. Normal premature • Consider potential problems related to
and term infants who are ill or were abnor- maternal pregnancy history or familial
mally stressed by labor and delivery have a disorders.
prolonged period of initial reactivity. Dur- • Allow the parents to ask any questions
ing the first hour of life, the infant spends and raise any concerns about their baby.
up to 40 minutes in a quiet alert state. This • Determine whether there is concern by
is often the longest period of quiet alert caregivers about the adequacy of parental
behavior during the first 4 days of life. After care of the baby following discharge.
this burst of activity, the baby passes into • Provide advice about preventive care.
a 1- to 2-hour period of decreased activity • Ensure that appropriate follow-up arrange-
and sleep. A second period of reactivity subse- ments are in place.
quently emerges between 2 and 6 hours of The clinician needs to find a method
age with many of the same motor and auto- that will enable him or her to perform a
nomic manifestations previously described comprehensive examination while mini-
for the first period of reactivity. Gagging mizing the disturbance of the baby. Gen-
and vomiting are often observed during this eral observation (hands and stethoscope
time. The duration of this phase is variable, off) is combined with a head-to-toe review.
lasting from 10 minutes to several hours. For In practice, these examinations are done
more information on the transition period, simultaneously, and an opportunistic
see Chapter 4. approach is adopted, for example checking
Box 5-2. Technique for New Ballard Score

Neuromuscular maturity Plantar surface: As with the hands, the
There is a general replacement of extensor tone presence of creases in the foot is a
by flexor tone in a cephalocaudal progression reflection of intrauterine activity as well
with advancing gestational age. as maturation. The absence of creases
Posture: Observe the unrestrained infant in the may indicate an underlying neurologic
supine position. problem as well as immaturity. Accelerated
Square window: Flex the wrist and measure the crease development is observed when
minimal angle between the ventral surface of oligohydramnios was present. An addition
the forearm and the palm. in the New Ballard Score (NBS) is the
Arm recoil: With the infant supine and the head requirement for measuring the plantar
midline, hold the forearm against the arm surface.
for 5 seconds, then fully extend and release Breast: The areola development is not
the arm. Note the time it takes the infant to dependent on adequacy of intrauterine
resume a flexed posture. nutrition. There is no difference in male or
Popliteal angle: Flex the hips with the thighs female infants.
on the abdomen. Then, without lifting the Ear cartilage: With maturation, the ear cartilage
hips from the bed surface, extend the knee becomes increasingly stiff and the auricle
as far as possible until resistance is met. thickens. Fold the top of the ear and assess
(One may overestimate the extent of exten- the recoil.
sion if one attempts to continue extending Eyelid opening: Used (incorrectly) by some as
the knee beyond the point where resistance a sign of nonviability. Dr. Ballard included
is first met.) the degree of fusion of the lids as a new
Scarf sign: Keeping the head in the midline, assessment tool. She defined tightly fused
pull the hand across the chest to encircle as both lids being inseparable by gentle
the neck as a scarf and note the position traction, and loosely fused as either lid
of the elbow relative to the midline. being able to be partly separated by gentle
Heel to ear: With the infant supine and the traction. Tightly fused lids were observed in
pelvis kept on the examining surface, 20% of infants born at 26 weeks’ gesta-
the feet are brought back as far as tion, and only 5% of babies delivered at
possible toward the head, allowing the 27 weeks. The presence of fused eyelids
knees to be positioned alongside the alone should never be used as a sign of
abdomen. nonviability.
Physical maturity External genitalia, male: Palpate for level of
Skin: With maturation, the skin becomes thicker, testicular descent and observe the degree of
less translucent and, eventually, dry and rugation.
peeling. External genitalia, female: The labia minora
Lanugo: This fine, nonpigmented hair is evenly and clitoris are prominent in the immature
distributed over the body and is most promi- newborn, at times leading the inexperienced
nent at 27 to 28 weeks’ gestation, then it examiner to suspect clitoromegaly. With
gradually disappears, usually first from the maturation, the labia majora becomes fat-
lower back. Although present over the entire filled and therefore prominent. The under-
body, the lanugo over the back is used for nourished fetus may have relatively thin labia
gestational age assessment. majora.
for red reflexes when the infant’s eyes are estimated date of delivery from ultrasound
open, but making sure that all aspects of and last menstrual period. Gestational age
the examination are covered. can also be assessed by physical examination
of the infant, using the New Ballard system,
BODY MEASUREMENTS AND as already described. Familiarity with the
GESTATIONAL AGE ASSESSMENT scoring system is helpful to be able to recog-
Note the birth weight and gestational age nize discrepancy between the infant matu-
and plot them on a growth chart. The ges- rity and maternal date of confinement or
tational age is usually based on the maternal when maternal date is uncertain. During the
Neuromuscular maturity
–1 0 1 2 3 4 5
Posture
Square
window
(wrist) >90° 90° 60° 45° 30° 0°
Arm recoil
180° 140°-180° 110°-140° 90°-110° <90°
Popliteal
angle
180° 160° 140° 120° 100° 90° <90°
Scarf sign
Heel to ear
Physical maturity Maturity Rating

Superficial Parchment, Score Weeks
Sticky, Gelatinous, peeling Cracking deep Leathery,
friable, red, Smooth, pink, &/or rash, pale areas, cracking, cracked, –10 20
Skin transparent translucent visible veins few veins rare veins no vessels wrinkled
–5 22
Bald Mostly
Lanugo None Sparse Abundant Thinning bald
areas 0 24
Heel-toe >50 mm Anterior Creases 5 26

Plantar 40-50 mm: –1 no Faint transverse Creases over
surface <40 mm: –2 crease red marks crease only anterior 2/3 entire sole 10 28
Raised 15 30
Stippled areola Full areola
Barely Flat areola, areola 3-4 mm 5-10 mm 32
Breast Imperceptible perceptible no bud 1-2 mm bud bud bud 20
Well-curved Formed 25 34
Lids fused Lids open, slightly curved pinna; & firm, Thick
Loosely:–1 pinna flat, pinna; soft; soft but instant cartilage, 30 36
Eye/ear Tightly:–2 stays folded slow recoil ready recoil recoil ear stiff
Testes 35 38
Scrotum Scrotum Testes in Testes down, Testes
Genitals, flat, empty, upper canal, descending, good pendulous, 40 40
male smooth faint rugae rare rugae few rugae rugae deep rugae
Prominent Prominent Majora Majora Majora 45 42
Clitoris clitoris, clitoris, & minora large, covers
Genitals, prominent, small enlarging equally minora clitoris 50 44
female labia flat labia minora minora prominent small & minora
Figure 5-5. New Ballard Score. (From Ballard J, Wednig K, Wang L, et al: New Ballard Score, expanded to include extremely
premature infants, J Pediatr 119:417, 1991.)
examination, the head circumference and of the first day of life, most newborns have a
the length are also measured and plotted on respiratory rate of 40 to 60 breaths per min-
a growth chart. This will assist identification ute and a heart rate of 120 to 160 beats per
of infants who have microcephaly or macro- minute. The temperature of the newborn
cephaly or who are abnormally short. will have been assessed using an axillary
measurement. A temperature between 35.5°
Vital Signs C and 37.5° C is normal. An elevated temper-
The respiratory rate and heart rate of the ature may represent a fever, but more com-
normal newborn vary considerably in the monly it is the result of external factors such
first few hours of life. During the remainder as overbundling or ambient heat source.
OBSERVATION abnormal and may indicate significant car-

Initially, the examiner uses only his or her diopulmonary disease. Occasionally, infants
eyes and unaided ears to evaluate the baby with polycythemia appear cyanotic despite
(hands and stethoscope off). This is usually adequate oxygenation because they have
best done in stages, observing the exposed a relatively high concentration of reduced
part of the baby in turn while undressing hemoglobin. As noted previously, polycy-
the baby. themia is more likely to present in postdate,
LGA, and IUGR infants, and in infants of
Respiratory Effort mothers with diabetes. The presenting fetal
The respiratory effort of the newborn var- parts may be bruised during the process of
ies with the sleep state of the infant. During birth, resulting in a localized bluish discol-
deep sleep, the infant usually has a regular oration. This can be particularly striking in a
breathing pattern, whereas during awake face presentation or when a transient venous
states, bursts of more rapid breathing are obstruction developed intrapartum (perhaps
often observed. Because of the newborn’s as the result of a nuchal cord), resulting in a
compliant chest wall and almost exclusive purple-headed baby. To differentiate between
diaphragmatic breathing, it is not unusual cyanosis and bruising, apply pressure to the
to observe mild subcostal and intercostal area. A bruise remains blue, whereas an area
retractions, as well as paradoxical movement of cyanosis blanches. In addition, petechiae
during inspiration, with the thorax being often accompany the ecchymosis. Finally,
drawn inward accompanied by outward the vigorous infant may turn nearly purple
abdominal excursion. Even though this when performing a Valsalva maneuver in
“see-saw” pattern is often seen in neonates preparation for crying. Occasionally, the
with respiratory distress, in the absence of harlequin color change is observed, wherein
further evidence of respiratory difficulties, there is a striking division into pale and red
this movement should not cause alarm. halves in an infant (typically positioned on
However, suprasternal and supraclavicular the side), with a line of demarcation along
retractions are not normal findings. Like- the midline from head to foot. This finding is
wise, asymmetrical chest wall movement of no consequence outside of initial conster-
is abnormal and may indicate unilateral nation in the nursery.
lesions of the diaphragm (diaphragmatic Although jaundice develops in many, if
hernia or diaphragmatic paralysis associated not most, newborns, this finding in the first
with a difficult delivery) or pleural space 24 hours of life is abnormal and requires
(effusion or pneumothorax). The normal investigation. Jaundice is best assessed
newborn thorax is configured as an oval, in natural light, by applying gentle pres-
with a relatively narrow anteroposterior sure and assessing the color of the under-
diameter. A barrel chest appearance suggests lying skin and subcutaneous tissue. The
cardiomegaly or air trapping, as may be seen cephalopedal progression of jaundice with
with transient tachypnea of the newborn, increasing bilirubin levels has been observed
meconium aspiration, or a pneumothorax. for more than a century, and the distribu-
Audible grunting results from the infant tion of jaundice can assist in estimating
expiring against a partially closed glottis in serum bilirubin levels. However, Jaundice
an effort to maintain a functional residual is suspected within the first 24 hours of
capacity in the face of atelectasis. This find- life, transcutaneous or serum measurement
ing should be assumed to indicate a poten- should be performed because clinical esti-
tially significant cardiopulmonary disorder mation is unreliable. Rarely, direct hyperbil-
until proven otherwise. irubinemia is seen in the first hours of life,
providing a green cast to the infant’s skin.
Color and Perfusion More commonly, greenish discoloration of
The normal newborn is pink. The finding the skin is the result of in utero staining by
of other colors such as blue, purple, yellow, meconium. Mottling may be observed in
or green; pallor; or mottling requires closer the well preterm or chilled newborn, or can
examination. Acrocyanosis (blue discolor- be a sign of significant systemic illness. Pal-
ation of the hands, feet, and perioral area) lor, in contrast, is never normal, and may
is common in the first day of life. Cen- result from poor cardiac output, subcutane-
tral cyanosis (involving the tongue and ous edema, asphyxia, or anemia. Finally, a
mucous membranes of the mouth) persisting grayish hue may be associated with signifi-
beyond the first few minutes of life is always cant metabolic acidosis.
Position and Movement Face and Crying

Observation of an infant’s position at rest The examiner must not become frustrated
(an indicator of underlying tone) and spon- if the baby begins to cry. There is much to
taneous movement provides a great deal of be gained by observing the face of both the
information about his or her neurologic sta- quiet and crying baby, and then by listen-
tus. Gestational age, illness, maternal medi- ing to the cry. Symmetry of the mouth and
cations, and sleep state influence tone and eyes is the normal finding. An asymmetric
spontaneous movements and must be con- mouth (the abnormal side does not “droop”
sidered during the evaluation. As is evident with crying) with an ipsilateral eye that
in the New Ballard examination, muscle tone does not close and a forehead that does not
generally progresses in a caudocephalad wrinkle usually indicates an injury to the
direction with advancing gestational age. peripheral facial nerve (cranial nerve VII).
In the infant of 28 weeks’ gestation, there is This situation must be differentiated from
little tone in either upper or lower extremi- a congenital degeneration or maldevelop-
ties, and the infant generally remains in the ment of the cranial nerve VI and VII nuclei
position in which the care provider places (Möbius sequence), which is typically mani-
him or her. By 32 weeks, the infant should fested by bilateral palsy. A palsy confined to
have developed tone of the legs, resulting in the lower portion of the face (central facial
flexion at the hips and knees. One month palsy) may indicate an intracranial hemor-
later, strong flexor tone is present in the rhage or infarct. This latter finding should
lower extremities, and the arms begin to dis- be distinguished from congenital absence
play some flexion. The normal, supine term of the depressor anguli oris muscle (asym-
infant in the quiet awake state holds all four metrical crying facies), a generally benign
extremities in moderate flexion. The hands condition, but one that may be associated
intermittently open, but most often, they with congenital cardiac anomalies.
are fisted with the thumb adducted and Most reassuring to a pediatrician is the
folded (cortical thumbs). Finally, when in lusty cry of a newborn baby. An abnormal cry,
the prone position, the term infant should on the other hand, often heralds underlying
be able to briefly lift his or her head above problems. A weak or whining cry may indi-
the plane of the body, and often elevates cate illness, developing respiratory distress,
the pelvis above the flexed hips and knees. depression from maternal narcotics, or central
The character of normal spontaneous nervous system disturbance. Central nervous
movements varies with gestational age. system problems may also result in persistent
Before 32 weeks, infants demonstrate ran- high-pitched crying. Hoarseness can be caused
dom, slow writhing movements with inter- by laryngeal edema resulting from airway
spersed myoclonic activity of the extremities. manipulation in the delivery room, hypocal-
This writhing quality often persists through cemia, or airway anomalies. Conditions result-
44 weeks’ gestational age. By 32 weeks, ing in either internal obstruction or external
flexor movements of the lower extremities compression of the airway often cause stridor,
begin to predominate and typically occur which is exacerbated by crying; therefore,
in unison. A month later, these movements stridor in the newborn infant must always be
alternate, a pattern seen more frequently in considered a potentially serious finding.
the term infant. This progression of findings
is entirely dependent on gestational, not Congenital Anomalies
postnatal, age. Finally, a quick survey for dysmorphic fea-
Normal babies of all gestational ages have tures, whether malformations or deforma-
symmetrical tone and movements. Find- tions, must be undertaken. All nurseries
ing more than mild asymmetry in position should have immediate access to detailed
and range of spontaneous movement may descriptions and illustrations of common
indicate the presence of local birth trauma neonatal malformation and deformation
(brachial plexus injury or fractures of the syndromes, either in a reference book or
clavicle, humerus, or femur), or, rarely, a electronically.
central nervous system insult, lesion, or
anomaly. Asymmetry of position may also HEAD-TO-TOE REVIEW
reflect in utero positioning, which should
improve with time. The finding of extremes Skin
of flexion or extension requires a more in- In the extremely premature infant (23
depth neurologic evaluation. to 28 weeks’ gestation), the skin can be
translucent with little subcutaneous fat and not exhibit the hyperpigmentation, mak-
easily visualized superficial veins. Because ing the diagnosis more difficult. The lesions
the stratum corneum is thin, the skin of contain an occasional polymorphonuclear
the extremely premature infant is easily leukocyte and cellular debris. Mongolian
injured by seemingly innocuous procedures spots are macular areas of slate-blue hyper-
or manipulation that results in denudation pigmentation seen predominantly over the
of the stratum corneum and a raw weeping buttocks or trunk; they are seen most com-
surface. Insensible losses of water through monly in African-American, Native American,
this immature integument can be consid- and Asian infants.
erable, resulting in marked fluid and elec- A large number of skin, nail, and hair
trolyte imbalances if measures such as high abnormalities may be found in the new-
humidity in the incubator are not taken to born. Some of these are important clues
reduce these losses. The stratum corneum in the identification of an underlying
of even the extremely premature infant syndrome or generalized disease process.
quickly matures so that by 1 to 2 weeks of Examination of the newborn’s skin should
age the insensible water losses are reduced be made to identify any congenital nevi,
to levels seen in the mature infant. By term, hemangiomas, areas of abnormal pigmenta-
skin is relatively opaque with considerable tion, tags, pits, unusual scaling, blistering,
subcutaneous fat. abnormal laxity, or dysplasia. The color,
By 35 to 36 weeks’ gestational age, at distribution, and texture of the body and
birth the infant is covered with greasy ver- head hair are noted. Nail hypoplasia, dys-
nix caseosa. The vernix thins by term and is plasia, aplasia, or hypertrophy should be
usually absent in the postterm infant. The further investigated. A large hemangioma
postmature infant has parchment-like skin on the face or neck can potentially cause
with deep cracks on the trunk and extremi- airway obstruction. Port wine stains (capil-
ties. Fingernails may be elongated, and peel- lary malformations), are usually on the face,
ing of the distal extremities is often evident but can be anywhere on the body. They are
in the postmature infant. pink macular lesions which become purple
A variety of transient skin conditions are with time. Satisfactory cosmetic treatment
found in the newborn. Erythema toxicum may be achieved with laser therapy, start-
neonatorum is a benign rash seen gener- ing in infancy. When the port wine stain
ally in term infants beginning on the sec- involves the distribution of the trigeminal
ond or third day of life. It is characterized nerve, it may be associated with a vascular
by 1- to 2-mm white papules (that may malformation of the meninges and cerebral
become vesicular) on an erythematous base cortex and cause seizures and developmen-
of varying diameter. The lesions appear and tal delay (Sturge-Weber syndrome). If the
disappear on different parts of the body, port wine stain involves the distribution of
are never found on the palms or soles, and the first and second divisions of the trigemi-
are relatively infrequent on the face. They nal nerve, congenital glaucoma may occur.
contain eosinophils. Milia, which are 1-
to 2-mm whitish papules, are frequently Head
found on the face of newborns. Miliaria is The scalp and size and shape of the head are
a result of eccrine sweat duct obstruction, next considered. Small lacerations or punc-
and it manifests as glistening vesiculopap- ture wounds may result from the placement
ular lesions over the forehead and on the of a fetal scalp electrode. Use of forceps can
scalp and skinfolds. Miliaria appears during result in superficial marks, edema, or bruis-
the first day and disappears within the first ing of the skin on the sides of the skull and
week after birth. Transient neonatal pustu- face, whereas the vacuum extractor can
lar melanosis, which is seen predominantly leave a circumferential area of edema, bruis-
in African-American infants, is a benign ing, and occasionally blisters. Use of either
generalized eruption of superficial pustules forceps or vacuum extractor is associated
overlying hyperpigmented macules. The with an increased likelihood of injuries to
pustules, which can be found on any body the extracranial structures. Caput succeda-
surface, including the palms and soles, may neum is a boggy area of edema located at
be removed when vernix is being wiped off the presenting part of the often molded
or during the first bath, so that the physi- head; it is present at birth, crosses suture
cian may see only macules surrounded by lines, and disappears within a few days.
a fine, scaly collarette. White infants may Cephalohematomas, present in 1% to 2% of
all newborns, are subperiosteal collections of trisomy 21. Palpation of the skull should
of blood that do not cross suture lines. They reveal bones with mobile edges along the
are often bilateral, and they usually increase sagittal, coronal, and lambdoidal suture
in size after birth. Depending on the amount lines. Initial overlapping of the sutures is
of blood present, cephalohematomas may normal. A palpable ridge along suture lines
be fluctuant or tense. Cephalohematomas should always be considered abnormal, pos-
rarely cause problems, but they may take sibly indicating premature closure of the
weeks to months to resolve. The subgaleal sutures (craniosynostosis). The impact of
hemorrhage is the least common of the craniosynostosis on the final configuration
extracranial injuries, but it is also the most of the skull depends on the suture involved.
dangerous. Newborns can lose tremendous The most commonly involved is the sagittal
amounts of blood from this injury, and they suture, with resultant dolichocephaly (“keel
must be monitored carefully for shock once head”). Even though most instances of cra-
the diagnosis is suspected. Like the caput, niosynostosis are isolated events, some syn-
this swelling can cross suture lines, but, as dromes (Apert, Crouzon) are characterized,
in the cephalohematoma, the lesion grows in part, by this finding. The normal width of
after birth, at times covering the entire scalp the various sutures of the skull is quite vari-
and extending into the neck. able. African-American infants tend to have
Unusual configuration of the scalp hair, wider metopic and sagittal sutures. Wide
such as double or anterior whorls or promi- lambdoidal and squamosal sutures in term
nent cowlicks, may be associated with infants may be a sign of raised intracranial
abnormalities of the skull or brain, particu- pressure. Craniotabes, soft pliable parietal
larly if there are associated unusual facies. bone along the sagittal suture, is a common
Especially unruly hair is associated with finding in preterm infants as well as in the
both trisomy 21 and Cornelia de Lange term infant whose head had been resting
syndrome. A low-set posterior hairline may on the pelvic brim for the last few weeks of
indicate a short or webbed neck as in Turner pregnancy. As its name implies, craniotabes
syndrome. Ectodermal defects, wherein a 2- can be seen in congenital syphilis, but this
to 5-cm diameter portion of the scalp is clearly the exception.
appears to be totally absent, may be an iso- Palpation of the anterior and poste-
lated problem, but it is also a common find- rior fontanelles should take place when
ing in trisomy 13. the infant is relatively quiet. The normal
Accurate measurement of the head cir- anterior fontanelle has slight pulsations
cumference is an important aspect of the accompanying the heart beat and is flat to
physical examination. Abnormally large or slightly sunken. There is a wide range of
small heads may indicate significant underly- normal for fontanelle size, and racial differ-
ing neuropathology. The final configuration ences have been noted. African-American
and even the circumference of the skull may babies have statistically larger fontanelles
be difficult to ascertain immediately after than do whites. Routine measurement of
birth because of the molding that occurs dur- fontanelles is not particularly useful and
ing the birth process, and some time may be not recommended. Finally, in infants with
required before one can be sure of the pres- unexplained heart failure, auscultation of
ence or absence of an abnormality. the head for bruits over the anterior fonta-
Babies delivered by cesarean section with- nelle and temporal arteries may identify an
out a trial of labor typically have little to arteriovenous malformation.
no molding, whereas vaginal delivery usu-
ally results in an enhanced occipitomental Eyes
dimension with a relatively narrow bipari- Salmon patches on the eyelids, mid-forehead,
etal diameter. Those infants who were in and nape of the neck are common. Those
breech presentation characteristically have on the face fade at 1 year, those on the nape
an accentuation of the occipitofrontal mea- are more persistent and may be present in
surement with a resultant occipital shelf adults but covered by hair. Dysmorphism
and apparent frontal bossing. The effects of of the eye and ocular region are the most
intrauterine positioning and birth are tran- frequently cited findings in malformation
sient, and should recede within days. If not, syndromes. Abnormal eyes may also indi-
underlying abnormalities should be consid- cate inborn errors of metabolism, central
ered. A head with a short occipitofrontal nervous system defects, or congenital infec-
dimension (brachycephaly) is characteristic tions. Although careful evaluation of the
eyes is clearly important, it is potentially one with experience. Many syndromes include
of the most difficult aspects of the examina- malformed auricles as part of their spectrum,
tion. Most infants will open their eyes dur- but the findings are not pathognomonic.
ing the course of the examination. The eyes The “low-set ears” so often mentioned in
of a crying baby cannot be examined. Gen- physical examinations is usually incorrect,
tly holding the infant upright and rocking the result of having the head positioned
backward and forward often prompts the at the incorrect angle or an unusual skull
baby to open his or her eyes. shape. The patency of the external ear canals
The size, orientation, and position of the should be ensured. If a preauricular skin tag
eyes should be noted. The diameter of the is present, consult a plastic surgeon. Check
cornea and eye at term is approximately 10 that the ear and hearing are normal. If
mm and 17 mm, respectively. Microphthal- there is an ear anomaly, some centers per-
mia is seen in a number of malformation form ultrasound evaluation of the kidneys
syndromes, including trisomy 13, whereas because there is a slight increase in risk of
an enlarged cornea should suggest congeni- renal abnormalities.
tal glaucoma. The eye that is positioned
with the palpebral fissures slanting upward Nose
from the inner canthus is typically seen in The nose may appear misshapen because
trisomy 21, whereas Treacher Collins, Apert, of in utero deformation, and it usually self-
and DiGeorge syndromes are characterized corrects in a few days. Conversely, nasal
in part by downward slanting palpebral asymmetry may be the result of septal dis-
fissures. A large number of syndromes are placement, which requires evaluation by
associated with hypertelorism (a wide inter- an otolaryngologist. Several syndromes
pupillary distance) (e.g., Apert syndrome and teratogens have nasal manifestations
and trisomy 13), whereas hypotelorism is including small (fetal alcohol syndrome) to
less commonly seen (holoprosencephaly large (trisomy 13) noses, and low (achon-
and, again, trisomy 13). droplasia) to prominent (Seckel syndrome)
Newborns often demonstrate random nasal bridges. Nasal obstruction may be
and, at times, disconjugate movements of caused by mucus or it may represent true
the eyes. Persistent strabismus should be anatomic obstruction caused by tumors,
further evaluated. Subconjunctival hemor- encephalocele, or choanal atresia. Choanal
rhage is, at times, frightening in appearance, atresia may be unilateral or bilateral, and
but it resolves spontaneously. The iris is may require the use of an oral airway or
blue in nearly all newborns, although some endotracheal intubation to maintain a pat-
more heavily pigmented infants have dark ent airway. Choanal atresia is often part of
irises at birth. Reaction of the pupil to light the CHARGE association (coloboma, heart
begins to appear by 30 weeks’ gestation, but disease, atresia choanae, restricted growth
reaction may not be consistently seen for and development and/or CNS anomalies,
another 2 to 5 weeks. Detailed visualization genital anomalies and/or hypogonadism,
of the retina is unnecessary in most infants. and ear anomalies and/or deafness).
The goal of routine funduscopic examina-
tions is to ensure the absence of intraocular Mouth
pathology and opacities of the cornea and Micrognathia is a component of many mal-
lens by establishing the presence of a nor- formation syndromes, with the Pierre-Robin
mal light reflex (red reflex). Whereas the sequence perhaps being the most obvious
normal light reflex is red in white infants, example. The interior of the mouth should
more darkly pigmented infants have a be evaluated with a light and tongue blade
pearly gray reflex. The finding of a white (if necessary) as well as a gloved finger. The
pupillary reflex (leukocoria) can suggest the frenulum labialis superior is a band of tis-
presence of a variety of ocular pathologies sue that connects the central portion of the
(cataracts, trauma, persistent hyperplastic upper lip to the alveolar ridge of the max-
primary vitreous, tumor, retinopathy of pre- illa. It may be prominent and be associated
maturity) and requires urgent evaluation by with a notch in the maxillary ridge where it
an ophthalmologist. originates. Likewise, the frenulum linguae is
a band of tissue that connects the floor of
Ears the mouth to the tongue. This may extend
Recognition of the wide variation of normal to the tip of the tongue (tongue-tie) but does
for the external ear configuration develops not usually interfere with suckling or later
speech. Natal (present at birth) and neona- performed while simply watching the infant
tal (present in the first month of life) teeth breathe. If the infant has respiratory distress,
are usually found in the mandibular central the stethoscope is used to assess the quan-
incisor region, and are bilateral approxi- tity, quality, and equality of breath sounds.
mately half of the time. They are removed Alveolar pathology (atelectasis, pneumonia)
if loose, to avoid the risk of aspiration. may be suggested by the presence of inspi-
White epithelial cysts on the palate known ratory crackles, whereas crepitant sounds
as Epstein pearls are present in most babies, heard both in inspiration and expiration are
and similar lesions may be seen along the usually the result of airway secretions.
gums. Clefts of the palate may be obvious The chest is evaluated for size, symmetry,
to the eye, or only found by palpation (sub- bony structure, musculature, and position of
mucous cleft). This latter abnormality may the nipples. The thorax may be malformed
be accompanied by a bifid uvula. or small in a variety of neuromuscular disor-
ders, osteochondrodysplasias, and processes
Face associated with pulmonary hypoplasia. The
One should be careful during the examina- presence of pectus excavatum (funnel chest)
tion not to focus too much on specific prob- and carinatum (pigeon breast) can be of con-
lems, but to consider the overall picture. siderable concern to the family, and both
Take a moment, step back, and just observe can be associated with Marfan, Noonan,
the baby to ensure that, as the saying goes, and other syndromes. Palpable pectoralis
you don’t “miss the forest for the tress.” Is major muscle tissue in the axillae assures
there anything that just looks unusual? the presence of the muscle, the absence of
which is suggestive of Poland syndrome.
Neck, Lymph Nodes, and Clavicles Supernumerary nipples, found inferome-
The neck of the newborn is relatively short; dial to the true breasts, are seen in approxi-
coincidentally, it has a relatively short list of mately 1% of the general population, with
possible abnormal findings. Redundant skin a higher incidence in African Americans.
along the posterolateral line (webbing) is Breast hypertrophy, at times asymmetri-
seen in approximately one half of girls with cal, can be seen in both male and female
Turner syndrome (XO), whereas the neck infants in response to maternal hormones,
of the infant with trisomy 21 is notable and may be accompanied by the secretion
for excess skin concentrated at the base of of “witch’s milk,” a thin milky fluid, for a
the neck posteriorly. A variety of branchial few days to weeks. Erythema and tender-
cleft remnants are manifested by pits, tags, ness of the breasts do not accompany this
and cysts. The most common neck mass is normal variant.
a lymphangioma (cystic hygroma), which is
a multiloculated cyst composed of dilated Cardiac System
lymphatics. Occasionally containing a hem- The goal of the cardiac examination gener-
angiomatous component, these are usually ally falls into one of two categories: (1) to
posterior to the sternocleidomastoid muscle ensure the absence of heart disease during
with potential extension into the scapulae the routine examination and (2) to deter-
and thoracic and axillary compartments. mine whether the heart is the source of the
The anterior neck should be evaluated for problem in the sick neonate.
a midline trachea, thyromegaly, and thyro- The normal resting heart rate of the term
glossal duct cysts. Lymph nodes are some- newborn is between 100 and 160 beats per
times palpable in the inguinal or cervical minute, although occasional brief fluctua-
areas in healthy newborns; congenital infections well above and below these values are
tions can also result in lymphadenopathy. expected. The premature infant’s baseline
Supraclavicular nodes are never normal. heart rate tends to be slightly higher. Per-
The clavicles are palpated for their presence sistent bradycardia or tachycardia can be an
or absence (cleidocranial dysostosis) and the indication of primary cardiac or, more com-
presence of fractures, which typically mani- monly, other systemic processes.
fest as asymmetrical arm movements, ten- Examination of the cardiovascular sys-
derness, and crepitus. tem begins with an assessment of general
appearance, color, perfusion, and respi-
Respiratory System and Chest ratory status. The presence of congenital
As stated previously, the most important anomalies increases the likelihood of asso-
part of the respiratory system examination is ciated congenital heart defects. Central
cyanosis accompanied by a comfortable murmur noted during their first week of life,
respiratory effort is suggestive of a structural most of these murmurs are related to ongo-
heart defect with diminished pulmonary ing circulatory adaptation to an extrauter-
blood flow (pulmonary atresia). Because of ine environment and they are transient and
the relative hypertrophy of the right ven- inconsequential. Innocent murmurs are soft,
tricle, the point of maximal impulse (PMI) systolic, at the left sternal edge or pulmonary
of the newborn is found just to the left of area. The infant is well and examination is
the lower sternum. In the term newborn, otherwise normal. The murmur of pulmo-
the precordial impulse is visible during the nary artery branch stenosis is best heard in
first few hours of life, but generally disap- the pulmonary area, is a systolic flow mur-
pears by 6 hours of age. Because of the lack mur best heard in the pulmonary area, and
of subcutaneous tissue in the preterm and radiates to the axilla and back. It resolves
growth-restricted newborn, the point of in a few weeks. Although uncommon, the
maximal impulse may be visible for a some- most concerning murmurs are those from
what longer time. Abnormal persistence of congenital heart disease, especially ductal-
the visible or easily palpated point of maxi- dependent lesions that may result in circu-
mal impulse is seen in transposition of the latory failure or cyanosis when the ductus
great vessels and structural defects char- arteriosus closes. Harsh grade 2 or 3 murmurs
acterized by right-sided volume overload. in the first hours of life (ventricular outflow
Palpation of the femoral pulses should be tract obstruction), pansystolic (atrioven-
carried out. The femoral pulses are dimin- tricular valve insufficiency), and to-and-fro,
ished in coarctation of the aorta, but may systolic-diastolic (absent pulmonary valve,
initially be palpable if blood flow is main- valvular regurgitation) murmurs require
tained by right-to-left shunting across the more extensive evaluation with echocar-
ductus arteriosus. diography. Finally, the disappearance of
Auscultation should begin with a a previously noted murmur in a baby who
warmed stethoscope. Identifying abnormal is clinically deteriorating should make one
heart sounds is made difficult by the fast suspect the closure of the ductus arteriosus
heart rate in the neonatal period. The first with a ductal-dependent lesion (coarctation
heart sound is typically single and is accen- of the aorta, tricuspid atresia, or pulmonary
tuated at birth and in conditions in which atresia).
there is increased flow across an atrioven- If a murmur is heard, the cardiac system
tricular valve. The second heart sound is is carefully evaluated. The definitive diag-
best heard at the upper left sternal border. nosis is by echocardiography. A chest x-ray
In most infants, the second heart sound and ECG are of limited value in establish-
(S2) is split, although this can be difficult to ing a diagnosis. Pulse oximetry will estab-
appreciate because of the high heart rate. lish if the arterial oxygen saturation is
The presence of a normally split S2 is an normal (>95%). If there are features of an
important physical finding. The absence innocent flow murmur, reassess the infant
of a split S2 can indicate the presence of a within a few days to check that the mur-
single ventricular valve (aortic atresia, pul- mur has disappeared. The parents need to
monary atresia, and truncus arteriosus) or be informed that they should seek medical
transposition of the great vessels (as a result assistance should the infant develop symp-
of the orientation of the valves). Widely toms suggestive of heart failure (slow feed-
split S2 is seldom indicative of increased ing, breathlessness, and sweating). If the
pulmonary blood flow (atrial septal defect) murmur persists or has pathologic features,
in neonates, but it can be heard in total or if the infant becomes unwell, referral to a
anomalous venous return and lesions char- pediatric cardiologist and echocardiography
acterized by an abnormal pulmonary valve. are indicated.
A narrowly split, accentuated S2 is charac- Blood pressure is not measured rou-
teristic of persistent pulmonary hyperten- tinely but it is performed in infants who are
sion of the newborn. unwell or preterm and require admission
The absence of a heart murmur does not to a neonatal unit. If the femoral pulses are
eliminate the possibility of important struc- diminished and coarctation of the aorta is
tural heart defects, and classic murmurs suspected, blood pressure is measured in the
ascribed to specific lesions in older chil- arms and legs. Blood pressure in the legs is
dren may not be present in the neonate. normally the same or slightly higher than
Even though some infants may have a heart that found in the arms, but is markedly
reduced if coarctation of the aorta is pres- The Genitalia

ent. Normal systemic blood pressure varies The appearance of the genitalia is certainly
with postnatal and gestational age. one of the first, if not the first, areas of inter-
est to the parents. If there is a disorder of
Abdomen sexual differentiation, assignment of the
Patience and warm hands are the keys to a infant’s gender should never be made until
successful abdominal examination. In most a detailed assessment has been performed.
infants, inspection reveals a rounded abdo-
men. A flat or scaphoid abdomen may be Male
observed in the presence of a diaphragmatic The penile size, position of the meatus,
hernia. A full upper abdomen in the pres- appearance of the scrotum, and position of
ence of a flattened lower abdomen suggests the testes must all be assessed. A penis of
a proximal bowel obstruction. Distention is the term infant stretched along its length
usually apparent at birth when there is mas- until resistance is met should be at least 2.5
sive ascites, meconium ileus and peritonitis, cm long. It is not necessary, and potentially
or intrauterine midgut volvulus. Clearly vis- painful and damaging, to retract the fore-
ible intestinal loops are not normal in the skin over the glans penis to determine the
term infant, but the thin abdominal wall of placement of the meatus. A meatal opening
the extremely premature baby may result on the ventral surface of the penis (hypo-
in easily observed loops and peristalsis. spadias) is relatively common and is readily
Abdominal wall defects (omphaloceles and apparent on inspection. Far less common
gastroschisis) are usually readily apparent; is an epispadias, in which the meatus is
these require urgent surgical intervention. present on the dorsal surface of the penis.
Bowel sounds are nearly always heard if aus- This is usually not an isolated defect, more
cultation is performed, and their absence is often being associated with exstrophy of
a concerning finding. the bladder. At the tip of the foreskin may
Palpation of the abdomen is facilitated by be found a 1-mm diameter pearly white
having the infant’s legs in a flexed position. sebaceous cyst. This is of no concern. The
Palpation should begin in the lower abdo- testes should be palpable in the scrotum of
men, with the hand allowed to rest there the term infant. In approximately 2% to 4%
until the infant relaxes. The kidneys are of term infants, either one or both testes
normally palpable bilaterally. Enlargement have not descended, but in three fourths of
of the kidneys caused by hydronephrosis or these infants the testes have descended at
cystic kidney disease is the most common 3 months of age. Premature infants are far
abdominal mass found in the newborn. The more likely to have an undescended testis
liver is usually palpable 1 to 3 cm below at birth than the term infant. A hydrocele
the right costal margin, and the left lobe can usually be distinguished from a hernia
extends across the midline. The liver should by a combination of palpation and transil-
be smooth and its edge should be soft and lumination.
thin. It may be enlarged from cardiac fail-
ure, congenital infections, extramedullary Female
hematopoiesis, tumors, and a variety of The appearance of the female genitalia
inborn errors of metabolism. The spleen is undergoes a maturational metamorphosis.
less frequently palpable than the liver and The premature infant has a prominent cli-
should be considered abnormally large if toris and labia minora, whereas in the term
palpable more than 1 cm below the left cos- infant, the labia majora completely covers
tal margin. these structures. The prominence of the cli-
The umbilical cord normally has two toris in the premature infant is a result of
umbilical arteries and one umbilical vein. this structure being fully developed by 27
A “two-vessel cord” (single umbilical artery) weeks’ gestation combined with a lack of
is a soft marker for chromosomal abnor- fat in the labia majora. In the term female,
malities; in an otherwise normal newborn outpouching of the vaginal mucosa (vagi-
there is an increased risk of renal malforma- nal skin tags) is often seen at the posterior
tion.63 Infants with limited fetal activity as fourchette. Vaginal skin tags are inconse-
a result of congenital neuromuscular disor- quential and regress within a few weeks.
ders, including Down syndrome, often have A mucous vaginal discharge, which is at
relatively short umbilical cords, which the times bloody, is often seen and may be of
obstetrician may note at the delivery. concern to parents. The passage of large
amounts of blood, or clots, is not normal. or girls with a positive family history.64
The hymen has some opening in the major- Although screening leads to earlier iden-
ity of females. A completely imperforate tification, 60% to 80% of the hips identi-
hymen may result in the development of fied as abnormal by physical examination
hydrometrocolpos. This is usually heralded and more than 90% of those identified by
by the bulging hymen which is particularly ultrasound resolve spontaneously. Avascu-
prominent with crying. Virilization of the lar necrosis of the hip is reported in up to
female infant consists of varying degrees of 60% of treated children and no screening
clitoral hypertrophy and labioscrotal fusion. method has been shown to reduce the need
A mass in the labia or groin may be a hernia, for operation for the disorder.65
but consideration must be given to the pos-
sibility of an ectopic gonad, which may be The Extremities
either an ovary or a testis. Careful inspection of the extremities alone
usually determines whether the extremities
Anus are well formed. Joint contractures, asym-
The presence, patency, and location of the metries, or dislocations should be noted.
anus should be noted. An absent (imperfo- Erb palsy is manifested by an arm that is
rate) anus will require surgery, but should extended alongside the body with internal
also bring to mind the possibility of rotation and demonstrates limited move-
other associated anomalies, in particular, ment. The humerus and femur are the sec-
esophageal atresia (VATER association— ond and third most commonly fractured
vertebral defects, anal defects, tracheoesoph- bones at delivery. Abnormalities of the
ageal atresia, renal defects or VACTERL digits (shortening, tapering, syndactyly,
association—vertebral defects, anal defects, polydactyly), single palmar creases, and
cardiac defects, tracheoesophageal atresia, nail hypoplasia can be important clues to
renal defects, limbs defects). dysmorphic syndromes. Variations caused
by intrauterine positioning are seen and
Hips need to be differentiated from true equino
Examination of the hips of the neonate is varus deformities. Positional deformities
performed on all infants to detect devel- of the foot can usually be distinguished by
opmental dysplasia of the hip (DDH). This the presence of a normal range of motion
disorder is more common in females, if and ability to establish a normal position
there is a family history, infants with under- and appearance of the foot with gentle
lying neurologic abnormalities, and those pressure.
presenting in the breech position. The
infant must be relaxed because crying or The Back
kicking results in tightening of the muscles The back is examined for the presence
around the hip. There may be asymmetry of abnormal curvatures and evidence of
of skinfolds around the hip and shortening an abnormality overlying the spine. The
of the affected leg. It should be possible to presence of a tuft of hair, a subcutaneous
abduct both hips; full abduction may not lipoma, sinus, hemangioma, dimples sepa-
be possible if the hip is dislocated. The Bar- rate from the gluteal crease, aplasia cutis,
low maneuver is performed to check if the or skin tag should raise suspicion regard-
hip is dislocatable posteriorly by adduct- ing the possibility of an underlying occult
ing a flexed hip with gentle posterior force dysraphic state. If these abnormalities are
to push the femoral head posteriorly out found, an ultrasound examination of the
of the acetabulum. The Ortolani maneu- involved area of the spine should be under-
ver checks if a dislocated hip can be relo- taken. Finding of a structural aberration
cated into the acetabulum by abducting a requires intervention in the neonatal period
flexed hip with gentle anterior leverage of or at least in very early infancy to prevent
the femur. If the examination is abnormal, the development of neurologic deficits.
a hip ultrasound and orthopedic consul-
tation should be arranged. The American CONCLUDING THE PHYSICAL
Academy of Pediatrics does not recom- EXAMINATION
mend routine ultrasound screening of all After completion of the examination, the
infants but only for female infants born in infant’s parents can usually be reassured
the breech position and optional hip ultra- that the examination was normal, and can
sound for boys born in the breech position be congratulated on their baby’s birth. Any
abnormalities or potential problems should

What types of problems can you anticipate
be explained to them. Parents should be pro-
that you will need to address in the delivery
vided with the opportunity to inquire about
room, and what measures will you take to
any concerns they have about their baby.
be prepared?
It also provides an opportunity to check
on feeding and preventive care includ- This is a complicated, but not uncommon, scenario.
ing immunization, universal neonatal bio- With a lack of regular obstetrical care, the gestational
chemical screening, hearing screening, and age of the baby is uncertain. The baby may be preterm
advice about prevention of sudden infant or term. In either case, the infant care center must be
death syndrome (SIDS). It also provides the warm, and towels for drying the baby must be avail-
opportunity to check that appropriate fol- able. If the infant is at term, he appears to be growth
low-up arrangements are in place. restricted and has shown evidence of not tolerating the
stress of labor. The necessary supplies for airway man-
agement and suctioning must be present in the area. If
the infant is preterm, meconium aspiration is less likely,
CASE 1 but respiratory distress is still a distinct possibility.
Baby Boy K is born at 40 weeks’ gestation with a At delivery, there was no meconium, and the baby
birth weight of 2200 g, a length of 46 cm, and a head needed only towel drying, clearing of the airway, and a
circumference of 32 cm. The physical examination is brief period of supplemental oxygen for resuscitation.
remarkable for short palpebral fissures, a small jaw, a In the delivery room, the following are noted: bilater-
smooth filtrum, and thin upper lip. ally descended testes, stiff ear cartilage, scant vernix
caseosa, well-developed areolae but poor breast tis-
What is this combination of features most sue development, and decreased muscle tone. The
consistent with? baby’s weight is 1800 g, length is 48 cm, and head
A. Trisomy 21 circumference is 32 cm. There are no obvious anom-
B. Fetal alcohol syndrome alies on the initial examination, and the examination of
C. Congenital cytomegalovirus infection the abdomen, heart, and lungs is normal.
D. Beckwith-Wiedemann syndrome
This constellation of findings is most suggestive of What is your assessment of his gestational
(B), fetal alcohol syndrome (FAS). All but (D) can be age and his classification?
associated with growth restriction, often “symmetri- This baby is likely a term, SGA infant. The findings
cal.” Beckwith-Wiedemann syndrome is typically as- of the descended testes, stiff ear cartilage, lack of
sociated with macrosomia. Other physical findings vernix, and well-developed areolae support this con-
suggestive of FAS include eyelid ptosis, short nose, tention. The decreased muscle tone may be related
small distal phalanges, and small fifth fingernails. to exposure to magnesium. A complete Ballard ex-
Long-term prognosis for these children is somewhat amination needs to be carried out during the first 24
guarded, with the majority being developmentally de- hours to confirm the gestational age.
layed, often to a severe degree.
What problems will you anticipate for this
infant in the next 24 to 48 hours?
As an apparently term SGA infant, he is at risk for
thermoregulation difficulties, hypoglycemia, polycythe
CASE 2 mia, and possibly hypocalcemia.
You are called to attend the delivery of Baby Boy
G at uncertain gestation, who is to be delivered by Why is this baby so small?
emergency cesarean section after fetal distress is Several features place this baby at risk for poor
manifested by late fetal heart rate decelerations with growth: teenage mother, poor maternal weight gain
uterine contractions. The fetal membranes are intact. during pregnancy, smoking, and apparent pregnancy-
The estimated fetal weight (determined by ultrasound associated hypertension. How far to pursue further
during labor) is 2 kg. The mother is a 15-year-old nul- evaluation for other etiologies (chromosomal abnor-
liparous female who had a prenatal course notable malities, congenital infections) will vary among clini-
for smoking, a weight gain of 12 pounds, and infre- cians, but in the absence of other clinical abnormalities,
quent visits to the clinic. She was admitted in ac- the yield from further investigations is very low.
tive labor and was found to have a blood pressure
of 160/110 and proteinuria. She was subsequently REFERENCES
given magnesium sulfate for preeclampsia for several
hours before the delivery.
The reference list for this chapter can be found
The Physical
Environment
Avroy A. Fanaroff and Marshall H. Klaus
6
The foetus was no larger than the palm of his hand, but the father…put his
son in an oven, suitably arranged…making him take on the necessary increase
of growth, by the uniformity of the external heat, measured accurately in the
degrees of the thermometer.
Laurence Sterne
An understanding of the thermal require- temperatures but varying humidity caused

ments of the high-risk infant was slow to no difference in survival.
develop. Pierre Budin,1 historically the first Hill, in part, clarified the profound effects
neonatologist, had perhaps the earliest of environmental temperature on survival
insight into the clinical importance of the observed by Silverman et al.4-6 working with
thermal environment. In 1907 in his book, kittens and guinea pigs; she found that in
The Nursling, he emphasized the need for 20% oxygen, oxygen consumption and rectal
temperature control after noting a markedly temperatures varied with the environmen-
increased survival rate when the infant’s rectal temperature (Fig. 6-1). She noted a set of
tal temperature was maintained (Table 6-1). thermal conditions at which heat production
He recommended an air temperature of 30° (measured as oxygen consumption) is mini-
C (86° F) for the small (1 kg), fully clothed mal, yet core temperature is within the nor-
infant. Sadly, his observations were neither mal range (neutral thermal environment).
fully understood nor appreciated in the first When the animals were cooled while breath-
50 years of the 20th century. In addition, ing room air, their oxygen consumption
during this period, the clinical value of two markedly increased and body temperature
variables (temperature and humidity) was was maintained. However, when they were
confused. given 12% oxygen and cooled, oxygen con-
The modern era of neonatology was her- sumption did not increase, and the animals’
alded by Silverman et al. in three sequen- body temperatures decreased. This, as well as
tial analyses,2-4 whereby they resolved the the work of Bruck and others,7 has empha-
importance and relationships between the sized that the human infant is a homeo-
incubator temperature and relative humid- therm and not a poikilotherm, as is a turtle.
ity. In the first study, the researchers com- If a nonhypoxic infant is cooled, the infant
pared high and low humidity in two groups maintains body temperature by increasing
of infants. Infants in the high humidity the consumption of calories and oxygen to
group had a lower mortality rate but higher produce additional heat. Homeotherms pos-
rectal temperatures. In the second study, to sess mechanisms that enable them to main-
end the confusion caused by two variables, tain body temperature at a constant level,
they controlled the humidity and examined more or less accurately, despite changes in
the effect of varying only environmental the environmental temperature. In contrast,
temperature. They noted a striking dif- the body temperature of a turtle decreases if
ference in survival rates. With only a 4° F it is placed in a cool environment.
increase in incubator temperature (from The increased survival rate in the warmer
85° F to 89° F), they observed a 15% increase environment observed by Budin and Silver-
in survival rate at the higher temperature man presumably resulted from the decreased
(68.1% versus 83.5%), with the biggest dif- oxygen consumption and carbon dioxide pro-
ference affecting the smallest infants. In a duction as environmental conditions approx-
further study, controlling environmental imated the neutral thermal environment. An
132
CHAPTER 6 The Physical Environment 133
Infants’ Temperatures the infant’s body and the warm air from the
Table 6-1. lungs over a given period if the mean body
and Survival Rate
temperature is to remain constant. A char-
Temperature Survival Rate acteristic of the homeothermic infant is the
32.5° C to 33.5° C 10%
ability to produce extra heat in a cool envi-
36.0° C to 37.0° C 77% ronment. In the adult, additional heat pro-
duction can come from (1) voluntary muscle
activity, (2) involuntary tonic or rhythmic
muscle activity (at high intensities, charac-
terized by a visible tremor known as “shiver-
ing”), and (3) nonshivering thermogenesis.
temperature (° C)
37 The latter is a cold-induced increase in oxy-

gen consumption and heat production,
Rectal
oxia which is not blocked by curare, a drug that

Hyp
Normal (21%) prevents muscle movements and shivering.
Hypoxia (12%) In the adult, shivering is quantitatively the
most significant involuntary mechanism
15 of regulating heat production, whereas in
Oxygen consumption
the infant, nonshivering thermogenesis is

probably most important. From animal and
(mL/kg/min)
10
human studies, it can be inferred that, in
the human infant, the thermogenic effector
5 organ—brown fat—contributes the largest
Hypoxia
Thermal neutral percentage of nonshivering thermogenesis.
zone
0 20 25 30 35 40 45
BROWN FAT
Environmental temperature (° C) More abundant in the newborn than in
Figure 6-1. Effect of environmental temperature on the adult, brown fat accounts for about 2%
oxygen consumption, breathing air, or a hypoxic mixture. to 6% of total body weight in the human
infant. Sheets of brown fat may be found
at the nape of the neck, between the scapu-
lae, in the mediastinum, and surrounding
immature infant with a minimal ability to the kidneys and adrenals.8 Brown fat dif-
transfer oxygen and excrete carbon dioxide fers from the more abundant white fat. The
across his or her lungs has the least chance cells are rich in mitochondria and contain
of becoming hypoxic or developing a respi- numerous fat vacuoles (as compared with
ratory acidosis—increased Paco2—if main- the single vacuoles in white fat). Brown fat
tained in an environment that minimizes contains a dense capillary network and is
oxygen consumption or metabolic rate. richly innervated with sympathetic nerve
Maintaining the neutral thermal environ- endings on each fat cell. The special prop-
ment became the first and foremost founda- erty of brown fat is the uncoupling pro-
tion of the modern era of neonatal intensive tein, which results in the oxidation of food
care. Recently, controlled cooling has been to heat rather than energy-rich phosphate
introduced to reduce the metabolic require- bonds. Its metabolism is stimulated by nor-
ments of the brain and so to reduce injury epinephrine released through sympathetic
in full-term infants with moderate to severe innervation, resulting in triglyceride hydro-
hypoxic-ischemic encephalopathy. lysis to free fatty acids (FFAs) and glycerol.
This chapter will summarize key elements The initiation of nonshivering thermo-
of thermal regulation in addition to other genesis at birth depends on cutaneous cool-
important factors in the physical environ- ing, separation from the placenta, and the
ment as they relate to the sick newborn. euthyroid state. The acute surge in thyroid
hormones at birth appears to be of limited
PHYSIOLOGIC CONSIDERATIONS importance with regard to the immediate
control of thermogenesis, whereas the intra-
HEAT PRODUCTION cellular conversion of T4 to T3 and the effects
The heat production within the body is a of norepinephrine appear to be of greater sig-
byproduct of metabolic processes and must nificance.9 Stimulation of the sympathetic
equal the heat that flows from the surface of nervous system by cold exposure markedly
134 CHAPTER 6 The Physical Environment
increases local norepinephrine turnover The heat transfers from the surface of the
within brown adipose tissue, which may body to the environment of water. This heat
not be reflected by an increase in circulating transfer is complex, and the contribution
catecholamines.10 This results in a marked of each component involves four means
increase in oxygen consumption without of loss: (1) by radiation; (2) by conduc-
any appreciable increase in physical activity. tion; (3) by convection; and (4) by evapo-
Interesting observations made in sheep ration—influenced by the temperature of
noted that cooling of the fetus results in the surroundings (air and walls), air speed,
very small increases in FFAs and a significant and water vapor pressure, Of special clinical
decrease in body temperature. Ventilation importance to the pediatrician is the consid-
of the fetus with increasing Po2 resulted in erable increase in radiant heat loss from the
a slight increase in FFAs, whereas clamping infant’s skin to the cold walls of incubators.
the cord resulted in a sharp increase in FFAs Radiant heat loss is related to the tem-
and glycerol. These and other observations perature of the surrounding surfaces, not air
suggest that before birth there is an inhibi- temperature. When incubators are in cool
tor to thermogenesis, probably produced by surroundings (e.g., during transfer) the inner
the placenta.11 Possible candidates for the surface temperature of the single-walled
inhibitor are adenosine or prostaglandin incubator declines well below that of the
E2. The nonshivering thermogenesis occur- air temperature in the incubator. In caring
ring in the brown fat during cooling can be for the infant, this problem is easily solved
turned off with hypoxia (see Fig. 6-1), and by wrapping him or her in a light covering
the sensory receptors for this are most prob- (transparent if necessary). The surrounding
ably the carotid body afferents. radiant temperature is then close to body
temperature and more under the influence
of the incubator air temperature.13
EDITORIAL COMMENT: There also appears to be a
relationship between feeding and brown adipose tis- EDITORIAL COMMENT: Because heat may be trans-
sue (BAT) activity in rats. Initiation of feeding is medi- ferred by four different routes, the physical characteris-
ated by a transient dip in blood glucose concentra- tics of the newer incubators and radiant heaters should
tion caused by stimulated glucose utilization in BAT. be familiar to the caretakers. Devices used to maintain
Feeding continues while BAT and core temperature thermal stability in preterm infants have advanced over
continue to rise. Termination is induced by the high time so that the latest, most advanced, user friendly,
level of core temperature brought about by the epi- and developmentally supportive microenvironment is
sode of stimulated BAT thermogenesis. The time be- possible for even the smallest, least mature infants. En-
tween initiation and termination determines the size of gineers continue to design the most efficient and effec-
the meal and depends on the balance between BAT tive means of assisting clinicians to achieve the neutral
thermogenesis and heat loss, and thus on ambient thermal environment, and at the same time offering the
temperature. The underlying cause of the episodic clinicians clear observation and access to the infant.
stimulation of sympathetic nervous system activity The current generation of combined incubator-radiant
is a decline in core temperature to a level recognized warmers improves their chances of survival (Giraffe ®,
by the hypothalamus as needing a burst of increased Omnibed ®, Versulet). Furthermore, as noted, meticu-
heat production. Thus, BAT thermogenesis is impor- lous attention to keeping babies warm in the delivery
tant in control of meal size, relating it to thermoregula- room has become the standard of care.
tory needs. The phenomenon is termed thermoregula-
tory feeding, to distinguish it from feeding initiated by
other stimuli.12 In very small infants (<1500 g), evapora-
tive heat loss is increased in the first days
of life, the result of very thin skin that is
The physiologic control mechanisms of unusually permeable to water (Fig. 6-2). For
the infant may alter the internal gradient further discussion, see Chapter 9.
(i.e., vasomotor) to change skin blood flow. The effect of environmental temperature
The external gradient is of a purely physi- on heat production (oxygen consumption)
cal nature. The large surface-to-volume ratio is considered in Figure 6-3. As the environ-
of the infant (especially those weighing less mental temperature is decreased below point
than 2 kg) in relation to the adult and the A (critical temperature), oxygen consump-
thin layer of subcutaneous fat increase the tion increases. Body temperature, however,
heat transfer in the internal gradient. is maintained if heat production is adequate.
Total heat production Evaporative heat loss
temperature
Body
60
37° C
50
kcals/kg/d
40
Inevitable
Thermoregulatory
30 Inevitable body body
range
cooling heating
20
10 Death from Death from
Summit heat
cold
0 metabolism
0.88- 1.25 1.25 - 1.75 1.75 - 2.25 2.25 - 2.88 Range of
oxygen consumption
Heat production or
Birth weight (kg) thermal
neutrality
Figure 6-2. Relative role of evaporative heat loss at
different birth weights.
Decreasing body Chemical
Increasing
temperature regulation
body
“B” “A” temperature
If cooling is severe and body temperature
drops below point B, with cold paralysis of Environmental temperature
the temperature regulation center, oxygen Figure 6-3. Effect of environmental temperature on
consumption also drops—two-to three-fold oxygen consumption and body temperature. (Adapted
for every 10° decrease in body temperature. from Merenstein G, Blackmon L: Care of the high-risk
Homeothermy can also be abolished by sed- newborn, San Francisco Children’s Hospital, 1971.)
ative drugs and brain injury. Not all babies
are homeotherms all the time. EDITORIAL COMMENT: Claiming that the opti-
Figure 6-3 shows that oxygen consump- mal thermal environment for sick preterm infants is
tion is minimal in two areas: the neutral unknown, Genzel-Boroviczény et al.16 in a random
thermal environment and severe hypother- manner, compared the effect of setting the incubator
mia. For many years, cardiac surgeons have temperature to an abdominal wall temperature of 36.5°
taken advantage of the minimal meta- C (neutral temperature [NT]) or to a minimal tempera-
bolic rate with body cooling (temperatures ture difference (<2° C) between abdominal wall and
below point B). More recently, cooling has extremities (comfort temperature [CT]). They correctly
been added to neuro-intensive care for term speculated that this could affect the microcirculation
infants with hypoxic-ischemic encepha- perfusion, which they assessed with near-infrared pho-
lopathy. Under normal circumstances in to-plethysmography (NIRP) at these two target temper-
the neonatal intensive care unit, caregiv- atures between days 1 and 4 of life in preterm infants
ers strive to maintain the infant in a warm with normal or impaired (RED group) microcirculation
environment (the neutral thermal environ- as determined by a clinical score. They concluded that
ment, or the so-called “zone of thermal com- increasing the incubator temperature to CT changes
fort”). It is important clinically to note that thermoregulatory flow to the extremities in preterm in-
the infant may not be in a neutral thermal fants with impaired microvascular perfusion and might
environment and yet the rectal temperature improve tissue flow. So the issue of how to best set
may be in the normal range. As emphasized the neutral thermal zone without measuring energy
by Hey and Katz,14 “body temperature alone expenditure remains unresolved. The old-fashioned in-
fails to indicate whether a baby is subjected crease in toe-tummy temperature differential is still a
to thermal stress: it can only alert us to situa- valuable indicator of ill health and potential sepsis.
tions in which the thermal stress has been so
severe that the baby’s normal thermoregula-
tory mechanisms have been at least partially Hypothermia and hyperthermia develop
overpowered.” Rectal temperature drops only more rapidly in the neonate than in the
when the baby’s maximum effort to preserve adult. The infant has a lower capacity for heat
and produce heat fails. The first mechanism storage because of the higher temperature
to preserve heat is vasoconstriction, and this of the body shell in relation to the environ-
phenomenon can easily be detected by mea- ment and the larger surface-to-volume ratio.
suring skin temperature at a peripheral part Thus, the thermoregulatory system of the
of the body. A sensitive method to detect homeothermic infant adjusts and balances
vasoconstriction is to measure both rectal heat production, skin blood flow, sweat-
and sole of the foot temperatures.15 ing, and respiration in such a way that the
body temperature remains constant within analgesia is associated with maternal fever
a control range of environmental tempera- due to inability of the mother to dissipate
tures. The control range refers to the range of heat. Nulliparity and dysfunctional labor are
environmental temperatures at which body also significant cofactors in the fever attrib-
temperature can be kept constant by means uted to epidural analgesia. Lieberman noted
of regulation. The control range of the infant intrapartum fever higher than 100.4° F
is more limited than that of the adult because in 14.5% of women receiving an epidural,19
of less insulation. For the nude human adult, but in only 1.0% of women not receiving
the lower limit of the control range is 0° C an epidural (adjusted odds ratio [OR] = 14.5,
(32° F), whereas for the full-term infant it is 95% CI = 6.3, 33.2). Neonates whose moth-
20° C to 23° C (68° F to 73.4° F). ers received epidurals were more often eval-
The insufficient stability of body tem- uated for sepsis and treated with antibiotics.
perature in the small premature infant does Although 63% of women received epidur-
not indicate an immaturity of temperature als, 96.2% of intrapartum fevers, 85.6% of
regulation because the system is intact. As neonatal sepsis evaluations, and 87.5% of
pointed out by Bruck,7 the insufficient sta- neonatal antibiotic treatment occurred in
bility “seems to be due to the discrepancy the epidural group. Compared with contin-
between efficiency of the effector systems uous infusion, intermittent epidural injec-
and body size.” The newborn infant has a tions appear to protect against intrapartum
well-developed temperature regulation but fever in the first 4 hours of labor analge-
a narrower control range than the adult. sia. This may be due to intermittent partial
recovery of heat loss mechanisms between
injections.20
EDITORIAL COMMENT: As emphasized by the late
Albert Okken, the body surface-to-mass ratio of very
immature and very low birth rate infants is about five EDITORIAL COMMENT: As noted above, the asso-
times higher than in adults. The disadvantage of this ciation between the use of epidural analgesia for pain
relatively very large surface area of the premature in- relief in labor and intrapartum maternal fever has been
fant observed at both ends of the thermal spectrum. established in both observational and randomized tri-
There is rapid heat loss in a cool environment and als. There has been a suggestion, too, of an increase
rapid overheating in a heat-gaining environment. in adverse neonatal outcomes with intrapartum ma-
ternal fever. Greenwell et al.* confirm that maternal
temperature above 100.4° F developed during labor
IN UTERO in 19.2% (535/2784) of women receiving epidural
While the fetus is in utero, the heat pro- compared with 2.4% (10/425) not receiving epidural.
duced is dissipated through the placenta to Furthermore, maternal temperature above 99.5° F was
the mother. If complete placental separation associated with adverse neonatal outcomes. The rate
occurs in utero, the temperature of the fetus of adverse outcomes (hypotonia, assisted ventilation,
increases rapidly. Normally the temperature 1-and 5-min Apgar scores below 7, and early-onset
of the fetus is 0.6° C above the mother’s seizures) increased two- to six-fold with maternal tem-
temperature. When the mother’s tempera- perature above 101° F. Without temperature elevation,
ture increases secondary to infection or epidural use was not associated with adverse neona-
move commonly with the use of an epidu- tal outcomes.
ral analgesia for labor, the fetal tempera- *Greenwell E et al: Intrapartum temperature elevation,
ture increases to about 0.6° C higher than epidural use, and adverse outcomes in term infants,
the mother’s. Approximately 30% to 40% Pediatrics 129:e447, 2012.
of women receiving an epidural anesthetic
in early labor are noted to have a fever in
late labor, the cause of which is unknown.17 AFTER BIRTH
The thermoregulatory system works well for Hypothermia is a major cause of morbidity
the fetus except during periods when the and mortality in infants; therefore, main-
mother has an increasing body temperature. taining normal body temperatures in the
Schouten et al. studied the temperatures delivery room is crucial. An understanding
of women during labor and observed that the of how infants produce heat and what can
mean temperature increased from 37.1° C be done to maintain normal body temper-
at the beginning of labor to 37.4° C after atures in full-term and preterm infants is
22 hours.18 Circadian temperature patterns essential for the preservation of thermal sta-
were not observed during labor. Epidural bility in this population.
At birth, the infant’s core temperature Cooling

decreases rapidly, owing mainly to evapora-
tion from his or her moist body. The infant’s Norepinephrine
Peripheral
small amount of subcutaneous tissue and vasoconstriction
large surface area-to-mass ratio compared
with the adult, together with the cold air
and walls of the delivery room, also result Pulmonary Increasing
vasoconstriction acidosis
in large radiant and convective heat losses.
Oxygen should always be warmed. Thus,
under the usual delivery room conditions, Pulmonary Anaerobic
deep body temperature of human newborns artery pressure metabolism
can decrease 2° C to 3° C unless special pre-
cautions are taken.
Although moderate to severe cooling may Right-to-left Hypoxia
shunting
result in metabolic acidosis, a lower arterial
oxygen level, and hypoglycemia in the new- Figure 6-4. The vicious circle resulting from cooling in the
neonate.
born infant, very slight cooling of the infant
may be beneficial in his or her adaptation to
extrauterine life. Cooling of the skin recep- Keeping vulnerable preterm infants warm
tors may play a significant role in initiating is problematic even when recommended
respiration and stimulating thyroid func- routine thermal care guidelines are followed
tion. The vasoconstriction and peripheral in the delivery suite. McCall et al. performed
resistance observed with mild cooling also a Cochrane review to assess efficacy and
alters systemic vascular resistance, thereby safety of interventions designed for pre-
reducing the right-to-left shunting of blood vention of hypothermia in preterm and/or
through the ductus arteriosus. With severe low-birth-weight infants applied within 10
cooling, a vicious circle can result in severe minutes after birth in the delivery suite com-
hypoxia and even death (Fig. 6-4). The pared with routine thermal care.23 Barriers to
neonatologist chooses to keep the infant heat loss such as plastic wraps or bags were
warm following delivery to prevent meta- effective in reducing heat losses in infants
bolic acidosis and possibly dangerous reflex less than 28 weeks’ gestation but not in
responses to cooling. infants 28 to 31 weeks’ gestation. Plastic
caps were effective in reducing heat losses in
infants less than 29 weeks’ gestation. There
was insufficient evidence to suggest that
EDITORIAL COMMENT: The body temperature of
either plastic wraps or plastic caps reduce the
preterm babies can drop precipitously after deliv-
risk of death during the hospital stay. There
ery.21 Reports of hypothermia in babies of all birth
was no evidence of significant differences in
weights, on admission to neonatal units have come
other clinical outcomes for either the plas-
from all over the world. Recent reports that showed
tic wrap/bag or the plastic cap comparisons.
that hypothermia on admission to neonatal units is
Stockinet caps were not effective in reducing
an independent risk factor for mortality in preterm
heat losses.
babies have refocused attention on the need for me-
External heat sources, including trans
ticulous thermal care immediately after birth and dur-
warmer mattresses and SSC, were shown
ing resuscitation. Their data lend weight to the view
to be effective in reducing the risk of hypo-
that conventional approaches to thermal care of the
thermia when compared to conventional
very preterm and low-birth-weight baby are out-
incubator care. The authors concluded that
moded. Bathing newborn babies shortly after birth
plastic wraps or bags, plastic caps, skin-to-
increases the risk of hypothermia despite the use of
skin care (SSC), and transwarmer mattresses
warm water and skin-to-skin (SSC) care for thermal
all keep preterm infants warmer, leading to
protection of the newborn.22 During the first 12 hours
higher temperatures on admission to neo-
of life, the temperature in extremely low-birth-weight
natal units and less hypothermia. However,
infants may also decrease with procedures such as
the small numbers of infants and studies
umbilical line insertion, intubation, obtaining chest
and the absence of long-term follow-up
x-rays, manipulating intravenous lines, repositioning,
mean that firm recommendations for clini-
suctioning, and even taking vital signs. Precautions
cal practice cannot be given.
should be undertaken to prevent heat loss during
Simon et al. compared thermal mat-
these procedures.
tresses (sodium acetate) with a plastic wrap
for extremely low gestational age newborns During the first day, the Tc was lower than
(ELGANs) between 24 and 28 weeks’ ges- the sole of the foot nearly 20% of the time,
tation with a birth weight less than 1250 suggesting a slow vasomotor response to
grams.24 Although the mattress was superior cold stress in these very immature infants.
to the plastic wrap and both improved the To prevent cold stress in this group, Tc was
thermal status of ELGANs, they concluded greater than 37.5° C 12% of the time. The
that all current interventions fall short of normal pattern of Tc greater than Tp was
fully protecting all these vulnerable infants seen more commonly after the first day.
from thermal stress. In infants weighing less than 1000 g, a Td
Trevisanuto et al. conducted a randomized greater than 2° C can be caused by poor per-
trial and concluded that for very preterm fusion resulting from hypovolemic shock.
infants,25 polyethylene caps are comparable In these infants, there was other evidence
with polyethylene occlusive skin wrapping of hypovolemia 11% of the time (such as
to prevent heat loss after delivery. Both these increasing heart rate or decreasing blood
methods are more effective than conven- pressure). With hyperthermia (Td less than
tional treatment; however, many babies are 1° C) heart rate increased. If the Tc was
still admitted with low temperatures. greater than 38° C with Td greater than 1° C,
the infant was investigated to rule out hypo-
TEMPERATURE CONTROL IN THE VERY volemia and sepsis.
LOW-BIRTH-WEIGHT INFANT For appropriate for gestational age infants
Even though infants with a birth weight weighing less than 1500 g, it is recom-
less than 1250 g make up less than 1% of mended that the infants be nursed in dou-
the total babies born annually in the United ble-walled incubators, with low air velocity
States, they frequently constitute a signifi- and additional humidity for the first week
cant percentage of the babies in the inten- of life. Td should be maintained at less than
sive care nursery. Very low-birth-weight 1° C. Modern incubators provide such an
(VLBW) infants’ limited ability to produce environment.
heat, their increased evaporative water loss
at birth secondary to extremely thin skin, NUTRITION AND TEMPERATURE
as well as their small heat capacity (the Because of the relationship between meta-
result of their large surface-to-volume ratio) bolic rate and body temperature, both fluid
make them unusually susceptible to cold and nutritional requirements for growth are
stress.10,26 intimately linked with temperature regu-
Because one of the first responses to lation. This is especially important to the
thermal stress in these infants is a change small premature infant maintained in a
in peripheral vasomotor tone with vasodi- slightly cool environment. Caloric intake is
lation when overheated and vasoconstric- limited by the small capacity of his or her
tion with cooling, a continuous assessment stomach. Fewer calories would be required
of central and peripheral temperatures for maintenance of body temperature if
and their difference is clinically helpful in the infant was in a warmer environment;
promptly interpreting the effect of the ther- thus, in the neutral thermal environment,
mal environment on the infant.15 caloric intake can be more effectively used
In a study of the first 5 days of life in 79 for growth.
infants weighing less than 1000 g and 71 The insensible loss of water parallels
infants weighing 1000 to 1500 g, central the metabolic rate, with 25% of total heat
temperature (Tc) was measured with an produced being dissipated in this manner.
abdominal skin probe over the liver and Thus, an elevated metabolic rate results in
peripheral temperature (Tp) on the sole of elevated fluid losses and, hence, increased
the foot to calculate the central-peripheral fluid requirements. The neutral thermal
temperature difference (Td). The nursing temperature allows for small feedings and
care attempted to keep the abdominal skin reduced caloric requirements for growth.
temperature between 36.8° C and 37.2° C to Glass et al. were able to quantitate the
maintain a Td of less than 1° C. The infants effect of temperature control on growth,28
were nursed in a double-walled incubator comparing 12 matched, healthy, small
with 80% humidity, and the nurses altered infants aged 1 week -who weighed between
the air temperature.27 In the heavier babies, 1 and 2 kg. These infants were divided into
the Tc had a constant median value of 36.7° C a “warm” group (abdominal skin tempera-
and increased to 36.9° C for the next 4 days. ture maintained at 36.5° C [97.7° F]) and
a “standard” group (abdominal skin tem- were thoroughly dried immediately after
perature maintained at 35° C [95° F]). Both birth and placed either on their mother’s
groups received 120 kcal/kg/d. Those in the chest and abdomen and covered with a light
warm group showed a significantly more blanket or wrapped in cotton blankets and
rapid increase in body weight and length; placed in a cot. The infants placed skin-to-
however, their cold resistance (ability to skin warmed significantly faster than those
prevent a decrease in deep body tempera- in the cot. Oxygen consumption measure-
ture in a cool environment) was diminished. ment while skin-to-skin revealed that they
Identical growth rates could be obtained by were in a neutral thermal environment.32
increasing caloric input intake the standard Thus, for the normal full-term infant, skin-
group. to-skin on the mother’s chest is an ideal
It is, therefore, difficult to decide whether location for the first 2 hours of life. Also,
the premature infant, after the early neo- this would allow the infant to crawl to the
natal period, should be maintained in the mother’s breast and begin to suckle on his
neutral thermal environment for optimal or her own.
growth or be prepared for some of the rigors Skin-to-skin care has been practiced in
of a cold apartment or house. primitive and high technology cultures for
body temperature preservation in neonates.
Karlsson measured regional skin tempera-
ture and heat flow in moderately hypother-
EDITORIAL COMMENT: Longitudinal data on rest-
mic term neonates (mean rectal temperature
ing energy expenditure (REE) in extremely immature
of 36.3° C) and observed that the mean
infants and full-term neonates are scarce, but are
rectal temperature increased by 0.7° C
necessary to understand the energy requirements in
when placed skin-to-skin on their mothers’
neonatal nutrition during the first weeks of life. REE
chests.33 Caution must be exercised when
values increased in all gestational age groups from
attempting this in very immature infants.
the first week to 5 to 6 weeks of postnatal age, with
Bauer noted no significant changes in tem-
the most pronounced increase in the smallest infants
perature or oxygen consumption in the first
(+140%) and the smallest increase in the full-term
postnatal week for infants between 28 and
neonates (+47%).29 Knowledge of the energy require-
30 weeks’ gestation34; however, infants of
ments is critical to meet the goals and ensure growth.
25 to 27 weeks of gestational age lost heat
Furthermore, the ability to modify energy expenditure
during skin-to-skin contact. They recom-
(EE) is extremely helpful when energy intake is limited,
mended postponing skin-to-skin care for
which is why careful attention to the thermal environ-
these infants until week 2 of life, when their
ment is so important for very immature babies. Music
body temperature remains stable and they
such as Mozart may help, too. Lubetsky et al. present
are calmer during skin-to-skin contact than
evidence that music generally may help premature
in the incubator.
infants by lowering stress hormone levels, leading to
enhanced weight gain and growth.30 INCUBATORS
In the United States, most intensive care
units have double-walled incubators in
PRACTICAL APPLICATIONS which the temperature of the inner wall
of the incubator is not affected by a cooler
DELIVERY ROOM room temperature. However, because sin-
The temperature of the delivery room is gle-walled incubators are still found in the
frequently set for the comfort of the medi- United States and many countries through-
cal staff rather than for the comfort of the out the world and the temperature of the
newborn. Careful and immediate drying single walls cannot be controlled, it should
of the infant’s entire body remains critical be emphasized that the radiant heat loss of
in minimizing evaporative heat loss. Many the infant to the wall of these incubators
pieces of equipment are available to warm varies. Figure 6-5 indicates how the tem-
the infant—in particular, incubators and perature of the inner wall of the incubator
radiant warmers. However, the warm body decreases with cooler room temperatures—
of the mother is well-suited to meet this a major disadvantage when nursing a sick
need. Christensson compared body tem- infant. If the nursery is cool (23.8° C to
peratures over the first 90 minutes of life in 15.6° C [75° F to 60° F]) or if the incubator
healthy full-term neonates cared for with is placed near a cool window or wall, it is
skin-to-skin with their mothers.31 Infants difficult—usually impossible—to locate and
b
32
Mean incubator radiant
wall temperature (°C)
30 Short wave
radiant heat a
from the sun
28 With shield
a
Without shield
Figure 6-6. Inner heat shield provides warm inner walls
10 20 30 to minimize radiant heat loss in cool nursery (a). Long
Room temperature (°C) wave radiant exchange between baby and heat shield
Figure 6-5. Effect of using heat shield (see Fig. 6-6) on and between inner wall of incubator and heat shield. Long
mean incubator wall radiant temperature at varying room wave radiant exchange between incubator walls and
temperatures. surroundings (b).
maintain the neutral thermal environment. Table 6-2 and Figure 6-7 are general
The infant loses heat to the cold incubator guides for roughly locating the neutral tem-
wall and needlessly increases oxygen and perature if the walls of the incubator are
caloric consumption in his or her efforts to warm and within 1° C of the incubator air
stay warm. The magnitude of this loss can temperature. When estimating neutral tem-
be predicted if room temperature is known. peratures in single-walled incubators, add
Hey and Katz found that operative tempera- 1° C to all the temperatures in the table for
ture (true environmental temperature, tak- every 7° C that incubator air temperatures
ing into account radiation and convection) exceed room temperatures. The abdominal
decreased 1° C below incubator temperature skin temperatures in very low-birth-weight
for every 7° C that incubator air exceeded infants during the first 5 days of life are
room temperature.14 Unless the incubator, depicted in Figure 6-9, B.
room air, and radiant surfaces have similar If an incubator is placed in the sunlight,
temperatures, innumerable thermal condi- the short wavelength radiant emission goes
tions can exist. through the plastic wall and can overheat
Different types of adaptations prevent the infant because long wave re-radiation
radiant heat loss and allow a precise and con- through the plastic wall is prevented (the
trolled thermal environment. One method is “greenhouse effect”) (see Fig. 6-6).
to warm the nude infant with warm air and
heated incubator walls (using either a layer RADIANT HEATERS
of warm water or electrically conductive plas- When radiant heat panels are placed above
tic paneling). the infant without a complete enclosure,
These expensive procedures have been there is a large increase in insensible water
obviated by Hey, who has developed a small loss. A minimal oxygen consumption can
clear plastic heat shield to be used within be achieved by servo-controlling the heat
the traditional single-walled incubator (Fig. panel according to the abdominal skin tem-
6-6). The warm incubator air heats the plas- perature and maintaining skin tempera-
tic wall of the shield to the same temper- ture between 36.2° C and 36.5° C (97° F
ature as the air within the incubator. The and 98° F). Darnall et al.37 comparing radi-
infant radiates heat only to the warm inner ant warmers with an incubator, found no
plastic shield because radiant waves from difference in minimal oxygen consump-
the infant (2 to 9 µm) do not penetrate the tion, whereas LeBlanc found a significant
plastic wall. increase in metabolic rate.38 Under a radi-
When the thermal conditions can be ant warmer, radiant losses were markedly
described and controlled, the neutral ther- reduced, or there was a net gain, whereas
mal environment for any nude infant can convective and evaporative losses were
easily be located by using the studies of increased. Increasing the skin temperature
Scopes and Ahmed.35 Generally, the thinner, above a set point of 36.5° C resulted in
smaller, and younger the infant, the higher significant hyperthermia in a minority of
the environmental temperature required to infants studied. Baumgart concluded that
achieve the neutral thermal environment.36 a moderate abdominal skin temperature
Table 6-2. Neutral Thermal Environmental Temperatures
Range of Range of
Age and Weight Temperature (° C) Age and Weight Temperature (° C)
0-6 hr 72-96 hr
<1200 g 34.0-35.4 <1200 g 34.0-35.0
1200-1500 g 33.9-34.4 1200-1500 g 33.0-34.0
1501-2500 g 32.8-33.8 1501-2500 g 31.1-33.2

>2500 g (and >36 wk) 32.0-33.8 >2500 g (and >36 wks) 29.8-32.8
6-12 hr 4-12 days

<1200 g 34.0-35.4 <1500 g 33.0-34.0
1200-1500 g 33.5-34.4 1501-2500 g 31.0-33.2
1501-2500 g 32.2-33.8 >2500 g (and >36 wks)
>2500 g (and >36 wk) 31.4-33.8 4-5 days 29.5-32.6
12-24 hr 5-6 days 29.4-32.3

<1200 g 34.0-35.4 6-8 days 29.0-32.2
1200-1500 g 33.3-34.3 8-10 days 29.0-31.8
1501-2500 g 31.8-33.8 10-12 days 29.0-31.4
>2500 g (and >36 wk) 31.0-33.7 12-14 days
24-36 hr <1500 g 32.0-34.0
<1200 g 34.0-35.0 1501-2500 g 31.0-33.2
1200-1500 g 33.1-34.2 >2500 g (and >36 wk) 29.0-30.8
1501-2500 g 31.6-33.6 2-3 wk
>2500 g (and >36 wk) 30.7-33.5 <1500 g 32.2-34.0
36-48 hr 1501-2500 g 30.5-33.0

<1200 g 34.0-35.0 3-4 wk
1200-1500 g 33.0-34.1 <1500 g 31.6-33.6
1501-2500 g 31.4-33.5 1501-2500 g 30.0-32.7
>2500 g (and >36 wk) 30.5-33.3 4-5 wk
48-72 hr <1500 g 31.2-33.0

<1200 g 34.0-35.0 1501-2500 g 29.5-32.2
1200-1500 g 33.0-34.0 5-6 wk
1501-2500 g 31.2-33.4 <1500 g 30.6-32.3
>2500 g (and >36 wk) 30.1-33.2 1501-2500 g 29.0-31.8
Adapted from Scopes J, Ahmed I: Range of critical temperatures in sick and newborn babies, Arch Dis
Child 41:417, 1966.
For their table, Scopes and Ahmed had the walls of the incubator 1° C to 2° C warmer than the ambient
air temperatures. Generally speaking, the smaller infants in each weight group require a temperature in
the higher portion of the temperature range. Within each time range, the younger the infant, the higher
the temperature that is required.
between 36.5° C and 37° C would probably in significantly less radiant heat needed
best correspond to a thermal neutral zone for infants to remain in a neutral thermal
for a naked infant supine on an open bed environment and also reduced evaporative
platform.39 He noted that there is a risk of water loss by 30%.41,42 Another concern
hyperthermia much above this level.40 A is the effect of the infrared spectrum ema-
semipermeable polyurethane membrane nating from the radiant warmer on imma-
(Saran) used as an artificial skin resulted ture skin and eyes. To date, relatively small
°C °F
36 36 36
95 Naked
Operative environmental temperature
32 90 32 32
85
28 28 28 Cot-nursed
80
24 75 24 24
70
20 20 20
65
Birth weight 1kg Birth weight 2kg Birth weight 3kg
16 60 16 16
0 10 20
10 30
20 030 0 10 20 30
Age in days
Figure 6-7. Range of temperatures to provide neutral environmental conditions for baby lying either dressed in cot or naked
on warm mattress in draft-free surroundings of moderate humidity (50% saturation) when mean radiant temperature is
same as air temperature. Hatched area shows neutral temperature range for healthy babies weighing 1, 2, or 3 kg at birth.
Approximately 1° C should be added to these operative temperatures to derive appropriate neutral air temperature for single-
walled incubators when room temperature is less than 27° C (80° F) and more if room temperature is much less than this.
studies reveal no cataracts, corneal opaci- not required. The development in full-term
ties, or ulcerations.43 infants of a nighttime temperature rhythm
(with a temperature decrease with sleep)
COT NURSING first begins to be noted between 6 and 12
An alternative approach that has been weeks of age.45
revived and studied in detail by Hey and
O’Connell is to care for the infant dressed HEATED WATER-FILLED MATTRESS
(cot nursed) rather than naked.44 In a nude The 8-L polyvinylchloride heated water-
infant, the resistance to heat loss is 1.07 clo filled mattress (HWM) is an effective low-
units, which is increased by 1.25 units when cost device that has been evaluated using
the infant is dressed in a shirt, diaper, and a thermal mannequin and trials with pre-
gown; additional resistance of 0.61 unit is mature infants.46 The mattress is heated by
added when a flannelette sheet and two lay- a thermocontrolled heating plate, and the
ers of cotton blankets are added. temperature display records the actual water
As emphasized by Hey, the major advan- temperature. The low electric power (50 W)
tage of cot nursing is the larger latitude of makes the heating slow (4.4° C/hour) so
safe environmental temperatures. If the that the mattress must be warm even when
incubator temperature decreases 2° C, the not in use. The large heat storage capacity of
naked infant must increase heat produc- the water, however, results in slow cooling
tion by 35% to prevent a decrease in deep (several hours) in case the electric current is
body temperature, whereas a 2° C increase interrupted.
results in the infant becoming febrile. Simi- A disadvantage in the use of the HWM
lar changes in room temperature would is that the quality of the thermocontrol of
have a negligible effect on the cot-nursed the mattress must be exact because the safe
infant. Hey calculated that for the same temperature range is narrow, from 35° C to
effects in the cot-nursed infant, the room only 38° C. Below this range, there is cool-
temperature must decrease to 19° C (66.2° F) ing, with the infant losing heat by conduc-
or increase to 31° C (87.8° F). Lightly dress- tion to the mattress; above this range, there
ing the infant minimizes the effects of fluc- is the possibility of overheating and burns.
tuation in environmental temperature. Cot In several clinical studies in which preterm
nursing is inexpensive and is clinically use- infants were either in a cot with an HWM or
ful when close, continuous observation is in an air-heated single-walled incubator, the
metabolic rate was lower during cot nursing 9

with an HWM.
Oxygen consumption (mL kg–1 min–1)

HATS 8
The relatively larger brain of the newborn is
a major heat source. (The brain of the infant
is 12% of body weight compared with 2%
in the adult.) Studies by Stothers reveal 7
that heat loss from the head is clinically
important and can be significantly reduced
with a three-layered hat made of wool and 6
gauze.47,48 Figure 6-8 illustrates how the
neutral thermal range is extended 1° C and
oxygen consumption is reduced in a cool 5
environment when a three-layered hat is 26 28 30 32 34
worn by a nude 1200-g infant. A tube gauze Environmental temperature (° C)
hat had no effect. The use of double-layered
Figure 6-8. Extension of neutral thermal range and
hats is recommended for all infants in the reduction of oxygen consumption in cool environment with
home and hospital who would benefit by a wearing of a three-layered hat by nude 1200-g infant.
controlled thermal environment.
SERVO-CONTROL
A completely different approach to caring starts to become febrile, the incubator tem-
for an infant in the neutral thermal environ- perature drops, but there is no change in
ment is to servo-control the heating device body temperature. In the other direction,
(whether it is a heat panel or incubator) to when an infant who is being servo-con-
the infant’s abdominal skin temperature. trolled dies, his or her body temperature is
If the infant’s skin temperature decreases, maintained because the incubator tempera-
the warming device increases its heat out- ture elevates.
put. The temperature of the skin at which
the incubator is servo-controlled is critical. DISORDERS OF TEMPERATURE
Maintaining the abdominal skin tempera- REGULATION
ture at 36.5° C (97.7° F) minimizes oxygen
consumption; at an abdominal skin temper- HYPOTHERMIA
ature of 35.9° C (96.6° F), oxygen consump- Hypothermia should be anticipated in low-
tion increases 10%.49,50 birth-weight infants, and the routine use of
Servo-control has been further refined by low-reading thermometers (from 29.4° C
Perlstein et al. who developed a computer- [85° F]) is advocated in their care, because
ized system to control the heat input into temperatures less than 34.4° C (94° F) are
the incubator.51 Their system was designed frequently not immediately detected with
to maintain the infant in a thermoneutral the routine clinical thermometers. Hypo-
zone, avoid wide temperature fluctuations thermia is seen particularly following resus-
that might induce apneic episodes, and rec- citation of asphyxiated premature infants. It
ognize the point at which an infant can be may be an early sign of sepsis or evidence of
weaned from the incubator. The use of this an intracranial pathologic condition, such as
system led to fewer deaths, although the meningitis, cerebral hemorrhage, or severe
impact of other portions of the computer central nervous system (CNS) anomalies.
information on the infant’s survival could CNS disease can also result in hyperthermia.
not be separated from the effect of incuba-
tor control. NEONATAL COLD INJURY
Two disadvantages of servo-controlled Neonatal cold injury following extreme
equipment are the increased expense and hypothermia occurs under both warm
required reorientation of nurses and phy- and cool climatic conditions, particularly
sicians when evaluating the infant’s con- with domiciliary maternity services. Low-
dition—both the infant and the incubator birth-weight infants are almost exclusively
temperatures must be compared together, affected, except for full-term infants with
so the infant’s true condition is not masked. problems such as intracerebral hemorrhage
When an infant who is under servo-control and major malformations of the CNS.
Clinical Features only when infection is suspected or docu-

A slight decrease in temperature may pro- mented.
duce profound metabolic change; however,
a significant decrease must occur before INDUCED HYPOTHERMIA
clinical features are evident. There is strong experimental evidence that
The infants feed poorly, are lethargic, prolonged cerebral hypothermia initiated
and feel cold to the touch. Mann and Elliott after a severe hypoxic-ischemic insult can
describe an “aura” of coldness about the reduce subsequent neuronal loss in neona-
body and skin over the trunk52; the periph- tal and adult animals.55,56
ery feels intensely cold and “corpselike.” Acute brain injury results from the com-
Core temperatures are depressed, often bined effects of cellular energy failure,
below 32.2° C (90° F). acidosis, glutamate release, intracellular
The most striking feature is the bright red calcium accumulation, lipid peroxidation,
color of the infant. This red color (which and nitric oxide neurotoxicity that disrupt
may lead the physician astray because the essential components of the cell, resulting
infant “looks so well”) is due to the failure in cell death. Many factors, including the
of dissociation of oxyhemoglobin at low duration or severity of the insult, influ-
temperatures. Central cyanosis or pallor ence the progression of cellular injury after
may be present. Respiration is slow, very hypoxia-ischemia. A secondary cerebral
shallow, irregular, and often associated with energy failure occurs from 6 to 48 hours
an expiratory grunt. Bradycardia occurs after the primary event and may involve
proportionate to the degree of temperature mitochondrial dysfunction secondary to
decrease. extended reactions from primary insults
Activity is lessened. Shivering is rarely (e.g., calcium influx, excitatory neurotox-
observed. The CNS depression is constant, icity, oxygen-free radicals, or nitric oxide
and reflexes and responses are diminished formation). Some evidence suggests that
or absent. Painful stimuli (e.g., injections) circulatory and endogenous inflammatory
produce minimal reaction, and the cry is cells or mediators also contribute to ongo-
feeble. Abdominal distention and vomiting ing brain injury.
are common. The goals of management of a newborn
Edema of the extremities and face is com- infant at risk for injury from an hypoxic-
mon, and sclerema is seen, especially on the ischemic insult include supportive care to
cheeks and limbs. Sclerema is hardening of facilitate adequate cerebral perfusion and
the skin; it is associated with reddening and delivery of nutrients to the brain, efforts
edema. It is observed particularly with cold to control seizures, maintenance of glucose
injury and infection and near the time of homeostasis, correction of anemia, and
death.53,54 management of renal, hepatic, cardiac, and
Metabolic derangements include meta- respiratory failure.
bolic acidosis, hypoglycemia, hyperkalemia, In recent years, it has become apparent
elevated blood urea nitrogen, and oliguria.52 that temperature can modify the extent of
Pulmonary hemorrhage in association with hypoxic-ischemic brain injury. There is an
a generalized bleeding diathesis is a com- increasing body of experimental and clinical
mon finding at autopsy. data showing a reduction in the extent of
brain injury after intrapartum hypoxia-isch-
Treatment emia with induced hypothermia (a reduc-
The infant should be warmed as mortality tion of body temperature by about 3° C)
is reduced significantly. The use of a saline initiated within 6 hours of birth.57,58 Cool-
push (10 mL/kg) early in the rewarming ing preserves cerebral energy metabolism,
period also may reduce mortality rate. reduces cerebral tissue injury, and improves
In addition to the rewarming, oxygen neurological function. Conversely, there is
is administered, blood sugar is monitored experimental evidence indicating a worsen-
closely, and metabolic acidosis is moni- ing of cerebral injury during or after ischemia
tored and corrected. The infant should under conditions of elevations in tempera-
be fed only by intravenous (IV) infusion ture. Randomized trials in full-term and
or gavage of dextrose solution until the near full-term newborns suggest that treat-
temperature is 35° C (95° F). Hypothermic ment with mild hypothermia (either selec-
infants should not be permitted to feed tive head or total body cooling) is safe and
by nipple. Antibiotics are administered improves survival without developmental
disabilities up to 18 months of age.59 Meta- outcomes in the cooling-treated group. The

analysis of these trials suggests that for every results may reflect underlying brain injury
six or seven infants with moderate to severe and/or adverse effects of temperature on
HIE who are treated with mild hypothermia, outcomes.
there will be one less infant who dies or has Regional heat loss and skin temperature
significant neurodevelopmental disability.60 changes in 25 healthy, full-term infants were
Nonetheless, mortality and severe morbid- studied under controlled conditions at envi-
ity still approaches 50% and additional ronmental temperatures of 28° C to 32° C.63
strategies are needed. These include the use Mean regional skin temperatures measured
of oxygen-free radical inhibitors and scaven- at 11 body regions followed the changes in
gers, excitatory amino acid antagonists, and environmental temperatures (Fig. 6-9, A).
growth factors; prevention of nitric oxide The regional dry heat losses closely followed
formation; and blockage of apoptotic path- the external temperature gradient, defined
ways. Other avenues of potential neuropro- as the difference between skin and environ-
tection that have been studied in immature mental temperatures. In eight of the infants,
animals include xenon inhalation, platelet- lowering the environmental temperature
activating factor antagonists, insulin-like 3° C to 4° C induced peripheral vasoconstric-
growth factor-1, and erythropoietin. They tion only in the feet. Many clinicians are
have been evaluated experimentally but enamored with the concept of differences
have not been rigorously tested in a system-
atic manner in the human neonate.
HYPERTHERMIA
37
Surface temperature (° C)
Elevation of the deep body temperature

may be caused by an excessive environmen- 36
tal temperature, infection, dehydration, or 35
alterations of the central mechanisms of
Rectal
heat control associated with cerebral birth 34
Trunk
trauma or malformations and drugs. 33
Head
Mean
The question of systemic infection is skin
32 Arm
invariably raised in infants with elevated Leg
Foot
deep body temperatures. Due consideration
should also be given to the environmen- 28 29 30 31 32
tal conditions that alter heat control. It is A Operative temperature (° C)
not uncommon to find an elevated core
Abdominal skin temperature (° C)
temperature following the increased heat

input with the commencement of the use 37.6
of phototherapy. This can also occur if the 37.4
incubator is placed in the sun (see Fig. 6-6). 37.2
A febrile baby overheated by the environ- 37
ment becomes vasodilated trying to lose 36.8
heat, and the infant’s extremities and trunk 36.6
are at almost the same temperature. A sep- 36.4
tic baby is usually vasoconstricted, and the 36.2
extremities become colder than the rest of 36
the body.61 Therefore, measuring the tem- 0 1 2 3 4 5
perature difference between the abdominal B Postnatal age (days)
skin (Tc) and the sole of the foot (Tp) is Figure 6-9. A, Rectal temperature, mean skin temperature,
sometimes helpful clinically. and regional skin temperatures for different body regions
It is important that asphyxiated infants at different operative temperatures. Asterisk, p <.05;
are not overheated. Relatively high tem- double asterisk, p <.01; triple asterisk, p <.001 compared
peratures during usual care after hypoxia- with 32° C. B, Mean (standard deviation) abdominal skin
temperature according to postnatal age. (A, From Karlsson
ischemia were associated with increased risk
H, Hanel SE, Nilsson K, et al: Measurement of skin
of adverse outcomes.62 The odds of death temperature and heat flow from skin in term newborn
or disability were increased 3.6 to 4-fold for babies, Acta Paediatr 84:605–612, 1995; B, From Lyon
each 1° C increase in the highest quartile of AJ, Pikaar ME, Badger P, et al: Temperature in very
skin or esophageal temperatures. There were low birthweight infants during first five days of life, Arch
no associations between temperatures and Dis Child 76:F47–F50, 1997.)
in the toe-tummy temperature as an indica-

tion of sepsis. Although it is reasonable to WEANING FROM THE INCUBATOR
consider sepsis, it is equally important to Weaning from the incubator67,68 can typi-
carefully evaluate the thermal environment cally be started when the infant is physi-
if a gradient is detected between the abdom- ologically stable, at least 32 weeks’ corrected
inal and foot temperature. gestational age, weighs at least 1500 g and
takes 100 kcals/kg/day, provided there is no
ASPHYXIA medical indication for continuing incuba-
With newborn infants, prolonged resusci- tor/warmer care, such as the need for close
tative attempts often are carried out on a observation.
damp towel, with precipitous decreases in Decrease incubator temperature by 1° C
body temperature. to 1.5° C daily until incubator tempera-
Temperature responses following deliv- ture is 28° C. When skin temperature is
ery are sometimes a guide to the state of the maintained at 36° C to 37° C for at least
infant during delivery.64 If the infant was 8 hours in an incubator at 28° C, attempt
severely asphyxiated or hypoxic, tempera- to transition to an open crib. The baby
ture control is reflexively turned off, and should be fully clothed and swaddled, and
body temperature is often not maintained maintained in a room with normal ambi-
immediately after delivery. ent temperature (68° F to 75° F). If the baby
The following resuscitative procedures fails an attempt to wean from the incuba-
should be performed with due attention to tor/warmer, as evidenced by low body tem-
heat control: perature or cessation of growth, the baby
1. Evaporative losses may effectively be should be placed back in an incubator and
reduced by immediately drying the infant. weaning should be attempted again in 24
2. Conductive losses can be eliminated by to 48 hours.
laying the infant on a dry, warm towel or
cloth.
3. A radiant source of heat in the form of PRACTICAL ADVICE (FROM RAINBOW
a radiant warmer provides a heat-giving BABIES AND CHILDREN’S HOSPITAL
environment. This is ideal for resuscita- NICU PROTOCOL)
tion, because the infant can be main- 1. Transition infant to open crib during the
tained nude and is readily accessible. day or early evening hours to optimize
Abdominal skin temperature should be success.
maintained. 2. Do not swaddle infants in blankets in
4. Convection must be controlled; there incubator.
should be no drafts in the room; and the 3. If an infant drops body temperature, do
oxygen must be warmed. not rewarm faster than 0.5° C to 1° C per
hour.
APNEA 4. Do not use warming lights during transi-
Despite the beneficial effects of maintaining tion to open crib—if infant cannot main-
a warm environment, a possible disadvan- tain temperature greater than 36° C in
tage is its effect on respiratory control. open crib, return to isolette at 28° C.
1. Immersing a normal infant in a bath 5. Do not feed infant orally unless skin tem-
equal to the maternal temperature some- perature is greater than 35.9° C. Monitor
times stops respiration. Rapid warming is glucose if no IV is in place.
also associated with apneic episodes. 6. Do not bathe infant for first 24 hours in
2. Observations in a group of low-birth-weight open crib or if demonstrating tempera-
infants having apneic attacks revealed that ture instability later.
lowering the servo-controlling tempera-
ture less than 1° C significantly reduced the
number of episodes.65 QUESTIONS
It is suggested, therefore, that a prema-
ture infant having apneic attacks should be True or False
maintained closer to the low range of neu- If the rectal temperature is maintained between
tral thermal environment, and most impor- 36.5° C and 37° C (97.7° F and 98.6° F), the infant
tantly, temperature fluctuations should be can be considered to be in the “neutral thermal
kept to a minimum.66 environment.”
A single measurement of temperature is of

little value in defining the neutral thermal True or False
environment. The infant may have an ele- The stimulus for an increased metabolic rate be-
vated metabolic rate and be “working” to gins immediately after onset of cold stimulus, even
maintain normal body temperature. There- before the deep body temperature has decreased.
fore, the statement is false.
Bruck has shown that it is not necessary for
body temperature to decrease before there is
True or False an increase in metabolic rate. Therefore, the
When trying to produce a neutral thermal environ- statement is true. Even mild cold stress (e.g.,
ment, take into account ambient air temperature, blowing cold air on the face) may result in
air flow, relative humidity, and temperature of sur- a significant increase in oxygen consump-
rounding objects. tion. This occurs when unwarmed oxygen is
blowing over the infant’s face.
The neutral thermal environment is that set
of thermal conditions associated with mini-
mal metabolic rate in a resting subject; thus, True or False
potential heat loss by conduction, convec- Maintaining an infant with respiratory distress
tion, radiation, and evaporation must be syndrome (RDS) in the neutral thermal environ-
considered. Therefore, the statement is true. ment plays an insignificant part in overall man-
agement.
True or False Many infants with RDS have a limited

Swaddling the infant should not influence the capacity to transfer oxygen, and the mainte-
temperature of the incubator when it is set to nance of the neutral thermal environment
achieve neutral thermal environment. is most important in their care.69 Therefore,
the statement is false.
The use of the Scopes tables to achieve the
neutral thermal environment refers to a set
of specific conditions—namely, that the True or False
incubator wall temperature is 1° C higher The rate of growth in body weight and length can
than the air temperature and that the be influenced by environmental temperature.
infants are nude. All the processes of heat
exchange are altered and reduced by cloth- Infants kept at a warmer environment
ing the baby. The ambient air temperature showed a significantly greater increase in
inside the clothing is warmer than ambient body weight and length over those main-
incubator air, and humidity is higher, too. tained in a cooler environment when both
Therefore, the statement is false. groups had the same caloric intake. Infants
in a cooler environment require more calo-
ries to regulate body temperature and thus
True or False have fewer calories available for growth.
Overheating the infant produces no noticeable Therefore, the statement is true.
clinical effects and can only be detected by moni-
toring deep body temperature.
True or False
Overheating is documented by monitor- When a fever develops in an infant who is being
ing deep body temperature. However, the monitored in a servo incubator, this is reflected by
infant would be flushed and panting, and an increase in incubator temperature.
the extremities and trunk would be at
the same temperature. The infant would As the infant’s temperature increases, the
hyperventilate and initially show irrita- abdominal skin temperature that is control-
bility and may have apnea. Sweating may ling the infant also increases, resulting in a
occur but is reduced in immature infants. decrease in incubator temperature. Thus, a
With prolonged hyperthermia, stupor, decrease in incubator temperature reflects
coma, and convulsions may occur, and an increase in the temperature of the infant
brain damage may be irreversible. The and vice versa. Therefore, the statement is
statement is false. false.
tal temperature of only 1° C to 2° C below the lower

True or False limit of the presumed range of thermal neutrality.
An elevated temperature during the first month of
life is common and no cause for concern. It has been suggested by some investigators
that the temperature range in which the
Too often an elevated temperature in a new- least amount of oxygen is consumed is also
born has been attributed to environmental the temperature range of thermal comfort
conditions, with disastrous consequences— for the neonate. Therefore, the statement is
for example, sepsis overlooked. A tempera- true.
ture elevation, particularly in infants at
home, should be carefully evaluated (see
Chapter 14). The answer is false. True or False
Swaddled full-term babies may not cry or other-
wise call attention to the fact that they are under
True or False severe cold stress.
Radiant heat losses are similar in adults and im-
mature infants because they are both homeo- This statement is true and is particularly
therms. important because the upper limit of heat
production is reached for cot-nursed, full-
Radiant heat loss is of less significance in term infants when the room temperature
adults because they are clothed. Radiant declines to about 10° C (50° F). In some situ-
heat loss has no bearing on the question of ations at night, bedrooms get colder, and
homeothermy. A homeotherm is an animal the infants become hypothermic.
that attempts to maintain a constant body
temperature despite alterations in environ-
ment—for example, metabolic rate increases True or False
in a cool environment. Therefore, the state- The signs and symptoms of hypothermia shortly
ment is false. after delivery may imitate the clinical picture of
RDS.
True or False The signs of RDS—notably grunting, acido-

The newborn infant loses equal amounts of heat sis, and an increased right-to-left shunt—
per unit of body mass compared with the adult. can all be observed in a hypothermic infant.
The statement is true.
Although at birth the infant’s body mass is
approximately 5% of that of the adult, the
surface area is nearly 15%. There is also less True or False
subcutaneous tissue, resulting in a higher The precipitous drop in temperature after delivery
thermal conductance and a higher skin tem- in preterm infants is inevitable, physiologic, and
perature at lower ambient temperatures. of no major consequence.
Bruck has estimated that, because of these
facts, the heat loss of the newborn infant per The body temperature of preterm babies can
unit of body mass is about four times that of drop precipitously after delivery, and this
the adult.7 Therefore, the statement is false. hypothermia is associated with an increase
in mortality and morbidity. Hypothermia
on admission to neonatal units is an inde-
True or False pendent risk factor for mortality in preterm
Full-term infants who have been cold stressed at babies.
birth may have a normal pH and low HCO3. During the first few hours of life,
extremely low-birth-weight infants may
A compensated metabolic acidosis probably become hypothermic during umbilical or
secondary to lactic acid production is some- other venous line insertions, endotracheal
times observed. Therefore, the statement is intubation, other procedures, including
true. x-rays and ultrasound, or even taking vital
signs. Anticipating the need for heat preser-
vation started at delivery by prewarming the
True or False delivery room, placing the baby in a plastic
The duration of sleep is markedly reduced when bag with a plastic head wrap and warming
small nude infants are exposed to an environmen- mattresses can assist the transition for these
babies and avoid hypothermia. The state-

ment is false. AMERICAN ACADEMY OF PEDIATRICS
POLICY FOR HYPOTHERMIA
PREVENTION
True or False • Radiant warmer to “full-on” prior to
The temperature in the delivery room should be delivery.
set to the zone of thermal comfort for the staff. • Delivery room temperature 72° F or
higher.
The temperature in the delivery room • Deliver infant, hemostat cord, place in
should be set to minimize the chances of bag feet first to torso.
cooling the newborn baby—term or pre- • Dry head, put on cap.
term. Suggested delivery room tempera- • Resuscitate as necessary per Neonatal
tures are tabulated in Table 6-3 displayed Resuscitation Program Guidelines.
subsequently. These temperatures may be • Clamp cord, remove hemostat, transport
uncomfortable for obstetrical staff, but it is to NICU in heated incubator.
of crucial importance to the newborn. The • Do not place heating pad under infant
statement is false. (hyperthermia risk).
CASE 1 (90.5° F), and the relative humidity is 80%. We can

Baby D. O. is an 1160-g male delivered at 31 weeks’ assume the temperature of the mattress to be the
gestation. No problems are encountered in the imme- same as the incubator air temperature.
diate neonatal period, and the pregnancy is uncompli-
cated. Delivery is by cesarean section with the mother With these available data, is the infant in
under caudal anesthesia. The Apgar score at 1 minute the neutral thermal environment?
is 6. On the second day of life, the rectal temperature No, the infant is not in the neutral thermal environment.
is noted to be 36.8° C (98.2° F). The incubator tem- Our indications of this are that the abdominal skin
perature at this time was 34.1° C (93.4° F). temperature is only 34.9° C (94.8° F) even with
the incubator air at 34.1° C (93.4° F). In Table 6-2,
What additional data is needed to define the appropriate temperature for this infant to be
the neutral thermal environment? in the neutral thermal environment is listed as an
To define the neutral thermal environment, one also environmental temperature of 34° C to 35° C (93.2°
requires the temperature of the mattress with regard F to 95° F), provided that the walls are 1° C higher
to conductive heat loss, the air flow in the incubator, than the air. Note that the side wall temperature is
the relative humidity, and the temperature of the in- only 32.5° C (90.5° F). The infant is losing heat by
ner walls of the incubator to determine the radiant radiation. Be aware that the baby exchanges heat
heat losses that can occur to the surrounding walls with its environment through radiation, convection,
of the incubator. A continuous recording of the ab- conduction, and evaporation and all these modalities
dominal skin temperature would permit a rough idea must be checked. Mechanisms of heat production
of whether the infant is in the neutral thermal zone. are limited as is the ability to reduce heat loss
When a servo incubator is controlled to maintain an by peripheral vasoconstriction. Furthermore, the
abdominal skin temperature of 36.5° C (97.7° F), oxy- immature baby, because of a high surface area-to-
gen consumption has been found to be minimal. In volume ratio and increased evaporation of fluid from
this case, the abdominal skin temperature is 34.9° the skin, easily loses heat and does not have the
C (94.8° F), the side wall of the incubator is 32.5° C capacity to generate heat.
Table 6-3. Suggested Delivery Room Temperatures by Gestational Age and Birth Weight
Estimated Gestational Age (EGA)

and/or Estimated Birth Weight (EBW) Delivery Room Temperature
≤26 wks EGA and/or ≤750 g EBW 76° F (24°C) or more; target: 78° F-80° F (25.5-26.5°C)
27-28 wks EGA and/or ≤1000 g EBW 74° F (23°C) or more; target: 78° F-80° F (25.5-26.5°C)
29-32 wks EGA and/or 1001–1500 g EBW 72° F (22°C) or more
33-36 wks EGA and/or 1501–2500 g EBW 72° F (22°C) or more
37-42 wks GA or ≥2501 g EBW 70° F (21°C) or more
CASE 2 REFERENCES
Baby H is delivered after a 42-week pregnancy; she The reference list for this chapter can be found
weighs 1600 g. No problems are noted in the im- online at www.expertconsult.com.
mediate neonatal period. The neurologic examination
is appropriate for an infant with a 42-week gesta-
tion, except that there is diminished neck flexor tone.
Head circumference is 33 cm. The infant is assumed
to be unable to increase her metabolic rate with cold
stress.
How can the optimal thermal environment

be found?
This is a difficult question to answer because no ta-
bles are available for this age and weight. The prob-
lem may best be managed by servo-control of the
incubator and maintaining the abdominal skin tem-
perature at 36.5° C (97.7° F). Another approach is to
use the “warmest” incubator possible to maintain a
normal temperature in the infant.
7
Nutrition and Selected
Disorders of the
Gastrointestinal Tract
PART ONE 5% fat. The fat is primarily structural with

only negligible amounts of subcutaneous fat;
NUTRITION FOR THE hepatic glycogen stores are virtually nonex-
istent. The growth of these infants lags con-
HIGH-RISK INFANT siderably after birth.1 Such infants, especially
those less than 1000 g birth weight (extremely
low birth weight [ELBW]), typically do not
David H. Adamkin, Paula G. Radmacher, regain birth weight until 2 to 3 weeks of age.
and Salisa Lewis The growth of most less than 1500 g (very
low-birth-weight [VLBW]) infants proceeds
at a slower rate than in utero, often by a large
The goal of nutritional support for the high- margin.1 Although many of the smallest
risk infant is to provide sufficient nutri- VLBW infants are also born small for gesta-
ents postnatally to ensure continuation of tional age (SGA), both appropriate for ges-
growth at rates similar to those observed in tational age (AGA), VLBW, and SGA infants
utero. The preterm infant presents a particu- develop “extrauterine growth restriction”
lar challenge in that the nutritional intake (EUGR). Figure 7-1 from the National Insti-
must be sufficient to replenish tissue losses tute of Child Health and Human Develop-
and permit tissue accretion. However, dur- ment (NICHD) Neonatal Research Network
ing the early days after birth, acute illnesses demonstrates the differences between nor-
such as respiratory distress, patent ductus mal intrauterine growth and the observed
arteriosus, and hyperbilirubinemia preclude rates of postnatal growth in the NICHD
maximal nutritional support. Functional study. These postnatal growth curves are
immaturity of the renal, gastrointestinal, shifted to the right of the reference curve in
and metabolic systems limits optimal nutri- each gestational age category. This “growth
ent delivery. Substrate intolerances are com- faltering” is common in ELBW infants.
mon, limiting the nutrients available for Nutrient intakes received by VLBW
tissue maintenance and growth. infants are much lower than what the fetus
During the last trimester of pregnancy, receives in utero—an intake deficit that per-
nutrient stores are established in prepara- sists throughout much of the infants’ stay
tion for birth at 40 weeks’ gestation. Fat and in the hospital and even after discharge.2
glycogen are stored to provide ready energy Although nonnutritional factors (comor-
during times of caloric deficit. Iron reserves bidities) contribute to the slower growth of
accumulate to prevent iron-deficiency ane- VLBW infants, suboptimal nutrient intakes
mia during the first 4 to 6 months of life. are critical in explaining their poor growth
Calcium and phosphorus are deposited outcomes. Considerable evidence exists
in the soft bones to begin mineralization, that early growth deficits, which reflect
which continues through early adult life. inadequate nutrition, have long-lasting
However, the infant who is delivered before effects, including short stature and poor
term has minimal nutrient stores and higher neurodevelopmental outcomes. The most
nutrient requirements per kilogram than convincing data concerning the neurode-
the full-term infant. velopmental consequences of inadequate
Infants weighing less than 1.5 kg have a early nutrition are those reported by Lucas
body composition of approximately 85% to et al.3,4 They demonstrated that premature
95% water, 9% to 10% protein, and 0.1% to infants fed a preterm formula containing a
151
152 CHAPTER 7 Nutrition and Selected Disorders of the Gastrointestinal Tract
2000 50th 10th
1500
Weight (g)
1000
500
24 28 32 36
Postmenstrual age (weeks)
Intrauterine growth (10th and 50th percentiles)

24-25 weeks
26-27 weeks
28-29 weeks
Figure 7-1. Mean body weight versus gestational age in weeks for infants with gestational ages at birth of 24 to 29 weeks.
higher content of protein and other nutri- of the total body weight, with approximately
ents over the first postnatal month of life 65% in the extracellular compartment, 25%
had higher neurodevelopmental indices at in the intracellular compartment, and 1%
both 18 months and 7 to 8 years of age com- in fat stores. The TBW and extracellular
pared with infants fed a term formula.4 fluid volumes decrease as gestational age
Nutritional management of VLBW infants increases; by term, the infant’s TBW repre-
is marked by a lack of uniformity from one sents 75% of total body weight with extra-
neonatal intensive care unit (NICU) to the cellular and intracellular compartments
next as well as within individual practices. comprising 40% and 35%, respectively.
This heterogeneity of practice persists from Compared with the full-term infant, the
the first hours after birth to hospital dis- preterm infant is in a state of relative extra-
charge and beyond. Diversity of practice cellular fluid volume expansion with an
thrives where there is uncertainty. Because excess of TBW. The dilute urine and nega-
under-nutrition is, by definition, nonphysi- tive sodium balance observed during the
ologic and undesirable, any measure that first few days after birth in the preterm
diminishes it is inherently good, providing infant may constitute an appropriate adap-
safety is not compromised. Avoiding inad- tive response to extrauterine life. Therefore,
equate nutrition is a priority in neonatal the initial diuresis should be regarded as
nutrition today. physiologic, reflecting changes in intersti-
This chapter addresses the nutrient needs tial fluid volume. This should be included
of the sick and LBW infant, methods for in the calculation of daily fluid needs. As a
provision of nutrients both parenterally and result, a gradual weight loss of 10% to 15%
enterally, and methods for assessing nutri- in a VLBW infant and 5% to 10% in a larger
tional status. Figure 7-2 provides an over- baby during the first week of life is expected
view of the important aggressive nutrition without adversely affecting urine output,
strategies that will be reviewed in a timeline urine osmolality, or clinical status. Provision
configuration based on a “typical” ELBW of large volumes of fluid (160 to 180 mL/
infant growth curve.5 kg/d) to prevent this weight loss appears to
increase the risk of the development of patent
FLUID ductus arteriosus, cerebral intraventricular
In the fetus at 24 weeks’ gestation, the total hemorrhage, bronchopulmonary dysplasia
body water (TBW) represents more than 90% (BPD), and necrotizing enterocolitis (NEC).
CHAPTER 7 Nutrition and Selected Disorders of the Gastrointestinal Tract 153
AGGRESSIVE NUTRITION:
PREVENTION OF EUGR
Time line
Reduce RTBW Catch-up

PWL earlier t growth
en
qu
bse
Su Post D/C
Early TPN Optimizing nutrition
MEN enteral
Goal
RTBW
NADIR
2 4 6 11 14 20 Discharge 9 mos
36 wks
Decrease IWL Days
Catch-up growth
• Humidified isolettes
• Caps
PTF >160 mL/kg/d Post discharge formula
Decrease ICF loss Fortified >160 mL/kg/d (Preterm formula)
Human milk Fortified human milk
• Early administration AA Hypercaloric (30 kcal/oz)
Early positive E/N balance >130 mL/kg/d
“2-5-1” Advance TPN Wt >15 g/kg/d
PGF Length >0.9 cm/wk
P = Protein H.C. >0.9 cm/wk
G = Glucose
F = Fat
(g/kg/d)
Figure 7-2. Aggressive nutrition and prevention of extrauterine growth restriction (EUGR). AA, Amino acid; D/C, discharge;
E/N, enteral nutrition; HC, head circumference; ICF, intracellular fluid; IWL, insensible water loss; MEN, minimal enteral
nutrition; PTF, preterm formula; PWL, postnatal weight loss; RTBW, [return to birth weight]; TPN, total parenteral nutrition.
(Adapted from Adamkin DH: Feeding the preterm infant. In Bhatia J, editor: Perinatal nutrition: optimizing infant health
and development, New York, 2005, Marcel Dekker, pp 165-190.)
Therefore, a careful approach to fluid man- Factors Affecting Insensible Water

agement is currently appropriate. It appears Box 7-1.
Loss in Preterm Neonates
that the preterm infant can adjust water
excretion within a relatively broad range of Severe prematurity
fluid intake (65-70 mL/kg/d to 140 mL/kg/d) Open warmer bed
without disturbing renal concentrating abili- Forced convection
ties or electrolyte balance. Phototherapy
Estimation of daily fluid requirements Hyperthermia
includes insensible water losses (IWLs) from Tachypnea
the respiratory tract and skin, gastrointesti-
nal losses (emesis, ostomy output, and diar-
rhea), urinary losses, and losses from drainage the use of open bed platforms with radiant
catheters (chest tubes). IWL is a passive pro- warmers as well as phototherapy lights may
cess and is not regulated by the infant. How- increase the IWL by more than 50%. This
ever, the environmental conditions in which excessive IWL may be reduced with the use
the infant is nursed should be controlled to of humidified isolettes to care for the infant.6
minimize losses (Box 7-1). The transepithelial The measurement of urine specific gravity is
losses are dependent on gestational age, the commonly used to predict urine osmolality.
thickness of the skin and stratum corneum, Although this is a reliable means of predicting
and blood flow to the skin. The preterm hyperosmolality (urine osmolality of greater
infant has a high body surface area-to-body than 290 mOsm/kg water with a urine spe-
weight ratio with thinner, more permeable cific gravity 1.012 or greater), its reliability in
skin that is highly vascularized. These factors predicting hypo-osmolality (urine osmolality
increase heat and fluid losses. In addition, of <270 mOsm/kg water with a urine specific
gravity 1.008 or less) is variable, ranging Box 7-2. Renal Solute Load Calculation
from 71% to 95% accuracy, and in predict-
ing iso-osmolality (urine osmolality of 270 to Potential renal solute load (PRSL):
290 mOsm/kg water with a urine specific grav- 4 (g protein/L) + mEq sodium/L +
ity of 1.008 to 1.012), the accuracy is even less. mEq potassium/L + mEq chloride/L =
In addition, glucose and protein in the urine PRSL (mOsm/L)
may increase the urine specific gravity, giv-
ing a falsely high estimate of urine osmolal- Example:
ity. Therefore, urine specific gravity should be Preterm formula24 (PT24) contains:
checked only to rule out hyperosmolar urine; a 22 g protein/L × 4 = 88
test for sugars and proteins in the urine should 15.2 mEq sodium/L × 1 = 15.2
be conducted at the same time. The maximal 26.9 mEq potassium/L × 1 = 26.9
concentrating capabilities in the neonate are 18.6 mEq chloride/L × 1 = 18.6
limited compared with those in adults; thus,
PRSL = 148.7 mOsm/L
an infant with a urine osmolality of approxi-
mately 700 mOsm/kg water (urine specific
Baby A is a 2-week-old former 32-week
gravity of 1.019) may be dehydrated. One can
AGA infant weighing 1400 g now receiving
estimate the urine osmolality by determining
150 mL/kg/d of PT24.
the potential renal solute load of the infant’s
feeding and the fluid intake (Box 7-2). Infants
Estimated fluid losses are:
at risk for high urine osmolality are those
Stool 10 mL/kg/d
who are receiving a concentrated formula and
Insensible water loss 70 mL/kg/d
those whose fluid intake is restricted.
Water balance may be maintained with Total water loss 80 mL/kg/d
careful attention to input and output.
Infants should be weighed nude and at 150 mL/kg/d intake – 80 mL/kg/d output =
approximately the same time of day. During 70 mL/kg/d available for urine output
the first week of life, VLBW infants should
be weighed daily; ELBW infants should be The PRSL of PT24 is 148.7 mOsm/L:
weighed twice daily. Meticulous records of
148.7 mOsm X mOsm
fluid intake (with the use of accurate infu- ×
sion pumps and careful measurement of 1000 mL 150 mL
enteral feedings) and output (by weigh- 22.3 mOsm = X
ing diapers and collecting urine, ostomy
output, and drainage from any indwelling This infant has 70 mL/kg/d to excrete
catheters) are necessary to compute fluid 22.3 mOsm of potential renal solute.
requirements. Serum glucose, electrolytes,
22.3 mOsm
blood urea nitrogen (BUN), and creatinine × 1000 = X mOsm / L
may be monitored two to three times per 70 mL
day during the first 2 days in critically ill 318.6 mOsm = X
ELBW infants and then daily or as needed Therefore, the estimated osmolality of the
thereafter. Urine glucose is routinely tested urine is 319 mOsm/L.
and urine specific gravity is measured as
necessary. AGA, Appropriate for gestational age.
Pauls et al. published data on 136 medi-
cally stable ELBW infants receiving early
and aggressive parenteral and enteral nutri-
tion.7 From their data, they developed a day 1 and increased by 0.5 g/kg/day up to
series of weight-stratified growth curves of 3 g/kg/day; (4) IV lipid started 1 g/kg/day
this population over the first months of life. at day 2 and increased 0.5 g/kg/day up to
The fluid and nutrient administration was 3 g/kg/day as long as triglyceride concentra-
uniform in these patients and included (1) tions remained normal; and (5) initial total
initiation of fluid intake at 60 to 70 mL/kg/ energy intakes of 27 kcal/kg/day, increas-
day on day 1 with 15 mL/kg daily increases ing by 10 kcal/kg/day to 100 kcal/kg/day.
up to a maximum of 160 to 180 mL/kg/day; In addition, minimal enteral feedings were
(2) targeted postnatal weight loss of 10% initiated on day 1 in the form of 24 calorie
below birth weight; (3) 1 g/kg/day intra- per ounce fortified human milk or preterm
venous (IV) amino acid intake started on formula and were advanced as tolerated. In
all groups, maximal weight loss averaged Hypochloremia has also been associated
10.1% ± 4.6% (SD), and occurred on day of with poor growth. Supplementation with
life 5.4 ± 1.7. The age at which birth weight chloride to normalize serum chloride con-
was regained was 11 ± 3.7 days. Small-for- centrations in infants with BPD resulted in
gestational age infants had lower maximal improved growth. Hypochloremia has been
weight loss and regained birth weight at a noted in infants with BPD who did not sur-
significantly earlier age. Mean weight gain vive; however, whether this is a predictor of
after day 10 was 15.7 ± 7.2 g/kg/day, which poor outcome or a symptom of severe ill-
is within the recommended in utero growth ness remains to be resolved.
rates of 14 to 20 g/kg/day. Although this was Potassium chloride (2 mEq/kg/day) is
a small study, it shows that aggressive nutri- added to the IV fluid within the first days
tional strategies with higher earlier amino of life as soon as urinary output is estab-
acid intakes are affecting the growth curves lished and hyperkalemia is not present. The
of these ELBW infants. However, the maxi- potassium dose may be adjusted dependent
mal fluid volumes may be excessive in this on urine output and use of diuretics. How-
population. If possible, the maximal fluid ever, it is often difficult to obtain accurate
volume should be limited to 140 mL/kg/day. determinations of serum potassium, espe-
cially when the blood samples are from
ELECTROLYTES heel-sticks, which may lead to excessive red
Often the electrolyte management of the blood cell hemolysis and spuriously high
infant is difficult due to the various sources serum potassium levels. If an elevated potas-
of electrolyte input. For example, in a 600-g sium concentration is obtained, a second
infant, the isotonic saline solution infused to blood sample from venipuncture should
maintain the patency of the umbilical arte- be obtained for confirmation of the level.
rial catheter may result in administration of If infused via a peripheral vein, concentra-
sodium and chloride in excess of estimated tions of potassium chloride up to 40 mEq/L
daily requirements. Although VLBW infants are usually tolerated and do not cause local-
are capable of regulating sodium balance by ized pain. However, if higher concentra-
altering renal sodium excretion, this may tions are needed because of fluid restriction,
not be sufficient to prevent changes in serum a central vein should be used.
sodium and serum chloride concentrations.
Because administration of high amounts of TOTAL PARENTERAL NUTRITION
sodium may increase the risk of hypernatre- Immaturity of the gastrointestinal tract in
mia in the VLBW infant, careful calculation VLBW infants precludes substantive enteral
of total intake of sodium, potassium, chloride, nutritional support. Thus, nearly all of these
glucose, and water from all sources (i.e., main- infants are supported with total parenteral
tenance IV fluids, flushes, medications, and nutrition (TPN), which has been a huge suc-
bolus injections) is necessary. As fluid require- cess, particularly in the management of the
ments are adjusted, recalculation should be ELBW infant.
done frequently to ensure that appropriate Historically, the initiation of TPN has
quantities of nutrients are given (Table 7-1). been delayed during the first week of life.
Sodium is required in quantities suffi- Reasons for this delay have not been clear
cient to maintain normal extracellular fluid but probably have been related to meta-
volume expansion, which accompanies tis- bolic derangements seen when solutions
sue growth. In animal studies, if insufficient designed for adults were infused in the neo-
amounts are provided, the extracellular natal population. There were also concerns
fluid volume expansion is suppressed and about VLBW infants’ ability to catabolize
there are subsequent alterations in quanti- amino acids. Data and clinical experience
tative and qualitative somatic growth. have defined the requirements for paren-
Catheter flushes (using isotonic saline teral nutrients and led to the development
solution) may contribute significant quan- of new products and new methods of deliv-
tities of electrolytes, including chloride, to ery designed specifically for use in the neo-
the infant’s total intake. Hyperchloremic nate.8 Guidelines for certain minerals and
metabolic acidosis in LBW infants has been vitamins were published in 1988 and then
associated with chloride loads greater than updated (Table 7-2).8 Tables 7-3 and 7-4
6 mEq/kg/day. The intake can easily be contain recommended vitamin and min-
decreased by substituting acetate or phos- eral intakes for parenteral and enteral nutri-
phate for chloride in the IV solution. tional support.
Table 7-1. Characteristics of Intravenous Fluids

Cations Anions
Na K Ca Cl HCO3* Osmolarity
Type of Fluid (mEq/L) (mEq/L) (mEq/L) (mEq/L) (mEq/L) (mOsm/L)†
DEXTROSE IN WATER SOLUTIONS
D5W 252
D10W 505
D20W 1010
D50W 2525
DEXTROSE IN SALINE SOLUTIONS
D5W and 0.2% NaCl 34 34 320
D5W and 0.45% NaCl 77 77 406
D5W and 0.9% NaCl 154 154 559
D10W and 0.9% NaCl 154 154 812
SALINE SOLUTIONS
1
⁄2 NS (0.45% NaCl) 77 77 154
NS (0.9% NaCl) 154 154 308
NS (3% NaCl) 513 513 1026
MULTIPLE ELECTROLYTE SOLUTIONS
Ringer’s solution 147 4 5 155 309
Lactated Ringer’s 130 4 3 109 28 273
D5W in Lactated Ringer’s 130 4 3 109 28 524
LIPID EMULSIONS
Lipid emulsions (20%) 258-315
An easy way to approximate the osmolarity of an IV fluid is to consider that for each 1% dextrose, there are 55
mOsm/L; for each 1% amino acids there are 100 mOsm/L; and for each 1% NaCl there are 340 mOsm/L. Therefore:
D10W and 0.45% NaCl (1⁄2 NS)
D10W = (10 × 55) = 550 mOsm/L
0.45% NaCl = (0.45 × 340) = 153 mOsm/L
Total 703 mOsm/L
12.5% dextrose and 17 g amino acids/L (or 1.7% amino
acids)
D12.5W = 12.5 × 55 = 687 mOsm/L
1.7% AA = 1.7 ×100 = 170 mOsm/L
Total 857 mOsm/L
Parenteral nutrition solutions with an osmolarity
>900 mOsm/L should be infused through a central line.
Adapted from Wolf BM, Yamahata WI: In Zeman FJ, editor: Clinical nutrition and dietetics, Lexington,
Mass, 1983, DC Heath.
*Or its equivalent in lactate, acetate, or citrate.
†Osmolarity of the blood is 285-295 mOsm/L.
Supporting an infant on TPN is not with- and organ size and maturation (Table 7-5).
out risk. This method of nutrient delivery Measurement of a true basal metabolic rate
should not be undertaken without knowl- requires a prolonged fast and cannot ethi-
edge of the potential metabolic and mechan- cally be determined in VLBW infants; there-
ical (or catheter-related) complications. Most fore, resting metabolic rate (RMR) is used
complications can be avoided with careful to estimate energy needs, dietary-induced
monitoring and prompt intervention. Com- thermogenesis, minimum energy expended
plication rates are minimized when paren- in activity, and the metabolic cost of
teral nutrition is administered with strict growth. The metabolic rate increases during
adherence to established protocols. the first weeks of life from an RMR of 40 to
41 kcal/kg/day during the first week to 62 to
ENERGY 64 kcal/kg/day by the third week of life. The
Energy needs are dependent on age, weight, extra energy expenditure is primarily due to
rate of growth, thermal environment, activ- the energy cost of growth related to various
ity, hormonal activity, nature of feedings, synthetic processes. The metabolic rate of
Table 7-2. Parenteral Multivitamin Dosing Guidelines

Product Guidelines
ASCN Recom- 30% Dose 65% Dose

mended Dose* for Infants <1 kg for Infants 1-3 kg
Weight ≤2500 g 500 g 950 g 1000 g 2000 g 3000 g
Lipid-Soluble
A (µg) 280 420 221 455 228 152
A (IU) 933 1380 726 1495 748 498
E (mg) 2.8 4.2 2.2 4.5 2.2 1.5
K (µg) 80 120 63 130 65 43
D (µg) 4 6 3.2 6.5 3.2 2.2
D (IU) 160 240 126 260 130 87
Water-Soluble
Ascorbic acid (mg) 32 48 25 52 26 17
Thiamin (mg) 0.48 0.72 0.34 0.78 0.39 0.26
Riboflavin (mg) 0.56 0.84 0.44 0.91 0.46 0.30
Pyridoxine (mg) 0.4 0.6 0.32 0.65 0.33 0.22
Niacin (mg) 6.8 10.2 5.4 11.1 5.6 3.7
Pantothenate (mg) 2.0 3.0 1.4 3.3 1.6 1.1
Biotin (µg) 8.0 12.0 6.3 13.0 6.5 4.3
Folate (µg) 56 84 44 91 46 30
Vitamin B12 (µg) 0.4 0.6 0.32 0.65 0.33 0.22
From Groh-Wargo S, Thompson M, Cox JH, editors: Nutritional care for high-risk newborns, rev ed 3,
Chicago, 2000, Precept Press, p 15.
*40% dose/kg body weight, maximum not to exceed term infant dose. The 1988 ASCN Subcommittee
report suggested that until a preterm parenteral multivitamin is available, pediatric formulations meeting
the 1975 AMA-NAG pediatric guidelines should be used at 40% of the standard dose per kg. The
maximum dose should not exceed 100% of the term infant dose. Infants weighing >2500 g receive 100%
of the standard dose.
the nongrowing infant is approximately 51 kilogram body weight basis because of their
kcal/kg/day, which includes 47 kcal/kg/day relatively high proportion of metabolically
for basal metabolism and 4 kcal/kg/day for active mass. Other factors that may increase
activity. metabolic rate are speculative; the effects
The contribution of activity to overall of fever, sepsis, and surgery on the infant’s
energy expenditure is speculative but seems energy requirements are uncertain.
to be small, between 3 and 5 kcal/kg/day Caloric intake above maintenance is used
to the total energy expenditure. Because of for growth. On average, for each 1-g incre-
the large amount of time spent in the sleep ment in weight, approximately 4.5 kcal
state, energy expenditure in muscular activ- above maintenance energy need are required.
ity in immature infants is relatively small in Therefore, to attain the equivalent of the
comparison to their resting metabolism. As third trimester intrauterine weight gain (10 to
infants mature, they become more active; 15 g/kg/day), a metabolizable energy intake
therefore, energy expenditure from activity of approximately 45 to 70 kcal/kg/day above
increases. the 51 kcal/kg/day required for maintenance
The exposure of infants to a cold environ- must be provided, or approximately 100 to
ment affects energy expenditure with small 120 kcal/kg/day. Increasing metabolizable
alterations in the thermal environment energy intakes beyond 120 kcal/kg/day with
making a significant contribution to energy energy supplementation alone does not result
expenditure. Infants nursed in an environ- in proportionate increases in weight gain.
ment just below thermal neutrality increase However, when energy, protein, vitamins,
energy expenditure by 7 to 8 kcal/kg/day; and minerals are all increased, weight gain
any handling adds to this energy loss. A with increases in rates of protein and fat accre-
daily increase of 10 kcal/kg/day should be tion can be realized. The higher the caloric
allowed to cover incidental cold stress in the intake, the more energy that is expended
preterm infant. Infants who are intrauterine through excretion, dietary-induced ther-
growth restricted, particularly the asym- mogenesis, and tissue synthesis. The energy
metrical type, have a higher RMR on a per cost of weight gain at 130 kcal/kg/day was
Table 7-3. Recommended Intakes of Parenteral and Enteral Vitamins

ELBW and VLBW
Day 0 Transition Growing

per kg/day per kg/day per kg/day
Vitamin A (IU) Parenteral 700-1500 700-1500 700-1500
Enteral 700-1500 700-1500 700-1500
Vitamin D (IU) Parenteral 40-160 40-160 40-160
Enteral 150-400 150-400 150-400
Vitamin E (IU) Parenteral 2.8-3.5 2.8-3.5 2.8-3.5
Enteral 6-12 6-12 6-12
Vitamin K (µg) Parenteral 500 IM per child 10 10
Enteral 500 IM per child 8-10 8-10
Thiamin (µg) Parenteral 200-350 200-350 200-350
Enteral 180-240 180-240 180-240
Riboflavin (µg) Parenteral 150-200 150-200 150-200
Enteral 250-360 250-360 250-360
Niacin (mg) Parenteral 4-6.8 4-6.8 4-6.8
Enteral 3.6-4.8 3.6-4.8 3.6-4.8
Vitamin B6 (µg) Parenteral 150-200 150-200 150-200
Enteral 150-210 150-210 150-210
Folate (µg) Parenteral 56 56 56
Enteral 25-50 25-50 25-50
Vitamin B12 (µg) Parenteral 0.3 0.3 0.3
Enteral 0.3 0.3 0.3
Pantothenic acid (mg) Parenteral 1-2 1-2 1-2
Enteral 1.2-1.7 1.2-1.7 1.2-1.7
Biotin (µg) Parenteral 5-8 5-8 5-8
Enteral 3.6-6 3.6-6 3.6-6
Vitamin C (mg) Parenteral 15-25 15-25 15-25
Enteral 18-24 18-24 18-24
Taurine (mg) Parenteral 0-3.75 1.88-3.75 1.88-3.75
Enteral 0-9 4.5-9 4.5-9
Carnitine (mg) Parenteral 0-2.9 0-2.9 0-2.9
Enteral 0-2.9 0-2.9 0-2.9
Adapted from Tsang RC, Uauy R, Koletzko B, et al, editors: Nutrition of the preterm infant, ed 2,
Cincinnati, 2005, Digital Educational Publishing, pp 415-416.
Day 0 = Day of birth.
Transition: The period of physiologic and metabolic instability following birth, which may last as long as
7 days.
reported to be 3.0 kcal/g of weight gain. How- a protein intake of 2.7 to 3.5 g/kg/day, pre-
ever, at an intake of 149 kcal/kg/day and 181 term infants exhibit nitrogen accretion and
kcal/kg/day, the energy cost of weight gain growth rates similar to in utero levels.
has been estimated to be 4.9 and 5.7 kcal/g The sources of energy for parenteral nutri-
of weight gain, respectively. In summary, to tion in infants are either as glucose or lipid,
increase lean body mass accretion and limit or a combination of the two. Although both
fat mass deposition, an increase in protein-to- glucose and fat provide equivalent nitro-
energy ratio in enteral diets is necessary. gen-sparing effects in the neonate, studies
The energy needs of the parenterally have demonstrated that a nutrient mixture
nourished infant differ from the enterally using IV glucose and lipid as the nonprotein
fed infant in that there is no fecal loss of energy source is more physiologic than sup-
nutrients. Preterm infants who are appro- plying glucose as the only nonprotein energy
priately grown for gestational age are able source. The amount of glucose required to
to maintain positive nitrogen balance when meet the total energy needs approximates
receiving 50 nonprotein calories (NPCs)/kg/ 7 mg/kg/min (10 g/kg/day). The excess glu-
day and 2.5 g protein/kg/day. At an NPC cose administered is converted to fat or tri-
intake of greater than 70 NPC/kg/day and glycerides. A nutrient mixture with glucose
Table 7-4. Recommended Mineral Intakes for Very Low Birth Weight Infants
ELBW and VLBW
Day 0 Transition Growing

per kg/day per kg/day per kg/day
Sodium (mg) Parenteral 0-23 46-115 69-115 (161*)
Enteral 0-23 46-115 69-115 (161*)
Potassium (mg) Parenteral 0 0-78 78-117
Enteral 0 0-78 78-117
Chloride (mg) Parenteral 0-35.5 71-178 107-249
Enteral 0-35.5 71-178 107-249
Calcium (mg) Parenteral 20-60 60 60-80
Enteral 33-100 100 100-220
Phosphorus (mg) Parenteral 0 45-60 45-60
Enteral 20-60 60-140 60-140
Magnesium (mg) Parenteral 0 4.3-7.2 4.3-7.2
Enteral 2.5-8 7.9-15 7.9-15
Iron (mg) Parenteral 0 0 0.1-0.2
Enteral 0 0 2-4
Zinc (µg) Parenteral 0-150 150 400
Enteral 0-1000 400-1200 1000-3000
Copper (µg) Parenteral 0 ≤20 20
Enteral 0 ≤150 120-150
Selenium (µg) Parenteral 0 ≤1.3 1.5-4.5
Enteral 0 ≤1.3 1.3-4.5
Adapted from Tsang RC, Uauy R, Koletzko B, et al, editors: Nutrition of the preterm infant, ed 2,
Cincinnati, 2005, Digital Educational Publishing, pp 415-416.
Day 0 = day of birth.
Transition: The period of physiologic and metabolic instability following birth, which may last as long as
7 days.
*May need up to 160 mg/kg/day for late hyponatremia.
control is adversely effected.9 A moderate IV

Estimation of the Energy
fat intake comprising approximately 35% of
Table 7-5. Requirement of the Infant
with Low Birth Weight.* the NPCs is preferred.
There is a paucity of studies available
Average Estimation, to examine energy expenditure in VLBW
kcal/kg/day infants on assisted ventilation. Technical dif-
ficulties and methodologic limitations affect
Energy expended 40-60
Resting metabolic rate 40-50*
interpretation of data. Leitch and Denne
Activity 0-5* reviewed 12 studies, with 29 of 75 patients
Thermoregulation 0-5* studied in the first 2 to 3 days of life.10 Early
Synthesis 15† studies suggest a mean energy expenditure
Energy stored 20-30† of approximately 54 kcal/kg/day.11,12
Energy excreted 15
Energy intake 90-120 Carbohydrates
Carbohydrates are the main energy substrate
Adapted from the Committee on Nutrition of the Preterm
Infant, European Society of Paediatric Gastroenterology and
for the preterm infant receiving parenteral
Nutrition, Bremer HJ, Wharton BA: Nutrition and feeding nutrition. At least at the outset, lipids play
of preterm infants, Oxford, 1987, Blackwell Scientific a minor role in supplying energy, although
and American Academy of Pediatrics: Pediatric nutrition
handbook, ed 6, Elk Grove Village, Ill, 2009, p 83. they play an important role at all times in
*Energy for maintenance. providing essential fatty acids. Clearly, the
†Energy cost of growth.
infant must eventually transition to enteral
feedings, which provide about half the
and lipids providing NPCs as well as essen- energy from fat. However, while receiving
tial fatty acids is suggested. TPN, carbohydrate remains the dominant
When 60% to 63% of the NPCs given to energy substrate.
LBW infants are derived from lipids, nitro- Glucose intolerance, defined as inabil-
gen retention is decreased and temperature ity to maintain euglycemia at glucose
administration rates of less than 6 mg/ significant risk of hypoglycemia.17,18 How-

kg/min, is a frequent problem in VLBW ever, excessive energy is associated with
infants, especially those weighing less than increased fat accretion, not accompanied
1000 g. Hyperglycemia in VLBW infants by lean mass or increase in head circumfer-
may also occur with nonoliguric hyperkale- ence, and little is known about its effects on
mia.13 These two comorbid conditions were counterregulatory hormone concentrations.
frequently observed in ELBW infants before A study examined the effect of insulin using
the practice of early initiation of amino a hyperinsulinemic-euglycemic clamp in
acids. Endogenous glucose production is ELBW infants receiving only glucose. These
elevated in VLBW infants compared with infants were normoglycemic before the
term infants and adults.14 Also, high glu- initiation of insulin. They demonstrated a
cose production rates are found in VLBW significant elevation in plasma lactate con-
infants who received only glucose com- centrations and the development of signifi-
pared to those receiving glucose plus amino cant metabolic acidosis.19
acids and/or lipids.15 Clinical experience The administration of amino acids early
with glucose intolerance suggests that glu- after birth appears to prevent the need for
cose alone does not always suppress glucose IV insulin, perhaps through stimulation
production in VLBW infants. It is not clear of insulin by amino acids (e.g., arginine
what circumstances or metabolic condi- and leucine).20 Improved glucose toler-
tions lead to glucose intolerance. It appears ance enables appropriate energy intake for
likely, however, that persistent glucose growth. Therefore, amino acids are adminis-
production is the main cause, fueled by tered aggressively from the first hours of life
ongoing proteolysis that is not suppressed to avoid the period of early neonatal mal-
by physiologic concentrations of insulin. nutrition.
There is uncertainty whether abnormally The human placenta actively transports
low peripheral glucose utilization is also amino acids to the fetus, and animal stud-
involved. ies indicate that fetal amino acid uptake
The glucose infusion rate should main- greatly exceeds protein accretion require-
tain euglycemia. Depending on the degree ments. Approximately 50% of the amino
of immaturity (<26 weeks), 5% glucose or acids taken up by the fetus are oxidized and
10% glucose may be used. Another objec- serve as a significant energy source. Urea
tive becomes the achievement of higher production is a by-product of amino acid
energy intakes. Glucose intolerance can oxidation. Relatively high rates of fetal urea
limit delivery of energy to the infant to a production are seen in human and animal
fraction of the resting energy expenditure, fetuses compared with the term neonate
leaving the infant in negative energy bal- and adult, suggesting high protein turn-
ance. Several strategies are used to manage over and oxidation rates in the fetus. There-
this early hyperglycemia in ELBW infants: fore, a rise in blood urea nitrogen, which is
(1) decreasing glucose administration until often observed after the start of TPN, is not
hyperglycemia resolves (unless the hyper- an adverse effect or sign of toxicity in the
glycemia is so severe that this strategy would absence of other signs of renal compromise
require infusion of a hypotonic solution); or severe dehydration. Several controlled
(2) administering IV amino acids, which studies have demonstrated the efficacy and
decrease glucose concentrations in ELBW safety of amino acids initiated within the
infants, presumably by enhancing endog- first 24 hours of life.21-23 There were no rec-
enous insulin secretion; (3) initiation of ognizable metabolic derangements, includ-
exogenous insulin therapy at rates to con- ing hyperammonemia, metabolic acidosis,
trol hyperglycemia16,17; and (4) using insu- or abnormal aminograms.
lin to control hyperglycemia and to increase A strong argument for the early aggres-
nutrient uptake.18 The first and third strat- sive use of amino acids is the prevention
egies prevent adequate early nutrition and of “metabolic shock.” Concentrations of
the safety of the last has been questioned some key amino acids begin to decline in
in this population because of the possible the VLBW infant from the time the cord is
development of lactic acidemia. Several cut. This metabolic shock may trigger the
studies have shown that insulin, used as starvation response, of which endogenous
a nutritional adjuvant, successfully low- glucose production is a prominent feature.
ers glucose concentrations and increases Irrepressible glucose production may be the
weight gain in preterm infants without cause of the so-called “glucose intolerance”
1.8 105
1.6 100
1.4 (+2%/day)
Body protein (g)

95
1.2
90
1
g/kg/d
1.5 85
0.8
1.1 80 (–1.5%/day)
0.6
0.7 75
0.4
0.2 70
Birth 1 2 3 4 5 6 7
0
26 32 Term Age (days)
Gestational age (wk) Fetus in utero
Figure 7-3. Protein losses measured in three groups Glucose alone
of infants receiving glucose alone at 2 to 3 days of age.
Protein losses are calculated from measured rates of Figure 7-4. Change in body protein stores in a theoretical
phenylalanine catabolism. (Adapted from Denne SC: 26-week gestation, 1000-g premature infant receiving
Protein and energy requirements in preterm infants, glucose alone with a fetus in utero. (Adapted from Denne
Semin Neonatal 6:377, 2001.) SC: Protein and energy requirements in preterm infants,
Semin Neonatal 6:377, 2001.)
that often limits the amount of energy that

can be administered to the VLBW infant. It a 1000-g–birth weight infant begins with
makes sense to smooth the metabolic tran- body protein stores of ~88 g. Without any
sition from fetal to extrauterine life. With- protein intake, the infant loses more than
holding TPN for days or even hours means 1.5% of body protein per day.26 Compare
unnecessarily sending the infant into a met- this with the normal fetus who would
abolic emergency. Thus, the need for par- accumulate body protein in excess of 2%
enteral nutrition may never be more acute per day. It is obvious that significant body
than right after birth. It is noteworthy that protein deficits can accumulate rapidly in
Rivera et al. made the unexpected obser- ELBW infants if early aggressive amino acid
vation24 that glucose tolerance was sub- administration is not offered.
stantially improved in the group receiving The first studies of early TPN used doses
early amino acids. Early amino acids may between 1 and 1.5 g/kg/day, an amount
stimulate insulin secretion, consistent with that will replace ongoing losses. Dosages
the notion that forestalling the starvation have recently been increased toward 3 g/kg/
response improves glucose tolerance. Recent day with initiation within hours of birth.
data show that ELBW infants receiving ear- Ultimate amino acid intake should be 3 g/
lier and higher dosages of amino acids (3 g/ kg/day; however, one can consider intakes
kg/day) had lower glucose levels than those of 3.5 to 4 g/kg/day for infants weighing
receiving early amino acids but at lower dos- less than 1200 g in situations where enteral
ages the first 5 days of life.25 feeds are extremely delayed or withheld for
prolonged periods. A desirable protein to
Dose of Amino Acids energy ratio is 25 kcal/kg for every gram of
Figure 7-3 shows protein loss that occurs in protein/kg or 2 to 3 mg/kg/min of glucose
mechanically ventilated, 26-week gestation per gram of protein intake.
900-g–birth weight infants at 2 days of age Protein quality, or amino acid composi-
who were receiving glucose alone.26 Clini- tion, in parenteral nutrition can influence
cally stable 32-week gestation premature nitrogen utilization as well as the meta-
infants and normal term infants are also bolic responses. Histidine is known to be
shown for comparison. It is clear that there necessary for protein synthesis and growth
is a significant effect of gestation on protein in the neonate but exact requirements are
metabolism because the rate of protein loss not known. Certain other amino acids are
in ELBW infants is twofold higher than in considered semi-essential or conditionally
normal term infants. essential in that the capacity to synthe-
The impact of this rate of protein loss is size them is limited in the preterm infant.
shown in Figure 7-4. At 26 weeks’ gestation, Therefore, if these conditionally essential
amino acids are not exogenously avail- Taurine, which is synthesized endog-
able or available only in limited amounts, enously from cysteine, is a sulfur amino
the infant’s requirements may not be met. acid, which is not part of structural proteins
Three of these semi-essential amino acids but is present in most tissues of the body;
are cysteine, tyrosine, and taurine. it is particularly high in the retina, brain,
Cysteine is synthesized in vivo from heart, and muscle. The biological function
methionine by the enzyme cystathionase. of taurine in mammals includes neuro-
Because the hepatic activity of cystathion- modulation, cell membrane stabilization,
ase has been found to be low or absent dur- antioxidation, detoxification, osmoregula-
ing fetal development and in the preterm tion, and bile acid conjugation; however,
and term neonate,27 it has been consid- its conjugation with bile acids is the only
ered an essential amino acid for the infant. adequately documented metabolic reaction
Zlotkin and Anderson observed reduced in humans. Depletion of taurine during
hepatic cystathionase activity in preterm long-term parenteral nutrition has resulted
infants compared with full-term infants at in abnormal electroretinograms in children
the time of birth with the activity increas- and auditory brainstem-evoked responses
ing in the preterm infant over the first in preterm infants. Taurine supplementa-
month of life28; however, mature levels tion of preterm infant formula has been
were not attained until approximately 8 shown to improve fat absorption, especially
months. When total cystathionase activity saturated fats, in LBW infants. Human milk
was estimated, which included the enzyme is rich in taurine; infants fed human milk
activity in the liver, kidneys, pancreas, have higher plasma and urine concentra-
and adrenal glands, they concluded that tions of taurine than infants fed unsupple-
even the preterm infant has the capacity mented infant formula. Infant formulas and
to endogenously produce adequate cyste- pediatric parenteral amino acid solutions
ine if adequate methionine is provided. In are supplemented with taurine.
fact, increased parenteral methionine has Currently, there are two kinds of crystal-
been shown to increase urinary cysteine line amino acid solutions available for use
excretion. Supplementation of parenteral in the neonate. The standard solutions orig-
amino acid solutions with cysteine hydro- inally designed for adults are often used for
chloride has not been shown to affect infants but are not ideal. The adult products
either nitrogen balance or growth in LBW contain little or no tyrosine, cysteine, or
infants. However, the two pediatric amino taurine, and contain relatively high concen-
acid solutions, Trophamine (McGaw, Inc., trations of glycine, methionine, and phe-
Irvine, Calif) and Aminosyn-PF (Abbott nylalanine. Because the plasma amino acid
Laboratories, Abbott Park, Ill), are low in patterns reflect the amino acid composi-
methionine content, 81 and 45 mg/2.5 g tion of the amino acid solution infused, the
of amino acids, respectively, and do not resulting abnormal plasma amino acid levels
contain cysteine. Therefore, supplementa- could be potentially harmful. Hyperglycin-
tion with cysteine hydrochloride is recom- emia, for example, may have adverse effects
mended. on the central nervous system because gly-
Tyrosine, which is endogenously syn- cine is a potent neurotransmitter inhibitor.
thesized from phenylalanine through the The pediatric amino acid solutions have a
activity of phenylalanine hydroxylase, has greater distribution of nonessential amino
also been considered an essential amino acids (particularly less glycine), greater
acid; however, the enzyme activity is not amounts of branched-chain amino acids,
low during development. The low plasma less methionine and phenylalanine, and
tyrosine concentrations seen in infants on more tyrosine, cysteine, and taurine.
tyrosine-free parenteral nutrition infusates Studies of these products have demon-
appear to be independent of the plasma strated improved nitrogen retention and
phenylalanine levels and not all infants on plasma aminograms resembling those of
tyrosine-free parenteral nutrition solutions full-term breast-fed infants at 30 days of
have low plasma tyrosine levels. In addi- life.27 However, studies of protein turnover
tion, extremely preterm infants have been and urea production (protein oxidation)
shown to convert substantial quantities of have not shown any difference between
phenylalanine to tyrosine.29 Therefore, the Trophamine and other amino acid mix-
requirement for an exogenous source of this tures.30 Because of the lower pH of the pedi-
amino acid remains uncertain. atric crystalline amino acid solutions, greater
concentrations of calcium and phosphorous pertinent to the ventilated VLBW infant

may be added without precipitation, which include adverse effects on gas exchange
is an advantage particularly for the preterm and displacement of bilirubin from albu-
neonate because the requirements for both min. Both Brans and Adamkin found no
minerals are quite high.8 difference in oxygenation between infants
randomly assigned to various lipid doses
Lipids (including controls without lipids) when
There are two roles for lipids as part of a TPN using lower rates and longer infusion times
regimen. The first function is to serve as a of IV lipids.33,34 The displacement of biliru-
source of linoleic acid. When used in small bin from binding sites on serum albumin
amounts, it can prevent or treat essential may occur even with adequate metabolism
fatty acid deficiency. The second function is of infused lipid. In vitro, displacement of
its use as an energy source. Larger quantities albumin-bound bilirubin by free fatty acids
serve as a partial replacement for glucose as (FFAs) depends on the relative concentra-
a major source of calories (Table 7-6). tions of all three compounds. An in vivo
The preterm neonate is especially suscepti- study has shown no free bilirubin gener-
ble to the development of essential fatty acid ated if the molar FFA to albumin ratio is
deficiency because tissue stores of linoleic less than 6.35 Data with lipid initiation at
acid are small and requirements for essential 0.5 g/kg/day of lipids in VLBW infants on
fatty acids are large because of rapid growth. assisted ventilation with respiratory distress
The human fetus depends entirely on pla- syndrome showed a mean FFA to albumin
cental transfer of essential fatty acids. A ratio of less than 1. No individual patient
VLBW infant with limited nonprotein calorie value exceeded a ratio of 3 when daily doses
reserve must mobilize fatty acids for energy were increased to 2.5 g/kg/day (in incre-
when receiving IV nutrition devoid of lipid. ments of 0.5 g/kg/day) over an 18-hour
Studies in these infants confirm other studies infusion time.36 Other investigators found
that show essential fatty acid deficiency can no adverse effect on bilirubin binding when
develop in the VLBW infant during the first lipid emulsion was infused at a dose of 2 g/
week of life on lipid-free regimens. kg/day over either 15 or 24 hours. Proper
The importance of long-chain polyun- use includes slow infusion rates (≤0.15 g/kg/
saturated fatty acids (LC-PUFAs) for the hr), slow increases in dosage, and avoidance
development of the brain and the retina has of unduly high doses (e.g., >3 g/kg/day).
been recognized.31,32 Infants are not capa- Concerns have been raised regarding
ble of forming sufficient quantities of LC- the possible adverse effects of IV lipids on
PUFAs from the respective precursor fatty pulmonary function, but these have gener-
acids (linoleic and α-linolenic acids), and ally proved to be unfounded. For the late
thus depend on an exogenous source of LC- preterm infant with increased pulmonary
PUFAs. Intravenous lipid emulsions contain vascular resistance (PVR) and respiratory
small amounts of these fatty acids as part disease, however, it appears that a more
of the egg phospholipid used as a stabilizer. prudent approach with IV lipids should be
The “routine” use of IV lipid emulsions taken. Significant concerns have been raised
has not been universally accepted in criti- because of the high polyunsaturated fatty
cally ill, ventilated VLBW infants because acid (PUFA) content of lipid emulsions as
of potential complications. Hazards most excessive omega 6 (linoleic acid, 18:2ω6)
Table 7-6. Composition of Intravenous Lipid Emulsions
Linoleic Acid Linolenic Acid Glycerin Osmolarity

Product Oil Base (%) (%) (%) (mOsm/L)
Intralipid* 100% Soybean 44-62 4-11 2.25 260
Nutrilipid† 100% Soybean 49–60 6-9 2.21 315
Soyacal‡ 100% Soybean 49-60 6-9 2.21 315
Liposyn III§ 100% Soybean 54.5 8.3 2.5 284
*KabiVitrum, Alameda, Calif. Data from product insert.

†McGaw, Inc., Irvine, Calif.
‡Alpha Therapeutic, Los Angeles, Calif.
§Abbott Laboratories, Abbott Park, Ill. Data from product insert.
Other sources: Drug facts and comparisons, St. Louis, 1990, JB Lippincott.
acids are required substrates for arachidonic Lipid emulsions are supplied as either
acid pathways which lead to synthesiz- 10% or 20% solutions, providing 10 or 20 g
ing prostaglandins and leukotrienes (Fig. of triglyceride/dL, respectively. Both con-
7-5).37 It is speculated the IV lipid infu- tain the same amount of egg yolk phos-
sion may enhance thromboxane synthesis pholipid emulsifier (approximately 1.2 g/
activity, which increases thromboxane pro- dL) and glycerol (approximately 2.25 g/dL).
duction.38 The prostaglandins may cause However, each contains more phospholipid
changes in vasomotor tone with resultant than is required to emulsify the triglyceride.
hypoxemia.39,40 In addition, the production The excess is formed into triglyceride-poor
of hydroperoxides in the lipid emulsion also particles with phospholipid bilayers called
might contribute to untoward effects by liposomes. For any given dose of triglyc-
increasing prostaglandin levels.40-42 eride, twice the volume of 10% emulsion
Although there is no firm evidence of must be infused compared with the 20%
the effects of lipid emulsions in infants emulsion. Therefore, for a fixed amount of
with severe acute respiratory failure with triglyceride, the 10% emulsion provides at
or without pulmonary hypertension, it least twice and perhaps up to four times the
appears prudent to avoid high dosages in amount of liposomes as the 20% emulsion.
these patients. For those with respiratory The 10% emulsion has been shown to be
diseases without increased pulmonary vas- associated with higher plasma triglyceride
cular resistance, provide IV lipids at a dos- concentrations and an accumulation of cho-
age to prevent essential fatty acid deficiency. lesterol and phospholipid in the blood of
For those with elements of persistent pul- the preterm infant, probably because of the
monary hypertension (PPHN), avoidance of higher phospholipid content. LBW infants
lipids during the greatest labile and critical infused with lipids at 2 g/kg/day of 10%
stages of their illness should be considered. emulsion had significantly higher plasma
When the infant is more stable, IV lipids at triglycerides, cholesterol, and phospholipids
a modest dosage can be initiated. than infants infused with 4 g lipid/kg/day
Common practice is to begin IV lipids on as 20% emulsion. It is speculated that the
the second day of life following initiation of excessive phospholipid liposomes in the
amino acids shortly after delivery. Starting 10% emulsion compete with the triglycer-
dose is 0.5 g/kg/day or 1.0 g/kg/day. Plasma ide-rich particles for binding to lipase sites,
triglycerides are monitored after each increase resulting in slow triglyceride hydrolysis. It
in dose and levels are maintained less than is, therefore, recommended that 20% lipid
200 mg/dL. A 20% lipid emulsion is used emulsions be used for the LBW and VLBW
exclusively with an infusion rate less than infants.
or equal to 0.15 g/kg/hr. Therefore, a dose of Adverse side effects of IV lipid emulsions
3 g/kg/day would be infused over 24 hours. have been reported, including displacement
of indirect bilirubin from albumin-bind-
ing sites, increasing the risk of kernicterus,
To tissues suppression of the immune system, coag-
Diet
Linoleic acid ulase-negative staphylococcal and fungal
(C18:2ω6) infection,43 thrombocytopenia, and accu-
Desaturation, Metabolized mulation of lipids in the alveolar macro-
elongation for energy phages and capillaries, subsequently altering
pulmonary gas exchange.44 As noted ear-
Arachidonic acid lier, because FFAs compete with bilirubin
Diet To tissues
(ARA)
for binding to albumin, the use of IV lipid
emulsions in jaundiced newborns has been
PPHN? (smooth questioned. However, it is more a theoretical
muscle contractions) concern, in that FFA concentrations do not
Eicosanoids reach high enough levels to cause displace-
Prostaglandins Increase vasomotor
tone
ment of bilirubin and increase free bilirubin
Thromboxanes
Leukotrienes to a very high range. Careful monitoring
Hold the lipids? of plasma triglycerides has been suggested
Figure 7-5. Metabolic derivatives of linoleic acid and ARA, when lipids are administered to babies with
PPHN, Persistant palmonary hypertension. (Adapted from hyperbilirubinemia.
Adamkin DH: Nutrition in very very low birth weight There may be a beneficial effect of infus-
infants, Clin Perinatol 13[2]:419, 1986.) ing lipids. Infusion of lipid emulsion exerts
a beneficial effect on the vascular endothe- PARENTERAL VITAMINS

lium of peripheral veins leading to longer The parenteral multivitamin guidelines
venous patency time. Malhotra et al. noted proposed by the American Medical Asso-
that hyperbilirubinemic infants given a ciation have been accepted for the pedi-
lipid infusion of 1 to 2 g/kg/day had a sig- atric formulation. A special committee of
nificant increase in lumirubin,45 a water- the American Society for Clinical Nutrition
soluble structural isomer of bilirubin that made recommendations for a new mul-
can be excreted in the bile without hepatic tivitamin preparation specifically for the
conjugation. Therefore, IV lipid infusions preterm infant.8 Although no preparation
may enhance the effect of, and may be a meets these guidelines, the committee rec-
useful adjunct to, phototherapy. ommends that MVI-Pediatric (Armour Phar-
Suppression of immune function and maceutical, Kankakee, Ill) should be used for
increased risk of sepsis have been associ- preterm infants at 40% of a vial (or 2 mL)
ated with the use of IV lipid emulsions. per kilogram body weight per day, not to
Diminished motility and metabolic activ- exceed a total daily dose of one vial (5 mL);
ity of polymorphonuclear (PMN) leukocytes infants and children should receive one vial
exposed to fat emulsion in vitro have been (5 mL) daily (see Table 7-2).
reported. However, this could not be dem- Intravenous vitamins, especially vitamin
onstrated in vivo in full-term and preterm A, riboflavin, ascorbic acid, and pyridoxine,
infants given lipid 0.5 to 3 g/kg/day over may be lost through adherence to the plastic
16 hours. On the contrary, some aspects of tubing or through photodegradation caused
PMN migratory properties and their oxida- by light exposure. There is often high light
tive metabolism improved during the study intensity in a special care nursery and the
period, most likely the result of chronologic TPN fluid in the tubing moves slowly; there-
and functional maturity.46 There have been fore, it is exposed to light for prolonged peri-
reports of fungal infections with Malasse- ods. For these reasons, vitamins are added to
zia furfur and coagulase-negative staphylo- the TPN shortly before infusing and some
cocci associated with lipid administration.43 nurseries have the TPN bags and infusion
Freeman and colleagues have reported that tubings covered with foil or opaque mate-
56.6% of all cases of nosocomial bactere- rial to minimize light exposure.
mia in two neonatal intensive care units
in Boston were highly correlated with lipid TRACE MINERALS
administration.43 However, they stress that Because the infant has minimal endoge-
the benefits derived from the lipids out- nous stores, trace minerals are added to the
weigh the apparent risk of infection. TPN solution (see Table 7-4). The need for
iron supplementation should be evaluated.
Carnitine Intravenous iron should be used with cau-
Carnitine is an essential cofactor required tion because excess iron can easily be given
for the transport of long-chain fatty acids and may result in iron overload, increased
(LCFAs) across the mitochondrial mem- risk of gram-negative septicemia, and an
brane for β-oxidation. Because the pre- increase in the requirement for antioxi-
term infant is born with limited carnitine dants, especially vitamin E.8
reserves and low plasma carnitine levels
develop when parenteral nutrition is not CALCIUM, PHOSPHORUS, MAGNESIUM,
supplemented with carnitine, several inves- AND VITAMIN D
tigators have suggested adding carnitine to Preterm infants require increased intakes of
parenteral nutrition with lipids for preterm calcium and phosphorus for optimal bone
infants.47,48 Addition of supplemental car- mineralization. The intrauterine accretion
nitine does increase oxidation of fat and rates for calcium in the last trimester range
circulating ketone body levels and results in from 104 to 125 mg/kg/day at 26 weeks’ ges-
increased tolerance to IV lipids. However, tation to 119 to 151 mg/kg/day at 36 weeks’
data on increase in weight gain and nitrogen gestation; phosphorus accretion rate is 63
retention are not as convincing.49 There- to 86 mg/kg/day. These levels of calcium
fore, carnitine is recommended only for and phosphorus intake cannot be attained
LBW infants who require prolonged (over 2 with conventional TPN solutions because
to 3 weeks) parenteral nutrition. IV carni- they would be insoluble. The pediatric crys-
tine dosage has been used at 8 to 10 mg/kg/ talline amino acids solutions, however,
without any observable side effects.50 have a lower pH, especially when cysteine
hydrochloride is added; therefore, greater infant has been debated for nearly a cen-
concentrations of calcium and phosphorus tury and remains controversial.51 As suit-
can remain in solution. able TPN solutions designed for neonates
VLBW infants should receive 60 to 80 mg/ became available, many physicians chose
kg/day of calcium, 45 to 60 mg/kg/day of to use parenteral nutrition alone in the sick,
phosphorus, 4 to 7 mg/kg/day of magne- ventilated, preterm infant because of con-
sium, and 25 IU of vitamin D.8 A calcium- cerns about necrotizing enterocolitis (NEC).
to-phosphorus ratio of 1.3 to 1 is suggested, Total parenteral nutrition was thought to be
although others have noted improved min- a logical continuation of the transplacental
eral retention with a 1.7 to 1 ratio. These nutrition the infants would have received
high calcium and phosphorus infusions in utero. However, this view discounts any
should be given through a central venous role that swallowed amniotic fluid may play
line and not through a peripheral line. in nutrition and in the development of the
gastrointestinal tract. In fact, by the end of
PRACTICAL HINTS FOR FLUID AND TPN the third trimester, the amniotic fluid pro-
MANAGEMENT vides the fetus with the same enteral vol-
• During the first few days of life, provide ume intake and approximately 25% of the
sufficient fluid to result in urine output of enteral protein intake as that of a term,
1 to 3 mL/kg/hour, a urinespecific grav- breast-fed infant. Parenteral nutrition does
ity of 1.008 to 1.012, checking urine for little to support the function of the gastro-
sugar and protein at the same time, and a intestinal tract. Enteral feedings have direct
weight loss of approximately 5% or less in trophic effects and indirect effects second-
full-term and approximately 15% or less ary to the release of intestinal hormones.
in VLBW infants. Lucas et al. demonstrated significant rises
• Weigh infants twice a day the first 2 days in plasma concentrations of enterogluca-
of life, then daily thereafter to accurately gon,52 gastrin, and gastric-inhibiting poly-
monitor input and output. peptide in preterm infants after milk feeds
• Use birth weight to calculate intake until of as little as 12 mL/kg/day. Similar surges
birth weight is regained. in these trophic hormones were not seen in
• Record fluid intake, output, and weight. IV-nourished infants.
• If the infant is hyperbilirubinemic, pro- Clearly, one of the important benefits of
vide lipids 0.5 to 1 g/kg/day, maintain- using TPN is that it allows feedings to be
ing a serum triglyceride no greater than advanced slowly, which probably increases
150 mg/dL. Serum triglyceride should be the safety of enteral feedings. However, how
checked before the start of the first lipid neonatologists feed VLBW neonates has tra-
infusion, as lipids are being advanced, ditionally been based on local practices and
and weekly thereafter. not subjected to rigorous scientific investi-
• Aim for a parenteral nutrition goal of 90 gation.53 Regardless of feeding strategy, the
to 100 kcal/kg/day and 2.7 to 3 g pro- advancement of feedings has been based
tein/kg/day with a nonprotein caloric-to- on the absence of significant pregavage
nitrogen ratio (NPC:N) of 150 to 250. The residuals or greenish aspirates. According
NPC:N ratio can be calculated as follows: to Ziegler and others, gastric residuals are
very frequent in the early neonatal period
lipid calories + dextrose calories NPC and are virtually always benign when not
= accompanied by other signs of gastrointes-
(grams of protein)(0.16) 1gN tinal abnormalities, that is not associated
with NEC.53,54 One study demonstrated that
in ELBW infants, excessive gastric residual
ENTERAL NUTRITION volume either determined by percent of the
When parenteral nutrition is used exclu- previous feed or an absolute volume (>2 mL
sively for the provision of nutrients, mor- or >3 mL) did not necessarily affect feeding
phologic, and functional changes occur in success as determined by the volume of total
the gut with a significant decrease in intes- feeding on day 14.55 Similarly, the color of
tinal mass, a decrease in mucosal enzyme the gastric residual volume (green, milky,
activity, and an increase in gut permeability. clear) did not predict feeding intolerance.56
The changes are due primarily to the lack of Nonetheless, the volume of feeding on day
luminal nutrients rather than the TPN. The 14 did correlate with a higher proportion
timing of the initial feedings for the preterm of episodes of zero gastric residual volumes
and with predominantly milky gastric resid- that feedings not be advanced by more than
uals. Thus, isolated findings related to gas- 20 mL/kg each day.58 This recommendation
tric emptying alone should not be the sole has found wide acceptance, although its valid-
criterion in initiating or advancing feeds. ity has not been confirmed in randomized
Stooling pattern, abdominal distention, and controlled trials. In a prospective random-
the nature of the stools should also be con- ized trial, Rayyis et al. compared increments
sidered.53 of 15 mL/kg/day with increments of 35 mL/
The etiology of NEC remains unclear. kg/day.59 They found that with fast advance-
Because NEC rarely occurs in infants who ment, return to birth weight occurred earlier;
are not being fed, feedings have come to be full intakes were achieved sooner; weight
seen as the cause of NEC. The pathophysi- gain set in earlier; and there was no differ-
ology of NEC is incompletely understood. ence in the incidence of NEC. Whether it
However, intestinal immaturity, abnormal protects against NEC or not, limiting feed-
microbial colonization and a highly immu- ing increments in VLBW infants to 20 mL/
noreactive intestinal mucosa appear to be kg/day has become acceptable practice. It
leading elements of a multifactorial cause. still permits achievement of full feedings in a
The association between feedings and NEC reasonable period (about 8 days). When ini-
is likely to be explained by the fact that feed- tiating early enteral feedings in infants with
ings act as vehicles for the introduction of umbilical artery catheters (UACs) in place,
bacterial or viral pathogens or toxins. They safety is often a concern. The presence of a
are more likely to survive the gastric barrier UAC has been associated with an increased
because of low acidity, against which the risk for NEC, and it is a common nursery
immature gut is poorly able to defend itself. policy to delay feedings until catheters are
Efforts aimed at minimizing the risk of NEC removed. However, few data from controlled
have focused on the time of introduction of studies support this policy. Davey et al.
feedings, on feeding volumes, and on the examined feeding tolerance in 47 infants
rate of feeding volume increments. One by weighing less than 2000 g at birth who had
one, the strategies that had been developed respiratory distress and UACs.60 Infants were
with the aim of reducing the risk of NEC assigned randomly to begin feedings as soon
were shown to be ineffective. as they met the predefined criterion of stabil-
One of the main strategies involved the ity or to delay feeding until their UACs were
withholding of feeding for prolonged peri- removed for 24 hours. Infants who were
ods of time. Although it was never shown fed with catheters in place, started feeding
that the prolonged withholding of feedings significantly sooner and required half the
actually prevented NEC, some form of the number of days of parenteral nutrition. The
strategy was widely adopted in the 1970s incidence of NEC was comparable for infants
and 1980s. The withholding of feedings fed with catheters in place and those whose
eventually came under scrutiny and was catheters were removed before initiation of
compared in a number of controlled trials feedings. In addition, large epidemiologic
with early introduction of feedings.57 A sys- surveys have not shown a cause-and-effect
tematic review of the results of these trials relation between low-lying umbilical artery
concluded that early introduction of feed- catheters and NEC.53,54
ings shortens the time to full feeds, as well The decision when to start these early
as the length of hospitalization, and does enteral or trophic feeds may be influ-
not lead to an increase in the incidence enced by what milk is available to feed the
of NEC. A controlled study involving 100 infant. Lucas and Cole,61 in a multicenter
VLBW infants confirmed these findings and feeding trial involving nearly 1000 pre-
found, in addition,58 a significant reduction term infants with birth weights less than
of serious infections when feedings were 1850 g, demonstrated that the incidence
introduced early. Another strategy aimed at of confirmed NEC was six times greater in
preventing NEC has been to keep the rate formula-fed infants than in those receiv-
increments low. The strategy was based on ing exclusive human milk. In addition,
the findings of Anderson and Kliegman,58 NEC was rare for infants greater than 30
who in their retrospective analysis of 19 cases weeks’ gestation who were fed exclusively
of NEC, found that in infants who went on to human milk, but this was not the case for
develop NEC, feedings were advanced more formula-fed babies. A delay of feeding in
rapidly than in control infants without NEC. the formula-fed group was associated with
Based on these findings, they recommended a reduced risk of NEC, whereas the use of
early human milk feedings versus delaying producing short-chain fatty acids, which
had no correlation with the occurrence of enhance mineral and water absorption and
NEC. Therefore, initiating feeds for indi- may stimulate growth and cell replication
vidual patients should take into account in the gut lumen. Thus, colonic salvage is
individual risk factors and the milk avail- apparently important in disposal of unab-
able for the infant. sorbed lactose; however, its exact quan-
Feedings should be started within the first titative contribution remains unknown.
days of life. A frequently encountered prob- Colonic bacterial fermentation of unab-
lem is that breast milk takes at least 2 days sorbed lactose to absorbable organic acids
to come in and often does not come in for enables the infant to reclaim this carbohy-
3, 4, or 5 days. During that time, only small drate energy and appears to prevent clinical
amounts of colostrum are available, which symptoms of diarrhea.
is very beneficial to the infant and must be Although pancreatic α-amylase, the ma
fed. Gastric residuals should not interfere jor enzyme in starch hydrolysis, is either
with feeding. Initial feeding volumes should absent or in very low concentrations in the
be kept low (1 to 2 mL/feed) and provided first 6 months of life, newborns are capable
at 3-hour intervals. Incremental advances of tolerating small amounts of starch with-
should be about 20 mL/kg/day when a deci- out side effects and preterm infants are able
sion is made to advance feedings. to hydrolyze glucose polymers. Several en-
For ELBW infants on life support with zymes may compensate for the physiologic
invasive monitoring, one may introduce tro- pancreatic amylase deficiency in infancy.
phic feedings with 1 mL/feed every 8 hours Glucoamylase, an enzyme found in the
for a period of a few days and then proceed brush border of the small intestine, is pres-
as above. Each nursery should establish crite- ent in the neonate in concentrations similar
ria for feeding readiness. These may include to those in adults. Also, salivary and hu-
normal blood pressure and pH, Pao2 greater man milk amylases may provide additional
than 55, at least 12 hours from last surfac- pathways for glucose polymer digestion in
tant or indomethacin dose, normal gastro- infancy.
intestinal exam, heme-negative stools, and Because lactase is found only at the tip
fewer than two desaturation episodes (Sao2 of the villus, it is very sensitive to mucosal
less than 80%) per hour. Collectively, these injury; therefore, lactose intolerance may
signs are a surrogate for establishing “physi- develop in infants with diarrhea, those suf-
ologic” stability prior to feeding initiation. fering from undernutrition, or those recov-
ering from NEC, necessitating temporary
CARBOHYDRATE use of a lactose-free formula. In contrast,
Carbohydrate provides 41% to 44% of the glucoamylase is able to survive partial intes-
calories in human milk and most infant for- tinal atrophy because it is located at the base
mulas. In human milk and standard infant of the villi, thus enabling glucose polymers
formulas, it is present as lactose, which has to be an alternative carbohydrate source
been shown to enhance calcium absorp- when enteritis is present and lactase may be
tion. In soy and other lactose-free formulas, found in low concentrations.
the carbohydrate is in the form of sucrose, In premature infant formulas, lactose
maltodextrins, and glucose polymers (corn has been partially replaced by glucose poly-
syrup solids or modified starches). The three mers, polysaccharides with chains of 5 to
major disaccharidases responsible for the 10 glucose residues joined linearly by 1,4-
digestion of disaccharides are lactase, malt- α linkages to decrease the osmolality of the
ase, and sucrase-isomaltase. Maltase and formula and to decrease the lactose load in
sucrase-isomaltase first appear at 10 weeks’ the diet. Glucose polymers are well tolerated
gestation, reaching approximately 70% of by preterm infants with glucose and insu-
newborn levels at 28 weeks’ gestation. How- lin responses similar to those of a lactose
ever, by 28 to 34 weeks’ gestation, lactase feeding.
has only 30% of the activity found in the
term infant; babies born before this time PROTEIN
may have relative lactase deficiency, result- The protein requirement of the preterm
ing in lactose intolerance. infant is estimated to be 3.2 to 4.2 g/kg/
When lactose is not hydrolyzed in the day for VLBW infants and 3.5 to 4.4 g/kg/
small intestine, bacterial fermentation of day for ELBW infants (Table 7-7). The qual-
the undigested portion occurs in the colon, ity and quantity of protein that the infant
Table 7-7. Recommended Nutrient Intakes for Very Low Birth-Weight Infants
ELBW VLBW
Growing Growing
Day 0 Transition Day 0 Transition
per kg/day per kg/day per kg/day per 100 cal per kg/day per kg/day per kg/day per 100 cal
Energy (Cal) Parenteral 40-50 75-85 105-115 100 40-50 60-70 90-100 100
Enteral 50-60 90-100 130-150 100 50-60 75-90 110-130 100
Fluid (mL) Parenteral 90-120 90-140 140-180 122-171 70-90 90-140 120-160 120-178
Enteral 90-120 90-140 160-220 107-169 70-90 90-140 135-190 104-173
Protein (g) Parenteral 2 3.5 3.5-4 3-3.8 2 3.5 3.2-3.8 3.2-4.2
Enteral 2 3.5 3.8-4.4 2.5-3.4 2 3.5 3.4-4.2 2.6-3.8
Carbohydrate (g) Parenteral 7 8-15 13-17 11.3-16.2 7 5-12 9.7-15 9.7-16.7
Enteral 7 8-15 9-20 6-15.4 7 5-12 7-17 5.4-15.5
Fat (g) Parenteral 1 1-3 3-4 2.6-3.8 1 1-3 3-4 3-4.4
Enteral 1 1-3 6.2-8.4 4.1-6.5 1 1-3 5.3-7.2 4.1-6.5
Linoleic acid (mg) Parenteral 110 110-340 340-800 296-762 110 110-340 340-800 340-889
Enteral 110 110-340 700-1680 467-1292 110 110-340 600-1440 462-1309
Docosahexaenoic acid Parenteral ≥4 ≥4 ≥11 ≥10 ≥4 ≥4 ≥11 ≥12
(mg) Enteral ≥4 ≥4 ≥21 ≥16 ≥4 ≥4 ≥18 ≥16
Arachidonic acid (mg) Parenteral ≥5 ≥5 ≥14 ≥13 ≥5 ≥5 ≥14 ≥16
Enteral ≥5 ≥5 ≥28 ≥22 ≥5 ≥5 ≥24 ≥22
Adapted from Tsang RC, Uauy R, Koletzko B, et al, editors: Nutrition of the preterm infant: scientific basis and practical guidelines, ed 2, Cincinnati, 2005, Digital
Educational Publishing, pp 415-416.
Day 0 = Day of birth.
Transition: The period of physiologic and metabolic instability following birth, which may last as long as 7 days.
Linoleate: linolenate: 5-15 for all phases.
CHAPTER 7 Nutrition and Selected Disorders of the Gastrointestinal Tract
169
receives are important. Although weight Dietary Reference Intakes

gain and growth of LBW infants fed pro- Table 7-8. (DRIs): Recommended Intakes
tein intakes of 2.2 to 4.5 g/kg/day of either a for Infants
casein- or whey-predominant formula have
been shown to be no different from those Nutrients 0-6 Months 7-12 Months
receiving pooled human milk, the meta- Protein, g/kg/day 1.52 1.05
bolic responses can be significantly differ- Carbohydrate, g/day 60* 95*
ent. Serum BUN, ammonia, albumin, and Fat, g/day 31* 30*
plasma methionine and cysteine concen- Linoleic acid, g/day 4.4* 4.6*
trations were higher in the infants receiv- Sodium, mg/day 120* 370*
ing high-protein formulas. Elevated levels Potassium, mg/day 400* 700*
of phenylalanine and tyrosine were seen in Chloride mg/day 180* 570*
infants fed the casein-predominant, high- Calcium mg/day 210* 270*
protein formula and lower concentrations Phosphorus, mg/day 100* 275*
of taurine were noted in infants fed casein- Magnesium, mg/day 30* 75*
Iron, mg/day 0.27* 11
predominant formulas regardless of quan-
Zinc, mg/day 2* 3
tity. Preterm infants fed soy protein formula Copper, mcg/day 200* 220*
supplemented with methionine exhibit Selenium, mcg/day 15* 20*
slower weight gain and lower serum protein Vitamin A, mcg/day 400* 500*
and albumin concentrations than infants Vitamin D, IU/day 200* 200*
fed a whey-predominant formula. Thus, Vitamin E, mg/day 4* 5*
premature infant formulas are whey-pre- Vitamin K, mcg/day 2* 2.5*
dominant with a 60 to 40 whey-to-casein Thiamin, mcg/day 200* 300*
ratio; soy protein-based formulas are not Riboflavin, mcg/day 300* 400*
recommended for the preterm infant.62 Niacin, mg/day 2* 4*
Human milk is considered to have the Vitamin B6, mcg/day 100* 300*
ideal amino acid distribution for the human Folate, mcg/day 65* 80*
Vitamin B12, mcg/day 400 500
infant. Preterm infants fed their own moth-
Pantothenic acid, 1.7* 1.8*
er’s milk have more rapid growth than mg/day
infants fed pooled, banked human milk Biotin, mcg/day 5* 6*
with accretion of protein and fat similar to Vitamin C, mg/day 40* 50*
that of the fetus.63 Human milk is lower in
mineral content, especially magnesium, cal- Source: http://www.iom.edu/CMS/3788/21370.aspx and
American Academy of Pediatrics: Pediatric nutrition
cium, phosphorus, sodium, chloride, and handbook, ed 6, Elk Grove Village, Ill, 2009, pp 1294-1296.
iron. To attain intrauterine growth rates, *The AI (Adequate Intake) represents the mean intake for
large volumes (180 to 200 mL/kg/day) of healthy breast-fed infants.
Bold Type: RDAs (Recommended Dietary Allowances) RDAs
human milk must be fed. are set to meet the needs of 97% to 98% of individuals in a
To improve growth and bone mineraliza- group.
tion, human milk fortifiers have been devel-
oped; VLBW infants fed their own mother’s
milk with human milk fortifier added have lipase, preterm infants malabsorb long-
improved growth and higher serum albu- chain triglycerides (LCTs), the majority with
min, transthyretin (prealbumin), and phos- chain lengths of 14 to 20 carbons.
phorus concentrations than those receiving Human milk contains a bile salt-activated
their mothers’ milk unfortified. Absorp- lipase that enhances lipid digestion in the
tion and retention of nutrients is similar to duodenum. Standard infant formulas con-
that in infants fed preterm infant formula. tain LCTs, which may be poorly digested by
The recommended dietary allowances for the premature infant, producing calcium
infants and children to age 12 months are soaps in the gut that render the calcium
listed in Table 7-8. unavailable for absorption.
Because of the relatively poor digestion of
LIPIDS LCTs, a theoretically attractive alternative is
Fat is a major source of energy for the use of medium-chain triglycerides (MCTs),
infant, with approximately 50% of the cal- oils with a carbon chain length of 8 to 12
ories in human milk derived from fat. The carbons. Unlike LCTs, MCTs do not require
preterm infant has limited capacity to digest bile for emulsification. MCTs are rapidly
and absorb certain fats. Because of a limited hydrolyzed in the gut and pass directly to
bile salt pool and lower levels of pancreatic the liver through the portal circulation,
whereas LCFAs must be reesterified once supplementation with vitamin A resulted in

absorbed and are transported via the lymph reduction of death or oxygen requirement at
system into the blood circulation where 1 month of age and oxygen requirement at
they are hydrolyzed by lipoprotein lipase. 36 weeks post-menstrual age (chronic lung
Medium-chain fatty acid (MCFA) metabo- disease) as well as trends toward reduction in
lism differs from that of LCFA in that it does oxygen requirement in survivors at 1 month
not require carnitine for transport into the of age.66
mitochondria and is not regulated by cyto-
solic acyl-CoA synthetase. MCFAs enter VITAMIN E
the mitochondria directly and are rapidly Vitamin E, or tocopherol, serves as an anti-
oxidized. Formulas with MCTs have been oxidant to protect double bonds of cellular
shown to improve nitrogen, calcium, and lipids. Vitamin E requirements are increased
magnesium absorption. Preterm infant for- with increasing polyunsaturated fatty acid
mulas have been developed with approxi- (PUFA) intake and in the presence of oxi-
mately half the fat as MCTs. dant stress, such as high iron intake. Vita-
min E deficiency is rarely seen in infants
VITAMIN A because infant formulas are supplemented
At birth, preterm infants less than 36 weeks’ with vitamin E in proportion to the PUFA
gestational age have been reported to have content. However, infants who are breast-
lower plasma retinol concentrations as com- fed and receiving supplemental iron should
pared with full-term infants, although the be given additional vitamin E. Preterm
measured levels are quite variable. There is infants have low serum vitamin E levels
a further decrease in the plasma retinol and and may be at increased risk for oxidative
retinol-binding protein levels during the damage to cell membranes. Studies to inves-
first 2 weeks after birth, particularly when tigate the effectiveness of pharmaceutical
sufficient amounts of vitamin A are not pro- doses of vitamin E on retinopathy of prema-
vided. The measured hepatic levels of retinol turity and BPD have not demonstrated ben-
expressed as µmol/g in preterm infants are efits of this therapy. Supplemental vitamin
reported to be the same as in infants born at E given during the first week of life may play
term gestation but lower than those in older a role in the prevention of intracranial hem-
children and adults. The recommended orrhage in infants, especially those weigh-
allowance for infants, based on the average ing 500 to 750 g.67 Further studies need to
retinol content of human milk (40 µg/100 be conducted before this becomes routine
mL) and average daily milk consumption, care for the ELBW infant. An increased risk
corresponds to 420 µg of retinol per day up of sepsis and NEC was seen in a group of
to 6 months of age. VLBW infants whose serum vitamin E levels
Retinol has been shown to be essential for were maintained over 3 mg/dL.68 Accord-
the growth and differentiation of epithelial ing to the American Academy of Pediatrics,
cells, has been suggested to have a role in serum vitamin E concentrations should be
prevention and repair of lung injury and maintained between 1 and 2 mg/dL.69
vitamin A deficiency state, and is associated
with histopathologic changes in the lung VITAMIN K
similar to those seen in bronchopulmonary Vitamin K, an important cofactor in the
dysplasia (BPD). Furthermore, infants dying activation of intracellular precursor proteins
of BPD were reported to have lower liver reti- to blood clotting proteins, is synthesized
nol ester levels. For these reasons, the impact endogenously by bacterial flora. However,
of vitamin A supplementation on BPD in because intestinal synthesis cannot be relied
VLBW infants has been examined.64,65 In a on because of a lack of gut colonization in
multicenter, blinded, randomized trial, the the neonate, it is recommended that 0.5 to
use of vitamin A 5000 IU (1.5 mg) adminis- 1 mg of vitamin K be given to all newborns
tered intramuscularly three times per week as protection against hemorrhagic disease
for 4 weeks improved the biochemical vita- of the newborn. Preterm infants may be
min A status and resulted in a modest advan- at particular risk for vitamin K deficiency
tage in relation to prevention of chronic because of low stores and frequent use of
lung disease.65 Vitamin A in such large doses broad-spectrum antibiotics. In addition,
was shown to have no clinically measur- asphyxiated infants have been shown to
able toxic effects. In a metaanalysis of seven have a reduction in vitamin K-dependent
randomized trials, results suggested that coagulant proteins.
Human milk is generally low in vitamin level is usually normal, but 1,25 dihydroxy-
K, and intestinal flora of breast-fed infants cholecalciferol (1,25-OH vitamin D) levels
may produce less vitamin K than formula- may be elevated as a result of increased para-
fed infants. Therefore, antibiotic therapy thyroid hormone levels and low serum phos-
may increase the risk of vitamin K defi- phorus levels. The incidence of rickets was
ciency in breast-fed infants by decreasing high before institution of the current nutri-
endogenous synthesis. ent practice of higher calcium and phospho-
rus levels in parenteral nutrient solution
CALCIUM, PHOSPHORUS, MAGNESIUM, and early enteral feedings. The etiology of
AND VITAMIN D rickets remains unclear but is thought to be
The amount of enteral calcium, phosphorus, primarily an inadequate intake of calcium
and magnesium intake required to match and phosphorus. Risk factors for rickets are
intrauterine accretion rates is high: calcium listed in Box 7-3. Confirming the diagnosis
185 to 200 mg/kg/day, phosphorus 100 to requires radiologic evidence of osteopenia.
113 mg/kg/day, and magnesium 5.3 to 6.1 Fortified human milk or premature infant
mg/kg/day. VLBW infants with minimal ill- formula is the preferred feeding for LBW
ness may require lower intakes.70 The Amer- infants. The use of soy formulas is not rec-
ican Academy of Pediatrics recommends ommended for infants with birth weight less
intakes of calcium of 185 to 210 mg/kg/day, than 1800 g. If continuous infusion feeding
phosphorus 123 to 140 mg/kg/day, and of human milk is necessary, the syringe and
magnesium 8.5 to 10 mg/kg/day. However, the pump should be placed upright to pre-
magnesium intake at this level with such vent loss of calcium, phosphorus and milk fat
high calcium and phosphorus intake results by separation and adherence to the tubing.
in negative magnesium balance; therefore, a
higher intake of magnesium, approximately WATER SOLUBLE VITAMINS
20 mg/kg/day, may be needed.71 Vitamin B12 requires intrinsic factor for its
The recommendation for vitamin D, absorption in the distal ileum; therefore,
which is required for normal metabolism of particular attention to this vitamin is neces-
calcium, phosphorus, and magnesium, has sary in infants who have had gastric resec-
ranged from 200 to 2000 IU per day for the tion or resection of the terminal ileum (e.g.,
preterm infant. VLBW infants can main- NEC surgery). The potential neurologic
tain normal vitamin D status with 400 IU/ complications of vitamin B12 deficiency are
day; high-dose vitamin D supplementation irreversible.
does not decrease the incidence of rickets in Serum folate levels may be low in the
VLBW infants. preterm infant. Folate is supplemented in
Human milk has concentrations of cal- the pediatric IV multivitamin preparation
cium and phosphorus that are appropri- (MVI-Pediatric) and in infant formulas. It
ate for full-term infants. These amounts is not available in the infant multivitamin
are inadequate for the VLBW infant. Breast drops because of its instability in the liquid
milk should be supplemented with addi- form. Folate plays an important role in DNA
tional calcium, phosphorus, and vitamin D, synthesis; deficiency of this vitamin may
which can easily be done with human milk result in megaloblastic anemia, neutrope-
fortifiers. Fortification yields better mineral nia, thrombocytopenia, and growth failure.
accretion than breast milk alone, similar to Requirements for water-soluble vitamins
that of VLBW infants fed a premature infant
formula.63
Inadequate intakes of calcium, phospho- Risk Factors for Metabolic Bone
Box 7-3.
rus, and vitamin D result in metabolic bone Disease of Prematurity
disease of prematurity, also called rickets of Extremely low birth weight (≤1000 g)
prematurity. This disease is characterized by Prolonged parenteral nutrition
reduced bone mineralization and, in severe Unsupplemented human milk
cases, frank radiologic evidence of rickets Use of elemental formulas and soy formulas
and spontaneous fractures. The biochemi- Chronic diuretic therapy (especially furose-
cal findings, although not highly sensitive, mide)
include an elevated alkaline phosphatase Chronic problems such as necrotizing entero-
(>500 U/L), decreased serum phosphorus colitis, bronchopulmonary dysplasia, cho-
(<4 mg/dL), and normal serum calcium; lestasis, and acidosis
25-hydroxycholecalciferol (25-OH vitamin D)
in VLBW and ELBW infants are shown in milk is low, averaging 0.8 mg iron/L, the
Table 7-3. Advisable intakes for infants 0 to bioavailability is high, with term infants
12 months are shown in Table 7-8. absorbing about 49% of the iron content
compared with 10% to 12% from iron-for-
IRON tified cow’s milk formula. Infants who are
There has been increased interest in iron breast fed exclusively can maintain normal
deficiency, with the data suggesting that hemoglobin and ferritin levels, and do not
mental and developmental test scores are need iron supplementation until 4 to 6
lower in infants with iron deficiency ane- months.
mia and that iron therapy sufficient to cor-
rect the anemia is insufficient to reverse the FLUORIDE
behavioral and developmental disorders in Due to reports of dental fluorosis in infants
many infants.72,73 This indicates that cer- and toddlers, fluoride supplementation is no
tain ill effects are persistent depending on longer recommended in the infant younger
the timing, severity, or degree of iron defi- than 6 months of age. The supplementation
ciency anemia during infancy. schedule (Table 7-9) recommended by the
Iron stores in the preterm infant are American Academy of Pediatrics and the
lower than in the term baby because iron American Dental Association should be fol-
stores are relatively proportional to body lowed according to the fluoride content of
weight.74 Iron depletion occurs around the the local water supply.75
time the baby doubles her/his birth weight
and thus iron therapy should begin by GROWTH IN THE NEONATAL
4 weeks of life in the preterm infant when INTENSIVE CARE UNIT INFLUENCES
enteral feedings are tolerated. Smaller pre- NEURODEVELOPMENTAL AND GROWTH
term infants may need as much as 4 to 6 OUTCOMES
mg/kg/day, with about 2 mg/kg/day pro- A multicenter cohort study from the NICHD
vided by iron-fortified formula and the included 600 infants with birth weights
remainder as iron supplementation at from 501 to 1000 g. These infants were strat-
2 to 4 mg/kg/day. A higher dose is also ified by 100-g–birth weight increments and
necessary for infants being given eryth- divided into quartiles based on in-hospital
ropoietin. Oral iron supplementation can growth velocity rates.76 As the rate of weight
interfere with vitamin E metabolism in the gain increased between quartile 1 and quar-
LBW infant,72 thereby further increasing tile 4, from 12 to 21.2 g/kg/day, the incidence
the need for vitamin E in an infant who of cerebral palsy, Bayley II Mental Develop-
is at risk for low serum tocopherol levels. mental Index (MDI) scores of less than 70,
Although premature infant formulas, both Psychomotor Developmental Index (PDI)
with and without iron fortification, are
manufactured with ample amounts of vita-
min E and a PUFA-to-E ratio of 6 or greater, Dietary Reference Intake
premature infants on human milk and Table 7-9.
for Fluoride
receiving supplemental iron can be also
supplemented with 4 to 5 mg (6 to 8 IU) Adequate Tolerable
of vitamin E per day. This can be readily Intake Upper Intake
accomplished by use of an oral multivita- Age Group (mg/day) (mg/day)
min with iron. Infants 0-6 mo 0.01 0.7
The impression that low-iron formulas are Infants 7-12 mo 0.5 0.9
associated with fewer gastrointestinal distur- Children 1-3 yr 0.7 1.3
bances is not supported by controlled stud- Children 4-8 yr 1 2.2
ies. Because the bioavailability of iron from Children 9-13 yr 2 10
iron-fortified infant cereals is somewhat low, Boys 14-18 yr 2 10
it is recommended that iron-fortified formu- Girls 14-18 yr 3 10
las or daily iron supplements be continued Males 19 yr and older 4 10
through the first year of life.72 Females 19 yr and 3 10
older
Among term infants, breast feeding usu-
ally provides adequate iron intake during Data from Institute of Medicine: Dietary reference intakes
the first 4 to 6 months of life and supple- for calcium, phosphorous, magnesium, vitamin D, and
fluoride, Washington, DC, 1997, National Academies Press
mentation during this time is not neces- and American Academy of Pediatrics: Pediatric nutrition
sary. Although the iron content of human handbook, ed 6, Elk Grove Village, Ill, 2009, p 1050.
scores of less than 70, abnormal neurologic then gavage the remainder. At first, the
examination findings, neurodevelopmental infant may be offered nipple feeding once
impairment, and need for rehospitalization in a 24-hour period; the number of feed-
fell significantly at 18 to 22 months cor- ings is then increased as the infant becomes
rected age. Similar findings were observed as more able to nurse. Because of the addi-
rate of head circumference growth increased tional work of sucking, the energy expen-
from 0.67 to 1.12 cm/week. Also, higher in- diture increases; therefore, an increased
hospital growth rates were associated with calorie intake may be required to maintain
a decreased likelihood of anthropometric adequate rate of growth. Weight gain during
measurements below the 10th percentile the start of nipple feeding should be closely
at 18 months’ corrected age. The influence monitored. It is not necessary for an infant
of growth velocity remained after control- to be able to bottle feed before attempting to
ling for variables known at birth or identi- breast feed. Infants who will be breast feed-
fied during the infants’ neonatal intensive ing may actually be able to nurse from the
care unit hospitalizations that affect out- breast sooner than they will be able to coor-
come including comorbid conditions such dinate bottle feeding. If an infant’s respira-
as NEC or BPD. This study emphasizes the tory rate is 70 to 80 breaths per minute or
importance of closely monitoring the rate more, he or she should be tube fed because
of in-hospital growth when birth weight of the increased risk of aspiration.
has been regained. Goals for growth includ- If an infant is unable to nipple feed, he or
ing head circumference gain of more than she needs to be fed through an orogastric or
0.9 cm/week and weight gain of 18 g/kg/ nasogastric tube or, rarely, transpylorically.
day from return to birth weight through Intragastric tube feedings are preferable in
discharge were associated with better neu- that it allows for normal digestive processes
rodevelopmental and growth outcomes. If and hormonal responses. The acid content
growth rates falter, the infants’ diets should of the stomach may impart bactericidal
be reviewed to ensure adequate nutritional effects; other benefits of intragastric tube
support including protein/energy ratios of feeding include ease of insertion of tube,
feeds and the use of caloric dense milks (>24 tolerance of greater osmotic loads with less
kcal/ounce). cramping, distention, and diarrhea, and less
risk of development of dumping syndrome.
METHOD OF FEEDING Continuous transpyloric feeding is rarely
An important consideration in feeding the used in infants who cannot tolerate feed-
newborn is the development of sucking, ings because of impaired gastric emptying
swallowing, gastric motility, and empty- or a high risk of aspiration. However, this
ing. Swallowing is first detected at 11 weeks’ route of infusion has a higher risk of perfo-
gestation and the sucking reflex is first ration of the gut, may not enable delivery of
observed at 24 weeks’ gestation. However, a large volume of feedings, and may result
a coordinated suck-swallow is not present in inefficient nutrient assimilation because
until 32 to 34 weeks’ gestation and even bypassing the gastric phase of digestion lim-
then, it is immature; the maturation of the its the exposure of food to acid hydrolysis
swallowing reflex is related to postnatal age. and the lipolytic effects of lingual and gas-
Swallowing must be coordinated with respi- tric lipases.
ration, in that the two processes share the If tube feeding is used, the decision to
common channels of the nasopharynx and feed intermittently or continuously must
laryngopharynx. The inability of the infant be made. There are differences seen in the
to coordinate this action results in choking, endocrine milieu between infants fed con-
aspiration of feedings, and vomiting. tinuously compared with those fed intermit-
To evaluate the suck-swallow reflex, one tently. The significance of these differences
should observe the number of swallows per is unclear and it is not possible to state
second. An infant with a good suck-swal- with certainty which method is best for
low reflex swallows approximately once the prematurely born neonate. It has been
per second. If greater than 2 per second are suggested that the cyclic changes in circu-
observed, the infant is probably not able lating hormones and metabolites as seen in
to coordinate the swallowing. With a good intermittent-bolus feeding may have quite
suck, the temporal muscle will bulge. different effects on cell metabolism,77 gall
When starting to introduce the nipple, a bladder emptying, and gut development.
rule of thumb is to bottle feed for 20 minutes Continuous infusion of human milk is not
recommended because there is a loss of fat HUMAN MILK

and, therefore, calories, in the tubing of the Although breast milk is considered the ideal
pump. Additionally, at the end of the infu- food for the term infant, for the preterm
sion, a large bolus of fat is delivered to the infant it provides inadequate amounts of
infant owing to the separation of the fat several nutrients, especially protein, vita-
during the infusion period. min D, calcium, phosphorus, and sodium. If
Gastrostomy feedings are chosen when it given in sufficiently large volume (180 mL/
becomes apparent that there will be long- kg/day), the energy content of human milk
term tube feeding (e.g., for a neurologically is sufficiently great to enable nearly all LBW
impaired infant), when there is persistent infants to gain weight at intrauterine rates
gastroesophageal reflux that is unresponsive (approximately 15 g/kg/day). However, the
to medical treatment, or when esophageal protein content is suboptimal, especially
anomalies prevent the use of an orogastric for VLBW infants weighing less than 1500
or nasogastric tube. g, resulting in lower serum albumin and
Positioning of the infant during feeding is transthyretin (prealbumin) levels, which
important for more efficient stomach emp- have been shown to be reliable indicators of
tying. Infants with respiratory distress fed protein nutriture in preterm infants.79 The
in the supine position have delayed gastric calcium and phosphorus content is low in
emptying. The stomach empties more rap- unsupplemented human milk in compari-
idly in the prone or right lateral positions; son to that required to achieve intrauterine
thus, these positions are preferred especially accretion rates, resulting in poor bone min-
in infants with respiratory distress and in eralization in VLBW infants. In addition,
those infants who have the potential for the sodium content of human milk results
feeding intolerance. in less sodium retention than intrauterine
The evaluation of an infant’s feeding tol- estimates and may result in hyponatremia.
erance is an ongoing process to determine In a large multicenter study on the short-
the appropriate feeding method, type of and long-term clinical and developmental
formula to feed, and increment of feeding outcomes of infants randomized to different
advancement. Vomiting, abdominal disten- diets, Lucas and colleagues found that, by
tion, significant gastric residuals, abnormal the time infants weighing less than 1200 g at
stooling patterns, and presence of reduc- birth who were fed unfortified human milk
ing substances or frank or occult blood in reached 2 kg,3,80 they were less than 2 stan-
the stool are indicators of intolerance. Sep- dard deviations below the mean for weight
sis and NEC may first manifest with one or for age. Infants weighing less than 1 kg at
more of these signs of feeding intolerance. birth who were fed unfortified human milk
Vomiting or spitting in the high-risk infant would be expected to take 3 weeks longer to
increases the risk of aspiration. reach a weight of 2 kg than infants receiving
formula. In a later nonrandomized study,
NONNUTRITIVE SUCKING Lucas et al. observed that infants receiving
Nonnutritive sucking, that is, placing a breast milk had a significantly higher intel-
nipple or pacifier in the infant’s mouth, has ligence quotient at 8 years than formula-fed
been related to accelerated weight gain and infants.4
early hospital discharge in preterm infants. The probability that human milk may
Reported benefits of nonnutritive sucking have certain nonnutritional advantages
include improved oxygenation, acceler- must also be considered. Human milk con-
ated maturation of sucking reflex, decreased tains immunocompetent cellular compo-
intestinal transit time, and accelerated tran- nents including secretory IgA, which has a
sition from gavage to oral feeding. Ernst and protective effect on the intestinal mucosa.
colleagues conducted a randomized trial in Since the composition of preterm milk
medically stable infants receiving tube feed- varies greatly from one mother to another
ings,78 controlling for caloric intake, birth and the concentration of nutrients in pre-
weight, and sex of the infant, and found no term milk changes over time, it is difficult to
difference in growth, gastrointestinal transit determine the actual macronutrient intake
time, fat excretion, or energy expenditure. of an infant. However, new technology
Even so, providing a pacifier to a tube-fed (infra-red spectrophotometry) allows accu-
infant may well give the infant great com- rate bedside analysis of the macronutrients
fort and enable the infant to calm more in human milk. To confer the potential non-
quickly. nutritional advantages yet provide optimal
nutrient intake, human milk should be Data like these and others suggest that
supplemented, or fortified, with protein, cal- exclusive human milk diets may exert pro-
cium, phosphorus, vitamin D, and sodium. tective effects,84,85 rather than threshold
There are many practical considerations effects with respect to NEC. Therefore, the
when feeding an LBW infant with his or her feeding of a species-specific milk may be
own mother’s milk. One of the common critical for protection against infection and
concerns is to provide sufficient volumes NEC.
of bacteriologically acceptable milk. The A new therapy under investigation is the
practice of culturing human milk before its use of lactoferrin in these VLBW infants to
first use and weekly thereafter remains con- prevent late-onset sepsis and NEC. A recom-
troversial. Refrigerated breast milk actually binant human lactoferrin product is being
decreases in bacterial content over a 5-day evaluated for its safety and efficacy and is
period, and fresh frozen milk inoculated now in Phase 2 trials.
with bacteria demonstrated significant inhi- A multicenter, double-blind, placebo con-
bition of bacterial growth. Many mothers trolled, randomized trial was done in VLBW
are unable to maintain adequate milk pro- infants in Italy comparing administration
duction even with frequent milk expression of a bovine lactoferrin (BLF) alone or in
with an electric breast pump. The assistance combination with Lactobacillus rhamnosus
of a health professional trained to counsel GG (LGG) to placebo.86 Invasive infections
and support breast-feeding mothers may (blood or cerebrospinal fluid or peritoneal
increase success rates within the hospital. fluid) were significantly lower in the treat-
It is difficult for the mothers of ELBW ment groups (5.9% for BLF and 4.6% for BLF
infants to provide sufficient volumes of plus LGG versus 17% for placebo).86 The
milk to meet their infant’s needs over the incidence of NEC was decreased in the BLF
entire hospitalization. Therefore, pasteur- plus LGG group (0% versus 6% in infants
ized human milk from donor milk banks receiving placebo).86
and industry have become available as a
potential proxy for the mother’s own milk.81 FORMULA TYPES
The studies showing a lower rate of NEC To be able to select the proper formula for
with donor milk were conducted before the feeding a sick infant, a clear understanding
use of human milk fortifiers. Many of these of the differences between formulas and
infants suffered growth failure and osteope- unique qualities of a given formula is neces-
nia of prematurity secondary to inadequate sary (Table 7-10).
protein, calcium and phosphorous in donor
milk. PREMATURE INFANT FORMULAS
Recently, a randomized controlled multi- Providing optimal nutrition to a preterm
center trial to evaluate an exclusively human infant is complicated by a lack of a natural
milk diet in extreme premature infants (500 standard. For the healthy full-term infant,
to 1250-g birth weight) was done and was human milk is considered the ideal food;
the first to use a human milk-based forti- therefore, it is used as the reference standard
fier.83 Three study groups received on aver- for the development of commercial infant
age 70% of their feeds as mother’s own milk. formulas. Although early milk of mothers
One group of infants received mother’s milk who deliver their infants prematurely is
fortified with powdered bovine fortifier. higher in nitrogen (early in lactation), fatty
When mother’s milk was unavailable, these acid content, sodium, chloride, magnesium,
infants received preterm formula. The other and iron, it is still inadequate in other nutri-
two groups were fed donor pasteurized milk ents, especially calcium and phosphorus. It,
when the mother’s own milk was not avail- therefore, cannot be used as a standard for
able and were fortified with human milk forti- the development of premature infant for-
fier.83 The rates of NEC (medical and surgical) mula. The special premature infant formu-
were lower in the exclusively human milk las have been developed from knowledge
fed infants, who only differed in the volume of the accretion rates of various nutrients
of human milk they were receiving at time of relative to the reference fetus, from studies
fortification. There was a 50% reduction in of the development of the gastrointestinal
medical NEC and almost a 90% reduction in tract that have defined absorptive efficiency
surgical NEC for the infants fed an exclusive and function, and from metabolic studies.
human milk diet compared to a diet contain- Premature infant formulas have a lower
ing bovine milk-based products.83 lactose concentration with approximately
Table 7-10. Comparison of Human Milk and Formula
Premature Term Infant

Preterm Premature Postdischarge Term Human Term Infant Term Infant Lactose-Free
Human Milk* Infant Formula Formula Milk Formula Soy Formula Formula
NUTRIENTS
Energy (kcal/oz.) 20-28 24 22 20 20 20 20
Protein (g/dL) 1.4-1.6 2.4 2.1 1.03 1.4-1.6 1.6-1.8 1.4-1.5
Source Whey- 60:40 60:40 or 50:50 Whey-predominant 60:40 or 18:82 Soy protein isolate Milk protein
predominant isolate
Fat (g/dL) 2.9-4.3 4.1-4.4 3.9-4.1 4.4 3.4-3.7 3.4-3.7 3.6-3.7
Source Human milk MCT Soy Coconut MCT SoyCoconut Human milk Palm Soy Coconut Palm Soy Coconut Palm Soy
HOSO HOSO Coconut HOSO
Carbohydrate (g/dL) 6.3-7.1 8.4-9 7.7-7.9 6.9 7.1-7.4 7-7.4 7.2-7.4
Source Lactose Lactose, CSS, Lactose, glucose Lactose Lactose CSS, sucrose CSS, sucrose
glucose polymers polymers,
maltodextrin, CSS*
Calcium (mg/dL) 24-34 134-146 78 32 52-55 70-71 55-57
Phosphorus (mg/dL) 6.8-11.8 67-81 46-49 14 28-31 42-51 31-38
Iron (g/dL) 0.03 1.4-1.5 1.3 0.03 1.2 1.2 1.2
From Tsang RC, Uauy R, Koletzko B, et al, editors: Nutrition of the preterm infant: scientific basis and practical guidelines, ed 2, Cincinnati, 2005, Digital Educational
Publishing, p 336 and American Academy of Pediatrics: Pediatric nutrition handbook, ed 6, Elk Grove Village, Ill, 2009, Author, pp 1250-1265.
CSS: Corn syrup solids; HOSO: high oleic safflower oil; MCT: medium chain triglycerides.
*Preterm, mature milk (days 22-30).
CHAPTER 7 Nutrition and Selected Disorders of the Gastrointestinal Tract
177
50% of the carbohydrate as lactose to reduce the day. One distinct advantage of prema-
the lactose load because of relative lactase ture infant formula is that, despite the high
deficiency. The remainder of the carbohy- concentration of nutrients, the 24-calorie/
drate is provided as glucose polymers, which oz. premature infant formula is iso-osmolar
are readily hydrolyzed by glucoamylase and with osmolalities ranging from 280 to 300
result in a product with low osmolality. mOsm/kg H2O.
The premature infant formulas are whey- Preterm infants fed human milk have
predominant, which has been shown to advanced neurodevelopmental outcome as
result in less metabolic acidosis in VLBW compared to formula-fed infants, measured
infants. The risk of lactobezoar formation is by electroretinograms, visual evoked poten-
reduced when a whey-predominant formula tials, and psychometric tests.31,87-89 The bet-
is used. In addition, the concentration of ter performance, in part, has been related to
protein per liter is approximately 50% greater dietary docosahexaenoic (DHA) and arachi-
than that of standard infant formula to pro- donic (ARA) acids because plasma and eryth-
vide 3.6 to 4.2 g protein/kg/day. The fat is rocyte phospholipid, contents of ARA and
approximately 50% LCTs and 50% MCTs. DHA are higher in breast-fed infants than
The vitamin concentration is higher because in infants fed formulas lacking these fatty
the volume of formula consumed is signifi- acids.90 Inadequate long-chain fatty acids in
cantly less in the tiny baby. The calcium and the diet may be related to performances on
phosphorus content is greater than standard tests of cognitive function.4,91 The inability
formula with variation between formula to synthesize enough DHA and ARA from
manufacturers. The calcium-to-phosphorus their precursors and the lack of preformed
ratio generally is 2 to 1 as compared to 1.4 DHA may be the cause of lower content of
to 1 to 1.5 to 1 with standard infant formu- these fatty acids in formula-fed infants. The
las. Too high of a concentration of calcium addition of these fatty acids to formulas in
and phosphorus may result in intestinal the United States has led to renewed interest
milk bolus obstruction. As with all formulas, and debate about the effects of long-chain
it is important to shake the formula before fatty acids on later neurodevelopmental out-
use, because precipitation may occur and come and has been reviewed elsewhere.92
the precipitate, containing high amounts of
calcium and phosphorus, may remain in the STANDARD INFANT FORMULAS
bottom of the container. The carbohydrate in standard infant formula
Premature infant formulas have always is 100% lactose and the fat is all long-chain
been low in iron content (3 mg elemental triglycerides of vegetable origin, usually soy
iron/L) because these infants were often and coconut oils. Most standard formulas
receiving transfusions and because the use are whey-predominant, with 60% of the
of iron would increase the requirement for protein whey and 40% casein. Standard
vitamin E. However, because some infants formulas are available in iron-fortified and
are receiving this type of formula for greater non–iron-fortified (or “low iron”) forms.
than 2 months and because the advantages Iron-fortified formula contains elemental
of continuing a baby on premature infant iron 12 mg/L or approximately 2 mg/kg/
formula after hospital discharge have been day for an infant receiving approximately
recognized, premature infant formulas have 108 kcal/kg/day. Low-iron formula contains
been available with low iron content (3 mg elemental iron 1.5 mg/L or 0.2 mg/kg/day.
elemental iron/L) and with iron fortification Most standard infant formulas are avail-
(15 mg elemental iron/L). able as ready-to-feed, liquid concentrate,
The sodium content of premature infant and powder. The concentrate and the pow-
formula is greater than human milk or der provide the option of concentrating the
standard infant formula. Because sodium formula to a higher caloric density. Con-
requirements vary considerably between centrations above 1 calorie per milliliter or
infants and are influenced by receipt of 30 calories per ounce are not recommended
diuretics, this amount may be inadequate to because of the high renal solute load that
maintain normal serum levels. Supplemen- results from the decrease in free water
tation with 3% sodium chloride (0.5 mEq intake. As the formula is concentrated, the
sodium and chloride/mL) may be necessary. osmolality increases to approximately the
Because this is a highly osmolar solution same degree as the concentration. Thus, for
(see Table 7-4), the dose should be divided a 20 kcal/oz formula with an osmolality of
and administered several times throughout 300 mOsm/kg H2O, if concentrated 135%,
or to 27 kcal/oz formula, the osmolality protein formulas have significantly lower

increases to approximately 405 mOsm/kg serum phosphorus and serum alkaline
H2O. If formula is to be concentrated, a writ- phosphatase levels and an increased risk of
ten recipe should be given to the caregiver development of osteopenia. Even when sup-
because over-concentration may be hazard- plemented with additional calcium, phos-
ous to small preterm infants. phorus, and vitamin D, VLBW infants fed
Caloric density of a formula may also be these formulas exhibit slower weight gain
increased by the addition of glucose poly- and lower serum protein and albumin con-
mers, which increases the osmolality of the centrations than infants receiving a whey-
formula, or by adding fat (e.g., vegetable predominant premature infant formula.
oil, MCT oil). However, when an infant for-
mula is supplemented with calories only, PROTEIN HYDROLYSATE FORMULAS
the intake of nutrients must be calculated Protein hydrolysate formulas are designed
and compared with recommended guide- for infants who are allergic to cow’s milk
lines (see Tables 7-3, 7-4 and 7-7) to ensure or soy proteins. Some protein hydrolysate
adequacy of intake. The distribution of cal- formulas are also elemental with the carbo-
ories will be affected using this method of hydrate in easily absorbable forms, such as
increasing calories; therefore, the percent of glucose polymers or monosaccharides, and
calories from carbohydrate, protein, and fat the fat as both medium-chain and long-
should be determined. Approximately 35% chain triglycerides. These are sometimes
to 65% of the total calories should be derived used in the management of infants with
from carbohydrate, 30% to 55% from fat, intestinal resection or intractable diarrhea.
and 8% to 16% from protein. LBW infants
fed a formula contributing 7.8% of calories FOLLOW-UP FORMULAS
as protein grew at a significantly slower rate Although considerable attention has been
than infants fed formulas with either 9.4% directed toward improving the nutrition of
or 12.5% of the calories from protein. hospitalized VLBW infants with nutrient-
enriched formulas and multinutrient for-
SOY FORMULAS tifiers for human milk, only recently has
Soybean-based formulas with soy protein attention been paid to nutrition support of
isolate or soybean solids with added methi- such infants after hospital discharge. The first
onine as the protein source are lactose-free postnatal year may provide an important
and, therefore, are recommended for infants opportunity for human somatic and brain
with galactosemia, with primary lactase growth to compensate for earlier deprivation.
deficiency, or recovering from secondary A key question is whether VLBW infants have
lactose intolerance. The carbohydrate is special nutrient requirements in the post-
provided as sucrose or corn syrup solids, discharge period. In more biological terms,
or as a combination of the two. The fat is it is reasonable to ask whether this period
provided as a vegetable oil (LCTs), usually is also critical for later health and develop-
soy and coconut oils. All soy formulas are ment because it is common for human milk
iron-fortified. Although soy formulas have fortifiers to be stopped or term formulas to
been used when cow’s milk protein allergy be substituted at hospital discharge. Avail-
is suspected, the American Academy of Pedi- able data suggest that preterm infants are in
atrics cautions that infants allergic to cow’s a state of suboptimal nutrition at the time
milk may also develop an allergy to soy- of discharge from the hospital and beyond.
based milk62; a protein hydrolysate formula Improving this situation would be beneficial
should be the initial formula of choice. in the short-term and, potentially, for longer-
Infants with a family history of allergy who term health and development.
have not shown clinical manifestations may Nutrient-enriched formula for preterm
benefit from soy protein formula; however, infants after hospital discharge (post-
such infants should be closely monitored discharge formula) is generally intermediate
for soy protein allergy. Soy protein formu- in composition between preterm and term
las are appropriate for infants of vegetarian formulas. Compared with term formula,
families who eat no animal products. preterm formula contains an increased
The use of soy protein formulas for VLBW amount of protein with sufficient additional
infants is not recommended because of energy to permit utilization. Post-discharge
the low calcium and phosphorus content formula contains extra calcium, phospho-
of these formulas. Preterm infants fed soy rus, and zinc, all of which are necessary to
promote linear growth. Additional vitamins observation and, for infants whose birth
and trace elements are included to support weights were less than 1250 g, growth in
the projected increased growth. A pilot head circumference was the most beneficial
study of 32 preterm infants was the first to effect.
show that infants randomized to receive Another study examined the use of pre-
the post-discharge formula up to 9 months term formula after discharge in 129 preterm
postterm showed significantly greater infants randomly assigned to one of three
weight and length gains and had higher dietary regimens until 6 months postterm:
bone mineral content in the distal radius term formula, preterm formula, or preterm
than infants who received a standard term formula until term followed by term formula
formula.93 Studies add additional insight to 6 months.95 Males fed preterm formula
into the role for post-discharge formula, after discharge showed significantly greater
suggesting that benefits may be related to weight and length gain and larger head cir-
birth weight,94 gender,2,95,96 and a “window cumference by 6 months postterm than
of opportunity” (a critical growth epoch) those fed term formula throughout the study
when supplemental nutrients can promote period. Infants fed preterm formula con-
catch-up and subsequent growth, even after sumed an average of 180 mL/kg/day, resulting
discontinuation of post-discharge formula. in a protein intake of approximately 4 g/kg/
The reports also raise the possibility that day. Those fed term formula took more milk
post-discharge nutrition may benefit long- and increased consumption to about 220 mL/
term development.95,96 kg/day, but their protein intake still did not
A total of 284 preterm infants received match that of the preterm formula group. At
either term formula or post-discharge for- 18 months postterm, boys previously fed pre-
mula for the first 9 months postterm. At 9 term formula were on average 1 kg heavier, 1
months postterm, post-discharge formula- cm longer, and had 1 cm greater head circum-
fed infants were significantly heavier (mean ference than those fed term formula. Body
difference, 370 g) and longer (1.1 cm) than composition measurement using dual x-ray
term formula-fed infants, and the length absorptiometry suggested that the additional
difference persisted to 18 months postterm weight gain was composed predominantly of
or 9 months after post-discharge formula lean tissue rather than fat.97 There were no
was discontinued. Differences between diet significant differences in neurodevelopment
groups were significantly greater in boys, measured using Bayley Scales of Infant Devel-
who had a length advantage of 1.5 cm at opment at 18 months.95
18 months if they received post-discharge Randomized studies demonstrate that
formula. There was no evidence that the the use of either preterm formula or post-
post-discharge formula had made infants discharge formula after discharge in preterm
fat. Their mean weight percentile was still infants results in improved growth, with
below the 50th percentile and skinfold differences in weight and length persisting
thickness was not increased. Head circum- beyond the period of intervention in two
ference and developmental outcomes at 9 studies. Such findings raise the hypothesis
or 18 months did not differ significantly that nutrition during the post-discharge
between groups, although post-discharge period may have longer-term effects on
formula-fed infants had a 2.8 ± 0.25 point growth trajectory. Evidence from three
advantage in the Bayley MDI Score.96 Carver randomized trials suggests that the effect
found improved growth in preterm infants of a nutrient-enriched post-discharge diet
who were fed a post-discharge formula after is greatest in boys, possibly reflecting their
discharge up to 12 months corrected age, higher growth rates and protein require-
with the significant differences in weight, ments. Whether the observed growth effects
length, or head circumference.2 This was persist or have consequences for other
more pronounced for smaller infants (birth aspects of health or development requires
weight <1250 g) and male infants. The further investigation.
differences in growth produced by post-
discharge formula occurred early (critical PRACTICAL HINTS FOR ENTERAL
growth epoch) but did not increase appre- NUTRITION
ciably over time, suggesting that the benefit • Start small breast milk or formula feedings
of post-discharge formula with respect to (10 to 20 mL/kg/day) as soon as possible.
catch-up occurred soon after discharge. The It is unnecessary to start with 5% glucose
benefits persisted throughout the period of water.
• Assess the infant’s ability to nipple feed. • Encourage the parents to feed the infant
Infants younger than 32 weeks’ gesta- after the infant is feeding well; it may be
tional age and infants with respiratory very frustrating for the parents to attempt
rates between 60 and 80 breaths per min- feeding when the infant is resistant.
ute need to be tube fed.
• Use premature infant formula or fortified NUTRITIONAL ASSESSMENT
breast milk for infants weighing less than An in-depth nutritional assessment requires
1800 g. Encourage the mother to provide anthropometric, biochemical, dietary, and
human milk. If breast milk is to be used, clinical data. However, interpreting anthro-
start feedings with unfortified breast milk pometric and biochemical measurements is
until tolerance is established, then add difficult; therefore, nutritional assessment
fortifier. in neonates receiving intensive care treat-
• Intermittent gavage feedings are preferred; ment is often confined to detecting fluctua-
continuous feedings or “compressed” tions in weight gain and in caloric intake.
feedings over an hour or so may be help- Nonetheless, it is necessary for the clinician
ful for infants with feeding intolerance. to be able to assess the neonate’s nutritional
• Monitor feeding tolerance. Vomiting, a status because of the potentially serious
sudden increase in abdominal girth, frank sequelae of malnutrition on multiple organ
or occult blood in the stool, with large systems and the importance of growth
gastric residuals may be signs of infection (especially brain growth) on developmental
or NEC. The feedings should be stopped, outcome.
the stomach should be aspirated, and an In nutritional assessment, one must con-
#8 Fr nasogastric tube should be inserted sider the length of gestation and adequacy of
for gastric decompression. intrauterine growth and nutrient tolerance.
• Record fluid intake, output, weight, type There should be a static assessment (cur-
of feeding given, and feeding tolerance. rent balance between intake and output) as
• Reduce parenteral feedings proportionate well as a dynamic assessment (evaluation of
to the increase of enteral feedings to pre- infant’s growth over time or growth veloc-
vent excess fluid intake. ity) of each infant. Also, the non-nutritional
• Increase feedings at a rate of 20 mL/kg/ factors such as disease state, medication, and
day and monitor tolerance to previous stress (e.g., infection and surgery) must be
volume before increasing rate. Feed the considered.
infant in a prone position to facilitate Weight gain is the most frequently used
gastric emptying and maintain better anthropometric measure. It is important to
oxygenation. Once the infant is receiving use the same scale, obtain weight measure-
90 to 100 mL/kg/day enterally, the TPN ments at the same time each day to avoid
should be discontinued; if greater fluid diurnal changes, and indicate any equip-
volume is required, provide it as an IV ment being weighed (especially arm boards
glucose-electrolyte solution. and dressings); if equipment is not recorded,
• Aim for a goal of 110 to 130 kcal/kg/ changes in weight may be spurious. In pre-
day and 3.5 to 4 g protein/kg/day with a term infants, weight gain should be expressed
weight gain of approximately 15 to 18 g/ on a gram per kilogram per day basis. Table
kg/day. 7-11 contains suggested weight gain goals.
• Offer a pacifier to the infant, especially When assessing weight, there are sev-
while being gavage fed. eral problems to consider. In the first week
Table 7-11. Growth Velocity of Preterm Infants from Term to 24 Months (Range includes ±1 SD)
Head Circumference
Age from Term (mo) Weight (g/day-1) Length (cm/mo-1) (cm/mo-1)
1 26-40 3-4.5 1.6-2.5
4 15-25 2.3-3.6 0.8-1.4
8 12-17 1-2 0.3-0.8
12 9-12 0.8-1.5 0.2-0.4
18 4-10 0.7-1.3 0.1-0.4
Adapted from Theriot L: Routine nutrition care during follow-up. In Groh-Wargo S, Thompson M, Cox JH,
editors: Nutrition care for high risk newborns, Chicago, 2000, Precept Press, p 570.
of life, all newborns lose weight as a result and HC measurements should be plotted on
of loss of free water and low intake; how- an appropriate growth chart. Daily weights
ever, most preterm infants are also calorie may be plotted on a number of charts.98,99
and fluid restricted during that period as a The Fenton growth curve is used most often
result of illness, so that it may be difficult now.100
to separate changes in growth measure- Skinfold measures of several sites have
ments caused by diuresis from those caused been used to estimate body fat stores and the
by poor protein-calorie intake. Weight gain percent of body fat in children and adults.
does not necessarily reflect growth, which is These determinations are made by using a
a deposition of new tissue of normal compo- variety of formulas that are based on the
sition; weight increase may reflect excessive assumption that the percent of total body
fat deposition or water retention, neither of water and fat distribution remains constant.
which is truly growth. In the neonate, these assumptions are not
Length measurements are the most inac valid because the percent age of body water
curate anthropometric measurement. Accu- decreases with increasing gestational age
rate technique is important in performing and postnatal age and fat increases with
length measurements to detect small changes. increasing gestational age.
Two trained individuals are needed to measure The biochemical assessment of nutri-
the infant on a measuring board containing a tional status may be more specific than
stationary head board, movable foot board, anthropometric measures and may be use-
and a built-in tape measure. Skeletal growth ful in combination with anthropometric
is often spared relative to weight in mildly indices for nutritional assessment of the
malnourished infants; therefore, initially, sick neonate. Many routine tests may signal
linear growth is often slow or stops. Serial nutrition-related problems. For example, an
length measures obtained weekly are helpful elevated alkaline phosphatase level (>500 IU)
in assessing nutritional status when plotted and a low serum phosphorus level (<4 mg/
over time; length measures are especially use- dL) may occur during the active phase of
ful in infants, such as those with BPD, whose rickets. This combination of biochemi-
weight fluctuates greatly. A gain in length of 1 cal findings indicates the need to obtain
cm per week is expected. diagnostic x-ray studies. However, abnor-
Increase in head circumference (HC), the mal alkaline phosphatase levels may occur
measurement of the largest occipitofrontal due to hepatic dysfunction; therefore, heat
circumference, correlates well with cellular fractionation of the isoenzyme is suggested
growth of the brain in normal infants. Dur- to determine its origin. As rickets begins
ing acute illness, the velocity of head growth to heal, the serum phosphorus levels nor-
for the sick preterm infant is less than that malize, whereas the alkaline phosphatase
of the normal fetus. During recovery, head continues to be elevated during the radio-
growth parallels that of normal fetal growth graphic picture of healing. Elevated alkaline
and subsequently rapid “catch-up” growth phosphatase levels generally precede radio-
in HC may occur. Normal growth does not logic changes by 2 to 4 weeks.
occur until the acute illness has resolved, Albumin is a serum protein commonly
despite high energy intake. Preterm infants measured in routine laboratory tests.
who were calorically deprived for the long Although it has limited value for nutri-
est periods showed slower growth rates and tional assessment, it may serve as an indi-
longer duration of catch-up growth. In this cator of inadequate energy and protein
respect, the longer these infants remain intake. The average serum albumin concen-
with suboptimal head size, the greater is tration in infants younger than 37 weeks’
their developmental risk. gestation ranges from 2 to 2.7 mg/dL. This
HC is usually measured once a week using relative hypoalbuminemia of the preterm
a paper tape; a new tape should be used infant appears to be a result of a more
for each infant. A goal of about 0.9 cm per rapid turnover of a small plasma pool ver-
week is to be expected. If hydrocephalus is sus a decreased rate of albumin synthesis;
of concern, more frequent measuring is war- the half-life of albumin is approximately
ranted. The initial HC may differ from sub- 7.5 days in the preterm infant versus 14.8
sequent measurements because of molding days in adults. Despite the relatively rapid
of the head. Measuring HC may be difficult turnover, serum albumin concentration
because of interfering equipment such as changes slowly in response to nutrition
IV lines on the scalp. Serial weight, length, rehabilitation.
To quickly assess response to nutrition

What is his caloric intake? Is it sufficient?
support, a serum protein with a shorter half-
life is necessary. Transthyretin (prealbumin), M. J. is receiving 18 oz./day of 24-calorie/oz. formula,
with a half-life of approximately 2 days which provides a total daily caloric intake of 432 kcal
in adults has been shown to be a suitable or 108 kcal/kg/day. This is an appropriate intake for
marker for evaluation of nutritional status a former full-term infant; however, for M. J. it is inad-
in VLBW infants.79 Because transthyretin equate to provide for catch-up growth. A weight gain
increases with gestational age as well as with of approximately 30 g/day, equivalent to the growth
protein and energy intake, the direction of rate of a 2-month-old infant at the 50th percentile,
change in serial tests may be more useful would result in accelerated growth and weight gain
than striving for absolute values. of 900 g in the next month, which would place him
Because of the various metabolic, renal, above the 3rd percentile at 3 months. Additional cal-
respiratory, and gastrointestinal abnormali- ories and protein (i.e., use of post-discharge formula)
ties to which VLBW infants are subjected, need to be given to enable this kind of weight gain.
close monitoring of blood gases, serum Therefore, if the infant’s intake can be increased to
electrolytes, calcium, phosphorus, glucose, 21 oz. each day or the caloric concentration is in-
BUN, and creatinine is necessary. Ongoing creased to 27 calories/oz., an intake of 122 calories/
nutritional assessment includes careful cal- kg/day would result, or an additional 56 calories/day.
culation of dietary intake relative to esti- Because 1 g of mixed tissue growth requires approxi-
mated requirements, determination of fluid mately 4.5 extra calories,55 in theory, it should result
balance and hydration status, and tolerance in an additional weight gain of 12 g/day. However,
to feeding method. In combination with increasing protein is critical.
anthropometric, clinical, and biochemical
data, adjustments in intake or method of What other information would you like
nutrient delivery can be made to achieve to know?
effective nutritional support. An accurate measure of linear growth using an
infant measuring board and an occipitofrontal head
circumference (HC) measurement is necessary for
CASE A-1 a more complete assessment of growth. HC should
catch up by 8 months’ corrected age, even if the
M. J. is a former 1160-g, 28-week gestational age in-
weight and length are still suboptimal.
fant who is returning to the clinic at 5 months of age.
Information on vitamin supplementation also
He has gained weight at a rate of about 18 g/day
would be helpful. A vitamin supplement should be
over the past 2 months and currently weighs 4 kg.
provided to infants whose enteral intake is less than
He is receiving 18 oz. of 24 calorie/oz. iron-fortified
750 mL of 20-calorie/oz. formula or the equivalent
standard infant formula per day. His mother states
in concentrated formula. This infant is receiving 540
he is a “good” eater; her friends advise her that he
mL/day of formula concentrated 120% (24 kcal/20
should be starting solid food. She wants to know
kcal = 1.2 × 100 = 120%) or the equivalent of the
what she should give him as his first feeding and how
nutrients found in 648 mL of 20-kcal/oz. formula (18
much she should give him.
oz. × 30 mL/oz. × 1.2 = 648 mL). If no vitamin sup-
Is this infant’s growth appropriate? plements have been used, there may have been a
period of inadequate vitamin intake; therefore, a sup-
Whenever assessing the growth of a former preterm
plement should be started and used over the next
infant, one must correct for gestational age at the
month. If a supplement has been used and if the
time of birth. To correct, simply subtract the number
formula is to be concentrated 135% to 27 kcal/oz.
of weeks preterm from the chronologic age. In this
or the total volume per day is increased to 21 oz. of
example, a former 28-week gestational age infant
24 kcal/oz. formula, this will provide the equivalent of
who is now 5 months old is, in fact, only 2 months
approximately 750 mL of 20-kcal/oz. formula and the
corrected age (5 months chronologic age minus 3
supplement may be stopped.
months premature = 2 months corrected age).
If his weight is plotted on the Benda and Babson
Should the mother start solid foods?
growth chart,98 his weight of 4 kg at 2 months’ cor-
rected age places him 2 standard deviations below An infant at 2 months has low concentrations of pan-
the mean or the third percentile. His average weight creatic amylase and may not completely digest the
gain of 18 g/day would result in a weight gain to ap- starch present in cereal; the developmental readiness
proximately 4.5 kg in 1 month, which, if plotted at 3 for solids is not yet present. The infant will still have a
months’ corrected age, would drop him below the strong tongue thrust, which would push solid foods
third percentile. out of the mouth instead of to the back of the mouth
mesentery. Multiple atresias may occur

in preparation for swallowing. Therefore, it should
throughout the intestinal tract, especially
be recommended to this mother that she wait until
in the jejunoileal segments.
the infant is 4 to 6 months’ corrected age or 7 to
Stenosis is a narrowing that may involve the
9 months’ chronologic age before solids are begun.
entire thickness of the bowel wall or may
Some infants develop feeding aversions after extend-
be merely a partial web.
ed periods of parenteral nutrition, tube feeding, and
Duplications may vary from simple cystlike
ventilatory support. In these infants, the introduction
projections into the mesentery to com-
of solids should occur at 4 months’ corrected age
plete replication of any length of the gas-
to provide the infant with ample time to learn to ac-
trointestinal tube, with or without luminal
cept the spoon. An occupational or speech therapist
continuity with the in-line segment. They
may need to become involved to teach the caregivers
may occur anywhere along the gastrointes-
techniques to use to stimulate feeding readiness.
tinal tract and manifest as obstructions, as
perforations, or simply as a palpable mass.
Functional obstructions are those that are
not associated with anatomic malforma-
tion. They include achalasia, pyloric ste-
PART TWO nosis, and aganglionic megacolon, all of
which have some component of myo-
SELECTED neural dyscoordination in their etiolo-
gies. Other functional obstructions, such
DISORDERS OF THE as meconium ileus and meconium plug
syndrome, are caused by abnormalities of
GASTROINTESTINAL intraluminal contents.
Understanding of the basic entities and
TRACT familiarity with some essential principles
help to differentiate the lesions. The follow-
ing basic principles are helpful when consid-
Avroy A. Fanaroff ering neonatal and infant bowel problems:
• Intestinal obstruction may be anticipated
in 1 of every 1000 births. Multiple anoma-
Anomalies of the gastrointestinal tract may lies occur frequently.
involve any part of the primitive tube from • Lesions producing obstruction of the
the hypopharynx to the anal dimple. The upper gastrointestinal tract may be associ-
most common lesions are atresias, stenoses, ated with maternal polyhydramnios and
duplications, and functional obstructions. large gastric aspirates at birth.
Vascular occlusions, sometimes resulting • Green vomitus is considered an indica-
from rotational anomalies and intussusception of bowel obstruction until proven
tions, may be in utero factors in atresias and otherwise.
stenoses. Presenting findings include the • Clinical features of intestinal obstruction
following: include vomiting, abdominal distention,
• History of hydramnios visible peristalsis, and delayed passage of
• Increased salivation, cyanosis, and chok- meconium. With upper gastrointestinal
ing with feedings obstruction, meconium may be passed
• Large gastric aspirate (>25 mL) in delivery but no transitional stool is seen.
room • Gastrointestinal obstruction between the
• Vomiting, especially bile stained pylorus and the ligament of Treitz is consid-
• Abdominal distention with or without ered malrotation until proven otherwise.
visible peristalsis • When the continuity of the gastrointesti-
• Failure to pass a stool or delayed passage nal tract is clearly demonstrated postna-
of stool tally by the passage of transitional stools,
air, or contrast medium, congenital atre-
DEFINITIONS sia can be excluded as the cause of the
Atresia is complete luminal discontinuity obstruction. Meconium may be passed
of the gastrointestinal tract, ranging from from the bowel distal to a complete
the shortest segment web to complete obstruction, so passage of meconium does
loss of a major segment of bowel and not exclude obstruction.
• Colonic obstruction may manifest with (meconium plug, left microcolon), and
the same constellation of symptoms as 60% had idiopathic bilious vomiting.
upper gastrointestinal obstruction. Par- The last group of infants had a benign
ticular note is taken of delayed passage of course. Of note, 56% of infants with surgi-
meconium (Hirschsprung disease, meco- cal lesions had negative plain films of the
nium plug syndrome). abdomen and required contrast studies to
• In patients younger than 2 years, it is establish the diagnosis. They concluded
hazardous to attempt to differentiate that, whereas isolated green vomiting in an
large from small bowel on the basis of otherwise normal neonate is not always a
plain abdominal radiographs, particu- surgical problem, a thorough investigation
larly because the frequent errors in this including contrast studies is warranted.
evaluation may lead to delay in diagno- With these principles in mind, the follow-
sis and therapy for an obstructive bowel ing illustrative cases deal with approaches
lesion. to some serious and frequently seen gastro-
• An entity that can obstruct the bowel may intestinal anomalies.
also lead to perforation and the resulting
signs and symptoms of peritonitis. Thus,
when peritonitis is the presenting symp-
CASE B-1
tom, an obstructing lesion must be sought
and corrected. A pregnancy is complicated by polyhydramnios. A
Imaging plays a major role in most neo- full-term male infant presents with increased sali-
natal gastrointestinal emergencies. The role vation and chokes with feedings. Vomitus is never
varies from helping to establish a diagno- bile stained. Subsequently, respiratory distress de-
sis to evaluating associated abnormalities velops. On physical examination, the infant is noted
and planning surgical solutions or therapy to be blue when crying and salivating excessively.
for such conditions as meconium ileus and The abdomen is distended. No obvious external
meconium plug syndrome. Plain radiographs malformation is noted. The x-ray film from the refer-
and bowel contrast examinations serve as ring hospital is reported to demonstrate aspiration
primary imaging modalities with ultrasound, pneumonia.
computed tomography (CT) scan, and mag-
netic resonance imaging (MRI) playing roles
in more complex cases.
EDITORIAL COMMENT: With a history of polyhy-
Ultrasound can help correctly identify
dramnios and increased salivation, the most likely
meconium ileus and meconium peritoni-
diagnosis is esophageal atresia. The presence of ab-
tis and is useful in the diagnosis of enteric
dominal distention suggests that atresia is associated
duplication cysts and intussusception. In
with a fistula. The absence of bile staining of the vomi-
malrotation and anorectal anomalies, CT
tus indicates obstruction proximal to the entry of the
and MRI can provide superb anatomic detail
common duct into the duodenum.
and added diagnostic specificity. Intesti-
A baby with esophageal atresia plus or minus tra-
nal duplications manifest as an abdominal
cheoesophageal fistula classically manifests with respi-
mass at radiography, contrast enema exami-
ratory distress, choking, feeding difficulties, and froth-
nation, or ultrasound. On CT scan, most
ing in the first few hours after birth. Neonates are unable
duplications manifest as smoothly rounded,
to swallow, which accounts for the overflow of saliva,
fluid-filled cysts or tubular structures with
and they are vulnerable to aspirate into their lungs.
thin, slightly enhancing walls. On MRI
A nasogastic tube will stick and coil in the upper
scan, the intracystic fluid has heteroge-
pouch.
neous signal density on T1-weighted images
The diagnosis may be suspected antenatally be-
and homogeneous high signal intensity on
cause of polyhydramnios and an absent fetal stomach
T2-weighted images. Familiarity with these
bubble detected on ultrasound. In the absence of oth-
gastrointestinal abnormalities is essential
er anomalies, the prenatal detection rate approaches
for correct diagnosis and appropriate man-
50%. A karyotype should be obtained because of
agement.
the high association with trisomy 18. Mortality is
Lilien et al. accumulated a series of 45
significantly higher in prenatally diagnosed infants
newborns101 initially thought to be nor-
and in infants with additional congenital anomalies.
mal, who had green vomiting in the first 72
Isolated esophageal atresia is associated with good
hours of life; 20% required surgical inter-
outcome.102
vention, 11% had nonsurgical obstruction
prevented by withholding all feedings and

Diagnostic Maneuver
continuously aspirating the pouch with a
Pass a radiopaque nasogastric tube until it stops
sump tube. Reflux of gastric juice into the
and obtain an x-ray film, including neck, chest, and
fistula is more damaging and more difficult
upper abdomen. When passing a nasogastric tube
to prevent but can be offset by attention to
for a diagnostic maneuver in suspected esophageal
optimal positioning and by early surgical
atresia, use as large a tube as will pass the nares. A
intervention. The child should be main-
small tube may enter the larynx and pass down the
tained in the prone, head-elevated position,
trachea, through the fistula to the esophagus, and
which allows the stomach to fall anteriorly
into the stomach, giving the false impression of es-
away from the esophagus and provides an
ophageal continuity. A large tube will not be tolerated
inclined esophagus as a retardant to reflux
in the larynx. If the tube passes through the esopha-
of gastric juice.
gus to the stomach, esophageal atresia is ruled out.
When the diagnosis is confirmed, rapid
Contrast medium should not be used in this
evaluation of the child for tolerance of surgi-
evaluation until continuity of the esophagus has been
cal correction should be undertaken. Criteria
demonstrated because the inhalation of contrast me-
for primary repair (transthoracic extrapleu-
dium from a blind esophageal pouch may produce
ral fistula ligation and end-to-end esopha-
pneumonia.
geal anastomosis) include the following:
• Chest is clear to auscultation and on
X-Ray Findings in Esophageal Atresia with
radiograph
Tracheoesophageal Fistula
• No life-threatening cardiac anomalies
1. There is a wide, air-filled pouch in the neck or up-
• Pao2 of 60 mm Hg or better in room air
per mediastinum.
(usually from an established arterial cath-
2. The nasogastric tube is seen to stop in the upper
eter, such as umbilical)
mediastinum at about T3.
If these criteria cannot be immediately
3. Aspiration pneumonia may be noted, usually in
satisfied, immediate gastrointestinal decom-
the right upper lobe.
pression by tube gastrostomy performed with
4. Parts of the abdomen show air in the intestines
the patient under local anesthesia should
(often as an excess amount). With atresia and no
be achieved, and intensive respiratory care
fistula there is a gasless abdomen.
should be instituted. Established aspiration
5. Often skeletal anomalies are present (vertebrae/
pneumonitis may require 2 to 3 weeks of
ribs).
intensive therapy to clear. If improvement is
6. The VATER association is a nonrandom asso-
not rapid, tracheostomy may be an essential
ciation of vertebral defects, imperforate anus,
therapeutic component, because the fistula
tracheoesophageal fistula, and radial and renal
may interfere with effective coughing.
dysplasia. The association may be broadened by
If prolonged preoperative care is required,
the inclusion of cardiac defects, and limb abnor-
nutritional support by TPN will be essential.
malities (VACTERL).
Feedings by gastrostomy are rarely toler-
ated as long as the tracheoesophageal fistula
remains.
MANAGEMENT CONSIDERATIONS IN Cervical esophagostomy in esophageal
ESOPHAGEAL ATRESIA102-106 atresia when initial repair cannot be made
More than 90% of all patients with esoph- makes sham feeding necessary. This teaches
ageal atresia have the common variety of the child the mechanics of swallowing and
blind upper esophagus with the lower seg- supports the oral gratification so essential
ment entering into the membranous poste- in this period for later motor development.
rior portion of the trachea above the carina An interposition procedure using colon
as a fistula. This connects the acid-filled or stomach will be required but is usually
stomach to the tracheobronchial tree. A delayed until after 6 months of age.
small percentage of cases have esophageal
atresia without tracheoesophageal fistula, EDITORIAL COMMENT: Spitz and associates re-
in which case the abdomen is airless. From ported on the outcome of 148 infants with esophageal
the first suspicion that a fistula exists until atresia encountered over 5 years at the Hospital for
complete separation of the esophagus from Sick Children,106 Great Ormond Street, the regional
the trachea is achieved, proper management referral center in London. The results were outstand-
is essential to prevent the fatal complica- ing, with deaths predominantly resulting from associ-
tion of aspiration pneumonia. Aspiration ated congenital cardiac anomalies. They reported that
from the proximal pouch into the larynx is
endoscopy provided valuable information in planning symptom and, if the obstruction is below the second
the surgery, which should be delayed if there is aspi- part of the duodenum, it will be bile stained. Duodenal
ration pneumonia. They recommended immobilization atresia is commonly associated with trisomy 21.
and mechanical ventilation of the infants for 5 days The diagnosis of duodenal atresia is made with a
after the operative repair. plain x-ray film of the abdomen revealing a “double-
Choudhury and colleagues have confirmed these bubble,” that is, the air- and fluid-filled stomach and
excellent results even in infants with birth weights less duodenum. The presence of air bubbles beyond the
than 1500 g.107 Death is associated with complex car- second part of the duodenum suggests incomplete
diac and chromosomal anomalies. obstruction. An upper gastrointestinal series is indi-
Overall survival now exceeds 90% in dedicated cated if malrotation is suspected.
centers. Associated congenital heart defects and low Killbride warned that infants with congenital duo-
birth weight can affect survival. Early mortality is usual- denal obstruction,109 particularly if breast fed, may not
ly due to cardiac and chromosomal abnormalities. Late present with classic findings of upper gastrointestinal
mortality is usually due to respiratory complications. obstruction in the first days of life. Careful in-hospi-
The Spitz classification has been used prognos- tal evaluation of infants with persistent regurgitation,
tically106: group I—birth weight greater than 1500 even low volume, is recommended to avoid missing
g, no major cardiac disease (survival 97%); group this diagnosis.
II—birth weight less than 1500 g or major cardiac St. Peter reported on 408 patients with duodenal
disease; group III—birth weight less than 1500 g atresia.110 There was a 28% incidence of trisomy 21.
plus major cardiac disease (survival 22%).(See also Only two patients (0.5%) were identified as having a
http://www.patient.co.uk/doctor/oesophageal-atresia second intestinal atresia. In this, the largest series of
.htm). duodenal atresia patients compiled to date, the rate of
a concomitant jejunoileal atresia is less than 1%. This
low incidence is not high enough to mandate exten-
DUODENAL OBSTRUCTION
sive inspection of the entire bowel in these patients,
The diagnosis of gastrointestinal obstruction and a second atresia should not be a concern during
in the fetus is difficult with only half of the laparoscopic repair of duodenal atresia.
lesions identified. Sonographic findings sug-
gestive of duodenal atresia include a dilated
fluid-filled stomach adjacent to a dilated
proximal intestinal segment (fetal “double JEJUNOILEAL ANOMALIES
bubble”). The diagnosis can be made in the Atresia is more common than stenosis, and
early second trimester, but more commonly ileal lesions are more common than jeju-
is made in the third trimester when the duo- nal lesions.111 It has been postulated that
denum becomes more dilated. Polyhydram- these lesions arise from intrauterine bowel
nios develops in up to 50% of cases. ischemia. Anomalies that produce obstruc-
tion of the small intestine may manifest
EDITORIAL COMMENT: Fetal dilated or echogenic
with bilious vomiting, abdominal disten-
bowel is a marker for a variety of conditions includ-
tion, and obstipation. The combination of
ing bowel obstruction, chromosomal and congenital
bilious vomiting and passage of blood by
infectious disorders, and cystic fibrosis. Jackson re-
rectum signifies vascular compromise of the
ported on 35 fetuses with echogenic bowel of whom
intestine, necessitating immediate operative
12 babies underwent surgery for intestinal atresia,108
intervention. Atresias and stenoses must be
meconium ileus, and duplication cysts. Postoperative
differentiated from meconium ileus and
courses and outcomes were good. They concluded
meconium peritonitis as described later.
that echogenic bowel on antenatal ultrasound is a
Plain radiographic studies may show
nonspecific marker for a variety of disorders includ-
nonspecific bowel dilation. It is extremely
ing intestinal atresia. Although associated with higher
difficult to distinguish small bowel from
rates of fetal loss, the majority of neonates are nor-
colon in the neonatal period. Contrast ene-
mal at delivery. Obstruction of the duodenum may be
mas may show a microcolon together with
complete or partial and caused by extrinsic (malrota-
one or more focal small bowel stenoses.
tion, annular pancreas) or intrinsic lesions (duodenal
Dalla Vecchia et al. encountered 277
atresia, duodenal stenosis). Malrotation is the most
neonates with intestinal atresia and steno-
common extrinsic lesion obstructing the duodenum
sis between 1972 and 1997.112 The level of
and, because of the potential for vascular compro-
obstruction was duodenal in 138 infants,
mise to the bowel, it constitutes a true emergency in
jejunoileal in 128, and colonic in 21. Of
the neonate. Vomiting is the predominant manifesting
the 277 neonates, 10 had obstruction in
more than one site. Duodenal atresia was
associated with prematurity (46%), maternal be intermittent. Alternatively, there may be

polyhydramnios (33%), Down syndrome a dramatic manifestation with bile-stained
(24%), annular pancreas (33%), and malrota- vomiting, abdominal distention, possi-
tion (28%). Jejunoileal atresia was associated bly an abdominal mass, shock, pallor, and
with intrauterine volvulus (27%), gastros- bloody stools. This manifestation signifies
chisis (16%), and meconium ileus (11.7%). a volvulus (i.e., a strangulation obstruction
Operative mortality for neonates with duo- with occlusion of blood flow to the gut).
denal atresia was 4%; with jejunoileal atresia, Plain films of the abdomen may reveal
0.8%; and with colonic atresia, 0%. Cardiac a double bubble, with air patterns vis-
anomalies (with duodenal atresia) and ultra- ible beyond the duodenum. Malrotation
short-bowel syndrome (<40 cm) requiring or volvulus must be diagnosed with upper
long-term total parenteral nutrition, which gastrointestinal contrast studies, because
can be complicated by liver disease (with the diagnosis is missed on plain films. The
jejunoileal atresia), are the major causes of major purpose of the study is to establish
morbidity and mortality. The long-term sur- the anatomic relationships and that the
vival rate for children with duodenal atresia duodenum crosses the midline. A sharp
was 86%; with jejunoileal atresia, 84%; and cutoff with curved narrowing of the distal
with colon atresia, 100%. duodenum is characteristic of an obstruc-
Infants with mild jejunal or ileal atresias tion secondary to a volvulus. If there is any
have an excellent prognosis and long-term doubt concerning the diagnosis, an explor-
survival. Severe atresias are associated with atory laparotomy is mandatory because the
longer parenteral nutrition support and integrity of the bowel may be rapidly com-
secondary procedures for intestinal failure. promised by vascular occlusion.
Associated anomalies adversely affect out-
comes in jejunoileal atresia.113 EDITORIAL COMMENT: Volvulus of the bowel can
be a fulminant and even fatal condition. Rapid diag-
MALROTATION/VOLVULUS nosis and prompt surgical intervention are mandatory
Incomplete rotation and fixation of the to maintain the integrity of the bowel. The traditional
embryonic intestine as it returns to the approach to a suspected volvulus was a barium en-
fetal abdominal cavity from its embryonic ema examination; however, this only provided indirect
extracoelomic position is referred to as mal- evidence of a volvulus if the cecum was not in the right
rotation.114 The normal alignment of the lower quadrant. Volvulus of the small bowel may oc-
gut has the distal duodenum crossing to cur with a normal rotation and position of the colon.
the left of the vertebral column to join the Therefore, an upper gastrointestinal approach has
jejunum at a normally positioned ligament been adopted to establish the diagnosis. Both the site
of Treitz with the cecum in the right lower of obstruction and often the cause can be identified
quadrant. With malrotation, the cecum in this manner. Concerns about the contrast medium
is undescended and situated in the right above the obstruction are unfounded. If the obstruc-
hypochondrium, abnormally fixed by bands tion is complete, surgery is indicated and the contrast
crossing the second part of the duodenum. can be removed during the operative procedure.
Fetal bowel obstruction has a prevalence
of 1 in 3000 to 5000 live births. Ultrasono-
graphic diagnosis is made by demonstrating Ultrasound is an additional means of eval-
distended loops of bowel, fetal ascites, or uating infants with suspected upper gas-
echogenic bowel. Echogenic bowel, defined trointestinal obstruction. Cohen et al.115
as small bowel more echogenic than liver using a fluid-aided ultrasound evaluation of
or bone, in addition to bowel obstruction, the stomach and duodenum, were able to
has also been associated with congenital obtain a dynamic view of duodenal rotation
infections, cystic fibrosis, and chromosomal and anatomy and correctly identify a num-
abnormalities. ber of lesions.
Malrotation may be associated with other
gastrointestinal lesions, including duodenal EDITORIAL COMMENT: Intestinal malrotation in ne-
atresia, small intestinal atresia, gastroschi- onates or infants requires urgent surgical treatment,
sis, omphalocele, and congenital diaphrag- especially when volvulus and vascular compromise
matic hernia as well as cardiac, renal, and of the midgut are suspected. Hagendoorn wished to
other major anomalies. Malrotation may determine whether laparoscopy for the treatment of
manifest with bile-stained vomiting and malrotation has a success rate equal to that of open
abdominal distention. The obstruction may
surgery.116 Successful laparoscopic treatment of in-

from fetal structures such as the omphal
testinal malrotation could be performed in 75% of the
omesenteric duct or urachus, or from fail-
cases (n = 28), and conversion to an open procedure
ure of closure of the umbilical fascial ring.
was necessary in 25% of the cases (n = 9). Postopera-
Persistence of the omphalomesenteric duct
tive clinical relapse due to recurrence of malrotation,
may lead to several anomalies including
volvulus, or both occurred in 19% of the laparoscopi-
umbilical sinus, umbilical cyst, Meckel
cally treated patients (n = 7). They concluded that “di-
diverticulum, or patent omphalomesen-
agnostic laparoscopy is the procedure of choice when
teric duct.118 A patent omphalomesenteric
intestinal malrotation is suspected. If present, malrota-
duct is usually associated with the ileum;
tion can be treated adequately with laparoscopic sur-
rarely, it may be associated with the cecum
gery in the majority of cases. Nevertheless, to prevent
or appendix. If the duct remains patent at
recurrence of malrotation or volvulus, a low threshold
the umbilicus, the umbilicus is constantly
for conversion to an open procedure is mandated.”
moist from intestinal secretions, whereas
persistence of a blind duct produces a
“strawberry” tumor at the umbilicus. Per-
sistence at the ileal end is noted in 2% of
MECONIUM ILEUS the population and results in Meckel diver-
Meconium ileus is a luminal obstruction ticulum, which often also contains ectopic
of the distal small intestine by abnormal gastric and pancreatic tissue. Meckel diver-
meconium, in contrast to meconium plug ticulum is rarely significant in the neonatal
syndrome, which is a colonic obstruction. period but may manifest with painless rec-
Meconium ileus is seen predominantly in tal bleeding (the result of ulceration caused
patients with cystic fibrosis. The infants by gastric secretions) or obstruction. The
present with bile-stained vomiting and diverticulum may also serve as the point for
abdominal distention and the meconium an intussusception.
filled loops have a doughy feel. The sono-
graphic findings associated with meconium COLONIC LESIONS
peritonitis in utero include polyhydramnios,
ascites, dilatation of the bowel, hyperechoic MECONIUM PLUG SYNDROME
bowel, and the tell-tale sign of intraabdomi- Meconium plug syndrome is part of the
nal calcification, which is pathognomonic spectrum of colonic hypomotility and is
of meconium ileus. seen predominantly in preterm infants and
Radiographic evidence exists of complete infants of diabetic mothers. Infants with
obstruction with a characteristic soap bub- meconium plug syndrome fail to pass meco-
ble appearance produced by the air trapped nium in the first 24 hours of life and present
in the thick meconium. Intrauterine per- with clinical and radiologic features of intes-
foration (meconium peritonitis) with the tinal obstruction. Rectal examination may
passage of sterile meconium into the perito- prompt passage of meconium with a charac-
neal cavity may be reflected by calcification teristic white plug; otherwise, a radiographic
and predisposes to intestinal obstruction contrast enema is indicated. This may serve
from adhesive bands. The diagnosis may the dual function of diagnosis and therapy.
be confirmed with a water-soluble diatri- Inspissated meconium may be documented
zoate enema, which may also be therapeutic in the distal colon with dilation above. The
because it facilitates passage of the tenacious contrast examination may precipitate pas-
meconium. The study is contraindicated if sage of the meconium plug and relieve the
signs of peritonitis or pneumoperitoneum symptoms. It is important to recognize that
are present. a meconium plug may be associated with
Gorter published a series of 43 patients cystic fibrosis and Hirschsprung disease.
from Amsterdam.117 Twenty-three of the Hence, if the symptoms persist or recur, the
patients (53.5%) were diagnosed as having infant should have a sweat chloride test and
cystic fibrosis. They concluded that the clin- rectal mucosal biopsy.
ical entity of meconium ileus represents a Failure of a small premature newborn to
spectrum of underlying pathologies. adequately evacuate meconium for days or
weeks has been attributed to probable nec-
MECKEL DIVERTICULUM rotizing enterocolitis (NEC), or “microco-
The omphalomesenteric duct usually oblit- lon of prematurity.” Extremely premature
erates spontaneously during embryonic infants may also present with intestinal
development. Umbilical anomalies arise obstruction and perforation secondary to
inspissated meconium in the absence of cys- the problem may be anticipated in the first
tic fibrosis. month of life. Management is expectant.
Krasna reported a series of 20 babies with
birth weights between 480 and 1500 g who CONGENITAL AGANGLIONIC
appeared to have an unusual type of “meco- MEGACOLON (HIRSCHSPRUNG DISEASE)
nium plug syndrome,”119 which required a Congenital aganglionic megacolon occurs
contrast enema or Gastrografin upper gas- in approximately 1 in 5000 births and is the
trointestinal series to evacuate the plugs and most common cause of large-bowel obstruc-
relieve the obstruction. Many of the mothers tion in the newborn. It can be life threaten-
were on magnesium sulfate or had eclamp- ing and should be considered in any neonate
sia. The plugs were diagnosed late rather with intestinal obstruction. It is more com-
than shortly after birth, and the plugs were mon in males, infants with trisomy 21,
significant, extending to the right colon. and siblings of children with the disorder.
Greenholz identified 13 patients who Hirschsprung disease is thought to result
underwent treatment for intestinal from defective migration of neural crest cells
obstruction secondary to inspissated meco- to the distal colon, leaving a segment of
nium.120 The average birth weight was bowel aganglionic and dysfunctional.
760 g. Prenatal and postnatal risk factors Only 10% to 20% of patients with this dis-
included intrauterine growth restriction, order are first seen in the newborn period. In
maternal hypertension, prolonged admin- the infant, symptoms may manifest as acute
istration of tocolytic agents, patent ductus obstruction, abdominal distention, vomit-
arteriosus, respiratory distress syndrome, ing, and delay in passing or failure to pass
and intraventricular hemorrhage. Stooling meconium (95% of normal term newborns
was absent or infrequent during the first 2 pass meconium in the first 24 hours of life).
weeks of life. The infants had abdominal Constipation is a prominent feature. Irrita-
distention or perforation between days bility, poor feeding, and failure to thrive are
2 and 17 of life. Twelve patients required other presenting features. Rectal examina-
operative intervention. Findings invari- tion or rectal stimulation such as with a rec-
ably included one or more obstructing tal thermometer may produce an explosive
meconium plugs with proximal distention, gush of gas, and meconium may obscure the
and the dilated segments were frequently diagnosis; however, in the absence of rectal
necrotic. None of the patients had cystic stimulation, no stools are passed.
fibrosis. The markedly premature infant Radiographic findings include nonspe-
is at risk for obstruction and eventual per- cific obstructive features, such as dilated
foration secondary to meconium plugs, loops of bowel and multiple fluid levels with
presumably formed in conjunction with the absence of air in the rectum. Barium
intestinal dysmotility. This entity must be studies should be performed without prior
distinguished from spontaneous intestinal cleansing enemas. The findings include
perforation, which occurs in the absence of proximal dilation and distal narrowing in
plugs (see later text). Prompt diagnosis and the aganglionic segment. Note, however,
timely intervention require a high index that the transition zone may not be clearly
of suspicion, including close attention defined in the neonate and the barium may
to stooling patterns, careful abdominal be retained for more than 24 hours. The
examinations, and screening radiographs diagnosis is established by biopsy, which
when indicated. Patients with this disorder must be of adequate depth to confirm the
should be evaluated for cystic fibrosis and absence of ganglia in the nerve plexus.
may need to undergo a rectal biopsy to rule Surgical treatment is mandated in the
out Hirschsprung disease. newborn. Generally, a colostomy in a seg-
ment of normally innervated bowel is
NEONATAL SMALL LEFT COLON required. Definitive correction had usually
Small left colon is a rare entity encountered been deferred until the end of the first year
predominantly among infants of diabetic of life. Hirschsprung disease can now be suc-
mothers. The presenting features characteris- cessfully treated in the neonatal period with
tically include delayed passage of meconium. a one-stage pull-through. The short- and
Radiographic evidence includes dilation of long-term results are as good as those with
the proximal colon, a clearly delineated tran- the three-stage procedure, with the child
sition zone, usually the splenic flexure, and usually benefiting by having a shorter hos-
narrowing of the distal colon. Resolution of pital stay and not requiring a stoma.
ABDOMINAL WALL DEFECTS INGUINAL HERNIA

Omphalocele and gastroschisis are major Inguinal hernias occur in 1% to 3% of all
defects of the abdominal wall resulting in children, more often in premature infants, in
parts of the gastrointestinal tract remaining boys much more frequently than girls, and
outside the abdominal cavity. An omphal more often on the right side than left, but can
ocele is covered by peritoneum and is fre- also occur on both sides. Hernias occur more
quently associated with other anomalies often in children with a parent or sibling
(congenital heart disease, trisomy 13 or 18, who had a hernia as an infant, cystic fibro-
urinary tract anomalies, and Beckwith-Wie- sis, developmental dysplasia of the hip, as
demann syndrome, which includes mac- undescended testes or urethral abnormalities.
rosomia, macroglossia, omphalocele, and They need to be differentiated from a hydro-
hypoglycemia;) (see Chapter 12). Malrota- cele, although both may occur together. The
tion is invariable with an omphalocele. The prevalence of incarceration of the hernia in
pentalogy of Cantrell refers to an ompha- infants discharged home is very low. Ingui-
locele accompanied by defects in the dia- nal hernia repair is one of the most common
phragm, sternum, heart, and pericardium. surgical procedures performed on premature
Gastroschisis is a cleft in the abdomi- infants. Improved survival rates in the NICU
nal wall to the right of the umbilicus. The have led to an increase in the incidence of
extruded loops of bowel are thickened and premature infants with inguinal hernias.
covered by a fibrinous peel that develops in Murphy et al. reported on a 5-year,
the latter part of the third trimester. Atresias, retrospective chart review of all prema-
strictures, adhesions, and stenoses of the ture infants undergoing inguinal hernia
bowel accompany gastroschisis, but other repair.122 Because the literature suggested
malformation syndromes are unusual. The that postoperative apneas occurred in up
atretic areas are secondary to vascular insults. to 49% of premature infants undergoing
Both lesions may be identified relatively anesthesia for inguinal hernia repair, their
early in gestation through alpha-fetoprotein practice is to monitor all of these babies
screening (see Chapter 2) and the lesions in the intensive care unit (ICU) overnight
can be accurately delineated with antenatal after surgery. In addition to the consider-
ultrasound. Delivery should take place at a able expense to the health care system,
tertiary center because these cases represent these cases are cancelled if no ICU bed is
complex management problems. The mode available. They reported that only 5 of 126
of delivery is determined by obstetric fac- (4.7%) had apnea after the repair. All five
tors; vaginal delivery has not been proved had a previous history of significant apnea,
to increase morbidity, mortality risk, or and these babies were less mature with a
length of stay. Thermal regulation, fluid and more complicated hospital course. They
electrolyte management, nutritional sup- concluded that selective use of postopera-
port, and measures to prevent infection are tive ICU monitoring for high-risk patients
needed to complement the surgical team. could result in significant resource and cost
savings to the health care system.
EDITORIAL COMMENT: Gastroschisis and omphal
ocele are usually considered together because both are
congenital abdominal wall defects, yet their anatomy,
CASE B-2
embryogenesis, clinical presentation, and associated An infant takes initial feedings and then vomits bile-
problems are quite different. For gastroschisis, evi- stained material. He is otherwise asymptomatic.
dence points to environmental teratogens as the cause Examination may or may not reveal abdominal dis-
with little evidence for a genetic cause,121 whereas for tention. The anus is patent, and meconium is usually
omphalocele, substantial data support genetic or fa- passed.
milial factors as a cause, with little evidence for envi- Any gastrointestinal obstruction distal to the entry
ronmental factors. Omphalocele and gastroschisis are of the common duct into the duodenum can lead to
recognized as congenital malformations with a high bile-stained vomiting. As a general rule (but not an in-
mortality. Only 60% of children with such malforma- fallible one), the earlier the onset of bile-stained vom-
tions survive until the end of the first year of age. It has iting, the higher the level of obstruction. Lower-level
been suggested that omphalocele and gastroschisis obstructions usually manifest initially with distention
are associated with other congenital malformations, and failure to pass meconium with bile-stained vomit-
concerning the bones, the heart, and the kidney. ing occurring hours to days later.
X-ray findings vary with the level and type of ob- EDITORIAL COMMENT: Intestinal malrotation is a
struction. They may be clearly diagnostic, as is the common cause of upper gastrointestinal obstruction
case with complete obstruction of the duodenum and manifests with duodenal obstruction caused by
(double bubble; duodenal atresia, annular pancreas, volvulus of the midgut loop. Patients are at risk of cat-
occasionally malrotation), or they may be equivocal, astrophic midgut infarction, and malrotation is a more
as in meconium ileus or Hirschsprung disease. frequent cause of duodenal obstruction in infants than
Eventual diagnosis is forthcoming in every duodenal atresia. Bilious vomiting and bloody stools
case, given enough time and persistence. In the are the two most common clinical presentations in
interim, effective nasogastric decompression and neonates. Rectal bleeding is an ominous sign. Most
parenteral fluid, electrolyte, and nutritional support patients manifesting such bleeding have a gangre-
by vein sustain most of these infants, even if sig- nous bowel. Urgent upper contrast studies are nec-
nificant time lapses before diagnosis and definitive essary. Ultrasound studies may also be helpful as a
therapy. Only those lesions that may lead to catas- characteristic pattern of echogenic ascites, thickened
trophe require urgent diagnosis and treatment, so bowel wall; dilated, fluid-filled bowel lumen; and lack
attention should be directed to recognizing these of peristalsis may be seen in children with gangrenous
disorders rapidly. These disorders include malrota- bowel.
tion, volvulus, bowel perforations, and aganglionic Note that a less invasive laparascopic approach is
megacolon. successful 75% of the time.
BLOOD IN STOOL
Blood in the stool123 is a frequent problem
CASE B-3 confronting the neonatal team. Whether
Bilious vomiting, usually with some abdominal disten- gross blood is present, streaks of blood are
tion, occurs in a baby who passed normal meconium on the outside of an otherwise normal-
and has an open anus. X-ray films may show duode- appearing stool, or only occult blood is pres-
nal obstruction and usually show some gas through- ent, a prompt and diligent search for the
out the abdomen. cause is mandatory. In many instances no
cause will be found; however, major patho-
Diagnosis: Malrotation logic disorders accounting for the blood in
Malrotation is the most malevolent lesion of infancy the stool must be ruled out.
because of its propensity toward volvulus with result- Disorders causing frank blood in the stool,
ant strangulation of the superior mesenteric artery. range from swallowed maternal blood, an
This catastrophe can lead to total destruction of the inconsequential problem, to life-threaten-
digestive-absorptive segment of the intestinal tract— ing disorders, including NEC, malrotation
the jejunoileum. Furthermore, compared with any with volvulus, disturbances of coagulation,
other single anomaly, this lesion is quite common. It ulcerative disorders, and infections. Blood-
must, therefore, always be in the differential diagnos- streaked stools are most commonly seen
tic forefront to be rapidly ruled in or out. The most di- with an anal fissure or following trauma to
rect method for doing so is by upper gastrointestinal the rectum with temperature probes and
contrast study, which demonstrates obstruction of thermometers. Occult blood may signify
the duodenum. If obstruction is incomplete, the study blood swallowed during breast feeding,
reveals that the duodenal C loop fails to complete its upper gastrointestinal disorders, milk intol-
normal course to a position in the left upper quadrant erance, hemorrhagic disorders, or NEC.
behind the stomach—the ligament of Treitz. Gastrointestinal bleeding in the new-
Contrast enemas, frequently recommended for born must be differentiated from swallowed
diagnosis of malrotation in the past, may be con- maternal blood caused by antepartum
fusing. The high-riding cecum with malpositioned hemorrhage, the episiotomy, or cracked,
appendix is diagnostic if clearly present, but often bleeding nipples. The Apt test distinguishes
the cecal position is equivocal and difficult to locate maternal from fetal red blood cells, in that
clearly. Reflux of dye into the ileum may mask the po- the fetal cells are resistant to alkali dena-
sition of the cecum. Therapeutic delay is intolerable turation (addition of sodium hydroxide).
here. One should quickly intervene operatively in any Hence, a solution containing maternal
duodenal obstruction not clearly caused by an entity blood changes from pink to brown. Other
other than malrotation. laboratory tests include a complete blood
count with a differential and smear; plate-
let count; coagulation studies such as partial
thromboplastin time, prothrombin time, The incidence varies among countries and
and fibrinogen level; blood culture; and among units. Uauy et al,126 reporting on
a plain film of the abdomen. These tests behalf of the National Institute of Child
should point to the cause of the bleeding, Health and Development Neonatal Multi-
which can then be managed appropriately. center Research Network, noted that 10%
of 2681 infants with birth weights between
SPONTANEOUS INTESTINAL 501 and 1500 g had proven NEC (Bell stage
PERFORATION II and beyond) (Table 7-12). Approximately
Another disorder has emerged among the 7% of all babies with birth weights below
ELBW infants. It has been designated spon- 1500 g will develop necrotizing enterocoli-
taneous intestinal perforation and may be tis. Most infants with NEC have a low birth
indistinguishable from NEC. Spontaneous weight, are inappropriately grown, and are
perforation, however, occurs much less fre- immature.127-129
quently than NEC in preterm infants. The Although patent ductus arteriosus, low
infants may have dramatic abdominal dis- Apgar scores, and umbilical catheters have
tention often associated with blue discolor- been implicated in the etiology, matched
ation of the abdominal wall. Obvious clinical studies did not identify these as risk fac-
signs of bowel perforation are infrequent tors. Nonetheless, the odds ratio for NEC
with spontaneous intestinal perforation. increased with antepartum hemorrhage,
Infants with spontaneous perforation are prolonged rupture of membranes beyond 36
smaller and born more prematurely when hours, and 5-minute Apgar scores below 7.
compared with infants who had NEC.124,125 The age of onset for NEC varies inversely
The onset of illness was earlier and was with gestation. In approximately half of the
associated with antecedent hypotension, term infants with NEC, symptoms manifest
leukocytosis, and a gasless appearance on in the first day of life. Specific risk factors for
abdominal radiograph. Infants with sponta- NEC among term infants include cyanotic
neous perforations are more likely to have heart disease, polycythemia, and twin ges-
received postnatal steroids or to have sys- tation. Whereas sporadic cases of endemic
temic candidiasis. Conditions associated NEC occur throughout the year, temporal
with fetal or neonatal hypoxia are important and geographic epidemic clusters are asso-
antecedents for this emerging distinct clini- ciated with gastrointestinal illness among
cal entity. Other factors implicated in the nursery staff.
etiology include indomethacin therapy, pat- Infection plays a prominent role and
ent ductus arteriosus, and intraventricular the disease occurs in clusters with various
hemorrhage. Peritoneal drainage alone may outbreaks reported from Escherichia coli
be considered definitive therapy for intesti- and Klebsiella, Salmonella, and Clostridium
nal perforation in the majority of extremely species. Viruses have also been implicated.
immature infants. The prognosis for spon- Recent reports suggest significant altera-
taneous intestinal perforation is better than tions in the gastrointestinal flora colonizing
for necrotizing enterocolitis (see later). critically ill neonates. An altered intestinal
microbiome coupled with an unbalanced
proinflammatory response in a high-risk
premature infant may lead to the final com-
mon pathway of intestinal necrosis.
PART THREE A review of peritoneal cultures from
infants undergoing surgery for NEC reveals
NECROTIZING a predominance of Klebsiella and Entero-
bacter species (63%), frequent E. coli (21%),
ENTEROCOLITIS coagulase-negative staphylococci (30%),
occasional anaerobes (6%) and Candida iso-
lates (10%). Clinical classifications and the
Deanne Wilson-Costello, pathogenesis of the disease are outlined in
Robert M. Kliegman, and Avroy A. Fanaroff Tables 7-12 and Box 7-4 and Figure 7-6. The
inciting event may be hypoxemia, sepsis,
low cardiac output, or factors within the
NEC remains the major gastrointestinal bowel such as hypertonic feeding. Although
cause of morbidity and mortality among feeding precedes the onset of symptoms in
the neonatal intensive care population. most cases, delayed feeding does not lower
Table 7-12. Modified Bell’s Staging Criteria for Neonatal Necrotizing Enterocolitis
Stage Systemic Signs Intestinal Signs Radiologic Signs Treatment

IA—Suspected NEC Temperature instability, Elevated pregavage Normal or intestinal Nothing by
apnea, bradycardia, residuals, mild abdomi- dilation, mild ileus mouth, antibiot-
lethargy nal distention, emesis, ics for 3 days
guaiac-positive stool pending cultures
IB—Suspected NEC Same as above Bright red blood from Same as above Same as above
rectum
IIA—Definite NEC: Same as above Same as above, plus Intestinal dilation, Nothing by
mildly ill diminished or absent ileus, pneumatosis mouth, antibiotics
bowel sounds with intestinalis for 7-10 days if
or without abdominal examination is
tenderness normal in 24-48 hr
IIB—Definite NEC: Same as above Same as above plus Same as stage Nothing by
moderately ill plus mild metabolic definite abdominal IIA with or without mouth, antibiot-
acidosis and mild tenderness, with or portal vein gas, with ics for 14 days,
thrombocytopenia without abdominal or without ascites NaHCO3 for
cellulitis or right lower acidosis
quadrant mass, absent
bowel sounds
IIIA—Advanced NEC: Same as IIB plus Same as above plus Same as stage IIB, Same as above
severely ill, bowel hypotension, signs of generalized definite ascites plus 200 mL/kg/
intact bradycardia, severe peritonitis, marked day fluids, fresh
apneas, combined tenderness, distention frozen plasma,
respiratory and of abdomen, and inotropic agents;
metabolic acidosis, abdominal wall intubation, ven-
disseminated intra- erythema tilation therapy;
vascular coagulation, paracentesis;
neutropenia, anuria surgical interven-
tion if patient
fails to improve
with medical
management
within 24-48 hr
IIIB—Advanced NEC: Same as stage IIIA Same as stage IIIA Same as stage IIB Same as above
severely ill, bowel plus pneumoperito- plus surgical
perforation neum intervention
NEC, Necrotizing enterocolitis.
the incidence of NEC and, in fact, may pro-

complement 5a, cytosolic beta-glucosidase, serum
mote its occurrence.130 It remains unclear
amyloid A, and salivary H secretor phenotype.134-136
whether the major factor is the formula
In these studies, most markers were measured at the
itself, the volume of formula, the rate at
time of NEC diagnosis, and unfortunately patients will
which feeding is advanced, or the effect of
only benefit if a marker is discovered that predicts NEC
the bacteria on the formula.
before the diagnosis is made. Chabaan has identified
Gut ischemia is a potential risk fac-
inter-alpha inhibitor protein (IaIp) as a potential mark-
tor for NEC. Intrauterine growth-restricted
er of necrotizing enterocolitis.137 Inter-alpha inhibitor
infants with aberrant fetal Doppler blood
proteins are serine protease inhibitors that modulate
flow velocity waveforms and infants born
endogenous protease activity and improve survival in
to cocaine-abusing mothers show increased
adult models of sepsis. The beneficial effects of IaIp ap-
rates of NEC.131-133 In addition, cocaine-
pear to be via suppression of proinflammatory cytokines
exposed infants with NEC are more likely to
such as TNF-α rather than augmentation of IL-10. The
require surgical intervention, have massive
impact of IaIp may be significantly greater than that of a
gangrene, or die.131
just as reliable predictive marker for NEC—IaIp may be
useful in the treatment of this dreaded disease. It has
EDITORIAL COMMENT: Michael Caplan MD: The been shown that serine proteases initiate a cell death
search for predictive markers of NEC has been inconsist- pathway in epithelial cells, and this mechanism may
ent, although some might have clinical utility, including contribute to the pathogenesis of NEC.138 If so, low IaIp
C-reactive protein, hydrogen breath test, interleukin-8 levels due to consumption or immaturity would lead to
(IL-8), platelet activating factor, and, most recently, prolonged serine protease exposure and may contribute
Neonatal Necrotizing Enterocolitis

Clinical Classification of Neonatal
Box 7-4. Hypoxemia
Enterocolitis*
Acidosis
Classic NEC Low cardiac output
Endemic Hypothermia
Epidemic
• Identifiable organism
• No organism identified Decreased splanchnic
blood flow
Benign NEC (Pneumatosis coli)
NEC following exchange transfusion
NEC following mucosal injury
Hypertonic
Hypertonic feeding feedings Mucosal edema
Allergic enteritis and ulceration
Nonspecific diarrhea
Polycythemia
Absence of Intestinal
Primary bowel pathologic findings normal colostrum; colonization
Spontaneous bowel perforation immature gut with E. coli,
Congenital intestinal obstruction immunity Klebsiella
Neonatal appendicitis Invasive infection
Neonatal pseudomembranous colitis by bowel flora
Adapted from Kliegman RM, Fanaroff AA: Necrotizing

enterocolitis, N Engl J Med 310:1093, 1984.
*Each category is a distinct clinical and pathologic Bacterial invasion
of portal system
entity. The inclusive heading of neonatal enterocolitis
and bowel lymphatics
includes classic idiopathic NEC (I, II), NEC associated
with other factors (III, IV), and those newborn dis-
eases that clinically resemble NEC (V, VI, VII). These
disease processes may be distinguished from each
Pneumatosis intestinalis Endotoxin release
other by history, clinical course, laboratory tests, and
Portal gas
pathologic examination. Septicemia
NEC, Necrotizing enterocolitis.
DIC
to increased epithelial cell death. It seems plausible Transmural
bowel necrosis
that exogenous IaIp could reduce serine protease
Sepsis
effects, and in animals, IaIp treatment has reduced the
Perforation
risk of death in a neonatal sepsis model.139 Additional
studies are needed to explore the possible role of IaIp in Vasomotor
the diagnosis and treatment of neonatal NEC. collapse
Figure 7-6. Possible factors in etiology and outcome
of neonatal necrotizing enterocolitis. DIC, Disseminated
In summary, NEC is a multifactorial dis- intravascular coagulation. (From Burrington JD: Necrotizing
order with a delicate balance between bowel enterocolitis in newborn infant, Clin Perinatol 5:29, 1978.)
perfusion, enteric organisms, and nutri-
tional intake. The disorder was reduced by
the prenatal administration of steroids,140 should, therefore, be encouraged to provide
although larger series have not confirmed breast milk for their own infants during
this, or possibly by the postnatal admin- their sojourn in the intensive care unit.
istration of immunoglobulin A.141 Breast Late-onset sepsis and NEC may result
milk is also protective, as shown by Lucas from bacterial translocation. Lactoferrin (LF)
and Cole in a multicenter study addressing is a member of the transferring family and
the role of diet in NEC.61 Furthermore, pas- a multifunctional protein. It has antimicro-
teurizing the milk did not reduce its effec- bial, antiinflammatory, immunoregulatory,
tiveness and the combination of breast milk and growth-promoting properties. All of
and formula was less likely to be associated these contribute to the prevention of bacte-
with NEC than formula alone. Breast milk rial translocation in VLBW infants. Manzoni
contains bifidus factor, which enhances gut et al. observed a significant reduction in late-
colonization with Lactobacillus. Mothers onset sepsis among VLBW infants fed bovine
lactoferrin (BLF).86 Incidence of late-onset coagulation, or acidosis. The discovery of

sepsis was significantly lower in the BLF and an abdominal mass and gas in the portal
BLF plus Lactobacillus rhanmosus GG (LGG) venous system is not necessarily an indica-
groups (5.9% and 4.6%, respectively), com- tion for surgery. Some infants may require
pared to the control group receiving placebo surgery at a later stage because of the devel-
(17.3%). The decrease occurred for both bac- opment of strictures. With present vigor-
terial and fungal sepsis. No adverse effects or ous medical and surgical management as
intolerances to treatment occurred. When outlined earlier, 75% of infants with birth
BLF and L. rhamnosus GG were given enter- weights above 1 kg should survive.
ally to the infants, NEC was significantly Perforated necrotizing enterocolitis is a
decreased compared to controls. major cause of morbidity and mortality in
Deshpande included 15 trials and nearly premature infants, and the optimal treat-
3000 infants in a metaanalysis that dem- ment is uncertain. Blakely documented that
onstrated significant reduction in death or survival to hospital discharge after opera-
necrotizing enterocolitis (30%) without any tion for necrotizing enterocolitis (NEC) or
significant side effects.142 However, probi- isolated intestinal perforation (IP) in ELBW
otics have not been available in the United (<1 kg) neonates was only 51%. Among the
States for use in preterm infants because of 156 enrolled infants, 80 underwent initial
problems in obtaining a standardized pro- peritoneal drainage and 76 had initial lapa-
biotic acceptable to the U.S. Food and Drug rotomy.145,146 Patients with a preoperative
Administration (FDA). diagnosis of NEC have a relative risk for
death of 1.4 compared with those with a pre-
CLINICAL FEATURES operative diagnosis of isolated intestinal per-
The clinical features of NEC are variable, foration. They could distinguish on the basis
and the signs and symptoms may not be of radiologic findings and age at surgery pre-
specific.143 Most often, temperature insta- operatively between NEC and isolated intes-
bility, lethargy, abdominal distention, and tinal perforation. The overall incidence of
retention of feedings develop. Occult blood postoperative intestinal stricture was 10.3%,
is present in the stools, which may some- wound dehiscence 4.4%, and intraabdomi-
times reveal frank blood. Reducing sub- nal abscess 5.8%, and did not significantly
stances are often detected before the onset of differ between groups undergoing initial
NEC. Apnea may be a prominent feature as laparotomy versus initial drainage. By 18 to
well as bilious vomiting, increased abdomi- 22 months, 78 (50%) had died; 112 (72%)
nal distention, acidosis, and disseminated had died or were shown to be impaired. Out-
intravascular coagulation. The characteristic come was worse in the subgroup with NEC.
x-ray features are pneumatosis intestinalis, Subsequently, Moss reported from a mul-
with bubbles or layers of gas in the wall of ticenter randomized trial that compared out-
the bowel as well as portal venous gas. Free comes of primary peritoneal drainage with
air within the peritoneum is associated with laparotomy and bowel resection in preterm
perforation of a viscus. Engel et al. demon- infants with perforated necrotizing enteroco-
strated that about 30% of the gas in the wall litis.147 At 90 days postoperatively, 19 of 55
of the bowel is hydrogen,144 the product of infants assigned to primary peritoneal drain-
bacterial fermentation of formula. age had died (34.5%), as compared with 22
Medical management includes nasogas- of 62 infants assigned to laparotomy (35.5%,
tric suction, IV fluids, and broad-spectrum P = 0.92). They concluded that the type of
systemic antibiotics (Appendix A-2). Fre- operation performed for perforated necrotiz-
quent abdominal examinations as well ing enterocolitis does not influence survival
as determination of abdominal girth and or other clinically important early outcomes
cross-table lateral x-ray films are important in preterm infants.147 Among ELBW infants,
to detect free air. Infants should be main- surgical NEC, which is likely to be associ-
tained on a regimen of nothing per os for ated with a greater severity of disease, is
up to 2 weeks while they receive all nutri- associated with significant growth delay and
tional support intravenously. The main adverse neurodevelopmental outcomes at 18
indication for surgery is perforation, which to 22 months’ corrected age compared with
is demonstrated by free air in the perito- infants who did not have NEC. 148 Medically
neum. However, surgery may also be con- treated NEC does not seem to confer addi-
sidered for infants with worsening clinical tional risk and the outcomes are similar to
status, refractory disseminated intravascular very low-birth-weight babies without NEC.
The incidence of surgical short bowel syn-

3. Barium swallow
drome in a cohort of 12,316 VLBW infants
4. Gastrografin enema
(<1.5 kg) was 0.7%.149 Necrotizing enteroco-
5. Anteroposterior and lateral film of abdomen
litis was the most common diagnosis asso-
6. Blood gases and serum electrolytes
ciated with surgical short bowel syndrome.
More VLBW infants with short bowel syn-
1. Because sepsis is present in many if not all of
drome (20%) died during initial hospitaliza-
these patients and many investigators believe
tion than those without NEC or short bowel
that infection is directly related to the pathogen-
syndrome (12%), but fewer than the infants
esis of the disease, blood, urine, stool, and cer-
with surgical NEC without short bowel syn-
ebrospinal fluid cultures should be obtained.
drome (53%). Among 5657 ELBW infants
2. A complete blood count, blood smear, and clot-
(<1 kg birth weight) the incidence of surgi-
ting profile should be ordered and the type and
cal short bowel syndrome was 1.1%. At 18 to
cross-match sent to the blood bank. Take specific
22 months, ELBW infants with short bowel
note of fragmented red blood cells (disseminated
syndrome were more likely to still require
intravascular coagulation), neutropenia (margina-
tube feeding (33%) and to have been rehos-
tion of white blood cells), and thrombocytopenia.
pitalized (79%). Moreover, these infants had
3. Barium swallow is not indicated immediately. If
growth delay with shorter lengths and smaller
there is evidence of obstruction without pneu-
head circumferences than infants without
matosis intestinalis on the flat film, then a barium
necrotizing enterocolitis or short bowel.
swallow may be necessary to exclude malrotation.
4. Gastrografin enema may be curative if there is a
CASE C-1 meconium plug but is contraindicated in this case
because the hyperosmolar contrast medium may
C. K. weighs 1300 g at 32 weeks’ gestation. His Ap-
produce further damage to already compromised
gar scores were 4 at 1 minute and 6 at 5 minutes.
bowel and result in perforation.
Respiratory distress syndrome (RDS) develops on
5. Abdominal x-ray films, both KUB (kidney, ureter,
the first day of life, an arterial catheter is placed at
and bladder) and cross-table lateral, should be
the level of T10, and 60% oxygen but no assisted
obtained to detect the presence of pneumatosis
ventilation is used. The RDS resolves by 48 hours of
intestinalis, hepatic portal gas, or free intraab-
life, and the catheter is removed. Standard formula
dominal gas, indicating a perforated viscus. If no
is first fed on the third day of life. On the eighth day,
free air is seen initially but there is pneumatosis in-
abdominal tenderness and distention are observed,
testinalis present, the cross-table lateral x-ray film
and the nurses reported guaiac-positive stools, 5 mL
should be repeated every 4 to 6 hours or sooner
residual from the last feeding, and a higher incubator
if there is clinical deterioration.
temperature required to maintain body temperature.
6. It is important to evaluate acid-base status and
serum electrolytes in infants with suspected gas-
What is the most likely preliminary trointestinal disturbances. Correction of these
diagnosis? metabolic derangements is crucial before sub-
1. Meconium plug syndrome mitting these precarious infants to major surgery.
2. Necrotizing enterocolitis The x-ray films reveal pneumatosis intestinalis
3. Septicemia with no air in the liver or free intraperitoneal air. The
4. Malrotation blood pressure is 55/35; blood gases pH 7.32, Pao2
5. Hirschsprung disease 65 and Pco2 40; bicarbonate 20; serum sodium 132;
Any neonate with a triad of abdominal distention, potassium 4.8; chloride 105; BUN 10; hematocrit
Hematest or guaiac-positive stools, and retention of 38%; white blood cell count 14,900 with 70% seg-
gastric formula should be suspected of having NEC mented cells; platelets adequate and clotting pro-
and should be immediately evaluated for it. The initial file normal. Pediatric surgeons were consulted and,
manifestation of NEC may be indistinguishable from together with the nursery staff, they managed the
septicemia, and a positive blood culture is obtained case.
from 30% of infants with NEC. The answer is 2,
necrotizing enterocolitis. The following treatments should be
instituted (True or False):
Initially, how should this patient be 1. Nasogastric suction, IV fluids, and nothing per os
evaluated? (NPO)
1. Culture of blood, urine, cerebrospinal fluid, and 2. Systemic and orogastric antibiotics
stool 3. Laparotomy
2. Complete blood count and clotting profile
4. Exchange transfusion that develops in the abdomen, which results from

5. Placement of central hyperalimentation line the inflammatory response and bowel necrosis.
These large fluid and protein losses result in hypo-
1. True. It is imperative to decompress the abdo- volemia and require urgent therapy. The mainstay
men with a large oral or nasogastric tube. Care- of treatment is to elevate the blood pressure by
fully record all intake and output, weigh the baby supporting the intravascular space with sufficient
twice daily, and measure abdominal girth fre- blood, plasma, or crystalloid to maintain the
quently. IV fluid therapy must take into considera- blood pressure and urine output. Whole blood is
tion significant third-space losses. Patients with preferred because it remains in the intravascular
documented NEC should be managed with NPO space, whereas other fluids leak through the dam-
for at least 7 to 10 days. aged capillaries and contribute to intestinal ede-
2. True. The patient was started on appropriate ma. Large volumes of crystalloid may be required.
doses of IV piperacillin and an aminoglycoside. Neutropenia may be documented in NEC without
Antibiotics via nasogastric tube has not proved to bacteremia. Margination of neutrophils is assumed
be efficacious. because marrow reserves are not depleted.
3. False. There is no clear-cut indication for laparot- 2. False. Although the sudden deterioration is sug-
omy at this stage. Whereas surgery is clearly in- gestive of perforation and evaluation by transil-
dicated for intestinal perforation, some centers lumination and an x-ray film is certainly indicated,
operate when medical management fails to cor- no perforation was present at the time. The wide
rect the shock-acidosis; if there is persistent cel- pulse pressure is not usually detected at the time
lulitis of the anterior abdominal wall; or if radio- of perforation.
logically a single dilated loop of bowel persists. 3. False. Tachycardia, edema, and wide pulse pres-
4. False. With normal clotting studies and no evi- sure are present with patent ductus arteriosus
dence of bleeding or significant hyperbilirubine- and congestive heart failure. However, the strik-
mia, exchange transfusion is not indicated. ing abdominal findings, together with the dimin-
5. False. TPN is going to be necessary for this infant. ished blood pressure, suggest that this is not the
However, with septicemia likely, it is advisable to primary problem. Patent ductus arteriosus, how-
wait until the sepsis has been controlled and the ever, is found frequently in infants with NEC.
general condition is stabilized before placing a cen- 4. False. This is unlikely, given the complete picture,
tral line for IV nutrition. Some centers provide all nu- particularly with a pink baby and wide pulse
tritive support with peripheral lines using glucose- pressure.
amino acid mixtures supplemented with IV lipid. Two hours later, x-ray films show increased dis-
Four hours later, the blood pressure drops from tention and no evidence of free air but the appear-
55/35 to 40/0. The urine output decreases to less ance of bowel “floating” in the abdomen.
than 1 mL/hour, and the abdomen is more distended,
edematous, and tender. On physical examination, the What is the significance of this finding?
infant is pink with a wide pulse pressure, tachycardia, Bowel floating in the abdomen in a patient with sepsis
and warm extremities. Repeat complete blood count and a distended tender abdomen indicates ascites
reveals white blood cell count of 3.1, with 10% seg- caused by peritonitis. Because many cases of “in-
mented cells and 10% bands. traabdominal sepsis” are caused by anaerobic bacte-
ria, anaerobic antimicrobial coverage should be start-
These data should be interpreted as (True ed following paracentesis. (Clindamycin is instituted
or False): for infants with suspected NEC and perforation.)
1. Septic shock On surgically introducing a drain into the left lower
2. Perforated abdominal viscus quadrant, 10 mL of purulent fluid is removed. The
3. Patent ductus arteriosus with congestive heart cell count shows 90,000 white blood cells with 75%
failure PMN leukocytes. Gram stain shows both gram-posi-
4. Pneumothorax tive and gram-negative rods.
5. Third-space loss The patient is noted to have blood oozing from
1 and 5, True. The patient as described—pink with venipuncture sites, with petechiae and a falling he-
wide pulse pressure, tachycardia, and warm ex- matocrit despite multiple blood transfusions.
tremities—has the classic features of warm shock.
When such cases are untreated, the blood pres- Laboratory Data
sure decreases further and vasoconstriction pre- CBC: Hct-28; platelets 5000; smear shows frag-
dominates, transforming the “warm” shock to mented red blood cells and burr cells
“cold” shock. A major factor contributing to shock Prothrombin time: patient, 50 seconds; control,
in patients with NEC is the massive third space 10 seconds
Partial thromboplastin time: patient, 180 seconds; iagnosed and is treated with medical management.
d
control, 30 seconds He recovers and begins enteral feedings 14 days
Fibrinogen: 50 mg/dL (normal 200 mg/dL) after the onset of acute NEC.
Fibrin split products: 4+ (normal not present) M. P. is discharged home at 6 weeks of age, hav-
Disseminated intravascular coagulation has coming tolerated full volume enteral feedings for 2 weeks.
plicated the picture, and therefore an exchange trans- Three weeks after discharge, he has acute abdomi-
fusion with fresh blood is performed (see Chapter 17). nal distention, vomiting, and hematochezia. Abdomi-
Blood pressure, urine output, and activity are nor- nal examination reveals guarding and tenderness.
mal for 3 days. The abdomen is softer, but there is
still some edema of the abdominal wall. Repeated x- What is the most likely diagnosis?
ray films fail to reveal free intraabdominal air. After 5 1. Clostridium difficile infection
days of relative stability, the patient becomes acutely 2. Intestinal stricture
distended with signs of respiratory embarrassment. 3. Anal fissure
4. Milk protein allergy
Which of the following management
options is appropriate? Strictures are one of the most common complica-
1. Repeat clotting profile and exchange transfusion. tions of NEC, occurring in 10% to 35% of all sur-
2. Percuss abdomen and then transilluminate while vivors.150,151 They result from healing and cicatricial
awaiting x-ray film. scarring of an ischemic area of bowel.152 Signs in-
3. Repeat blood cultures and change antibiotics. clude hematochezia, vomiting, abdominal distention,
4. Measure blood gas and increase environmental and sudden bowel obstruction. Strictures usually
oxygen. manifest in the first 2 months following acute NEC,
but may occur as late as 6 months afterward.
1. This acute episode following a period of stabil-
ity cannot entirely be attributed to disseminated Which of the following management
intravascular coagulation. options is appropriate?
2. This acute change is probably due to intestinal per- 1. Perform stool culture and start oral antibiotics.
foration. Abdominal percussion used to demon- 2. Change infant to soy formula feedings.
strate the absence of hepatic dullness and positive 3. Obtain abdominal x-ray, do barium enema, and
transillumination may confirm suspicions before the consult pediatric surgery.
cross-table lateral x-ray film has been developed. 4. Reassure the mother that rectal bleeding is com-
The film in this instance demonstrated free air. mon; send child home with office follow-up in 1 to
3. Blood culture should be repeated, but there is no 2 days.
reason to change antibiotics at this time. 1, 2, and 4, False. Any neonate with history of NEC fol-
4. This is only symptomatic management. The basic lowed by the onset of hematochezia and vomiting
cause for the abdominal distention and respiratory should undergo evaluation to rule out strictures.
embarrassment must be determined. The blood Recent reports have suggested that clinical obser-
gas will indicate the need for ventilatory support. vation alone is associated with significant morbid-
ity in this population. Failure to rapidly detect and
The child is brought to the operating room where the manage stricture complications has resulted in
perforated area of ileum is resected and an ileostomy intestinal perforation and life-threatening sepsis.153
and colostomy are performed. Two days postopera- 3, True. Proper management includes abdominal x-
tively a central line is placed in the NICU operating rays, barium enema, and pediatric surgical evalu-
room and TPN is administered via this route for 21 ation.
days. After 14 days of being NPO, he was started on Abdominal x-rays reveal acute intestinal obstruc-
breast milk and did well. tion. Barium enema demonstrates multiple strictures
of the ileum, transverse and descending colon, and
rectosigmoid region, as well as perforation with intra-
CASE C-2 peritoneal contrast extravasation.
Emergency ileostomy is performed. Postopera-
M. P. is born at 34 weeks’ gestation, weighing 1200 tively, M. P. has a rocky course, complicated by mul-
g. His perinatal course is complicated by intrauter- tiple episodes of sepsis and feeding intolerance. He
ine growth restriction, hyperbilirubinemia, and poly- is given several courses of antibiotics and nearly 3
cythemia, requiring a single volume exchange trans- weeks of total parenteral nutrition.
fusion done through an umbilical venous catheter. Approximately 1 month after surgery, M. P. is
At 8 days of age, abdominal distention, hemato- noted to have direct hyperbilirubinemia, poor growth,
chezia, acidosis, and hypotension develop. NEC is hepatomegaly, and elevated liver function tests.
Work-up includes a negative hepatitis panel, normal REFERENCES

hepatic and gallbladder ultrasound, negative sepsis, The reference list for this chapter can be found
TORCH (toxoplasmosis, rubella, cytomegalovirus, online at www.expertconsult.com
and herpes simplex) work-ups, and a normal new-
born screen.
What is the most likely diagnosis?

1. Biliary atresia
2. TPN cholestasis
3. α1-Antitrypsin deficiency
4. Cystic fibrosis
Although all of the above are possible, the most
likely diagnosis is TPN cholestasis. It typically devel-
ops after 2 or more weeks of enteral fasting with TPN
providing the sole nutritional support. With initiation of
trophic feeding to enhance bile flow, TPN cholestasis
gradually resolves over 1 to 3 months. If symptoms
persist despite enteral feeding, a full diagnostic work-
up is indicated.
By 6 weeks after operation, M. P. has advanced
to full-volume enteral feedings with slow resolution
of the TPN cholestasis. However, he continues to
demonstrate poor growth and develops increasing
stool output through the ileostomy. He undergoes a
second surgery to reanastomose the bowel. Follow-
ing reanastomosis, M. P.’s nutritional status improves
and he is discharged to home. At 10 months of age,
he is tolerating a normal diet, although he remains at
the third percentile for all growth parameters.
Care of the Parents
Marshall H. Klaus, John H. Kennell,
and Jonathan M. Fanaroff
Unfortunately…a certain number of mothers abandon the babies whose needs they
8
have not had to meet, and in whom they have lost all interest. The life of the little
one has been saved, it is true, but at the cost of the mother.1
A renewed interest in the first minutes, task. If she senses the needs and responds
hours, and days of life has been stimu- to them in a sensitive and timely manner,
lated by several provocative behavioral and mother and infant will establish a pattern
physiologic observations in both mother of synchronized and mutually rewarding
and infant. These assessments and measure- interactions. It is our hypothesis that as the
ments have been made during labor, birth, mother-infant pair continues this dance
the immediate postnatal period, and the pattern day after day, the infant will more
beginning breast feedings. They provide a frequently develop a secure attachment,
compelling rationale for major changes in with the ability to be reassured by well-
care in the perinatal period for both mother known caregivers and the willingness to
and infant. Surprisingly, these findings form explore and master the environment when
a novel way to view the mother-infant dyad. caregivers are present.
To understand how these observations fit This chapter describes studies of the pro-
together, it is necessary to appreciate that cess by which a parent becomes attached to
the period of labor, birth, and the ensuing the infant, and the physiologic and behav-
several days can probably best be defined as ioral components in the newborn, and sug-
a “sensitive period.” During this time, the gests applications of these findings to the
mother and probably, the father, are espe- care of the parents of a normal infant, a pre-
cially open to changing their later behavior mature or malformed infant, and a stillbirth
with their infant depending on the quality or neonatal death.
of their care during the sensitive period.
Winnicott also described this period.2 PREGNANCY
He reported a special mental state of A mother’s and father’s actions and
the mother in the perinatal period that responses toward their infant are derived
involves a greatly increased sensitivity to, from a complex combination of their own
and focus upon, the needs of her baby. He genetic endowment, the way the infant
indicated that this state of “primary mater- responds to them, a long history of inter-
nal preoccupation” starts near the end of personal relations with their own families
pregnancy and continues for a few weeks and with each other, past experiences with
after the birth of the baby. A mother needs this or previous pregnancies, the absorp-
nurturing support and a protected environ- tion of the practices and values of their cul-
ment to develop and maintain this state. tures, and probably most importantly, how
This special preoccupation and the open- each was raised by his or her own mother
ness of the mother to her baby is probably and father. The parenting behavior of each
related to the bonding process. Winnicott woman and man, his or her ability to tol-
wrote that “Only if a mother is sensitized erate stresses, and his or her need for spe-
in the way I am describing, can she feel cial attention differ greatly and depend on
herself into her infant’s place, and so meet a mixture of these factors. Figure 8-1 is a
the infant’s needs.” In the state of “primary schematic diagram of the major influences
maternal preoccupation,” the mother is bet- on paternal and maternal behavior and the
ter able to sense and provide what her new resulting disturbances that we hypothesize
infant has signaled, which is her primary may arise from them.
201
202 CHAPTER 8 Care of the Parents
observations are beginning to piece together

Parental background Care practices some of the various phases and times that
are helpful for this process (Box 8-1). Preg-
nancy for a woman has been considered a
process of maturation,9,10 with a series of
adaptive tasks, each dependent on the suc-
Parent Infant cessful completion of the preceding one.
Many mothers are initially disturbed by
feelings of grief and anger when they become
pregnant, because of factors ranging from
economic and housing hardships to interper-
Effective caretaking Parenting sonal difficulties. However, by the end of the
and attachment disorders first trimester, the majority of women who
Figure 8-1. Algorithm of major influences on parent-infant initially rejected pregnancy have accepted it.
attachment and resulting outcomes. This initial stage as outlined by Bibring is the
mother’s identification of the growing fetus
as an “integral part of herself.”9
Included under parental background are The second stage is a growing perception
the parent’s care by his or her own mother, of the fetus as a separate individual, usually
genetics of parents, practices of their culture, occurring with the awareness of fetal move-
relationships within the family, experiences ment. After quickening, a woman generally
with previous pregnancies, and planning, begins to have some fantasies about what
course, and events during pregnancy. Strong the baby may be like; she attributes some
evidence for the importance of the effect of human personality characteristics, and
the mother’s own mothering on her care- develops a sense of attachment and value
taking comes from an elegant 35-year study toward the baby. At this time, further accep-
by Engel et al. that documented the close tance of the pregnancy and marked changes
correspondence between how Monica (an in attitude toward the fetus may be observed;
infant with a tracheoesophageal fistula) was unplanned, unwanted infants may seem
fed during the first 2 years of life,3 how she more acceptable. Objectively, the health
then cared for her dolls, and how as an adult worker usually finds some outward evidence
she fed her own four children. of the mother’s preparation in such actions
Included under care practices are the as the purchase of clothes or a crib, selecting
behavior of physicians, nurses, and hospital a name, and arranging space for the baby.
personnel, care and support during labor, The increased use of amniocentesis and
first days of life, separation of mother and ultrasound has appeared to affect parents’
infant, and rules of the hospital. perceptions of babies in a rather unexpected
Included under parenting disorders are fashion. Many parents have discussed the
the vulnerable child syndrome,4 child
abuse,5,6 failure to thrive,7 and some devel-
Box 8-1. Steps in Attachment
opmental and emotional problems in high-
risk infants.8 Other determinants—such as Before pregnancy
the attitudes, statements, and practices of Planning the pregnancy
the nurses and physicians in the hospital, During pregnancy
whether the mother is alone for short peri- Confirming the pregnancy
ods during her labor, whether there is sepa- Accepting the pregnancy
ration from the infant in the first days of Experiencing fetal movement
life, the nature of the infant, his or her tem- Beginning to accept the fetus as an individual
perament, and whether he or she is healthy,
sick, or malformed—will affect parenting Labor
behavior and the parent-child relationship. Birth
The most easily manipulated variables in After birth
this scheme are the separation of the infant Touching and smelling
from the mother and the practices in the Seeing the baby
hospital during the first hours and days of Breast feeding
life. It is here, during this period, that stud- Caring for the baby
ies have in part clarified some of the steps Accepting the infant as a separate individual
in parent-infant attachment. A diversity of
CHAPTER 8 Care of the Parents 203
disappointment they experienced when reduce the length of labor and perinatal
they discovered the sex of the baby. Half of problems for women and their infants dur-
the mystery was over. Everything was pos- ing childbirth.
sible, but once the amniocentesis was done
and the sex of the baby known, the range of EFFECTS OF SOCIAL
the unknown was considerably narrowed. AND EMOTIONAL SUPPORT
However, the tests have the beneficial result ON MATERNAL BEHAVIOR
of removing some of the anxiety about the This short, but highly significant time in a
possibility of the baby having an abnormal- woman’s life, has been explored in depth
ity. We have noted that, following the pro- because the care during labor appears to
cedure, the baby is sometimes named, and affect a mother’s attitudes, feelings, and
parents often carry around a picture of the responses to her family, herself, and espe-
very small fetus. This phenomenon requires cially her new baby to a remarkable degree.
further investigation to understand the sig- In a well-conducted trial of continuous
nificance of these reactions to the bonding social support in South Africa, both moth-
process. ers with and without doula support were
Cohen suggests the following questions interviewed immediately after delivery and
to learn the special needs of each mother11: 6 weeks later.14,15 Women who had doula
• How long have you lived in this imme- support during labor had significantly
diate area, and where does most of your increased self-esteem, believed they had
family live? coped well with labor, and thought the
• How often do you see your mother or labor had been easier than they had imag-
other close relatives? ined. Women who received this support
• Has anything happened to you in the past reported being less anxious 24 hours after
(or do you currently have any condition) birth compared with mothers without a
that causes you to worry about the preg- doula. Doula-supported mothers were sig-
nancy or the baby? nificantly less depressed 6 weeks postpar-
• What was the father’s reaction to your tum, as measured on a standard depression
becoming pregnant? scale, than mothers who had no doula.
• What other responsibilities do you have Also, doula-supported mothers had a signif
outside the family? icantly greater incidence of breast feeding
When planning to meet the needs of the without supplements (52% versus 29%),
mother, it is important to inquire about how and they breast fed for a longer period.
the pregnant woman was mothered—did The supported mothers said it took them
she have a neglected and deprived infancy an average of 2.9 days to develop a relation-
and childhood or grow up with a warm and ship with their babies compared with 9.8 days
intact family life? for the nonsupported mothers. This feeling
of attachment and readiness to fall in love
LABOR AND DELIVERY with their babies made them less willing to
Newton and Newton noted that those moth- leave their babies alone. They also reported
ers who remain relaxed in labor,12 who are picking up their babies more frequently
supported, and who have good rapport with when they cried than did nonsupported
their attendants, are more apt to be pleased mothers. The doula-supported mothers
with their infants at first sight. were more positive in describing the spe-
A recent Cochrane review looked at cial attributes of their babies than were the
the importance of continuous support for nonsupported mothers. A higher percent-
women during childbirth. Looking at 21 age of supported mothers not only consid-
trials involving 15,061 mothers, the results ered their babies beautiful, clever, healthy,
showed that women who had continuous and easy to manage, but also believed
social support during labor and birth had their infants cried less than other babies.
labors that were significantly shorter, were The supported mothers believed that their
more likely to have a spontaneous vagi- babies were “better” when compared with
nal birth, and less likely to have intrapar- a “standard baby,” whereas the nonsup-
tum analgesia.13 They also were less likely ported mothers perceived their babies as
to have a cesarean section or instrumented “almost as good as” or “not quite as good
vaginal birth, regional anesthesia, or a baby as” a “standard baby.” “Support group
with a low 5-minute Apgar score. This low- mothers also perceived themselves as closer
cost intervention may be a simple way to to their babies, as managing better, and as
communicating better with their babies and able to follow during the first hour of
than control-group mothers did,” the study life if maternal sedation has been limited
reported. A higher percentage of the doula- and the administration of eye drops or
supported mothers indicated that they were ointment is delayed.
pleased to have their babies, found becom- Additional information about this early
ing a mother was easier than expected, and period was provided by Wolff,19 who
thought that they could look after their described six separate states of conscious-
babies better than any other person could. ness in the infant, ranging from deep sleep
In contrast, the nonsupported mothers to screaming. The state in which we are
perceived their adaptation to motherhood most interested is state 4, the quiet, alert
as more difficult and believed that others state. In this state, the infant’s eyes are
could care for their baby as well as they wide open, and he or she able to respond
could. to his or her environment. The infant may
A most important aspect of emotional only be in this state for periods as brief
support during childbirth may be the most as a few seconds. However, Emde et al.
unexpected internalized one—that of the observed that the infant is in a wakeful
calm, nurturing, accepting, and holding state on the average for a period of 38 min-
model provided for the parents by the doula utes during the first hour after birth.20 It
during labor. Maternal care needs model- is currently possible to demonstrate that
ing; each generation is influenced from the an infant can see, has visual preferences,
care received by the earlier one. Social sup- has a memory for the mother’s face at
port appears to be an essential ingredient 4 hours of age, will turn his or her head to
of childbirth that was lost when birthing the spoken word, and moves in rhythm to
moved from home to hospital. the mother’s voice in the first minutes and
hours of life—a beautiful linking and syn-
THE DAY OF DELIVERY chronized dance between the mother and
Mothers after delivery appear to have com- infant. After this, however, the infant goes
mon patterns of behavior when they begin into a deep sleep for 3 to 4 hours.
to care for their babies in the first hour of Therefore, during the first 60 to 90 min-
life. Filmed observations reveal that when a utes of life, the infant is alert, responsive,
mother is presented with her nude,16 full- and especially appealing. In short, the
term infant in privacy, she begins with fin- infant is ideally equipped to meet his or her
gertip touching of the infant’s extremities parents for the first time. The infant’s broad
and within a few minutes proceeds to mas- array of sensory and motor abilities evokes
saging, encompassing palm contact of the responses from the mother and begins the
infant’s trunk. Mothers of premature infants communication that may be especially
also follow this sequence, but proceed at a helpful for attachment and the initiation of
much slower rate. Fathers go through some a series of reciprocal interactions.
of the same routines.17 Observations by Condon and Sander
A strong interest in eye-to-eye contact reveal that newborns move in rhythm
has been expressed by mothers of both full- with the structure of adult speech.21 Inter-
term and premature infants. Tape record- estingly, synchronous movements were
ings of the words of mothers who had found at 16 hours of age with both of the
been presented with their infants in pri- two natural languages tested, English and
vacy revealed that 73% of the statements Chinese.
referred to the eyes. The mothers said, “Let Mothers also quickly become aware of
me see your eyes” and “Open your eyes their infant. Kaitz et al. demonstrated that
and I’ll know you love me.” Robson has after only 1 hour with their infants in the
suggested that eye-to-eye contact appears first hours of life,22,23 mothers are able to
to elicit maternal caregiving responses.18 discriminate their own baby from other
Mothers seem to try hard to look “en face” infants. Parturient women know their
at their infants—that is, to keep their faces infant’s distinctive features after minimal
aligned with their baby’s so that their eyes exposure using olfactory and tactile cues
are in the same vertical plane of rotation (touching the dorsum of the hand), whereas
as the baby’s. Complementing the moth- discrimination based on sight and sound
er’s interest in the infant’s eyes is the early takes somewhat longer to develop. Fathers
functional development of the infant’s are good at quickly recognizing their new-
visual pathways. The infant is alert, active, born through visual-facial cues, though not
quite as good as mothers at recognizing to move toward the breast 30 to 40 minutes

olfactory cues.24 after birth.
WHEN DOES LOVE BEGIN? THE BREAST CRAWL

The first feelings of love for the infant are One of the most exciting observations
not necessarily instantaneous with the ini- made is the discovery that the newborn
tial contact. has the ability to find her mother’s breast
MacFarlane et al. helped to answer this all on her own and to decide for herself
question by asking 97 mothers, “When did when to take her first feeding. In order not
you first feel love for your baby?”25 The replies to remove the taste and smell of the moth-
were as follows: during pregnancy—41%; at er’s amniotic fluid, it is necessary to delay
birth—24%; first week—27%; and after the washing the baby’s hands. The baby uses
first week—8%. the taste and smell of amniotic fluid on her
In another study of two groups of pri- hands to make a connection with a certain
miparous mothers (n = 112 and n = 41), 40% lipid substance on the nipple related to the
recalled that their predominant emotional amniotic fluid.
reaction when holding their babies for the The infant usually begins with a time of
first time was one of indifference.26 The rest and quiet alertness, during which he
same response was reported by 25% of 40 rarely cries and often appears to take plea-
multiparous mothers. In both groups, 40% sure in looking at his mother’s face. Around
felt immediate affection. 30 to 40 minutes after birth, the newborn
begins making mouthing movements,
CARE OF THE NORMAL INFANT AND sometimes with lip smacking, and shortly
PARENTS FOLLOWING BIRTH after, saliva begins to pour down onto his
After birth, the newborn should be thor- chin.31 When placed on the mother’s abdo-
oughly dried with warm towels so as not to men, babies maneuver in their own ways to
lose heat, and once it is clear that he has reach the nipple. They often use stepping
good color and is active and appears nor- motions of their legs to move ahead, while
mal (usually within 5 minutes), he can horizontally moving toward the nipple,
go to his mother. At this time, the warm using small push-ups and lowering one arm
and dry infant can be placed between the first in the direction they wish to go. These
mother’s breasts or on her abdomen or, if efforts are interspersed with short rest peri-
she desires, next to her. The new NRP guide- ods. Sometimes babies change direction in
lines emphasize that babies who do not the midst of their journey. These actions
need resuscitation should not be separated take effort and time. Parents find patience
from their mother.27 worth every minute if they wait and observe
When newborns are kept close to their their infant on his first journey.
mother’s body or on their mother, the In Figure 8-2, one newborn is seen suc-
transition from life in the womb to exis- cessfully navigating his way to his moth-
tence outside the uterus is made much er’s breast. At 10 minutes of age, he first
easier for them. The newborn recognizes begins to move toward the left breast, but
his mother’s voice and smell,28,29 and her 5 minutes later, he is back in the midline.
body warms his to just the right tempera- Repeated mouthing and sucking of the
ture.30 In this way, the infant can experi- hands and fingers is commonly observed.
ence sensations somewhat similar to what With a series of push-ups and rest periods,
he felt during the last several weeks of he makes his way to the breast completely
uterine life. on his own, placing his lips on the areola
In the past, many caretakers believed that of the breast. He begins to suckle effectively
the newborn needs help to begin to nurse. and closely observes his mother’s face.
So often, immediately after birth, the baby’s In one group of mothers who did not
lips are placed near or on the mother’s nip- receive pain medication and whose babies
ple. In that situation, some babies do start were not taken away during the first hours
to suckle, but most babies just lick the nip- of life for a bath, vitamin K administra-
ple or peer up at the mother. They appear tion, or application of eye ointment, 15 of
to be much more interested in the mother’s 16 babies placed on their mother’s abdo-
face, especially her eyes, even though the men were observed to make the trip to their
nipple is right next to their lips. They most mother’s breast, latch on their own, and
commonly begin, when left on their own, begin to suckle effectively.32
thus reducing bleeding. The stimulation

and suckling also helps in the manufacture
of prolactin, and the suckling enhances the
closeness and new bond between mother
and baby. Mother and baby appear to be
carefully adapted for these first moments
together.
To allow this first intimate encounter,
the injection of vitamin K, application of
eye ointment, washing, and any measur-
ing of the infant’s weight, height, and head
circumference may be delayed for at least 1
hour. More than 90% of all full-term infants
A
are normal at birth. In a few minutes, they
can be easily evaluated to ensure that they
are healthy. They can then, after thorough
drying, be safely placed on their mother’s
chest if the parents wish.
The odor of the nipple appears to guide a
newborn to the breast.29,33 If the right breast
is washed with soap and water, the infant
will crawl to the left breast, and vice versa.
If both breasts are washed, the infant will
go to the breast that has been rubbed with
the amniotic fluid of the mother. The spe-
cial attraction of the newborn to the odor
of his mother’s amniotic fluid may reflect
B the time in utero when, as a fetus, he swal-
lowed the liquid. Although it is not breast
milk, amniotic fluid probably contains a
substance that is similar to a secretion of
the breast. Amniotic fluid on the infant’s
hands probably also explains part of the
interest in sucking the hands and fingers
seen in the photographs. This early hand-
sucking behavior is markedly reduced when
the infant is bathed before the crawl. With
all these innate programs, it almost seems as
if the infant comes into life carrying a small
computer chip with these instructions.
At a moment such as childbirth, we come
C
full circle to our biological origins. Many
Figure 8-2. A, Infant about 15 minutes after birth, sucking separate abilities enable a baby to do this.
on the unwashed hand and possibly looking at mother’s left Stepping reflexes help the newborn push
nipple. B, An arm push-up, which helps the infant to move to against his mother’s abdomen to propel him
mother’s right side. C, At 45 minutes of age, the infant moved toward the breast. Pressure of the infant’s
to the right breast without assistance and began sucking
feet on the abdomen may also help in the
on the areola of the breast. The infant has been looking at
the mother’s face for 5 to 8 minutes. (Photographed by
expulsion of the placenta and in reduc-
Elaine Siegel. From Klaus PH: Your amazing newborn, ing uterine bleeding. The ability to move
Cambridge, Mass, 1998, Perseus, pp 13, 16, 17.) his hand in a reaching motion enables the
baby to claim the nipple. Taste, smell, and
vision all help the newborn detect and find
This sequence is helpful to the mother the breast. Muscular strength in the neck,
as well, because the massage of the breast shoulders, and arms helps newborns to bob
and suckling induce a large oxytocin surge their heads and do small push-ups to inch
into her bloodstream, which helps contract forward and side to side. This whole sce-
the uterus, expelling the placenta and clos- nario may take place in a matter of minutes;
ing off many blood vessels in the uterus, it usually occurs within 30 to 60 minutes,
but it is within the capacity of the newborn. feedings every 4 hours, which was the cus-
It appears that young humans, like other tom throughout the United States at that
baby mammals, know how to find their time. In follow-up studies, 10 children in
mother’s breast. the routine care group experienced parent-
When the mother and infant are resting disorders, including child abuse, failure
ing skin-to-skin and gazing eye-to-eye, they to thrive, abandonment, and neglect during
begin to learn about each other on many the first 17 months of life compared with
different levels. For the mother, the first two children in the experimental group
minutes and hours after birth are a time who had 12 additional hours of mother-
when she is uniquely open emotionally to infant contact. A similar study in North
respond to her baby and to begin the new Carolina that included 202 mothers during
relationship. the first year of life did not find a statisti-
cally significant difference in the frequency
A SENSITIVE PERIOD? of parenting disorders7; 10 infants failed to
Many studies have focused on whether addi- thrive or were neglected or abused in the
tional time for close contact of the mother control group compared with seven in the
and infant alters the quality of attach- group that had extended contact. When the
ment.16,34,35 These studies have addressed results of these two studies are combined
the question of whether there is a sensitive in a metaanalysis (P = .054), it appears that
period for parent-infant contact in the first simple techniques, such as adding addi-
minutes, hours, and days of life that may tional early time for each mother and infant
alter the parents’ later behavior with their to be together and continuous rooming-in,
infant. In many biological disciplines, these may lead to a significant reduction in child
moments have been called sensitive periods. abuse. A much larger study is necessary to
However, in most of the examples of a sen- confirm and validate these relatively small
sitive period in biology, the observations studies.
are made on the young of the species rather Swedish researchers have shown that the
than on the adult. Evidence for a sensitive normal infant,30 when dried and placed
period comes from the following series of nude on the mother’s chest and then cov-
studies. Note that in each study, increasing ered with a blanket, will maintain his or
mother-infant time together or increased her body temperature as well as when elab-
suckling improves caretaking by the mother. orate, high-tech heating devices that usu-
In six of nine randomized trials of only ally separate the mother and baby are used.
early contact with suckling (during the first The same researchers found that when the
hour of life), both the number of women infants are skin-to-skin with their moth-
breast feeding and the length of their lac- ers for the first 90 minutes after birth, they
tation were significantly increased for early cry hardly at all compared with infants
contact mothers compared with women in who were dried, wrapped in a towel, and
the control group. placed in a bassinet. It is likely that each of
In addition, studies of Brazelton and oth- these features—the crawling ability of the
ers have shown that if nurses spend as little infant, the decreased crying when close to
as 10 minutes helping mothers discover the mother, and the warming capabilities
some of their newborn infant’s abilities,36 of the mother’s chest—are adaptive fea-
such as turning to the mother’s voice and tures that have evolved to help preserve the
following the mother’s face, and assist- infant’s life.
ing mothers with suggestions about ways When the infant suckles from the breast,
to quiet their infants, the mothers become it stimulates the production of oxytocin in
more appropriately interactive with their both the mother’s and the infant’s brains,
infants face-to-face and during feedings at and oxytocin in turn stimulates the vagal
3 and 4 months of age. motor nucleus, releasing 19 different gas-
O’Connor et al. carried out a randomized trointestinal hormones, including insulin,
trial with 277 mothers in a hospital that had cholecystokinin, and gastrin. Five of the 19
a high incidence of parenting disorders.37 hormones stimulate growth of the baby’s
One group of mothers had their infants and mother’s intestinal villi and increase
with them for 6 additional hours on the first the surface area and the absorption of cal-
and second day, but no early contact. The ories with each feeding.38 Stimuli for this
routine care group began to see their babies release are touch on the mother’s nipple
at the same age but only for 20-minute and the inside of the infant’s mouth. The
increased gut motility with each suckling between mother and baby. In humans,
may help remove meconium with its large there is a blood-brain barrier for oxytocin,
load of bilirubin. and only small amounts reach the brain via
These research findings may explain some the bloodstream. However, multiple oxyto-
of the underlying physiologic and behavioral cin receptors in the brain are supplied by
processes and provide additional support de novo oxytocin synthesis in the brain.
for the importance of 2 of the 10 caregiving Increased levels of brain oxytocin result in
procedures that the United Nations Interna- slight sleepiness, euphoria, increased pain
tional Children’s Emergency Fund (UNICEF) threshold, and feelings of increased love for
is promoting as part of its Baby Friendly Ini- the infant. It appears that, during breast
tiative to increase breast feeding: (1) early feeding, elevated blood levels of oxytocin
mother-infant contact, with an opportunity are associated with increased brain levels;
for the baby to suckle in the first hour, and women who exhibit the highest plasma
(2) mother-infant rooming-in throughout oxytocin concentration are the most sleepy.
the hospital stay. Measurements of plasma oxytocin lev-
Following the introduction of the Baby els in healthy women who had their babies
Friendly Initiative in maternity units in skin-to-skin on their chests immediately
several countries throughout the world, an after birth reveal significant elevations com-
unexpected observation was made. In Thai- pared with the prepartum levels and a return
land,39 in a hospital where a disturbing num- to prepartum levels at 60 minutes. For most
ber of babies are abandoned by their mothers, women, a significant and spontaneous peak
the use of rooming-in and early contact with concentration was recorded about 15 min-
suckling significantly reduced the frequency utes after delivery, with expulsion of the
of abandonment from 33 in 10,000 births placenta.42 Most mothers had several peaks
to 1 in 10,000 births a year. Similar observa- of oxytocin up to 1 hour after delivery. The
tions have been made in Russia, the Philipp vigorous oxytocin release after delivery and
ines, and Costa Rica, where early contact with breast feeding not only may help con-
and rooming-in were also introduced. tract the uterine muscle to prevent bleed-
These reports are additional evidence that ing, but may also enhance bonding of the
the first hours and days of life are a sensitive mother to her infant. These findings may
period for the human mother. This may be explain an observation made in France in
due in part to the special interest that moth- the 19th century when many poor mothers
ers have shortly after birth in hoping that were giving up their babies. Nurses recorded
their infant will look at them and to the that mothers who breast fed for at least
infant’s ability to interact in the first hour of 8 days rarely abandoned their infants. We
life during the prolonged period of the quiet hypothesize that a cascade of interactions
alert state. There is a beautiful interlocking between the mother and baby occurs during
at this early time of the mother’s interest in this early period, locking them together and
the infant’s eyes and the baby’s ability to ensuring further development of attach-
interact and to look eye-to-eye. ment. The remarkable change in maternal
A possible key to understanding what behavior with just the touch of the infant’s
is happening physiologically in these first lips on the mother’s nipple, the effects of
minutes and hours comes from investiga- additional time for mother-infant contact,
tors who noted that, if the lips of the infant and the reduction in abandonment with
touch the mother’s nipple in the first hour early contact, suckling, and rooming-in, as
of life, a mother will decide to keep her well as the elevated maternal oxytocin lev-
baby 100 minutes longer in her room every els shortly after birth in conjunction with
day during her hospital stay than another known sensory, physiologic, immunologic,
mother who does not have contact until and behavioral mechanisms all contribute to
later.40 This may be partly explained by the attachment of the parent to the infant.
the small secretions of oxytocin (the “love
hormone”) that occur in both the infant’s EARLY AND EXTENDED CONTACT
and mother’s brains when breast feeding FOR PARENTS AND THEIR INFANT
occurs. In sheep,41 dilation of the cervical Although debate continues on the inter-
os during birth releases oxytocin within pretation and significance of some of the
the brain which, acting on receptor sites, research studies regarding the effects of
is important for the initiation of maternal early and extended contact for mothers and
behavior and for the facilitation of bonding fathers on bonding with their infants, both
sides agree that all parents should be offered father more time to learn about their baby
such contact time with their infants. A and to gradually develop a strong tie in the
recent Cochrane Review looked at 30 studies first weeks of life.
involving 1925 participants (mother-infant From these many findings are the fol-
dyads) and concluded that early skin-to-skin lowing recommendations for changing the
contact for mothers and their healthy new- perinatal period for mother and infant.
borns reduced crying, improved mother- • Every mother should have continuous
baby interaction, kept the baby warmer, and physical and emotional support during
helped women to breast feed successfully.43 the entire labor by a knowledgeable, car-
On the basis of observations and the ing woman (e.g., doula, obstetric nurse, or
reports of parents, every parent has a task midwife) in addition to her partner.
to perform during the postpartum period. • Childbirth educators and obstetric care-
The mother, in particular, must look at and givers should discuss with every pregnant
“take in” her real live baby and then recon- woman the advantages of an unmedi-
cile the fantasy of the infant she imagined cated labor to avoid interference with the
with the one she actually delivered. infant’s ability to interact, self-attach, and
Evidence suggests that many of these successfully breast feed.
early interactions also take place between • Immediately after birth and a thorough
the father and his newborn child. Parke has drying, an infant who has good Apgar
demonstrated that when fathers are given scores and appears normal should be
the opportunity to be alone with their new- offered to the mother for skin-to-skin con-
borns,44 they spend almost exactly the same tact, with warmth provided by her body
amount of time as mothers in holding, and a light blanket covering the baby. The
touching, and looking at them. baby should not be removed for a bath,
How strongly should physicians and footprinting, or administration of vita-
nurses emphasize the importance of parent- min K or eye medication until after the
infant contact in the first hour and extended first hour. The baby thus can be allowed
visiting for the rest of the hospital stay? De- to decide when to begin his first feeding.
spite a lack of early contact experienced by • The central nursery should be used infre-
many parents in hospital births in the past, quently. All babies should room-in with
almost all these parents became bonded to their mothers throughout the short hos-
their babies. The human is highly adapt- pital course unless this is prevented by ill-
able, and there are many fail-safe routes to ness of mother or infant.
attachment. Parents who miss the bonding • Early and continuous mother-infant con-
experience can be assured that their future tact appears to decrease the incidence of
relationship with their infant can still devel- abandonment and increase the length
op as usual. Mothers who miss out on early and success of breast feeding. All moth-
and extended contact are often those at the ers should begin breast feeding in the first
limits of adaptability and who may benefit hour, nurse frequently, and be encour-
the most—the poor, the single, the unsup- aged to breast feed for at least the first 2
ported, and the teenage mothers. weeks of life, even if they plan to return
At least 60 minutes of early contact in to work. Early, frequent breast feeding
privacy should be provided, if possible, for has many advantages, including earlier
parents and their infant to enhance the removal of bilirubin from the gut as well
bonding experience. If the health of the as aiding in mother-infant attachment.
mother or infant makes this impossible,
then discussion, support, and reassurance THE SICK OR PREMATURE INFANT
should help the parents appreciate that Although parental visiting has been permit-
they can become as completely attached to ted in the intensive care nursery, a number
their infant as if they had the usual bond- of studies have revealed that most par-
ing experience. The infant should only be ents continue to suffer severe emotional
with the mother and father if she is known stress.45-48 Harper et al. noted that,46 even
to be physically normal and if appropri- when parents have close contact with their
ate temperature control is used. The baby infants in the intensive care nursery, they
should remain with the mother as long as experience prolonged stress.
desired throughout the hospital stay so that Newman described “coping through com
the mother and the baby can get to know mitment” as an intense yet variable involve-
each other. This permits both mother and ment in the care of a low-birth-weight
infant.48 In contrast, “coping through dis- INTERVENTIONS FOR FAMILIES

tance” was a slower acquaintance process in OF PREMATURE INFANTS
which the parents expressed fear, anxiety,
and at times denial before they accepted the TRANSPORTING THE MOTHER TO BE
surviving infant. NEAR HER SMALL INFANT
Highly interacting mothers visit and tele- With the development of high-risk perina-
phone the nursery more frequently while tal centers, an increasing number of moth-
the infants are hospitalized and stimulate ers are transported to the maternity division
their infants more at home. Mothers who of hospitals with a neonatal intensive care
stimulate their infants very little in the nurs- nursery just before delivery or shortly after.
ery also visit and telephone less frequently If there is not sufficient time to arrange for
and provide only minimal stimulation to her transport before she gives birth, it is
them at home. Most perceptively, Minde strongly recommended that the mother be
et al. noted that mothers who touched and moved as soon as possible.
fondled their infants more in the nursery
had infants who opened their eyes more ROOMING-IN FOR THE PARENT
often.49 He and his associates observed OF A PREMATURE INFANT
the contingency between the infant’s eyes When Tafari and Ross in Ethiopia permitted
being open and the mother’s touching mothers to live within their crowded pre-
and between gross motor stretches and the mature unit 24 hours each day,52 they were
mother’s smiling. They could not determine able to care for three times as many infants
to what extent the sequence of touching in their premature nursery, and at the end
and eye opening was an indication of the of 1 year, the number of surviving infants
mother’s primary contribution or whether had increased 500%. Mother-infant pairs
it was initiated by the infant. Thus, New- were discharged when the infants weighed
man and Minde et al. predict that mothers an average of 1.7 kg, and most infants were
who become involved with,49,48 interested breast fed. Before this, most of the infants
in, and anxious about their infants in the had gone home and were bottle fed, and
intensive care nursery will have an easier usually died of intercurrent respiratory and
time when the infant is taken home. gastrointestinal infections. When the cost of
Field has demonstrated the close con- prepared milk amounts to a high proportion
nection between what a mother does and of the parents’ weekly income, policies in
her infant’s arousal level.50 Whereas most support of the mother rooming-in and breast
mothers of full-term babies adopt a moder- feeding in premature nurseries have a direct
ate level of activity that is associated with impact on infant mortality. In several other
optimal arousal in their babies, some moth- countries throughout the world, including
ers of “preemies” either overreact or under- Argentina, Brazil, Estonia, and South Africa,
react. Field found that mothers of premature mothers of premature infants live in a room
infants who were overreactive during early adjoining the premature nursery or they
face-to-face interactions were more likely to room in. This arrangement appears to have
be overprotective and over-controlling dur- multiple benefits. It allows the mother to
ing interactions with their infants 2 years continue producing milk, permits her to take
later.50 on the care of the infant more easily, greatly
reduces the caregiving time required of the
staff for these infants, and allows a group of
EDITORIAL COMMENT: Recent studies have found an
mothers of premature infants to talk over
alarmingly high rate of psychologic pathology and trau-
their situation and gain from discussion and
matic stress in parents of infants in the NICU. Lefkowitz
mutual support. This procedure is probably
et al. had 86 mothers and 41 fathers complete meas-
appropriate for 50% of the world.
ures of acute stress disorder (ASD) and found that
Torres,53 in a special care unit in the
3 to 5 days after the infant’s NICU admission,10 35% of
slums of Santiago, Chile, achieved excel-
mothers and 24% of fathers met diagnostic criteria for
lent, low perinatal mortality and morbidity
acute stress disorder. Additionally, 30 days later, 15%
rates by placing special care units for low-
of mothers and 8% of fathers actually met diagnostic
birth-weight infants in the maternity unit,
criteria for posttraumatic stress disorder. In some units,
thus maintaining babies under professional
a psychiatrist is available to regularly meet with parents
observation for only as long as necessary.
who wish to speak with him/her; this is an extremely
Technological improvements and the
helpful and necessary program.51
resulting ability to continuously monitor
sick premature infants even from a distance The self-help parents also touched, talked,
has allowed single-room neonatal intensive and looked at their infants more in the en
care units (NICUs) to become a reality, and face position and rated themselves as more
parents are encouraged to room-in with competent than the control group on infant
their babies in the NICU. care measures. The mothers in the group
continued to show more involvement with
NESTING their babies during feedings and were more
In the United States, James and Wheeler concerned about their general development
first described the successful introduction of 3 months after their discharge from the
a care-by-parent unit to provide a homelike nursery.
caretaking experience.54 Parents of prema-
ture infants received nursing support before KANGAROO BABY CARE
discharge. Allowing a mother to hold the infant skin-
For several years “nesting” has been to-skin for prolonged periods in the hos-
studied—namely, permitting mothers to pital is known as kangaroo care and it has
live in with their infants before discharge. salutary effects (Fig. 8-3). Several trials have
When babies reached 1.72 to 2.11 kg, each noted that, if the usual precautions are
mother was given a private room with taken, such as hand washing, there is no
her baby where she provided all caregiv- increase in the infection rate or problems
ing. Impressive changes in the behavior of in oxygenation, apnea, or temperature con-
these women were observed clinically. Even trol. A significant medical benefit appears
though the mothers had fed and cared for to be a significant increase in the mother’s
their infants in the intensive care nursery milk supply and success at nursing.55,56 A
on many occasions before living-in, eight of recent randomized controlled trial in Mad-
the first nine mothers did not sleep during agascar also found a significantly increased
the first 24 hours so they could learn more proportion of exclusive breast feeding at
about their infant’s behavior. However, in 6 months of age with earlier initiated contin-
the second 24-hour period, the mothers’ uous kangaroo mother care.57 Several stud-
confidence and caretaking skills improved ies noted that the mother’s own confidence
greatly. At this time, mothers began to dis-
cuss the proposed early discharge of their
infants and, often for the first time, began
to make preparations at home for their
arrival. Several mothers insisted on taking
their babies home earlier than planned.
Early discharge, preceded by a period of
isolation of the mother and infant, may
help to normalize mothering behavior in
the intensive care nursery. Encouraging the
increasing possibilities for mother-infant
interaction and total caretaking may reduce
the incidence of mothering disorders among
mothers of small or sick premature infants.
PARENT GROUPS
A number of NICUs have formed groups of
parents of premature infants who meet once
each week or more often for 1- to 2-hour
discussions. Documented clinical reports
from these centers suggest that parents find
support and considerable relief in being able
to talk with each other and to express and
compare their inner feelings.
Minde et al.47 in a controlled study of
a self-help group, reported that parents
who participated in the group visited their
infants in the hospital significantly more Figure 8-3. Small immature infant (on ventilator)
often than did parents in the control group. skin-to-skin with his mother.
in her caretaking improved along with an adapting to premature infants who are
eagerness for discharge, and many women more responsive.
reported feeling an increased closeness to Further emphasizing the importance of
the infant compared with a control group the home and family in the final result is
of mothers. At the first skin-to-skin experi- a very large, randomized, well carried out
ence, the mother is usually tense, so it is trial (985 premature infants) in eight cen-
best for the nurse to stay with her to answer ters in the United States.60 The study dem-
questions and make any necessary adjust- onstrated that a comprehensive program
ments in position and ensure that warmth with weekly home visits in the first year of
is maintained. A few mothers find that life; group meetings for mothers during all 3
one such experience is enough. However, years; and daily attendance by the child at
most mothers find repeated kangaroo care a developmental center from 1 to 3 years of
experiences especially pleasurable. How- age resulted in a significant improvement in
ever, there is not adequate information intelligence quotient (IQ) scores, as well as
to support discharge of appropriate-for- reports by mothers of fewer developmental
gestational-age (AGA) infants weighing less problems.
than 1700 g on solely kangaroo care with- In assessing the effects of any interven-
out daily nursing visits. tion following discharge from the hospital,
it is important to remember that more than
EARLY DISCHARGE one half the variance in IQ can be accounted
Derbyshire and associates have studied for by social conditions that include paren-
discharging premature infants when they tal occupation, education, minority status,
weighed about 2 kg and found no delete- anxiety, and mental illness. As the social
rious effects associated with this early dis- conditions for the population are improved,
charge.58 To make this workable and to so will the outcome for the low-birth-weight
prevent complications, experienced person- infant.
nel should visit the home to organize the
families and, after discharge, to help super- FAMILY-CENTERED CARE IN THE NICU
vise infant care. Studies of early discharge Providing the optimal hospital environ-
have not revealed any adverse effects on the ment for a critically ill newborn clearly
physical health of the infants. involves a great deal of care and consider-
Another approach for the mother with ation for the needs of the family as well.
emotional distress after the birth of a small Modern NICU design and planning ideally
premature infant is to alter the responses incorporate features such as healing art,
of the developing infant, an area of intense family/social spaces, and respite areas for
study by Als et al.59 In a series of creative stud- staff.61 One randomized, controlled trial in
ies, they demonstrated that individualized Stockholm found that allowing parents to
nursing care plans for high-risk, low-birth- stay in the NICU reduced the total length
weight infants involving their behavioral of hospital stay by 5.3 days.62 Every facil-
and environmental needs remarkably altered ity, no matter what level of resources, can
their outcome. Their requirements for light, take steps to improve the environment for
sound, position, and detailed nursing were infants and their families by developing a
only developed after a sensitive, detailed unit vision and philosophy that promotes
behavioral assessment. the principles of family-centered care. Mul-
In randomized trials using the preceding tidisciplinary groups have created tools
procedure, infants receiving individualized and lists of potentially better practices for
behavioral management required shorter family-centered care.63
stays on a respirator and fewer days on sup- Some practices that may be considered for
plemental oxygen; their average daily wak- implementing family-centered care include
ing time increased; they were discharged the following64:
earlier; and they had a lower incidence • The unit vision and philosophy should
of intraventricular hemorrhage. In addi- clearly articulate the principles of family-
tion, following discharge, their behavioral centered care.
development progressed more normally • Leaders at the center and the unit level
and their parents more easily developed should clearly promote the principles of
ways of sensing their needs and respond- family-centered care.
ing and interacting with them in a pleasur- • Parents are not “visitors.” Rather, parents
able fashion. Parents have an easier time should be treated as essential components
of the care team. Policies should be baby’s strength and healthy features may
revised to reflect this view. “Visiting Poli- be long remembered and appreciated.
cies” should be revised to address nonpar- • The father should be encouraged to fol-
ent family members and friends, whereas low the transport team to the hospital so
policies related to parents should be more he can see what is happening with his
appropriately addressed as participants baby. He uses his own transportation so
in care. that he can stay in the premature unit for
• Neonatal care is multidisciplinary and 3 to 4 hours. This extra time allows him
based on mutual respect among provid- to get to know the nurses and physicians
ers for their roles and expertise. Parents in the unit, to find out how the infant is
are integral to care and should be encour- being treated, and to talk with the physi-
aged to participate in patient care rounds, cians about what they expect will happen
communication with personnel at the with the baby in the succeeding days. He
change of shifts, and in the bedside care can help by acting as a link between the
of their infant. Parents should have access NICU and his family by carrying informa-
to information in their infant’s medical tion back to the mother. He should visit
record, and many units have initiated par- the baby in the NICU before visiting the
ent documentation into the record. mother so that he can let her know how
• The physical environment should provide the baby is doing. Taking pictures, even if
for the needs of parents. Parents’ needs for the infant is on a respirator, allows him to
accessing information, rest, nutrition, pri- show and describe to the baby’s mother
vacy, childcare for siblings, and support in detail how the baby is being cared for.
for their infants by breast milk pumping Mothers often tell us how valuable the
are often inadequately addressed. picture is in allowing them to maintain
• Nursery staff should receive the support some contact with the infant, even while
they need to provide optimal family- physically separated.
centered care. This support includes an • Transporting the mother and baby together
environment that allows staff a time to to the medical center that contains the
rest to meet their own needs and ongo- intensive care nursery should be encour-
ing education and resources to support aged for its immediate and long-term
family-centered care. benefits.
Families should be incorporated at various • The intensive care nursery should be
levels as advisors. The perspective of expe- open for parental visiting 24 hours each
rienced families should be integral to the day and should be flexible about visits
unit administrative activities. These could from others such as grandparents, sup-
include parents as teachers during orienta- portive relatives, and sometimes siblings.
tion and continuing education of staff, and If proper precautions are taken, infection
parent advisory committees to collaborate transmission will not be a problem.
in planning of new policies or space and • Communication is essential. The health
ongoing quality improvement activities. care workers should communicate with
the mother about her condition and
PRACTICAL HINTS FOR PARENTS about the baby’s condition. This is impor-
OF SICK OR PREMATURE INFANTS tant before, during, and after the birth
• The obstetrician of a high-risk mother of the baby, even if the information is
should consult the pediatrician early and brief and incomplete. Clinically, there
continue to involve him or her in deci- may be devastating and lasting unto
sions and plans for the management of ward effects on the mothering capacity
the mother and baby. of women who have been frightened by a
• If the baby must be moved to a hospital physician’s pessimistic outlook about the
with an intensive care unit, it is always chance of survival and normal develop-
helpful to give the mother a chance to see ment of an infant. For example, when the
and touch her infant, even if the baby has newborn premature baby is doing well,
respiratory distress and is in an oxygen but the mother is told by a physician that
hood. The house officer or the attending there is a likelihood that the baby may
physician should stop in the mother’s not survive, the mother will often show
room with the transport incubator and evidence of mourning (as if the baby were
encourage her to touch her baby and look already dead) and reluctance to “become
at her at close hand. A comment about the attached” to her baby. Such mothers may
refuse to visit or will show great hesitation possibility of death or brain damage can
about any physical contact. When dis- never be completely erased. Remember,
cussing such a situation with the physi- words are like a sword, and families remem-
cian who has spoken pessimistically with ber forever the remarks of their caregivers.
the mother, it is important to share all Remember too, nonverbal communica-
concerns with her so that she will be pre- tion is also important and the demeanor
pared in case of a bad outcome. This may of the caregivers will affect the response to
be acceptable once there is a close and information.
firm bond between the mother and infant • Before the mother comes to the neonatal
(which may only occur after an infant has unit, the nurse or physician should describe
been home for several months). However, in detail what the baby and the equipment
while the ties of affection are still fragile will look like. When she makes her first
and forming, they can be easily inhib- visit, it is important to anticipate that she
ited, altered, or possibly permanently may become distressed when she looks at
damaged. Physicians should be truthful her infant. Always have a stool nearby so
because parents will quickly sense their that she can sit down, and a nurse stays at
true feelings, but statements must be based her side during most of the visit, describ-
on the facts of the current situation, not ing in detail the procedures being carried
on improbable outcomes that are causing out, such as the monitoring of respiration
concern for the physician. The physician and heart rate. The nurse should be nearby
should be forthright about all the medical so questions may be answered and support
conditions and express appropriate con- given during the difficult period when the
cern related to these problems. Describe mother first sees her infant.
what the infant looks like to the medi- • It is important to remember that feel-
cal team and how the infant will appear ings of love for the baby are often elicited
physically to the mother. Rather than talk through contact. Therefore, turn off the
about chances of survival and giving per- lights and remove the eye patches from
centages, stress that most babies survive an infant under phototherapy lights, so
despite early and often worrisome prob- that the mother and infant can see each
lems. Do not emphasize problems that other.
may occur in the future. Try to anticipate • When the immature infant has passed
common developments (e.g., the need for the acute phase, both the father and the
bilirubin reduction lights for jaundice in mother should be encouraged to touch,
small premature infants). massage, and interact with their infant.
• It is useful to talk with the mother and This helps the parents get to know the
father together. When this is not possible, baby, reduces the number of breathing
it is often wise to talk with one parent pauses (if this is a problem), increases
on the telephone in the presence of the weight gain, and hastens the infant’s dis-
other. At least once each day discuss how charge from the unit. Initially, if the infant
the child is doing with the parents; talk is acutely ill, touching and fondling some-
with them at least twice each day if the times results in a decrease in the level of
child is critically ill. It is essential to find blood oxygen; therefore, parents should
out what the mother believes is going to begin this contact when the infant is sta-
happen or what she has read about the ble and the nurse or physician agrees that
problem. Move at her pace during any the infant is ready. Firm massage of pre-
discussion. term infants 15 minutes three times a day
• The physician should not relieve his anxi- results in markedly improved growth, less
ety by burdening the family with unnec- stress behavior, improved performance on
essary concerns. For example, if there is a the Brazelton Neonatal Behavior Assess-
possibility that the child has Turner syn- ment scale, and better performance on a
drome, it is not necessary to share this with developmental assessment at 8 months.65
the parents while the infant is still acutely • The mother and father can receive feed-
ill with other problems and while affec- back from their baby in response to their
tional bonds are still weak. If the physician caregiving. If the infant looks at their eyes,
is worried about a slightly elevated biliru- moves in response to them, quiets down,
bin level that would respond promptly to or shows any behavior in response to
phototherapy, it is not necessary to dwell their efforts, the parents’ feeling of attach-
on kernicterus. Once mentioned, the ment is encouraged. Practically speaking,
this means that the mother must catch the physician who will care for the affected
the baby’s glance and be able to note child and his family. Although previous
that some maneuver on her part, such as investigators agree that the child’s birth
picking up the baby or making soothing often precipitates major family stress,66
sounds, actually triggers a response or qui- relatively few have described the process of
ets the baby. Suggest to parents, therefore, family adaptation during the infant’s first
that they think in terms of trying to send year of life.66 Solnit and Stark’s conceptu-
a message to the baby and of picking one alization of parental reactions emphasized
up from them in return. Small premature that a significant aspect of adaptation is
infants do see and are especially inter- the mourning that parents must undergo
ested in patterned objects, can hear, and for the loss of the normal child they had
evidence suggests they will benefit greatly expected.67 Observers have also noted
from receiving messages. pathologic aspects of family reactions,
• Continue to study interventions such as including the chronic sorrow that envelops
rooming-in, nesting, and early discharge the family of a defective child.68 Less atten-
as well as transporting a healthy prema- tion has been given to the more adaptive
ture infant to be with his mother. It is aspects of parental attachment to children
necessary to test these various interven- with malformations.
tions in different hospital settings and to Parental reactions to the birth of a child
evaluate their ability to reduce the severe with a congenital malformation appear to
anxiety that many parents experience follow a predictable course. For most par-
during the prolonged hospitalization and ents, initial shock, disbelief, and a period
the early days following discharge. of intense emotional upset (including sad-
• Nurses should support and encourage ness, anger, and anxiety) are followed by
mothers during these early days and a period of gradual adaptation, which is
weeks.1 The nurse’s guidance in helping marked by a lessening of intense anxiety
a mother with simple caregiving tasks and emotional reaction (Fig. 8-4). This
can be extremely valuable in helping her adaptation is characterized by an increased
to overcome anxiety. In this sense, the satisfaction with and ability to care for the
nurse assumes the role of the mother’s baby. These stages in parental reactions are
own mother and contributes much more similar to those reported in other crises,
than teaching her basic techniques of such as those that occur with terminally ill
caregiving. children. The shock, disbelief, and denial
• To begin an intervention with parents reported by many parents seem to be an
early, it is necessary to identify high-risk understandable attempt to escape the trau-
parents who are having special difficul- matic news of the baby’s malformation,
ties in adapting. Generally, these parents news so at variance with their expecta-
visit rarely and for short periods,18 appear tions that it is impossible to register except
frightened, and do not usually engage the gradually.
medical staff in any questioning about
the infant’s problems. Sometimes the par-
ents are hostile or irritable and show inap-
propriately low levels of anxiety. I.Shock
• As a further understanding of the process V. Reorganization
by which normal mothers and infants
Intensity of reaction
interact with each other during the first

II. Denial III. Sadness and anger
months and year of life is developed, it
appears that some recommendations for
stimulation may be detrimental to nor-
mal development. Rather than suggest-
ing stimulation, it may be important for IV.
Equilibrium
a mother naturally and unconsciously to
use imitation to learn about and get to
know her own infant. Relative time duration
Figure 8-4. Hypothetical model of normal sequence of
CONGENITAL MALFORMATIONS parental reactions to birth of malformed infant. (Adapted
The birth of an infant with a congenital mal- from Drotar D, Baskiewicz A, Irwin N, et al: Pediatrics
formation presents complex challenges to 51:710, 1975. Reproduced by permission of Pediatrics.)
The intense emotional turmoil described the mother-child relationship following

by parents who have produced a child with the stresses associated with the news of the
a congenital malformation corresponds to a child’s anomaly and, in many instances,
period of crisis (defined as “upset in a state the separation of mother and child in the
of equilibrium caused by a hazardous event hospital. Lampe et al. noted a significantly
that creates a threat, a loss, or a challenge for greater amount of visiting if an infant with
the individual”). A crisis includes a period an abnormality had been at home for a short
of impact, an increase in tension associated while before surgery for a cleft lip repair.69
with stress, and finally a return to equilib-
rium. During such crisis periods, a person is PRACTICAL SUGGESTIONS FOR
at least temporarily unable to respond with PARENTS OF MALFORMED INFANTS
his or her usual problem-solving activities • If medically feasible, it is far better to leave
to solve the crisis. Roskies note a similar the infant with the mother and father for
“birth crisis” in her observations of moth- the first 2 to 3 days or to discharge them.
ers of children with limb defects caused by If the child is rushed to the hospital where
thalidomide.66 special surgery will eventually be done,
With the birth of a child with a malfor- the mother and father will not have
mation, the mother must mourn the loss of enough opportunity to become attached
her expected normal infant.67 In addition, to her. Even if immediate surgery is neces-
she must become attached to her actual sary, as in the case of bowel obstruction,
living, damaged child (Fig. 8-5). However, it is best to bring the baby to the mother
the sequence of parental reactions to the first, allowing her to touch and handle
birth of a baby with a malformation differs her, and to point out to her how normal
from that following the death of a child in her baby is in all other respects.
another respect. Because of the complex • The parents’ mental picture of the anom-
issues raised by the continuation of the aly may often be far more alarming than
child’s life and hence the demands of his the actual problem. Any delay greatly
physical care, the parents’ sadness, which heightens their anxiety and causes their
is initially important in their relationship imaginations to run wild. Therefore, it
with the child, diminishes in most instances is helpful to bring the baby to both par-
when they take over the physical care. Most ents when they are together as soon after
parents reach a point at which they are delivery as possible.
able to care adequately for their child and • Parents should not be given tranquiliz-
to cope effectively with disrupting feelings ers, which tend to blunt their responses
of sadness and anger. The mother’s initia- and slow their adaptation to the problem.
tion of the relationship with her child is a However, a sedative at night is sometimes
major step in the reduction of anxiety and helpful.
emotional upset associated with the trauma • Parents who are adapting reasonably well
of the birth. As with normal children, the often ask many questions and indeed at
parents’ initial experience with their infant times appear to be almost over-involved
seems to release positive feelings that aid in clinical care. There is more concern
about the parents who ask few questions
and who appear stunned or overwhelmed
Mother’s by the problem. Parents who become
mental image involved in trying to find out what pro-
(during pregnancy) Real baby cedures are best and who ask many ques-
tions about care are sometimes frustrating,
but often adapt best in the end.
• It best to move at the parents’ pace. It is
Happy, beneficial to be a good listener, ask the
beautiful parents how they view their infant, and
active boy to express their concerns, which can then
(blue-eyed) be addressed.
• Each parent may move through the pro-
cess of shock, denial, anger, guilt, and
Figure 8-5. Change in mental image that mother with adaptation at a different pace. If the par-
malformed baby must make following delivery. Normal ents are unable to talk with each other
mental portrait must be changed to that of her real baby. about the baby, their own relationship
may be disrupted. Use the process of early abdomen; lack of muscular power; and
crisis intervention and meet several times an intense subjective distress described as
with the parents. During these discussions, tension or mental pain
ask the mother how she is doing, how she • Preoccupation with the image of the de
feels the father is doing, and how he feels ceased infant
about the infant. Then reverse the ques- • Feelings of guilt and preoccupation with
tions and ask the father how he is doing one’s negligence or minor omissions
and how he thinks the mother is progress- • Feelings of hostility toward others
ing. Many times a parent is surprised by • Breakdown of normal patterns of conduct
the responses of his or her partner. The Originally it was believed that loss of
hope is that the parents not only will an infant was similar to the loss of a close
think about their own reactions, but also relative; however, based on clinical stud-
will begin to consider each other’s. For fur- ies and observations, it fits far more closely
ther discussion on this subject, see Case 2. with the concepts proposed by Furman72
• One of the major goals of postpartum and Lewis.73 Furman eloquently notes these
discussions is to keep the family together reactions:
during this early period and in subsequent Internally, the mourning process consists
years. This is best done by working hard of two roughly opposing mechanisms. One
to bring out issues early and by encour- is the generally known process of detach-
aging the parents to talk about their dif- ment, by which each memory that ties
ficult thoughts and feelings as they arise. the family to the person who is deceased
It is best for them to share their problems has to become painfully revived and pain-
fully loosened. This is the part of the pro-
with each other. Some couples who do cess that involves anger, guilt, pain, and
not seem to be close previously may move sadness. The second process is commonly
closer together as they work through the called “identification.” It is the means by
process of adaptation. As with any pain- which the deceased or parts of him are
ful experience, the parents may be much taken into the self and preserved as part of
stronger after they have gone through the self, thereby soothing the pain of loss.
these reactions together. It is helpful In many instances, a surviving marriage
when the father stays with his partner partner takes over hobbies and interests
during the hospitalization. Sometimes the of the deceased spouse. These identifica-
stresses of having a malformed, sick baby tions soothe the way and make the pain of
detachment balanced and bearable.
will ultimately disrupt the relationship of For the surviving parents, the death of a
the parents. newborn is special in several ways. Because
mourning is mourning of a separate per-
STILLBIRTH OR DEATH son, the process can apply only to that
OF A NEWBORN small part of the relationship to the new-
Despite the advances in obstetrical and neo- born that was characterized by the love of
natal care, many mothers encounter a great a separate person, but there has not been
disappointment with an early abortion or time to build up strong ties and memories
the perinatal loss of an infant. A mourn- of mutual living. It is also not possible for
ing reaction in both parents after the death parents—adults functioning in the adult
world—to take into themselves any part
of a newborn is universal.70 Whether the of a helpless newborn and make it adap-
baby lives 1 hour or 2 weeks, whether the tively a part of themselves; the mecha-
baby is a nonviable 400 g, or weighs 4000 g, nism of identification does not work. But
whether or not the baby was planned, and what about the part of the newborn that
whether or not the mother has had physi- was still part of the self and that cannot be
cal contact with her baby, clearly identifi- mourned? To understand this part, one has
able mourning will be present. Mothers and to look at the different process by which
fathers who have lost a newborn show the individuals cope with a loss of a part of the
same mourning reactions as those reported self (e.g., amputation or loss of function).
by Lindemann,71 who studied survivors of Insofar as the newborn remains a part of
the parent’s self, the death has to be dealt
the Coconut Grove fire. Lindemann con- with as would the amputation of a limb or
cludes that normal grief is a definite syn- the loss of function of the parent’s body.
drome. It includes the following aspects: Detachment is the mechanism with which
• Somatic distress with tightness of the the victim deals with such tragedies, but it
throat, choking, shortness of breath, need is detachment of a different kind. Accep-
for sighing, and an empty feeling in the tance that one will never ever again have
that part of oneself is very different from before the birth of a baby often have such
the detachment that deals with the mem- strong feelings after an infant’s death that
ories of living together with a loved one. they are unable to share their thoughts and,
The feelings that accompany this detach- therefore, have an unsatisfactory resolution
ment are similar in kind and intensity:
to their grieving. In the United States, it is
anger, guilt, fury, helplessness, and hor-
ror. In the case of the loss of a part of the expected that men will be strong and not
self, however, they are quite unrelieved by show their feelings, so a physician should
identification. encourage a father and mother to talk
Next, with such a tragedy there must be together about the loss and advise them not
a readjustment in one’s self-image. It is, to hold back their responses—“Cry when
however, altogether different to have to you feel like crying.” Unless told what to
readjust to thinking of oneself as an imper- expect, their reactions may worry and per-
fect human being, a human being that plex them, and this may tend further to
cannot walk or cannot see. That is a pain disturb the preexisting father and mother
of a different kind, and the feelings that
relationship.
accompany it are emptiness, loss of self-
esteem, and feeling low. Because the inter- At the time of the baby’s death, it is
nal self never materialized in those arms important to tell the parents together
and has not had a chance to be detached, about the usual reactions to the loss of a
it is very different from the process of child and the length of time these last. It
mourning. is desirable to meet a second time with
These feelings are made particularly dif- both parents before discharge to go over
ficult because people around the parents the same suggestions, which may not have
are not there to help. At a conscious level, been heard or may have been misunder-
people say they simply do not understand stood under the emotional shock of the
about losing part of the self, and, indeed,
baby’s death. The pediatrician or social
they do not. Subconsciously, they under-
stand it all too well. It fills them with fear worker should plan to meet with the par-
and anxiety and makes them turn away. ents together again 3 or 4 months after the
Parents of a dead newborn often experi- death to check on the parents’ activities
ence this isolation. They quite often are and on how the mourning process is pro-
shunned, and they may not rely on the ceeding. The autopsy findings may be dis-
sympathy that is usually accorded the cussed and any further questions asked by
bereaved. the parents may be addressed. At this visit,
This grief syndrome may appear imme- the pediatrician or social worker should be
diately after a death or may be delayed or alert for abnormal grief reactions, which,
apparently absent. Those who have studied if present, may guide the physician to
mourning responses have indicated that a refer the parents for psychiatric assistance.
painful period of grieving is a normal and It is important that these recommenda-
necessary response to the loss of a loved tions do not become an exact prescrip-
one and the absence of a period of grieving tion for every parent. As noted by Leon,75
is not a healthy sign but rather a cause for “Such protocols can lead to a regimented
alarm. assembly-line approach—which impedes
Without any therapeutic intervention, attempts to attune to parents individually
a tragic outcome for the mother has been and empathetically—the very essence of
shown in one third of the perinatal deaths. providing support.”
Cullberg found that 19 of 56 mothers stud- Lindemann noted that pathologic mourn
ied 1 to 2 years after the deaths of their ing reactions represent distortion of normal
neonates had developed severe psychiatric grief. On the basis of his observations, he
disease (psychoses, anxiety attacks, pho- lists 10 such reactions.71
bias, obsessive thoughts, and deep depres- • Overactivity without a sense of loss
sions).74 Because of the disastrous outcome • Acquisition of symptoms belonging to
in such a high proportion of mothers, it is the last illness of the deceased
necessary to examine in detail how to care • Psychosomatic reactions such as ulcerative
for the family following a neonatal death. colitis, asthma, or rheumatoid arthritis
In observations of parents who have lost • Alterations in relation to friends and rela-
newborns, the disturbance of communica- tives
tion between the parents has been a par- • Furious hostility against specific persons
ticularly troublesome problem. A father • Repression of hostility against specific
and mother who have communicated well persons
• Repression of hostility, leading to a The clinical relevance of this subject can

wooden and formal manner resembling best be appreciated by the following case
schizophrenic pictures examples and the questions they raise. The
• Lasting loss of patterns of social interaction words chosen in any discussion depend
• Activities detrimental to one’s own social on the needs and problems of individual
and economic existence patients at that moment. Answers are not
• Agitated depressions given as a specific formula, but to show the
For further discussion on this subject, see reader how parents are approached.
Case 4.
Cullberg’s report about severe psychiat-
ric reactions following stillbirth or neonatal CASE 1
death in Swedish mothers was published in Mrs. W had a normal pregnancy until 24 weeks’ ges-
1966, when the field of neonatology was in tation, when she unexpectedly went into labor and
its infancy. Following other reports about delivered a 2 lb, 15 oz (1332 g) female infant in a
parents’ turbulent and prolonged mourning community hospital. The baby cried promptly, but
reactions, changes in the care of bereaved then moderate respiratory distress developed, re-
families were introduced. quiring arterial catheterization, intubation, surfactant
In a systematic study of 380 women fol- administration, and ventilator care up to and during
lowing a stillbirth, Rädestad observed that transfer to a tertiary level NICU at the medical center.
mothers of stillborn infants had a dimin- The following questions should be answered
ished risk of symptoms 3 years after the when caring for this mother, father, and infant.
death if there was a short time between
diagnosis of death and initiation of the What is the ideal method of communicating
delivery,76 if the mother was allowed to with both parents?
meet and say farewell to her child as long as The best method of communicating with both par-
she wished, and if there was a collection of ents is to have them sit down with you in a quiet,
tokens of remembrance (hand or footprints, private room. You will be most effective if you can lis-
lock of hair, and photograph). They noted ten to the parents, let them express their worries and
that mothers living alone may have special feelings, and then give simple, realistically optimistic
needs for support. explanations.
How should advice be given when

discussing the situation with the parents?
EDITORIAL COMMENT: Katherine Shear and Harry
What should they be told about their infant
Shair have written about the concept of “Complicated
and her chances for survival?
Grief” which may occur with ineffective coping after When first discussing the situation with the parents,
the death of a loved one. They note as follows77: advice should be given promptly, simply, and opti-
Bereavement is a highly disruptive experience that mistically. As soon as possible after the birth, the
is usually followed by a painful but time-limited period mother and father can be told that the baby is small
of acute grief. An unfortunate minority of individuals ex- but well formed. When it is clear that the baby has
perience prolonged and impairing complicated grief, an respiratory distress, you can explain to the parents
identifiable syndrome that differs from usual grief, ma- that the baby has a common problem of premature
jor depression, and other DSM-IV diagnostic entities. infants (“breathing difficulty”) caused by the complex
Underlying processes guiding symptoms are not well adjustments she must make from life in utero to life
understood for either usual or complicated grief. We outside. This is called respiratory distress syndrome
propose a provisional model of bereavement, guided (RDS). In addition, it should be stated that because
by Myron Hofer’s question: ‘‘What exactly is lost when this condition is common, the neonatologists at the
a loved one dies?’’ We integrate insights about biobe- tertiary NICU in a medical center know best how to
havioral regulation from Hofer’s animal studies of infant treat it, and their results with infants who are this
separation, research on adult human attachment, and weight infant are very good.
new ideas from bereavement research. In this model,
death of an attachment figure produces a state of trau- What should the mother and father be told
matic loss and symptoms of acute grief. These symp- about the ventilator?
toms usually resolve following revision of the internal- Some of the parents’ anxiety can be relieved by
ized representation of the deceased to incorporate the pointing out that the ventilator is augmenting the ba-
reality of the death. Failure to accomplish this integra- by’s breathing; that is, the baby is still able to breathe,
tion results in the syndrome of complicated grief.2 but this is helping. Explaining that the baby is not able
to cry audibly when an endotracheal tube is present off the ventilator. She agrees with the diagnosis of
relieves another common concern. RDS and comments that “RDS often runs a course
of increasing symptoms for a day or two and then
Can the parents see the baby before the breathing gradually becomes easier. With RDS
transfer? there is stress on the whole baby, so as the lungs
Yes, you can explain that the mother, father, and improve, other organs such as the intestines, may
siblings will be given time and an opportunity to see show problems. Distention or fullness of the ab-
and touch the baby in the transport incubator with a domen may develop, and it may be necessary to
nurse or neonatologist present to monitor and sup- progress slowly with feedings. Throughout the first
port the baby, siblings, and parents. Pictures of the few days, routine blood tests, ultrasound, x-rays,
baby will be obtained before the transfer. and other studies may be obtained repeatedly to
be certain that the diagnosis and treatment are cor-
Is it wise to discuss breast feeding and the rect and to check that no other problem such as
value of breast milk for a baby that will be infection has developed. The overall outlook for your
transferred? daughter is good.”
Yes, emphasizing the importance of pumping milk The physician says that she will be giving their
right away will increase the odds that Mrs. W will be daughter routine care for a premature infant. She
able to provide breast milk for her baby. Discuss- says, “When I have had time to complete more tests
ing breast feeding at this time when the parents are and observations, if there is any change in what I have
extremely anxious about their baby conveys to the told you, I will call you. I will keep you posted on the
parents that you expect their baby to do well. You baby’s progress. I would like you to call at other times
can explain that the staff will help the mother start if you have questions. I am pleased that you both
pumping her breasts because her breast milk will be came in together. In the next days, if one of you is
an essential part of the treatment for her daughter, here and I have something new to report, I will plan to
not only for her nutrition, but also to decrease the talk to one of you on the telephone while the other is
risk of infection and to improve the baby’s brain de- in the office with me. I would like you to come to the
velopment. It will also enhance the mother’s bonding nursery as often as you can. I want you to become
with her daughter, particularly when Mrs. W begins well acquainted with your daughter and her care.
to directly breast feed her daughter and repeatedly Your milk will be a very important part of her treatment
experiences the let-down reflex. and you may find your milk flows more abundantly
when you are with your baby, particularly when you
What other arrangements should be made are skin-to-skin in kangaroo care. I will tell you more
before the baby is transferred? about this when I think the baby is ready.”
Communication with both the referring and receiv-

Can the nurses help the mother adapt to
ing centers and the obstetrician is necessary. Most
the premature infant?
obstetricians want to know when a baby is trans-
ferred. They can help the family by arranging for the The nurses can aid the mother in adapting to the pre-
early discharge of the mother, when medically ap- mature infant by standing with her and explaining the
propriate, so she can go to her baby in the medical equipment being used for the baby, by welcoming the
center. Sometimes mother and baby can both be mother by name, and with personalized comments at
transferred. each visit and encouraging her to come back soon,
Baby Girl W is transported to the NICU at the by carefully considering the mother’s concerns and
medical center. She receives surfactant and gradually feelings, by explaining to her that the baby will ben-
begins to wean off the ventilator. After 4 hours, the efit from her visits, and by showing her how she can
ventilator settings have decreased to Fio2 27%, peak gradually assume more of the baby’s care, and do
inspiratory pressure 22 mm Hg, positive end-expira- the mothering better than the nurses. Together, they
tory pressure 5 mm Hg, and pulse rate 25. An arterial may identify events such as loud noises and bright
blood gas (ABG) reveals pH 7.33, Paco2 41 mm Hg, lights that appear to be stressful to the baby, as well
and Pao2 62 mm Hg. When the mother and father ar- as environmental changes that appear to relax her.
rive, the neonatologist meets with them in her office. Then they can plan modifications in positioning, feed-
The physician asks “Would you please tell me ing, and times for medications as well as environ-
what the doctors at the community hospital told you mental adjustments to increase the amount of time
and what you understand about your daughter’s when the baby appears to be free of stress.
condition?” After hearing the answer, the physician
explains that the baby tolerated the transfer well What are the normal processes that a
and that they are beginning to wean their daughter mother goes through when she delivers
a premature infant and how can the responded to the sepsis treatment, Mrs. W called to
physicians and nurses assist her? say she was sick with the flu and would not come to
The premature delivery often occurs before a moth- the NICU. She called each day for 10 days and her
er is thoroughly ready to accept the idea that she husband brought in the breast milk she had pumped.
is going to have an infant. Such a mother is faced In this case, the timing of going home depended on
with a baby who is thin, scrawny, and very different the mother, whose visiting pattern was regular until
from the ideal full-sized baby she has been picturing the last week. At that time, Baby Girl W’s nurse sug-
in her mind. She may have to grieve the loss of this gested that the mother spend 3 or 4 hours with her
anticipated ideal baby as she adjusts to the real- baby, give her a bath, and feed her. Mrs. W agreed,
ity of the premature baby with all her problems and enjoyed this, and spent 6 to 8 hours caring for her
special needs. baby girl over the next 3 days. Mrs. W has a bassinet
All of the equipment and activities of a premature and equipment to care for her daughter at home and
nursery are new and may be frightening to a mother. her husband has canceled his out-of-town trips for
The tubes, the flashing lights, the alarms, and other the next 3 weeks.
instruments used in a premature nursery are disturb- Baby Girl W went home in the winter so the par-
ing. If the functions of these items are explained to ents were advised to avoid contact with children
the mother, her concerns will decrease. For example, with colds. Because she has a sibling younger than
“The two wires on the baby’s chest and the beep- 5 years of age, Baby Girl W was given the first injec-
ing instrument tell us if the baby slows down in her tion of Synagis (palivizumab) to be followed by two
respirations so we can rub her skin to remind her more injections to protect her against respiratory syn-
to keep breathing. This is frequently necessary dur- cytial virus infection.
ing the first few days with a tiny infant.” It may be
helpful for the mother and infant to be together as
much as possible in the early days. The mother’s CASE 2
guilt and anxiety, and the fear that touching the infant Mrs. J, a 25-year-old primiparous mother, delivered a
will harm her, sometimes leads her to turn down an full-term infant after a 12-hour uneventful labor. The
offer to visit the infant. No mother should be forced infant was found to have a cleft lip and palate. The
to visit her infant against her wishes; however, it is following questions should be answered concerning
important for the hospital personnel to reassure her the care of this infant and mother.
and encourage her visits, but always to move at the
mother’s pace. Should the father be told about this before
the mother has returned to her room?
What should the mother be told when she Every effort should be made to tell the mother and
asks, “How is the baby doing?” father together about this problem; however, this is
It is a common reflex in physicians and nurses to such an obvious defect that the father will notice it
prepare patients for a possible poor outcome and to and the mother will at least sense that something is
think in a problem-oriented manner. It is of great im- wrong. If this is the case, the doctor should indicate
portance to provide encouragement to the mother so that there is a problem, but that he wants to check
that mother-infant affectional ties develop as easily as the baby over thoroughly and will then tell both par-
possible, so it is desirable to approach this question ents about the problem and what will be done about
in an optimistic but realistic manner. It is wise to start it. It is popularly believed that the father is in much
out by asking the mother how she thinks the baby better condition to learn about difficulties right after
is doing. delivery than the mother, but often a woman is better
able to accept news about an illness or abnormality
When should these parents take the baby in her baby—in an emotional sense—than the father.
home? Any plan to give one bit of news or a different shad-
At 2 weeks, Baby Girl W developed an episode of ing about the prognosis to one parent and not the
suspected sepsis with abdominal distention that re- other interferes with the communication between
sponded to nothing-by-mouth and antibiotics. The the parents. It is extremely important to support and
cultures were negative. At 4 weeks, Baby Girl W encourage communication. The infant should be
weighs 3 lb, 14 oz (1758 g). brought to the parents as soon as the mother and
The baby has been breast feeding one or two the infant are in satisfactory condition and after the
times a day for the past 4 days and taking breast milk caregiving physician (obstetrician or pediatrician) has
from the bottle. She is gaining weight and has good the details of the baby’s problem clearly in mind and
temperature control without an incubator. There is aware of the baby’s health status. The baby should
is no infection in the home. Shortly after the baby be kept in the delivery room for the examinations
and then brought to the mother’s bed. The appear- CASE 3

ance of a baby with an uncorrected cleft palate and At birth, the male infant of a white 28-year-old mother
lip is grotesque and shocking for anyone who has was scrawny with decreased subcutaneous fatty tis-
not seen this before. Allowing the parents time to sue and axillary and gluteal skinfolds. At 35 weeks’
observe, react, and ask questions will be necessary. gestational age, the weight was 3 lb, 4.5 oz (1480 g),
The experienced physician or nurse will point out the more than 2 standard deviations below the mean and
underlying structures, emphasize that they are nor- fiftieth percentile for 31 weeks. The length was in the
mal, and demonstrate how the surgeon will pull the low normal range and the head circumference was
skin edges of the cleft together to cover the exposed at the 2nd percentile line. The baby breathed and
underlying tissue. Before and after pictures of sur- cried promptly. The mother was upset with his thin-
gically repaired infants are helpful and may enable ness, saying her two previous babies were full term
parents to appreciate why the physician has been so and “filled out.” When blood was drawn and an intra-
optimistic about the baby’s future appearance and venous (IV) line with glucose started, the infant was
normal developmental potential. It is worthwhile to noted to be jittery. Glucose, calcium, electrolytes, and
repeat and emphasize the general good health and blood counts were normal. Examination showed no
well-being of the baby. malformations.
Who should tell the mother: the obstetri What other causes should be considered?
cian, the pediatrician, the nurse, or the The previous record of the mother was not found.
father? When asked about prenatal care, she indicated that
The obstetrician, whom the mother has known for she had attended two prenatal visits with an obstetri-
many months, is usually the best person to tell the cian at the medical center. She said she had planned
mother. He or she needs information from a pediatri- to deliver there but when labor pains started, she had
cian about the nature of the problem and the general thought it best to go to the nearby community hos-
health of the baby. Even better, the obstetrician and pital. This was an unusual course of action. Obstetric
the pediatrician may go together to tell the parents patients do not often change obstetrician and hospi-
about the problem. If the obstetrician can speak tal with onset of labor.
briefly and calmly to the mother, then the pediatrician Shortly after delivery, a well-dressed, polite father
can continue with a brief explanation about the prob- arrived and immediately inquired which laboratory
lem. Under most circumstances, neither the nurse tests had been sent on his wife and son. The father
nor the father will be in a position to provide enough remained with his wife during all postnatal care, often
reassurance to the mother to make this first encoun- answering questions for her. Upon seeing his new-
ter progress optimally. born son attached to an IV line, he insisted, “My child
is perfectly well, just small and cold. I want both my
How should the problem be presented to wife and son discharged today.”
the parents? Perplexed by the excessive anxiety of the family
It is desirable whenever possible to emphasize to the as well as the continued jitteriness of the baby, the
parents the normal healthy features of the baby. For neonatologist sent infant urine and stool toxicology
example, “Mr. and Mrs. Jones, you have a strong screens, which were positive for cocaine. At this
8-pound baby boy who is kicking, screaming, and point, the father picked up the baby, and with his
carrying out all the normal functions of a healthy wife, started to leave. Security personnel were called
baby. There is one problem present that fortunately and stopped the father. He had a gun in his pocket.
we will be able to correct, so it will not be a continu- Emergency custody for the baby was obtained.
ing problem for your son. As far as I can tell, the baby
is completely well otherwise. I would like to show the What other concerns should be checked
baby and this problem to you.” when a baby is positive for cocaine?
This is often just the tip of an iceberg. Spouseal abuse,
Should the baby be present? human immunodeficiency virus infection, and the
Yes. As ugly as a cleft palate and lip may appear safety of other children in the home must be seriously
to a mother, exposure to the reality of the problem considered.
is important and is usually less disturbing than the When the mother was examined, there were large
mother’s imagination. bruises on her trunk. When asked in privacy, she said
her husband hit her. She agreed to go into treatment
for her cocaine addiction. As an adult, she could not
be kept in the hospital if she did not wish to stay.
Photographs of the mother and her bruises were
taken before she left, and she was told that these they are managing, to go over the details once
and the records of what she said would be kept if she more, and to indicate availability for any questions
needed them in the future. Custody of the baby was or problems. At the postpartum checkup, the ob-
given to the maternal grandmother. Later, the mother stetrician should take time to ask how the parents
said she came to this community hospital because are managing and should evaluate the normality
she thought there would be no testing for cocaine. of their mourning and their communication. When
Because of this incident, the hospital has installed there are other children in the family, the pediatri-
surveillance cameras. Some hospitals have coded cian should inquire about their responses. Parents
bracelets for the baby’s arms or ankles, or umbilical are in emotional pain and are distracted with their
tags that set off an alarm if a baby is taken. Others own thoughts after a perinatal loss. It is desirable
have a hospital public address code for a missing to have someone else—a grandparent or a friendly
baby, e.g., “Baby White.” neighbor—be attentive to the surviving children and
to listen to their questions and concerns. It should
be explained (if appropriate) that changes in the ap-
CASE 4 pearance or behavior of their parents are because
A 1 lb, 15-oz (880 g) infant of a 29-year-old mother they feel so badly about the death. This “surrogate
with a 2-year-old and a 4½-year-old child died sud- parent” should reassure the siblings that the baby
denly at 26 hours. The pregnancy was planned. The died because of its premature birth and that noth-
mother had not held or touched her baby. ing they thought or did caused the baby to be sick
or to die.
What are the processes this mother and About 3 or 4 months after the death of the baby,
father will go through? the physician should set aside a time to meet with
both parents to present and discuss the autopsy re-
The parents in this situation will go through intense
sults, review the present status of the parents and
mourning reactions. It will help the parents to see
their children, and go over what has occurred since
and hold the baby after the death. They may wish to
the death, their understanding of the death, and the
bathe or undress and dress the baby. There should
normality of their reactions. If the mourning response
be no restriction on the time with their infant. The
is pathologic, the physician should then refer the
mother and father may desire to have a nurse with
parents for additional assistance. Using these proce-
them or to be alone and may want relatives or friends
dures, Forrest et al. noted significantly less depres-
or the two siblings to see the baby. If the parents
sion and anxiety in parents compared with control
can cry together, they themselves can best help each
subjects.78 Also, they noted that an early pregnan-
other. The use of drugs, except for a night’s sleep,
cy (<6 months after the loss) was strongly associ-
is, therefore, not indicated. Even though the mother
ated with high depression and anxiety scores at
did not handle the infant, she and the father will be
14 months.
expected to show strong mourning responses, which
This short enumeration of guidelines may incor-
will be intense for 1 or 2 months, and under opti-
rectly convey the impression of a mechanical quality
mal circumstances will be decreased by 6 months.
to these discussions, which is not at all our intent.
In the United States, where the expression of emo-
Parents appreciate evidence of human concern and
tion is not encouraged, the father will often force
reactions in a physician at times such as these, so
himself to hold back his emotions to provide “strong
it is appropriate for physicians to show the sadness
support” for the mother. This is actually harmful, be-
they feel and to allow the parents to express their
cause a free and easy communication between the
pent-up feelings by making a statement such as “I
parents about their feelings is highly desirable for the
know you both must feel very sad and upset.”
resolution of mourning. On the basis of the studies
that have been carried out, the stronger the mourn-
ing reaction in the early days and weeks, the more
favorable the outcome. SUMMARY
In most instances, the hospital determines
How can the physician help them? the events surrounding birth and death,
It is important for the physician to describe the de- stripping these two most important events
tails of the baby’s death to both parents together in life of the long-established traditions and
within a few hours of the death of the baby. At that support systems established over centuries
time, he should explain the type of mourning reac- to help families through these transitions.
tion they will go through. Then, at a minimum, the Because the newborn baby completely
physician should again meet with the parents 3 or depends on his or her parents for survival
4 days later, or after the funeral, to find out how and optimal development, it is essential
to understand the process of attachment.
Although we are only beginning to under- consider measures that promote parents’
stand this complex phenomenon, those experiences with their infant.
responsible for the care of mothers and
infants would be wise to reevaluate the hos- REFERENCES
pital procedures that interfere with early, The reference list for this chapter can be found
sustained parent-infant contact and to online at www.expertconsult.com.
9
Nursing Practice
in the Neonatal
Intensive Care Unit
Linda Lefrak and Carolyn Houska Lund
The planning and delivery of nursing care 6. Describes parental contact and attach-
to critically ill neonates is a complex pro- ment behaviors
cess that necessitates thorough, ongoing Thorough assessment by the NICU nurse
evaluation to determine effectiveness of is followed by the identification of specific
both nursing and medical therapies. This patient problems that require either nurs-
unique evaluation takes into account (1) ing or medical intervention. Once problems
the frequent introduction of new treatment are identified, the process of planning and
modalities, (2) the lack of verbal commu- implementing of interventions is under-
nication with the patient, (3) the narrow taken. The signs and signals that nurses
margin between safe and adverse responses perceive may be the first indication that a
to therapy, (4) the lack of disease-specific major problem is beginning.
symptoms because of immature develop- The nurse is also responsible for the safe
ment, and (5) the patient’s extreme vulner- and appropriate use of technical equip-
ability, particularly in the most premature ment in the care of these critically ill new-
or sick infants. borns. Since the 1970s, the number of
Neonatal nursing involves a variety of electrical devices used for a single patient
unique functions, skills, and responsibilities has steadily increased, beginning with the
that are essential in assessing, understand- use of a single warming device (the incu-
ing, and safely supporting the newborn bator) and progressing to the current stan-
infant and family during this critical time. dard use of 10 to 12 devices per patient.
Neonatal intensive care unit (NICU) nurses The nurse is responsible for using these
must anticipate problems and systemati- devices with a level of expertise such that
cally evaluate the infant and all the support problems can be recognized. An essential
systems to identify any new problems as component of the nursing role involves
early as possible. Each nurse completes the the relationship between the nurse and the
following head-to-toe assessment and pre- parents and family of each infant. Because
pares the associated documentation at least initial phases of attachment develop dur-
every 8 to 12 hours: ing this time of crisis, the whole family is in
1. Observes physical characteristics such as a vulnerable position as members begin to
color, tone, skin integrity, perfusion, and establish their relationship with the baby.
edema The neonatal nurse assists the parents in
2. Assesses organ systems, including chest beginning to know and appreciate their
auscultation, peripheral pulses, heart baby in a highly technical environment
sounds, urine output, bowel sounds, and where touching and holding are sometimes
presence of reflexes difficult to accomplish (see Chapter 8). The
3. Checks patency and function of all intra- modeling of communication and inter-
vascular devices and security of endotra- action with fragile newborns is a particu-
cheal tubes and other invasive devices larly effective method of assisting parents
4. Verifies presence and appropriate func- with this process. The explanation of the
tion of all respiratory equipment and treatments and continual reinforcement of
monitors information provided by the infant’s phy-
5. Assesses neurobehavioral activity, includ- sicians regarding current condition and
ing level of pain or discomfort in relation prognosis are necessary during this crisis.
to treatment Nurses often become a major source of
225
226 CHAPTER 9 Nursing Practice in the Neonatal Intensive Care Unit
social support, especially during long or clustering of nursing and medical inter-
complicated hospitalizations. ventions, and positioning the infant using
swaddling or containment techniques. The
Newborn and Infant Developmental Care
EDITORIAL COMMENT: As the nurse cares for both and Assessment Program (NIDCAP) was
the infant and the family, there is a delicate balance designed to combine these elements in a
to achieve in preventing the mother from feeling jeal- way that is specific to individual infants,
ous as well as inept. A positive comment by the nurse using a detailed assessment system.
describing a caretaking task in which the mother was Studies using NIDCAP methodology have
successful will certainly improve her self-esteem. Inter- reported improved developmental and med-
views of mothers following their baby’s discharge from ical outcomes for premature infants cared
the premature nursery often describe both jealousy to- for in a developmentally supportive envi-
ward the nurses caring for their infants and pleasure at ronment with caregivers specially educated
how devoted and skilled the nursing staff was. in assessing premature infant behavior and
modifying care practices to reduce nega-
tive or stressful responses.1-3 A Cochrane
Neonatal nurses play a major role as pro- Systematic Review of 36 randomized con-
tector, advocate, and, at times, nurturer to trolled trials involving four major groups
the infant in the NICU. Because the nurse’s of developmental care reported limited
scope of responsibility is limited to a small benefit to preterm infants in the following
number of patients at any given time (gen- areas: decreased moderate to severe chronic
erally two to three), and because of the lung disease,4 decreased incidence of nec-
need to be almost constantly present at rotizing enterocolitis, and improved fam-
the bedside of these patients, the nurse’s ily outcome. An increase in mild chronic
observations and evaluations often guide lung disease and length of stay with devel-
any interventions. For example, an observa- opmental care compared to controls was
tion regarding an infant’s adverse reaction also reported. There is limited evidence of
to noise or handling may guide the team to improved neurodevelopmental behavioral
alter interventions or physical examination. performance. Reviewers identified a signifi-
Nurses provide a vital link between the cant methodologic concern with these stud-
patient and the health care team through ies, in that the assessments were performed
their knowledge, proximity to the patient, by non-blinded staff.
and skill at interpreting physiologic, behav- Despite ongoing skepticism and critique
ioral, and technical information. The fol- of developmental research, the modern
lowing discussion provides an overview of NICU appears quite different than its pre-
nursing practice that currently exists in the decessor: for example, dimmed lights, crib
NICU, touching on four areas: developmen- covers, swaddling and supported position-
tal care, skin care, venous access, and iatro- ing, and dB meters are becoming familiar
genic complications. sights. The reactions of staff to reduced
noise are reported to be positive, although
DEVELOPMENTAL CARE reduced light levels are not as favorable.5
A significant aspect of providing nursing Future research to better understand the
care to infants in the NICU is to create an effects and contributions of each interven-
environment that reduces noxious stimuli, tion for the infant and NICU staff may pro-
promotes positive development, and mini- vide more information about the impact of
mizes the negative effects of illness, early these interventions. The following section
delivery, and separation from parents. Neo- addresses the effects of noise, light, posi-
natal nurses have become increasingly con- tioning, and handling during routine care,
cerned about the negative effects of the NICU and it suggests modifications in each area
environment and have begun to identify that can reduce the detrimental effects.
preventive strategies and integrate changes
in this highly technical, over-stimulating NOISE IN THE NEONATAL INTENSIVE
environment. CARE UNIT
Developmental care is the term used to Much of the technology used to support the
describe interventions that can minimize newborn in the NICU generates a significant
the stress of the NICU environment. These amount of noise and activity. Excessive noise
include elements such as control of external can over-stimulate the premature or ill term
stimuli (vestibular, auditory, visual, tactile), newborn and lead to agitation and crying.
CHAPTER 9 Nursing Practice in the Neonatal Intensive Care Unit 227
This agitation has been shown to cause 3. Measure dB levels to identify baseline
decreased oxygenation, increased intracra- sounds as well as any problem areas
nial pressure, elevated heart and respiratory and times.
rates, and increased apnea.6 Autonomic ner- 4. If possible, avoid overhead paging sys-
vous system arousal using skin conductance tems.
measurements in response to a noise stim- 5. Remove loud devices from patient
uli has been reported in premature infants, care areas.
and correlates with increases in heart rate.7 6. Observe carefully individual infant’s
Noise also disrupts the sleep-wake cycle and responses to auditory stimulation such
may delay recovery and the ability to have as music boxes and tape recorders.
positive interactions with parents and care- 7. Consider offering only one sensory
givers because of fatigue and overwhelming stimulus at a time, such as talking or
overstimulation.8 Noise levels in the NICU singing without visual, tactile, or ves-
range from 50 to 80 dB. Inside the incubator tibular stimuli.
even higher levels are reached. Damage to 8. Gently open and close isolette doors.
delicate auditory structures has been asso- 9. Pad doors and drawers of storage closets.
ciated with prolonged exposure to greater 10. Design NICUs with noise-absorbing
than 90 dB in adults. In neonates, the dB materials.
levels that result in hearing damage have
not been identified.
Incubator motors generate an average of EDITORIAL COMMENT: The intensity of sound is
55 to 60 dB; equipment and activity inside or expressed in dB and measured on a semi-logarithmic
around the incubator can add an additional scale, which means that an increase of about 10 dB
10 to 40 dB. Routine care activities such as represents a doubling of the sound intensity. The 2006
placing glass formula bottles on the bed- Recommended Standards for Newborn ICU Design
side table, closing storage drawers, or open- calls for NICU sound levels to remain below 50 dB the
ing packaged supplies have been recorded at majority of the time.15 Infant sleep is usually not dis-
sound levels from 58 to 76 dB; alarms from turbed at this level. Much of the “background” noise in
intravenous (IV) pumps and cardiorespiratory a typical NICU comes from the building itself —audible
monitors have also measured 57 to 66 dB.9 sound or vibrations from activity outside the hospital
Noise from respiratory therapy equipment, and from machinery within the hospital, and sounds
monitors, staff talking, and infant fussiness generated by airflow through the heating, ventilation,
also contribute to higher sound levels.10 The and air conditioning system (HVAC). Without sufficient
American Academy of Pediatrics Committee attention to these sources, the background noise in
on Environmental Health expressed concern a NICU, even before any equipment or personnel are
that exposure to environmental noise in the brought in, can be greater than 40 dB. Ventilators,
NICU may result in cochlear damage and CPAP, and compressed air all add to the noise levels
may disrupt normal growth and develop- as do monitors, alarms, telephones, and the staff talk-
ment. The Committee to Establish Recom- ing and carrying out their duties. Hence, the recom-
mended Standards for Newborn ICU Design mended hourly loudness equivalent (Leq) of 45 dB of
advises that average noise levels not exceed acceptable noise (dBA), L10 of 50 dBA and Lmax of
45 dB,11 and intermittent high levels not 65 dBA remains an elusive goal.16
reach 65 dB or greater. However, several stud-
ies report levels that are consistently higher
despite renovations and other measures to LIGHT IN THE NEONATAL INTENSIVE
address noise levels.10,12,13 Noise awareness CARE UNIT
educational programs may improve staff The effect of continuous light exposure is
knowledge about the problem of noise in the another topic of interest when providing an
NICU and result in strategies that improve environment that is developmentally sup-
environmental modifications.14 portive for babies in the NICU. Premature
infants have thin, translucent eyelids that
Interventions to Reduce Noise Levels are ineffective in blocking light transmis-
1. Modify staff behaviors such as loud sion, and have limited capacity for pupil
talk and playing radios near radiant constriction to modulate light; both of these
warmers and incubators. deficits can interfere with sleep and rest.
2. Institute “quiet hours” several times Cycled lighting, involving periods of time
each day when noise-producing activi- with greater light intensity with periods of
ties are curtailed and lights are dimmed. dim light, has been studied in the NICU
population, and findings include increased ability, midline orientation, flexion, and self-
organization of physiologic functions such soothing and self-regulatory abilities can be
as heart rate, respiratory rate, and energy enhanced through facilitating body positions.
expenditure.17,18 Thus, cycling of light peri- Head shape is also affected by position-
ods should be considered in nurseries to ing. Premature infants in particular are
help infants begin their regulation of sleep- prone to develop dolichocephaly (narrow
wake periods. head shape) or plagiocephaly (asymmetri-
Safe levels of light in the NICU have not cal head shape). These conditions can be
yet been established and further research is avoided to some extent, or minimized by
needed to define the optimal approaches careful positioning.22 All infants should be
for lighting the immediate environment placed in supine position for sleep before
for the NICU patient. However, shielding discharge from the NICU. This may require
infants from light in incubators or on warm- an adjustment period for some infants
ing tables is relatively easy and may prove before they are comfortably sleeping in the
beneficial in promoting rest, behavioral sta- supine position, so this is best undertaken
bility, and recovery. The use of fabric incu- before discharge from the NICU. Position-
bator and crib covers is common practice in ing a sleeping infant with rolls, nests and
today’s NICU, although the type of cover other containment devices are not appro-
may be an important factor in reducing priate for unmonitored infants, and should
the light levels. One study found that cov- be discontinued well before discharge.23
ers made with dark fabrics are more effec- Implementation of these recommendations
tive than those made from light-colored or remains inconsistent in NICUs because of
bright-patterned fabrics.19 knowledge deficits about the guidelines,
and routines such as prone position for
Interventions to Reduce Light Levels sleeping.24 Gestational age, degree of ill-
1. Shade head of table, crib, or incubator ness, and use of neuromuscular blocking
whenever possible using cloth crib covers, medications all influence positioning deci-
blankets, or quilts; tenting over the head sions. Global hypotonia in infants younger
can be used if constant visual observation than 30 weeks’ gestation requires signifi-
of the infant is needed. cant intervention. Critically ill prema-
2. When infants are stable, consider mark- ture and term infants cannot expend any
edly reducing nursery light levels for energy to move and require assistance to
12-hour periods each day. attain any body position. Infants receiv-
3. Consider individual lighting over each ing neuromuscular blocking agents, such
bedside with a dimmer switch to control as pancuronium, must receive positioning
light intensity and individualize lighting assistance to maintain basic physiologic
needs. stability. Thus, selecting an appropriate
body position and assisting the patient into
POSITIONING it are important considerations for nurses
Because body alignment is known to affect in the NICU.
many physiologic and neurobehavioral
parameters, the positioning of neonates is Interventions to Position Neonates
important. Proper positioning can prevent 1. Change the infant’s position every 2 to
postural deformities such as hip abduc- 3 hours for extremely ill or immature
tion and external rotation, ankle eversion, infants.
retracted and abducted shoulders, increased 2. Promote hand-to-mouth behavior by
neck hyperextension and shoulder eleva- allowing the hands to be free when the
tion, cranial molding, or dolichocephaly, caregiver is present; side-lying position-
and can improve neuromuscular developing also assists in this goal.
ment. Positioning can also alter respiratory 3. Attempt to “nest” the infant with
physiology. Placing an infant in the prone blanket rolls or other positioning aids
position increases oxygenation, tidal vol- (Fig. 9-1).
ume, and lung compliance, and reduces 4. Place rolls under the infant’s hips when
energy expenditure when compared with the infant is prone to prevent hip
the supine position.20,21 abduction.
Body position affects gastric emptying and 5. Roll the infant’s shoulders gently forward
skin integrity as well as neurobehavioral devel- with soft rolls when both prone and
opment. Activities such as hand-to-mouth supine to prevent shoulder extension.
procedures such as blood sampling and

chest tube insertion penetrate the skin’s
barrier. Repair of the skin after tissue injury
also requires a large consumption of energy.
When the skin is damaged, evaporative heat
loss and the risk of toxicity from topically
applied substances are increased. In addi-
tion, there is an increased portal of entry
for microorganisms including common skin
flora such as coagulase-negative Staphylo-
coccus and Candida. Thus, significant mor-
bidity and even death can potentially be
attributed to practices that cause trauma or
Figure 9-1. Nesting the infant. alterations in normal skin function.
DEVELOPMENTAL VARIATIONS
6. Use water- or air-filled pillows under the IN PREMATURE SKIN
infant’s head to minimize cranial mold- The term infant has a well-developed epider-
ing; frequent position changes (every 2 mis, although structurally different from adult
to 3 hours) from side to side and mid- skin; the stratum corneum, the uppermost
line also facilitate this goal. layer of the epidermis, is 30% thinner and
7. Support the infant’s soles of the feet contains keratinocyte cells that are smaller.25
with rolls to prevent ankle extension. As measured by transepidermal water loss
8. Swaddle the infant with blankets or (TEWL) techniques, full-term newborns have
buntings when the infant is stable to been shown to have similar barrier function
promote flexion and self-regulatory compared to adult skin. However, there is
behavior. now some evidence that the stratum cor-
9. Consider gentle massage to promote neum does not function as well as adult skin
skin blood flow in infants on neuro- throughout the first year of life.26 The prema-
muscular blocking agents; reposition ture infant has fewer layers of stratum cor-
the infant every 2 hours to prevent neum and is histologically thinner, with the
pressure sores. cells of all strata more compressed. This results
10. Position infants with right side down in increased permeability and transepidermal
or prone to promote gastric emptying. water loss. Clinical implications of these dif-
Prone position is best for minimizing ferences include increased evaporative heat
effects of gastroesophageal reflux. In pre- loss, increased fluid requirement, and risk of
term infants, it improves oxygenation. toxicity from topically applied substances.
11. Elevate head of bed after feedings to Despite acceleration in the maturation of the
reduce pressure of full stomach against stratum corneum during the first 10 to 14
the diaphragm and improve respiratory days of life in premature infants, higher trans
capacity. epidermal water losses, and decreased barrier
12. Hold stable infants, even when on the function may last up to 28 days. In infants of
ventilator; holding may be soothing 23 to 25 weeks’ gestation, skin barrier func-
and provides vestibular stimulation tion reaches mature levels more slowly, tak-
similar to fetal experience. ing as long as 8 weeks after birth, or until the
infants reaches 30 to 32 weeks’ postconcep-
SKIN CARE tional age, regardless of the postnatal age.
Protection and preservation of the skin of In premature infants, the numerous fibrils
term and premature newborns are signifi- connecting the epidermis to the dermis are
cantly important, because this organ acts fewer and more widely spaced than in the
as a barrier against infection and is a major term infant. Thus, premature infants are
contributor to temperature control. It is a more vulnerable to blistering and a tendency
challenge to maintain the integrity of this toward stripping of the epidermis when
delicate organ when providing care to pre- adhesives are removed because the adhesives
mature infants in the NICU. Trauma to skin may be more firmly attached to the epider-
can occur when life support or monitoring mis than the epidermis is to the dermis.
devices that have been securely attached to The functional capacity of the skin to
the skin are removed or replaced, or when form an “acid mantle” also differs. Normally
in both adults and children, skin surface care to newborns. In 51 nurseries, the overall
pH is less than 5. In the term newborn, the skin condition of 2820 newborn infants was
pH immediately after birth is alkaline, with evaluated in terms of skin dryness, erythema,
a mean pH of 6.34, with a decline to 4.95 and breakdown using the Neonatal Skin
within 4 days. Premature infants have been Condition Score (NSCS), and was found to
shown to have a pH greater than 6 on the be improved after each nursery implemented
first day of life, decreasing to 5.5 over the the evidence-based practices.33 The Neonatal
first week and gradually declining to 5 by Skin Care Guideline has recently been revised
the fourth week. Bathing and other topical to include new studies pertinent to neonatal
treatments transiently affect the skin pH,27 skin and skin care practices.34
and diapered skin has a higher pH due to the
combined effects of urine contact and occlu- Bathing
sion.28 An acid skin surface is credited with The daily bath is traditionally administered to
bacteriocidal qualities against some patho- all hospitalized patients, including newborns
gens and serves in the defense against infec- in the NICU. Newborns are bathed to remove
tion. A shift in skin surface pH from acidic to waste materials, improve general aesthetic
neutral can result in an increase in total num- qualities, and reduce microbial colonization.
bers of bacteria, a shift in the species present, Bathing full-term infants immediately after
and an increase in transepidermal water loss. delivery can potentially compromise temper-
Another developmental variation affect- ature regulation and cardiorespiratory stabil-
ing newborn skin is the presence of vernix ity, and should be delayed until the infant
caseosa. Vernix is a protective fetal skin has achieved thermal and cardiorespiratory
covering, unique to humans, that acts as a stability, and has had time for skin-to-skin
chemical and mechanical barrier in utero contact with the mother.34
and facilitates postnatal adaptation to the Cleansers that are used for routine bathing
extrauterine, dry environment. Production include alkaline soaps, neutral pH synthetic
of vernix begins at the end of the second tri- detergents, and deodorant-type cleansers
mester, accumulating on the skin in a ceph- that contain antimicrobial properties. Bath-
alocaudal manner.29 Vernix detaches from ing infants has been shown to cause an
the skin as levels of pulmonary surfactant increase in the skin’s pH and a decrease in its
rise, resulting in progressively more turbid- fat content, most significantly with alkaline
ity of the amniotic fluid. Vernix contains soap. Skin surface pH is enhanced if vernix
antimicrobial peptides and proteins that is retained and not mechanically removed,
may be protective against bacteria, assist in even after bathing with a mild cleanser.32
pH development, and assist in cleansing.30,31 Although some studies involve bathing with
Studies about this important substance are water alone in the first week of life,35 a com-
generating interest in the possibility of using parison of four different bathing regimens
vernix as a prototype of a new barrier cream including water alone, water plus washing
to facilitate the development of the stratum gel, and water plus moisturizer—with or
corneum in premature neonates.32 without the wash gel—fail to show signifi-
cant influences on skin parameters, although
SKIN CARE PRACTICES the use of the moisturizer did transiently
Skin care practices performed daily by nurses improve barrier function measurements.36
in the NICU include bathing, moisturizing Water hardness, pH, and osmolarity are also
with emollients, antimicrobial skin prepara- potential irritants. In addition, washing with
tion, umbilical cord care, and affixation of water alone may not remove some substances
adhesives for life support and monitoring that soil the skin, are not water soluble but
devices. These activities have the potential fat soluble, and there may be benefit from
for causing trauma and altering the skin pH, using a mild cleanser.27 Routine bathing
thereby disrupting the barrier function of the should be no more frequent than every other
skin. In 2001, two national nursing organi- day, as bathing does not reduce skin coloni-
zations in the United States, the Association zation with pathogenic microorganisms,37
of Women’s Health, Obstetric and Neonatal leads to drier skin surfaces,28 and may lead to
Nurses (AWHONN) and the National Asso- behavioral and physiologic instability.38 Pre-
ciation of Neonatal Nurses (NANN) collabo- mature infants less than 32 weeks are recom-
rated on the formulation of evidence-based mended to have water bathing only for the
neonatal skin care guidelines that encompass first 2 weeks of life due to considerations for
these and other aspects of providing skin their overall skin immaturity, as well as the
potentially physiologic instability that may most common disinfectants that are used
occur as a result of bathing.34 in newborns include 70% isopropyl alco-
Although the first and subsequent baths hol, povidone-iodine, and chlorhexidine
in many hospitals are sponge baths, tub gluconate, both an aqueous solution and
or immersion bathing may be beneficial. one combined with 70% isopropyl alcohol.
Immersion bathing places the infant’s entire There have been anecdotal reports of skin
body, except the head and neck, into warm blistering, burns, and sloughing from iso-
water (100.4° F), deep enough to cover the propyl alcohol and chlorhexidine gluconate
shoulders. A randomized controlled trial of products in premature infants.42,43 Povi-
immersion versus sponge bathing in 102 done-iodine has been associated with case
newborns for their first bath and subsequent reports of high iodine levels, iodine goiter,
baths showed that the immersion-bathed and hypothyroidism. Several prospective
infants had significantly less temperature studies of routine povidone-iodine use in
loss, appeared more content, and their moth- neonatal intensive care units found elevated
ers reported more pleasure with the bath; urinary iodine levels and alterations in thy-
there was no difference in umbilical cord roid function in premature infants because
healing scores between immersion or sponge of iodine absorption through the skin.
bathing.39 Bathing is also an opportunity to A sequential study of 254 premature and
educate parents about how to physically care term infants in the NICU found IV catheter
for their babies as well as integrating infor- colonization to be reduced in sites prepared
mation about neurobehavioral status and with 0.5% chlorhexidine in alcohol solu-
social characteristics. Infants who may bene- tion compared with povidone-iodine.44
fit from immersion bathing include healthy, Because of the risk of skin injury from
full-term newborns with the umbilical clamp isopropyl alcohol and methanol-containing
in place, and stable preterm infants after chlorhexidine gluconate products,43 there is
umbilical catheters are discontinued.34 currently no single disinfectant that can be
recommended for all neonates.34 Aqueous
Moisturizers 2% chlorhexidine gluconate is available in
The degree of hydration in the stratum cor- 4 ounce bottles and must be poured onto a
neum is related to the capacity of this layer to sterile gauze sponge for application, and 2%
absorb and retain water. Moisturizers improve chlorhexidine gluconate in 70% isopropyl
skin function by restoring intercellular lipids alcohol is available in single-use products
in dry or injured stratum corneum. These are but is approved by the U.S. Food and Drug
products such as emollients, creams, lanolin, Administration (FDA) only in infants older
mineral oil, or lotions; many include petrola- than 2 months of age. Although some nurs-
tum as an ingredient because of its excellent eries elect to use this product “off-label,”
hydrating and healing qualities.40 there is significant risk of skin injury in pre-
Although there may be beneficial effects matures infants. Many nurseries continue
of routine emollient use in premature infants to use 10% povidone-iodine. When any
younger than 33 weeks’ gestation, an associa- of the skin disinfectant solutions are used,
tion has been shown between routine (twice it is necessary to remove the preparation
daily) applications of petrolatum-based emol- completely when the procedure is finished.
lient and S. epidermidis blood stream infec- Water or saline is preferred for removing
tions in a randomized, controlled trial of 1191 disinfectants to reduce the risk of further
premature infants less than1000 grams.41 skin injury from these caustic preparations.
Routine use of an emollient to prevent or
treat excessive drying, skin cracking, or fis- Adhesive Application and Removal
sures is not recommended. However, dry, Traumatic effects of adhesive removal for
scaling, or cracking skin will benefit from an premature infants include reduced barrier
emollient that is free of perfumes or dyes; function, increased transepidermal water
products containing perfumes or dyes that loss, increased permeability, erythema, and
can be absorbed and may result in later sensi- skin stripping. Solvents have been used in
tization or toxicity are not recommended.41 hospitals for a number of years to remove
tape and adhesives. Although effective,
Skin Disinfectants these products should not be used in the pre-
Use of skin disinfectants before invasive mature infant because of the risk of toxicity
procedures is commonplace in hospitalized from absorption and because of the poten-
full-term and premature newborns. The tial for skin irritation and injury. Bonding
agents that increase the adherence of adhe- pulling adhesives at a very low angle, par-
sives may also cause more skin stripping allel to the skin surface, while holding the
and damage because they form a stronger surrounding skin in place may reduce epi-
bond between the adhesive and the epider- dermal stripping.46 Silicone-based adhesives
mis than the fragile bond between epider- are primarily used in wound care products,
mis and dermis, especially in the premature although silicone tapes are also available
infant. Plastic polymer skin protectants are and have been shown to improve adherence
available to protect skin from adhesives and to wounds and reduce discomfort when
do not increase adhesive aggressiveness.45 removed.47 This technology holds promise
Products that do not contain isopropyl alco- for developing future adhesive products for
hol are preferred because the alcohol can newborns.
also irritate newborn skin.
Skin barriers made from pectin and meth- Skin Care Recommendations
ylcellulose are used between skin and adhe- Bathing: Use neutral pH cleansers on infants.
sive; they mold well to curved surfaces, and Bathe the infant with cleansers infre-
maintain adherence in moist areas. Although quently—two to three times per week; at
there is less visible trauma to skin with pectin other times, use warm water baths. For
barriers, evaporimeter measurements of skin infants with very immature skin, less than
barrier function shows that pectin causes a 32 weeks’ gestation, clean with warm
similar degree of trauma as commonly used water and cotton balls for the first week.
plastic tape. Even more mature newborns Moisturizers: Use a petrolatum-based, water-
are at risk for trauma from adhesive removal. miscible emollient that does not con-
However, hydrocolloid products continue tain perfume or dyes. Apply moisturizer
to be helpful in the hospitalized newborn sparingly to cracked or fissured areas on
owing to improved adherence as the product an as-needed basis. If the infant’s skin is
warms to skin temperature, and the ability colonized with Candida, use antifungal
to mold to surfaces better than many other ointment instead of petrolatum-based oint-
products. These adhesives do require care on ment. Routine use of emollients in infants
removal, similar to adhesive tapes. less than 1000 grams is not recommended.
Transparent adhesive dressings made Antimicrobial skin preparation: Use aqueous
from polyurethane are impermeable to chlorhexidine or povidone-iodine solu-
water and bacteria but allow the free flow of tion before any invasive procedure that
air, thereby enabling the skin to “breathe.” penetrates the skin surface; remove the
Uses for transparent dressings include secur- solution completely with water or saline.
ing IV catheters, percutaneous catheters, Avoid the use of isopropyl alcohol to
and central venous lines, nasogastric tubes, remove skin disinfectants.
and nasal cannulas. They can also be used Adhesives and adhesive removal: Limit the
to prevent skin breakdown over areas that amount of tapes and adhesives used to
have the potential for friction burns or pres- secure equipment. Do not use solvents,
sure sores, such as the knees, elbows, or but remove tape with water-soaked cotton
sacrum, or as a dressing over surface inju- balls. Tincture of benzoin and other bond-
ries. Semipermeable dressings have proven ing agents are not routinely recommended
to be very beneficial for selective taping for very immature infants because this can
procedures, such as IV and central venous create a stronger bond of adhesive to the
catheter dressings, nasogastric tubes, and epidermis than the bond between epider-
chest tubes. The potential for skin damage mis and dermis. Consider use of hydro-
when removed is similar to other adhesive colloid adhesives, such as pectin barriers,
tapes. between tape and skin for better adherence.
Preventing trauma from adhesives can Use hydrogel adhesives for electrodes, soft
be accomplished by minimizing use of tape gauze wraps for pulse oximeter probes, and
when possible, dabbing cotton on tape to transparent adhesive dressings to secure IV
reduce adherence, using hydrogel adhesives catheters, central venous catheters, naso-
for electrodes, and delaying tape removal gastric tubes, or oxygen cannulas.
for more than 24 hours when the adhesive
attaches less well to skin. Removal can be PAIN MANAGEMENT IN THE NEONATE
facilitated by applying warm water or an Nurses collaborate with medical and surgical
emollient or mineral oil if reapplication of staff to assess and treat pain in neonates related
adhesives at the site is not necessary. Slowly to disease processes, invasive treatments, and
surgical procedures. The attitudes of staff and Pain should be assessed using all of the
parents continue to have an impact on the information available to the bedside nurse
use of pharmacologic interventions. Barriers including the biochemical indicators of
include, but are not limited to, the follow- stress such as elevated blood glucose and
ing: (1) lack of clinical trials for pain assess- metabolic acidosis, as well as the context
ment and treatment in the neonate, (2) fear of the infant’s current condition. In infants
of side effects of the treatment, (3) concern who have undergone a surgical procedure
over dependence and or neurologic sequelae or invasive procedure, pain is clearly pres-
with the use of pain medications, (4) pharma- ent regardless of the pain tool score. Addi-
cologic and individual differences of the drug tionally, waiting for an increase in scores
used to treat pain, (5) lack of agreement about may not be reasonable for pain medication
the adverse effects of pain, and (6) shortcom- administration in the postoperative infant.
ings of all tools in the nonverbal patient.48,49 Pain is more efficiently treated if “pre-
Even the most immature infant perceives pain empted.” Many neonatal units have written
and there are real and ongoing physiologic postoperative pain protocols that start with
and potentially neurodevelopmental conse- regularly scheduled or “around-the-clock”
quences of inadequately treated pain.48,49 dosing when pain source is clear and scoring
Significant advances have been made in remains the most difficult. Pain assessment
the assessment and treatment of neonatal should be comprehensive, multidimen-
pain since The Joint Commission (TJC) sional, and include the contextual, behav-
made this a survey standard. Pain treat- ioral, and physiologic indicators available to
ment has improved significantly in the past bedside nurses.51
decade for neonatal patients. Successful Postoperative pain protocols have been
pain management is best facilitated by (1) developed through teams working together
staff orientation on pain assessment and to develop consensus on appropriate medi-
treatment, (2) use of a neonatal pain tool, cations, dosing, and method of adminis-
(3) development of pain management stan- tration. These protocols should include an
dards that address procedural, postopera- initial postoperative dose based on last oper-
tive and disease-related pain, (4) ongoing ative opiate dose and then an “around-the-
efforts to reduce painful procedures that clock” dosing schedule. Continuous opiate
are not necessary, and (5) interdisciplin- infusions have the advantage of steady-state
ary collaboration with surgery, anesthesia, dose delivery, less opening of IV lines, and
neonatology, nursing, and other ancillary fewer opportunities for error in calculation.
personnel about the standards of pain man- There is some concern that tolerance devel-
agement. ops more rapidly with opiate infusions, but
Currently, many neonatal units are using tolerance can be handled by tapering the
tools such as the PIPP (Premature Infant drug dose if the drip exceeds a 5-day course.
Pain Profile) or N-PASS (Neonatal Pain, Agi- Many postoperative pain protocols advise
tation, and Sedation Scale) that assess dif- drip opiates for 48 to 72 hours for major
ferences in the premature infant who may thoracic and abdominal procedures with a
not mount a vigorous behavioral response transition to as-required (p.r.n.) opiate dos-
to pain.50 Most neonatal tools use a coming and introduction of acetaminophen.
bination of behavioral and physiologic Morphine has advantages over fentanyl in
indicators to help assess pain. Behavioral that it has a longer duration of action. When
indicators include, but are not limited to, given slowly and in appropriate doses, there
crying, grimacing, brow bulge, eye squeeze, is minimal to no effect on blood pressure,
gaze aversion, clenched fingers and toes, CO2 response, or oxygen requirements.
arching, kicking, inconsolability, or lack of
movement and decreased tone. Physiologic Postoperative Pain Management Protocol
indicators include, but are not limited to, for Infants After a Major Abdominal or
increased heart rate and blood pressure, Thoracic Procedure
mottled or pale skin color, increased oxygen 1. Give a 0.02 to 0.1 mg/kg IV bolus of
requirements, palm sweating, and decreased morphine sulfate within 1 hour of last
or labile oxygen saturations. The FLACC intraoperative opiate dose.
(face, legs, arms, crying, and consolability) 2. Begin continuous drip of morphine sul-
is a behavioral tool that can be used in set- fate at 0.01 to 0.02 mg/kg/hour, adjust
tings where monitoring is not available, drip rate as needed based on pain assess-
such as a newborn nursery. ment, and source.
3. Acetaminophen rectally 15 mg/kg removal, or tube insertion. Many units

around the clock for 48 hours to poten- have improved procedural pain manage-
tiate opiates; frequency is based on ges- ment by reducing the number of painful
tation (term infants every 6 hours, >32 procedures to which each infant is exposed.
weeks every 8 hours, <32 weeks every Laboratory blood draws are coordinated
12 hours), then p.r.n. as pain intensity and tests “batched” to avoid multiple
lessens. punctures. Many units have eliminated
The pharmacokinetics of analgesia and routine suctioning and only suction when
opiate clearance and tolerance are extremely there are clinical indications. Examples
variable based on gestation, and opiate of procedural pain management are (1)
experience. Infants who have had recent or oral sucrose for heel sticks, tape removal,
repeated opiate doses may require higher eye examinations, nasogastric tube inser-
doses than infants who are opiate “naïve” tion, intramuscular injections, and other
and very immature. Premature infants have minor painful procedures, (2) subcutane-
prolonged clearance times of opiates and sed- ous or topical anesthetics (4% lidocaine)
atives which improve with postconceptual for starting IVs and as an adjunct to a
age. Clearance reaches adult values at about local anesthetic for lumbar punctures,
1 month of age. Unlike other medications, chest tube insertion, and peripheral arte-
both opiates and sedatives can be readily rial catheter insertion, (3) systemic opiates
reversed or partially reversed if adverse side for intubations, chest tube insertion, and
effects occur. It is important to remember peritoneal taps.
that there are significant adverse effects of Oral sucrose has been used for many
inadequately treated pain, such as reduced years for minor pain management and the
gut motility, urinary retention, hypercoag- efficacy and safety has been confirmed in
ulation, decreased tidal volume, increased multiple studies. A recent study was unable
splinting, hypoxia, atelectasis, hypermetab- to demonstrate a difference in nociceptive
olism, protein catabolism, and exaggerated brain activity after a heel lance, but did
stress response. Infants treated on a proto- demonstrate a significant difference in pain
col are likely to be extubated faster, have scores in infants who received sucrose ver-
less postoperative fluid retention, and need sus sterile water.53
less drug overall than infants who were not Current practice should evaluate pain
on a protocol.52 behaviors after a pharmacologic interven-
The success of postoperative pain man- tion, with preprocedural sucrose to reduce
agement requires that the nurse consult crying and pain scores. Sucrose is most effec-
with the neonatologist, surgeon, and anes- tive when dipped on a pacifier prior to the
thesiologist. It is essential to determine the
relative pain potential based on similar pro-
cedures in verbal children or adults and to
EDITORIAL COMMENT: Pain management is an in-
determine any intraoperative procedures
tegral part of modern neonatal intensive care. How-
that may lessen postoperative pain such as
ever, there are still many unanswered questions.
a caudal anesthetic or local instillation of
Stevens et al. completed a Cochrane review that
an anesthetic. For surgical procedures such
included forty-four studies enrolling 3496 infants.54
as ventricular-peritoneal shunt placement,
Results from only a few studies could be combined
simple colostomy for imperforate anus, or
in metaanalyses. Sucrose significantly reduced dura-
laparoscopic gastrostomy, the postopera-
tion of total crying time, but did not reduce duration
tive pain medication of choice is less clear.
of first cry. Although true pain perception cannot be
An option for low-dose opiate by intermit-
measured in nonverbal populations, neural activity in
tent bolus infusion with acetaminophen is
nociceptive pathways is a more direct measure than
a good starting point with pain assessment
behavioral and physiologic assessment. Slater et al.
and tool scores to guide the management.
found that sucrose does not change neural activity,53
Procedural pain management requires
which strongly suggests that pain perception is not
group consensus from medical and nurs-
affected by this intervention. Nonetheless, Lasky and
ing staff. Most units begin by evaluating
van Drongelen noted,55 “… until we better understand
all invasive procedures to see if they are
pain pathways and the short-term and long-term se-
essential to care or if they can be modified
quelae of painful procedures, it seems premature to
or reduced. This process includes review-
conclude that sucrose might not be an effective anal-
ing all procedures and protocols that
gesic for newborn babies.”
require blood sampling, suctioning, tape
procedure. It does not reach the stomach, have an adverse response if the medication
and can therefore be used in infants who are is abruptly discontinued. Opiates should
receiving nothing by mouth. It has not been be tapered with abstinence scoring every
associated with a rise in blood glucose when 4 hours—or more often—to reduce the
administered by pacifier dipping. It should adverse effects of withdrawal. The length
be used with caution in very low-birth- of the taper depends on the length of drug
weight intubated infants due to concerns of use or exposure. For example, for an infant
choking. 52,56,57 undergoing a staged abdominal wall defect
Topical lidocaine (4%) has also been closure the opiate exposure from the first
shown to be safe and efficacious and requires surgical procedures through the second pro-
only a 20-minute application to achieve cedure may be 6 to 8 days. The dose should
effect to about 4-mm depth.58 It does need then be tapered by no more than 10% to
to be used sparingly to just the area of the 25% every 24 to 48 hours depending on
pain source. Data are sparse in very prema- scores. The Finnegan Scoring Tool (Fig. 9-2)
ture infants. can be used for this purpose, with a score of
It is important to use a combination of less than 8 being used to reduce dose. Pain
the pharmacologic interventions available must also continue to be scored during the
with the nonpharmacologic measures such tapering process.
as swaddling, containment, nonnutritive Concerns about the long-term develop-
sucking, and massage. Nonpharmacologic mental effects of using opiates and seda-
measures do not replace the need for topical tives in neonates and young infants are
and subcutaneous anesthetics, nerve blocks, ongoing.55,63 Pain medications should be
or systemic opiates. Many procedures in the used for the treatment of pain and tapered
NICU have been completed with a higher or discontinued when the pain source is no
success rate and less morbidity when pain longer present. No absolute test determines
management is successful. One example is if pain is being experienced in a neonate.
the use of premedication for intubation, Nurses need to develop knowledge and
with a 50% reduction in time to intubation, skill at assessing pain behaviors, continue
success on the first attempt, and minimal or to advocate for their patients, and provide
no bradycardia or hypoxia being reported.59 the nonpharmacologic and pharmacologic
Intubation induction protocols include a interventions to treat pain. Barriers to treat-
systemic opiate such as fentanyl, atropine, ment include difficulties of assessment,
and a fast-acting neuromuscular blockade attitudes about the competing goals of post-
agent. Procedural pain management in the operative care, and knowledge of pain treat-
NICU remains variable and surveys show ment options in the neonate.
that many units continue not to premedi-
cate infants for the same procedures where VASCULAR ACCESS
premedication is a standard for older chil- IV access is used in the NICU to deliver
dren or infants in Pediatric Intensive Care medications, therapeutic agents, nutri-
Units of the same age.60-62 tional support, and hydration. There are
There are many practical aspects of numerous options for IV access that need
improving the safety of pain management. to be evaluated for risk and benefit on a
They include staff education on medication patient-by-patient basis. Peripheral access
dosing and side effects used in pain man- is predominately provided by Teflon
agement. Medication references should “intracath” devices. Stainless steel needles
be readily available for dosing ranges and are available but the dwell time is short
strategies. Protocols should be written and and they are not the preferred method if IV
agreed on by nursing and medical staff to catheters are available. When IV access is
guide pain treatment. Staff should be famil- needed, the duration of therapy, size of the
iar with the reversal agents for adverse opiate infant, skill of the bedside caregivers, type
and sedative effects, naloxone and flumaze- of IV fluid and/or medication required, and
nil. Consultation with a pain service and/or number of veins available should be taken
anesthesia practitioner should be available into consideration. For short-term therapy
for difficult cases. Finally, nurses and physi- (3 to 5 days), peripheral therapy is usu-
cians should use an opiate-weaning protocol ally, but not always, adequate. In infants
when the use of opiates equals or exceeds requiring 7 to 10 days of antibiotics, medi-
5 days. Infants, as adults, may become tol- cations known to be associated with vein
erant or dependent to the opiate and may irritation, total parenteral nutrition, high
Analgesia/sedation orders (drug/dose/frequency) Addressograph
Date
Drug
Administration time
Dose ↑ or ↓ or frequency
Time:
Choose one:
Crying/agitated 25%-50% of interval 2
Crying/agitated >50% of interval 3
Choose one:
Sleeps <25% of interval 3
Sleeps 26%-75% of interval 2
Sleeps >75% of interval 1
Choose one:
Hyperactive Moro 2
Markedly hyperactive Moro 3
Choose one:
Mild tremors, disturbed 1
Moderate/severe tremors, disturbed 2
Increased muscle tone 2
Temperature 37.2 °C-38.4 °C 1
Temperature >38.4 °C 2
Respiratory rate >60 (extubated) 2
Suction > twice/interval (intubated) 2
Sweating 1
Frequent yawning (>3-4/interval) 2
Sneezing (>3-4/interval) 1
Nasal stuffiness 1
Emesis 2
Projectile vomiting 3
Loose stools 2
Watery stools 3
Total score
Adjusted score
Initials of person scoring
Directions: Score every 2-4 hours per guideline. Score greater than 8-12 may indicate withdrawal.
Figure 9-2. Assessment form for drug withdrawal: Opiate weaning flow sheet. (Adapted from Finnegan LP, Connaughton JF Jr,
Kron RE, et al: Neonatal abstinence syndrome: assessment and management, Addict Dis 2:141, 1975. Version 1/94.)
glucose infusions, or IV calcium therapy, Vitrase, a hyaluronidase-containing formu-

it is often reasonable to consider central lation, does not contain preservatives and
venous access. For those infants with a comes as 200 mg/mL that requires a 1:10
peripheral IV, management and assess- dilution before administration of the 20-mg
ment of the IV line are essential for patient dose in five divided injections of 0.2 mL ali-
safety. The following recommendations quots around the swelling. Phentolamine
may reduce complications: is used when a vasoactive drug has infil-
1. Select an IV catheter that is of high trated and directly counteracts the drug and
quality and smooth; Teflon, silicone, or improves skin perfusion.64-66 The dose is
polyurethane 0.25-0.5 mg diluted to 1 mL. When the infil-
2. Develop a staff training program that tration includes vasoactive drugs and mainte-
includes education on vein selection, nance fluids such as TPN, the phentolamine
procedural pain management, IV inser- should be administered first until the color
tion, stabilization, and documentation. improves and then the hyaluronidase should
3. Experienced nurses should train and be administered. Using a 23-gauge needle for
supervise new employees. the injection of the drugs can also allow the
4. Use IV models for skill practice (avail- infiltrated fluid to leak out. Placing the site
able from companies who manufacture on a clean surface and dripping warm saline
IV devices). will keep the puncture sites open and allow
5. Have written procedures for inserting, more fluid to be drained.
securing, and assessing hourly.
6. Limit the glucose concentration to CENTRAL VENOUS ACCESS
D12.5%, amino acids to 2%, and cal- Central venous access can be achieved using
cium gluconate to 200 mg/100 mL. umbilical venous catheters (UVCs), surgi-
Avoid IV calcium if possible for older cally placed catheters, tunneled, such as
infants with normal calcium levels. Broviac (Bard Access Systems, Salt Lake City,
7. Use infusion pumps that have safety Utah) or, non-tunneled such as a Cook (Cook
options or air detection, no runaway Medical, Bloomington, Ind), or percutane-
option, and occlusion alarms. ously placed central catheters (PICCs). The
8. Instruct on the signs of infiltration that adoption of standardized, evidence-based
include swelling, redness, blanching, central line insertion and maintenance
larger size than contralateral extremity, bundles significantly reduces NICU central-
crying or grimacing with flushing, lack line-associated bloodstream infection rates
of blood return, and skin temperature (Box 9-1). These catheters can be placed in
difference. high-flow, large vessels such as the superior
9. Use a second opinion from an experi- vena cava (SVC) or inferior vena cava (IVC).
enced nurse when there is doubt. The advantages are less risk of infiltration
10. Use an IV infiltration scale to guide for high concentration glucose and protein
treatment and reporting. and irritating medications (vesicants) such
11. Use an infiltration protocol that involves as acyclovir and calcium salts, provision of
hyaluronidase (Vitrase) or (phentol- a steady system for infusion, and reduction
amine Regitine) with hydrogel treat- in the number of painful procedures that
ment for residual tissue injury. may be required for peripheral IVs. The risks
12. Report and track all adverse effects of IV of central venous access include thrombus,
therapy, such as infiltrates resulting in infection, and rarely, pleural and pericardial
tissue injury and loss of access. effusion. These risks can be reduced with
Hyaluronidase is a protein enzyme that the use of the small-sized silicone or poly-
helps diffuse IV infiltrates by modifying urethane catheters that are placed percuta-
the permeability of the connective tissue. neously through a peripheral vein (PICC).67
The needle used to give the drug around PICC catheters come in multiple sizes that
the circumference of the swelling also has the can be used in neonates ranging from 1.2
effect of allowing the fluid to drain from the to 3 Fr. They are threaded through a variety
puncture sites; this multiple puncture tech- of introducer needles to achieve a central
nique has also been shown to be effective if venous tip location and then the introducer
hyaluronidase is not available. Both the drug is removed from the system. Catheter tips
and the punctures will decrease the swelling, should be in the SVC or IVC to reduce effu-
allow the infiltrated fluid to leak from the sion risk. These small catheters made from
puncture sites and improve tissue perfusion. silicone and polyurethane reduce the risk of
Central-Line Insertion reduce complications and infections.68,69

Box 9-1. New split septum “ports” have been shown
and Maintenance Bundle Elements
to reduce the contamination of the fluid
Insertion bundle path if a 15-second scrub with alcohol pre-
Establish a central line kit or cart to consoli- cedes any catheter entry. Dwell time can
date all items necessary for the procedure. be weeks to months and, therefore, reduce
Perform hand hygiene with hospital-approved painful procedures for IV starts, provide
alcohol-based product or antiseptic- uninterrupted vascular access, and allow
containing soap before and after palpating for hyperosmolar IV solutions to be used.
insertion sites and before and after insert- When frequent blood sampling or blood
ing the central line. product administration is needed, then a
Use maximal barrier precautions (including surgical line, tunneled or non-tunneled, or
sterile gown, sterile gloves, surgical mask, a 3 Fr PICC should be considered. Tunneled
hat, and large sterile drape). catheters (such as a Broviac are available in
Disinfect skin with appropriate antiseptic (e.g., 2.7 and 4.2 Fr sizes and can be used for blood
2% chlorhexidine, 70% alcohol) before draws and blood product administration.
catheter insertion. These catheters can be used for long-term
Use either a sterile transparent semiperme- access in cases of short bowel syndrome or
able dressing or sterile gauze to cover the other complicated surgical conditions. Cook
insertion site. catheters can be placed percutaneously in
Maintenance bundle the subclavian or femoral vein, are available
Perform hand hygiene with hospital approved in 3 and 4 Fr, and have double lumen options
alcohol-based product or antiseptic- for critical infants. Units using PICCs should
containing soap before and after accessing consider the following recommendations
a catheter or before and after changing the for standards of care that include:
dressing. 1. Place lines early before peripheral veins
Evaluate the catheter insertion site daily for signs are damaged.
of infection and to assess dressing integrity. 2. Safe insertion sites include the basilic,
At a minimum, if the dressing is damp, soiled, cephalic, saphenous, or preauricular vein
or loose change dressing aseptically and in the scalp. The axillary vein can be used,
disinfect the skin around the insertion site but is technically more difficult to stabi-
with an appropriate antiseptic (e.g., 2% lize, and is close to the artery. The jugu-
chlorhexidine, 70% alcohol). lar veins should be avoided due to high
Develop and use standardized intravenous bacterial counts found at that site and the
tubing set-up and changes. technical difficulties with dressings.
Maintain aseptic technique when changing 3. Maximize barrier precautions for inser-
intravenous tubing and when entering the tion; cover site after x-ray confirmation
catheter including “scrub the hub”. with a transparent dressing.
Daily review of catheter necessity with prompt 4. Change dressings only when soiled or
removal when no longer essential. adhesion is lost to minimize skin injury
with adhesive removal and potential
From Schulman J, Stricof R, Stevens TP, et al: loss of line during the process.
Statewide NICU central-line-associated bloodstream 5. Confirm tip location using an injection
infection rates decline after bundles and checklists, of radiopaque contrast such as Optiray
Pediatrics 127:436, 2011. (Covidien, Mansfield, Mass) to better
visualize tip, have arm or leg in flexed
position during the film because extrem-
thrombus. The catheter is soft and flexible ity position affects the tip location.70
and can be maintained without arm boards, 6. Minimize opening of the line to reduce
sutures, or limits of patient positioning. introduction of bacteria.
They are made by several manufacturers 7. Change IV medications to oral as soon
and now come in a double lumen option. as possible.
Infections can be reduced by standard- 8. Avoid use for blood samples or blood
izing the insertion technique, the dress- product administration.
ing, the procedure for changing the tubing, 9. Avoid the use of small-bore syringes
and the procedure for administering medi- (1 and 3 mL), which will increase the
cations. Research has also shown that a pressure in the catheter and may lead to
small dedicated team of inserters will also catheter rupture.
10. Track all complications and nonelective 3. A checklist is used to ensure all insertion practices
removal to identify staff knowledge and are followed.
skill deficits or systems problems that 4. There is a policy or program to empower staff to
need to be addressed to improve safety stop a nonemergent central line insertion if proper
and dwell time. procedures are not followed.
11. Educate nursing and medical staff 5. There is an education or training program for
about complications, troubleshooting, staff responsible for insertion and maintenance of
and line repair. catheters.
12. Train a core group of nurses to insert 6. Chlorhexidine is the preferred agent for skin
PICCs in adequate numbers to ensure cleansing for central line insertion and/or mainte-
a high skill level and to meet patient nance.
needs.
13. Standardize all insertion, dressings, line
changes, and medication delivery into a
procedure and checklist. COMPLICATIONS OF CARE
All venous access is monitored and main- In light of the serious emotional, biologi-
tained by nurses. Nurses should actively cal, and social burdens to which complica-
participate in the selection of appropriate IV tions of therapy can lead, it is imperative
devices for patients’ needs. Practice should that nurses collaborate with members of
be standardized with procedures, proto- the medical team to identify and reduce
cols, and policy to reduce related risks and these complications.74 Reducing errors can
improve patient safety. only occur through comprehensive pro-
grams that address the spectrum of what
EDITORIAL COMMENT: Nosocomial infections occur
can go wrong with the systems and human
worldwide and are among the major causes of death
aspects that contributed to the error. It is
and increased morbidity among hospitalized patients.
also clear that patient safety is best achieved
Neonatal hospital-acquired infections add to func-
when errors can be reported in a nonpu-
tional disability and emotional stress of the family and
nitive environment. The concept of psy-
may lead to neuro-cognitive impairment. The financial
chological safety fosters the belief by staff
costs are considerable with the increased length of
that “well intended actions will not lead to
stay contributing most to the added costs. Efficient
punishment or rejection by others.” Staff
progress in decreasing neonatal nosocomial infection
will report their errors and ask for help if
rates can be achieved when statewide quality-
the likelihood of rejection or embarrass-
improvement collaboratives using structured interven-
ment is low. This “no blame” environment
tions (“tool kits”) are augmented with brief interactions
does not stop managers from evaluating
that introduce, orient, and motivate potential users.71-73
staff practice. Individuals continue to have
These interventions are simple and require maintaining
the responsibility to be knowledgeable
a checklist of the steps in the procedure. Ensuring steril-
and skilled in medication preparation and
ity, making certain that all items necessary to complete
administration, and to follow the rules.
the placement of the line are present before starting the
Individuals who engage in recurrent unsafe
procedure, and providing routine care of the dressings
practices need to be given a plan for prac-
and tubing must be a priority. Careful care of the hub
tice improvement and a time frame to meet
when the line is in place and asking the question daily
a knowledge or skill deficit. NICUs should
as to the need for the central line are all important ele-
consider creating staff competencies that
ments of the “bundle” to prevent central line infections.
test and review for knowledge, skill, and
Key elements of the bundle to prevent nosocomial
safe practice guidelines.
infection include:
All nursing care delivery should be orga-
1. Use a central line associated blood stream infec-
nized in a systematic way that includes staff
tions (CLABSI) insertion bundle (e.g., chlorhexidine
orientation and education, written policies,
for skin antisepsis, maximal sterile barrier precau-
protocols and procedures, education, and
tions, and hand hygiene). A properly applied and
staff development for all employees, and a
maintained PICC dressing is the first line of de-
method of audits and safety checks to ensure
fense to minimize the risk of complications such as
that practice standards are met. Staff educa-
dislodgement, migration, and infection.
tion requires a combination of skill train-
2. All needed supplies are “bundled” in one area (e.g.,
ing, knowledge of pathophysiology, periodic
a cart or kit) to ensure items are available for use
review of the evidence for practice, and inter-
before starting the procedure.
personal relationship skills. Policies state what
the standard is, such as “two identifiers will
be used for all patient testing and reports and Nurses should also be encouraged to inspect
they are the name and medical record num- all supplies before they are used on patients
ber.” Procedures are the psychomotor skills and save the packaging for tracking if the
required to complete a task such as perform- device is defective or broken. Lot numbers
ing a bladder catheterization. Procedures can and identifying information is essential in
incorporate policy (e.g., what type of prepara- the problem solving process. Cost contain-
tion is used for an invasive procedure or how ment, participation in buying cooperatives,
many attempts one nurse can try before ask- and the push for standardization often
ing for assistance). Protocols are sets of instruc- places supplies and equipment at the NICU
tions or information about how to care for a bedside that is substandard or not suited for
patient receiving a particular therapy such as infants. Manufacturing problems can occur
phototherapy or total parenteral nutrition. in a previously reliable product. Timely
These documents set standards, clarify prac- reporting of adverse patient impact result-
tice, and can be used for reference by new ing from a product can facilitate prompt
staff or in unusual circumstances. Nursing removal from the area and change to a
care that differs from the identified standard product that meets patient needs and safety
can be justified and, at times, in the patient’s requirements.
best interest, modified with team discussion Other new concepts in patient safety
and supportive documentation. All of these include the use of forcing functions. Designs
documents should be readily available elec- or steps have been established that make it
tronically for ease of access and evaluated at less likely or impossible for the error to be
intervals to include new evidence and prac- made. An example is the use of specialized
tice change. Recently, the use of checklists has tubing for infused enteral feeds that cannot
been recommended to provide a shortened be connected to an IV line. Redundancies
version of a long protocol or procedure. These are double, triple, and quadruple checks of
checklists help define critical steps, reduce critical processes that can identify an error.
the reliance on short-term memory, and have These checking processes have been used
been shown to improve patient safety. for the calculations of high-risk drugs such
Nursing staff should participate in all as opiates, anticoagulants, potassium, and
equipment and supply selection and evalu- digoxin. Double checks have also been suc-
ation. Nurses should be clear about how to cessfully used to check breast milk feedings.
handle equipment or supplies that malfunc- Confirmation bias is a concept that leads to
tion or break. The Safe Medical Device Act errors. The category of “look-alike, sound-
(SMDA) requires that equipment or sup- alike” medication or formula errors occur
plies that cause patient harm, or could have because the first few letters are the same.
caused patient harm, must be reported. Nurses may be performing a task that they
These reports provide a database for prod- have done many times and can go through
uct recalls and directs intervention with the process and not read the label correctly;
the manufacturer from the FDA (MedSun, they see what is familiar or what they want to
Medical Product Safety Network) for inves- see, rather than what is actually there. These
tigation about the product problem. For errors can be reduced by putting in place a
example, if a new IV pump is marketed process that slows the individual down,
and in setting the rate it is possible to get reduces distractions, and creates labeling
a double entry if the button is pressed for that is clearer. Lastly, creating areas where
too long, an overinfusion of fluids may the nurse performing critical procedures
occur. Through SMDA reporting the FDA such as preparing medications, mixing feed-
can quantify the problem and work with ings, or reporting of patient information is
the manufacturer to make design changes protected from distractions that can lead to
to reduce this risk. The reports are tradition- an omission or error.75 It is a concept taken
ally done through a hospital safety officer from the airline industry where pilots are
or the biomedical engineering department only allowed to talk about landing at 10,000
and nurses only need to send basic infor- feet or below. See also Box 9-2.
mation to an individual who then collects The introduction of new technology has
all of the details. All problem reporting also helped reduce errors related to medica-
should be designed to be clear, simple, and tion administration. Computerized Physi-
efficient. Nurses should focus their time on cian Order Entry (CPOE) systems have been
patients and families and have support staff introduced in NICUs since around 2002.
work on risk reduction from their reports. These systems provide several advantages
Box 9-2. Medication Errors drug doses, and has allowed nurseries to use
standardized concentrations instead of the
Types of errors “rule of six” (mathematical formula used
Adverse drug event in the preparation of infusions for pediatric
Adverse reaction causing injury from a intensive care units and neonatal intensive
drug-related intervention care units, stating that the number of mil-
Administration ligrams of drug to be added to 100 mL of IV
Wrong fluid is equal to the weight (in kilograms) of
• Drug the child multiplied by six; when the fluid
• Patient is infused at 1 mL per hour, it will deliver
• Dose 1 µg/kg per minute).
• Technique Smart pumps incorporate computer tech-
• Time nology for storing drug information, making
• Route calculations, and checking entered patient
• Documentation information (weight and dose/kg/hour)
Omission errors against dosing parameters. These pumps
have reduced calculation errors and utilize
Pharmacy-related
premixed bags. Bar coding technology has
Dispensing error
reduced administration errors in that the
Labeling error (instructions or information)
drug, patient, and nurse are scanned at the
Education deficit
time of administration and electronically
Human factors checked against the medical record order.
Communication errors, phone or verbal Neonatal-specific medication information
Education deficit is now also available electronically and can
Order errors be loaded onto computer desktops for staff
• Ambiguous or incomplete access or downloaded into handheld devices
• Illegible handwriting for personal use. Neofax and the Pediatric
• Misplaced/missing zeros and decimal Dosage Handbook provide the most up-to-
points date accurate information. The Institute for
• Confirmation bias (errors induced by Safe Medication Practice (ISMP) provides
familiarity with procedures and materials) monthly safety alerts, and nurse advice alerts
Error reduction online. This publication includes articles
User friendly, non–punitive-based error about labeling problems, sound-alike, look-
reporting system alike drug (SALAD) errors, and recommen-
Rate collection method dations on safe practice based on national
Access to national reporting database, trends and safety initiatives, research, and
problems and solutions practical implementation guidelines for
Documentation of event safety measures. A strong relationship with
Planning for intervention when error occurs the pharmacy is essential in reducing medi-
Intradisciplinary error review process cation errors.76-78 A NICU pharmacy liaison
Identification of causes has a profound effect on the safety of medi-
Improvement or change in contributing factors cation dosing and monitoring. They have
Evaluation of intervention also been successfully employed to monitor
drug use when concerns of overuse or misuse
Adapted from Cohen MR, editor: Medication errors, have been identified. Similar liaisons should
ed 2, Washington, DC, 2007, American Pharmacists be developed with biomedical engineering,
Association. the safety officer, infection control nurse,
and risk management. These disciplines can
provide safety-specific consultations when
including legibility, electronic interface needed by NICU staff.
with the pharmacy, reduced turnaround It is essential to patient safety that teams
time for dispensing, a decrease in “rule (for- representing the NICU disciplines meet
mal policy, department-specific procedures, regularly to review reported errors in a sys-
or informal understandings) violations,” tematic way. Even though reports indicate
and an option to customize order screens only a fraction of actual errors made, they
to prompt safe dose and lock out doses that provide a representation of the types of
are too high or too low. Smart pump tech- errors that occur. Each error or “near miss”
nology is now available to calculate critical should be seen as an opportunity to make
changes that would decrease the probability

Ga) and ointment works well. The best option for the
of it being made again. The changes should
ECG electrodes is hydrogel adhesive.
be planned, assigned, and then evaluated to
see if they had the desired effect. This pro-
What are the best ways to approach
cess requires time, dedication, and a certain
bathing and moisturizing?
aptitude for the investigative process. These
teams operate under names such as prac- Areas of the skin that become soiled (with blood or
tice improvement, quality improvement, stool) can be cleansed with warm water and cotton
safety, and leadership. Practice improve- balls for the first 2 weeks. After this time, twice weekly
ment teams also improve safety by utiliz- baths with neutral pH cleanser are begun, with warm
ing the failure mode effect analysis (FMEA) water baths given on alternating days. Twice daily
process. This process in used to discover the application of petrolatum-based emollient promotes
potential risks in a product or a system by better skin barrier function.
examining ways that it might fail. It can be
used for introducing new equipment, pro- What is the safest way to prepare the skin
cedures, medications, and treatments. Once surface before invasive procedures?
identified, systems can be put into place to The skin is prepped with povidone-iodine or aque-
reduce these risks. Including a bedside nurse ous chlorhexidine solution before any procedure and
on this team is essential to the process. the disinfectant is then removed entirely with sterile
Serious complications and sentinel events saline water after the procedure. Isopropyl alcohol
should be reviewed using the Root Cause alone or disinfectants that contain isopropyl alcohol
Analysis (RCA) process. This can be down- are to be avoided until the skin matures because it
loaded from The Joint Commission website causes drying and can be absorbed. It has been re-
for a template of steps. This process includes ported to cause burns in the very low-birth-weight
selecting a team of disciplines involved in infant.
the event and selecting a leader who was not
involved in the incident and has experience
in the process. The steps leading to the event
are flow-charted. Once the steps are charted, CASE 2
there is discussion about the contributing B. N. is born at 32 weeks’ gestation after an uncom-
factors, both systems and human. A list of plicated delivery. She recovers from her respiratory
“root causes” is agreed on and action plans distress syndrome (RDS) and is on room air by 5 days
are created to address each root cause. NICUs of age. At 12 days, she is taking full enteral feeds,
require dedicated teams to look at systems but necrotizing enterocolitis (NEC) develops and
and human factors to keep patients safe and she requires resection of 13 cm of terminal ileum.
to provide an environment for staff that Postoperatively, she is managed on peripheral total
reduces their chance of making a mistake. parenteral nutrition (TPN). An IV infiltrate is found, and
the site, the left foot, is white and cool to the touch.
“There are some patients we cannot help, but
none that we cannot harm.” What is the recommended treatment of the
Florence Nightingale site?
Treatment is with hyaluronidase (Vitrase, Alliance
CASE 1 Medical Products, Irvine, Calif), 20 U injected subcu-
An infant born at 26 weeks’ gestation weighing 680 taneously in four or five sites surrounding the area of
g is admitted to the neonatal intensive care unit. His infiltrate. The 20 U is divided into 0.2 mL injections.
skin is extremely translucent in appearance, and
there is already an area of skin excoriation on the right Within what time frame should the treat
side of the chest where an electrocardiogram (ECG) ment occur?
electrode has been removed. The treatment should occur as soon as possible, but
is thought to be of benefit if instituted within 1 hour of
What is the recommended treatment for identifying the extravasation.
the area of excoriation?
This area can be covered with a transparent adhesive What is a logical alternate IV access in this
dressing to promote healing and reduce the risk of infant?
infection through the site, or coated with petrolatum- For this preterm infant needing TPN until the bowel
based emollient. The combination of a silicone dress- has rested and feedings are established, a percu-
ing (such as Mepitel, Mölnlycke Healthcare, Norcross, taneous central venous line is recommended. This
ccess would allow the infant to receive a high-calo-

a REFERENCES
rie, high-protein solution that would optimize wound The reference list for this chapter can be found
healing and growth. It would also provide long-term online at www.expertconsult.com.
access that would reduce time and pain associated
with intermittent IV insertion. This method has addi-
tional benefits in that it does not require an incision,
does not require vein ligation, and costs less to insert
than surgically placed venous catheters.
Respiratory
Problems
Richard J. Martin and Moira A. Crowley
10
When one considers the complexity of the to that observed in later life. Specifically,
pulmonary and hemodynamic changes occur- lung compliance (change in lung volume
ring after delivery, it is surprising that the expressed in mL of air/cm of H2O pressure
majority of infants make the transition from change/mL of lung volume) and vital capac-
intrauterine to extrauterine life so smoothly ity increase briskly in the first hours of life,
and uneventfully. Nonetheless, the staff reaching values proportional to those in the
working in the intensive care nursery spends adult.
a lion’s share of their time caring for neonates Chemical control of respiration is, in
with respiratory problems that are responsible general, similar in the newborn infant and
for much of the morbidity and mortality in the adult. As inspired (and arterial) Pco2 is
this period. increased, both infants and adults increase
their ventilation, although the neonatal ven-
PHYSIOLOGIC CONSIDERATIONS tilatory response is smaller. The ventilation
of the newborn is also transiently increased
NORMAL DEVELOPMENTAL CHANGES when inspired gas mixtures contain less
Before birth, the lung is a fluid-filled organ than 21% oxygen; this response suggests
receiving 10% to 15% of the total cardiac that the carotid body chemoreceptors are
output. Within the first minutes of life active at birth. The infant, however, differs
a large portion of the fluid is absorbed or from the adult in that if hypoxic exposure
expelled, the lung fills with air, and the continues beyond about 1 minute, respira-
blood flow through the lung increases eight- tion is depressed during the first weeks of
to tenfold. This considerable increase results life. Hypoxia thus appears to depress the
from a decrease in pulmonary arterial tone respiratory center, negating the hypoxic
and other physiologic changes that convert stimulation via peripheral chemoreceptors.
the circulation from a parallel arrangement This hypoxic respiratory depression in the
to a series circuit. newborn appears to depend on the presence
The high vascular resistance in the fetal of suprapontine structures in the brain. Even
lung is caused by pulmonary arterial vaso- though hypoxic respiratory depression may
constriction. The pulmonary arterial vaso- be useful to the fetus (who maintains a nor-
dilation observed following delivery results, mal Pao2 of 20 to 25 mm Hg), persistence
in part, from the large increase in oxygen of this phenomenon into postnatal life may
tension, from the small decrease in CO2 ten- enhance vulnerability of neonatal respira-
sion, and the corresponding increase in pH, tory control.
biochemical changes, such as elevated pros- The effects of pulmonary stretch recep-
taglandins, and from the mechanical effect tor activity on the timing of respiration
of lung inflation. (Hering-Breuer reflex) are more readily elic-
At the same time, an adequate functional ited in the newborn than in the adult. In
residual capacity (FRC = volume of air in the infants, a sustained increase in FRC causes
lungs at end expiration) is quickly attained. a marked slowing of respiratory rate by pro-
In healthy term infants, the first breaths are longing expiratory time.2 In the first days of
characterized by short deep inspirations and life, a brisk lung inflation causes a deep gasp
prolonged expirations through a partially (Head’s paradoxical gasp reflex) followed by
closed glottis to ensure lung inflation. In apnea, which is, again, a manifestation of
preterm infants, continuous positive airway the Hering-Breuer inflation reflex. The deep
pressure (CPAP) enhances lung inflation.1 gasp observed in the first day of life with
By 1 hour, the distribution of air with each low inflation pressures may explain the
breath in the newborn is already similar clinical observation that very low pressures
244
CHAPTER 10 Respiratory Problems 245
(10 to 15 cm H2O) are often effective in 100 °C

PH
20
Percent oxygen saturation

resuscitating the apneic newborn at birth PCO2
by stimulating a gasp reflex. 80 DPG
°C 15
The partial pressure of carbon dioxide PH
Volume (%)
PCO2
60
(Pco2) reflects the ability of the lung to DPG
10
remove CO2. The HCO3 concentration is
40
controlled by the kidney. When the pH and
CO2 are determined, the HCO3 can be cal- 20
5
culated by using the Henderson-Hasselbalch O2 dissolved in plasma
equation: 0 0
HCO3 10 30 50 70 90 100 300 500
pH = 6.1 + log Oxygen tension (mm Hg)
Pco2 × 0.03
Figure 10-1. Factors that shift oxygen dissociation curve
If only the pH is measured, the cause of of hemoglobin. Fetal hemoglobin is shifted to left as
the acidosis or alkalosis cannot be deter- compared with that of adult. DPG, Diphosphoglycerate.
(From Fanaroff AA, Martin RJ, Walsh MC, editors:
mined. With metabolic acidosis, HCO3
Neonatal-perinatal medicine, ed 9, Philadelphia, 2011,
is decreased. To compensate for this, the Elsevier.)
infant hyperventilates, lowering arterial
Pco2. With respiratory acidosis caused by
pulmonary disease, apnea, or hypoventila-
tion, the arterial Pco2 increases. The kid- globin (Hb) is 10 g/dL, then 9 g Hb is
ney attempts compensation by retaining bound to oxygen. Thus, the oxygen con-
HCO3 and excreting hydrogen ions. Only tent of this 100 mL sample is 12.06 mL
by measuring the Pco2 and pH and calcu- O2 bound to Hb (1.34 × Hb 9) + 0.15 mL
lating HCO3 can the cause of an abnormal- O2 (0.3 × Hb 50/100) dissolved in plasma
ity in acid-base balance be determined. for a total of 12.21 mL O2. Naturally, if
The normal newborn quickly regulates his the hemoglobin is doubled, then for the
or her pH to near adult values, although same saturation, the O2 transported by
HCO3 may be lower than normal adult hemoglobin is also doubled (1.34 × Hb
values. 18 = 24.12 mL O2) without changing the
amount dissolved. The dissociation curve
OXYGEN DELIVERY of fetal blood is shifted to the left and, at
Oxygen is carried in the blood in chemical any Pao2 less than 100 mm Hg, fetal hemo-
combination with hemoglobin and also in globin binds to more oxygen compared to
physical solution. The oxygen taken up by adult hemoglobin. The shift is the result
both processes depends on the partial pres- of the lower affinity of fetal Hb for diphos-
sure of oxygen (PO2). phoglycerate (DPG). In contrast, the dis-
At ambient pressures, the amount of dissociation curve is shifted to the right by
solved oxygen is only a small fraction of the increasing acidosis and temperature. The
total quantity carried in whole blood (0.3 clinical significance of the shift to the left
mL O2/dL plasma/100 mm Hg at 37° C). for fetal Hb is that fetal blood will take up
Most of the oxygen in whole blood is bound more oxygen at a given O2 tension (PO2).
to hemoglobin (1 g of hemoglobin can max- However, tissue PO2 will need to decrease
imally bind to 1.34 mL of oxygen at 37° C). to a lower level to unload adequate oxy-
The quantity of oxygen bound to hemoglo- gen. Thus, oxygen delivery to the tissues
bin depends on the partial pressure and is is determined by a combination of cardiac
described by the oxygen dissociation curve output, total hemoglobin concentration,
(Fig. 10-1). The blood is almost completely and hemoglobin oxygen affinity in addi-
saturated* at an arterial oxygen tension tion to arterial PO2.
(Pao2) exceeding 90 mm Hg. The shift in dissociation curve induced
As an example, if the arterial PO2 is by fetal hemoglobin makes clinical recog-
50 mm Hg, saturation is 90%, and hemo- nition of hypoxia (insufficient amount of
oxygen molecules in the tissues to cover the
*The arterial oxygen saturation is the actual oxygen bound
normal aerobic metabolism) more difficult,
to hemoglobin divided by the capacity of hemoglobin for
binding oxygen.
because cyanosis is observed at a lower oxy-
gen tension. Cyanosis is first observed at
mL O2 bound to Hb
% sat . = × 100 saturations from 75% to 85%, which corre-
Hb (g) × 1.34 spond to oxygen tensions of 32 to 42 mm Hg
246 CHAPTER 10 Respiratory Problems
on the fetal dissociation curve. Cyanosis

in the adult is observed at higher ten- 100
sions. The flattening of the upper portion
of the S-shaped dissociation curve makes 90
it almost impossible to monitor oxygen
tensions above 60 to 80 mm Hg by follow-
SpO2 (%)
80
ing arterial oxygen saturation. Although
the shape of the oxygen dissociation curve 70 Pre-ductal
limits the usefulness of pulse oximetry to Post-ductal
detect high Pao2 values, keeping satura-
60
tion measured via pulse oximeter between
92% and 95% is one of the most effective
and practical ways of reducing the risk of 50
1 2 3 4 5 6 7 8 9 10 1112 1314 15
hyperoxemia.
Minutes after birth
The partial pressure of oxygen in arterial
blood not only depends on the ability of the Figure 10-2. Pre- and postductal Spo2 levels during the
first 15 minutes after birth (median; IQR), inter quartile
lung to transfer oxygen, but also is modi-
ranges Postductal Spo2 levels were significantly lower than
fied by the shunting of venous blood into preductal Spo2 levels at 3, 4, 5, 10, and 15 minutes(*p <
the systemic circulation through the heart .05). (From Mariani G, Dik PB, Ezquer AJ, et al: Pre-
or lungs. Breathing 100% oxygen for a pro- ductal and post-ductal O2 saturation in healthy term
longed time partially corrects desaturation neonates after birth, J Pediatr 150[4]:418, 2007.)
resulting from alveolar hypoventilation,
diffusion abnormalities, or ventilation/per-
fusion inequality. Measurements of Pao2
while breathing 100% oxygen are, there- EDITORIAL COMMENT: Dawson et al. defined the
fore, useful diagnostically in determining reference ranges for pulse oxygen saturation (Spo2)
whether arterial desaturation is caused by values in the first 10 minutes after birth for 468 infants
an anatomic right-to-left shunt, in which who received no medical intervention in the delivery
case oxygenation will fail to improve the room. For all 468 infants, the 3rd, 10th, 50th, 90th, and
condition (hyperoxia testing). 97th percentile values at 1 minute were 29%, 39%,
After birth, Pao2 increases to between 66%, 87%, and 92%, respectively; those at 2 minutes
60 and 90 mm Hg. During the first days were 34%, 46%, 73%, 91%, and 95%; and those at
of life, 20% of the cardiac output is nor- 5 minutes were 59%, 73%, 89%, 97%, and 98%. It
mally shunted from right to left, in either took a median of 7.9 minutes (interquartile range: 5 to
the heart or lungs. When the normal adult 10 minutes) to reach an Spo2 value of >90%. Spo2
breathes 100% oxygen, Pao2 increases to values for preterm infants increased more slowly than
600 mm Hg as compared with approxi- those for term infants (see also Chapter 3).
mately 300 to 500 mm Hg in healthy neo-
Dawson JA, Kamlin CO, Vento M, et al: Defining the
nates, which results from the substantial reference range for oxygen saturation for infants after
shunting in infants. birth, Pediatrics 125:e1340, 2010.
At the end of the first hour of life, per-
fusion of the lung is distributed in pro-
portion to the distribution of ventilation.
In the healthy newborn baby, oxygen PRACTICAL CONSIDERATIONS
saturations rise slowly over the initial
few minutes of life, however, they do not OXYGEN THERAPY
reach 90% in the first five minutes. The Oxygen supplementation is critical for the
postductal oxygen saturation levels are survival of many infants with respiratory
usually lower than the preductal measure- problems. Previous restricted use resulted in
ments for as long as 15 minutes, indicat- an increase not only in mortality rate, but also
ing a persistence in elevated pulmonary in neurologic handicaps. Additionally, recog-
vascular resistance for a significant period nition of the toxic effects of excessive or pro-
of time after birth3 (Fig. 10-2). The speed longed oxygen therapy is imperative when
with which pulmonary ventilation and treating newborn infants. This has resulted in
perfusion is uniformly distributed is an curtailed use of supplemental oxygen during
indication of the remarkable adaptive neonatal resuscitation of both term and pre-
capacities of the newborn infant for the term infants (see Chapter 3). Therefore, oxy-
maintenance of homeostasis. gen administration must be performed with
great precision, while carefully monitoring concentration. Both inspired oxygen

arterial oxygen tension or assessing oxygen- concentration and flow rate are pre-
ation via noninvasive techniques. cisely adjusted and the infant’s oxy-
genation is closely monitored, typically
OXYGEN ADMINISTRATION via pulse oximetry. Administration of
For spontaneously breathing infants, a oxygen by nasal cannula requires close
small hood to provide supplemental oxygen monitoring because in active infants,
prevents fluctuations in inspired oxygen the cannula is easily displaced from the
when opening the incubator. This has been nose. Also, changes in respiratory pat-
largely replaced by low flow nasal cannulae tern and oral breathing may entrain
to deliver gas mixtures. Because improper different amounts of room air around
oxygen administration can be detrimen- the prongs, changing the true inspired
tal, the following practical considerations oxygen concentration. Finally, high gas
should be highlighted: flows via nasal prongs are under evalua-
1. Peripheral cyanosis may be present in a tion, although safety concerns remain.
neonate with a normal or high arterial 8. When the infant with respiratory dis-
oxygen tension. tress syndrome (RDS) is improving,
2. Inspired oxygen concentration should environmental oxygen should be low-
be continuously monitored in all ered in small decrements while contin-
infants receiving supplementary oxy- uously monitoring oxygenation.
gen or assisted ventilation. 9. Any inspired oxygen concentration
3. Oxygen therapy without concurrent above room air can be damaging to pul-
assessments of arterial oxygen tension monary tissue if maintained over sev-
is dangerous. A noninvasive monitoring eral days. Oxygen therapy is continued
device to measure oxygen saturation by only if necessary.
pulse oximetry or transcutaneous PO2 10. All premature infants 30 weeks’ ges-
should be used continuously in preterm tation or less, or older if they had an
infants receiving any supplemental unstable course or need for significant
oxygen. In the presence of an arterial supplemental oxygen, receiving addi-
line during the acute phase of illness, tional oxygen for extended periods of
measure Pao2 at least every 4 hours if time should be examined by an expe-
the infant is receiving oxygen. rienced ophthalmologist by the later of
4. In preterm infants, arterial oxygen ten- 31 weeks’ postmenstrual age (PMA) or
sion should be maintained between 50 four weeks after birth for treatable reti-
and 80 mm Hg during the acute phase nopathy of prematurity (ROP).5
of respiratory failure. In the absence of Carlo et al. performed a randomized trial
available Pao2 monitoring, SaO2 should with a 2-by-2 factorial design to compare tar-
be kept in the 90% to 95% range,4 get ranges of oxygen saturation of 85% to to
although this remains a subject of 89% or 91% to to 95% among 1316 infants
intense investigation. who were born between 24 weeks 0 days and
5. The development of retinopathy of pre- 27 weeks 6 days of gestation.4 The primary
maturity (ROP) is related to high arterial outcome was a composite of severe retinopa-
oxygen tension levels, and these may thy of prematurity (defined as the presence
rise above the normal range even with of threshold retinopathy, the need for surgi-
relatively low inspired oxygen con- cal ophthalmologic intervention, or the use
centrations. Whereas initial hyperoxia of bevacizumab), death before discharge from
stunts retinal vascular development, the hospital, or both. All infants were also
later hypoxia appears to stimulate dam- randomly assigned to CPAP or intubation and
aging vascular proliferation. surfactant. The rates of severe retinopathy or
6. When infants receiving supplemental death did not differ significantly between
oxygen require mask-and-bag ventila- the lower oxygen saturation group and the
tion, both oxygen concentration and higher oxygen saturation group. However,
inflating pressures must be monitored death before discharge occurred more fre-
closely. quently in the lower oxygen saturation group
7. Use of a nasal cannula for prolonged (in 20% of infants versus 16%; relative risk,
oxygen therapy allows greater mobil- 1.27; 95% CI, 1.01 to 1.60; P = .04), whereas
ity for the infant and enables oral severe retinopathy among survivors occurred
feeding without manipulating oxygen less often in this group (8.6% versus 17.9%;
relative risk, 0.52; 95% CI, 0.37 to 0.73; P Differential Diagnosis of Neonatal
<.001). There were no significant differences Box 10-1.
Respiratory Distress
in the rates of other adverse events. These
results have been replicated in another trial Pulmonary disorders
that terminated prematurely. Hence, because Respiratory distress syndrome
of concerns regarding the increased mortality Transient tachypnea
in the lower oxygen saturation group, despite Meconium aspiration syndrome
the better retinopathy outcome, the recom- Pneumonia
mendation has been to maintain the oxygen Air leak syndromes
saturation between 90% and 95%. Pulmonary hypoplasia
Systemic disorders
NEONATAL PROBLEMS Hypothermia
Metabolic acidosis
DIAGNOSIS Anemia/polycythemia
The initial objective is to establish an etiologic Hypoglycemia
diagnosis for any observed respiratory symp- Pulmonary hypertension
toms. A major error in care can easily be made Congenital heart disease
if other organ systems are not considered ini- Anatomic problems of the respiratory
tially. Not every rapidly breathing infant has system
respiratory distress syndrome or even respi- Upper airway obstruction
ratory disease. Hypovolemia, hyperviscos- Airway malformations
ity (polycythemia), anemia, hypoglycemia, Space-occupying lesions
congenital heart disease, hypothermia, met- Rib cage anomalies
abolic acidosis of any etiology, or even the Phrenic nerve injury
effects of drugs or drug withdrawal may all Neuromuscular disease
mimic primary respiratory disorders. Appro-
priate care depends on the diagnosis. For
example, rewarming should rapidly relieve unless there is deterioration as manifested by
respiratory symptoms in a mildly hypother- marked respiratory distress and an oxygen
mic infant; otherwise, sepsis must be strongly requirement exceeding 40% to 50%.
considered. Although the newborn has a relatively
A working classification of some of these larger cardiac output and a lower peripheral
disorders is presented in Box 10-1. When- resistance and blood pressure than the older
ever faced with these respiratory symptoms, child and adult, measurements of blood pres-
the next steps (following a history and sure must be routine. It has been shown that
physical examination) should be to obtain hypotension in sick preterm infants need not
the following: be associated with hypovolemia. Hypother-
• Chest x-ray mia or acidemia results in severe peripheral
• White blood cell count with differential vasoconstriction and will confound blood
and hematocrit (Peripheral hematocrits can volume estimates from measurement of blood
be higher than intravascular hematocrits.) pressure. In a hypovolemic infant, blood pres-
• Blood sugar sure often declines only after acidemia and
• Assessment of blood gas status via an arte- hypoxemia are corrected. Blood pressure can
rial stick or capillary blood gas. A capillary be measured with a blood pressure cuff of cor-
blood gas reliably estimates Paco2 and pH, rect size placed on one or all extremities (if
but not Pao2. coarctation of the aorta is suspected), employ-
• Pulse oximetry to assess oxygenation ing either oscillometric or Doppler ultrasound
The decision to catheterize the umbili- techniques. Alternatively, direct arterial mea-
cal artery (see Appendix D) depends on the surements may be made via indwelling cath-
infant’s condition. The umbilical artery and/ eters. Normal blood pressures and ranges may
or vein may need to be catheterized if sig- be found in Appendix C.
nificant metabolic acidosis or blood loss is If the initial hematocrit is less than 30%
suspected or if the infant remains severely without blood incompatibility or if the blood
distressed (as defined by continued hypox- pressure is reduced, it is reasonable to assume
emia and severe respiratory distress). On the blood loss (e.g., an acute fetomaternal hem-
other hand, if the infant has tachypnea and orrhage) and consider immediate correction
grunting with retractions but is active and of blood volume. With acute blood loss,
pink, it is possible to withhold catheterization hypotension prevails over anemia, whereas
after chronic blood loss, anemia dominates PHYSIOLOGIC ABNORMALITIES

the clinical picture and perfusion is less com- • Lung compliance reduced to as much as
promised. Saline is initially used and blood is one fifth to one tenth of normal (Fig. 10-3)
requested, starting with a push infusion of 10 • Large areas of lung not ventilated (right-
mL/kg, observing blood pressure, heart rate, to-left shunting of blood)6
and the infant’s general condition. One must • Large areas of lung not perfused
be extremely careful with rapid infusions of • Decreased alveolar ventilation and increased
any solution in the critically ill premature work of breathing
infant because of the risk of increasing the • Reduced lung volume
incidence of intraventricular hemorrhage These changes result in hypoxemia, often
(IVH) by rapid volume expansion. Once a hypercarbia, and, if hypoxemia is severe,
diagnosis has been made, it is necessary to metabolic acidosis.
determine whether the neonatal unit has all
of the facilities that might be needed during PATHOLOGIC FINDINGS (ANATOMIC,
the course of the illness. The following sec- BIOPHYSICAL, BIOCHEMICAL)
tion discusses RDS in great depth because • Gross—the lung is collapsed, firm, dark
this has been the primary model for under- red, and liver-like.
standing pathophysiology and management • Microscopic—alveolar collapse, with over-
of neonatal respiratory disease. distention of the dilated alveolar ducts,
pink-staining membrane on alveolar ducts
RESPIRATORY DISTRESS (composed of products of the infant’s
SYNDROME blood and destroyed alveolar cells); hence
RDS is still probably the most common ini- the earlier term hyaline membrane disease.
tial problem in the intensive care nursery • Electron microscopic—damage and loss
among premature infants, weighing less of alveolar epithelial cells (especially type
than 1500 g. However, in preterm infants II cells); disappearance of lamellar inclu-
whose mothers have received antenatal ste- sion bodies.
roids, and after postnatal intratracheal sur- • Biophysical and biochemical—deficient,
factant therapy, the characteristic clinical or absent pulmonary surfactant,7 espe-
course for RDS may not be apparent. The cially phospholipid (surface-tension low-
following lists give the common symptoms, ering) component; abnormal pressure
the physiologic abnormalities, and the volume curve, as shown in Figure 10-3.
pathologic findings.
ETIOLOGY
SIGNS AND SYMPTOMS The distal respiratory epithelium respon-
• Difficulty in initiating normal respiration. sible for gas exchange features two distinct
The disease should be anticipated if the
infant is premature, the mother has dia-
betes, or if the infant has suffered perina-
30
tal asphyxia.
• Expiratory grunting or whining (caused
by closure of the glottis), is a most impor-
tant sign that sometimes may be the only
Air volume (mL/g)
20 Normal
early indication of disease; this maintains
air in the immature lungs during expira-
tion, and a decrease in grunting may be Respiratory
the first sign of improvement. 10 distress
syndrome
• Sternal and intercostal retractions (sec-
ondary to decreased lung and increased
rib cage compliance)
• Nasal flaring 0 10 20 30 40
• Cyanosis (if supplemental O2 is inadequate) Pressure (cm H2O)
• Respirations—rapid (or slow when seri-
Figure 10-3. Air pressure volume curves of normal and
ously ill) abnormal lung. Volume is expressed as milliliters of air
• Extremities edematous—after several hours per gram of lung. Lung of infant with respiratory distress
(altered vascular permeability) syndrome (RDS) accepts smaller volume of air at all
• X-ray film showing reticulogranular, ground- pressures. Note that deflation pressure volume curve
glass appearance with air bronchograms closely follows inflation curve for the RDS lung.
cell types in the mature infant lung. Type surfactant pool size without inhibiting
I pneumocytes cover most of the alveolus, endogenous surfactant production.7
in close proximity to capillary endothelial It is widely accepted that RDS is the
cells. Type II cells have been identified in result of a primary absence or deficiency
the human fetus as early as 22 weeks’ ges- of this highly surface-active alveolar lining
tation, but become prominent at 34 to 36 layer (pulmonary surfactant). Surfactant, a
weeks of gestation. These highly meta- complex lipoprotein rich in saturated phos-
bolically active cells contain the cytoplas- phatidylcholine molecules, binds to the
mic lamellar bodies that are the source of internal surface of the lung and markedly
pulmonary surfactant. Surfactant synthe- lessens the forces of surface tension at the
sis is a complex process that requires an air-water interphase, thereby reducing the
abundance of precursor substrates, such pressure tending to collapse the alveolus. By
as glucose, fatty acid, and choline, and a equalizing the forces of surface tension in
series of key enzymatic steps that are reg- alveolar units of varying size, it is a potent
ulated by various hormones, including anti-atelectasis factor and is essential for
corticosteroids. normal respiration. Alteration or absence of
Phosphatidylcholine is the dominant the pulmonary surfactant would lead to the
surface tension-lowering component of sequence of events shown in Figure 10-4.
surfactant. In addition, surfactant-specific This results in decreased lung compliance
proteins have been characterized and their (stiff lung) and thus an increase in the work
functions partially elucidated. Of particular of breathing. The additional work would
interest is surfactant protein B (SP-B), which soon tire the infant, leading to a sequence
is critical for minimizing surface tension and of reduced alveolar ventilation, atelectasis,
whose absence results in the phenotypic and alveolar hypoperfusion.
expression of lethal RDS at term.8 Follow- Asphyxia would induce pulmonary vaso-
ing secretion from lamellar bodies within constriction; blood would bypass the lung
the type II alveolar cells, the key phospho- through the fetal pathway (patent ductus
lipid and protein components of surfactant arteriosus, foramen ovale), lowering pulmo-
are conserved by recycling and subsequent nary blood flow; and a vicious circle would
regeneration of surfactant. Exogenously be promoted. The resulting ischemia would
administered surfactant appears to contrib- be an added insult and may further reduce
ute to this recycling program by increasing lung metabolism and surfactant production.
Surfactant Structural
Deficiency Immaturity
Atelectasis
V/Q inequality Hypoventilation
Hypoxemia + hypercarbia
Respiratory and metabolic High inspired O2 and

acidosis barotrauma
Epithelial and endothelial

Pulmonary injury Inflammatory cell,
vasoconstriction cytokine influx
Figure 10-4. Pathophysiology

of neonatal respiratory distress
syndrome (RDS). V̇ / Q̇ . Ventilation-
RDS/Lung Injury
perfusion ratio.
GENERAL PREVENTIVE MEASURES tube resulted in a dramatic decrease in

A major effort in treating this disease should inspired oxygen and ventilator pressures.
continue to focus on its prevention, includ- Other studies confirmed this initial suc-
ing elective cesarean deliveries performed cess, employing calf and pig lung extract,
without adequate documentation of pulmo- pooled human surfactant obtained from
nary maturity from amniotic fluid testing. amniotic fluid, and purely synthetic phos-
The prolongation of pregnancy with bed pholipid preparation.14
rest or drugs that inhibit premature labor, as Subsequent collaborative multicenter trials
well as the induction of pulmonary surfac- employed multiple doses of purely synthetic
tant with maternally administered steroids, and mixed natural/synthetic preparations
plays an important role in reducing the inci- and confirmed clinical efficacy, leading in
dence of this disease (see Chapter 2). the 1990s, to the widespread introduction of
Antenatal steroids not only enhance sur- exogenous surfactant therapy into neonatal
factant production but also may improve care. The most efficacious mixed surfactant
pulmonary function (e.g., tissue elasticity) products are all protein-containing prepara-
by non-surfactant mechanisms.9 Therefore, tions derived from bovine or porcine tissue.
the combined use of prenatal corticoste- Both prevention (delivery room administra-
roids and postnatal surfactant therapy is tion) and rescue (administration for estab-
complementary.10 Antenatal steroids also lished RDS) protocols have their advocates.15
reduce the incidence of periventricular Of particular interest, as summarized in Box
hemorrhage in preterm infants, possibly 10-2, is the ability of surfactant to decrease
secondary to enhanced vascular integrity
in the germinal matrix. Concern about the
possibility of increased infection with ante- Surfactant Therapy for
Box 10-2.
natal steroids in mother or infant appears Respiratory Distress Syndrome
unfounded. Therefore, antenatal steroids
Resolved
are now standard of practice for pregnan-
Greatest benefit when combined with
cies at risk of preterm delivery, although
antenatal corticosteroids
precise limits are still being defined. Thy-
Major surface tension-lowering ingredient:
roid hormones enhance surfactant produc-
phosphatidylcholine
tion; however, maternally administered
Administration of fluid suspension requires
thyrotropin-releasing hormone (TRH) com-
endotracheal tube
bined with antenatal steroids failed to offer
Improvement in arterial oxygenation
any advantage over glucocorticoid therapy
Surfactant proteins enhance speed of action
alone.11
Exogenous surfactant enhances rather than
SURFACTANT THERAPY inhibits endogenous surfactant synthesis
Decrease in incidence of air leaks
Since the discovery that surfactant defi-
Improved mortality rate
ciency was a prominent feature of the
Prevention more effective than rescue up to
pathophysiology of RDS, investigators
<29 weeks
have attempted to administer artifi-
cial aerosolized phospholipids to these Unresolved
infants.12 Limited therapeutic success was Ideal preparation: role of surfactant proteins in
encountered in these early studies. In con- improving respiratory function
trast, animal models, in which natural Role of ventilatory strategy in optimizing sur-
surfactant compounds were used, yielded factant response-rapid wean to nasal CPAP
promising results. This stimulated Fujiwara Effect on incidence and severity of chronic
et al. to develop a mixture of both natu- lung disease
ral and synthetic surface-active lipids for Role of surfactant therapy in other neonatal
use in humans.13 The goal was to achieve respiratory disorders: meconium aspiration,
alveolar stability with less potential risk for pneumonia, pulmonary hypoplasia, con-
a reaction to foreign protein than would genital diaphragmatic hernia, pulmonary
be the case with exclusively natural sur- hemorrhage
factant. When administered to an initial
group of 10 preterm infants with severe Adapted from Hamvas A: Pathophysiology and
management of respiratory distress syndrome. In
RDS who were not improving despite arti-
Martin RJ, Fanaroff AA, Walsh MC, editors: Neonatal-
ficial ventilation, a single 10-mL dose of perinatal medicine, ed 9, St. Louis, 2011, Elsevier.
surfactant instilled into the endotracheal
the number of deaths in low-birth-weight received CPAP treatment, as compared with infants
infants without significantly reducing the who received surfactant treatment, less frequently re-
incidence of bronchopulmonary dysplasia quired intubation or postnatal corticosteroids for BPD
(BPD) in the smallest infants. The latter may (P <.001), required fewer days of mechanical venti-
be a consequence of the enhanced survival lation (P = .03), and were more likely to be alive and
caused by surfactant administration to very free from the need for mechanical ventilation by day 7
preterm infants or to the multifactorial etiol- (P = .01). The rates of other adverse neonatal outcomes
ogy of BPD. did not differ significantly between the two groups.
Surfactant therapy currently requires the These data support consideration of CPAP as an alter-
presence of an endotracheal tube, although native to intubation and surfactant in preterm infants.
less invasive techniques of administration
are under study. Multiple doses may be SUPPORT Study Group of the Eunice Kennedy Shriver
needed for optimal benefit. The dramatic NICHD Neonatal Research Network, Finer NN, Carlo
WA, Walsh MC, et al: Early CPAP versus surfactant in
improvement in oxygenation is not accom- extremely preterm infants, N Engl J Med 362:1970, 2010.
panied by an immediate improvement in
Paco2 or lung compliance unless ventilator
settings are rapidly weaned.16 Data suggest
that the increase in lung volume, induced GENERAL CLINICAL MANAGEMENT
by surfactant, needs to be accompanied by The same principles of basic care for RDS can
ventilator and supplemental oxygen wean- be applied to infants with many other neo-
ing. Hypotension and bradycardia may natal pulmonary problems. During the acute
occur acutely during surfactant therapy; phase, every maneuver is directed toward
therefore, caution must be exercised when ensuring the infant’s survival with mini-
using this treatment to avoid potential iat- mal risk of chronic morbidity. The infant
rogenic complications. is placed in a neutral thermal environment
Since the genes that code for the sur- (see Chapter 6) to reduce oxygen require-
factant proteins have been characterized, ments and CO2 production. To meet fluid
recombinant DNA technology will make and partial caloric requirements (dependent
production of modified human surfactant on environmental conditions, maturity,
proteins possible. In combination with syn- renal function, risk for patency of the duc-
thetic phospholipids, this will allow the tus arteriosus, and hydration), the infant is
widespread availability of a protein-con- typically begun at 60 to 80 mL/kg/day of a
taining artificial surfactant. Although no 10% dextrose solution. This is increased to
adverse immunologic consequences of for- 120 to 160 mL/kg/day by the fifth day, rec-
eign tissue protein administration have yet ognizing that there is a high risk for either
been reported in the recipients of natural fluid overload or dehydration if clinical sta-
surfactant therapy, close follow-up of these tus, fluid balance, and electrolytes are not
high-risk survivors of neonatal intensive closely monitored in the smallest infants
care is always imperative. with RDS, who may require much more
than 160 mL/kg/day. Administration of an
amino acid solution should begin the first
EDITORIAL COMMENT: There are limited data to in-
day, supplemented with small volume feeds
form the choice between early treatment with CPAP
as respiratory status stabilizes. Respiration,
and early surfactant treatment as the initial support
heart rate, blood pressure, and oxygenation
for extremely low-birth-weight infants. Finer et al. ran-
(via noninvasive techniques) are monitored
domly assigned 1316 immature infants to intubation
continuously and complemented by blood
and surfactant treatment (within 1 hour after birth) or
gas sampling at least every 4 to 6 hours dur-
to CPAP treatment initiated in the delivery room, with
ing the acute phase of illness.
subsequent use of a protocol-driven limited ventilation
Most important in the prescription is
strategy. Infants were also randomly assigned to one
skilled nursing and physician management.
of two target ranges of oxygen saturation.4 The primary
Vital signs must be noted and observa-
outcome was death or BPD as defined by the require-
tions made in such a fashion as not to dis-
ment for supplemental oxygen at 36 weeks (with an
turb the infant continually, yet the patient
attempt at withdrawal of supplemental oxygen in ne-
must always be observed. Modern electronic
onates who were receiving less than 30% oxygen).
monitoring of heart rate, respiration, tem-
The rates of the primary outcome did not differ sig-
perature, and oxygenation makes gentler
nificantly between the CPAP group and the surfactant
care easier to administer. Noninvasive mon-
group (47.8% and 51.0%, respectively). Infants who
itoring of oxygenation has confirmed the
importance of minimizing simple maneu- Almost all infants with RDS require venti-
vers such as taking a rectal temperature, latory support in the form of CPAP. Some of
vigorous oral, pharyngeal, or endotracheal these infants do not stabilize on CPAP and
suctioning, and vigorous auscultation of the require ventilator support and surfactant
chest. The real skills of a unit can be tested therapy (Fig. 10-5). Indications for placing
by noting attentiveness to small details in an infant on a ventilator include: respira-
neonatal respiratory management. Is the tory acidosis with a pH of less than 7.20,
environmental oxygen at the correct per- apnea, and/or a need for a high concentra-
centage and flow rate? Is the arterial oxygen tion of inspired oxygen (i.e., ≥40%).
permitted to go too high or too low for a Other criteria for a ventilator include a
prolonged period? Does the unit anticipate respiratory acidosis with a pH of less than
future needs of the infant or does it always 7.20 (and possibly 7.25) and apnea compli-
treat complications? As an example, if dur- cating the course of RDS.
ing the acute phase, an infant with RDS has After 72 hours of age (or earlier after sur-
increasing apneic episodes, it usually signi- factant therapy), most infants with classic
fies that the infant’s condition is deteriorat- RDS start the recovery phase. Respiratory rate
ing and additional intervention is indicated. and retractions decrease, and Pao2 increases
Waiting for a Pao2 of 30 mm Hg and a severe without evidence of further CO2 retention.
respiratory and metabolic acidosis before
beginning ventilatory therapy is not ade- EDITORIAL COMMENT: This recovery phase is pre-
quate anticipation. While basic care is being ceded by a period of spontaneous diuresis during which
arranged (metabolic rate minimized, fluid there is improved gas exchange, lung compliance, and
and electrolyte needs met), the essentials of functional residual capacity. Since the improved pulmo-
care involve maintaining an adequate Pao2 nary function occurs after diuresis, it is important that
and pH and closely observing for changes in the clinician anticipate the recovery phase and reduce
the infant’s state. ventilatory support to prevent barotrauma.
A general plan is to maintain the Paco2 Waldemar Carlo
in the abdominal aorta between 50 and 80
mm Hg, Paco2 in the 40 to 55 mm Hg range,
and pH above 7.25. Because clinical differen- During this phase, expertise in oxygen
tiation from group B streptococcal (or other management is required. Oxygen satura-
bacterial) pneumonia is not possible, a blood tion via pulse oximetry is the mainstay
culture should be obtained and antibiotics of assessing oxygenation during recov-
should be administered for at least 48 hours. ery of respiratory distress. Levels are typi-
It is equally important to discontinue broad- cally maintained between 90% and 95%,
spectrum antibiotics as soon as the pos-
sibility of infection is ruled out to prevent
nosocomial fungal and bacterial infections. Management of RDS
Correction of severe metabolic acidosis

Initiate CPAP
with alkali has many theoretical physiologic
benefits. With normalization of pH, myo- Sustained respiratory Apnea or FiO2 0.4
cardial contractility is increased, pulmonary effort and FiO20.4
vascular resistance is reduced, and the length Continue CPAP
of survival with asphyxia is prolonged. *
However, the rapid injection of hypertonic FiO2 0.4; FiO20.4;
solutions such as NaHCO3 is associated pH 7.2 pH7.2
with a marked change in osmolality. Stud- Maintain Intubate for
ies have revealed that excessive and rapid strategy surfactant
NaHCO3 administration may be associated *
with an increased incidence of intracranial *Obtain ABG FiO20.3; pH 7.25 FiO2 0.3
hemorrhage.17,18 Current consensus is that
Rapid extubation Redose
NaHCO3 administration is of very limited
to CPAP or surfactant
benefit.19 Because administered NaHCO3 is nasal IPPV
converted to CO2 and is dependent on the Figure 10-5. Algorithm suggesting management strategy
lung for its removal, NaHCO3 is contraindi- of respiratory distress syndrome (RDS). ABG, Arterial blood
cated in the presence of respiratory acidosis gas; CPAP, continuous positive airway pressure; Fio2,
without some form of controlled or assisted fraction of inspired oxygen; IPPV, intermittent positive-
ventilation if it is to be administered. pressure ventilation.
although determination of the optimal satu- before initiating either pharmacologic or

ration within this range is still under study. surgical closure of the ductus arteriosus (see
In infants of very low-birth-weight, even Chapter 15). (Table 10-1). Although prophy-
in the absence of severe RDS over the first few lactic indomethacin administration appears
days, recovery may be prolonged. This may to reduce the frequency of large left-to-right
be attributed to impaired respiratory drive ductal shunts, there is no clear evidence that
or respiratory muscle failure, persistent atel- routine early indomethacin therapy reduces
ectasis not related to surfactant deficiency, longer-term morbidity in susceptible infants.
nutritional compromise, intercurrent infec- An additional benefit of prophylactic indo-
tion, congestive heart failure, or some com- methacin may be to decrease the incidence
bination of these interrelated factors. of IVH. Ibuprofen therapy also promotes
Enteral feedings can begin during the ductal closure and is less likely to impair
recovery phase, when bowel sounds are renal blood flow and renal function when
present, and respiratory status has stabi- compared to indomethacin. Surgical closure
lized. Many very low-birth-weight infants should be a last resort as infants subject to
require prolonged assisted ventilation and ductal ligation may be at greater risk for later
prolonged supplemental oxygen. Small vol- neurodevelopmental impairment. The case
ume gavage feeds, preferably of breast milk, problems and questions in this chapter fur-
can begin, despite continuing ventilatory ther illustrate the care of these infants.
support. This is a valuable adjunct to amino
acid-glucose IV alimentation. As the infant PERSISTENT PULMONARY
recovers, apneic periods may be observed, HYPERTENSION
but they do not have the ominous signifi- Persistent pulmonary hypertension (PPHN),
cance as when observed in the acute phase. rather than the previous nomenclature, per-
The complications of RDS may occur sistent fetal circulation (PFC), more aptly
spontaneously or result from well-intended describes the syndrome characterized by
therapeutic interventions. Major problems pulmonary hypertension resulting in severe
may be a consequence of arterial catheter hypoxemia secondary to right-to-left shunt-
placement, oxygen administration, mechan- ing through the foramen ovale and ductus
ical ventilation, and the use of endotracheal arteriosus in the absence of structural heart
tubes, as discussed in Chapter 11. As the disease. Pulmonary hypertension in these
number of very low-birth-weight survivors infants is thought to result from pulmonary
grows, the time and effort devoted to pre- vasospasm, presumably because of altered
venting and treating respiratory morbidity pulmonary vasoreactivity and, at times, it
in this population steadily increases. may be accompanied by an increase in mus-
During or following the recovery phase cle mass in the pulmonary vascular bed. The
of RDS, cardiac failure secondary to a large increase in pulmonary arterial smooth mus-
left-to-right shunt through the patent ductus cle tone may develop in response to intra-
arteriosus may occur as pulmonary vascular uterine stress and can be associated with a
resistance declines. This may initially mani- decrease of a circulating (or local) pulmo-
fest as inability to wean oxygen or ventilator nary vasodilator such as nitric oxide (NO)
support. Bounding pulses, a wide pulse pres- or an increase in the amount of circulating
sure, and a systolic murmur are most useful (or local) pulmonary vasoconstrictors such
in making a clinical diagnosis. In most cases, as endothelin. This syndrome was initially
conservative medical management with cau- described in term infants with respiratory
tious fluid administration and diuretics will distress and cyanosis without demonstrable
control the congestive heart failure, and the cardiac, pulmonary, hematologic, or cen-
patent ductus arteriosus will close as the tral nervous system (CNS) disease. How-
infant grows. Although the patent ductus ever, this same hemodynamic pattern can
arteriosus will close spontaneously in most occur in preterm and term infants with
cases, intervention to close it may reduce the primary pulmonary disease (e.g., surfac-
risk of chronic pulmonary overflow, edema, tant deficiency, pneumonia, or meconium
and prolonged ventilator dependence. aspiration syndrome), polycythemia, or
Although cardiomegaly is often noted on pulmonary hypoplasia (e.g., congenital dia-
x-ray examination, an enlarged liver and phragmatic hernia) or following neonatal
edema are not usually found with cardiac fail- asphyxia. Among preterm infants, pulmo-
ure. Evaluation of the magnitude of shunt- nary hypoplasia and sepsis appear to be asso-
ing by echocardiography is usually indicated ciated with a higher incidence of pulmonary
hypertension.20 Sometimes no clear etiol- The management of PPHN can be com-

ogy for the PPHN or underlying lung dis- plex and very difficult, because the severe
ease can be assigned. The result is cyanosis, hypoxemia may be poorly responsive to high
tachypnea, and acidemia, which can super- oxygen therapy or pulmonary vasodilators.
ficially resemble cyanotic congenital heart Every attempt should be made to anticipate,
disease, primary pulmonary disease, or car- and possibly prevent, the development of
diomyopathy. The initial roentgenographic PPHN in patients with severe meconium
descriptions of PPHN stressed the absence aspiration syndrome or neonatal pneumo-
of pulmonary parenchymal disease and nia, and early and aggressive treatment of
decreased vascular markings; however, the hypoxemia should be provided. These babies
chest x-ray study may, instead, reflect the are exquisitely sensitive to changes in envi-
concurrence of underlying pulmonary dis- ronmental oxygen. Most require an environ-
ease such as meconium aspiration or pneu- mental oxygen approaching 100% and may
monia. Echocardiography is invaluable as a show little improvement without mechani-
guide to assessing elevated pulmonary artery cal ventilation. Some infants have benefited
pressure and pulmonary vascular resis- from modest alkalinization, brought about
tance and, more importantly, as a means of by hyperventilation or the administration of
excluding most anatomic cardiac malforma- NaHCO3, which may relieve the intense pul-
tions (see Chapter 15) and demonstrating monary vasospasm and allow oxygenation
right-to-left shunting at the level of the fora- to improve. This approach has mainly been
men ovale and ductus arteriosus. abandoned with the focus on improving
Table 10-1. Supportive Care for Infants with Respiratory Distress Syndrome
Treatment Logic
Trained staff nurses, respiratory therapists, and Early management of complications and notification of change
monitoring equipment in course (e.g., apnea, bleeding from catheter)
Available trained physicians, nurse practitioners
Precise temperature control to maintain infant in Maintains minimal oxygen consumption and carbon dioxide
neutral temperature production
pH, Pao2, Paco2, and HCO3 measurements at Permits continual assessment of infant’s condition and limits
least every 4-6 hr. Maintain Pao2 at 50-80 mm Hg. toxic effects of oxygen or hypoxic injury
Continuous Pao2 or Sao2 is optimal.
Monitor blood pressure. Recognizes hypoperfusion, hypovolemia, patent ductus arteriosus
Attempt to keep pH >7.25. If Paco2 >60 or Permits continual assessment of infant’s condition and limits
Pao2 <50 mm Hg, change treatment. toxic effects of oxygen or hypoxic injury
Lower environmental oxygen slowly when RDS Prevents greater than expected decrease in Pao2 when
infant is still ill. environmental oxygen is reduced (right-to-left shunt etiology?)
Surfactant therapy (requires endotracheal tube) Therapeutic approach to underlying etiology of RDS
Glucose-containing IV fluid 60 mL/kg first day, 80-100 Need to balance fluid and partial caloric requirements while
mL/kg second day with body weight determination minimizing the risk of fluid overload problems (e.g., patent duc-
for small infants to calculate if larger amounts of H2O tus arteriosus)
required. May require 150 mL/kg or more.
Controlled oxygen administration: via ventilatory Prevents large swings in environmental oxygen concentration
support, cannula, or hood
Continually monitor respiration, heart rate, and Prevents hypoxemia and acidemia with apneic episodes
temperature as well as blood pressure.
Frequent determinations of blood sugar, Necessary for calculating general metabolic requirements
hematocrit and electrolytes (Na, K, and Cl)
Transfuse if central hematocrit <35 during acute For adequate oxygen-carrying capacity
phase of illness
Record all observations (laboratory, nurse’s notes, Permits immediate correlation of many variables
etc.) on single form.
Urinary output, blood urea nitrogen, creatinine, Evaluation of renal function and blood flow to the kidney
and when indicated, urinary pH, electrolytes, and An increase in output occurs as the infant starts to improve.
osmolality
Obtain blood culture; treat with ampicillin and Cannot radiographically separate RDS from group B streptococ-
gentamicin until cultures are available. cal (or other) pneumonia
Minimize routine procedures such as suctioning, Prevents iatrogenic decreases in Pao2
handling, and auscultation.
RDS, Respiratory distress syndrome.

oxygenation and decreasing pulmonary vas- More data suggest that sildenafil, an inhibi-
cular resistance with inhaled nitric oxide. tor of cGMP-specific phosphodiesterase,
Similarly, Pao2 is maintained at the upper may effectively induce pulmonary vasodi-
recommended levels (80 to 100 mm Hg) to lation by increasing endogenously released
minimize hypoxic pulmonary vasoconstric- cGMP.22 Nonetheless, ECMO remains a life-
tion while minimizing barotrauma. Polycy- saving treatment modality in infants who
themia, hypoglycemia, hypocalcemia, and fail to respond to ventilatory and pharma-
hypotension should be treated if present. In cologic management of severe PPHN.23
fact, maintenance of systemic blood pres-
sure at the high range of normal is often MECONIUM ASPIRATION SYNDROME
required to exceed excessively high pulmo- Meconium is present in the amniotic fluid
nary artery pressures and thereby counteract in 10% of all births, and its presence sug-
right-to-left shunting. Pharmacologic pres- gests that the infant may have suffered some
sor support (e.g., dopamine or dobutamine) asphyxial episode in utero. Evidence of this
may be preferable to volume expansion, is derived from studies such as postmor-
because excessive fluids are poorly tolerated. tem data demonstrating severe structural
Adequate sedation and, at times muscle abnormalities in the muscular walls of the
paralysis, may be necessary to combat the pulmonary arterial vascular bed, suggesting
hypoxemia associated with agitation. chronic in utero hypoxia in infants with
A major breakthrough in the treatment fatal meconium aspiration.24 It is doubtful
of PPHN has been the use of inhaled nitric that amniotic fluid alone can produce any
oxide (NO) at doses of 20 ppm or less to airway obstruction. However, pulmonary
produce pharmacologic selective pulmo- disease is definitely observed in infants
nary vasodilation without producing sig- who have aspirated meconium (Fig. 10-6),
nificant systemic hypotension. Among and mortality and morbidity are significant
preterm infants, the likelihood of a success- without immediate aggressive management.
ful response to inhaled NO increases with Interestingly, the passage and subsequent
advancing gestational age.20 Inhaled NO, aspiration of meconium are almost never
together with other therapeutic approaches seen before 34 weeks’ gestation.
such as surfactant therapy and high fre- In order to prevent significant morbidity
quency ventilation, has been reported to and mortality associated with meconium
significantly reduce the need for ECMO.21 aspiration, traditional practice has been that
Meconium aspiration
Mechanical Chemical Surfactant

obstruction inflammation inactivation
Air trapping Atelectasis
Uneven Intrapulmonary
ventilation shunting
Persistent
Air leaks Hypoxemia, pulmonary
acidosis hypertension
Figure 10-6. Pathophysiology of cardiorespiratory problems accompanying meconium aspiration syndrome.
every infant with frank meconium staining lung; differentiation from pneumonia and
of the amniotic fluid requires the following retained lung fluid may be difficult.
preventive measures: The lung can remove meconium rapidly.
1. Immediate suctioning of the nasophar- Infants with mild cases usually recover after
ynx by the obstetrician as soon as the 48 hours of life. However, in sicker infants,
head appears on the perineum. Interest- respiratory compromise may be severe, with
ingly, this practice of routine intrapar- mechanical obstruction, hyperinflation, and
tum suctioning of the upper airway may atelectasis producing severe gas maldistribu-
not decrease the incidence of meconium tion with ventilation-perfusion mismatching.
aspiration syndrome.25 One complication of partially blocked, over-
2. If there is cardiorespiratory depression expanded areas of lung, occurring in 20% to
immediately after delivery, visualiza- 50% of infants with MAS, is the development
tion of the cords by laryngoscopy and of air leaks, such as pneumothorax. Pneu-
direct suctioning of the trachea through mothorax should be suspected if the clini-
an endotracheal tube. This endotracheal cal status of the infant deteriorates suddenly.
suctioning should be done before stimu- Additional pulmonary pathology caused
lation of the infant or positive pressure by meconium aspiration includes chemical
ventilation, although this population pneumonitis, interstitial edema, and surfac-
has not been subjected to a well-designed tant inactivation. Frequently, PPHN with
randomized trial. severe superimposed hypoxemia develops in
Because asphyxia is often the basis for infants with significant meconium aspiration
the presence of meconium in the amniotic syndrome (see Fig. 10-6). Respiratory failure
fluid, the infant who aspirates meconium at is associated with a significant mortality rate
birth is often depressed and requires some in these infants. Several studies have demon-
resuscitation. Positive pressure resuscitation strated that surfactant replacement therapy
should be delayed in these infants if possible improves oxygenation, reduces pulmonary
until adequate laryngotracheal toilet has air leaks, reduces the need for ECMO, and
been performed, to prevent pushing meco- improves outcome in infants with meco-
nium farther into the small airways. Current nium aspiration syndrome.27 Nevertheless,
recommendations do not include aggres- severe respiratory failure and hypoxemia
sive laryngotracheal suctioning in vigor- may require additional treatment modalities
ous infants (see Chapter 3). In support of such as high frequency ventilation and nitric
a conservative approach to such infants, a oxide administration, with ECMO therapy
multicenter, multinational trial to assess for those who fail to respond.
whether intubation and suctioning of appar-
ently vigorous, meconium-stained neonates
would reduce the incidence of meconium-
EDITORIAL COMMENT: Dargaville et al. conducted a
aspiration syndrome (MAS) enrolled 2094
randomized controlled trial that enrolled 66 ventilated
neonates. Compared with expectant man-
infants with meconium aspiration syndrome. Infants
agement, intubation and suctioning of
randomized to lavage received two 15-mL/kg aliquots
the apparently vigorous meconium-stained
of dilute bovine surfactant instilled into, and recovered
infant did not result in a decreased incidence
from, the lung. Control subjects received standard
of MAS or other respiratory disorders. There
care, which in both groups included high-frequency
were few and only short-lived complications
ventilation, nitric oxide, and where available and nec-
of intubation. Obstetricians have applied
essary, ECMO. Fewer infants who underwent lavage
transcervical amnioinfusion in labor when
died or required ECMO: 10% (3 to 30) compared with
meconium-stained amniotic fluid is present;
31% (11 to 35) in the control group. Lavage transiently
however, a conclusive positive effect on neo-
reduced oxygen saturation without substantial heart
natal outcome remains to be demonstrated.26
rate or blood pressure alterations. Mean airway pres-
Meconium aspiration syndrome is char-
sure was more rapidly weaned in the lavage group after
acterized by respiratory distress ranging
randomization. Thus, lung lavage with dilute surfactant
from tachypnea to gasping respirations.
does not alter duration of respiratory support, but may
Rales and wheezing may be heard. The
reduce mortality, especially in units not offering ECMO.
infant may appear barrel-chested with an
increase in the anteroposterior diameter of Dargaville PA, Copnell B, Mills JF, et al: Less MAS Trial
the chest. A chest radiograph shows areas of Study Group: Randomized controlled trial of lung lavage
with dilute surfactant for meconium aspiration syndrome,
increased density and areas of overexpan-
J Pediatr 158:383-389.e2, 2011.
sion irregularly distributed throughout the
will differentiate a pneumothorax from a

PNEUMOTHORAX pneumomediastinum.
Pulmonary air leaks comprise a spectrum Clinical findings include cyanosis, tachyp
of disorders that includes pneumomedia nea, grunting, nasal flaring, or intercostal
stinum, pneumopericardium, pulmonary retractions. If the pneumothorax is unilat-
interstitial emphysema, and pneumothorax. eral and under tension, the cardiac impulse
An asymptomatic pneumothorax is found may be shifted away from the affected
in approximately 1% of all routine newborn side and ipsilateral breath sounds may be
chest radiographic examinations. Consider- decreased. A distended abdomen with an
ing the high negative intrathoracic pressures easily palpable liver or spleen pushed down
recorded during the first minutes of life, it is by the diaphragm is often a useful clinical
surprising that pneumothorax does not occur feature signifying a tension pneumotho-
more frequently. When air leak occurs, air rax. This may be useful in differentiating a
from the ruptured alveolus dissects up the vas- left-sided tension pneumothorax manifest-
cular sheath into the mediastinum and from ing in the delivery room from a (typically
there into the pleural space. In some series, left-sided) congenital diaphragmatic hernia.
as many as half of the symptomatic patients Both are characterized by mediastinal shift
had aspirated meconium or blood. This sug- to the right hemithorax; however, in the
gests that obstruction with a ball-valve action hernia patient, a scaphoid (rather than dis-
may be the basis for the rupture. A pneumo- tended) abdomen is a presenting feature.
thorax frequently develops in infants with If the pneumothorax causes only minor
pulmonary interstitial emphysema, in whom symptoms, no specific therapy is necessary,
there is a tracking of air from ruptured alveoli but the infant’s color, heart rate, respira-
into the perivascular pulmonary tissues, usu- tory rate, blood pressure, and oxygenation
ally during prolonged assisted ventilation. should be monitored. If severe respiratory
Multiple studies of various exogenous surfac- distress is noted or the infant has under-
tant preparations have demonstrated a sig- lying pulmonary disease, a thoracostomy
nificant reduction in pneumothorax among tube should be placed. Lung perforation has
surfactant-treated infants.28,29 Pneumotho- been described following chest tube place-
rax, manifesting with concurrent hypoten- ment, and care should be exercised when
sion, is associated with increased risk of IVH, guiding the catheter into the pleural space.
probably via impairment of venous return. Traumatic events may be reduced with
Pneumothorax should be suspected in a pigtail catheter. The catheter should be
any newborn with respiratory distress or in placed in the pleural space anterior to the
a baby on a respirator whose condition sud- lung. This is best achieved by insertion near
denly worsens. In infants with RDS, a pneu- the third intercostal space just lateral to the
mothorax may develop when the severity of anterior axillary line. Occasionally, with a
disease is decreasing and lung compliance large area of rupture or bronchopleural fis-
is increasing. Bilateral pneumothoraces are tula, chest tube placement may be required
often observed in infants with hypoplastic for several days. Pneumomediastinum does
lungs accompanying renal agenesis (Potter not require intervention, and asymptom-
syndrome), other forms of renal dysplasia, atic pneumopericardium should be man-
or congenital diaphragmatic hernia. In fact, aged conservatively. Pneumopericardium
the presence of otherwise unexplained extra- may manifest with profound hypotension
pulmonary air in the early neonatal period if there is accompanying gas tamponade,
should raise the question of an underlying and pericardiocentesis will be lifesaving.
renal or pulmonary malformation. Both pneumopericardium and pulmonary
A high-intensity transilluminating light, interstitial emphysema (PIE) are almost
using a fiberoptic probe, is especially help- invariably complications of assisted venti-
ful in quickly diagnosing a pneumothorax. lation. In an attempt to avoid air leak and
If the infant’s clinical condition is relatively to manage air leak when present, mechani-
stable, it is wise to check the diagnosis radio- cal ventilatory pressures should be kept at a
graphically before treatment. An anteropos- safe minimum. The use of high-frequency
terior film may underestimate the size of a ventilation appears to be effective in treat-
large anterior pneumothorax, in which case ing air leak and may actually reduce the
a horizontal-beam lateral film of the supine risk of development of air leak in preterm
infant is helpful. A cross table lateral film infants with severe respiratory failure30 (see
with the suspected pneumothorax side up also Chapter 11).
EDITORIAL COMMENT: Neonatal respiratory dis-

TRANSIENT TACHYPNEA
tress is associated with changes in β-epithelial sodium
OF THE NEWBORN
channel (β-ENaC) and aquaporin (AQP5) expression.
Transient tachypnea of the newborn (TTN) The various roles of β ENaC and aquaporin in respira-
often follows an uneventful delivery at (or tory distress and transient tachypnea of the newborn
close to) term. The major presenting symp- (TTN) serve as a reminder that it is not only surfactant,
tom is a persistently high respiratory rate. oxygen, and CPAP or mechanical ventilation that must
Cyanosis may be present but is usually be considered in the delivery room, but also the shift
not of great significance, with few infants in the function of the lung from secretion to absorption
requiring more than 35% to 40% oxygen of fluid. AQP5 expression enhances reabsorption of
to remain pink. Air exchange is good and, postnatal lung liquid, and aids in the rapid recovery of
therefore, rales and rhonchi, expiratory infants with transient tachypnea of the newborn.* Tran-
grunting, and intercostal retractions are sition for the fetus from a liquid environment with gas
minimal; arterial pH and Paco2 measure- exchange through the placenta to air breathing must
ments are usually within normal limits. The occur efficiently and effectively. Given all the physical
chest x-ray reveals central perihilar streak- and biochemical switching, it is a miracle that most
ing because fluid remains in the periarterial babies accomplish this seemingly without effort. A key
tissue, often with fluid in the interlobar fis- element in this transition is the clearance of lung fluid.
sure, and occasionally there is a small pleu- This is accomplished by a combination of decreased
ral effusion; the cardiac silhouette may be secretion, increased absorption, and to a lesser ex-
slightly enlarged. If the radiologic picture tent, excretion accompanying the big squeeze of the
includes patchy infiltrates, which probably thorax during the birth process. The bulk of this fluid
reflect liquid-filled lobes, then TTN probably clearance is mediated by transepithelial sodium reab-
cannot be initially distinguished from infil- sorption through amiloride-sensitive sodium channels
trates associated with meconium aspiration in the alveolar epithelial cells with only a limited con-
or bacterial pneumonia. The clinical picture tribution from mechanical factors and Starling forces.
of increased respiratory rate improves grad- Disruption of this process can lead to retention of fluid
ually during the first 5 days of life. in air spaces, setting the stage for alveolar hypoventi-
The pathogenesis appears to involve lation. When infants are delivered near-term, especial-
delayed resorption of fetal lung fluid, a ly by cesarean section (repeat or primary) before the
process that requires activation of airway onset of spontaneous labor, the fetus is often deprived
epithelial sodium channels.31 In experimen- of these hormonal changes, making the neonatal tran-
tal situations, catecholamines have been sition more difficult.
found to stimulate fetal lung fluid resorp- Barker noted that the mechanisms for lung liquid
tion. Infants delivered by cesarean section clearance during the neonatal period develop gradu-
without antecedent labor are found to ally during the latter part of the third trimester of preg-
have decreased catecholamine levels and nancy,† but the phenotypic switch of the lung epithe-
an increased likelihood of development of lium from net secretion to net absorption triggered by
transient tachypnea.32 In fact, the respi- events at birth, is sudden. Although lung liquid ab-
ratory morbidity associated with elective sorption at birth is “a performance without rehearsal,”
repeat cesarean delivery before 39 weeks is the lung may be called on for an encore in later life
typically TTN.33 Infants of diabetic mothers when these same mechanisms are activated to clear
are also at increased risk of transient tachy- accumulated edema liquid.
pnea, thought to be due to the interference Bioelectrical studies of human infants’ nasal epi-
by insulin on the β-adrenergic response of thelia demonstrate that transient tachypnea of the
the lung.34 newborn and RDS have defective amiloride-sensitive
The presence of unabsorbed lung fluid pro- Na+ transport. Neonatal respiratory distress syndrome
duces decreased lung compliance, whereas the has, in addition to a relative deficiency in surfactant,
infant’s increased respiratory rate attempts to defective Na+ transport, which plays a mechanistic
minimize respiratory work. Ultrasound has role in the development of the disease.
been reported to demonstrate a unique dif-
ference in lung echogenicity between upper *Li Y, Marcoux MO, Gineste M, et al: Expression of water
and lower lung areas in TTN.35 The syndrome and ion transporters in tracheal aspirates from neonates
with respiratory distress, Acta Paediatr 98:1729, 2009.
appears to be self-limited, and there have †BarkerPM, Olver RE: Lung edema clearance: 20 years of
been no reported complications. The use of progress. Invited review, J Appl Physiol 93:1542, 2002.
diuretics such as furosemide has not been
found to be effective in decreasing the symp-
toms or duration of illness.36
gasping respirations and peripheral vaso-

PULMONARY HEMORRHAGE constriction. Blood-stained hemorrhagic
The signs of pulmonary hemorrhage range edema is then seen welling from the tra-
from blood-tinged tracheal or pharyngeal chea. Pulmonary hemorrhage can often be
secretions to massive intractable bleeding. successfully treated by mechanical ventila-
Most studies define significant pulmonary tion employing extra positive end-expira-
hemorrhage as bright red blood from the tory pressure (PEEP) and transfusion of fresh
endotracheal tube in amounts that increase blood; occasionally, high-frequency ventila-
the need for ventilatory support or produce tion may be required.
chest x-ray changes. Historically, pulmonary
hemorrhage was associated with intrapar- BRONCHOPULMONARY DYSPLASIA/
tum asphyxia, infection, hypothermia, and NEONATAL CHRONIC LUNG DISEASE
defective hemostasis. Although occasionally In 1967, Northway et al. first described BPD
manifesting in low-birth-weight infants who as a clinical syndrome associated with the
have previously appeared well, it more often use of assisted ventilation and high con-
affects infants who are already suffering centrations of oxygen.41 Their patients had
from other life-threatening abnormalities or been on respirators using greater than 70%
illnesses. The composition of the lung efflu- oxygen for longer than 5 to 6 days. During
ent in infants with massive pulmonary hem- the prolonged recovery, the infants exhib-
orrhage in most cases is a filtrate of plasma ited persistent respiratory difficulty and a
with a small admixture of whole blood, pro- characteristic radiographic progression that
ducing a hemorrhagic edema fluid, presum- resulted in cystic lung changes. Increased
ably formed because of increased pulmonary concentrations of oxygen were required for
capillary pressure. Factors that might predis- several weeks before slow improvement was
pose infants to development of hemorrhagic noted. Autopsy revealed that their lungs
pulmonary edema includes those favoring were diffusely involved with areas of emphy-
filtration of fluid (hypoproteinemia, over- sema and collapse, interstitial fibrosis, and
transfusion), those causing damage to lung changes in the epithelium of the airway.
tissue (infection, RDS, and mechanical ven- The radiographic sequence initially
tilation in high inspired oxygen), and abnor- described by Northway et al. is no longer
malities of coagulation. commonly seen, and stage I is essentially
In a retrospective cohort study, pulmo- indistinguishable from uncomplicated RDS.
nary hemorrhage was associated with the Dense parenchymal opacification, as seen
presence of a clinically significant patent in stage II BPD, may commonly simulate
ductus arteriosus before, or at the time of, the another process, such as congestive heart
hemorrhage.37 In fact, left-to-right shunting failure from a patent ductus arteriosus or
through a patent ductus arteriosus should an infection. The bubbly pattern of stage
be considered the primary etiology for pul- III BPD is not necessarily seen, and when
monary hemorrhage in a preterm infant it does appear, it may not follow a period
who is often recovering from RDS. Surfac- of parenchymal opacity. Finally, roent-
tant therapy, by improving lung mechanics genographic development of bronchopul-
and decreasing pulmonary vascular resis- monary dysplasia (BPD) (stage IV) may be
tance, may enhance the process. Pulmonary more insidious than originally described.
hemorrhage is probably not an indication The characteristic picture of BPD ultimately
to withhold surfactant therapy because the appears at around 20 or 30 days of age. The
blood products in the lung parenchyma may major features of stage IV disease include
inactivate surfactant.38 On rare occasions, hyperinflation and nonhomogeneity of pul-
aspiration of blood around the time of deliv- monary tissues, together with multiple fine,
ery may simulate pulmonary hemorrhage as lacy densities extending to the periphery.
a cause of neonatal respiratory distress when Since the original description of BPD by
other risk factors for pulmonary hemorrhage Northway et al., the problem of chronic
are absent.39 Pulmonary hemorrhage has respiratory disease in infants has steadily
also been seen in several neonates following increased because of aggressive respiratory
treatment with extracorporeal life support.40 management and increased survival of very
Pulmonary hemorrhage occurs most low-birth-weight infants. In the absence of
commonly on the second to fourth days of clear diagnostic criteria for BPD, the fol-
life. The usual mode of presentation is the lowing definitions for BPD are in current
development of bradycardia, apnea, or slow use: (1) oxygen dependence beyond 28 days
of age with persistent chest x-ray changes infection, and nutritional deficiencies to the
after mechanical ventilation; and (2) oxy- overall pathologic picture of BPD (Fig. 10-7).
gen dependence beyond 36 weeks’ corrected Recent attention has focused on the role of a
postnatal gestational age.42,43 BPD has been dysmorphic vascular structure that is promi-
correlated with subsequent abnormal pul- nent in animal models of BPD and the resul-
monary findings at follow-up. It has been tant marked decrease in alveolarization, as
proposed that the more nonspecific term, well as a role for genetics in contributing to
neonatal chronic lung disease, be employed; BPD.45
however, BPD is still most widely used. Most
very low-birth-weight infants who develop Oxygen Toxicity
BPD may never have had severe RDS with The lung is the organ exposed directly to
high inspired oxygen or ventilator require- the highest partial pressure of inspired
ments. Laughon found that 68% of infants oxygen. Although oxygen itself is essen-
who develop BPD never required more than tially nonreactive, its potential for toxicity
an Fio2 of 30% in the first 7 days of life.44 is derived from the formation of reactive
oxygen species during normal cell metabo-
PATHOPHYSIOLOGIC AND CLINICAL lism, and even more so during exposure
FEATURES to high concentrations of oxygen. These
Controversy surrounds the individual contri- oxygen-free radicals are cytotoxic because
butions of immaturity, inhaled oxygen, ven- of their potential for interaction with all of
tilator pressures, endotracheal tube injury, the principal cellular components, resulting
Prematurity/Respiratory Failure
Volutrauma Oxygen toxicity Inflammation Edema

Mechanical High inspired Infection PDA
ventilation oxygen
Large tidal Deficient antioxidant Inflammatory mediators Excessive
volume systems Elastase-proteinase/ fluid intake
Decreased lung Nutritional deficiencies inhibitors imbalance Increased
compliance pulmonary
blood flow
Acute Lung Injury

Inflammatory Response
Airways damage Vascular injury Interstitial damage
Metaplasia Increased permeability ↑ Fibronectin

Smooth muscle Smooth muscle ↑ Elastase
hypertrophy hypertrophy ↓ Alveolar septation
↓ Vascularization
Airway obstruction Pulmonary edema Tissue damage

Emphysema-Atelectasis Hypertension Fibrosis
Decreased number of
alveoli
Bronchopulmonary Dysplasia
Figure 10-7. Pathogenesis of bronchopulmonary dysplasia. PDA, Patent ductus arteriosus.

in inactivation of enzymes, lipid peroxida- lung protection, although some show con-
tion in cellular and organelle membranes, siderable promise. Clinical trials of vitamin
and damage to DNA. The precise concen- E failed to demonstrate a lung protective
tration of oxygen that is toxic to the lung effect; more recently, however, vitamin A
probably depends on a large number of (which may enhance lung development
variables, including maturation, nutritional and repair via multiple mechanisms) has
and endocrine status, and duration of expo- been shown to modestly reduce the pri-
sure to oxygen and other oxidants. A safe mary outcome variable, death or BPD.47
level of inspired oxygen has not been estab- In addition, administration of antioxidant
lished; it is even possible that exposure of enzymes, particularly superoxide dismutase,
the extremely immature lung to 21% oxy- might provide protection of the lung from
gen may represent a cytotoxic challenge. oxidant damage.48 Other agents that could
To combat the detrimental effects of oxy- potentially be protective include such iron-
gen toxicity, cells have evolved a complex sys- binding agents as deferoxamine or transfer-
tem of antioxidant defenses to scavenge and rin, which could function via reduction of
detoxify reactive oxygen-free radicals. These iron-catalyzed free radical formation.
antioxidant defenses include both chemical Epidemiologic data suggest that BPD
antioxidants, such as vitamin E, ascorbate, may not primarily relate to oxidant lung
and glutathione, and the antioxidant enzyme damage. Specifically, BPD has been found
system, consisting mainly of superoxide dis- to occur with significant frequency in very
mutase, catalase, and glutathione peroxidase. low-birth-weight infants without preceding
Studies have demonstrated a late gestational RDS, and with minimal early supplemental
developmental pattern of pulmonary anti- oxygen exposure. Therefore, antioxidant
oxidant enzyme maturation in numerous augmentation alone may not be adequate to
species. Therefore, experimental animals, completely eradicate BPD from premature
and presumably the human infant as well, if infant populations.
delivered prematurely, would be denied late Abnormal pulmonary function is char-
gestational increases in antioxidant enzyme acterized by decreased lung compliance
activities. This could partially explain the resulting from areas of fibrosis, overdisten-
vulnerability of the premature infant to oxi- tion, and atelectasis and increased pulmo-
dant lung damage. Similarly, studies in rab- nary resistance caused by airway damage.49
bits have shown that the preterm rabbit is Wheezing may be episodic and markedly
not capable of inducing a protective increase contribute to the increased work of breath-
in antioxidant enzymes in response to hyper- ing and oxygen requirement. Increased
oxia exposure,46 which may offer an addi- airway reactivity is a major problem at fol-
tional explanation for the vulnerability of low-up of preterm infants, especially those
the premature infant to hyperoxic exposure. with BPD.50,51 Chronic respiratory acidosis
Additional factors may contribute to is accompanied by elevated bicarbonate and
the negative influence of hyperoxia on the close-to-normal pH. This increase in serum
neonatal lung. When the lung is continu- bicarbonate is frequently exaggerated by
ously exposed to high oxygen, an influx chronic diuretic therapy.
of polymorphonuclear leukocytes contain- Pulmonary edema is a prominent com-
ing proteolytic enzymes, such as elastase, plication of BPD, largely caused by the
occurs, resulting in proteolytic damage of increased pulmonary vascular pressure and
structural elements in alveolar walls. Loss of permeability. Hypoxic pulmonary vasocon-
mucociliary function may be an additional striction and injury to the pulmonary vascu-
pathogenetic component, in that exposure lar bed appear to be involved. Exacerbations
to 80% oxygen has resulted in a cessation of congestive heart failure may manifest
of ciliary movement after 48 to 96 hours in with wheezing, fluid retention, and hepa-
cultured human neonatal respiratory epithe- tomegaly. The underlying disease may
lium. Finally, lung growth and development mask the chest x-ray changes of pulmonary
appear to be highly sensitive to oxygen expo- edema including cardiomegaly.
sure with reduced total alveolar number and Infection and the resultant inflammatory
lung internal surface area, as well as abnor- response frequently complicate the clini-
mal alveolar architecture in BPD infants. cal course of chronic neonatal lung injury.
Studies designed to enhance antioxidant Inflammatory mediators released by either
capabilities in the human infant have yet infection or high inspired oxygen may
to show any sustained benefit in terms of aggravate the bronchoconstriction and
vasoconstriction to which the lungs of these volumes as determined by follow-up MRI.57

infants are predisposed. Therefore, hydrocortisone therapy has been
Nutritional deficiencies and inadequate proposed as an alternative to dexametha-
caloric intake can interfere with normal alve- sone because hydrocortisone treatment for
olar development and with the repair process BPD may not be associated with the adverse
of injured lung tissue. It can also negatively neurobehavioral effects seen on follow-up of
affect the antioxidant mechanisms. The dexamethasone treatment.58 An additional
problem is compounded because contributes concern is a reported relationship between
to the increased work of breathing these gastrointestinal perforation and indometh-
infants’ elevated oxygen consumption52 acin treatment for patent ductus arteriosus
in hydrocortisone-treated infants.59 Current
MANAGEMENT recommendations for postnatal steroid use
With skillful and patient management, in BPD include taking a cautious approach,
most of these infants will recover, although avoidance of treatment in the first week of
abnormalities in pulmonary function may life or for a prolonged period, and tapering
persist into childhood. Prolonged need for therapy over approximately 1 week.60
supplemental oxygen over several months is Inhaled nitric oxide has emerged as an
associated with a greater incidence of neu- alternative approach for treatment of BPD
rodevelopmental disorders when compared by inhalation over approximately 21 days.
with infants with less severe lung disease.53 This therapy appears to enhance several
The key to survival for infants with severe parameters of lung maturation resulting in
lung disease depends on close attention to a reduction in BPD rate in some, but not all,
details such as vigorous treatment of right- studies.61-63 Caution is also advised with this
sided heart failure, precise fluid balance, approach pending longer term respiratory
use of diuretics, and gradual weaning from and neurodevelopmental outcome data.
mechanical ventilation and raised environ- Many of these infants require prolonged
mental oxygen. The latter may need to occur hospitalization, and a well-organized pro-
in decrements of 1% to 2% of inspired oxy- gram of infant stimulation may help the
gen. Oxygenation is typically monitored via child achieve maximum potential. Parents
pulse oximetry, and oxygen saturation is must be encouraged to assume some of the
maintained in the low to mid-90s. Furose- responsibility for medical procedures, such
mide (Lasix), 1 to 2 mg/kg/day, is the most as chest physiotherapy, and, where possible,
widely used diuretic, although prolonged use a consistent medical team should oversee
has been associated with nephrocalcinosis. the infant’s care and be available for con-
These infants need to be closely watched tinuing parental support. Finally, adequate
for early signs of infection because pneu- nutritional management is very important
monia generally results in a setback. Bron- because malnutrition delays somatic growth
chodilators are of benefit, especially when and the development of new alveoli in these
there are clinical signs of acute bron- high-risk, labile infants.
chospasm. They may be administered as
systemic theophylline or as β-agonist inha- APNEA IN THE IMMATURE INFANT
lation therapy.54 Controlled trials of both Periodic breathing (short, recurring pauses
diuretic therapy and bronchodilator inhala- in respiration) of 5 to 10 seconds’ dura-
tion have revealed encouraging short-term tion is common in the immature infant
improvements in airway resistance, even in and should be considered a normal respi-
the absence of wheezing.55 ratory pattern at this age. Apnea, however,
Steroids administered systemically or by has been defined as either (1) a given time
inhalation have also been used to amelio- period with complete cessation of respira-
rate BPD or to assist in weaning these infants tion (typically >15 to 20 seconds) or (2) the
from the ventilator56; however, reports of time without respiration after which func-
an increased incidence of cerebral palsy tional changes are noted in the infant, such
after postnatal systemic steroid use for BPD as a decrease in heart rate to about 80 beats
are of concern. This has led to considerable per minute or oxygen saturation to about
controversy as to the role, duration, and 80%. Although the use of a standard apneic
timing of postnatal systemic steroid therapy duration appears to simplify routine nursery
for BPD. Of particular concern is evidence management, some small infants (usually
that postnatal dexamethasone therapy may <1000 g) appear to have oxygen desatura-
be associated with reduced cerebral tissue tion if the apneic period extends beyond as
little as 10 seconds. The problem increases explanation completely describes these

substantially in incidence and severity with apneic spells, Table 10-2 lists factors that
decreasing gestational age. singly or together make the immature infant
The relationship between apnea, desatu- more susceptible to apnea.80-83
ration, and bradycardia is not simple, as
summarized in Figure 10-8. Decreased cen- TREATMENT
tral respiratory drive is the usual initiating Because prolonged apnea may cause clini-
event, with reflex bradycardia presumably cally significant hypoxemia, and because
triggered by the resultant desaturation. Exci- these spells occur so commonly, hospitalized
tation of inhibitory reflexes occasionally premature infants are typically continuously
precipitate apnea and bradycardia.64 A par- monitored until no clinically significant
ticularly perplexing problem is the frequent apneic episode has occurred for up to 5 to
occurrence of oxygen desaturation and 7 days. Because apnea with an obstructive
bradycardia in intubated, ventilated, very
low-birth-weight infants. In such infants,
hypoventilation is probably the initiating Factors Related to Apnea
Table 10-2.
event associated with impaired lung func- in the Immature Infant
tion and ineffective ventilation.65,66 Observation Explanation
Hypoglycemia, fluid and electrolyte
imbalance, temperature fluctuations, sep- Hypoxemia causes Hypoxemic depression
respiratory depression of respiration in young
sis, anemia with or without a patent duc- and results in hypoventi- infant is centrally mediated
tus arteriosus, and severe brain lesions can lation in neonate instead and appears to override
be heralded by apneic spells and should be of sustained hyperventi- stimulation from peripheral
ruled out when apneic episodes first begin. lation as in adult. chemoreceptors.*
In a small number of infants, usually close to Hypercapnia causes Decreased hypercapnic
hyperventilation as in ventilatory response in
term, apneic spells may be the manifestation adult, with diminished apneic infants is probably
of a seizure disorder. However, the majority response in apneic ver- secondary to immature
of apneic periods occur in infants who are sus non-apneic infants. central neural mechanisms.*
immature and have no organic disease. An Obstructed inspiratory Pharyngeal hypotonia and
exception is an apneic episode in an infant efforts may occur during failure of upper airway
with severe RDS, which usually indicates the apnea and may be respiratory muscles
misdiagnosed as primary (genioglossus, alae nasi) to
presence of hypoxia and acidemia or sepsis, bradycardia when contract during inspiration
and is a clear indication for immediate inter- breathing movements may compromise upper
vention, such as assisted ventilation. persist.82 airway patency.*
The premature infant in whom specific Apnea is more common During active sleep,
causes for apnea have been reasonably during active sleep. respiration is irregular, lung
volume and oxygenation
excluded may be considered to have true may decrease.
idiopathic apnea of prematurity. Although
no single physiologic or neurochemical *Data from references 80, 81, 83.
Decreased respiratory drive

Impaired pulmonary function
Apnea,
hypoventilation
Pulmonary
vasoconstriction
Inhibitory
reflexes
Decreased O2
delivery
Bradycardia Desaturation
Figure 10-8. Neonatal apnea, Carotid

bradycardia, and desaturation. body
component (so-called mixed apnea) may agents decreases apnea remains unclear.70
not trigger a respiration alarm, simultane- Proposed mechanisms include generalized
ous heart rate must always be monitored. enhancement of central respiratory drive
In these infants, oxygen saturation is a use- via adenosine receptor antagonism, more
ful adjunct to cardiorespiratory monitoring. efficient diaphragmatic contraction, and
Most episodes of 15 to 20 seconds’ duration reversal of hypoxic respiratory depression.
of apnea resolve spontaneously. Most of the Although long-term sequelae from xanthine
remainder cease with gentle diffuse cutane- use have not appeared, care must be taken to
ous stimulation. However, a mask and bag avoid short-term side effects such as tachy-
should be available near every monitored cardia and diuresis, probably more so with
infant, to be used if breathing does not begin theophylline than with caffeine because
promptly after stimulation. Inspired oxygen the latter appears to have a greater margin
concentration depends on the infant’s prior of safety. Caffeine therapy does significantly
oxygen requirement. shorten duration of supplemental oxygen
A marked reduction in apnea has been administration and assisted ventilation.71
noted with a low CPAP and respiratory stim- Its use is associated with a transient increase
ulants such as theophylline or caffeine.67-69 in metabolic rate and impaired weight gain.
Box 10-3 illustrates principles in the man- Data suggest longer term neurodevelopmen-
agement of idiopathic apnea. The order in tal benefit from caffeine therapy.72 Caffeine
which these therapeutic steps are under- therapy will require longer term follow-up
taken is based on the assessment of each and improved understanding of the mecha-
individual patient. nism underlying this benefit.
A reasonable principle is to commence
with a therapy that carries a low potential RESOLUTION OF NEONATAL APNEA
for short- or long-term side effects. Nasal Apnea may persist longer in preterm infants
CPAP at 3 to 5 cm H2O is particularly effec- than was generally acknowledged. Such epi-
tive in treatment of apneic episodes with an sodes may be accompanied by desaturation
obstructive component.69 The most prob- and/or bradycardia and often persist beyond
able mechanisms for the beneficial effect of 40 weeks of age in infants delivered before 28
CPAP include maintenance of upper airway weeks’ postconceptional age.73,74 Persistent
patency, increase in FRC and Pao2, and stabi- apnea may also be asymptomatic in a large
lization of the chest wall. The use of xanthine proportion of very low-birth-weight infants.75
therapy (theophylline, caffeine) is widespread Prolonged apnea, often manifesting as brady-
in the management of neonatal apnea. The- cardia in these very low-birth-weight infants,
ophylline is metabolized to caffeine in sub- is often associated with chronic neonatal lung
stantial amounts in neonates; their precise disease. Persistence of symptomatic apnea
mechanism whereby either of these xanthine and bradycardia prolongs the hospitalization
of very premature infants and raises questions
about the margin of safety for their discharge
Box 10-3. Management of Idiopathic Apnea as well as about the indications for,76 and util-
ity of, home apnea monitoring.
Diagnosis and treatment of specific causes What is the overall significance of these
(e.g., hypoglycemia, anemia, sepsis) events in former preterm infants? Evidence
Nasal continuous positive airway pressure does not link the persistence of these events
(4 cm H2O)* to sudden infant death syndrome (SIDS). Per-
Xanthine (caffeine or theophylline) therapy, sistence of these cardiorespiratory events may
commencing with a loading dose followed be part of the spectrum of normal postnatal
by maintenance therapy, and serum level maturation. However, the possibility exists
monitoring, especially for theophylline that they represent a subtle marker for neuro-
Increased environmental oxygen as neces- developmental or sleep disturbances, or other
sary to maintain adequate baseline oxygen disorders of childhood. Data from several
saturation; often associated with treatment sources suggest that persistence of apnea of
of anemia prematurity and accompanying bradycardia
Assisted ventilation if all else fails may be a risk factor for later impairment in
neurodevelopmental outcome.77-79 However,
*From Miller MJ, Carol WA, Martin RJ: Continuous
establishment of a causal, rather than associa-
positive airway pressure selectively reduces obstruc-
tive apnea in preterm infants, J Pediatr 106:91, 1985.
tive, relationship between these events and
later outcome remains problematic.
inspired oxygen concentration to maintain

QUESTIONS
the Pao2 between 50 and 80 mm Hg should
not predispose the infant to lung or retinal
True or False injury as appropriate readjustments to the
As long as the arterial Pao2 remains less than inspired oxygen content can be made in
100 mm Hg, there will be no retinal damage when response to an improved condition. Alterna-
using high concentrations of oxygen (>40%) for tively, the infant could be placed on CPAP,
the treatment of RDS. or if the infant is already on CPAP, the flow
can be increased—to increase the mean air-
The answer is false. When Pao2 is closely way pressure—which, in turn, would lead to
monitored and remains less than 100 mm improved oxygenation. Also, evaluation of
Hg, retinal damage still develops in some the underlying reason for the deterioration
very low-birth-weight infants. There are sev- in Pao2 would be important so the derange-
eral possible explanations: (1) blood from a ment can be rectified.
large right-to-left ductal shunt is directed to
the sampling site in the lower aorta, while
the retinal vessels receive unmixed blood True or False
with a higher Pao2; (2) Pao2 constantly fluc- Maintaining the Pao2 between 50 and 80 mm Hg will
tuates between arterial measurements; and prevent pulmonary oxygen toxicity and lung injury.
(3) factors other than Pao2 are involved
in retinal injury. Continuous monitoring The answer is false. Pulmonary oxygen tox-
should help detect the Pao2 fluctuations. icity is related to the inspired concentration
Placing a skin Po2 electrode or pulse oxim- of oxygen, not the arterial oxygen concen-
eter on the right upper extremity to measure tration, and any oxygen concentration more
the saturation in the preductal blood should than room air can be damaging to pulmo-
help detect any large right-to-left shunts and nary tissue. It should be noted, however, that
is useful to guide management in these situ- oxygen toxicity is not the only contributor
ations. Nevertheless, even with continuous to neonatal lung injury. Other factors such
monitoring of the oxygen level, retinopathy as volutrauma, barotrauma, atelectrauma,
of prematurity still occurs. Any infant born and lung inflammation also play important
at less than 30 weeks of gestation or having roles in injury to the developing lung.
a birth weight less than 1500 g, or infants
who do not fit those categories but have
had a significant exposure to supplemen- True or False
tal oxygen during their early life should be Your sister is 36 weeks pregnant and is scheduled
examined by an experienced pediatric oph- for an elective cesarean section next week. You
thalmologist at 4 weeks of age or a corrected are concerned because you believe that the infant
age of 31 weeks’ postmenstrual age, which- may be at risk for developing respiratory distress.
ever is later, for retinopathy of prematurity.
The answer is true. Respiratory distress syn-
drome is the result of a primary absence
True or False of surfactant production and affects most
You are taking care of a 2-day-old, 1200-g male in- premature infants; however, in certain
fant with moderate RDS. During the first 2 days of circumstances it can affect term and near-
life, he has not been apneic and has maintained a term infants as well. Surfactant is produced
reasonable pH, Paco2, and Pao2 on 40% oxygen. by type II pneumocytes, which become a
However, the most recent Pao2 measurement has prominent cell in the alveolus at ~34 to 36
decreased to 45 mm Hg (still on 40% oxygen). weeks of gestation. In general, surfactant
This environmental oxygen concentration should secretion is increased during labor, and
be left the same because raising it beyond 40% therefore, if an infant is born via cesarean
predisposes the infant to oxygen toxicity. section before the onset of labor, they are
at risk for decreased production and there-
The answer is false. A decrease in Pao2 to fore, respiratory distress after delivery. If a
45 mm Hg suggests worsening of the infant’s cesarean section is to be pursued prior to 39
condition. His condition may deteriorate weeks’ gestation, an explanation of the indi-
rapidly if he remains on 40% oxygen. If the cation for the delivery must be documented
arterial oxygen is monitored closely (contin- in the chart and documentation of lung
ually or at least every 4 hours), elevating the maturity should be done prior to delivery.
For each of the following cases, the blood gas full-term infant in CPAP is done with extreme caution,
information will be given in the following format: pH/ and some would argue that intubation is the better
Paco2/ Pao2/Hco3. All information necessary will be choice of the two when treating a term infant with
given to you within the question. significant lung disease.
CASE 1 CASE 2
Baby A is a 3900-kg female with meconium aspira-
Baby B is a 2100-g, small-for-gestational-age, term
tion syndrome. She is transferred to the NICU soon
male who has been grunting since birth. A chest x-
after birth and umbilical venous and arterial catheters
ray shows no significant lung disease. The results of
are placed. She is initially placed in an oxyhood for
a blood gas at 30 minutes of life are: pH 7.14, Paco2
oxygen desaturation, and by 8 hours of age, she re-
35, Pao2 30, and HCO3 11.4. At that time, the in-
quires 70% oxygen.
fant is also noted to have a core body temperature of
34° C, heart rate of 140, respiratory rate of 60, and a
At 8 hours of age, the baby’s left leg turns mean arterial blood pressure of 39 mm Hg.
dusky. What should be done?
Initially, try warming the opposite extremity which What are this infant’s obvious problems?
should cause a reflexive vasorelaxation in the ex-
This infant is hypothermic, hypoxemic, and has meta-
tremity of interest. If the blanching does not improve
bolic acidosis. The hypoxemia and acidosis may be
quickly, then the umbilical arterial catheter must be
the result of hypothermia due to inadequate ther-
removed immediately.
moregulation after delivery. Infants, especially those
who are small for gestational age, are at particular risk
If the catheter is removed, how should of hypothermia during the first hours of life because
the infant’s oxygenation be managed? of their relatively large head-to-body surface area.
There is no substitute for the combination of continu- However, sepsis must be a first consideration in the
ous oxygen monitoring (via pulse oximetry) and inter- differential diagnosis of a hypothermic, acidotic infant.
mittent arterial blood sampling via an indwelling arte-
rial catheter in an acutely ill neonate. Placement of a How should these problems be handled?
peripheral arterial line (e.g., radial artery line) should
The infant should be warmed by being placed under
be attempted to continue arterial sampling in this pa-
a radiant warmer or in an incubator. While the infant’s
tient to monitor pH, Paco2, and Pao2.
body temperature is improving, the acidosis and hy-
When arterial catheterization is impossible, heel-
poxemia should also be addressed. The infant should
stick or venous blood sampling can be used to
be placed on supplemental oxygen to treat the hy-
monitor pH and Paco2, but not Pao2. In that case,
poxemia. Appropriate cultures should be obtained
noninvasive oxygen monitoring is needed to control
and antibiotics begun to treat the potential diagnosis
supplemental oxygen delivery.
of neonatal sepsis. Treating the infant’s acidosis initial-
ly with bicarbonate is somewhat controversial. First,
The arterial gas obtained at 8 hours of age one could consider giving this infant a normal saline
is: pH 7.16, Paco2 60, Pao2 50, and HCO3 bolus (10 mL/kg) in anticipation of possible hypovo-
17. How should this infant’s ventilation and lemia, and if the acidosis does not improve, repeat the
oxygenation be managed at this time? bolus and then consider giving bicarbonate (2 mEq/
Given this infant’s respiratory acidosis and borderline kg). In addition, many would feel more comfortable in-
oxygenation at a relatively high inspired oxygen con- tubating this hypoxic infant before giving bicarbonate
centration, the infant requires endotracheal intuba- to provide a controlled manner in which to ensure
tion with mechanical ventilation. Arterial blood gases CO2 elimination. The placement of an umbilical arterial
should continue to be monitored every 2 to 4 hours to catheter should be considered so that frequent blood
adjust both ventilator and oxygen support required by gas samples can be drawn to monitor the infant’s re-
the infant to resolve the respiratory acidosis and hy- sponse to the interventions that have been made.
poxia. If the hypoxia is not resolving and it is thought
that the infant has developed pulmonary hyperten- At 1 hour of age, after the infant has been
sion, inhaled nitric oxide should be added to the ther- in an incubator, placed on a nasal cannula
apy. If this was a preterm infant with RDS, placing the at 1 liter per minute (LPM) with an Fio2 of
infant on CPAP would be an alternative to intubation. 40%, and given a normal saline bolus of
However, in a full-term infant, CPAP is not always well 10 mL/kg, the repeat arterial blood gas is:
tolerated and could lead to a worsening of respiratory pH 7.28, Paco2 36, Pao2 90, and HCO3 16.4.
status and possibly cause a pneumothorax; placing a At this time, the core body temperature is
36° C, HR 120, RR 70, and the mean arterial There has been a great deal of flexibility with regard to
blood pressure is 22. What problem(s) does the redosing of surfactant. However, given the fact that
the infant have now? her pH is greater than 7.25 and her Fio2 is less than
Hypoxemia or acidemia alone or in conjunction with 30%, it would be reasonable to extubate this infant to
one another can result in an elevation of blood pressure either CPAP or another form of noninvasive ventilation
due to their effect on peripheral vasoconstriction. In this and not to administer another dose of surfactant.
patient, partial correction of the metabolic acidosis and
increasing the Pao2 probably caused a decrease in pe- What are the complications of surfactant
ripheral vascular resistance, reflected as a decrease in therapy?
the mean arterial blood pressure. The low blood pres- Significant oxygen desaturation occurs in a small per-
sure suggests a severely reduced blood volume, which centage of infants shortly after receiving surfactant
should be expanded with isotonic fluid and/or blood therapy, which is usually quick to resolve as the sur-
products, if necessary. Of note, acidosis can worsen factant is absorbed and ventilation and perfusion
initially after fluid resuscitation as the build-up of lactate improve. There have also been concerns about pul-
in the tissue is now mobilized into the circulation and monary hemorrhage associated with surfactant ad-
large fluid replacement volumes may be necessary. ministration. This appears to be a more significant
problem in the most immature infants (those weighing
<750 g and <25 weeks’ gestation) and is likely due
CASE 3 to changes in lung compliance in the face of an open
ductus arteriosus. Also, there is a risk of developing a
Baby C is a 900-g female delivered at 27 weeks’
pneumothorax after surfactant administration as lung
gestation. Her Apgar scores are 1 and 7 at 1 and 5
compliance improves if the inspiratory pressure used
minutes, respectively. She is initially placed on CPAP
to inflate the less compliant lungs before surfactant
in the delivery room and transferred to the NICU for
administration is not decreased appropriately.
further management. A chest x-ray is consistent with
the diagnosis of RDS. Umbilical lines are placed, and
an initial arterial blood gas result is: pH 7.19, PaCO2
55, Pao2 60, HCO3 19.5 on CPAP 5, and Fio2 is 50%. CASE 4
There have been no apneic episodes noted. Baby D is a 2000-g male who has been grunting
since birth. His chest x-ray reveals questionable RDS.
Should surfactant therapy be administered? He is placed in 70% oxygen.
Over recent years, there has been a shift in neona-
tology practice from automatically intubating very low At 3 hours, a blood gas is obtained: pH
and extremely low-birth-weight infants for surfactant 7.36, Paco2 40, Pao2 280, and HCO3 22.2.
administration to an approach of initially starting some What should be done, if anything?
of these infants on noninvasive modes of ventilation This infant is hyperoxic on 70% Fio2, thus the oxy-
(i.e., CPAP, noninvasive positive pressure ventilation, gen concentration should be decreased to 60% im-
etc.) in the delivery room. The question then becomes mediately, and pulse oximetry should be placed (if it
when, if ever, should these infants be treated with has not been already) for rapid weaning of oxygen.
surfactant. Surfactant has improved survival, reduced Plan to decrease the Fio2 by 2% to 5% every 5 to 10
the incidence of air leaks, and probably reduced the minutes while maintaining a pulse oximeter reading of
severity and incidence of CLD in infants with respira- 92% to 96%. A repeat blood gas should be obtained
tory distress. In infants who have RDS and are not in 2 to 4 hours or earlier if desaturation occurs.
initially intubated, there are some guidelines available
to help decide when and if a preterm infant should At 5 hours of age, the repeat blood gas is:
be intubated for surfactant, which takes into ac- pH 7.36, Paco2 43, Pao2 45, and HCO3 24 on
count gestational age, respiratory drive, and inspired an Fio2 of 40%. What happened and how
oxygen concentration (see Fig. 10-5). In the case of should it be addressed?
this patient, although the infant has a strong respi- The patient demonstrated a greater than expected
ratory drive, given the need for supplemental oxygen decrease in Pao2 when the oxygen concentration
of 50%, it would be recommended to administer sur- was weaned and is now hypoxic. This can generally
factant to this infant. be avoided with continuous monitoring. To resolve
the problem, first, return the Fio2 to 60% to 70%.
At 5 hours of age, the infant is weaned Second, transilluminate the chest to rule out the
from an Fio2 of 60% to 27% and the blood possibility of a pneumothorax, which can manifest
gas is: pH 7.28, Pa co 255, Pa o 2, 62, and as a sudden drop in the Pao2; if transillumination is
HCO3 22. Should surfactant be repeated? inconclusive, an x-ray should be obtained. Fifteen to
20 minutes after the Fio2 has been increased, repeat At 6 hours of life, a blood gas is obtained:
the blood gas to determine what effect increasing the pH 7.35, Paco2 34, Pao232, and HCO3 19.
oxygen concentration has made. What is the infant’s main problem at this
time?
The repeat blood gas after increasing the The infant is markedly hypoxemic on 100% oxygen;
Fio2 to 60% is: pH 7.37, Paco2 45, Pao2 70, however, the infant is not hypercarbic. It is unusual for
and HCO3 22. What is the explanation for such a degree of hypoxemia without CO2 retention
what happened between our first and last to be attributable solely to meconium pneumonitis.
blood gases? It appears that this infant’s condition is compounded
There is not a complete physiologic explanation by persistent pulmonary hypertension secondary to
underlying this phenomenon. It is assumed that, in neonatal asphyxia.
some infants, the pulmonary vessels are particularly
sensitive to changes in oxygen tension, and lowering How should this be treated?
the environmental oxygen results in pulmonary vaso- The response of the hypoxemia to ventilator support in
constriction and an increased right-to-left shunt. Un- such an infant is variable. Nonetheless, assisted ven-
der these circumstances, the Pao2 decreases out of tilation should be continued with the goal to normal-
proportion to what might ordinarily be expected when ize the pH without maintaining the Paco2 below 40.
the inspired oxygen concentration is reduced, thus The goal is to improve any acidemia because this can
explaining the decrease in the Pao2 seen at 5 hours cause pulmonary vasoconstriction that will worsen hy-
of age, which improved after increasing the oxygen. poxia, which can be achieved by administering bicar-
bonate. If oxygenation fails to improve, other therapies
such as increasing peripheral arterial blood pressure,
sedation, surfactant, and inhaled nitric oxide should
CASE 5
be employed. ECMO should be reserved for those in-
Baby D is a 3000-g infant born at 41 weeks’ ges-
fants who do not respond to maximal medical therapy.
tation and is covered with thick meconium. Labor
was complicated by late deceleration. Apgar scores
are 2, 5, and 7 at 1, 5, and 10 minutes, respectively.
The infant is immediately intubated and suctioned for
meconium below the cords. After, the infant is brady- REFERENCES
cardic with poor respiratory effort and requires posi- The reference list for this chapter can be found
tive pressure ventilation and intubation to improve the online at www.expertconsult.com.
heart rate, and is transported to the NICU for further
care. Chest x-ray shows bilateral patchy infiltrates.
Umbilical lines are placed and the infant is maintained
on a ventilator and 100% oxygen.
Assisted Ventilation
Waldemar A. Carlo and
Namasivayam Ambalavanan 11
But that life may, in a manner of speaking, be restored to the animal, an opening
must be attempted in the trunk of the trachea, into which a tube or reed or cane
should be put; you will then blow into this so that the lung may rise again and the
animal take in air. Indeed, with a single breath in the case of this living animal,
the lung will swell to the full extent of the thoracic cavity and the heart become
strong and exhibit a wondrous variety of motions…when the lung long flaccid has
collapsed, the beat of the heart and arteries appears wavy, creepy, twisting, but
when the lung is inflated, it becomes strong again and swift and displays wondrous
variations…as I do this, and take care that the lung is inflated at intervals, the mo-
tion of the heart and arteries does not stop.
Andreas Vesalius
De Humani Corporis Fabrica (1543)
The primary objective of assisted ventila- invariably) present; in many instances, arte-
tion is to support gas exchange until the rial oxygenation can be normalized if the
patient’s ventilatory efforts are sufficient. inspired oxygen is increased. Infants with
Ventilation may be required during imme- hypoxemic respiratory failure have a pre-
diate care of the depressed or apneic infant, dominant problem of oxygenation, usually
before evaluation and during treatment of the result of right-to-left shunt or severe
an acute respiratory disorder, or for pro- ventilation-perfusion mismatch. Respira-
longed periods of treatment for respiratory tory failure can occur because of disease in
failure. Trained personnel and equipment the lungs, or in other organs and systems
for emergency ventilation should be avail- (Figure 11-1). Assisted ventilation is usu-
able in every delivery room and newborn ally required when severe respiratory fail-
nursery. Positive pressure ventilation effec- ure ensues (Box 11-1). Depending on many
tively stabilizes most infants who require clinical considerations (e.g., extreme prema-
resuscitation. turity), assisted ventilation may be initiated
This chapter is an introduction to assisted earlier.
ventilation. Before undertaking assisted
ventilation of any form, it must be recog-
nized that the techniques demand time, CLINICAL MANIFESTATIONS OF
resources, and experienced personnel. Pro- RESPIRATORY FAILURE IN THE
longed ventilation should only be used in NEWBORN
units where expert nurses, respiratory thera- The following are findings that should make
pists, and medical personnel are continu- the clinician suspect respiratory failure:
ously available. • Worsening hypercapnia and/or hypoxemia
• Increase or decrease in respiratory rate
RESPIRATORY FAILURE • Increase or decrease in respiratory efforts
Hypercapnic respiratory failure is the inabil- (grunting, flaring, retractions)
ity to remove CO2 by spontaneous respi- • Periodic breathing with increasing pro-
ratory efforts and results in an increasing longation of respiratory pauses
arterial Pco2 (Paco2) and a decreasing pH. • Apnea
Assisted ventilation is most commonly • Decreasing blood pressure with tachycar-
needed to treat hypercapnic respiratory dia associated with pallor, circulatory fail-
failure. Hypoxemia is usually (but not ure, and ultimately bradycardia
270
CHAPTER 11 Assisted Ventilation 271
NEONATE WITH ACUTE RESPIRATORY DISTRESS
Yes Abnormal lungs No

by chest radiograph
Abnormalities in
Common Uncommon Perfusion Neuro- Diaphragm

Respiratory Diaphragmatic BP muscular or chest
distress hernia HCT findings wall
syndrome Tracheoesophageal
Transient fistula
tachypnea Cysts and tumors Anemia Asphyxia Chest wall
Pneumonia Congenital lobar Polycythemia Intracranial disorders
aspiration emphysema Hypotension hemorrhage Diaphragmatic
syndromes Pulmonary Hypovolemia Neuromuscular disorders
Pneumothorax hypoplasia disorders
and air leaks Accessory or Drugs
Pulmonary edema sequestered lobes
Pleural effusion Pulmonary
Airway CVS Abdominal Other
Pulmonary lymphangiectasia
findings findings findings or mixed
hemorrhage Pulmonary
or echo findings
arteriovenous
fistula
Upper airway Persistent fetal Ascites Sepsis

Laryngeal circulation Necrotizing Acidosis
airway Cyanotic congenital enterocolitis Hypothermia,
Lower airway heart disease Abdominal cold stress
Congestive heart mass Hyperthermia
failure Omphalocele Hypoglycemia
Gastroschisis Methemoglobinemia
Figure 11-1. Diagram of causes of respiratory distress in neonates. BP, Blood pressure; CVS, cardiovascular system;
echo, echocardiogram; HCT, hematocrit.
Indications for Assisted also be misleading. In infants with severe

Box 11-1.
Ventilation pulmonary hypertension and right-to-left
shunt, Pao2 may not elevate with 100% oxy-
Respiratory acidosis with pH less than 7.20
gen. Alternatively, Pao2 may increase more
to 7.25
than 100 mm Hg early in life in infants with
Hypoxemia while on 100% oxygen or continu-
forms of cyanotic heart disease with high
ous positive airway pressure with 60% to
pulmonary blood flow (e.g., total anoma-
100% oxygen
lous pulmonary venous return). Echocar-
Severe apnea
diography should be used to distinguish
between cardiac and pulmonary disease
when hypoxemia is unresponsive to ventila-
CARDIAC VERSUS PULMONARY DISEASE tory support.
The clinician may frequently need to distin-
guish between cardiac and pulmonary dis- ENDOTRACHEAL INTUBATION
ease in the sick newborn infant. Cyanotic Most infants should receive positive pressure
heart disease may mimic respiratory disease. ventilation before attempting endotracheal
One possible way to differentiate between intubation. This improves oxygenation and
the two is to perform a hyperoxia test: place decreases Paco2, thereby decreasing the like-
the infant in 100% oxygen for 10 minutes lihood of bradycardia during endotracheal
and then obtain an arterial Po2 (Pao2). In intubation. Positive pressure ventilation is
infants with pulmonary disease, Pao2 usu- impractical for prolonged periods but can
ally increases to more than 100 mm Hg, be used for the following:
whereas infants with cyanotic heart disease • Immediate resuscitation
show little change in Pao2. The hyperoxia • Stabilization before and after endotra-
test, although useful diagnostically, may cheal intubation
272 CHAPTER 11 Assisted Ventilation
• Ventilation in infants whose condition is 14

deteriorating without obvious cause Naso-
12
• Ventilation during transport to intensive tracheal
tube length (cm)

Endotracheal
care facilities when mechanical ventila- 10 Oro-
tion is unavailable tracheal
Mechanical ventilation is a highly inva- 8
sive therapy and is indicated only when the
6
benefits outweigh the burdens. In situations
where there is little reasonable chance of 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
survival, there should be honest discussions Body weight (kg)
with the family regarding of the appro- Figure 11-2. Graph for determination of length of insertion
priateness of aggressive measures such as of endotracheal tubes. The tip of the endotracheal tube is
intubation. aimed at the midtrachea. (From Lough MD, Carlo WA:
Clinical care techniques. In Carlo WA, Chatburn RL,
ENDOTRACHEAL TUBE SIZE editors: Neonatal respiratory care, Chicago, Year Book,
1988, p 122.)
It is preferable to use relatively small endo-
tracheal tubes to prevent tracheal damage.
The endotracheal tube should fit loosely
enough to allow a leak of gas between tube be placed midway between the carina and
and trachea when 10 cm H2O inspired pres- the glottis. The length of insertion of the
sure is generated. Tube size can be related endotracheal tube is shown in Figure 11-2.
to infant size or gestational age. Recom- The following measurements can be used
mended sizes are as follows: for endotracheal tube placement:
Endotracheal Endotracheal Tube

Tube Size Insertion Length
Gestational Birth Weight (mm internal Infant Weight (g) (tip to lip, cm)
Age (wk) (g) diameter) 1000 7
Below 28 Below 1000 2.5 2000 8
28-34 1000-2000 3.0 3000 9
35-38 2000-3000 3.5 4000 10
Above 38 Above 3000 3.5-4.0
At these lengths, the distal end of the

INTUBATION endotracheal tube should be at the midtra-
Insertion of an endotracheal tube should be chea. It is easy to inadvertently pass the
performed with universal precautions under tube into the right mainstem bronchus,
a radiant heat source to keep the infant but using these insertion length guidelines
warm. Free-flow oxygen should be adminis- prevents this complication. Breath sounds
tered as necessary. should be equal bilaterally. A CO2 detec-
Intubation can be a painful procedure tor should be used to confirm endotracheal
and so premedication with an analgesic placement. The tube should be secured so
agent (morphine, fentanyl, or remifentanil) that movement of the head and neck will
should be used for all non-emergent intu- not dislodge it. Lightweight plastic connec-
bations in neonates.4 A muscle relaxant tors can be used to prevent kinking the tube.
(paralytic agent) should only be used with The endotracheal tube position should be
analgesia. Other agents which may be con- checked radiographically.
sidered include sedatives (midazolam) and
vagolytic agents (atropine). The ideal com- ORAL INTUBATION
bination and sequence of premedications The advantages of oral intubation are the
in neonates has not yet been established. relative ease of insertion and that a sty-
Each unit should develop protocols and let can be used to aid insertion. Oral tubes
lists of preferred medications to maximize should always be used in emergencies. The
safety. disadvantages of oral intubation are the
The infant should receive positive pres- increased tube mobility if the tube is inad-
sure ventilation and oxygen as needed equately secured and the greater difficulty
between attempts. The tip of the tube should in keeping the tube in position.
A laryngoscope with a Miller number 0 lesions in the trachea at the site of the suc-
or 1 blade inserted in the vallecula is used tion catheter tip. Use of a special endotra-
to pull upward to visualize the glottis while cheal tube connector allows mechanical
leaving the head in a neutral position. It is ventilation during suctioning and prevents
important not to traumatize the gums and the catheter tip from going beyond the
tooth buds. The heart rate should be moni- endotracheal tube.
tored continuously with auditory and visual
signals during attempts at intubation. Con- EDITORIAL COMMENT: Suctioning of the endotracheal
tinuous O2 saturation or transcutaneous tube will decrease oxygenation and pulmonary function.
Po2 monitoring is invaluable because oxy- I would advocate being guided by pulse oximetry during
genation can worsen abruptly. It is helpful the procedure, which may require transiently increasing
if the tube has been previously curved. To inspired oxygen concentration by 10% to 15% imme-
stiffen the tube for orotracheal intubation, a diately before and following the period of suctioning. I
stylet may be used or it may be cooled. would also advocate avoiding the practice of “routine”
suctioning except as secretions warrant.
NASAL INTUBATION John Kattwinkel
The advantage of nasal intubation is the
improved stability with the reduced likelihood
of slippage into the right mainstem bronchus CHANGING AN ENDOTRACHEAL TUBE
or accidental extubation. The disadvantages An endotracheal tube change is required
are trauma to the nares and nasal septum, only if the tube becomes dislodged or
greater difficulty in insertion of the tube, occluded or if the infant outgrows it. Rou-
possibility of an increased number of gram- tine change is not indicated.
negative nasal superinfections, and potential
trauma to the developing eustachian tubes APPLIED PULMONARY MECHANICS
and sinuses. Nasotracheal intubation should The following principles are helpful in
always be performed as an elective procedure understanding mechanical ventilation. A
and should not be done in emergencies. pressure gradient between the airway open-
Using a laryngoscope blade, the lubri- ing and alveoli must exist to drive the flow
cated endotracheal tube is inserted through of gases during both inspiration and expi-
the nares until it is visualized in the oro- ration. The pressure gradient required to
pharynx. The McGill forceps are used to inflate the lungs is determined largely by the
guide the tube into the glottis. It is helpful compliance and the resistance of the lungs.
if the endotracheal tube has been previously
lubricated with a nontoxic, water-soluble COMPLIANCE
lubricant. A stylet is never used for nasotra- Compliance is a property of distensibility
cheal intubation. (i.e., of the lungs and chest wall) and is cal-
culated from the change in volume per unit
SUCTIONING change in pressure:
Suctioning can be done if there are copious Δ Volume
amounts of secretions or suspicion of endo- Compliance =
tracheal tube occlusion by secretions, but Δ Pressure
routine suctioning is not necessary. Strict The higher the compliance, the larger the
sterile technique with disposable gloves and delivered volume per unit of pressure. Com-
suction tubes is necessary. The infant should pliance in babies with normal lungs ranges
be allowed to recover between episodes of from 3 to 6 mL/cm H2O. Compliance in
suctioning by maintaining stable O2 satura- infants with respiratory distress syndrome
tions with increases in inspired oxygen con- (RDS) ranges from 0.1 to 1 mL/cm H2O.
centrations as needed and by reexpanding
the lung with 10% to 20% more pressure RESISTANCE
than used for routine ventilation. Saline Resistance is a property of the inherent
instillation is done to facilitate removal of capacity of the gas-conducting system (i.e.,
secretions when secretions are thick. airways, endotracheal tube, and lung tissue)
Although sometimes necessary, suction- to oppose airflow and is expressed as the
ing is potentially dangerous; it may cause a change in pressure per unit change in flow:
hypoxic episode owing to discontinuation
Δ Pressure
of ventilation, extraction of gas from small Resistance =
airways, or atelectasis. It may also produce Δ Flow
Resistance in babies with normal lungs
Chest wall motion

Short TI Optimal TI Long TI
ranges from 25 to 50 cm H2O/L/second. Inadequate tidal volume Inspiratory plateau Long plateau
Resistance is not dramatically altered in
infants with RDS but is increased in intu-
bated infants and ranges from 50 to 150 cm
H2O/L/second. Time
TIME CONSTANT
Chest wall motion

Short TE Optimal TE Long TE
Time constant is a measure of the time Gas trapping, inadvertent PEEP
Expiratory plateau Long expiratory plateau
(expressed in seconds) necessary for 63% of
a step change (e.g., airway pressure gradi-
ent) toward equilibration. A step change in
airway pressure occurs between the begin- Time
ning and the end of a machine-delivered Figure 11-3. Estimation of optimal inspiratory (TI) and
inspiration (during pressure-limited, time- expiratory (TE) times. Inspiratory and expiratory times are
optimal when inspiration and expiration are complete
cycled ventilation). The product of com-
but the times are not too prolonged. (See text for further
pliance and resistance determines the time details) PEEP, Positive end-expiratory pressure.
constant of the respiratory system:
Time constant = Compliance × Resistance
when respiratory drive is normal and
For example, in an infant with normal pulmonary disease is not overwhelming.
lungs: Continuous distending pressure can be
applied with continuous positive airway
One time constant = 0.005 L/cm H2 O pressure (CPAP) or continuous negative
× 25 cm H2 O/L/second pressure around the chest wall. Because
= 0.125 second of the ease of delivery, CPAP is the usual
mode of delivery of continuous distending
In an intubated infant with RDS: pressure.
Surfactant deficiency in infants with RDS
One time constant = 0.001 L/cm H2 O predisposes to alveolar collapse. The result-
× 50 cm H2 O/L/second ing atelectatic areas of the lungs are the
= 0.050 second sites of right-to-left shunting. When alveoli
are prevented from closing by maintain-
It takes three time constants to achieve 95% ing a continuous positive transpulmonary
of the pressure change to be equilibrated pressure throughout the respiratory cycle,
throughout the lungs; it takes five time con- functional residual capacity increases. In
stants for 99% equilibration. Thus, to allow addition, ventilation of perfused areas of
for a fairly complete inspiration and expi- the lung increases, which reduces intrapul-
ration, inspiratory and expiratory times set monary shunt.
on the ventilator should last about three to A simple system for CPAP was described
five time constants. In this example of an by Gregory et al. in 19711 (Fig. 11-4). A suit-
intubated infant with RDS, the duration able air-oxygen mixture passes through a
of three to five time constants is 0.150 to humidifier. Gas passes through the tub-
0.250 second. A very short inspiratory time ing, which is attached to an endotracheal
can lead to inadequate tidal volume because tube. The screw clamp on the reservoir con-
ventilatory pressures may not equilibrate trols the flow of gas and maintains a con-
throughout the lungs (Fig. 11-3). A very stant positive pressure within the system,
short expiratory time can lead to gas trap- as indicated on the pressure manometer.
ping because exhalation may not be com- The side arm acts as an underwater safety
pleted. Very long inspiratory or expiratory valve by ending under a column of water.
times are also not beneficial. Nasal CPAP is simple and effective; it is
usually applied with nasal or nasopharyn-
CONTINUOUS POSITIVE AIRWAY geal prongs, although other techniques for
PRESSURE delivery can be used (Table 11-1). Problems
Respiration can also be assisted by expan- with CPAP generally revolve around feeding
sion of the lungs with continuous distend- difficulties, maintaining a good seal, and
ing pressure. This technique is valuable nasal trauma. Nursing and medical care are
However, the control infants in these trials

received mechanical ventilation, and it is
possible that mechanical ventilation with-
out surfactant causes lung injury. Recent
trials have compared the effects of CPAP
to mechanical ventilation with surfactant
administration. A large trial showed that in
very immature infants CPAP resulted in less
need for intubation, fewer days of mechani-
cal ventilation, and less need for postnatal
steroid treatment for BPD than treatment
with surfactant.5 In addition, there was a
trend for less BPD and/or death in the CPAP
group. Similar trends in reduction of BPD
Figure 11-4. Nasal continuous positive airway pressure and/or death with early CPAP have been
(CPAP) unit in place on infant.
reported in other clinical trials and meta-
analyses show significant reductions in BPD
and/or death. In bigger preterm infants,
Techniques of Applying CPAP results in benefits comparable to that
Table 11-1. Continuous Positive of surfactant.6 Together, these studies indi-
Airway Pressure
cate that CPAP is an effective alternative to
Method Advantages Disadvantages intubation and surfactant in the treatment
Nasal prongs Simple Trauma to of RDS in most preterm infants.
t urbinates and
septum; excessive
crying; variation EDITORIAL COMMENT: In a multicenter randomized
in Fio2; increased
work of breathing trial, Dunn et al. compared approaches to the initial
Nasopharyngeal Relatively May become respiratory management of preterm neonates (26 to
prongs simple, blocked or kinked 29 weeks’ gestation): prophylactic surfactant followed
fixation easy by a period of mechanical ventilation (prophylactic
Endotracheal Effective Requires surfactant [PS], prophylactic surfactant with rapid ex-
intubation; nursing tubation to bubble nasal continuous positive airway
and medical skills
as for ventilator pressure (intubate-surfactant-extubate [ISX], or initial
Head box Noninvasive Neck seal a management with bubble nasal continuous positive
problem; suction airway pressure and selective surfactant treatment
difficult; nerve (nCPAP).7 Forty-eight percent were managed without
palsies intubation and ventilation and 54% without surfactant
Face mask Simple, Abdominal
treatment. The primary outcome was death or BPD.
inexpensive distention,
pressure on Preterm neonates who were initially managed with
face and eyes; either nCPAP or PS with rapid extubation to nCPAP
CO2 retention; had similar clinical outcomes to those treated with PS
cerebellar followed by a period of mechanical ventilation. An ap-
hemorrhage
proach that uses early nCPAP leads to a reduction in
Face chamber Good seal, Expensive; baby
minimal inaccessible the number of infants who are intubated and given sur-
trauma to face factant. These results reinforce the SUPPORT date.5
Dunn Ms, Kaempf J, de Klerk A et al, Vermont Oxford

Network DRM Study Group: Randomized trial comparing
3 approaches to the initial respiratory management of
similar to those undertaken during mechan- preterm neonates. Pediatrics 128:e1069, 2011.
ical ventilation.
Trials performed before the era of surfac-
tant showed that CPAP decreased death and GENERAL GUIDELINES FOR CONTINUOUS
the need for mechanical ventilation, but POSITIVE AIRWAY PRESSURE
increased the risk for pneumothorax.2 Sub- 1. CPAP should be initiated soon after birth
sequent surfactant trials showed that surfac- in the most immature infants (less than
tant treatment in the first 2 hours after birth ~29 weeks’ gestation) with presumed
decreased mortality, air leaks, and death RDS. In more mature infants, CPAP can
or bronchopulmonary dysplasia (BPD).3 be initiated when the infant requires
more than 40% to 50% oxygen or when of neonatal care. Mechanical ventilation
the infant has recurrent apnea. allows the survival of previously nonviable
2. Initially, nasal CPAP of 5 to 6 cm H2O infants, stimulating the development of a
can be used. If there is no improvement, new era in neonatology.
the pressure can be increased in incre- Conventional mechanical ventilators
ments of 2 cm H2O up to 8 to 10 cm H2O. achieve a pressure gradient between the air-
Very high CPAP levels may overdistend way opening and lungs, producing a flow of
the lungs, decrease their compliance, gas into the lung. This is usually created by
and increase the risk for pneumotho- intermittently building up a positive pres-
rax. Nasal synchronized intermittent sure in the proximal airway. Ventilators for
mechanical ventilation can be added to infants are usually one of the following types:
augment the benefits of CPAP. 1. Pressure-controlled ventilators. These ven-
3. Continuous measurement of transcuta- tilators deliver a preset peak inspiratory
neous Po2 and Pco2, and oxygen satura- pressure (PIP), thus delivering a variable
tion with a pulse oximeter are of great tidal volume depending largely on lung
value and can decrease the need for fre- compliance. A constant flow of gas passes
quent blood gas measurements. through the ventilator. Intermittently,
4. Because these positive pressures are not the expiratory relief valve closes and the
completely transmitted to the pleural gas flows to the infant. Pressure is limited
space due to reduced lung compliance, to the desired magnitude. When the expi-
venous return and cardiac output are usu- ratory relief valve has been closed for the
ally not compromised. However, if Paco2 preset time, the valve opens, and inspira-
increases and Pao2 decreases, a reduction tion ceases. Pressure-controlled ventila-
in CPAP pressure should be considered. tion is usually used with the technique
of synchronized intermittent mandatory
EDITORIAL COMMENT: Thoracic wall elastic recoil is ventilation, which allows spontaneous
almost nonexistent in extremely preterm babies (e.g., breathing between ventilator breaths.
29 weeks’ gestation or less), so that the resting vol- PIP depends largely on the desired tidal
ume of the lung is very close to the collapsed volume. volume and the compliance of the lungs. Sug-
Also, the compliant chest wall tends to collapse as the gested initial ventilator settings are as follows:
diaphragm descends, resulting in an ineffective tidal
volume. Early use of CPAP may improve the efficiency
of ventilation in these very immature babies. Normal RDS
John Kattwinkel Lungs Lungs
PIP (cm H2O) 10-15 15-20
PEEP (cm H2O) 2-3 4-5
WEANING FROM CONTINUOUS POSITIVE Rate (per min) 10-20 40-80
AIRWAY PRESSURE I/E ratio 1:2-1:10 1:1-1:2
I/E, Inspiratory/expiratory; PEEP, positive end-expiratory
1. Inspired oxygen can be reduced in steps pressure; PIP, peak inspiratory pressure; RDS, respiratory
of 2% to 5% when the O2 saturation distress syndrome.
exceeds 93% to 95%.
2. CPAP can be reduced when the O2 satu-
ration is more than 93% to 95% and the 2. Volume-controlled ventilators. These venti-
inspired oxygen is less than 30% to 40%. lators deliver a preset tidal volume with
a variable PIP depending largely on lung
compliance. When this gas has been
EDITORIAL COMMENT: With small babies (<1500 g),
delivered by the piston, inspiration is
if recurrent apneic spells are a problem, we may contin-
terminated.
ue low-pressure CPAP (<5 cm H2O) until inspired oxy-
The tidal volume delivered by the venti-
gen concentrations have been reduced to 21% to 30%.
lator must be adequate to normalize arterial
John Kattwinkel
oxygen and carbon dioxide. Important con-
siderations are as follows:
See Chapter 10 for a discussion of the use • Infant’s tidal volume (4 to 8 mL/kg)
of CPAP for apnea of prematurity. • Compression loss in the ventilator tubing
(if ventilator tubing volume is large, this
MECHANICAL VENTILATION may be appreciable)
Mechanical ventilation is one of the most • Volume losses by leaks from the tubing
important breakthroughs in the history around the endotracheal tube
Pressure-controlled ventilators have been and failure of the ventilator to cycle at

the most frequently used types in neonates, the proper time.
but volume-controlled neonatal ventilators 6. Humidification or nebulization—to satu-
are being used increasingly because recent rate the inspired gases with water. The
evidence suggests that lung injury is most temperature of the inspired gas close to
likely related to volutrauma.7 Theoretical the endotracheal tube should be mea-
advantages of volume ventilation include sured continuously and used to servo-
consistency of delivered tidal volume, abil- control the humidification system.
ity to prevent excessive volume delivery, 7. Positive end-expiratory pressure (PEEP)—
and automatic weaning of pressure as lung to maintain functional residual capacity.
compliance improves. Volume ventilation 8. Exhalation assist—to reduce the end-
results in reductions or trends for reductions expiratory pressure to desired levels
in duration of ventilation, pneumothorax, when rapid rates are used. Inadvertent
intracranial hemorrhage, and BPD. The cli- PEEP can be a problem with some pedi-
nician should learn about and understand atric ventilators because of a high expira-
one or two types of ventilators versus trying tory resistance.
to be an expert in many types.
• Independent of the type of ventilator used, ALTERNATIVE MODES OF
Fio2 should initially correspond to the Fio2 MECHANICAL VENTILATION
necessary to maintain an adequate Pao2 Technologic advances, including improve-
(40 to 60 mm Hg) or oxygen saturation ment in flow delivery systems, breath termina-
(90% to 95%). The clinician should watch tion criteria, guaranteed tidal volume delivery,
for elevated oxygen saturation after start- stability of PEEP, air leak compensation, pre-
ing mechanical ventilation because effec- vention of pressure overshoot, pulmonary
tive mechanical ventilation may result in a function monitoring, and triggering systems,
sudden reduction in oxygen requirement. have resulted in better ventilators.8 Patient-
Ventilators have the following features: initiated mechanical ventilation, patient-trig-
1. Gas mixer (blender)—to allow easy adjust- gered ventilation, synchronized intermittent
ment of the inspired oxygen concentra- mandatory ventilation, and noninvasive
tion between 21% and 100%. ventilation are increasingly being used in
2. Time adjustment—to allow altering of neonates.
the inspiratory and expiratory times. This 1. Patient-triggered ventilation/synchronized
permits prolongation of inspiratory time intermittent mandatory ventilation. Patient-
in patients with a long inspiratory time triggered ventilation uses spontaneous
constant or widespread atelectasis as well respiratory efforts to trigger the ventila-
as its shortening if the time constant is tor. Airflow, chest wall movements, air-
short (see Fig. 11-3). Expiratory time way pressures, esophageal pressures, or
should be prolonged when gas trapping diaphragmatic electrical activity are used
is present or when the expiratory time as indicators of the onset of the inspira-
constant is long. Expiratory time can be tory effort. When the ventilator detects
shortened when the respiratory time con- an inspiratory effort, it delivers a ventila-
stant is short. tor breath of predetermined settings (PIP,
3. Expiratory relief valve—to limit the PIP. inspiratory duration, flow). Synchronized
When used in combination with the inspi- intermittent mandatory ventilation
ratory time adjustment, it allows the peak achieves synchrony between the patient
pressure to be held, generating a pressure and the ventilator breaths. Synchrony
plateau (see Fig. 11-3). A very long plateau occurs easily in most neonates because
is not beneficial. This valve also allows one strong respiratory reflexes during early
to limit the peak pressure to reduce the life elicit relaxation of respiratory muscles
likelihood of volutrauma or barotrauma. at the end of lung inflation. Furthermore,
4. Pressure gauge—to measure the applied inspiratory efforts usually start when
airway pressures accurately. An adequate lung volume is decreased at the end of
pressure monitor must be placed close to exhalation. Synchrony may be achieved
the endotracheal tube to measure correct by nearly matching the ventilator fre-
peak inspiratory and positive end-expira- quency to the spontaneous respiratory
tory pressures. rate or by simply ventilating at relatively
5. Alarms—to warn of inadvertent discon- high rates (60 to 120 breaths/minute).
nections, pressure loss, high pressures, Triggering systems can be used to achieve
synchronization when synchrony does manufacturers on terminology has been

not occur with these maneuvers. established, so similar modes have differ-
2. Proportional assist ventilation. These ven- ent names. To date, these combination
tilators reduce work of breathing. Both modes have not been proven superior to
modes of patient-initiated mechanical the traditional modes.
ventilation discussed earlier (patient-trig- 4. Noninvasive ventilation. Noninvasive ven-
gered ventilation, synchronized intermit- tilation delivered nasally is being increas-
tent mandatory ventilation) are designed ingly used to supplement nasal CPAP.
to synchronize the onset of the inspira- Noninvasive ventilation has been shown
tory support. In contrast, proportional to reduce apnea and the need for ventila-
assist ventilation matches the onset and tion. Further research is needed to deter-
duration of both inspiratory and expira- mine efficiency and safety of this mode
tory support and provides ventilation in of ventilation.
proportion to the volume or flow of the
spontaneous breath. Thus, the ventilator CARBON DIOXIDE ELIMINATION
can selectively decrease the elastic or resis- CO2 elimination largely depends on the
tive work of breathing. The magnitude of amount of gas that passes in and out of the
the support can be adjusted depending on alveoli (Fig. 11-5). The total amount of gas
the patient’s needs. When compared with that passes in and out of the lungs (including
conventional and patient-triggered ven- alveoli and airways) is called minute ventila-
tilation, proportional assist ventilation tion. Minute ventilation may be calculated
may reduce ventilatory pressures while from the product of the tidal volume and
maintaining or improving gas exchange.9 respiratory frequency. Thus, increases in tidal
Randomized clinical trials are needed to volume or frequency increase minute ventila-
determine whether proportional assist tion, increase CO2 elimination, and decrease
ventilation leads to major benefits when Paco2. Some of the tidal volume distributes
compared with conventional mechanical to parts of the lungs (dead space) that are not
ventilation. involved in gas exchange (e.g., airways).
3. Combination modes. Many of the newer Tidal volume may be increased by increas-
generation ventilators offer combina- ing the pressure gradient between inspiration
tions of volume and pressure ventilation. and expiration. This may be accomplished
Often these modes use pressure ventila- by increasing PIP or by decreasing PEEP.
tion with a guarantee of a certain volume. Tidal volume is usually independent of
No agreement among different ventilator inspiratory and expiratory times. However,
CO2
elimination
Minute
ventilation
Tidal
Frequency Resistance
volume
Figure 11-5. Determinants of CO2 elimination

Exp. Insp. Time during pressure-limited, time-cycled ventilation.
time time constant Ventilator-controlled variables are shaded.
The relations between the circles that are
I:E Pressure joined by solid lines are described by simple
Compliance mathematical equations. Exp, Expiration;
ratio gradient
insp, inspiration. (Adapted from Chatburn
RL, Lough MD: Mechanical ventilation. In
End exp. Peak insp. Lough MD, Doerschuck C, Stern R, editors:
pressure pressure Pediatric respiratory therapy, ed 3, Chicago,
Mosby Year Book, 1985, p 161.)
depending on the time constant of the respi- concentration and the mean airway pressure
ratory system, very short inspiratory times (Fig. 11-6). Oxygenation increases linearly
may limit tidal volume delivery. with increases in mean airway pressure,
Frequency is the other major determinant largely because functional residual capacity
of minute ventilation. In addition to the fre- can be optimized with mean airway pressure
quency set on the ventilator, the infant may adjustments resulting in improved V̇ / Q̇
take spontaneous breaths because neonatal match. Mean airway pressure is a measure of
ventilators provide a continuous flow of gas the average pressure to which the lungs are
during the expiratory phase. exposed during the respiratory cycle. Mean
Hypercapnia can be caused by hypoven- airway pressure may be calculated from the
tilation or ventilation-perfusion (V̇ / Q̇ ) area under the curve divided by the dura-
mismatch. Hypoventilation is a very impor- tion of the cycle (Fig. 11-7). The equation is
tant cause of hypercapnia. Hypercapnia as follows.
occurs when alveolar ventilation decreases. Mean airway pressure =
Hypercapnia caused by hypoventilation is (TI )
easily managed with mechanical ventila- K(PIP − PEEP) + PEEP
(TI + TE )
tion. Hypercapnia secondary to severe V̇ / Q̇
mismatch may be more difficult to manage
with mechanical ventilation. Optimal V̇ / Q̇
matching occurs when the ratio of alveolar
ventilation and alveolar perfusion is approx-
imately 1. V̇ / Q̇ mismatch is probably the FiO2 Oxygenation
most important mechanism of gas-exchange
impairment in infants with respiratory fail-
ure of various causes, including RDS.
OXYGENATION Mean
airway
Hypoxemia can be due to V̇ / Q̇ mismatch, pressure
shunting, diffusion abnormalities, and
hypoventilation.10 V̇ / Q̇ mismatch is a major Peak insp.
Flow
cause of hypoxemia in infants with RDS pressure
and in neonates with other causes of respi-
ratory failure. In these patients, the alveoli End exp. I:E
are poorly ventilated relative to their perfu- pressure ratio
sion. In neonates with persistent pulmonary
hypertension or cyanotic congenital heart Figure 11-6. Determinants of oxygenation during
disease, shunting is the predominant mech- pressure-limited, timed-cycle ventilation. Circles depicting
anism that leads to hypoxemia. Diffusion ventilation-controlled variables are shaded. Solid arrows
abnormality, typical of interstitial lung dis- represent mathematical relationships.
ease and other diseases that affect the alve-
olar-capillary interface, is not prominent
in neonates with RDS and does not cause
severe hypoxemia. Hypoventilation usually Pressure 2
causes mild hypoxemia unless severe hyper-
capnia ensues.
Unlike other causes of hypoxemia, shunt-
ing usually is unresponsive to oxygen sup- 1 5 3 4
plementation and mechanical ventilation PIP-PEEP
unless the shunt is reversed. Hypoxemia
resulting from V̇ / Q̇ mismatch can be dif- PEEP
ficult to manage, but may be resolved if T
I T
an increase in airway pressure reexpands Time
E
atelectatic alveoli. Hypoxemia caused by
Figure 11-7. Methods to increase airway pressure.
impaired diffusion or hypoventilation usu- Interventions: 1. Increase PEEP; 2. Increase PIP;
ally responds to oxygen supplementation 3. Increase I/E or TI; 4. Increase rate; 5. Increase flow.
and mechanical ventilation. I/E, Inspiratory-to-expiratory ratio; PEEP, positive end-
In infants with RDS, oxygenation expiratory pressure; PIP, peak inspiratory pressure;
depends largely on the inspired oxygen TE, expiratory time; TI, inspiratory time.
where K is a constant that depends on major effects are summarized in Table 11-2.
the rate of increase of the airway pressure Although effects may vary, these basic prin-
curve, PIP is peak inspiratory pressure, ciples should serve as guidelines. However,
PEEP is positive end-expiratory pressure, when faced with an abnormal blood gas
Ti is inspiratory time, and Te is expiratory result, several alternative ventilator setting
time. Therefore, mean airway pressure is changes may be acceptable. Controversy
increased by increasing any of the follow- still exists as to the optimal way to ventilate
ing (see Fig. 11-7): infants. It is generally preferred to provide an
1. PEEP adequate tidal volume and then adjust the
2. PIP frequency to achieve sufficient CO2 elimi-
3. Inspiratory to expiratory (I/E) ratio or nation. Mean airway pressure can then be
inspiratory time changed to optimize oxygenation. The use of
4. Rate very high frequencies, in which short inspi-
5. Inspiratory flow (increases K) ratory time decreases tidal volume delivery
Although a direct relationship usually or short expiratory time causes gas trapping
exists between mean airway pressure and and inadvertent PEEP, is not advocated.
oxygenation, several limitations follow: In summary, major concepts of gas
1. For the same change in mean airway pres- exchange in infants with RDS are that CO2
sure, increases in PIP and PEEP enhance elimination is proportional to minute ven-
oxygenation more than increases in I/E tilation and that oxygenation is related
ratio. directly to mean airway pressure. Based on
2. Increases in PEEP are not as effective these concepts, ventilatory strategies have
when an elevated level (more than 5 to been developed11 that should provide an
6 cm H2O) is reached. organized, logical, and consistent means of
3. Very high mean airway pressure may achieving desired blood gas results, thereby
cause lung overdistention, right-to-left supporting the clinician in ventilator man-
shunting in the lungs (by redistribution agement decisions. Studies in neonates with
of blood flow to poorly ventilated areas), RDS, who were managed with such an algo-
or decreased cardiac output. rithm, revealed more frequent correction of
4. Long inspiratory times increase the risk blood gas derangements and more appropri-
for pneumothorax. ate efforts to wean the infant from ventila-
tory assistance.10
VENTILATOR SETTING CHANGES
AND GAS EXCHANGE MONITORING THE INFANT DURING
From the earlier discussion, the effects of MECHANICAL VENTILATION
the changes in individual ventilator settings During mechanical ventilation, the clini-
on blood gases can be extrapolated. The cian undertakes the responsibility for the
Table 11-2. Effect of Ventilator Setting Changes on Blood Gases
Change Paco2 Pao2 Comments

PIP ↑ ↓ ↑ Use of high PIP increases risk of barotrauma (e.g., pneumothorax,
↓ ↑ ↓ interstitial emphysema)
PEEP ↑ ↑ ↑ An increase in PEEP prevents alveolar collapse and improves ventila-
tion/perfusion relationship. A PEEP of 2 to 3 cm H2O is physiologic.
A higher PEEP is indicated in babies with RDS.
↓ ↓ ↓ A decrease in PEEP may improve compliance and may improve CO2
retention. Very high PEEP (e.g., >6 cm H2O) is not very effective in
increasing Pao2.
Frequency ↑ ↓ — High ventilator frequencies may allow the use of low PIP and reduce
↓ ↑ — the risk of pneumothorax. If I/E ratio is kept constant, frequency
changes do not alter mean airway pressure and do not substantially
affect Pao2.
I/E Ratio ↑ — ↑ I/E ratio changes do not usually alter tidal volume or CO2 elimination
↓ — ↓ unless inspiratory time or expiratory time, or both, are too short.
Flow ↑ ±↓ ±↑ The effects of flow changes on blood gases have not been well stud-
↓ ±↑ ±↓ ied in infants.
I/E ratio, Inspiratory to expiratory ratio; PEEP, positive end-expiratory pressure; PIP, peak inspiratory
pressure; RDS, respiratory distress syndrome.
infant’s gas exchange. Hence, monitoring • Tension pneumothorax. Diminished breath

the patient’s condition is vital and requires sounds are heard on the affected side and
continuous observation. there may also be abdominal distention
The goal should be to maintain Pao2 and an easily palpable liver and spleen; the
between 40 and 60 mm Hg, Paco2 at more condition is usually critical. Action—Emer-
than 40 mm Hg, and pH between 7.25 and gency relief of tension pneumothorax by
7.40. Continuous monitoring with a pulse inserting a chest tube or a 22-gauge cath-
oximeter and transcutaneous Pco2 and Po2 eter attached to a three-way stopcock and
electrodes or a catheter electrode is invaluable a 20-mL syringe into the third intercostal
during intubation, stabilization procedures, space at the midclavicular line or the fourth
or weaning because blood gases can change or fifth intercostal space at the anterior axil-
abruptly. Because arterial CO2 equilibrates lary line. Remove gas until the condition
with alveolar CO2, quantitative end-tidal improves. If the infant has deteriorated do
CO2 monitoring can be used to estimate arte- NOT wait for a chest radiograph to perform
rial CO2. However, in patients with alveolar the procedure. After stabilizing the infant,
disease, there is incomplete equilibration of obtain a chest radiograph and consider
arterial and alveolar CO2; therefore, end-tidal inserting a chest tube.
CO2 can underestimate arterial CO2. Neo- If gas entry is diminished unilaterally,
natal qualitative exhaled CO2 monitoring check for the following causes:
is extremely useful in determining endotra- • Tube in mainstem bronchus. It is usually
cheal tube placement because the diagnostic in the right mainstem bronchus, produc-
accuracy approximates 100%.12 ing decreased gas entry on the left. Action–
Verify endotracheal tube measurement at
CHANGES IN BLOOD GAS STATUS the lip level. Withdraw tube 0.5 to 1 cm.
Immediate improvement in gas entry will
A Practical Approach result. Recheck position by chest x-ray.
1. A sudden decrease in Pao2 accompanied • Unilateral pneumothorax. Radiologic con-
by an increase in Paco2 associated with firmation of clinical diagnosis is obtained
rapid clinical deterioration of the infant. To if the condition of the infant warrants a
differentiate whether the problem is with delay in initiating therapy. If not, treat as
the ventilator or the infant, disconnect for tension pneumothorax.
the ventilator from the infant and manu- If gas entry is not diminished and the
ally inflate the infant’s lungs. infant does not improve with manual lung
If the infant’s condition improves, the inflation, this suggests a nonrespiratory
problem is with the ventilator. Check the cause such as intraventricular hemorrhage,
following: pneumopericardium, convulsions, hypo-
• Concentration of inspired oxygen going glycemia, hypotension, or overwhelming
to the ventilator sepsis. The incidence of intraventricular
• Presence of leaks or disconnected tubing hemorrhage is greatly increased in infants
• Mechanical or electrical failure who have a pneumothorax. The occasional
If the infant shows no clinical improve- occurrence of pneumoperitoneum, owing
ment with manual inflation, the problem is to forcing gas through the diaphragm in the
with the infant. Check gas entry bilaterally periaortic spaces, can seriously mislead the
by auscultation, listen over the stomach, clinician into the assumption that a rup-
and determine the position of the heart and tured viscus has occurred and abdominal
trachea. If gas entry is diminished bilater- surgery is indicated.
ally, look for the following causes:
• Tube displaced into nasopharynx. There
may be gas entry heard over the stomach,
EDITORIAL COMMENT: Airway sounds are easily
and gas may be visibly escaping at the
transmitted across a small chest, and therefore evalu-
mouth or via a nasogastric tube with the
ation of breath sounds can be terribly misleading in
end placed under water. Action—Replace
small infants. Even with “adequate” breath sounds, I
the tube.
would transilluminate the chest, check the placement
• Tube blocked. Tube blockage occurs espe-
of the endotracheal tube with a laryngoscope, and
cially after a few days of ventilation and
perhaps replace the endotracheal tube before attrib-
afterward because of the increased accumu-
uting the problem to a nonrespiratory etiology.
lation of secretions. Action—Suction tube
John Kattwinkel
briefly. If this has no effect, replace the tube.
2. Gradual decrease in Pao2 accompanied by in degree of atelectasis. Because of the

an increase in Paco2 associated with grad- toxic effect of high inspired oxygen on
ual deterioration of the infant. This sug- lung tissue but the benefits of maintain-
gests inappropriate ventilator settings. ing lung inflation, it is generally better
A decrease in Pao2 suggests increasing to reduce the concentration of inspired
intrapulmonary shunting resulting from oxygen to less than 40% to 70% before
progressive atelectasis. attempting to markedly reduce ventila-
To improve Pao2, consider the following tor parameters.
measures:
• Increase PIP ROUTINE CARE OF THE INFANT
• Increase PEEP Monitoring of blood gases and respiratory
• Increase tidal volume by 1 to 2 mL/kg status is an important aspect of supportive
(increases PIP; volume ventilator) treatment, but attention must also be paid
• Increase the I/E ratio or the inspiratory to temperature control, caloric and fluid
time intake, and metabolic balance. Clinicians
• The responses to these maneuvers may should avoid excessive and unnecessary
vary, and blood gas analyses must be handling of the infant. Measures such as ele-
obtained. vating the head of the bed 15 to 30 degrees,
3. Gradual increase in Paco2 without gross mouth care, daily assessments of readiness
changes in Pao2. A gradual increase in for extubation, and strict attention to hand
Paco2 is usually due to insufficient alveo- hygiene may decrease the incidence of ven-
lar ventilation (insufficient tidal volume tilator associated pneumonia.
or frequency, or both). A gradual increase
in Paco2 can also be due to increased “ana- SPECIAL CIRCUMSTANCES
tomic” (i.e., airways, tubing) or “physi-
ologic” (i.e., nonventilated but perfused PULMONARY INTERSTITIAL EMPHYSEMA
alveoli) dead space. An increase in Paco2is Infants with severe RDS and those who have
an indication for an increase in alveolar pulmonary interstitial emphysema (PIE) on
ventilation by increasing PIP or decreas- chest x-ray may respond better to a rapid
ing PEEP during pressure ventilation, by ventilating rate (60 to 150 breaths/minute),
increasing tidal volume during volume low peak pressure, low PEEP, and high-
ventilation, or by increasing cycling fre- frequency ventilation.
quency. A reduction of anatomic dead
space (e.g., shortening the endotracheal PULMONARY HYPERTENSION/
tube) may relieve hypercapnia. MECONIUM ASPIRATION SYNDROME
To improve Paco2, increase minute venti- Infants with severe pulmonary hyperten-
lation by the following measures: sion with or without meconium aspiration
• Increase PIP by 2 to 5 cm H2O (pressure syndrome may benefit from inhaled nitric
ventilator) oxide, a selective pulmonary vasodilator.
• Increase tidal volume by 1 to 2 mL/kg Nitric oxide reduces the need for extracor-
(increases PIP; volume ventilator) poreal membrane oxygenation (ECMO) in
• Increase ventilator rate by 5 to 10 breaths/ neonates with pulmonary hypertension.13
minute Other therapies include oxygen, surfactant,
4. A decrease in Paco2 caused by overventila- sedation, analgesia, and inotropic support,
tion. A decrease in Paco2 is potentially but there are limited data to support their
dangerous because alkalosis is associated clinical efficacy.
with decreases in cerebral blood flow and
tissue oxygen delivery. Hypocarbia is NEONATAL SURGERY
also associated with periventricular leu- Intubation of the very low-birth-weight
komalacia as well as deafness. The lungs infant in the intensive care nursery and use
may be subjected to volutrauma if the of a ventilator during surgery are preferable.
low Paco2 is the result of ventilation with In this way, inspired oxygen and inspired gas
large tidal volumes. Hence, a low Paco2 temperature can be carefully controlled, as
is an indication for a reduction in overall can pain management. Continuous oxygen
alveolar ventilation. saturation and intermittent arterial blood gas
5. Increase in Pao2 unaccompanied by changes analyses are monitored throughout surgery
in Paco2. This suggests a decrease in to maintain the infant with adequate blood
intrapulmonary shunting and reduction gases.
DRUG THERAPY WEANING FROM VENTILATOR

The use of muscle paralysis may be invalu- Ventilator weaning can be attempted when
able in infants who “fight” the ventila- the concentration of inspired oxygen is
tor when Paco2 is increasing and Pao2 is approximately 50% or less. The PIP is gradu-
decreasing on “maximum” ventilation. A ally reduced as is the ventilator rate to allow
marked improvement in oxygenation may the patient to contribute more to his or her
be observed, particularly in infants with ventilation. When the ventilator breaths
pulmonary hypertension. elicit minimal chest rise, ventilator frequency
is minimal (~10/minute), and the infant has
adequate blood gases, the infant should be
EDITORIAL COMMENT: Muscle paralysis for babies accomplishing almost all of the minute ven-
on ventilators must be viewed with caution. The his- tilation spontaneously. At this point, most
tamine-releasing effect of competitive neuromuscular infants can be successfully extubated to CPAP.
blocking agents (particularly curare) can cause hypo-
tension and, rarely, bronchospasm. Some patients HIGH-FREQUENCY VENTILATION
may require higher ventilator settings after paralysis Although conventional mechanical ventila-
as their own respiratory efforts are eliminated. Also, a tion has contributed to a substantial reduc-
system failure (e.g., extubation, tubing disconnection) tion in neonatal mortality, air leaks or BPD
in a paralyzed patient will be rapidly fatal. occurs in about 20% to 40% of ventilated
John Kattwinkel infants. Although the precise pathophysi-
ologic mechanisms underlying these forms of
lung injury have not been determined, high
Sedatives and analgesics are increas- ventilatory pressures and the resultant volu-
ingly being used in the care of neonates trauma are thought to be contributing factors.
requiring assisted ventilation. These agents High-frequency ventilation encompasses
may be used in combination with muscle modes of assisted ventilation that employ
paralysis. However, when it is desirable smaller tidal volumes and higher frequencies
to preserve the patient’s own respiratory than conventional techniques. The charac-
effort, sedatives or analgesics may be used teristics of the various high-frequency ven-
without muscle paralysis. Fentanyl and tilators overlap (Table 11-3). Furthermore,
morphine sulfate are commonly used seda- clinicians may employ widely varying venti-
tives/analgesics. Sedatives and analgesics latory strategies. High-frequency ventilation
may decrease respiratory drive and should may improve blood gases because, in addi-
be used carefully. Routine opiate adminis- tion to the gas transport by convection, other
tration during conventional ventilation in mechanisms may become active at high fre-
neonates has not been shown to improve quencies (for example, variable velocity pro-
outcomes.14 files of gas during inspiration and exhalation,
Antibiotics should be used whenever a gas exchange between parallel lung units,
bacterial infection is suspected. increased turbulence, and diffusion may
Preextubation systemic corticosteroids and improve blood gases).
postextubation racemic epinephrine reduces High-frequency positive-pressure ventila-
airway resistance when there is laryngeal tors employ standard ventilators modified
edema. However, if the endotracheal tube is with low-compliance tubing and connectors
not too large, is well positioned, and is not so that an adequate tidal volume may be
mobile during ventilation, problems with delivered despite very short inspiratory times.
the glottis following extubation are rarely High-frequency jet ventilation is characterized
observed. by the delivery of gases from a high-pressure
Table 11-3. Techniques for High-Frequency Ventilation
HFPPV Jet Ventilation Flow Interruption Oscillatory Ventilation

Tidal volume > Dead space > or < Dead space > or < Dead space < Dead space
Expiration Passive Passive Passive Active
Airway pressure Variable Triangular Triangular Sine wave
waveform
Frequency 60-150/min 60-600/min 300-900/min 300-900/min
HFPPV, High-frequency positive pressure ventilation; >, larger than; <, smaller than.
source through a small-bore injector cannula. EDITORIAL COMMENT: The technique of high-
It is possible that the fast flows out of the can- frequency ventilation requires major changes in the
nula produce areas of relative negative pressure concept of gas flow in the lung. Currently it is believed
that entrain gases from their surroundings. that by vibrating the gas column, gas exchange is pro-
High-frequency flow interruption also deliv- moted by setting up asymmetric flow within the airways
ers small tidal volumes by interrupting a flow rather than by convection, which is the predominant
of pressure source, but in contrast to jet ven- mechanism of conventional ventilation. Studies suggest
tilation, it does not use an injector cannula. that high-frequency ventilation may improve ventilation/
High-frequency oscillatory ventilation can perfusion matching throughout the respiratory cycle,
exchange gas adequately with small volumes thus permitting lower peak inflation pressures and low-
(even smaller than dead space at times) at er inspired oxygen concentrations. High pressure, high
extremely high frequencies. Oscillatory venti- volume and high oxygen have all been implicated in the
lation is unique because exhalation is actively development of bronchopulmonary dysplasia.
generated, as opposed to other forms of high- John Kattwinkel
frequency ventilation, in which exhalation is
passive.
RESPIRATORY DISTRESS SYNDROME COMPLICATIONS OF ASSISTED

There has been extensive clinical use of the VENTILATION
various high-frequency ventilators in neo- Despite major improvements in equipment
nates with RDS. High-frequency positive and increased expertise in the applications
pressure using rates of 60 breaths/minute of assisted ventilation, the care of smaller
(with inspiratory times less than 0.5 sec- and sicker infants may result in many com-
onds) versus 30 to 40 breaths/minute for plications (Table 11-4). Pulmonary air leaks
conventional mechanical ventilation with are one of the most common complications
inspiratory times longer than 0.5 seconds) and occur in approximately 5% to 10% of
decreases air leaks.15 High-frequency oscil- ventilated patients. Pneumothorax may
lator ventilation does not offer important occur due to the lung disease or may result
advantages over conventional ventilation. from the use of high PIP and inspiratory
High frequency oscillator ventilation may time, particularly in infants who “fight”
decrease BPD but it may increase air leaks.16 the ventilator. However, spontaneous pneu-
mothoraces are commonly observed, even
AIR LEAKS in healthy neonates without lung disease.
High-frequency ventilation has been used Transillumination of the chest is extremely
to treat established air leaks. Jet ventila- useful for immediate diagnosis, but radio-
tion in neonates with pulmonary intersti- graphic confirmation should be obtained if
tial emphysema may accelerate resolution the patient’s status is not life threatening.
of the air leak.17 However, air leaks may be PIE, an air leak usually secondary to the use
increased with oscillatory ventilation.16 of high airway pressures, is associated with
gas trapping and impaired gas exchange.
Bronchopulmonary dysplasia, a form
Complications of Assisted of chronic lung disease that occurs in neo-
Table 11-4. nates, is one of the most important compli-
Ventilation
cations associated with assisted ventilation.
Pulmonary air Pneumothorax, pneumomediastinum, BPD was initially defined as an oxygen
leaks pneumoperitoneum, pulmonary inter-
stitial emphysema, pneumopericar-
requirement and characteristic chest x-ray
dium, pulmonary venous air embolism at 28 days of life. With the increasing sur-
Airway injury Erosion, granuloma, palatal groove, vival of ELBW infants, the definition was
subglottic stenosis, necrotizing changed to an oxygen requirement at
tracheobronchitis 36 weeks’ postmenstrual age. The chest x-ray
Endotracheal Dislodgement, extubation, atelectasis, of infants with BPD often shows opacifica-
tube related occlusion, tracheal stenosis, vocal
cord paralysis tion of the lung fields, atelectasis, fibrosis,
Infection Pneumonia, septicemia, meningitis and overdistention. Although its precise
Miscellaneous Volutrauma, bronchopulmonary pathophysiology remains obscure, volu-
dysplasia, hyperinflation, impaired trauma appears to be a contributing factor.
cardiac output, intracranial hemor- The increasing incidence of BPD is largely
rhage, patent ductus arteriosus, due to improved survival rates of infants with
retinopathy of prematurity
immature or ill lungs. The incidence of BPD
varies widely and may be as high as 50% in Pulmonary artery vasodilators have been
infants weighing less than 1000 g who require used in treatment of these infants, but the
assisted ventilation from birth. Management systemic vasodilatory effects have precluded
of these patients must be multidimensional, efficacy and widespread use. Nitric oxide, a
with particular emphasis on prevention of molecule produced endogenously by endo-
further lung injury, maintenance of adequate thelial cells and other cell types, regulates
oxygenation and nutrition, and prevention pulmonary artery tone in utero and after
of infection and fluid overload. The effect birth. Exogenous nitric oxide reduces pulmo-
of differences in care practices on the inci- nary vascular resistance during the perinatal
dence of BPD suggests that optimal respira- period. Inhaled nitric oxide has been shown
tory management of very low-birth-weight to improve oxygenation and reduce the
infants may decrease the incidence of BPD.18 need for ECMO in well-designed, large, ran-
As discussed previously, clinical trials of early domized, controlled trials in term and late
CPAP and minimal ventilation strategies preterm neonates with severe hypoxemic
have shown moderate reductions in the inci- respiratory failure.19 However, inhaled nitric
dence of death and/or BPD. oxide has not been shown to have consistent
benefits in preterm infants with RDS.20
EXTRACORPOREAL MEMBRANE
OXYGENATION SUMMARY
ECMO is a technique whereby blood drains Survival of infants with severe pulmonary
from the patient; then the blood passes disease has dramatically improved with the
through a membrane for extracorporeal introduction of techniques of assisted venti-
exchange of oxygen and carbon dioxide; and lation. Meticulous care is necessary with the
is then routed back to the patient. ECMO following: strategies to optimize conventional
is particularly useful in neonates with tran- ventilation; placement of endotracheal tubes;
sient pulmonary artery hypertension and frequent blood gas determinations; continu-
severe hypoxemia resulting from a right-to- ous monitoring of oxygen saturation, trans-
left shunt. Common conditions associated cutaneous Po2, and transcutaneous Pco2; and,
with pulmonary hypertension include meco- fluid, caloric, and thermal balance. However,
nium aspiration syndrome, RDS, idiopathic most of the difficulty with adequately venti-
pulmonary hypertension of the neonate, lating small infants resides not in the ventila-
pneumonia/sepsis, asphyxia, and congenital tor, but in the infant’s lungs and airways. The
diaphragmatic hernia. Neonates with these clinician should identify and correct atelec-
and other conditions are considered candi- tasis, increased dead space, and gas trapping
dates for ECMO if they have severe impair- and treat the patient’s pulmonary problems
ment of oxygenation. The alveolar-to-arterial with appropriate ventilatory strategies rather
oxygen gradient (A/aDO2) is frequently used than look for a better ventilator to solve the
to evaluate impairment of oxygenation. An problems. Long-term morbidity associated
alveolar-arterial oxygenation gradient of 600 with mechanical ventilation is still a major
to 620 for 8 to 12 hours despite maximal problem. Because assisted ventilation is a
therapy is usually considered an indication critical part of neonatal intensive care, a thor-
for ECMO. In the past, predicted survival rate ough understanding of pulmonary mechan-
for infants with such severe respiratory failure ics and gas exchange, as well as knowledge
was as low as 20%. In marked contrast, fol- of the techniques and alternative modes of
lowing the introduction of ECMO, survival ventilation, is essential to optimize its use.
currently approximates 90% in these infants.
Complications during ECMO may be
related to the primary disease or to technical
QUESTIONS
aspects of the circuit. Intracranial hemor-
rhage and infarction, hemodynamic altera-
tions, and hematologic disturbances occur True or False
occasionally. The improved survival rate If you set a pressure-limited safety valve on a
has not been accompanied by an increase in volume-controlled ventilator at 30 cm H2O, a
permanent morbidity. pneumothorax will not occur.
INHALED NITRIC OXIDE Although pneumothorax is particularly asso-

High pulmonary artery resistance is com- ciated with high inflation pressures, it can
mon in infants with pulmonary disease. occur at any time during either mechanical
or spontaneous ventilation—even at low some of these atelectatic areas, reducing the

PIP. The statement is false. degree of shunting, with an ensuing increase
in Pao2. However, a large right-to-left shunt
may not increase Paco2 markedly because
True or False the arteriovenous difference for CO2 is only
The larger the volume of ventilator tubing, the less 4 mm Hg. Resolution of the shunt may not
the compression volume at any given pressure. decrease Paco2, so the statement is true.
During ventilation, a proportion of the gas

delivered by the pump (“compression vol- True or False
ume”) does not reach the alveoli. The larger During mechanical ventilation, pH remains con-
the volume of ventilator tubing, the greater stant as long as the Paco2 does not change.
the compression volume. Hence, ventilator
tubing should be low volume and nondis- The pH depends on the Paco2 and the
tensible. The statement is false. bicarbonate level. Metabolic and respira-
tory factors are often closely associated
(e.g., a period of apnea is associated with an
True or False increase in Paco2 and a decrease in Pao2, the
Condensation of water in ventilator inspiratory latter leading to tissue anoxia and anaero-
tubing can be reduced by placing as much tubing bic metabolism). However, metabolic and
as possible inside the incubator. respiratory factors may operate quite inde-
pendently. The statement is false.
A temperature gradient exists between air
outside and inside the incubator. Water
vapor condenses at lower temperatures, and CASE 1
droplets appear in tubing exposed to low You are called to attend the delivery of a 26 weeks’
temperatures. If water condensation occurs gestational-age infant whose mother received a full
in the tubing, the gas delivered to the infant course of antenatal steroids.
will have a water saturation lower than gas
coming out of the humidifier. Heated venti- After resuscitation with bag and mask
lator tubing can also reduce condensation. ventilation, the infant requires 30% Fio2. A
The statement is true. trial of CPAP is indicated in this infant. True
or false?
CPAP used early in preference of mechanical ventila-
True or False tion reduces lung injury. The statement is true.
If a small leak develops between the trachea and
the endotracheal tube during pressure-controlled Surfactant should be given as soon as
ventilation, there will be adequate compensation possible to this infant because it has been
by the ventilator. shown to improve outcomes. True or false?
Surfactant prophylaxis and early surfactant were shown
A pressure-controlled ventilator delivers gas to reduce mortality and air leaks when compared to in-
until a preset pressure is attained. Although tubation without surfactant. However, the new trials of
it is possible to compensate for a small leak CPAP versus early surfactant have shown no benefits of
(e.g., around the endotracheal tube); a large prophylactic or early surfactant. The statement is false.
leak may cause failure to reach the desired
PIP. The statement is true.
CASE 2
True or False Before mechanical ventilation using a pressure-limit-
ed ventilator, the Pao2 is 30 mm Hg and the Paco2 is
During mechanical ventilation with 80% oxygen
60 mm Hg in 100% oxygen in a preterm baby. Thirty
(for RDS), an increase in PIP may increase the Pao2
minutes after initiating therapy, a blood gas analysis
to 200 mm Hg without altering Paco2 significantly.
is performed.
When breathing a high concentration of Pao2 has risen to only 35 mm Hg, and Paco2
oxygen, a low Pao2 indicates venous admix- is still 60 mm Hg. It is advisable to switch
ture or shunting. This shunting is thought to a volume-controlled ventilator because
to occur primarily through areas of atelec- the lungs are too stiff to be adequately
tatic lung. Effective ventilation may open
ventilated by a pressure-controlled Paco2 and pH are satisfactory, but oxygenation is too

machine. True or false? low. PEEP can be increased to increase mean airway
The statement is false. The initial ventilator settings pressure. The statement is false.
were probably somewhat subjective and should be
adjusted to the infant’s requirements. The high Paco2 The arterial oxygen tension is 56 mm
indicates hypoventilation, and an attempt should Hg; pH is 7.23, and Pa co 2 is 26 mm Hg
be made to increase minute ventilation by increas- on low ventilator settings. Although
ing PIP. The increase in PIP should also improve the pH is within normal range, there is
oxygenation. Adjustments should be made every severe metabolic acidosis, which should
10 minutes, checking blood gases until oxygen satu- be corrected with intravenous sodium
ration is higher than 85% and Paco2 is less than ap- bicarbonate. True or false?
proximately 50 mm Hg. Spontaneous hyperventilation on the ventilator may
be due to compensation for a metabolic acidosis.
Pao2 is only 35 mm Hg and Paco2 is 35 mm Correction of severe metabolic acidosis is indicat-
Hg. It might be helpful to increase PEEP ed with intravenous bicarbonate. However, search
before increasing PIP further. True or false? should be made for the etiology of the acidosis, such
A positive end-expiratory pressure of 5 to 6 cm H2O as reduced cardiac output, anemia, sepsis, or pneu-
will help to prevent small airway closure. This may mothorax, and the underlying cause corrected.
prevent atelectasis and reduce the degree of right-to-
left shunt. The statement is true.
CASE 4
The Pao2 has risen to 140 mm Hg. This is During mechanical ventilation, an infant becomes
a dangerous level, and the concentrations cyanotic. He is noted to be making very vigorous
of inspired oxygen should be reduced at respiratory efforts with considerable intercostal and
once. True or false? sternal retractions out of phase with the ventilator.
In immature infants, arterial oxygen tensions in that
range have been associated with retinopathy of pre- This is a good indication for sedation and
maturity. The statement is true. Priority should be giv- adjusting the ventilator to accommodate
en to reducing the concentration of inspired oxygen in the infant’s respiratory pattern. True or
this situation versus altering other ventilator settings. false?
Decrease inspired oxygen concentrations frequently Although “out of phase” respiration could account for
and continuously monitor oxygen saturation. this clinical picture, an obstructed endotracheal tube,
a pneumothorax, or other major problem must first
be excluded. The statement is false.
CASE 3
A blood gas analysis is performed during mechani- Gas entry is diminished over the left lung
cal ventilation on 80% oxygen. There has been no field. The diagnosis is pneumothorax,
change in the clinical condition of the infant since the which should be relieved immediately. True
previous estimation. or false?
Diminution of gas entry over the left lung field may be
It is found that Paco2 has changed from 36 due to (1) the endotracheal tube slipping into the right
to 24 mm Hg and pH has risen from 7.38 mainstem bronchus or (2) pneumothorax. The steps
to 7.56. This is a sign that the infant is should be to check the endotracheal tube length of
recovering and ventilator settings should insertion (at the lip) and, if necessary, to withdraw the
remain unchanged. True or false? endotracheal tube slightly. If this fails to improve the
A Paco2 of 24 mm Hg suggests overventilation. The infant’s condition, a chest x-ray is indicated unless
resulting alkalosis is dangerous because it causes a the infant is deteriorating rapidly and the left side of
reduction in oxygen delivery and cerebral blood flow the chest is tympanic, transillumination is positive, and
and may be associated with lung injury. The Paco2 the heart is displaced. Emergency relief of a pneumo
should be brought back to a more physiologic range thorax is then indicated. The statement is false.
by reducing minute ventilation (i.e., by reducing PIP,
tidal volume, or frequency). The statement is false. A sample for blood gas estimation is
obtained immediately and resuscitative
The arterial oxygen tension is 30 mm Hg; pH measures are started. When the blood
is 7.30; and Paco2 is 45 mm Hg. The ventilator sample is analyzed 1 hour later, the results
should not be changed. True or false? show Pao2 to be 127 mm Hg and Paco2 to
be 8 mm Hg. This suggests that the infant 1. Increase PIP

had been crying before this cyanotic spell. 2. Increase PEEP
True or false? 3. Increase frequency
The most likely explanation for these bizarre blood 4. Decrease I/E ratio (e.g., 1:3 to 1:3.5)
gas findings is that an air bubble was left in the syringe 5. Increase Fio2
and equilibration has occurred between gas in the The patient has hypoxemia with adequate ventilation
blood and gas in the air. The values tend to approxi- and relatively low Fio2. The best answer is to increase
mate the Pao2 and Paco2 of room air. Samples drawn Fio2.
for blood gases must be bubble free, capped, iced,
and analyzed immediately. The statement is false. At 12 hours of age, the ventilator settings
and arterial blood gas values are pressure
Following prolonged mechanical 20/4 cm H2O, frequency 50 breaths/minute,
ventilation and extubation, an infant I/E ratio 1:1.5, Fio2 80%, pH 7.16, Paco2 55
may have some stridor and copious mm Hg, and Pao2 135 mm Hg. What is the
secretions. The stridor usually decreases most appropriate change at this time?
spontaneously. True or false? 1. Decrease PIP and decrease Fio2
Despite the use of nontoxic endotracheal tubes, 2. Increase PEEP and decrease Fio2
there can be some laryngeal edema. This, together 3. Increase frequency and decrease Fio2
with large quantities of secretions and lack of tracheal 4. Increase I/E ratio and decrease Fio2
cilia, may lead to some degree of upper airway ob- 5. Decrease I/E ratio and decrease Fio2
struction, which decreases in 2 to 3 days. The state- The patient has hyperoxemia and mild respiratory ac-
ment is true. idosis. Of the alternatives given, increasing frequency
is the most effective way to increase minute ventila-
tion and resolve the respiratory acidosis. Fio2 should
be decreased.
CASE 5
A 1500-g male infant delivered precipitously after At 18 hours of age, the ventilator settings and
31 weeks’ gestation, whose mother had not received arterial blood gas values are pressure 20/5
antenatal steroids, had signs of respiratory distress at cm H2O, frequency 70 breaths/minute, I/E
birth. Apgar scores were 4 and 7 at 1 and 5 minutes, ratio 1:1, Fio2 90%, pH 7.19, Paco2 52 mm Hg,
respectively. At initial assessment, the infant was tach- and Pa o 2 35 mm Hg. What is the most
ypneic (60 breaths/minute) and had nasal flaring and appropriate change at this time?
retractions. Breath sounds were equal but diminished
1. Increase PIP
bilaterally. Dubowitz examination was consistent with
2. Increase PEEP
maternal dates. Immediate chest x-ray showed diffuse
3. Increase frequency
granularity and air bronchograms. Blood sugar was 45
4. Increase I/E ratio
mg/dL, hematocrit 43%, blood pressure 50/32 (mean
5. Increase Fio2
40 mm Hg), and temperature 36.3° C. In 55% oxygen
Respiratory acidosis is still present but is now ac-
by CPAP, arterial blood gas values from an umbilical
companied by hypoxemia. Increasing peak PIP is the
catheter were as follows: pH 7.15, Pco2 55, and Po2
best choice because the resultant increase in minute
40. The infant was intubated, given surfactant, and
ventilation and mean airway pressure should improve
placed on a pressure-limited ventilator at PIP of 15 cm
Paco2 and Pao2. Increasing frequency is also an ac-
H2O, PEEP of 4 cm H2O, frequency (rate) of 50 breaths/
ceptable alternative.
minute, I/E ratio of 1:5, and Fio2 of 50%. The patient ini-
tially responded well, but 2 hours later, arterial blood gas
values were as follows: pH 7.30, Pco2 46, and Po2 35.
NOTE: There may be several arterial blood gases
REFERENCES
and ventilator changes between each situation pre-
sented. Assume good breath sounds, chest rise, and The reference list for this chapter can be found
blood pressure throughout, unless otherwise stated. online at www.expertconsult.com.
Attempting to answer questions by looking at data
subsequently presented is only confusing.
Select the best answer, although more than one
answer may be acceptable.
What is the most appropriate ventilator

setting change at this time?
12
Glucose, Calcium,
and Magnesium
Michael R. Uhing and Robert M. Kliegman
These infants are remarkable not only because like foetal versions of Shadrach,
Meshach and Abednego, they emerge at least alive from within the fiery metabolic
furnace of diabetes mellitus, but because they resemble one another so closely that
they might well be related. They are plump, sleek, liberally coated with vernix
caseosa, full-faced and plethoric. … They convey a distinct impression of having
had such a surfeit of both food and fluid pressed upon them by an insistent hostess
that they desire only peace so that they may recover from their excesses. And on
the second day their resentment of the slightest noise improves the analogy while
their trembling anxiety seems to speak of intrauterine indiscretions of which we
know nothing.
James W. Farquhar*
The newborn emerges from a uterine envi- severe hypoglycemia and hypocalcemia
ronment in which glucose, calcium, and infrequent problems.
magnesium have been continuously pro-
vided and fetal plasma levels are closely GLUCOSE
regulated, in part by maternal metabolic
homeostasis and placental exchange, as FETAL AND NEONATAL ENERGY
well as by fetal regulatory mechanisms. METABOLISM
Abrupt termination of nutrient supply at A composite picture of fetal and neonatal fuel
birth requires profound changes in energy metabolism has emerged from studies in ani-
and mineral metabolism, depending on the mals and humans.1 Fetal energy consump-
provision of exogenous nutrients and the tion is high, deriving from growth needs and
mobilization of endogenous fuel and min- energy storage as well as metabolic mainte-
eral stores. The result is the potential for nance. Maternal glucose crosses the placenta
rapid changes in plasma glucose and cal- via facilitated diffusion (primarily by the glu-
cium levels during the first days of life. The cose transporters GLUT1 and GLUT3) and
infant who is premature, growth restricted, serves as the principal energy source for the
stressed, or born to a diabetic mother is at fetus. There is a linear relationship between
increased risk for problems with homeosta- maternal and fetal glucose concentrations,
sis, and hypoglycemia or hypocalcemia can with fetal concentrations 60% to 80% of
develop. maternal concentrations.2 This linear rela-
Broad surveys using modern analytic tionship is present even during episodes of
methods demonstrated that glucose and cal- maternal hyperglycemia secondary to mater-
cium problems are common, are frequently nal diabetes or glucose infusions.
asymptomatic, and thus often go unrec- Under normal circumstances, fetal gluco-
ognized in high-risk infants. Since that neogenesis is negligible; however, fetal glu-
time, changing routines of care to include coneogenesis may occur during episodes of
prevention, early identification, and meta- prolonged maternal hypoglycemia or starva-
bolic support of the sick newborn has made tion. Glucose alone cannot account for the
total oxygen consumption of the fetus. Other
substrates such as lactate, free fatty acids,
*Farquhar JW: The child of the diabetic woman, Arch Dis ketones, and amino acids cross the placenta
Child 34:76, 1959. and are potential energy sources for the fetus.
289
290 CHAPTER 12 Glucose, Calcium, and Magnesium
Energy is stored rapidly near term. Fat must supplement glycogenolysis. Lipolysis
storage exceeds 100 kcal/day in the ninth begins at birth, with the respiratory quotient
month and accounts for 14% of total body decreasing from 1.0 in the fetus to less than
weight at term.3 Glycogen stores, a vital 0.8 during the first day as most tissues switch
source of energy in the first hours of life, to burning fat. Metabolism of free fatty acids
increase toward term to reach about 5% by and ketones stabilizes blood glucose levels by
weight in liver and muscle and up to 4% (1) sparing glucose utilization in heart, liver,
in heart muscle. These energy stores are muscle, and brain (ketones) and (2) support-
compromised by prematurity and by intra- ing hepatic gluconeogenesis by producing
uterine growth restriction. Acute perinatal the reduced form of nicotinamide adenine
distress or chronic fetal hypoxia can partic- dinucleotide (NADH).
ularly diminish glycogen stores and predis- In the newborn, basal glucose production
pose the infant to hypoglycemia after birth. and utilization is 4 to 6 mg/kg/min. This
Insulin and glucagon do not cross the high glucose utilization compared with the
placenta and are present in the fetus by 12 adult is primarily due to the higher ratio of
and 15 weeks, respectively. The fetal insu- brain weight to body weight in the newborn
lin response to glucose infusion is poor infant. During euglycemic conditions most
very early in gestation. At the end of gesta- of the brain’s metabolic needs are met by
tion, the insulin response is improved but oxidation of glucose. When the availabil-
remains blunted. Fetal blood insulin levels ity of glucose is limited, alternative cerebral
gradually rise toward term, whereas fetal fuels such as lactate and ketone bodies may
glucagon levels remain low. The resulting by used. Although these alternative fuels
high insulin-to-glucagon ratio promotes provide some protection to reduce the risk
the accumulation of hepatic glycogen stores of hypoglycemia-induced brain injury in
and suppresses gluconeogenesis. the newborn, the brain requires a continu-
Insulin is an important hormone for fetal ous glucose supply; thus, these alternative
growth. The presence of maternal hypergly- substrates are unable to completely replace
cemia and fetal hyperinsulinemia as seen in glucose as a fuel for brain metabolism.
the infant of a diabetic mother is associated Blood glucose level at birth is 60% to
with macrosomia with elevated liver glyco- 80% of the simultaneous maternal plasma
gen and total body fat stores.4,5 Macrosomia concentrations. Glucose concentrations nor-
in the presence of fetal hyperinsulinemia mally decrease over 1 to 2 hours, stabilize
without maternal hyperglycemia is seen at a minimum of 40 to 45 mg/dL, and
in infants with Beckwith-Wiedemann syn- then increase by 6 hours to 50 to 60 mg/
drome and in the rare infant with hyperin- dL in healthy unstressed newborns (Fig.
sulinemic hypoglycemia, which suggests that 12-1). The current practice of early oral or
fetal insulin and not maternal hyperglycemia intravenous alimentation avoids the many
may be the important growth-promoting fac- instances of neonatal hypoglycemia previ-
tor. Furthermore, infants born with pancre- ously reported when neonates fasted for 24
atic aplasia and those with transient neonatal hours (Fig. 12-2).
diabetes mellitus have little or no insulin
present and demonstrate severe intrauterine METHODOLOGY
growth restriction.
At birth, cold stress, work of respiration, Sampling Problems
and muscle activity cause increased energy Several factors need to be considered when
demands. Because of the interrupted supply interpreting glucose concentrations. First,
of maternal glucose, the newborn must call blood glucose concentrations are 10% to
on stored fuels to maintain blood glucose 15% lower than simultaneous plasma con-
levels. This transition at birth is facilitated by centrations. This is particularly pronounced
increased catecholamine and glucagon levels, when the hematocrit is very high.6 Second,
which promote lipolysis and glycogenolysis. use of capillary samples from unwarmed
Decreased insulin levels and increased corti- heels may lead to an underestimation of
sol levels also facilitate glucose homeostasis venous glucose concentration because
at birth. Rapid glycogenolysis causes hepatic of stasis. Finally, glucose concentrations
glycogen to fall to low levels within 24 hours decline as much as 18 mg/dL/hr at room
in a fasted neonate. Because the newborn temperature while analysis is awaited. Thus,
has a twofold greater basal fasting glucose all samples should be analyzed immediately
utilization than the adult, gluconeogenesis or placed on ice.
CHAPTER 12 Glucose, Calcium, and Magnesium 291
Glucose FFA offers the advantage of speed. The sensitivity

100 1.0
Normal for detecting hypoglycemia ranges from 80%
IDM
to 100% and the negative predictive values
mg/100 mL
µ mol/mL
ranges from 80% to 96% depending on the
50 0.5 device and parameters used.7,8 Therefore,
confirmatory plasma glucose concentra-
tions should be measured if hypoglycemia is
0 0 detected using a POC device or if the infant
has symptoms consistent with hypoglyce-
Glycerol β -OHB mia even if the POC test value shows a nor-
0.30 90 mal blood glucose concentration.6
µ moles/mL
µ mol/mL
0.15 45
EDITORIAL COMMENT: Accurate measurement of
0 blood glucose levels in the newborn is important, but
0
120 UV UV 60
60 120 although POC glucose testing provides rapid results
Minutes with small sample volumes and permits quick clinical
Figure 12-1. Fuel metabolism in infants of “controlled” responses, the common thresholds for the diagnosis
diabetic mothers. Glucose, free fatty acid (FFA), of hypoglycemia in the newborn (blood glucose con-
β-hydroxybutyrate (βOHB) in normal infants (open circles) centration of <2.0 mmol/L or <2.6 mmol/L, 35 to 45
and infants of diabetic mothers (IDMs) (filled circles). Note mg/dL) and hyperglycemia (blood glucose concentra-
that not only does blood glucose level decline more abruptly tion of >10 mmol/L, 170 mg/dL) are at the limits of
in the IDMs, but FFA and ketones increase less. The blood
accuracy for many POC glucose analyzers. Therefore,
glucose concentration spontaneously increases over the
although useful for screening, such devices cannot be
next 4 to 6 hours. (From Persson B, Gentz J, Kellum
M, et al: Metabolic observations in infants of strictly relied upon for accurate diagnosis of hypoglycemia.
controlled diabetic mothers. II. Plasma insulin, FFA, Also, with intermittent blood sampling there may be
glycerol, β-hydroxybutyrate during intravenous glucose many hours between measurements when both hy-
tolerance test, Acta Paediatr Scand 65:1,1976.) poglycemia and hyperglycemia may be undetected
clinically. Continuous glucose monitoring has the po-
tential to help improve glucose assessment and man-
agement in the high-risk neonate. Harris et al used a
110
continuous glucose monitoring system (CGMS) in 102
100 IV group infants of 32 weeks’ gestation or less who were at risk
Fasted group
90 Nos. = Determinations for hypoglycemia.9 The babies received routine treat-
Blood glucose (mg%)
for each point ment, including intermittent blood glucose measure-

80
46 ment using the glucose oxidase method, and blinded
70 47 45 45 continuous interstitial glucose monitoring. The inves-
48 45
60
48 44
43 41 tigators documented 265 episodes of low interstitial
49 40
43 42 39 glucose concentrations, 215 (81%) of which were not
50 44 43
43 detected with blood glucose measurement. One hun-
51 46
40 47 48 dred seven episodes in 34 babies lasted longer than
30 30 minutes, and 78 (73%) of these were not detected
with blood glucose measurement. Platas et al also
20
studied continuous glucose monitoring.10 Hypergly-
0
12 24 36 48 60 72 84 96 120 cemia was detected in 22 of 38 patients (58%) and
Hours after birth
lasted a mean of 20 ± 30 hours. Hypoglycemia was
Figure 12-2. Mean blood glucose concentration as a detected in 14 (37%) and lasted a mean of 2.45 ± 2.3
function of age in infants receiving early intravenous (IV)
hours. However, the CGMS was not able to provide
feedings and in fasted infants. Bars indicate ±1 standard
real-time glucose concentration data. Continuous glu-
deviation. (From Mamunes P, Baden M, Bass J, et al:
Early intravenous feeding of low birth weight neonate, cose monitoring via a subcutaneous sensor gives a
Pediatrics 43:241,1969. Reproduced by permission of safe and useful estimate of glucose levels in very low-
Pediatrics. Copyright 1969.) birth-weight infants, revealing abnormal glucose levels
at a much higher rate than expected by usual sam-
pling. The physiologic significance of these previously
Point-of-Care Testing
undetected episodes is unknown. A CGMS may be
Although plasma glucose determination in
very useful in providing information on the influence of
the laboratory using the glucose oxidase reac-
hyperglycemia and hypoglycemia on short- and long-
tion is the optimum method, point-of-care
term outcomes in very low-birth-weight infants.
(POC) testing using reflectance glucometers
HYPOGLYCEMIA does not support a specific concentration of glucose

that can discriminate normal from abnormal or can
Definition
potentially result in acute or chronic irreversible neu-
The definition of hypoglycemia is controver- rologic damage.15 Early identification of the at-risk
sial.11-13 Several factors contribute to this infant and institution of prophylactic measures to pre-
controversy, including the poor correlation vent neonatal hypoglycemia are recommended as a
between glucose concentrations and symp- pragmatic approach despite the absence of a consis
toms; the nonspecific nature of the symp- tent definition of hypoglycemia in the literature.” This
toms of hypoglycemia; the performance report noted that the generally adopted level used to
of epidemiologic studies under differing define neonatal hypoglycemia is less than 47 mg/dL
conditions (i.e., fed versus fasted states, for- (2.6 mmol/L) and proposed an operational threshold of
mula feeding versus breast feeding); and the 45 mg/dL (2.5 mmol/L) as a target glucose level before
poor correlation between low glucose val- routine feeds.
ues and adverse long-term outcome. Rather
than making the diagnosis of hypoglycemia
when the plasma glucose concentration is Symptoms
below a specific value, a consensus state- Hypoglycemia in newborns is often asymp-
ment recommends the use of an “opera- tomatic. The most frequent symptoms are
tional threshold” that defines the glucose jitteriness and cyanosis. Other symptoms
concentration below which clinical inter- include convulsions, hypotonia, coma, poor
vention to raise the plasma glucose should feeding, apnea, congestive heart failure,
be considered.14 These threshold values are high-pitched cry, abnormal eye movements,
pragmatic rather than diagnostic and rec- and temperature instability with hypother-
ognize the uniqueness of each individual’s mia. In small sick infants, symptoms may
physiologic characteristics while providing easily be missed. When symptoms are pres-
an adequate safety margin to prevent long- ent, the age of onset is most commonly
term sequelae. The recommended thresh- between 24 and 72 hours.
olds for asymptomatic and symptomatic Because these symptoms are nonspecific,
infants are plasma glucose concentrations they often occur in newborns who are normo-
of less than 36 mg/dL (2.0 mmol/L) and less glycemic and have other problems. For exam-
than 45 mg/dL (2.5 mmol/L), respectively. ple, jitteriness, the most common symptom,
The diagnosis of hypoglycemia can be made is found in up to 44% of normal newborns
when all components of the Whipple triad as well as in infants with a variety of other
have been observed: (1) low plasma glucose conditions (Box 12-1). Hypoglycemia must
concentration, (2) signs and symptoms con- therefore always be confirmed by chemical
sistent with hypoglycemia, and (3) resolu- analysis and by response to treatment.
tion of these signs and symptoms when
the glucose concentration is normalized. Transient Neonatal Hypoglycemia
As a practical matter, most nurseries use a Transient neonatal hypoglycemia is the
screening blood glucose level of 40 mg/dL most common type of hypoglycemia in a
or less or the presence of signs and symp- well-baby nursery and an intensive care
toms consistent with hypoglycemia as a nursery. It may occur within 1 to 2 hours
threshold for obtaining a plasma glucose of birth and resolves within hours to days.
measurement and evaluating the need for Asymptomatic patients exceed those with
further intervention. Because blood glucose symptoms by about 10 to 1. Transient hypo-
values are 10% to 15% below plasma glu- glycemia typically occurs in “high-risk”
cose values, this allows for a safety margin infants in association with either alterations
when using POC test devices. in maternal metabolism or other neonatal
problems (Box 12-2).16
EDITORIAL COMMENT: In 2011, a position state-
The pathogenesis involves multiple factors
ment issued by the Committee of the Fetus and New-
affecting glucose supply and demand, includ-
born (COFN)12 of the American Academy of Pediatrics
ing hyperinsulinism; inadequate total body
(AAP) discussed the challenge of defining clinically
energy reserves; high energy requirement—
significant hypoglycemia based on blood glucose
particularly a large, glucose-requiring brain;
concentrations. “This report provides a practical guide
and inordinate energy demands imposed by
and algorithm for the screening and subsequent man-
disease. There is an association with central
agement of neonatal hypoglycemia. Current evidence
nervous system (CNS) injury or anomaly,
which may reflect a subtle control problem.
Differential Diagnosis of period dramatically reduce the incidence of

Box 12-1. Jitteriness and Tremors hypoglycemia. High-risk infants should be
in the Newborn screened for hypoglycemia as soon as pos-
sible after birth at intervals of 1 to 2 hours
Metabolic disorders initially and then every 2 to 4 hours until
• Hypoglycemia their condition is definitely stabilized.
• Hypocalcemia
• Hypomagnesemia Infants of Diabetic Mothers
• Hyponatremia Hypoglycemia occurs in infants of diabetic
• Hypernatremia mothers soon after birth, with a nadir at 1 to
Neonatal drug withdrawal 2 hours of age that may be as low as 10 mg/
• Opiates dL (see Fig. 12-1). A spontaneous increase in
• Selective serotonin reuptake inhibitors glucose concentration usually follows, with
(SSRIs) acceptable levels reached by 4 to 6 hours of
• Cocaine age. Few infants of diabetic mothers become
Central nervous system disorders symptomatic. Infants of mothers with gesta-
• Malformations tional diabetes have a less dramatic decline
• Hypoxic-ischemic encephalopathy in glucose level.
• Intracranial hemorrhage Fluctuating maternal hyperglycemia
Polycythemia results in fetal hyperglycemia, pancreatic beta
Sepsis, meningitis cell hyperplasia, and hyperinsulinism. After
birth, hyperinsulinemia persists, as evidenced
by accelerated use of exogenous glucose and
Classification of Transient
Box 12-2. diminished endogenous glucose production.
Neonatal Hypoglycemia
Furthermore, levels of free fatty acids and
Hyperinsulinism ketones are low (see Fig. 12-1). In addition to
• Infant of diabetic mother (IDM) having increased insulin levels, infants of dia-
• Intrapartum glucose administration betic mothers have increased concentrations
• Erythroblastosis fetalis of leptin, insulin-like growth factor I, and
• Maternal use of β-sympathomimetics insulin propeptides.18-20 Infants of diabetic
• Maternal use of oral hypoglycemic mothers have multiple problems in addition
agents to hypoglycemia (Box 12-3).21-27 Congenital
• Large for gestational age (non-IDM) anomalies occur in 4.2% to 12.1% of infants
Decreased substrate of mothers with type 1 diabetes.21,23,27 The
• Prematurity rate of anomalies decreases with improved
• Small for gestational age preconceptual glycemic control.21,28 Infants
• Asphyxia of mothers with gestational diabetes do not
• Discordant twins have an increased risk of congenital anoma-
• Intrauterine growth restriction lies but continue to have a high rate of the
Altered metabolism other morbidities (see Box 12-3). Achieving
• Polycythemia tight metabolic control in pregnant diabetic
• Hypothermia women during pregnancy and preventing
• Severe illness, respiratory distress syn- hyperglycemia in labor ameliorates excess
drome fetal weight and helps prevent perinatal
• Sepsis, infection deaths and reduces the incidence of neo-
natal hypoglycemia and hypocalcemia.29
Early oral feeding is both prophylactic and
Healthy term infants do not require rou- therapeutic. Poor feeding, respiratory dis-
tine screening for hypoglycemia if they do tress, or additional problems (congenital
not have clinical manifestations.17 “At-risk” anomalies) may require intravenous glu-
infants (see Box 12-2), including all infants cose administration.
admitted to the intensive care nursery or
those with clinical manifestations, should Maternal Drugs (e.g., β-Sympathomimetics,
undergo screening blood glucose deter- β-Blockers, Oral Antidiabetic Agents)
mination. Providing caloric support with β-Sympathomimetics (e.g., terbutaline,
early feeding or intravenous glucose by 1 to ritodrine) are used as tocolytic agents and
2 hours of age and maintaining a continu- may cause maternal hyperglycemia and
ous energy supply throughout the neonatal fetal hyperinsulinism leading to neonatal
Morbidities of Infants prematurity have inadequate glycogen

Box 12-3. stores, which leads to decreased glucose
of Diabetic Mothers
production after birth. Glucose homeostasis
Fetal demise is further complicated in these infants by
Prematurity reduced fat stores, increased brain-to-body
Macrosomia weight ratios, immature hepatic enzymes,
Birth injury and an inadequate cortisol response.32
Hyperbilirubinemia Infants who are small for gestational age or
Hypoglycemia experienced intrauterine growth restriction
Hypocalcemia have inadequate stores due to fetal malnu-
Hypomagnesemia trition, which is often associated with pla-
Polycythemia cental insufficiency, maternal preeclampsia,
Respiratory distress syndrome maternal hypertension, and severe maternal
Thrombosis (renal vein) diabetes with vascular disease.33 Premature
Cardiac malformations and abnormalities infants fail to undergo the normal deposi-
• Intraventricular septal hypertrophy tion of glycogen and fat that occurs during
• Ventricular septal defect the third trimester of pregnancy.
• Dextrocardia A subset of infants with intrauterine
• Transposition of the great arteries growth restriction and small size for gesta-
• Truncus arteriosus tional age have prolonged hypoglycemia
• Tricuspid atresia associated with hyperinsulinism. These
• Pulmonary valve abnormalities infants are most often male, are born by
Genitourinary malformations cesarean section, and have a history of peri-
• Renal agenesis or dysgenesis natal stress.34
• Obstructive lesions
• Hypospadias Hyperviscosity-Polycythemia
Central nervous system malformations Hypoglycemia occurs in approximately 13%
• Anencephaly to 40% of infants with polycythemia. An
• Spina bifida increased rate of glucose disposal without
• Hydrocephaly hyperinsulinemia is part of the syndrome
Limb abnormalities of hyperviscosity; it responds to exchange
• Caudal regression transfusion to reduce the hematocrit.
Small left colon syndrome
Erythroblastosis Fetalis
Infants with erythroblastosis show islet cell
hypoglycemia. Use of β-blockers may lead to hyperplasia, increased cord blood insulin lev-
hypoglycemia by blocking catecholamine els, and hypoglycemia both shortly after birth
release at birth, which results in decreased and reactively following exchange transfu-
lipolysis and glycogenolysis. sion. It is speculated that glutathione release
First-generation sulfonylurea oral antidi- from severe hemolysis stimulates insulin pro-
abetic agents (e.g., chlorpropamide, tolbu- duction.35 The severity of the problem relates
tamide) cross the placenta and have a long inversely to cord hemoglobin level and is
half-life in the newborn. These agents cause decreased by intrauterine transfusion.35
increased insulin release and may cause
prolonged hypoglycemia.30 Newer oral Other Causes of Transient Hypoglycemia
antidiabetic agents do not lead to signifi- Excess intrapartum glucose administration
cant neonatal hypoglycemia, either because leads to acute maternal and fetal hyper-
they do not cross the placenta in significant glycemia. The subsequent transient hyper-
concentrations (second-generation sulfo- insulinemia can lead to rebound neonatal
nylureas such as glipizide and glyburide) hypoglycemia.
or because they do not enhance insulin Hypoglycemia is also associated with
production (biguanides and α-glucosidase infection, asphyxia, and hypothermia. The
inhibitors).31 cause of hypoglycemia in these conditions
is multifactorial but is most often due to
Intrauterine Growth Restriction, Small Size for increased glucose utilization. Perinatal
Gestational Age, Prematurity asphyxia may occasionally be associated
Infants with intrauterine growth restric- with hyperinsulinism requiring high glu-
tion, small size for gestational age, and cose infusion rates.
Infusion of glucose through an umbili- Classification of Persistent

cal artery catheter located above the celiac Box 12-4.
Neonatal Hypoglycemia
axis may lead to hyperinsulinemic hypogly-
cemia from direct infusion of glucose into Hyperinsulinemia
the pancreatic artery with resulting beta cell Persistent hyperinsulinemic hypoglycemia
overstimulation. of infancy
• Sporadic
Persistent or Recurrent Hypoglycemia • Familial
Persistent or recurrent hypoglycemia refers to • Focal beta-cell adenoma
conditions in which the hypoglycemia per- • Hyperammonemic hyperinsulinism
sists for more than several days. Many of Beckwith-Wiedemann syndrome
these conditions require prolonged therapy Endocrine disorders
and may continue beyond the neonatal Panhypopituitarism
period (Box 12-4). In contrast with infants Growth hormone deficiency
with transient hypoglycemia, the majority Adrenocorticotropic hormone deficiency
of these infants are symptomatic. Adrenal insufficiency
Glucagon deficiency
Persistent Hyperinsulinemic Hypoglycemia Epinephrine deficiency
of Infancy
Glycogen storage disease (GSD)
Persistent hyperinsulinemic hypoglycemia
Glucose-6-phosphatase deficiency
of infancy (PHHI) is caused by abnormali-
(GSD type I)
ties in the regulation of insulin secretion.
Debrancher deficiency (GSD type III)
This condition was previously known as
nesidioblastosis, in reference to a histopatho- Disorders of gluconeogenesis
logic finding that implied abnormal islet Fructose 1,6-diphosphatase deficiency
formation; however, this histologic pattern Pyruvate-carboxylase deficiency
has been found to be common in the devel- Phosphoenol pyruvate-carboxykinase
oping pancreas of infants without hypogly- deficiency
cemia in the first year of life.36,37 Disorders of fatty acid oxidation
PHHI occurs in both sporadic and famil- Carnitine-acylcarnitine translocase deficiency
ial patterns. The majority of cases involve Very long-chain acyl-CoA dehydrogenase
mutations on chromosome band 11p14- deficiency
15.1, leading to abnormalities in one of the Long-chain acyl-CoA dehydrogenase
two components of the islet beta cell aden deficiency
osine triphosphate–sensitive potassium Medium-chain acyl-CoA dehydrogenase
channel (KATP channel), either the sulfonyl- deficiency
urea receptor (SUR1) or the inward rectifier Multiple acyl-CoA dehydrogenase deficiency
K+ channel (Kir6.2).38,39 The inability to Disorders of amino acid and organic acid
open the islet beta cell KATP channel causes metabolism
membrane depolarization and calcium Maple syrup urine disease
influx resulting in inappropriate insulin Propionic acidemia
release. Usually these mutations are auto- Methylmalonicacidemia
somal recessive and associated with diffuse Isovalericacidemia
beta cell hyperplasia. Multiple carboxylase deficiency
Milder autosomal dominant forms of 3-Hydroxy-3-methylglutaryl CoA lyase
the disease are caused by mutations in the deficiency
glutamate dehydrogenase gene or the glu-
Mitochondrial disorders
cokinase gene.40,41 These mutations cause
3-Methylglutaconicaciduria
an increase in the ratio of ATP to adenosine
diphosphate (ADP) in the beta cell, which Glycosylation disorders
inappropriately closes the structurally nor- Systemic disorders
mal KATP channels. These forms of PHHI are Hepatic failure
also usually associated with diffuse beta cell Congestive heart failure
hyperplasia.
Focal beta cell hyperplasia is found when CoA, Coenzyme A.
abnormalities of the beta cell KATP chan-
nel are associated with unbalanced expres-
sion of one or more growth suppression
Clinical Features of Beckwith- venous and portal venous insulin sam-

Box 12-5. pling using interventional radiology was
Wiedemann Syndrome
used to identify focal or diffuse disease
Macrosomia preoperatively. Positron emission tomog-
Abdominal wall defects raphy, a less invasive technique, has now
• Omphalocele been shown to be more accurate in diag-
• Diastasis recti nosing whether the disease is focal or dif-
• Umbilical hernia fuse.51 Neurodevelopmental impairment
Craniofacial features secondary to frequent and severe episodes
• Macroglossia of hypoglycemia is common in PHHI.52,53
• Ear lobe creases Complications of pancreatectomy include
• Posterior helical pits diabetes mellitus and pancreatic exocrine
• Nevus flammeus insufficiency.
• Prominent occiput
• Metopic ridge Beckwith-Wiedemann Syndrome (Hyperplas-
Neonatal hypoglycemia tic Fetal Visceromegaly)
Neonatal polycythemia Beckwith-Wiedemann syndrome (BWS) is
Visceromegaly an overgrowth syndrome associated with
Congenital heart defects macrosomia (88% of cases), macroglossia
Hemihypertrophy (97% of cases), abdominal wall defects
Clitorimegaly (80% of cases), usually an omphalocele,
Cryptorchidism hypoglycemia in the neonatal period,
Embryonal malignancies and embryonal cancers of infancy and
early childhood (4% of cases). Other
clinical features of BWS are listed in Box
genes due to focal loss of the maternal 12-5. The frequency of hypoglycemia in
DNA on chromosome band 11p15.42,43 BWS is between 30% and 63%, and the
Other genetic mutations associated with hypoglycemia is caused by hyperinsulin-
PHHI have been described but occur less ism. 54 The hypoglycemia may be asymp-
frequently.44 tomatic and usually resolves within the
Infants with PHHI are large for gesta first 3 days of life. Fewer than 5% of
tional age with profound, symptomatic infants will have hypoglycemia beyond
hypoglycemia. Plasma insulin and C-peptide the neonatal period requiring either con-
concentrations are inappropriately ele- tinuous feeding or, in rare cases, partial
vated during episodes of hypoglycemia.45 pancreatectomy. 55 The genetics of BWS is
Plasma free fatty acid and ketone concentra- complex and involves defects in imprinted
tions are low. Ketonuria is absent. Glucagon gene expression in the 11p15 region.56,57
infusion results in a glycemic response in The majority of cases are sporadic but 10%
the presence of hypoglycemia.45 Mutation to 15% occur in an autosomal dominant
in the glutamate dehydrogenase gene also pattern, with maternal transmission asso-
causes elevated ammonia concentrations.46 ciated with increased penetrance. The risk
Hyperinsulinemia may be temporarily of BWS is higher after the use of assisted
managed with diazoxide (which opens the reproductive therapies.58 Seventy percent
KATP channel) or the long-acting somatosta- of cases can be detected by DNA methyla-
tin analog octreotide (which opens recti- tion analysis at the differentially meth-
fier K channels).45,47 These therapies are ylated regions 1 (regulating insulin-like
most effective when the KATP channel is growth factor II) and 2.59 The similarity
intact but is closed due to altered ATP/ADP of affected gene regions in BWS and PHHI
concentrations. Other potential therapies may provide a molecular basis for hypo-
include nifedipine, which inhibits insulin glycemia in BWS, particularly for the occa-
release, and glucagon, which increases glu- sional patient with hypoglycemia requiring
coneogenesis.45 a partial pancreatectomy.60
The majority of neonates do not respond
to medical management and require either Endocrine Deficiencies
a partial pancreatectomy (for focal lesions) Hypopituitarism with deficiencies in growth
or a 95% pancreatectomy (for diffuse dis- hormone and adrenocorticotropic hor-
ease).48-50 Previously, selective pancreatic mone (ACTH) is often associated with facial
arterial calcium stimulation with hepatic and genital abnormalities (microphallus).
Cortisol deficiency secondary to congenital 120

(23) (23)
adrenal hyperplasia or adrenal hemorrhage (20)
is associated with hypoglycemia. These dis- 100
Plasma glucose (mg/dL)

(23) (22)
(23)(23)
orders may cause electrolyte abnormalities *
80
and cardiovascular collapse. Congenital * * **
adrenal hyperplasia causes virilization in 60
female infants.
40 Mean ± SD
Metabolic Diseases 200 mg/kg minibolus
Metabolic disorders associated with per- 20 followed by 8 mg/kg / min
sistent neonatal hypoglycemia are all very (23) * P < .001** P < .02
rare.61,62 Box 12-4 lists the disorders that 0
0 5 10
30 40 50 60 20
manifest in the neonatal period. Many Minutes
other metabolic syndromes are associated Figure 12-3. Minibolus therapy for neonatal hypoglycemia
with hypoglycemia but present later in achieves euglycemia without excessively high glucose
infancy or childhood. Clues to the diag- levels, which may further stimulate insulin release and later
nosis include lactic acidosis, excessive or result in rebound hypoglycemia. Numbers in parentheses
reduced ketonuria, persistent emesis and indicate the number of determinations at each point. (From
coma despite correction of hypoglycemia, Lilien L, Pildes R, Srinivasan G, et al: Treatment of
neonatal hypoglycemia with minibolus and intravenous
hepatomegaly, family history, and elevated
glucose infusion, J Pediatr 97:295, 1980.)
values on liver function tests (e.g., ammo-
nia, direct bilirubin).
Glycogen storage diseases result in Treatment is indicated for all hypoglyce-
impaired ability of hepatic glucose release. mic infants (plasma glucose level of <36 mg/
Neonatal presentation is most common with dL if asymptomatic, <45 mg/dL or higher if
glycogen storage disease type I (glucose-6- symptomatic). Asymptomatic infants with
phosphatase deficiency). Glycogen storage transient hypoglycemia and no other medi-
disease type III (Debrancher deficiency) may cal illness may be given enteric formula or
be detected after prolonged fasting. These breast milk. Blood glucose concentration
diseases also are associated with lactic aci- should be monitored every 30 minutes to
dosis, ketosis, and hepatomegaly. determine adequacy of response. If glucose
Disorders of fatty acid oxidation, particu- concentrations do not increase or if enteric
larly disorders of very long-chain and long- alimentation is contraindicated, intrave-
chain fatty acid metabolism, may occur in nous glucose, 4 to 8 mg/kg/min, should
the neonatal period. These disorders are often begin. If hypoglycemia is severe (plasma
accompanied by hyperammonemia, liver glucose level of <20 to 25 mg/dL) or if
disease, and cardiac disease. Usually keto- symptoms are present, intravenous glucose
sis is absent. Medium-chain acyl–coenzyme should be initiated starting with a bolus of
A (CoA) dehydrogenase deficiency is the 200 mg/kg glucose (2 mL/kg of 10% dex-
most common disorder of fatty acid oxida- trose in water) followed by a continuous
tion but only rarely presents in the neonatal infusion of 6 to 8 mg/kg/min of glucose
period. (Fig. 12-3).63 The bolus of glucose should be
Amino acid and organic acid disorders no greater than 200 mg/kg to prevent exces-
are also associated with hypoglycemia but sive hyperglycemia and rebound hypogly-
often ketosis, lactic acidosis, and hyperam- cemia. Blood glucose concentrations should
monemia are present. be monitored every 30 to 60 minutes until
stable. This bolus and infusion is adequate
Treatment of Hypoglycemia for most infants; however, if plasma glu-
Prevention is key and consists of early oral cose concentrations remain low the glucose
or enteral tube feeding of breast milk or for- infusion should be increased in increments
mula if appropriate. For those infants who of 2 mg/kg/min. On rare occasions, refrac-
are not able to be fed enterally, early initia- tory hypoglycemia may require as much as
tion of intravenous fluids with 10% dextrose 20 mg/kg/min.
at a glucose infusion rate of 4 to 8 mg/kg/ For those infants with persistent hypo-
min is indicated. Glucose infusion should glycemia requiring high glucose infusion
be continuous and steady, by pump, and rates (>12 to 14 mg/kg/min), additional lab-
should be continued until replaced calori- oratory studies should be considered. These
cally by enteral feeding. studies should be performed during episodes
of hypoglycemia and include plasma insu- Boluyt et al attempted to assess the effect of epi-
lin, cortisol, and growth hormone concen- sodes of neonatal hypoglycemia on subsequent neu-
trations. For severe persistent hypoglycemia rodevelopment.65 A comprehensive search revealed
additional therapies may be required, includ- 18 eligible studies. The overall methodological qual-
ing hydrocortisone, diazoxide, octreotide, ity of the included studies was considered poor in
or glucagon. 16 studies and high in 2 studies. None of the stud-
ies provided a valid estimate of the effect of neona-
Prognosis tal hypoglycemia on neurodevelopment. Boluyt et al
Symptomatic, prolonged, or recurrent hypo- concluded, “Recommendations for clinical practice
glycemia may cause neurologic impairment.64 cannot be based on valid scientific evidence in this
Although the degree of neurologic injury field. To assess the effect of neonatal hypoglycemia
correlates with the severity and duration of on subsequent neurodevelopment, a well-designed
hypoglycemia, scientific analysis does not prospective study should be undertaken.”
allow one to define a specific level or duration
of hypoglycemia at which harm occurs.64-67
Infants with asymptomatic, transient hypo-
glycemia do well.68 Infants with hypogly- HYPERGLYCEMIA
cemic seizures have the poorest outcome. Hyperglycemia (glucose concentration of
Neurologic impairment is also more likely >150 mg/dL) is a common, serious prob-
when other risk factors such as asphyxia and lem of very immature infants. Risk factors
intrauterine growth restriction are present. include low birth weight (especially when
Infants with hyperinsulinemic hypoglycemia <1000 g), earlier gestational age, administra-
or with inborn metabolic errors have a prog- tion of intravenous glucose infusions (espe-
nosis related to their primary illness. cially glucose infusion rates of >6 mg/kg/
In infants of diabetic mothers, long- min), high illness severity, and glucocorti-
term neurologic outcome is also related to coid therapy (Box 12-6). Factors contributing
maternal metabolic factors independent of to hyperglycemia in premature infants are
postnatal glucose concentrations.69 reduced glucose-induced insulin secretion,
immature insulin processing, and increased
EDITORIAL COMMENT: To define the relationship
ratio of GLUT1 to GLUT2 in tissues.71,72
between magnetic resonance imaging (MRI) findings
Hepatic glucose release may fail to decrease
and hypoglycemia, Burns et al studied 35 term in-
when exogenous glucose is given. Stress
fants who underwent early brain MRI scanning after
from illness increases catecholamine release,
symptomatic neonatal hypoglycemia (median glucose
which may further elevate glucose levels by
level: 1 mmol/L) without evidence of hypoxic-ischemic
inhibiting glucose use and insulin release.
encephalopathy and assessed neurodevelopmental
outcome at a minimum of 18 months.70 White matter
Risk Factors for Neonatal
abnormalities occurred in 94% of infants with hypogly- Box 12-6.
Hyperglycemia
cemia and was severe in 43%, with a predominantly
posterior pattern in 29% of cases. Cortical abnormali- Preterm birth
ties occurred in 51% of infants; 30% had white matter Intrauterine growth restriction (IUGR)
hemorrhage; 40% had basal ganglia/thalamic lesions; Increased stress hormone levels
and 11% had an abnormal posterior limb of the inter- • Increased catecholamine infusions
nal capsule. Three infants had middle cerebral artery • Increased glucocorticoid concentrations
territory infarctions. At 18 months, 23 infants (65%) (from use of antenatal steroids, postna-
demonstrated impairments, which were related to the tal glucocorticoid administration, and
severity of white matter injury and involvement of the stress)
posterior limb of the internal capsule. • Increased glucagon concentrations
Patterns of injury associated with symptomatic ne- Early intravenous (IV) lipid infusion and high
onatal hypoglycemia were more varied than described rates of infusion
previously. White matter injury was not confined to the Higher-than-needed rates of IV glucose
posterior regions; hemorrhage, middle cerebral artery infusion
infarction, and basal ganglia/thalamic abnormalities Insufficient pancreatic insulin secretion (pre-
were seen, and cortical involvement was common. term and IUGR)
Surprisingly, early MRI findings were more instruc- Absence of enteral feedings, leading to dimini
tive than the severity or duration of hypoglycemia for shed “incretin” secretion and action, which
predicting neurodevelopmental outcomes. limits potential to promote insulin secretion
Hyperglycemia has been associated with “There is insufficient evidence from trials comparing
increased length of hospitalization, risk of lower with higher glucose infusion rates to inform
death, and incidence of intraventricular clinical practice. Large randomized trials are needed,
hemorrhage.18,73 The mechanism of injury powered on clinical outcomes including death, major
may involve increases in plasma osmolarity morbidities, and adverse neurodevelopment.” With re-
(a glucose level of 450 mg/dL is equivalent gard to insulin infusion, they noted that “the evidence
to an additional 24 mOsm/L) and glucosuria reviewed does not support the routine use of insulin
leading to renal water and electrolyte losses infusions to prevent hyperglycemia in very low-birth-
and vascular fluid shifts. weight neonates. Further randomized trials of insulin
Treatment and prevention are accom- infusion may be justified. They should enroll extremely
plished by adjusting the glucose infusion low-birth-weight neonates at very high risk for hyper
rate to that tolerated by each individual glycemia and neonatal death.”
infant. Rates of 4 to 8 mg/kg/min are usu-
ally tolerated; however, lower glucose infu-
sion rates may be needed. Glucose infusion Neonatal Diabetes
rates should be expressed as milligrams per Neonatal diabetes is a rare disorder. Most
kilogram per minute, because variations in infants with neonatal diabetes are born
either the volume or glucose content of the at or near term, with marked intrauter-
fluid result in alterations in actual deliv- ine growth restriction reflecting low levels
ery of glucose to the infant. Along with of insulin and insulin-like growth factor I.
improving nitrogen balance, early amino Weight loss, dehydration, hyperglycemia,
acid administration at the time of birth and occasional ketosis usually appear in the
in low-birth-weight infants decreases the first month of life. Seventy to eighty percent
incidence of hyperglycemia, possibly due of cases involve an abnormality on chro-
to improved insulin release.74,75 Occasion- mosome band 6q24 caused by uniparental
ally, an insulin infusion starting at 0.01 disomy of chromosome 6, duplication of
U/kg/min but increasing to 0.1 U/kg/min paternal 6q24, or loss of methylation at the
if needed is indicated in those infants in differentially methylated region at the 6q24
whom decreasing the glucose infusion rate locus.79,80 Treatment is with insulin, with a
is inadequate or improved caloric intake is usual daily dose of 2 to 6 U.
desired. Frequent monitoring of blood glu- The transient form of the disease usually
cose concentration is crucial both to deter- resolves within a few months. However,
mine the adequacy of therapy and to avoid many infants subsequently develop diabe-
episodes of hypoglycemia. tes later in childhood or early adulthood.
Approximately 50% of patients have per-
EDITORIAL COMMENT: Among very low-birth-weight
manent neonatal diabetes and remission
infants, early neonatal hyperglycemia is common and
never occurs.81 Permanent neonatal dia-
is associated with increased risk of death and major
betes is associated with activating muta-
morbidities. Sinclair et al wished to assess effects on
tions to the KATP channel in the pancreatic
clinical outcomes of interventions for preventing hy-
beta cell, causing the channel to remain
perglycemia in very low-birth-weight neonates receiv-
open and preventing insulin secretion.
ing full or partial parenteral nutrition.76 They searched
Some of these patients are responsive to
for randomized or quasi-randomized controlled trials
sulfonylurea, which binds to the sulfonyl-
of interventions for prevention of hyperglycemia in
urea receptor and helps to close the KATP
neonates with a birth weight of less than 1500 g or
channel.81,82
a gestational age of less than 32 weeks. They found
only four eligible trials. Two trials compared lower and CALCIUM
higher rates of glucose infusion in the early postnatal
FETAL AND NEONATAL CALCIUM
period. These trials were too small to assess effects
METABOLISM
on mortality or major morbidities. Two trials, one a
moderately large multicenter trial,77,78 compared insu-
The placenta actively transports calcium to
lin infusion with standard care. Insulin infusion therapy
the fetus and maintains fetal total and ion-
reduced hyperglycemia, but increased death before 28
ized calcium levels at about 1 mg/dL above
days and was complicated by hypoglycemia. Reduc-
the respective maternal levels. Between
tion in hyperglycemia was not accompanied by sig-
28 weeks’ gestation and term, fetal weight
nificant effects on major morbidities; effects on neu-
triples, but calcium content quadruples
rodevelopment are awaited. The authors concluded,
as bone mineral density progressively
increases (Fig. 12-4). Fetal acquisition of
0.110 the maintenance of serum calcium concen-

Intrauterine BMC
growth curve
tration requires rapid changes in endocrine
0.100 BMC experimental feeding
function and in the equilibrium between
mean ± SEM serum and bone. The factors affecting cal-
BMC routine feeding cium in the neonate can be summarized as
Bone mineral content (g/cm)
0.090 mean ± SEM

follows:
1. PTH mobilizes calcium from bone, pro-
0.080 motes calcium absorption from the gut,
and increases renal phosphate excretion.
Levels are low in cord blood, suppressed
0.070 by the mild hypercalcemia caused by
placental transport. Postnatally, PTH
0.060 concentrations rise for the first 48 hours,
decreasing by the end of the first week.
A similar pattern occurs in preterm
0.050
infants.83 Parathyroid secretion and
function require magnesium.
0.040 2. Vitamin D is required for effective PTH
action on both bone and gut. Fetal
0.030
concentrations of 25-hydroxyvitamin
30 32 34 36 38 40 42 D and 24,25-dihydroxyvitamin D vary
Postconceptual age (wks) directly with gestational age and mater-
4 Birth
6 2 8 10 12 nal plasma concentrations. Newborn
Postnatal age (wks) stores are usually adequate unless there is
Figure 12-4. Bone mineral content (BMC) in premature significant maternal dietary inadequacy
infants compared with intrauterine bone mineralization. or poor exposure to sunlight. Levels of
Hatched area is the in utero rate of BMC increase and 1,25-dihydroxyvitamin D depend on both
shows progressive bone mineralization during gestation maternal plasma concentrations and syn-
until term. Premature infants fed Similac 20 (triangles) have thesis in the fetal kidney. Concentrations
diminished bone mineral accumulation; in contrast, infants of 1,25-dihydroxyvitamin D are elevated
fed formula with calcium (1260 mg/L), phosphorus (630 in term and preterm infants.83
mg/L), and vitamin D (1000 U/L) (circles) have intrauterine 3. Calcitonin inhibits calcium mobilization
rates of bone mineralization. These latter infants received
from bone. Levels are high in neonates
calcium, 220 to 250 mg/kg/day, and phosphorus, 110
to 125 mg/kg/day. This calcium intake exceeds the in
and are further elevated by asphyxia and
utero rate of calcium accumulation (150 mg/kg/day); the prematurity.
failure of BMC to exceed intrauterine rates in this group is 4. Serum phosphate level increases after
possibly a result of fecal losses. SEM, Standard error of birth, and even more so after birth
the mean. (From Steichen J, Gratton T, Tsang R, et al: asphyxia.
Osteopenia of prematurity: the cause and possible 5. The calcium-sensing receptor (CaSR)
treatment, J Pediatr 96:528, 1980.) is present in the parathyroid chief cells
and renal tubular cells. The CaSR gene
is located on chromosome band 3q13.3-
calcium averages 150 mg/kg/day through- 21. The CaSR monitors extracellular Ca2+
out this period. concentrations, allowing appropriate
Placental active transport allows fetal PTH secretion and renal tubular handling
bone calcification to proceed normally. of calcium.84 Several clinical disorders
The calcium drain causes a modest decrease that result from molecular abnormali-
in maternal calcium levels near term. ties of the CaSR leading to either loss or
Maternal parathyroid activity, 1,25-dihy- gain of function have been described.
droxyvitamin D level, calcium absorp- Loss of function causes the hypercalce-
tion, and calcium mobilization from mic disorders, familial benign hypocal-
bone are all increased.83 Parathyroid hor- ciuric hypercalcemia and neonatal severe
mone (PTH) and calcitonin do not cross hyperparathyroidism. Autosomal domi-
the placenta, whereas 25-hydroxyvitamin nant hypocalcemia with calciuria results
D does. from gain in function.85
At birth, the constant placental calcium There is normally a decrease in the serum
supply is interrupted. Although the prema- calcium level in the first hours after birth
ture baby has skeletal reserves of calcium, that continues for 24 to 48 hours; serum
calcium then rises to stable levels by 5 to Causes of Neonatal

10 days of age. In healthy full-term infants, Box 12-7.
Hypocalcemia
mean total calcium levels fall from 2.3 to
2.9 mmol/L (9.0 to 11.4 mg/dL) at birth to Early onset
1.9 to 2.6 mmol/L (7.8 to 10.2 mg/dL) at Prematurity
24 hours. Mean ionized calcium levels fall Infant of diabetic mother
from 1.3 to 1.6 mmol/L (5.2 to 6.4 mg/dL) at Asphyxia
birth to 1.1 to 1.36 mmol/L (4.4 to 5.4 mg/ Late onset
dL) at 24 hours. Levels rise gradually, so that Secondary hypoparathyroidism
by 1 week of age mean ionized calcium lev- • Maternal hyperparathyroidism
els reach 1.4 mmol/L (5.6 mg/dL). Healthy • Maternal hypercalcemic hypocalciuria
premature infants 33 to 36 weeks of age • Hypomagnesemia
have lower calcium levels at 24 to 48 hours Primary hypoparathyroidism
but otherwise are not different from term • Transient congenital hypoparathy-
infants. Reference values for smaller preterm roidism
infants have not been well characterized. • DiGeorge syndrome
• Familial X linked
METHODOLOGY • Familial autosomal dominant
Serum total calcium level, as routinely • Pseudohypoparathyroidism
reported by clinical laboratories, represents Vitamin D deficiency
the sum of protein-bound calcium (40%), • Maternal anticonvulsant therapy
diffusible but complexed calcium (e.g., • Diet
citrate bound, 10%), and free ionized cal- • Malabsorption
cium (50%). Only the ionized calcium frac- • Renal insufficiency (↓ 1,25-dihydroxyvita-
tion, normally 1.10 to 1.36 mmol/L (4.4 to min D)
5.4 mg/dL), is physiologically active, trans- • Hepatic disease (↓ 25-hydroxyvitamin D)
ported across membranes, and regulated Hyperphosphatemia
homeostatically. • Cow’s milk–based formulas
Variations in the two inert calcium frac- • Excessive phosphate administration
tions occur commonly due to alterations
in serum protein level, albumin level, and
pH; thus, correlation of total and ionized
calcium is difficult. Various formulas have
been used to estimate ionized calcium levels below 1.0 mmol/L (4.0 mg/dL) are
from total calcium by correcting for these abnormal in preterm infants.
alterations in serum albumin level, total Early neonatal hypocalcemia occurs in
protein level, and pH.86 In general, these the first 3 days of life. Late-onset hypocal-
formulas have a low sensitivity and a high cemia occurs after 3 days of age. Although
false-negative rate for predicting hypo- overlap occurs, the age of onset is often
calcemia in critically ill patients. Because helpful in determining the cause of neona-
most laboratories are currently able to tal hypocalcemia (Box 12-7).
measure ionized calcium in small blood Hypocalcemia is often asymptomatic
volumes, direct determination of ionized but may cause twitching, “hyperalertness,”
calcium is the method of choice for evalu- increased tone, hyperreflexia, jitteriness,
ating calcium homeostasis in critically ill and convulsions. Cyanosis, vomiting or
patients.87 intolerance of feedings, and a high-pitched
cry have also been noted. Late-onset hypo-
HYPOCALCEMIA calcemia frequently presents with seizures.
Like hypoglycemia, seizures secondary to
Symptoms and Definition hypocalcemia may be either focal, unilat-
Hypocalcemia has traditionally been defined eral, or general. The Chvostek sign does not
as total calcium levels below 2 mmol/L (8.0 have value in premature infants and occurs
mg/dL) in term infants and 1.75 mmol/L in only 20% of hypocalcemic term or older
(7.0 mg/dL) in preterm infants. In term infants. Because the symptoms of hypocal-
infants, ionized calcium concentrations cemia are nonspecific and are commonly
below 1.1 mmol/L (4.4 mg/dL) should be found in other high-risk infants as well as
considered abnormal. Although ionized cal- in those with hypoglycemia and other elec-
cium concentrations are not as well defined, trolyte abnormalities, hypocalcemia must
be confirmed both by the laboratory and leads to hypocalcemia. Because current

by response to specific treatment (see Box commercial formulas contain 280 to 360
12-1). mg/L of phosphorus (molar Ca/P ratio of 1.4
Serum calcium concentration should be to 1.6), classic neonatal tetany has become
determined daily for all infants at risk of rare. With breast-milk feeding, it should not
hypocalcemia, and supportive treatment occur.
should be considered when low levels are
encountered. The differential diagnosis of Secondary Hypoparathyroidism
hypocalcemia is noted in Box 12-7. Maternal Hyperparathyroidism
Maternal hypercalcemia leads to fetal hyper-
Early Neonatal Hypocalcemia calcemia and suppression of neonatal PTH
Early neonatal hypocalcemia represents an secretion.90 The mother’s disease is frequently
exaggeration of the physiologic decrease in clinically silent. Vague maternal symptoms,
serum calcium level during the first 2 days a history of pancreatitis or renal stones, or
of life. In 30% to 40% of low-birth-weight a history of having a previous infant with
infants, chemical hypocalcemia develops. neonatal tetany may be present. Calcium
A smaller number of infants become symp- and phosphorus determinations should be
tomatic. The following factors identify obtained for the mother whenever neona-
infants at high risk: tal hypocalcemia is prolonged or resistant to
• Male sex treatment.
• Delivery in early spring (low maternal
vitamin D level)83 Maternal Hypercalcemic Hypocalciuria
• Prematurity Loss of function of the CasR results in famil-
• Neonatal asphyxia and fetal distress88 ial benign hypocalciuric hypercalcemia, an
• Neonatal illness—respiratory distress autosomal dominant disease. Unaffected
syndrome, cerebral injury, hypoglyce- infants born to mothers with this condition
mia, and sepsis may develop hypocalcemia secondary to
• Maternal diabetes89 high fetal calcium concentrations.
The pathogenesis is a failure of homeo-
static control of the calcium partition Hypomagnesemia
between bone and serum. Interruption of Magnesium deficiency causes impaired PTH
placental calcium supply, transient para- secretion and also causes resistance to PTH
thyroid hypofunction, hypercalcitonin- action. Hypocalcemia cannot be corrected
emia, and increased endogenous phosphate with calcium therapy until hypomagnese-
loading contribute to the hypocalcemia in mia has first been corrected.
each of the aforementioned conditions.
Bicarbonate therapy may aggravate hypo- Primary Hypoparathyroidism
calcemia by decreasing calcium release Transient Congenital Idiopathic
from bone. In premature infants, resistance Hypoparathyroidism
to 1,25-dihydroxyvitamin D action may Transient congenital idiopathic hypopara-
exist. In infants of diabetic mothers, a low thyroidism is a benign, self-limited hypo-
magnesium concentration with associated parathyroid state persisting from 1 to 14
hypoparathyroidism has been proposed as a months and responding to calcium or
contributing factor.89 moderate-level vitamin D supplements.
The mother is euparathyroid.
Classic Neonatal Tetany/
Hyperphosphatemia Permanent Hypoparathyroidism
Classic neonatal tetany occurs typically DiGeorge syndrome is classically charac-
at 5 to 7 days of age. It is most commonly terized by conotruncal cardiac anomalies
seen in infants fed cow’s milk or evapo- (truncus arteriosus, interrupted aortic arch,
rated milk with a high phosphate con- tetralogy of Fallot), thymic dysplasia, and
tent. Cow’s milk contains approximately hypocalcemia.91 Approximately 60% of
956 mg/L of phosphorus (molar Ca/P ratio patients develop hypocalcemia. Hypopara-
of 1.0) compared with 150 mg/L in breast thyroidism may be transient in the neonatal
milk (molar Ca/P ratio of 1.5 to 1.6). The period, permanent, or latent.92 Other asso-
resulting hyperphosphatemia is aggravated ciated features include dysmorphic facies
by immaturity of the parathyroid, vitamin and velopharyngeal incompetence. Many
D metabolism, and renal function, which affected infants do not have congenital
heart disease, which often results in a delay required. An infusion of 1 to 2 mL/kg of

in the diagnosis until later infancy or child- 10% calcium gluconate (9 to 18 mg/kg of
hood.93 Severe immunodeficiency occasion- elemental calcium) is administered over 10
ally occurs due to thymic aplasia.94 The minutes.96 The dose may be repeated in 10
majority of patients have a microdeletion in minutes if there is no response. The hazards
the chromosome 22q11 region. of intravenous calcium injection include bra-
CATCH 22 is a medical acronym for car- dycardia, cardiac arrest, cutaneous necrosis,
diac defects, abnormal facies, thymic hypo- cerebral calcifications, and intestinal gan-
plasia, cleft palate, hypocalcemia, and a grene. Care should be taken to ensure the
variable deletion on chromosome band patency of intravenous lines, with labels used
22q11. Catch 22 includes three syndromes to avoid inadvertent flushing. Intraarterial
with overlapping phenotypes: DiGeorge calcium administration should be avoided.
syndrome, velocardiofacial syndrome, and Failure of hypocalcemia to respond to paren-
conotruncal anomaly face syndrome.95 teral therapy suggests hypomagnesemia.
Several other familial forms of hypopara-
thyroidism have been described, including Continued Treatment
X-linked, autosomal dominant, and autoso- Following the bolus infusion, continuous
mal recessive forms. Autosomal dominant calcium infusion at a rate of 75 mg calcium/
hypocalcemia with calciuria results from a kg/day is indicated. If the infant is in stable
gain in function in the CasR causing inap- condition and can tolerate enteral feedings,
propriate PTH response to hypocalcemia.85 oral calcium therapy can be initiated and
intravenous therapy tapered. Oral calcium
Other Hypocalcemic Syndromes salts, calcium gluconate (9 mg/mL elemen-
Severe maternal calcium and vitamin D tal calcium) or calcium glubionate (23 mg/
deficiency can cause rickets in infants mL elemental calcium), can be initiated at
and neonatal hypocalcemia.83 Maternal 75 mg/kg/day of elemental calcium divided
anticonvulsant therapy alters vitamin D equally into 4 to 6 doses. In infants at risk of
metabolism, potentially leading to neonatal necrotizing enterocolitis or malabsorption,
hypocalcemia. Pseudohypoparathyroidism calcium gluconate is preferred to calcium
is a condition in which peripheral response glubionate because of its lower osmolar-
to PTH is inadequate. ity (700 mOsm/L versus 2500 mOsm/L).
After normocalcemia is achieved, treatment
Treatment of Hypocalcemia should be tapered. Often, therapy can be
Prevention discontinued by 2 to 4 weeks.
Supportive treatment may be given to In patients with hyperphosphatemia, the
asymptomatic infants at risk. If possible, phosphate load needs to be reduced. Low-
early enteral feedings should be initiated. phosphorus formula (Similac PM 60/40
For infants requiring intravenous fluids, cal- [Abbott Nutrition, Columbus, Ohio], phos-
cium may be added to the solution (18 to 36 phorus 190 mg/L, molar Ca/P ratio of 1.5)
mg/kg/day of elemental calcium). Alterna- or breast milk should be used. Additional
tively intravenous bolus injections may be oral calcium supplementation (10 to 20 mg
given every 6 to 8 hours. Calcium cannot elemental calcium/kg/day) helps to further
be mixed with bicarbonate in intravenous increase the relative absorption of calcium
solutions. Cardiac monitoring is required to phosphorus. Oral calcium supplementa-
during calcium infusions. Calcium infu- tion can usually be discontinued beginning
sions should preferably be given through a in 1 week and routine formula started in 2
central line whenever possible. Peripheral to 4 weeks.
administration may result in skin sloughs In patients with hypoparathyroidism,
from infiltration of intravenous solution. both oral calcium supplementation and vita-
min D supplementation, usually in the form
Symptomatic Hypocalcemia of calcitriol (1,25-dihydroxy vitamin D), is
A slow intravenous calcium push is poten- required.
tially hazardous but is indicated in infants
with seizures or extreme irritability as a ther- Prognosis
apeutic trial while laboratory confirmation Hypocalcemia with seizures may present an
of hypocalcemia is awaited. An established immediate threat to life in an infant with
intravenous line should be used. Continu- other problems with which to contend.
ous cardiac monitoring for bradycardia is Unlike with hypoglycemia, however, there
Box 12-8. Causes of Hypercalcemia D synthesis.101 Other causes are listed in

Box 12-8.
Neonatal hyperparathyroidism (transient vs. Hypercalcemia may present with non
permanent) specific symptoms including poor feeding,
Maternal hypoparathyroidism ileus, failure to thrive, polyuria, dehydra-
Excessive calcium supplementation tion, lethargy, and irritability. Chronic
Excessive vitamin D supplementation hyperparathyroidism may be associated
Williams syndrome (↑ 1,25-dihydroxyvitamin D) with bone demineralization and fractures.
Familial hypocalciuric hypercalcemia Initial treatment includes discontinua-
Phosphate depletion tion of all calcium and vitamin D supple-
Hypervitaminosis A mentation, and hydration with furosemide
Use of thiazide diuretics to increase calcium excretion. Other thera-
Hyperthyroidism pies include calcitonin, glucocorticoids, and
Adrenal insufficiency dialysis. Specific treatment is directed to the
Subcutaneous fat necrosis underlying disorder.
Aluminum toxicity
Hypophosphatasia MAGNESIUM
Primary chondrodystrophy (metaphyseal
dysplasia) FETAL AND NEONATAL MAGNESIUM
METABOLISM
Magnesium is actively transported from
seems to be no structural damage to the cen- mother to fetus. Unlike with calcium, this
tral nervous system.97 Thus, hypocalcemia transfer is adversely affected both by pla-
alone has a good prognosis. If hypocalcemia cental insufficiency and by maternal mag-
is complicating other serious conditions nesium deficiency caused by poor diet or
such as asphyxia, the prognosis is deter- disease. Approximately 65% of total body
mined by the other problems.97 magnesium (versus 99% of calcium) is con-
tained in bone, 34% in the intracellular
HYPERCALCEMIA space, and 1% in the extracellular space.
Hypercalcemia is most often iatrogenic sec- Because the fraction of magnesium in the
ondary to excessive calcium administration, extracellular fluid is low, plasma magne-
excessive vitamin D administration, use of sium concentrations do not adequately
thiazide diuretics that reduce renal calcium reflect total body magnesium content.
excretion, or phosphate depletion usually Parathyroid function has a small direct
caused by poorly constituted hyperalimenta- effect on serum magnesium levels. Magne-
tion solutions or human milk feedings.98 Pri- sium, on the other hand, is critically neces-
mary neonatal hyperparathyroidism occurs sary for normal parathyroid function.
both sporadically and by autosomal reces- Normal newborn serum magnesium
sive inheritance. It is due to abnormalities concentration is 1.5 to 2.8 mg/dL (0.62 to
in CasR function resulting in increased PTH 1.16 mmol/L) and relates directly to the
levels.85 Familial hypocalciuric hypercal- mother’s level.102 Through the first week
cemia is a related disorder also caused by of life, magnesium levels show small varia-
abnormalities in the CasR but is benign and tions, correlating directly with changes in
inherited in an autosomal dominant pat- serum calcium level and inversely with
tern.85,99 PTH levels are normal with low to phosphorus level.
normal urinary calcium excretion in familial
hypocalciuric hypercalcemia.100 Individu-
als who are homozygous for the familial EDITORIAL COMMENT: Fetal exposure to mag-
hypocalciuric hypercalcemia gene muta- nesium sulfate in women at risk of preterm delivery
tion develop severe neonatal hyperparathy- significantly reduces the risk of cerebral palsy without
roidism.99 Secondary hyperparathyroidism increasing the risk of death.103
occurs due to chronic maternal hypocal-
cemia (usually caused by maternal hypo-
parathyroidism), which leads to transient HYPOMAGNESEMIA
neonatal parathyroid overstimulation. The Magnesium levels of less than 1.5 mg/dL are
hypercalcemia associated with subcutaneous encountered in the following conditions:
fat necrosis and Williams syndrome may be • In intrauterine growth restriction of any
related to increased 1,25-dihydroxyvitamin cause, including multiple gestation, or in
association with maternal malnourish- gastrointestinal motility. Prolonged mater-

ment or hypomagnesemia nal magnesium administration has been
• In association with maternal gestational associated with abnormal bone mineraliza-
diabetes and diabetes mellitus, in which it tion.106 Hypermagnesemia may also occur
correlates with the severity of the moth- during excessive magnesium administration
er’s disease89 with total parenteral nutrition. Treatment
• With hyperphosphatemia and after is expectant, because magnesium levels
exchange transfusion (magnesium, like decline by 48 hours. If severe symptoms
calcium, is subject to citrate complexing) are present, administration of calcium may
• In hypoparathyroidism reverse these effects, and forced saline diure-
• Secondary to diarrhea or malabsorption sis may speed magnesium excretion.
states in older infants
• In a specific magnesium malabsorption METABOLIC BONE DISEASE
syndrome that is secondary to mutations OF PREMATURITY (FORMERLY
in the transient receptor potential chan- OSTEOPENIA–RICKETS OF
nel 6 (TRPM6) protein mapping to chro- PREMATURITY)
mosome band 9q22.104,105 Although osteopenia and rickets have been
• Secondary to renal losses (primary or the traditional terminology, metabolic bone
induced by drugs, e.g., amphotericin B) disease of prematurity is now the preferred
Hypomagnesemia can cause symptoms nomenclature.
similar to those caused by hypocalcemia but The major factor in metabolic bone dis-
is unresponsive to calcium therapy. ease and rickets of prematurity is mineral
deficiency.107,108 Bone mineralization in
Coexistence of Hypomagnesemia and utero increases to term (see Fig. 12-4). Pre-
Hypocalcemia mature infants miss the large accumula-
Hypomagnesemia and hypocalcemia, two tion of calcium and phosphorus that occurs
metabolic problems, frequently coexist. They during the last trimester in pregnancy and
have common antecedents, such as mater- are therefore very susceptible to mineral
nal diabetes, hypoparathyroidism, malab- deficiency. The most susceptible infants
sorption, exchange transfusion, and excess are those that have very low birth weight
dietary phosphorus. (<1000 g) and have chronic problems, such
Magnesium deficiency causes failure of as bronchopulmonary dysplasia and necro-
PTH release and of PTH’s effect on serum cal- tizing enterocolitis, that preclude adequate
cium level. Treatment with calcium will not intake or require treatment with calciuric
correct hypocalcemia until hypomagnese- drugs (e.g., furosemide). In one study of
mia is corrected. Magnesium appears crucial extremely low-birth-weight infants, 33%
for normal bone-serum calcium homeostasis. had low bone mineral content. Hepatic and
renal disease may contribute by impairing
Treatment of Hypomagnesemia vitamin D metabolism.
Hypomagnesemia with tetany is treated Metabolic bone disease may be asymp-
with 25 to 50 mg/kg of magnesium sulfate tomatic or manifest as classic rickets at 1 to
administered intravenously or intramuscu- 4 months of age with undermineralized
larly every 6 to 8 hours. Serum magnesium bone, pathologic fractures, craniotabes,
concentration should be rechecked every rachitic rosary, hypocalcemia, hypophospha-
24 hours. Hypermagnesemia with hypoto- temia, and elevated levels of PTH, alkaline
nia may occur with overtreatment. Alter- phosphatase, and 1,25-dihydroxyvitamin D
natively, magnesium may be given with levels (if not caused by vitamin D deficiency).
feedings. The sulfate, gluconate, chloride, or Prevention begins with achieving ade-
citrate salt may be used in an initial dosage quate calcium and phosphorus intake. Rec-
of 100 to 200 mg magnesium per kilogram ommended minimum parenteral intakes
per day given in divided doses every 6 hours. of calcium, phosphorus, and vitamin D are
Excessive dosages have a laxative effect. 500 to 600 mg/L (12.5 to 15 mmol/L), 400
to 450 mg/L (12.9 to 14.5 mmol/L), and 160
HYPERMAGNESEMIA IU/kg/day (maximum 400 IU/day), respec-
Magnesium that crosses the placenta after tively.109,110 Smaller infants may require
treatment for toxemia or preterm labor higher intakes, but care must be taken to
may produce hypotonia, flaccidity, respira- ensure the solubility of calcium and phos-
tory depression, poor suck, and decreased phorus in the parenteral fluid.
Early enteral feeding is key to disease, usually the lesions are conotruncal
revention. Bone mineralization improves
p defects (e.g., interrupted aortic arch, trun-
with increasing calcium and phospho- cus arteriosus, tetralogy of Fallot). Patients
rus supplementation. Term formulas and with isolated ventricular septal defects
unsupplemented human milk provide are unlikely to have DiGeorge syndrome.
inadequate calcium and phosphorus for Therefore the answer is 1 (hypoglycemia).
premature infants. Preterm formulas and This highlights the need to calculate glu-
human milk supplemented with fortifiers cose infusion rates in milligrams per kilo-
at recommended dosages provide enough gram per hour, and not to be seduced by
calcium (1000 to 1460 mg/L) and phospho- the concentration, when assessing patients
rus (550 to 850 mg/L) to prevent rickets in with hypoglycemia or hyperglycemia.
most infants.109 Calcium and phosphorus
intake is also improved through the use of A 1800-g male infant is born at 40 weeks’ gestation.
premature discharge formulas, which have
higher calcium and phosphorus content Infants with intrauterine growth restric-
than term infant formulas. Adequate pro- tion can have hypoglycemia, hyperglyce-
tein intake is also important for calcium mia, or hypocalcemia (answers 1, 2, and 3).
retention. Hypoglycemia may occur because of inad-
For infants at risk, calcium, phosphorus, equate glycogen stores or hyperinsulinism.
and alkaline phosphatase levels should be Infants with neonatal diabetes are hypergly-
monitored. If results are consistent with cemic and growth restricted because of low
developing metabolic bone disease, addi- intrauterine insulin concentrations. Intra-
tional calcium and phosphorus supplemen- uterine growth–restricted infants can be
tation may be required. Only infants with hypocalcemic secondary to low magnesium
cholestasis or renal disease may require concentrations or fetal distress. Hypercalce-
additional vitamin D beyond the recom- mia is not usually associated with intrauter-
mended 400 IU/day.109 ine growth restriction.
A 5-day-old infant shows jerking movements of

the left arm and leg. On close evaluation, the
QUESTIONS child is also found to have an abnormal-appear-
ing facies with mild hypertelorism, short philtrum,
Match the clinical scenarios with the following mildly low-set ears, micrognathia, and downslant-
conditions and state the reasons for selection ing palpebral fissures.
(more than one condition may be correct):
This infant has features consistent with
1. Hypoglycemia DiGeorge syndrome. Hypoplasia of the
2. Hyperglycemia parathyroid gland leads to hypoparathy-
3. Hypocalcemia roidism and hypocalcemia. Therefore the
4. Hypercalcemia answer is 3 (hypocalcemia). Many patients
with DiGeorge syndrome do not have car-
A 3400-g 7-day-old infant with a large ventricular diac disease and are therefore not diagnosed
septal defect becomes jittery. Earlier in the day, immediately after birth.
the child’s intravenous fluids were decreased
from 20 mL/hr to 11 mL/hr because of conges- A 2600-g newborn has a hemoglobin level of 26
tive heart failure. The concentration of dextrose in g/dL.
the total parenteral nutrition was increased from
12.5% to 15%. Hypoglycemia is frequent in plethoric infants.
A high hemoglobin level may be a factor in
Although the concentration of dextrose in hypoglycemia in infants of diabetic mothers
the intravenous fluids was increased, this and in those with Beckwith-Wiedemann syn-
did not offset the decrease in the rate of drome. The answer is 1 (hypoglycemia).
fluid administration. Therefore, the glucose
infusion rate decreased from 12.3 mg/kg/ A newborn exhibits jitteriness and seizures.
min to 8.1 mg/kg/min. An acute decrease
in the glucose infusion rate may lead to These symptoms are present with hypogly-
hypoglycemia. Although patients with cemia and hypocalcemia. The answer is 1
DiGeorge syndrome often have cardiac and 3 (hypoglycemia and hypocalcemia).
Box 12-1 lists many other conditions that

hyperinsulinemic. This may occur in infants of diabetic
have similar symptoms.
mothers (diagnosed and undiagnosed) or in large-for-
gestational age infants without maternal diabetes.
May be a clue to undiagnosed disease in the mother.
The plasma glucose concentration 1 hour later is
25 mg/dL.
In a large-for-date infant, early hypogly-
cemia should be sought and may indicate
What is your management now?
unsuspected maternal diabetes. Neonatal
hypocalcemia may be a clue to maternal Despite early feeding, the plasma glucose level fell;
hyperparathyroidism or familial hypocalci- therefore, prompt intravenous therapy is indicated.
uric hypercalcemia (FHH). Neonatal hyper- The infant should be given a minibolus of dextrose (2
parathyroidism with hypercalcemia may be mL/kg 10% dextrose in water, 200 mg/kg of glucose)
present when both parents have FHH and followed by a continuous glucose infusion starting at
the infant is homozygous for the FHH gene 6 to 8 mg/kg/min. Enteral feeding may be continued
mutation. The answer is 1, 3, and 4. if tolerated. Glucose concentrations should be meas-
ured at least hourly until values are stable.
Associated with iatrogenic excessive administra- The infant continues to have intermittent episodes
tion of Vitamin D or A. of hypoglycemia requiring an increase in the glucose
infusion to 18 mg/kg/min over the next 72 hours.
Excess vitamin D or vitamin A administra-
tion leads to hypercalcemia. The answer is 4 What additional laboratory studies should
(hypercalcemia). be performed?
The prolonged hypoglycemia, need for a high rate of glu-
Cannot be corrected if hypomagnesemia is present. cose infusion, macrosomia, and lack of other congenital
anomalies (e.g., abdominal wall defect, macroglossia)
Normal magnesium concentrations are make persistent hyperinsulinemic hypoglycemia of in-
necessary for normal parathyroid function. fancy most likely. Plasma insulin concentrations should
Hypocalcemia cannot be corrected in the be measured when the infant is hypoglycemic. Although
presence of hypomagnesemia. Therefore, the early onset of hypoglycemia and lack of midline fa-
the answer is 3 (hypocalcemia). cial defects (i.e., cleft palate) make metabolic and endo-
crine disorders unlikely, cortisol, growth hormone, blood
pH, and ammonia concentrations should be obtained.
True or False Ammonia concentrations also need to be measured to
Prematurity is the single most important risk factor evaluate for hyperammonemic hyperinsulinism caused
for the development of metabolic bone disease. by mutation of the glutamate dehydrogenase gene.
This case shows the need for continued reevalu-
The frequency of metabolic bone disease is ation of infants. Initially, when a patient like this is en-
inversely related to gestational age and birth countered, the most common diagnosis is transient
weight. Other factors include prolonged hyperinsulinemic hypoglycemia. The persistence of
total parenteral nutrition with delayed hypoglycemia and the lack of improvement should
enteral feeding, and the failure to fortify prompt one to perform further evaluation and con-
human milk. The statement is true. sider other potential diagnoses.
CASE 1
EDITORIAL COMMENT: Hyperinsulinism/hyper-
A 3900-g infant born at 38 weeks’ gestation after ammonemia (HI/HA) syndrome is the second most
an uncomplicated pregnancy has a plasma glucose common form of congenital hyperinsulinism.17 Chil-
concentration of 30 mg/dL at 1 hour of age. The in- dren affected by this syndrome have both fasting
fant is asymptomatic. and protein-sensitive hypoglycemia combined with
persistently elevated ammonia levels. The disorder
What is your initial management? is identified in infancy when the child experiences
Because the infant is asymptomatic and the glucose hypoglycemic seizures after brief periods of fast-
concentration is higher than 25 mg/dL, the infant should ing or the ingestion of a high-protein meal. Gain-
be fed and a repeat glucose determination ordered of-function mutations in the mitochondrial enzyme
in 30 minutes. The infant most likely has transient hy- glutamate dehydrogenase are responsible for HI/HA
poglycemia, which is usually asymptomatic. The pres- syndrome. Glutamate dehydrogenase is expressed
ence of macrosomia indicates that the infant is probably in the liver, kidney, brain, and pancreatic beta cells.
Patients with HI/HA syndrome have an increased What factors may be important in the
frequency of generalized seizures, especially ab- pathogenesis of the hypocalcemia?
sence-type seizures, in the absence of hypoglycemia. The high serum phosphorus concentration indicates
The hypoglycemia of HI/HA syndrome is well control- that dietary phosphorus load, relative hypoparathy-
led with diazoxide, a KATP channel agonist. roidism, and renal immaturity with retention of phos-
Glutamate dehydrogenase has also been impli- phate are important factors in the hypocalcemia.
cated in another form of hyperinsulinism, short-chain
3-hydroxyacyl-CoA dehydrogenase (SCHAD) defi- What management should be instituted?
ciency–associated hyperinsulinism.
A low-phosphorus formula or formula with a favo-
HI/HA syndrome provides a rare example of an
rable Ca/P ratio (Similac PM 60/40 or human milk)
inborn error of intermediary metabolism in which the
should be fed. Additional calcium supplementation
effect of the mutation on enzyme activity is a gain of
(elemental calcium 20 to 80 mg/kg/day) can be used
function.111
to increase the Ca/P ratio in the feedings to further
decrease phosphate absorption.
CASE 2 What is the prognosis?

You are called to see a 5-day-old infant because of The prognosis is excellent. Supplemental calcium
irritability and jerking movements of the left arm and may be tapered and withdrawn at 3 to 4 weeks of
leg. He was the product of a full-term pregnancy and age. Serum calcium level should be monitored at this
had a birth weight of 2800 g. Pregnancy was com- time to be sure hypocalcemia does not recur. There
plicated by third-trimester bleeding. Delivery was by should be no long-term sequelae.
cesarean section because of placenta previa. One-
minute Apgar score was 6; 5-minute Apgar score
was 9. Feeding with evaporated milk formula was
CASE 3
begun at 16 hours of age, and he did very well until
a few hours ago when he became tremulous and fed A 2-month-old infant has increasing respiratory distress
poorly. Intermittent convulsions were noted. Exami- and an “incidental” finding on chest radiograph. He
nation reveals irritability but no other abnormalities. was a 27-week, 800-g infant at delivery and has had
However, as the examination ends, the child has an- respiratory distress syndrome necessitating 1 month
other seizure. of mechanical ventilation via respirator and 1 month of
continuous positive airway pressure therapy. Multiple
What diagnostic tests and procedures episodes of cor pulmonale requiring long-term diuretic
would you perform initially? therapy and failure to establish enteral alimentation
have necessitated total parenteral alimentation. Direct
The symptoms shown by this baby are nonspecific.
reacting hyperbilirubinemia was evident at 1 month.
Central nervous system injury or infection is possible,
and a lumbar puncture must be done. There is noth-
Figure 12-5 shows what important
ing in the case history to suggest hypoglycemia as a
findings?
probable cause of the seizures, but some less com-
mon hypoglycemic syndromes (inborn error of me- In addition to chronic lung disease and cardiomegaly,
tabolism, islet adenoma) may present this way, and metabolic bone disease is evident. Poorly mineral-
glucose testing should be performed. Serum should ized bone, rachitic rosary, and pathologic fractures
be drawn for determination of electrolyte, calcium, are present.
blood urea nitrogen, and glucose levels.
Several features of this case suggest the possibil- What common deficiency may be present?
ity of hypocalcemia, notably stormy obstetric course, In preterm infants, acquired nutritional rickets is usu-
milk feedings, the age of onset of symptoms after the ally due to deficiencies in calcium and phosphorus
initially benign course, and irritability and tremulous- intake. In this patient, cholestasis contributes to the
ness as cardinal symptoms. These features justify a problem by leading to vitamin D deficiency, and long-
trial with parenteral calcium after initial studies are term diuretic therapy (i.e., furosemide) may potentiate
done. renal calcium losses.
The therapeutic infusion is 2 mL/kg of 10% cal-
cium gluconate over 10 minutes into an established What therapy should be started?
intravenous line with ECG monitoring. Subsequent to Maximize calcium intake by oral and parenteral
immediate evaluation and treatment, the laboratory routes. If hypophosphatemia is present, maximize in-
reports an ionized calcium level of 0.5 mmol/L and a take of phosphorus. In the presence of hepatic dys-
phosphorus level of 11.5 mg/dL. function (cholestasis) or suspected malabsorption,
vitamin D (1000 U/day) should be added. The use of CASE 5

drugs that increase renal calcium loss (e.g., furose A 1-day-old 1900-g infant born at 33 weeks’ gesta-
mide) should be minimized. tion to a diabetic mother has a focal seizure. Initial
laboratory testing reveals an ionized calcium level of
Why did this patient have pulmonary 0.5 mmol/L.
deterioration?
Rachitic muscle weakness or rib cage dysfunction What is your initial treatment?
may result in pulmonary insufficiency. The initial treatment is 1.9 to 3.8 mL of 10% calcium
gluconate infused intravenously over 10 minutes.
A similar patient also demonstrates Calcium should be added to the intravenous fluids to
periosteal bone elevation, anemia, and provide 75 mg/kg/day of elemental calcium.
neutropenia. What rarer nutritional
deficiency is present? A repeat ionized calcium concentration is
In infants receiving prolonged hyperalimentation, 0.5 mmol/L. What is the most likely reason
trace mineral deficiency may occur. In this particular for the lack of response to therapy?
infant, copper intake was deficient. Premature infants and infants of diabetic mothers are
at risk for hypomagnesemia. Magnesium is neces-
sary for proper PTH secretion; therefore, calcium
concentrations will not increase if hypomagnesemia
is present. Magnesium concentration should be
checked, and if it is low the infant should be treated
with 25 to 50 mg/kg of magnesium sulfate.
True or False
The primary nutritional deficiency associated
with metabolic bone disease in preterm infants is
Figure 12-5. Radiographic findings in a 2-month-old, phosphorus deficiency.
800-g-birth-weight infant with respiratory distress (Case 3).
The statement is factually correct. Risk fac-
tors for metabolic bone disease include
CASE 4 prematurity and feeding practices as enun-
You attend the delivery of an infant at 37 weeks’ ciated in the answer to the preceding ques-
gestation. The mother has preeclampsia and has re- tion as well as drugs that deplete calcium
ceived magnesium sulfate for the last 24 hours. At from bone (corticosteroids, diuretics such as
the time of delivery the infant is hypotonic and ap- furosemide, and methylxanthines). Other
neic, and requires intubation and positive pressure factors include lack of movement, vitamin
ventilation. D deficiency, and aluminum toxicity. The
statement is true.
What is the most likely diagnosis and
management? REFERENCES
Magnesium crosses the placenta, with fetal plasma The reference list for this chapter can be found
concentrations directly correlating with maternal online at www.expertconsult.com.
plasma concentrations. Maternal magnesium sul-
fate therapy leads to hypermagnesemia in the new-
born infant. The diagnosis is most consistent with
hypermagnesemia secondary to maternal therapy.
Treatment is supportive. As long as urine output is
adequate, magnesium levels will fall without further
intervention.
13
Neonatal
Hyperbilirubinemia
M. Jeffrey Maisels and Jon F. Watchko
Care of the high-risk neonate usually refers its structure is conventionally represented
to care of the low-birth-weight infant or in linear fashion as shown in Figure 13-2,
the sick term newborn. Although hyperbili- the actual structure of bilirubin revealed
rubinemia is certainly a matter of concern by x-ray crystallography is similar to that
in these infants, the decisions that must be shown in Figure 13-3, in which the biliru-
made regarding jaundice in the high-risk bin molecule is stabilized by the presence of
neonate are, in general, less complex than intramolecular hydrogen bonds (indicated
those that must be made in the healthy by the dashed lines). In this conforma-
full-term infant. For the term and late pre- tion, the hydrophilic, polar COOH and NH
term infant, shorter hospital stays, the need groups are not available for the attachment
for outpatient surveillance and manage- of water, whereas the hydrophobic hydro-
ment, and the occasional disturbing case carbon groups are on the perimeter, which
of extreme hyperbilirubinemia and even makes the molecule insoluble in water but
kernicterus raise new issues in the manage- soluble in nonpolar solvents such as chlo-
ment of neonatal jaundice. Bilirubin has roform. The addition of methanol or etha-
both salutary and toxic effects. At physi- nol interferes with hydrogen bonding and
ologic levels it exerts important antioxidant results in an immediate diazo reaction—the
effects.1 Although its toxic effects are well basis for measurement of indirect bilirubin
documented, there are also some concerns by the van den Bergh reaction.
that aggressive use of phototherapy in very In the jaundiced newborn in whom
low-birth-weight infants may not be entirely the primary problem is excessive bilirubin
innocuous.2 formation or limited hepatic uptake and
Most neonatal jaundice is the result of a conjugation, unconjugated (i.e., indirect)
combination of events—an increase in the bilirubin appears in the blood. When biliru-
rate of bilirubin production, reabsorption of bin glucuronide excretion is impaired (i.e.,
bilirubin into the plasma from the gut (the in cholestasis), conjugated bilirubin mono-
enterohepatic circulation), and inability of glucuronide and diglucuronide (direct react-
the liver to clear sufficient bilirubin from ing bilirubin) accumulate in the plasma and,
the plasma. because of their solubility, also appear in the
urine. A fourth bilirubin fraction, known as
FORMATION, STRUCTURE, AND delta bilirubin, is formed nonenzymatically
PROPERTIES OF BILIRUBIN from conjugated bilirubin, is covalently
Bilirubin is the end product of the catabo- bound to albumin, and reacts directly with
lism of iron protoporphyrin, or heme, the diazo agent.
which comes predominantly from circulat-
ing hemoglobin (Fig. 13-1). Bilirubin is a NEONATAL BILIRUBIN METABOLISM
tetrapyrrole compound with specific substi- Heme degradation leads to bilirubin pro-
tutions in the side chains of the four pyrrole duction from two major sources (Fig. 13-4).
rings. The outer pyrrole rings are linked to Approximately 75% of the daily bilirubin
the inner ones by methene bridges (con- production in the newborn comes from
taining one double bond each), but the senescent erythrocytes (the catabolism of 1
two central rings are joined by a methane g of hemoglobin yields 35 mg of bilirubin),
bridge (no double bond). Normally, the but 25% is contributed by nonhemoglobin
methene bridge oxidized in heme is in the heme contained in the liver (in enzymes
α-position, and the resultant isomer is bili- such as cytochromes and catalyses and in
rubin IX-α (see Fig. 13-3), the predominant free heme) and in muscle myoglobin, or
isomer of bilirubin in the body. Although comes from ineffective erythropoiesis in the
310
O O
H O C C O H
γ
8 10 12
CH3 7 9 11 CH3
B C 13
N N
6 14
Heme 1
β 5 Fe 15 δ
4 N N 16
CH2
3 A D
19 17 CH3
1
2 20 18
α
CH3 CH2 NADPH + O2
Heme oxygenase
O O CO + Fe + NADP + H2O
H O C C O H
CH3 CH3
B C
Biliverdin 2
N N
H
H H
N N
CH2
A D
O O CH3
CH3 CH2 NADPH
Biliverdin reductase
O O NADP
H O C C O H
CH2
H H
O CH3 CH3 CH3
D B C
H
N N N
O 3 H H
H
C O H H
H CH3 N N
N C CH2
4 A D
O O CH3
CH3
B CH3 CH2
N C
H COOH COOH
O CH2 CH2
O CH3 CH3 CH3 CH3
H
N
CH2 H
A O 5 A B C D
O O
N N CH2 N N
CH3 H H H H
Bilirubin
Figure 13-1. Chemical structures depicting the conversion of heme to bilirubin. Bilirubin is frequently represented by any of
the three structures (3 to 5) shown at the bottom. NADP, Nicotinamide adenine dinucleotide phosphate; NADPH, reduced
form of nicotinamide adenine dinucleotide phosphate. (Redrawn from Gourley GR: Neonatal jaundice and disorders of
bilirubin metabolism. In Suchy FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children, ed 3, New York, 2007,
Cambridge University Press.)
312 CHAPTER 13 Neonatal Hyperbilirubinemia
diglucuronide pigments that are more water

soluble and sufficiently polar to be excreted
COO– into the bile or filtered through the kidney.
O
The enzyme catalyzing this reaction is uri-
N N dine diphosphate glucuronosyltransferase,
H H H
O N N a single form of which (UGT1A1) accounts
–OOC for almost all of the bilirubin glucuronide in
the human liver. The enzyme arises from the
A UGT1A1 gene complex situated on chromo-
some 2 at 2q37. Mutations and amino acid
O substitutions at different loci on this gene
H are responsible for the inherited unconju-
N N gated hyperbilirubinemias: Crigler-Najjar
H H O
O H O H syndrome types I and II, and Gilbert syn-
O N N
drome. Data suggest a role for another bili-
H rubin transporter, the hepatic solute carrier
O organic anion transporter 1B1 (SLCO1B1).3
Gene polymorphisms of SLC1B1 may lead
B to hyperbilirubinemia by limiting hepatic
Figure 13-2. Chemical structure of bilirubin. A, Bilirubin bilirubin uptake. Once conjugated, biliru-
dianion, with two free carboxyl groups; bilirubin monoanion
bin is excreted via the bile canaliculi into
has one free carboxyl group. B, Bilirubin diacid, the
predominant form of free bilirubin in plasma at physiologic
the small intestine. A detailed review of the
pH. (From Brodersen R: Bilirubin transport in the chemistry and metabolism of bilirubin can
newborn infant, reviewed in relation to kernicterus, be found elsewhere.4,5
J Pediatr 96:349–356, 1980.)
NORMAL SERUM BILIRUBIN LEVELS
AND THE NATURAL HISTORY OF
5 NEONATAL JAUNDICE
Unconjugated bilirubin is transported effi-
C O ciently via the placenta from fetal blood
N H HN H into the maternal circulation by passive
O
O diffusion.6 The mean total serum bilirubin
O CH2
O H H (TSB) levels in cord blood range from 1.4
H N N to 1.9 mg/dL (24 to 32 µmol/L), whereas
O C maternal TSB levels are less than 1 mg/dL
(17.1 µmol). For years it has been taught
15 that the TSB concentration in normal term
Figure 13-3. X-ray crystallographic structure of bilirubin infants increases from birth, reaches its apex
IX-α. Dashed lines indicate hydrogen bonding. on about the third or fourth day of life, and
then declines, reaching normal levels by 7
bone marrow. Once it leaves the reticuloen- to 10 days. When bilirubin levels are studied
dothelial system, bilirubin is transported in in large populations using transcutaneous
the plasma, bound tightly to albumin, so bilirubin (TcB) measurements, however, it is
that at physiologic pH the solubility of bili- clear that in those at or above the 50th per-
rubin is very low (about 4 nm/L [0.24 mg/ centile, the peak does not occur until about
dL]). When the bilirubin-albumin complex 96 hours and remains at that level through
comes into contact with the hepatocyte, a 120 hours (Fig. 13-5).7 On the other hand,
proportion of the bilirubin, but not albu- there are significant differences in the natu-
min, is transported into the cell, where it is ral history in term and late preterm infants
bound to ligandin and then transported to for each week of gestation.8 In those with
the smooth endoplasmic reticulum for con- a gestational age of 40 weeks or longer, the
jugation. peak TcB occurs at about 60 hours, whereas
Conversion of unconjugated bilirubin in those with a gestational age of 35 to 396⁄7
to its water-soluble conjugate must occur weeks it does not occur until 96 hours or
before it can be excreted; this is achieved later (Fig. 13-6).7,8 Because of intervention
when bilirubin is combined enzymati- with phototherapy, no recent data are avail-
cally with a sugar, glucuronic acid, which able on the natural history of bilirubinemia
produces bilirubin monoglucuronide and in infants of 34 weeks’ gestation or less.
CHAPTER 13 Neonatal Hyperbilirubinemia 313
RE system Early peak

Catabolism Ineffective erythropoiesis
of effete RBC - bone marrow
Tissue heme } Liver
Heme proteins
75% 25%
Heme Heme Heme
RE oxygenase
system
Biliverdin
Biliverdin
reductase
Bilirubin
+
Serum albumin
Ligandin
Smooth
endoplasmic
reticulum Glucuronosyl
transferase
Enterohepatic
circulation
bilirubin
Bilirubin glucuronide
β-Glucuronidase
Bilirubin
Figure 13-4. Neonatal bile pigment metabolism.

RBC, Red blood cell; RE, reticuloendothelial. (From
Maisels MJ: Jaundice. In Avery GB, Fletcher
MA, MacDonald MG, editors: Neonatology:
Fecal bilirubin pathophysiology and management of the newborn,
Urobilinogen (minimal) Philadelphia, 1999, JB Lippincott, pp 765–819).
DEVELOPMENTAL JAUNDICE most neonatologists would treat this bili-

The normal increase of TSB levels in the rubin level with phototherapy. Thus, TSB
newborn has been termed physiologic jaun- levels well within the physiologic range are
dice, but there is good reason to consider considered potentially hazardous and are
abandoning this term.9 Depending on eth- commonly treated with phototherapy. The
nic characteristics, breast feeding, and other natural history of hyperbilirubinemia in this
factors, there are significant differences in population is never observed, and defining
TSB levels in different populations, so that these bilirubin levels as physiologic in such
what is physiologic for one infant may well infants seems illogical and potentially dan-
be nonphysiologic for another. Particularly gerous. A better term for this phenomenon
for low-birth-weight infants being cared for is developmental jaundice.9
in the neonatal intensive care unit (NICU), The jaundice seen in almost every new-
the term physiologic jaundice has little mean- born results from a combination of mecha-
ing and is potentially dangerous. If no treat- nisms:
ment is given, low-birth-weight infants • The normal neonate produces about 6 to
have prolonged and exaggerated hyperbili- 8 mg/kg/day of bilirubin, which is about
rubinemia—the lower the birth weight, the 2.5 times the rate of bilirubin production
higher the peak bilirubin level. A TSB of in the adult.10
10 mg/dL (171 µmol/L) on day 4 in a 750-g • The newborn reabsorbs significant amounts
neonate is a normal bilirubin level for that of unconjugated bilirubin from the
infant and requires no investigation to iden- intestine (the enterohepatic circulation).
tify a cause for the jaundice. Nevertheless, Unlike the adult, newborns have few
16 95th percentile
14
75th percentile
12
TcB (mg/dL) 50th percentile
10
8 25th percentile
6
4
5th percentile
2
0
12 24 36 48 60 72 84 96 108 120
Postnatal age (hr)
Figure 13-5. Smoothed curves from 14,035 transcutaneous bilirubin (TcB) measurements in 2646 newborns (gestational
age ≥35 weeks and birth weight ≥2000 g). (From Fouzas S, Mantagou L, Skylogianni E, et al: Transcutaneous bilirubin
levels for the first 120 postnatal hours in healthy neonates, Pediatrics 125:e52, 2009).
bacteria in the small and large bowel and diagnose “clinically significant” jaundice
they have greater activity of the decon- varies widely, and this can lead to impor-
jugating enzyme β-glucuronidase. As a tant errors in management.12-14 In addition,
result, conjugated bilirubin (which can- whether the TSB level is “clinically signifi-
not be reabsorbed), is not converted to cant” depends both on the actual TSB level
urobilinogen but is hydrolyzed to uncon- and the infant’s age, in hours (Figs. 13-5 to
jugated bilirubin. This can be reabsorbed 13-7). Currently, experts recommend that
and increases the bilirubin load on the before discharge, TSB or TcB should be mea-
liver. sured in all newborns.15,16
• There is a decrease in clearance of biliru-
bin from the plasma. This is the result of NONINVASIVE BILIRUBIN
a deficiency in ligandin, the predominant MEASUREMENTS
bilirubin-binding protein in the hepato- TcB measurements are being used with
cyte, and a deficiency of UGT1A1, which, increasing frequency in hospital nurseries,
at term, has approximately 1% of the in outpatient settings, and in the preterm
activity found in the adult. population.7,17-25 They reduce significantly
the number of TSB measurements needed
AN APPROACH TO THE JAUNDICED in both the term nursery and the NICU,
INFANT and they are invaluable in the outpatient
The overwhelming majority of both pre- setting.19,22,26 TcB measurements provide
term and term infants who are jaundiced are instantaneous information while reducing
not jaundiced as a result of any pathologic the likelihood that a clinically significant
process. Their jaundice is the result of the TSB will be missed. There is good evidence
mechanisms described earlier, and the rel- that TcB measurements provide excellent
evant clinical and laboratory risk factors for estimates of the TSB level, although they are
the development of severe hyperbilirubine- not a substitute for TSB values.27
mia in the term and late preterm infant are The TcB value is a measurement of the yel-
well documented.11 The pathologic causes low color of the blanched skin and subcuta-
of indirect hyperbilirubinemia are listed in neous tissues, not the serum bilirubin level,
Box 13-1. and should be used as a screening tool to
help determine whether the TSB level should
WHO IS JAUNDICED? be measured. Because TcB measurements are
Jaundice is a clinical sign, and for years cli- noninvasive, they can be repeated several
nicians have assessed the intensity of jaun- times during the birth hospitalization and
dice and used this assessment to decide provide useful information about the rate of
whether to obtain a serum bilirubin mea- rise of the bilirubin level. When plotted on a
surement. But the ability of clinicians to nomogram (see Figs. 13-5 to 13-7), TcB levels
Gestational Age 35-37 6 7 Weeks
16
14
Transcutaneous bilirubin (mg/dL)

95th percentile
12 75th percentile
10 50th percentile
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Age (hr)
Gestational Age 38-39 6 7 Weeks

16
14
12 95th percentile
10 75th percentile
8
50th percentile
6
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Age (hr)
Gestational Age 40+ Weeks

14
12
95th percentile
10
75th percentile
8
50th percentile
6
0
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Age (hr)
Figure 13-6. Nomogram for transcutaneous bilirubin measurements in healthy newborns according to gestational age.
(From Maisels MJ, Kring E: Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of
35 or more weeks’ of gestation, Pediatrics 117:1169, 2006.)
Causes of Indirect Discharge Diagnosis in 306

Box 13-1. Hyperbilirubinemia in Newborn Table 13-1. Infants Admitted with Severe
Infants Hyperbilirubinemia*
Increased bilirubin production Diagnosis Number Percentage
or load on the liver
Hyperbilirubinemia 290 94.8
Hemolytic disease of unknown cause or
Immune mediated breast milk jaundice
• Rh alloimmunization Cephalhematoma or 3 1.0
• ABO and other blood group incompat- bruising
ABO hemolytic 11 3.6
ibilities
disease†
Heritable Anti-E hemolytic 1 0.3
Red cell membrane defects disease
• Spherocytosis,* elliptocytosis, stomato- Galactosemia 1 0.3
cytosis, pyknocytosis Sepsis 0
Red cell enzyme deficiencies From Maisels MJ, Kring E: Risk of sepsis in newborns with
• Glucose-6-phosphate dehydrogenase severe hyperbilirubinemia, Pediatrics 90:741, 1992.
deficiency,* pyruvate kinase defi- *Infants were readmitted after discharge as newborns. Mean
age at admission was 5 days (range: 2-17 days), and mean
ciency, and other erythrocyte enzyme bilirubin level was 18.5 ± 2.8 mg/dL (range: 12.7-29.1 mg/dL).
deficiencies †Mother was type O, infant was type A or B, direct Coombs
Hemoglobinopathies test result was positive.

α-thalassemia, γβ-thalassemia
Unstable hemoglobins
Heinz body hemolytic anemia that are crossing percentiles indicate the need
for additional observation and evaluation.
Other causes of increased production
Sepsis*† LABORATORY EVALUATION—SEEKING
Disseminated intravascular coagulation A CAUSE FOR JAUNDICE
Extravasation of blood; hematoma; pulmonary,
In the NICU, many neonates are jaundiced
cerebral, or other occult hemorrhage
simply because they were born prematurely
Polycythemia
and have extremely limited UGT1A1 activ-
Macrosomic infants of diabetic mothers
ity (0.1% of adult levels at 30 weeks’ gesta-
Increased enterohepatic circulation tion). Even among term and late preterm
of bilirubin infants who are readmitted to the hospital
Breast milk jaundice in the first 2 weeks of life with TSB levels of
Pyloric stenosis 18 to 20 mg/dL (308 to 340 µmol/L), only
Small or large bowel obstruction or ileus about 5% have an identifiable pathologic
Decreased clearance cause for jaundice (Table 13-1).28
Prematurity The guideline of the American Academy
Glucose-6-phosphate dehydrogenase of Pediatrics (AAP) recommends laboratory
deficiency evaluation for the cause of hyperbilirubine-
Metabolic mia in infants of 35 weeks’ gestation or more
Crigler-Najjar syndrome types I and II, Gilbert whose TSB levels exceed the 95th percentile
syndrome or in whom the rate of increase appears to
Tyrosinemia† be crossing percentiles.11 In preterm infants,
Hypermethioninemia† laboratory evaluation is indicated in any
Hypothyroidism infant who meets the criteria for photo-
Hypopituitarism† therapy. Table 13-2 provides an approach to
the clinical and laboratory evaluation of the
Modified from Watchko JF: Indirect hyperbilirubi- jaundiced newborn, and Box 13-1 lists the
nemia in the neonate. In Maisels MJ, Watchko JF, causes of indirect hyperbilirubinemia in the
editors: Neonatal jaundice, London, 2000, Harwood newborn.
Academic Publishers, p 52. The timing of the onset of jaundice is
*Decreased clearance is also part of the pathogenesis important; jaundice that appears within
of indirect hyperbilirubinemia. the first 24 hours or increases rapidly and
†Elevation of direct-reacting bilirubin also occurs.
crosses percentiles is due to excessive bili-
rubin production (hemolysis) until proven
otherwise. Most newborns whose TSB levels
Laboratory Evaluation group O mothers. Because approximately

Table 13-2. 45% of Americans of Western European
of the Jaundiced Infant
descent have type O blood and a similar per-
Indications Assessments centage are type A, A-O incompatibility is
Jaundice in first Measure TcB and/or TSB
the most common form of ABO incompat-
24 hr ibility encountered in the United States.31
Infant meets Perform blood typing and Although about one of every three group
criteria for Coombs test, if not done on A or B infants born to a group O mother
phototherapy* or cord blood. has anti-A or anti-B antibodies attached
TSB rising rapidly Perform complete blood count,
(i.e., crossing reticulocyte count, and smear
to their red cells, only one in five of those
percentiles [see examination. with a positive result on a direct antibody
Fig. 13-5]) Measure direct or conjugated test (DAT) develops a modest to significant
bilirubin. degree of hyperbilirubinemia. In an Israeli
Consider G6PD testing. population of 162 DAT-positive group A
Repeat TSB in 4-24 hr. depend-
ing on infant’s age and TSB or B newborns born to group O mothers,
level. 52% developed a TSB higher than the 95th
TSB concentration Perform investigations as above percentile on the Bhutani nomogram.32
approaching and G6PD testing and albumin Forty-eight percent of O-B babies developed
exchange levels or level. hyperbilirubinemia in the first 24 hours
not responding to
phototherapy
compared with 26% of O-A babies.33 Of 258
Elevated direct Do urinalysis and urine culture; Canadian infants who developed TSB levels
(or conjugated) evaluate for sepsis if indicated of more than 425 µmol/L (24.9 mg/dL), 48
bilirubin level by history and physical exami- (16.7%) had ABO hemolytic disease.34 There
nation. appears to be considerable variation in the
Jaundice present Measure total and direct (or frequency with which ABO hemolytic dis-
at or beyond age conjugated) bilirubin level.
2-3 wk, or sick If direct bilirubin elevated, evalu- ease is responsible for severe hyperbilirubi-
infant ate for causes of cholestasis. nemia (see Table 13-1).
Check results of newborn thy- The diagnosis of ABO hemolytic disease
roid and galactosemia screen, as opposed to ABO incompatibility should
and evaluate infant for signs or
symptoms of hypothyroidism.
generally be reserved for infants who have
a positive DAT finding and clinical jaundice
*Because phototherapy is used at low TSB levels in low- within the first 12 to 24 hours of life (icterus
birth-weight infants (see Table 13-9), these investigations are praecox). Reticulocytosis and the presence of
often unnecessary in low-birth-weight infants who meet the
criteria for phototherapy. microspherocytes on the smear support the
G6PD, Glucose-6-phosphate dehydrogenase; TcB, diagnosis (Box 13-2). Underscoring the impor-
transcutaneous bilirubin; TSB, total serum bilirubin.
tance of a positive DAT result in support of the
diagnosis of ABO hemolytic disease, Herschel
et al concluded that in DAT-negative new-
exceed the 75th percentile on the Bhutani borns of ABO-incompatible mother-infant
nomogram (see Fig. 13-7) have evidence of pairs who have significant hyperbilirubine-
hemolysis.11,29 mia, a cause other than isoimmunization
should be sought.35 On the other hand,
Kaplan and associates36 found that 43% of
PATHOLOGIC JAUNDICE DAT-negative, ABO-incompatible infants
who were homozygous for the variant UGT
HEMOLYTIC DISEASE
promoter associated with Gilbert syndrome
Immune-Mediated Hemolytic Disease had a TSB level of 15 mg/dL (256 µmol/L)
The combination of antepartum and post- or higher compared with none of the ABO-
partum prophylaxis with Rh(D) immu- incompatible DAT-negative infants who
noglobulin has dramatically reduced the were homozygous normal (for the promoter
incidence of erythroblastosis fetalis result- element) (Fig. 13-8). There was no differ-
ing from the Rh9 (D) antigen, and the inci- ence between ABO-incompatible and ABO-
dence of Rh hemolytic disease is currently compatible DAT-negative newborns, as long
estimated to be about 1 in 1000 live births. as the ABO-incompatible neonates did not
Approximately half of affected newborns have Gilbert syndrome. This observation
require little or no treatment.30 confirms that if another icterogenic factor is
ABO hemolytic disease generally occurs present, then ABO-incompatible newborns
in infants of blood group A or B born to are at risk for hyperbilirubinemia even if they
25 430
20 340
95th percentile
Serum bilirubin (µmol/L)

Serum bilirubin (mg/dL)
High risk zone
ne 75th percentile
k zo
15
iate ris 40th percentile
255
r med zon
e
nte e ris
k
High-i diat
rme
-inte
10 Low 170
Low risk zone

5 85
0 0
0 12 24 36 48 60 72 84 96 108 120 132 144
Postnatal age (hr)
Figure 13-7. Risk designation of term and near-term well newborns based on their hour-specific serum bilirubin values.
(Dotted extensions are based on <300 total serum bilirubin values per epoch.) (From American Academy of Pediatrics,
Subcommittee on Hyperbilirubinemia: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of
gestation, Pediatrics 114:4, 2004.)
Incidence of hyperbilirubinemia (%)
Criteria for Diagnosing ABO 50

Box 13-2. Hemolytic Disease as the Cause
ABO incompatible
of Neonatal Hyperbilirubinemia 40 Control
Mother group O, infant group A or B
30
and
Positive result on DAT
20
Jaundice appearing within 12-24 hr
Microspherocytes on blood smear
10
Negative DAT result but homozygous for Gilbert
syndrome mutation 0
Homozygous Heterozygous Homozygous
DAT, Direct antibody test. variant normal
UGT promoter genotype
Figure 13-8. Incidence of hyperbilirubinemia defined
are DAT negative.36 There are other possible as total serum bilirubin level of 15 mg/dL (256 µmol/L) in
explanations for the finding of ABO hemo- ABO-incompatible direct antibody test (DAT)-negative and
lytic disease in the absence of a positive DAT ABO-compatible (control) infants according to the uridine
result. Some cases may reflect the insensitiv- diphosphate glucuronosyltransferase (UGT) promoter
ity of the DAT or may occur in infants who genotype. ABO-incompatible DAT-negative infants who
have a paucity of A and B antigens on their were also homozygous for the variant UGT promoter
red cells or unusually efficient absorption of (Gilbert syndrome) had a significantly higher incidence of
hyperbilirubinemia than did ABO-incompatible DAT-negative
serum antibody by A and B antigen epitopes
infants who were homozygous normal for the UGT promoter.
present in body tissues and fluids. The former subgroup also had a significantly greater incidence
of hyperbilirubinemia than any of the three UGT promoter
Heritable Causes of Hemolysis genotype subgroups in the control (ABO-compatible) infants.
Defects in the red cell membrane include (From Kaplan M, Hammerman C, Renbaum P, et al:
hereditary spherocytosis, elliptocytosis, Gilbert’s syndrome and hyperbilirubinaemia in ABO
stomatocytosis, and infantile pyknocyto- incompatible neonates, Lancet 356:652, 2000.)
sis. Although these conditions can occur in
the newborn period, newborns frequently and, when present, suggest the diagnosis of
exhibit substantial variations in red cell hereditary spherocytosis or ABO hemolytic
size and shape, and it is not always easy to disease. A recent observation suggests that
establish one of these diagnoses. Sphero- a mean corpuscular hemoglobin concentra-
cytes are not usually seen on red cell smears tion of 36 g/dL or more is a useful marker
to identify neonates who might have sphe- homozygous for the variant promoter and
rocytosis.37 Because hereditary spherocyto- have 7 repeats—(TA)7 TAA (7/7) instead of
sis has an autosomal dominant inheritance the more usual 6 repeats—(TA)6 TAA (6/6).
pattern, a family history can often be elic- Heterozygotes have 1 allele each of the wild-
ited. In addition, the presence of severe type and variant promoter (6/7). In Israel,
jaundice in neonates with hereditary sphe- G6PD-deficient infants with TSB levels of
rocytosis is closely related to an interaction 15 mg/dL (257 µmol/L) more, only 10%
with the Gilbert syndrome allele, a phe- were homozygous for the normal UGT1A1
nomenon also observed (as noted earlier) promoter (6/6), whereas 50% were homo-
in infants with glucose-6-phosphate dehy- zygous for the variant Gilbert UGT1A1 pro-
drogenase (G6PD) deficiency.38 moter (7/7). TSB levels ≥15 mg/mL did not
develop in either the neonates with G6PD
Red Cell Enzyme Deficiencies deficiency alone or in those with only the
G6PD deficiency is a problem that affects variant UGT1A1 promoter (7/7).38
hundreds of millions of people around the Pyruvate kinase deficiency is an autoso-
world. Nevertheless, most neonatologists in mal recessive disorder that is less common
the United States do not (but should) think than G6PD deficiency but may present with
about this enzyme deficiency as a likely cause significant jaundice, anemia, and reticulo-
of significant hyperbilirubinemia. Although cytosis. In particular, pyruvate kinase defi-
G6PD deficiency occurs in approximately ciency should be considered in neonates
12% of African American males and 4% of of Amish descent with marked neonatal
African American females,39 severe hyperbil- hyperbilirubinemia.
irubinemia does not develop in most G6PD-
deficient newborns. Nevertheless, extreme Unstable Hemoglobins
hyperbilirubinemia and kernicterus have The term unstable hemoglobins is applied to
been described in G6PD-deficient infants hemoglobins exhibiting reduced solubil-
of African American descent.40 In the ker- ity or higher susceptibility to oxidation of
nicterus registry, G6PD deficiency was the amino acid residues within the individual
cause of the hyperbilirubinemia in 21% of globin chains.43 More than 100 structur-
cases.40 G6PD deficiency is an X-linked dis- ally different unstable hemoglobin mutants
order, and hemolysis can occur following have been documented, and the clinical
exposure to an oxidative challenge. Agents syndrome associated with unstable hemo-
potentially involved include naphthalene (a globin disorders is often called congenital
component of mothballs), dyes, and infec- Heinz body hemolytic anemia. Some of these
tion, but more often than not, no offending infants can manifest severe hemolytic ane-
agent is identified. Interestingly, in some, mia and hyperbilirubinemia.
but not all, G6PD-deficient infants in whom
severe hyperbilirubinemia develops, there OTHER CAUSES OF INCREASED
are no signs of overt hemolysis (anemia and BILIRUBIN PRODUCTION OR LOAD
reticulocytosis),41 and significant hyperbili- ON THE LIVER
rubinemia associated with G6PD deficiency The hemoglobinopathies rarely manifest
is primarily the result of abnormal biliru- themselves as jaundice in the neonatal period,
bin clearance rather than hemolysis. Other although such cases have been described
researchers disagree with this view and sug- occasionally. Cephalhematomas, intracranial
gest that overt signs of hemolysis are not or pulmonary hemorrhage, or any occult
found because the hemolysis is self-limited bleeding may lead to an elevated TSB level
and extravascular, and involves an older from breakdown of the extravascular eryth-
fraction of the red cell population.42 rocytes. In some studies, the presence of
The identification of a molecular marker periventricular-intraventricular hemorrhage
for Gilbert syndrome in the promoter region has been associated with an increase in TSB
of the UGT1A1 gene has demonstrated a levels in very low-birth-weight infants, but
remarkable association between hyper- others have not found this association. Poly-
bilirubinemia, G6PD deficiency, and Gil- cythemia is usually listed as a cause of hyper-
bert syndrome. The most common genetic bilirubinemia, because the catabolism of 1 g
polymorphism encountered in whites with of hemoglobin produces 35 mg of bilirubin.
Gilbert syndrome is an additional TA inser- Nevertheless, mean bilirubin levels and the
tion in the TA TAA box of the UGT1A1 incidence of hyperbilirubinemia are simi-
gene promoter. Affected individuals are lar in polycythemic infants receiving partial
exchange transfusion and in those receiving 9% of the population, and both autosomal
symptomatic treatment. dominant as well as recessive inheritance
Any small or large bowel obstruction, ileus, patterns have been found. The identifica-
or delayed passage of meconium exaggerates tion of the genetic basis for this disorder
the enterohepatic circulation of bilirubin (a variant promoter for the gene encoding
(this is also thought to be the mechanism for UGT1A1) has permitted its identification
hyperbilirubinemia associated with pyloric in the newborn. Newborns who are homo-
stenosis). In any of these conditions, correc- zygous for the A(TA)7TAA polymorphism
tion of the obstruction produces a prompt have somewhat higher TSB levels in the
decline in bilirubin levels. Macrosomic first days of life than do heterozygous or
infants of mothers with insulin-dependent normal infants, although the effect is mod-
diabetes are at an increased risk of hyperbili- est.45 The Gilbert syndrome genotype is also
rubinemia, probably as a result of increased an important contributor to the prolonged
bilirubin production. indirect hyperbilirubinemia found in some
breast-feeding infants. Twenty-seven per-
DECREASED BILIRUBIN CLEARANCE cent of breast-fed infants who had TSB levels
of more than 5.8 mg/dL (100 µmol/L) at age
Inherited Unconjugated 28 days had the Gilbert syndrome genotype,
Hyperbilirubinemia—Inborn Errors and 16 of 17 breast-fed Japanese infants with
of Bilirubin UGT1A1 Activity prolonged jaundice had at least 1 mutation
UGT1A1 accounts for almost all of the of the UGT1A1 gene,46 primarily of the
bilirubin glucuronidation activity in the G7IR type.47 The association of the Gilbert
human liver, and three degrees of inher- genotype with significant jaundice in G6PD-
ited UGT1A1 deficiency are recognized. deficient infants, ABO-incompatible DAT-
Crigler-Najjar syndrome type I is inher- negative infants (see Fig. 13-8), and infants
ited in an autosomal recessive pattern with with hereditary spherocytosis has been dis-
marked genetic heterogeneity, and more cussed earlier.
than 30 different genetic mutations have
been identified. Infants with this condition Other Inborn Errors of Metabolism
have virtually complete absence of bilirubin Jaundiced infants who have vomiting, exces-
UGT1A1 activity, severe jaundice develops sive weight loss, hepatomegaly, and sple-
in the first 2 to 3 days of life, and intensive nomegaly should be suspected of having
phototherapy and, often, exchange transfu- galactosemia. In galactosemia, the hyper-
sions are required.44 Unless these children bilirubinemia during the first week of life
receive a liver transplant, which is curative, is almost exclusively unconjugated, but the
they are committed to lifelong photother- conjugated fraction tends to increase dur-
apy, which becomes less and less effective ing the second week, which probably reflects
as they get older. liver damage. A test of the urine for reduc-
Type II Crigler-Najjar disease, also known ing substances using alkaline copper sul-
as Arias syndrome, has a pattern of inheri- fate reagent tablets (Clinitest, Bayer Corp.,
tance that is usually autosomal recessive, Elkhart, Ind.) helps to make the diagnosis.
but it may also be autosomal dominant. Infants with tyrosinemia and hypermethi-
The disorder is characterized by low but oninemia are jaundiced primarily as a result
detectable activity of bilirubin UGT1A1, of the presence of neonatal liver disease, so
and the hyperbilirubinemia usually shows that indirect hyperbilirubinemia is generally
some response to phenobarbital therapy. accompanied by some evidence of cholesta-
Although jaundice is generally less severe sis. Prolonged indirect hyperbilirubinemia
than in patients with Crigler-Najjar syn- is one of the clinical features of congenital
drome type I, marked hyperbilirubinemia hypothyroidism, a condition that should
develops in some children with Crigler- be identified by routine metabolic screen-
Najjar syndrome type II, and kernicterus ing programs currently used for newborns.
can also occur.44 Other causes of prolonged indirect hyperbili-
At one time the diagnosis of Gilbert syn- rubinemia are listed in Box 13-3.
drome was never made until adolescence,
when it manifests as a mild, benign, chronic Breast Feeding and Jaundice
unconjugated hyperbilirubinemia with no A strong association between breast feeding
evidence of liver disease or overt hemoly- and an increased incidence of neona-
sis. Gilbert syndrome affects approximately tal hyperbilirubinemia has been found in
Causes of Prolonged Indirect Most Likely Causes of Cholestasis

Box 13-3.
Hyperbilirubinemia Box 13-4. in Infants 2 Months of Age or
Younger
Breast milk jaundice
Hemolytic disease Obstructive cholestasis
Hypothyroidism Biliary atresia
Extravascular blood Choledochal cyst
Pyloric stenosis Gallstones or biliary sludge
Crigler-Najjar syndrome Alagille syndrome
Gilbert syndrome genotype in breast-fed infants Inspissated bile
Cystic fibrosis
Congenital hepatic fibrosis/Caroli disease
Hepatocellular cholestasis
most40,48-50 but not all studies.51 The primary Idiopathic neonatal hepatitis
contributors to jaundice associated with Viral infection
breast feeding are a decreased caloric intake • Cytomegalovirus
in the first few days of life and an increased • HIV
enterohepatic circulation.52 Breast-fed infants Bacterial infection
usually receive fewer calories in the first days • Urinary tract infection
after birth than do those fed formula, and • Sepsis
caloric deprivation itself appears to enhance • Syphilis
the enterohepatic circulation of bilirubin. Genetic/metabolic disorders
Increasing the frequency of breast feeding • α1-antitrypsin deficiency
significantly reduces the risk of hyperbili- • Tyrosinemia
rubinemia, which provides further support • Galactosemia
for the important role of caloric depriva- • Hypothyroidism
tion and the enterohepatic circulation in • Progressive familial intrahepatic cho-
the pathogenesis of breast-feeding jaundice. lestasis (PFIC)
The stools of breast-fed infants weigh less, • Cystic fibrosis
and the cumulative wet and dry stool out- • Panhypopituitarism
put of breast-fed infants is lower than that of Toxic/secondary disorders
formula-fed infants.53 • Parenteral nutrition-associated cholestasis
From Moyer V, Freese DK, Whitington PF, et al:

MIXED FORMS OF JAUNDICE
Guideline for the evaluation of cholestatic jaundice
Sepsis in infants: recommendations of the North American
Jaundice is one sign of bacterial sepsis, but Society for Pediatric Gastroenterology, Hepatology
and Nutrition, J Pediatr Gastroenterol Nutr 39:115,
septic infants almost always have other
2004.
signs and symptoms. Unexplained indi-
rect hyperbilirubinemia as the only sign of
sepsis is rare (see Table 13-1), and lumbar
punctures or blood and urine cultures in disorders associated with conjugated (or
jaundiced infants who otherwise appear direct reacting) hyperbilirubinemia. Such
well are not recommended.28 On the other jaundice indicates inadequate bile secretion
hand, those who appear sick or have direct or biliary flow. Although it is frequently
hyperbilirubinemia or other findings in the transient in sick low-birth-weight infants,
physical examination or laboratory evalua- particularly those receiving parenteral
tion that are out of the ordinary should be nutrition, a pathologic cause must always
evaluated for possible sepsis. Other causes of be ruled out. For a detailed discussion of the
mixed forms of jaundice include congenital causes and management of cholestatic jaun-
syphilis, the TORCH (toxoplasmosis, other dice, refer to a review of this subject.54
infections rubella, cytomegalovirus infec- Conditions most likely associated with
tion, herpes simplex) group of intrauterine conjugated hyperbilirubinemia in the neo-
infections, and Coxsackie B virus infection. natal period are listed in Box 13-4. Cho-
lestasis occurs in about 1 in 2500 infants
Cholestatic Jaundice and can be categorized as obstructive or
Cholestasis refers to a reduction in bile flow hepatocellular. Most cases of conjugated
and is the term used to describe a group of hyperbilirubinemia in early infancy are the
Recommended Approach to the Identification and Evaluation of Cholestasis

Table 13-3.
in Infants
Recommendation Level of Evidence
It is recommended that any infant noted to be jaundiced at 2 weeks of age be clinically C
evaluated for cholestasis with measurement of total and direct serum bilirubin. However,
breast-fed infants who can be reliably monitored and who have an otherwise normal history
(no dark urine or light stools) and physical examination may be asked to return at 3 weeks of
age, and if jaundice persists, total and direct serum bilirubin are m easured at that time.
Retest any infant with an acute condition or other explanation for jaundice whose jaundice D
does not resolve with appropriate management of the diagnosed condition.
Ultrasonography is recommended for infants with cholestasis of unknown cause. A
Liver biopsy is recommended for most infants with cholestasis of unknown cause. A
Measurements of γ-glutamyl transpeptidase and lipoprotein X are not routinely recommended C
in the evaluation of cholestasis in young infants.
Scintigraphy and analysis of duodenal aspirate are not routinely recommended but may be A
useful in situations in which other tests are not readily available.
Magnetic resonance cholangiopancreatography and endoscopic retrograde C
cholangiopancreatography (ERCP) are not routinely recommended, although ERCP may be
useful in experienced hands.
From Moyer V, Freese DK, Whitington PF, et al: Guideline for the evaluation of cholestatic jaundice in
infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology
and Nutrition, J Pediatr Gastroenterol Nutr 39:115, 2004.
Level A, Recommendation based on two or more studies that compared the test with a criterion
standard in an independent, blind manner in an unselected population of infants similar to those
addressed in the guideline.
Level B, Recommendation based on a single study that compared the test with a criterion standard in
an independent, blind manner in an unselected population of infants similar to those addressed in the
guideline.
Level C, Recommendation based on lower quality studies or studies for which inadequate information is
provided to assess quality, together with expert opinion and consensus of the committee.
Level D, No studies available; recommendation based on expert opinion and consensus of the
committee.
result of neonatal hepatitis or biliary atre- of most newborns is nearly colorless). This
sia. Neonatal hepatitis is characterized by simple approach ensures timely evaluation
prolonged conjugated hyperbilirubinemia and treatment of infants with extrahepatic
without any obvious evidence of bacterial biliary atresia.
or viral infection or the other causes listed The initial treatment of extrahepatic bili-
in Box 13-4. Extrahepatic biliary atresia ary atresia is a portoenterostomy or Kasai
occurs when there is obliteration of the procedure in which a loop of small intes-
lumen of part of the biliary tract or absence tine is anastomosed to the porta hepa-
of some or all of the extrahepatic biliary sys- tis following excision of the atretic ducts.
tem. Extrahepatic biliary atresia occurs in 1 About one third of patients who undergo
in 10,000 to 19,000 newborn infants, and the Kasai procedure survive for longer than
it is important to make the diagnosis expe- 10 years without liver transplantation.55
ditiously before irreversible sclerosis of the About one third have adequate bile drain-
intrahepatic ducts occurs,54 particularly if age, but complications of cirrhosis develop
the biliary atresia is a component of the bili- and liver transplantation is necessary before
ary atresia splenic malformation syndrome the age of 10 years. The remaining one third
or is the cystic form of biliary atresia (see require earlier liver transplantation because
later discussion). The identification of cho- bile flow is inadequate following portoen-
lestatic jaundice and initiation of the nec- terostomy and progressive fibrosis and cir-
essary diagnostic investigations will occur rhosis develop. Overall survival of these
in a timely fashion if every infant who is children, including those undergoing liver
clinically jaundiced beyond the age of 2 to transplantation, is now about 90% at age
3 weeks undergoes measurement of direct- 4 years.56 Portoenterostomy must be done
reacting bilirubin (Tables 13-2 and 13-3, before there is irreversible sclerosis of the
and Fig. 13-9).54 Earlier laboratory investiga- intrahepatic bile ducts, but the effect of the
tions are mandatory in any jaundiced infant timing of the Kasai procedure on outcome
who has pale stools or dark urine (the urine remains controversial.55,57 Although recent
Jaundiced infant
2 to 8 weeks old
1
Condition
Is the patient acutely ill?
Require urgent care? Question
Yes 2 No
Action
• Manage the acute illness Is there direct
• Consider urinary tract or other infection, hyperbilirubinemia?
4
galactosemia, tyrosinemia, hypopituitarism,
fructosemia, iron storage disease, metabolic
disorders, acute common duct obstruction, Measure serum Normal
hemolysis direct bilirubin
3 5
Abnormal
Cholestatic Indirect
jaundice hyperbilirubinemia
7 6
History Evaluate further

Physical exam (see AAP guideline)
8
Urinalysis
Urine culture
9
Evaluate Yes Findings of

further specific disease?
10 11
No
Yes Is the newborn screen

Refer for further
positive for galactosemia
management
12 or hypothyroidism?
13
No
Does bilirubin normalize No • Consult pediatric GI
by 6 weeks of age? • CBC, platelet count
14
• Total and direct bilirubin, ALT,
Yes AST, alkaline phosphatase,
No glucose
hyperbilirubinemia • Prothrombin time, albumin
16 α1-antitrypsin
• Urine-reducing substances
• Abdominal ultrasound 15
• Pi typing Yes
• Further Low α1-antitrypsin? Choledochal cyst?
management 18 19
17 No No
Consider Yes
• Percutaneous liver biopsy • Duodenal aspirate
• Scintiscan • ERCP
20
Is there evidence of biliary Yes • Consult

obstruction? pediatric
21 surgery
No • Operative
cholangiogram
Medical evaluation 22
• Infection • Genetic disorders
• Metabolic disorders • Other
23
Figure 13-9. Cholestasis clinical practice guideline. Algorithm for a 2- to 8-week-old-infant. AAP, American Academy of
Pediatrics; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; ERCP, endoscopic
retrograde cholangiopancreatography; GI, gastroenterology; Pi, protease inhibitor. (From Moyer V, Freese DK, Whitington
PF, et al: Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition, J Pediatr Gastroenterol Nutr 39:115, 2004.)
data from France suggest that the outcome triangular or tube-shaped echogenic density
following this procedure is best when the just cranial to the portal vein bifurcation
procedure is performed before age 31 days,55 on a transverse or longitudinal ultrasound
data from the United Kingdom show no dif- scan) can distinguish infants with extrahe-
ference in outcome of isolated biliary atresia patic biliary atresia (in whom the triangu-
regardless of whether the Kasai procedure lar cord is present) from those who have
is performed before 40 days or between 41 other causes of cholestasis.58,59 The cord
and 60 days.57 On the other hand, there is represents the fibrous remnant in the porta
a major deleterious effect of delaying sur- hepatis, and when it is seen, the authors
gery in those infants whose biliary atresia recommend prompt laparotomy without
is a component of the biliary atresia splenic further investigation. When it is absent,
malformation syndrome (splenic malfor- hepatic scintigraphy is done.58,59
mation, situs inversus, preduodenal portal
vein, absence of the vena cava) and in those Treatment of Cholestasis
with cystic biliary atresia.57 The treatment of neonatal cholestasis
By far the most common association with involves treating the cause, although some
cholestasis in the NICU is prolonged use of pharmacologic agents have been used in an
intravenous alimentation. When total par- attempt to stimulate bile flow. Phenobarbi-
enteral nutrition (TPN) is used for 2 weeks tal increases the uptake of bilirubin by the
or longer, and particularly when such use liver, induces conjugation, enhances bile
is exclusive of enteral feedings, cholestatic acid synthesis, and increases bile flow. The
jaundice may appear. Cholestasis develops administration of phenobarbital before per-
in as many as 80% of infants who receive formance of hepatic scintigraphy has helped
TPN for longer than 60 days, and 50% of to improve the reliability of this diagnostic
those with birth weights of less than 1000 g test, but the therapeutic use of phenobar-
are affected. The pathogenesis of TPN- bital to improve bile flow and lower serum
associated cholestasis is not clear, but it is bilirubin concentrations in conditions such
thought to be related to a combination of as TPN-associated cholestasis has been dis-
factors, including immaturity of bile secre- appointing.
tion in preterm infants, a decrease in bile The use of ursodeoxycholic acid (UDCA)
flow that occurs with no enteral feeding, appears to offer more promise. UDCA is a
the use of omega-6 poly unsaturated fatty hydrophilic bile acid with a significant cho-
acids, and potential toxicity of both trace leretic effect. It appears to be a relatively safe
elements and amino acids. agent when used in children who do not
The term neonatal hepatitis, which implies have a fixed obstruction to bile flow. It has
an inflammatory or infectious process, is a been used in the treatment of cholestatic
misnomer. The term transient neonatal cho- jaundice in infants with cystic fibrosis, as
lestasis is preferred because the clinical and well as in erythroblastosis fetalis. UDCA may
biopsy findings are the result of a combi- also be of value in the treatment of extreme
nation of factors, including (1) immaturity hyperbilirubinemia in older children with
of bile secretion associated with prematu- Crigler-Najjar syndrome.60 The mechanism
rity; (2) chronic or acute ischemia-hypoxia of action of UDCA is not well understood,
of the liver following intrauterine growth but it may affect the enterohepatic circula-
restriction, acute perinatal distress, or lung tion of endogenous bile salts and increase
disease; (3) liver damage caused by perina- hepatic bile flow.
tal or postnatal sepsis; and (4) decrease in
bile flow resulting from delays in enteral BILIRUBIN TOXICITY
feeding. The presence of bilirubin pigment at
An approach to the evaluation of infants autopsy in the brains of infants who were
with cholestatic jaundice is provided in severely jaundiced was observed more than
Figure 13-9. Imaging findings may permit 100 years ago, and the term kernicterus was
some shortcuts and even avoid the neces- applied to infants who died and demon-
sity for liver biopsy in some cases. Magnetic strated bilirubin staining of the “kern,”
resonance cholangiography provides visual- or nuclear region of the brain. The areas
ization of the extrahepatic bile ducts. Fail- of the brain most commonly affected are
ure to see the bile ducts is highly suggestive the basal ganglia, particularly the subtha-
of biliary atresia. Other studies suggest that lamic nucleus and the globus pallidus (Fig.
identification of the “triangular cord” (a 13-10); the hippocampus; the geniculate
was thought to represent irreversible dam-

age, but with urgent intervention using
phototherapy and exchange transfusion, a
normal outcome is possible in some cases.
The diagnosis of kernicterus can be con-
firmed by magnetic resonance imaging
(MRI).62,63 (see Fig. 13-10). The character-
istic image is a bilateral, symmetric, high-
intensity signal in the globus pallidus seen
on both T1- and T2-weighted images. High
signal intensity may also be found in the
hippocampus and thalamus, with the sub-
thalamic nucleus commonly involved.62
In addition, hyperechogenicity on cranial
ultrasonography has been seen in the basal
ganglia and globus pallidus in term and pre-
term infants who subsequently manifested
signs of kernicterus.62
Although there is no doubt about the
relationship between extremely high bili-
rubin levels and acute bilirubin encepha-
lopathy, it is possible that this outcome is
only the most obvious and extreme mani-
Figure 13-10. Magnetic resonance image for a 21-month- festation of a spectrum of bilirubin toxicity.
old male infant who had erythroblastosis fetalis and At the other end of the spectrum might lie
manifested extreme hyperbilirubinemia and clinical signs more subtle forms of neurodevelopmen-
of kernicterus at age 54 hours. Note the symmetric, tal impairment (NDI) that occur at lower
abnormally high-intensity signal from the area of the globus
bilirubin levels and in the absence of any
pallidus on both sides (arrows). (From Grobler JM, Mercer
MJ: Kernicterus associated with elevated predominantly
obvious clinical findings in the neonatal
direct-reacting bilirubin, S Afr Med J 87:146, 1997.) period.64,65 Nevertheless, prospective stud-
ies of large populations of hyperbilirubin-
emic infants have not found evidence of
body; various brain stem nuclei, including subtle NDI.66
the inferior colliculus, oculomotor, vestibu-
lar, cochlear, and inferior olivary nuclei; KERNICTERUS IN THE TERM AND LATE
and the cerebellum, especially the dentate PRETERM NEWBORN
nucleus and vermis.61 Neuronal necrosis is Kernicterus remains a significant problem
the dominant histopathologic feature after in the developing world and still occurs
7 to 10 days of postnatal life. in the United States, Canada, and Western
The areas of neuronal injury explain Europe.40,67-74 Contrary to the experience in
the clinical sequelae of bilirubin encepha- the 1940s and 1950s, however, these are not
lopathy. In classic kernicterus, markedly infants with Rh hemolytic disease; rather,
jaundiced infants pass through three clini- most are term and late preterm newborns
cal phases. Initially, the infant becomes who are apparently healthy at the time of
lethargic and hypotonic, and sucks poorly. discharge but who subsequently develop
Subsequently, hypertonia, fever, and a extreme hyperbilirubinemia (usually a TSB
high-pitched cry develop. The hypertonia level of >30 mg/dL).40 Such bilirubin levels
is characterized by backward arching of the occur in only about 1 in 10,000 infants, and
neck (retrocollis) and trunk (opisthotonos). the risk of kernicterus at these TSB levels
After about a week, the hypertonia subsides is about 1 in 7, or 14%.75 Some of the fac-
and is replaced by hypotonia. In those who tors that appear to have contributed to this
survive, extrapyramidal disturbances (cho- situation are short hospital stays and inad-
reoathetosis), auditory abnormalities (sen- equate follow-up for newborns; increased
sorineural hearing loss most severe in the incidence of hyperbilirubinemia related to
high frequencies), gaze palsies, and dental an increase in breast feeding; less concern
enamel hypoplasia develop. The presence of by pediatricians about jaundice; and failure
retrocollis and opisthotonos (the acute inter- to interpret bilirubin levels according to the
mediate phase of bilirubin encephalopathy) baby’s age in hours, not days.
Short Hospital Stays for Newborns otherwise healthy neonates without hemo-
There is evidence that early discharge is asso- lytic disease, TSB levels that do not exceed
ciated with an increased risk of significant approximately 25 mg/dL (428 µmol/L) do
hyperbilirubinemia. The AAP recommends not place these infants at risk of NDI. In
that infants discharged at less than 72 hours such infants, there has been no convinc-
be seen within 2 days of discharge unless ing demonstration of any adverse affect of
the risk of hyperbilirubinemia is very low.16 these bilirubin levels on IQ, definite neuro-
A recent commentary provides detailed logic abnormalities, or sensorineural hear-
guidelines for risk assessment and follow-up ing loss.66,84
(see later discussion).16 Figures 13-5 to 13-7 A relationship has been described between
make one thing clear: If newborns leave the neurologic and psychometric abnormalities
hospital before they are 36 hours old, their and the duration of exposure to elevated TSB
peak bilirubin level will occur after they are levels. In a Turkish study, exposure to TSB
discharged. Thus, jaundice is now primarily levels of more than 20 mg/dL (342 µmol/L)
an outpatient problem, and monitoring and for fewer than 6 hours was associated with
surveillance following discharge are essen- a 2.3% incidence of neurologic abnormal-
tial if extreme hyperbilirubinemia is to be ity. The incidence increased to 18.7% if
prevented.16 exposure lasted 6 to 11 hours and to 26%
with 12 or more hours of exposure.85 In the
HEMOLYTIC DISEASE AND OUTCOME large National Institute of Child Health and
Initial observations in the late 1940s and Human Development (NICHD) collabora-
early 1950s showed a strong relationship tive phototherapy trial, a 6-year follow-up
between increasing TSB levels (particularly of 224 control group infants who did not
levels of >20 mg/dL [>342 µmol/L]) and receive phototherapy and who had birth
the risk of kernicterus in infants with Rh weights of less than 2000 g show no associa-
hemolytic disease. Hsia et al reported that tion between IQ and duration of exposure
the incidence of kernicterus in their eryth- to elevated bilirubin levels.86
roblastotic population was 8% for those
with TSB levels of 19 to 24 mg/dL (325 to HYPERBILIRUBINEMIA AND THE
410 µmol/L),77 33% for those with TSB lev- PRETERM INFANT
els of 25 to 29 mg/dL (428 to 496 µmol/L), Compared with term infants, sick very low-
and 73% for those with levels higher than birth-weight infants are at greater risk of
30 mg/dL (513 µmol/L). Subsequent stud- developing kernicterus and autopsy-proven
ies, however, found strikingly different “low bilirubin kernicterus” at TSB levels of 5
outcomes. In a study of 129 infants born to 7 mg/dL. Although pathologic kernicterus
between 1957 and 1958, all of whom in premature newborns is now rare, it has not
had indirect bilirubin levels of more than disappeared completely, and whether or not
20 mg/dL (342 µmol/L), neurodevelopmen- modest elevations of TSB cause brain dam-
tal damage was seen in only 2 of 92 (2%) age in preterm infants is controversial.87 Two
who underwent detailed psychometric, neu- studies of large populations of extremely low-
rologic, and audiologic evaluations at 5 to birth-weight infants suggest an association
6 years of age.78 The presence of hemolysis between NDI and small increases in TSB.2,88
is considered to be a risk factor for bilirubin Higher peak TSB levels were associated with an
encephalopathy, although the reason for increased risk of death, hearing loss, and NDI
this is not clear. Recent studies have shown in extremely low-birth-weight infants (<1000 g
that infants with TSB levels of 25 mg/dL birth weight) born between 1994 and 1997.88
(428 µmol/L) or more and a positive DAT In a randomized controlled trial of aggres-
result are at greater risk for low IQ scores at sive versus conservative phototherapy for
ages 5 to 8 years.66,79 extremely low-birth-weight infants, there
was no difference between treatment groups
OUTCOME IN INFANTS WITHOUT in the primary outcome of death or NDI at
HEMOLYTIC DISEASE 18 to 22 months of corrected age.2 Among
The relationship between hyperbilirubine- survivors, however, aggressive phototherapy
mia and poor developmental outcome in produced a significant decrease in NDI, hear-
full-term and late preterm infants who do ing loss, profound impairment, and athetosis
not have hemolytic disease has been stud- compared with conservative phototherapy
ied extensively.80-83 When analyzed as a (see Table 13-4 for the details of how pho-
whole, the data tend to demonstrate that, in totherapy was used in this study). Mean
Criteria for Initiating Phototherapy and Exchange Transfusions in the National

Table 13-4.
Institute of Child Health and Human Development Neonatal Research Network Trial
BIRTH WEIGHT AGGRESSIVE MANAGEMENT CONSERVATIVE MANAGEMENT
Phototherapy Exchange Phototherapy Exchange

Begins Transfusion Begins Transfusion
mg/dL µmol/L mg/dL µmol/L mg/dL µmol/L

501-750 g ASAP after ≥13.0 ≥222 ≥8.0 ≥137 ≥13.0 ≥257
enrollment
751-1000 g ASAP after ≥15.0 ≥257 ≥10.0 ≥171 ≥15.0 ≥257
enrollment
From Morris BH, Oh W, Tyson JE, et al: Aggressive vs conservative phototherapy for infants with
extremely low birth weight, N Engl J Med 359:1885, 2008.
Enrollment is expected within the period 12-36 hr after birth, preferably between 12 and 24 hr.
TSB levels in infants with hearing loss were is believed to dictate the biological effects of
6.5 ± 1.7 mg/dL versus 5.5 ± 1.5 mg/dL in bilirubin in jaundiced newborns, including
those with no hearing loss (P < .001). Peak its neurotoxicity. Elevations of Bf have been
TSB levels in infants with NDI were 8.6 ± associated with kernicterus in sick preterm
2.3 versus 8.3 ± 2.3 in unimpaired survivors infants. In addition, elevated Bf concentra-
(P = .02). Whether these small differences tions are more closely associated than TSB
in TSB levels or the use of aggressive photo- with transient abnormalities in the brain
therapy was responsible for the outcomes is stem auditory evoked potential in both term
difficult to say. and preterm infants. Although a Bf level of
Sugama et al documented hypotonia and more than 1.0 mg/dL may predict the pres-
choreoathetosis, together with the classi- ence or absence of NDI in preterm neonates
cal MRI findings of kernicterus at follow- with high sensitivity and specificity, there
up, in two preterm infants of 31 and 34 is no agreement about what constitutes
weeks’ gestation.89 Neither of these infants the neurotoxic Bf threshold91; that is, the
was acutely ill in the newborn period, and threshold at which Bf produces changes in
their peak TSB levels were 13.1 mg/dL (224 cellular function culminating in perma-
µmol/L) and 14.7 mg/dL (251 µmol/L). In nent cell injury and cell death. In addition,
a study from the Netherlands, classical MRI clinical laboratory measurement of Bf is not
findings of kernicterus were found in five generally available.
sick preterm infants (25 to 29 weeks’ gesta- The ratio of bilirubin (in milligrams per
tion) with peak TSB levels ranging from 8.7 deciliter) to albumin (in grams per decili-
to 11.9 mg/dL (148 to 204 µmol/L).63 Serum ter) does correlate with measured Bf in new-
albumin levels in these infants were strik- borns and has been used as an approximate
ingly low (1.4 to 2.1 g/dL). surrogate for the measurement of Bf, and
the AAP has endorsed this approach.76 A
Unbound or Free Bilirubin randomized controlled trial in the Nether-
Recognition that a peak TSB level, by itself, lands (the BARTrial) is testing the use of the
is a rather poor predictor of the likelihood bilirubin-to-albumin ratio in conjunction
of NDI or kernicterus raises the question with the TSB to determine when photother-
of whether measurements of unbound or apy and/or exchange transfusion should be
“free” bilirubin (Bf) or the ratio of biliru- used and will evaluate neurodevelopmen-
bin to albumin to predict hyperbilirubine- tal outcomes at 18 to 24 months’ corrected
mia risk should be used.83,90 Bilirubin (B) age.92 It must be recognized, however,
is transported in the plasma as a dianion that albumin-binding capacity varies sig-
bound tightly but reversibly to serum albu- nificantly among newborns, is impaired in
min (A): sick infants, and increases with increasing
gestational age and postnatal age. A recent
B2 − + A ↔ AB2 − study of very low-birth-weight infants at
Most bilirubin in the circulation is bound one NICHD Neonatal Network institution
to albumin, and a relatively small fraction confirmed that bilirubin-binding capacity
remains unbound. The concentration of Bf was lower and unbound bilirubin higher
in unstable neonates than in stable neo- albumin is not affected by changes in serum
nates.93 An increase in unbound bilirubin pH, but a decrease in pH does increase the
was associated with higher rates of death binding of bilirubin to cells in the central
or NDI. TSB levels were also associated with nervous system.
an increased risk of death or NDI but only Drugs can affect bilirubin-albumin bind-
in unstable and not in stable infants.93 ing both singly and in combination. Because
In fact, in stable infants, an increase in of their bilirubin-displacing capabilities,
TSB levels was associated with a decrease drugs that should be avoided in the period
in death or cerebral palsy, a puzzling and immediately after birth, or at least until
currently unexplained finding.93 In the serum bilirubin levels are less than 5 mg/dL
NICHD phototherapy trial involving 224 (85 µmol/L), include ethacrynic acid, azlo-
infants who were born between 1974 and cillin, carbenicillin, cefotetan, ceftriaxone,
1976 with birth weights of less than 2000 g moxalactam, sulfisoxazole, and ticarcillin.
and who were evaluated at age 6 years,
no relation was seen between measures of ENTRY OF BILIRUBIN INTO THE BRAIN
bilirubin-albumin binding and IQ scores Under normal circumstances, there is a con-
at follow-up.94 It will be instructive to see stant influx and efflux of bilirubin in and
how the bilirubin-to-albumin ratio corre- out of the brain, and changes in the brain
lates with neurodevelopmental outcome in stem auditory evoked response can be dem-
the BARTrial.92 onstrated at modest elevations of serum
Crucially important in the measurement bilirubin. These changes reverse as the bili-
of Bf is the bilirubin-albumin binding con- rubin level decreases. Bilirubin also enters
stant k, a term whose numeric value actually the brain when there is a marked increase in
may vary considerably depending on condi- the serum level of unbound bilirubin. Even
tions, including, among other factors, sam- bilirubin bound to albumin can enter the
ple dilution, albumin concentration, and the brain when the blood-brain barrier is dis-
presence of competing compounds.83,90,91 rupted, and in all of these situations, acido-
Moreover, the risk of bilirubin encephalopa- sis increases deposition of bilirubin in brain
thy is likely not simply a function of the Bf cells.
concentration alone or the TSB level but of
a combination of several factors—namely, NEUROTOXICITY OF BILIRUBIN
the total amount of bilirubin available (the It is not known exactly how bilirubin exerts
miscible pool of bilirubin), the tendency of its toxic effects, and no single mecha-
bilirubin to enter the tissue (the Bf concen- nism of bilirubin intoxication has been
tration), and the susceptibility of the cells of demonstrated in all cells. Bilirubin lowers
the central nervous system to be damaged membrane potential, decreases the rate of
by bilirubin.95 The bilirubin-to-albumin tyrosine uptake and dopamine synthesis in
ratio can therefore be used together with, dopaminergic striatal synaptosomes, and
but not in lieu of, the TSB level as an addi- impairs substrate transport, neurotransmit-
tional factor in determining the need for ter synthesis, and mitochondrial functions
exchange transfusion. Clarifying and defin- in neurons.96 Unconjugated bilirubin also
ing clinically germane Bf concentrations, activates glial cells with the release of proin-
bilirubin-to-albumin ratios, exposure con- flammatory cytokines such as tumor necro-
ditions, and exposure durations, as well as sis factor, interleukin-1β, and interleukin-6,
improving, standardizing, and validating Bf which suggests that inflammatory processes
measurements, are important lines of clini- can contribute to the toxic effects of biliru-
cal and translational research. bin on nerve cells.97
In calculating the risks of bilirubin tox-
icity, factors that affect the binding of
bilirubin to albumin should be taken into CLINICAL MANAGEMENT
account. One of these factors is the con- PREVENTION OF SEVERE
centration of free fatty acids that compete HYPERBILIRUBINEMIA IN THE TERM AND
with bilirubin for its binding to albumin, LATE PRETERM NEWBORN
although this does not occur until the molar
ratio of free fatty acids to albumin exceeds Risk Assessment
4:1. Such ratios are generally not achieved Because severe hyperbilirubinemia in the
with doses of up to 3 g/kg of intralipid given term and late preterm newborn now oc
over 24 hours. The binding of bilirubin to curs predominately, but not exclusively,
Risk Factors for Severe and for additional TSB measurements (see
Hyperbilirubinemia to Be Table 13-2).11
Box 13-5. Considered with the Gestational Because the measurement of predis-
Age and the Predischarge TSB charge TSB or TcB combined with assess-
or TcB Level* ment of clinical risk factors currently
provides the best prediction of the risk of
Exclusive breast feeding, particularly if
subsequent hyperbilirubinemia, a predis-
nursing, is not going well and/or weight loss
charge TSB or TcB value should be obtained
is excessive (>8%-10%)
for every infant.16 The TSB can be measured
Isoimmune or other hemolytic disease (e.g.,
on the same sample that is drawn for the
glucose-6-phosphate dehydrogenase defi-
metabolic screen, which saves an additional
ciency, hereditary spherocytosis)
heel stick. The TSB or TcB is plotted on
Previous sibling with jaundice
the nomogram to determine the risk zone
Cephalhematoma or significant bruising
and combined with the previously deter-
East Asian race
mined and relevant clinical risk factors (see
Box 13-5) to assess the risk of subsequent
From Maisels MJ, Bhutani VK, Bogen D, et al:
Hyperbilirubinemia in the newborn infant >35 weeks’
hyperbilirubinemia and to formulate a
gestation: an update with clarifications, Pediatrics plan of management and follow-up (see
124(4):1193, 2009. Fig. 13-11).16 When combined with the risk
*The gestational age and the predischarge TSB or zone, the factors that are most predictive
TcB level are the most important factors that help of hyperbilirubinemia risk are lower ges-
to predict the risk of hyperbilirubinemia. The risk tational age and exclusive breast feeding.
increases with each decreasing week of gestation The lower the gestational age, the greater
from 42 to 35 weeks (see Fig. 13-11). the risk of hyperbilirubinemia.102,103 When
TcB, Transcutaneous bilirubin; TSB, total serum two or more successive TSB or TcB mea-
bilirubin.
surements are obtained, it is helpful to plot
these data on the nomogram to assess the
rate of rise. Hemolysis is likely if the TSB
in infants who have been discharged fol- or TcB is crossing percentiles on the nomo-
lowing birth, a systematic evaluation of the gram, and further testing and follow-up
potential risk of subsequent severe hyper- are needed (see Table 13-2 and Fig. 13-11).
bilirubinemia should be carried out before Note that even with a low predischarge TSB
discharge for all term and late preterm new- or TcB value, the risk of subsequent hyper-
borns. Box 13-5 lists factors that are most bilirubinemia is not zero, so that appropri-
consistently associated with an increase in ate follow-up should always be provided
the risk of severe hyperbilirubinemia and (see Fig. 13-11).102
should be used in conjunction with Figure
13-11 in performing a risk assessment before RESPONSE TO PREDISCHARGE TSB
discharge. MEASUREMENTS AND FOLLOW-UP
AFTER DISCHARGE
Universal Newborn Bilirubin Screening Figure 13-11 provides a guideline for man-
First described by Bhutani et al in 1999,32 agement and follow-up according to pre-
measurement of a predischarge TSB or TcB discharge screening and also provides
level has been shown in different popu- suggestions for evaluation and management
lations to be a good predictor of the risk at the first follow-up visit.16
of an infant’s subsequently developing or
not developing hyperbilirubinemia.98-101 MEASURING BILIRUBIN PRODUCTION
Evidence suggests that combining pre- When heme is catabolized, carbon monox-
discharge measurement of the TSB or TcB ide (CO) is produced in equimolar quantities
with evaluation of clinical risk factors with bilirubin, and measurements of blood
will improve the accuracy of this predic- carboxyhemoglobin levels or end-tidal CO,
tion.102,103 In addition, measurement of corrected for ambient CO (ETCOc), pro-
the TSB or TcB, when interpreted using the vide the only available methods for quan-
hour-specific nomogram (see Fig. 13-7), tifying hemolysis.104 Unfortunately neither
provides a quantitative assessment of the of these techniques is currently available
degree of hyperbilirubinemia and indicates for routine clinical use. Routine measure-
the need (or lack of) for additional testing ment of ETCOc at 30 ± 6 hours of life does
to identify the cause of hyperbilirubinemia not improve the prediction of subsequent
Gestational Age 35-37 6 7 Weeks +

Other Hyperbilirubinemia Risk Factors
Predischarge TcB/TSB
Assign bilirubin risk zonea
High High-Intermediate Low-Intermediate Low
Evaluate for Evaluate for If discharging <72 hr, If discharging <72 hr,
phototherapyb phototherapyb follow up within 2 days follow-up within 2 days
TSB in 4-8 hr TSB/TcB in 4-24 hrc Consider TSB/TcB at
follow-up
Other hyperbilirubinemia risk factors

• Exclusive breast feeding, particularly if nursing is not
going well and/or weight loss is excessive (>8%-10%)
• Isoimmune or other hemolytic disease (e.g., G6PD
deficiency, hereditary spherocytosis)
• Previous sibling with jaundice
• Cephalhematoma or significant bruising
• East Asian race
Gestational Age 35-37 6 7 Weeks and No Other

Hyperbilirubinemia Risk Factors
OR
Gestational Age ≥38 Weeks + Other Hyperbilirubinemia Risk Factors
Evaluate for Evaluate for If discharging <72 hr, If discharging <72 hr,
phototherapyb phototherapy follow-up within 2 days follow-up within 2-3 days
TSB in 4-24 hrc TcB/TSB within 24 hrc

• East Asian race
Figure 13-11. For legend see following page.
Gestational Age ≥38 Weeks + No Other Hyperbilirubinemia Risk Factors
Evaluate for Follow-up within 2 days If discharging <72 hr, If discharging <72 hr, time
phototherapyb Consider TcB/TSB at follow-up within 2-3 days follow up according to age
TSB in 4-24 hrc follow-up at discharge or concerns
other than jaundice (e.g.,
breast feeding)d
• East Asian race
Figure 13-11, cont'd. Algorithm providing recommendations for management and follow-up according to predischarge
bilirubin measurements, gestational age, and other risk factors for subsequent hyperbilirubinemia.
• Provide lactation evaluation and support for all breast-feeding mothers.
• Recommendation for timing of repeat TSB measurement depends on age at measurement and how far the TSB level is
above the 95th percentile (see Fig. 13-7). Higher and earlier initial TSB levels require an earlier repeat TSB measurement.
• Perform standard clinical evaluation at all follow-up visits.
• For evaluation of jaundice see Table 13-3.
aSee Figure 13-7. bSee Figure 13-12. cIn hospital or as outpatient. dFollow-up recommendations can be modified according
to level of risk for hyperbilirubinemia; depending on the circumstances, in infants at low risk later follow-up can be
considered. G6PD, Glucose-6-phosphate dehydrogenase; TcB, transcutaneous bilirubin; TSB, total serum bilirubin. (From
Maisels MJ, Bhutani VK, Bogen D, et al: Hyperbilirubinemia in the newborn infant ≥35 weeks’ gestation: an update
with clarifications, Pediatrics 124[4]:1193, 2009.)
hyperbilirubinemia, but measurements of treatment.105 There is little doubt, how-

ETCOc and carboxyhemoglobin have proven ever, that if significantly jaundiced infants
very useful in research studies, where they were identified and these guidelines were
can identify infants who have increased bili- followed, kernicterus would be extremely
rubin production. rare. Effective use of phototherapy in these
infants is described later (see “Photother-
TREATMENT apy: Effective Use of Phototherapy”).
TERM AND LATE PRETERM NEWBORNS BREAST-FED INFANTS

The AAP guidelines for the use of photo- Of infants who have TSB levels high enough
therapy and exchange transfusion in infants to require phototherapy and who do not
of 35 weeks’ gestation or more are provided have evidence of isoimmunization or other
in Figures 13-12 and 13-13. These guide- obvious hemolytic disease, 80% to 90%
lines have achieved widespread acceptance are fully or partially breast fed.28 Much of
and are used throughout the United States this hyperbilirubinemia is associated with
and in many other countries. Neverthe- inadequate breast feeding, and attention
less, a recent analysis of the phototherapy to increasing the frequency of breast feed-
guidelines suggests that they are not inter- ing during the first few days after birth will
nally consistent and could be modified to decrease TSB levels. Supplemental feedings
decrease the number of infants who need of water or dextrose water should not be
25 428
Total serum bilirubin (mg/dL)

20 342
15 257
µmol/L
10 171
5 85
0 0
Birth 24 hr 48 hr 72 hr 96 hr 5 days 6 days 7 days
Age
Infants at lower risk (≥38 wk and well)

Infants at medium risk (≥38 wk + risk factors or 35-376 7 wk and well)
Infants at higher risk (35-376 7 wk + risk factors)
Figure 13-12. Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation.
• Use total bilirubin level. Do not subtract direct reading or conjugated bilirubin.
• The lines for lower, medium, and higher risk refer to risk of neurotoxicity.
• Risk factors for neurotoxicity are isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase deficiency,
asphyxia, significant lethargy, temperature instability, sepsis, acidosis, and albumin level of less than 3.0 mg/dL (if
measured).
• For well infants of 35 to 376⁄7 weeks’ gestation, one can adjust total serum bilirubin (TSB) levels for intervention around
the medium risk line. It is an option to intervene at lower TSB levels for infants closer to 35 weeks and at higher TSB
levels for those closer to 376⁄7 weeks.
• It is an option to provide conventional phototherapy in hospital or at home at TSB levels of 2 to 3 mg/dL (35 to
50 µmol/L) below those shown, but home phototherapy should not be used for any infant with risk factors.
Note: These guidelines are based on limited evidence and the levels shown are approximations. The guidelines refer to
the use of intensive phototherapy, which should be used when the TSB level exceeds the line indicated for each category.
Infants are designated as “higher risk” because of the potential negative effects of conditions affecting albumin binding of
bilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin.
“Intensive phototherapy” implies irradiance in the blue-green spectrum (wavelengths of approximately 430 to 490 nm) of at
least 30 µW/cm2/nm (measured at the infant’s skin directly below the center of the phototherapy unit) and delivered to as
much of the infant’s surface area as possible. Note that irradiance measured below the center of the light source is much
greater than that measured at the periphery. Measurements should be made with the spectroradiometer specified by the
manufacturer of the phototherapy system.
A TSB level that does not decrease or continues to rise in an infant who is receiving intensive phototherapy strongly
suggests the presence of hemolysis. (From American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia:
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation, Pediatrics 114:297, 2004.)
provided to breast-fed infants, because this died in the NICU. Some of this could be the
does not lower their TSB levels. If supple- result of liberal use of phototherapy. Pho-
mentation is deemed necessary in an infant totherapy has dramatically decreased the
with hyperbilirubinemia, formula should be necessity for exchange transfusion in low-
provided. It is always undesirable to inter- birth-weight infants, so that these proce-
rupt nursing, and when the TSB level in a dures are becoming increasingly rare in the
breast-fed infant reaches a level at which NICU.2,106 In the recent NICHD Neonatal
intervention is being considered, breast Research Network study,2 only 5 of 1974
feeding may be continued while the infant extremely low-birth-weight infants (0.25%)
undergoes treatment with intensive photo- required an exchange transfusion. Table
therapy (see “Phototherapy”). 13-4 provides an approach to the use of pho-
totherapy and exchange transfusion based
LOW-BIRTH-WEIGHT INFANTS on birth weight. There is no solid evidence
Over the last 2 to 3 decades, there has been base for the recommendations provided. The
a remarkable decrease in the incidence of recommended treatment levels are based
kernicterus found at autopsy in infants who on operational thresholds or therapeutic
30 513
Total serum bilirubin (mg/dL)

25 428
µmol/L
20 342
15 257
10 171
Birth 24 hr 48 hr 72 hr 96 hr 5 days 6 days 7 days
Age
Infants at lower risk (≥38 wk and well)

Infants at medium risk (≥38 wk + risk factors or 35-37 6 7 wk and well)
Infants at higher risk (35-376 7 wk + risk factors)
Figure 13-13. Guidelines for exchange transfusion in infants of 35 or more weeks’ gestation.
• The dashed lines for the first 24 hours indicate uncertainty caused by a wide range of clinical circumstances and a range
of responses to phototherapy.
• Immediate exchange transfusion is recommended if the infant shows signs of acute bilirubin encephalopathy (hypertonia,
arching, retrocollis, opisthotonos, fever, high-pitched cry) or if total serum bilirubin level (TSB) is ≥5 mg/dL (85 µmol/L)
above these lines.
• The lines for lower, medium, and higher risk refer to risk of neurotoxicity.
• Risk factors for neurotoxicity are isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase deficiency,
asphyxia, significant lethargy, temperature instability, sepsis, and acidosis.
• Measure serum albumin level and calculate the ratio of bilirubin to albumin (see table).
• Use total bilirubin level. Do not subtract direct reacting or conjugated bilirubin.
• If the infant is well and of 35 to 376⁄7 weeks’ gestation (median risk) one can individualize TSB levels for exchange based
on actual gestational age.
Note: These guidelines are based on limited evidence and the levels shown are approximations. During birth
hospitalization, exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy. For
readmitted infants, if the TSB level is above the exchange level, repeat TSB measurement every 2 to 3 hours and consider
exchange if the TSB remains above the levels indicated after intensive phototherapy for 6 hours.
The following bilirubin-to-albumin ratios can be used together with, but in not in lieu of, the TSB level as an additional factor
in determining the need for exchange transfusion.
Ratio of Bilirubin to Albumin at Which Exchange

Transfusion Should Be Considered
Risk Category TSB (mg/dL)/Alb (g/dL) TSB (µmol/L)/Alb (g/L)

Infants ≥38 ⁄7 wk
0
8.0 137
Infants 350⁄7 -366⁄7 wk and well or ≥380⁄7 wk if higher risk 7.2 123
or isoimmune hemolytic disease or G6PD deficiency
Infants 350⁄7 -376⁄7 wk if higher risk or isoimmune 6.8 116
hemolytic disease or G6PD deficiency
If the TSB is at or approaching the exchange level, send blood for immediate typing and cross matching.
Blood for exchange transfusion is modified whole blood (red cells and plasma) cross-matched against
the mother and compatible with the infant.136 Alb, Albumin; G6PD, glucose-6-phosphate dehydrogenase;
TSB, total serum bilirubin.
(Modified from American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia: Management of hyperbilirubinemia in the
newborn infant 35 or more weeks of gestation, Pediatrics 114:297, 2004.)
normal levels (a level beyond which spe- to 36 hours to receive either aggressive or
cific therapy will likely do more good than conservative phototherapy. The protocol
harm).107 In the NICHD Neonatal Research used in that study is shown in Table 13-4. In
Network, 1974 extremely low-birth-weight infants assigned to the aggressive photother-
infants were randomly assigned at age 12 apy group, the mean TSB levels were lower
Suggested Use of Phototherapy and Exchange Transfusion in Preterm Infants

Table 13-5
Less Than 35 Weeks’ Gestational Age
Phototherapy Exchange Transfusion
Initiate Phototherapy
Gestational Age Total Serum Bilirubin Total Serum Bilirubin
(wk) (mg/dL) (mg/dL)
<28 5-6 11-14
280⁄7-296⁄7 6-8 12-14
300⁄7-316⁄7 8-10 13-16
320⁄7-336⁄7 10-12 15-18
340⁄7-346⁄7 12-14 17-19
From Maisels MJ, Watchko JF, Bhutani VK, et al: An approach to the management of hyperbilirubinemia
in the preterm infant less than 35 weeks of gestation, J Perinatol 2012, in press.
• This table reflects recommendations for operational or therapeutic TSB thresholds—bilirubin levels at, or above which,
treatment is likely to do more good than harm.58 These TSB levels are not based on good evidence and are lower than those
suggested in recent UK11 and Norwegian5 guidelines.
• The wider ranges and overlapping of values in the exchange transfusion column reflect the degree of uncertainty in making
these recommendations.
• Use the lower range of the listed total serum bilirubin (TSB) levels for infants at greater risk for bilirubin toxicity, e.g., lower
gestational age; serum albumin levels <2.5 g/dL; rapidly rising TSB levels, suggesting hemolytic disease; and those who are
clinically unstable.31 When a decision is being made about the initiation of phototherapy or exchange transfusion, infants
are considered to be clinically unstable if they have one or more of the following conditions: blood pH <7.15; blood culture-
positive sepsis in the previous 24 hours; apnea and bradycardia requiring cardiorespiratory resuscitation (bagging and or
intubation) during the previous 24 hours; (d) hypotension requiring pressor treatment during the previous 24 hours; and (e)
mechanical ventilation at the time of blood sampling.31
• Recommendations for exchange transfusion apply to infants who are receiving intensive phototherapy to the maximal sur-
face area but whose TSB levels continue to increase to the levels listed.
• For all infants, an exchange transfusion is recommended if the infant shows signs of acute bilirubin encephalopathy (e.g., hyper-
tonia, arching, retrocollis, opisthotonos, high-pitched cry), although it is recognized that these signs rarely occur in VLBW infants.
• Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin from the total.
• For infants ≤26 weeks’ gestation, it is an option to use phototherapy prophylactically starting soon after birth.
• Use postmenstrual age for phototherapy ( e.g., when a 290⁄7-week infant is 7 days old, use the TSB level for 300⁄7 weeks.
• Discontinue phototherapy when TSB is 1-2 mg/dL below the initiation level for the infant’s postmenstrual age.
• Discontinue TSB measurements when TSB is declining and phototherapy is no longer required.
• Measure the serum albumin level in all infants.
• Measure irradiance at regular intervals with an appropriate spectroradiometer.
• The increased mortality observed in infants ≤1000 g who are receiving phototherapy 17,25,37 suggests that it is prudent to use less
intensive levels of irradiance in these infants. In such infants, phototherapy is almost always prophylactic—it is used to prevent
a further increase in the TSB, and intensive phototherapy with high irradiance levels usually is not needed. In infants ≤1000 g,
it is reasonable to start phototherapy at lower irradiance levels. If the TSB continues to rise, additional phototherapy should be
provided by increasing the surface area exposed (phototherapy above and below the infant, reflecting material around the incu-
bator). If the TSB, nevertheless, continues to rise, the irradiance should be increased by switching to a higher intensity setting on
the device or by bringing the overhead light closer to the infant. Fluorescent and LED light sources can be brought closer to the
infant, but this cannot be done with halogen or tungsten lamps because of the danger of a burn.
than those in the conservative photother- mortality in the infants with birth weights
apy group (4.7 ± 1.1 versus 6.2 ± 1.5 mg/dL). of 501 to 750 g. Although this difference was
There was no difference between the groups not statistically significant, a post hoc Bayes-
in the primary outcome (death or NDI), but ian analysis estimated an 89% probability
in survivors at 18 to 20 months of corrected that aggressive phototherapy increased the
age, aggressive phototherapy was associated rate of deaths in the subgroup. The rea-
with a significant decrease in NDI, profound sons for these findings are not clear, but
impairment (mental or psychomotor devel- these tiny infants have gelatinous, thin skin
opmental index of ≤50 or severe gross motor through which light will penetrate readily,
impairment), severe hearing loss, and ath- reaching more deeply into the subcutaneous
etosis. The authors noted that the reduction tissue. There is some evidence that photo-
in NDI was “attributable almost entirely to therapy can produce oxidative injury to cell
there being fewer infants with profound membranes, and such injury could have a
impairment in the aggressive phototherapy negative effect on these tiny infants.108 The
group.” These results suggest that aggressive investigators planned to use a “target irra-
phototherapy, as used in this trial, signifi- diance level” of 15 to 40 µW/cm2/nm, and
cantly reduced the risk of neurodevelop- the mean irradiance levels achieved were 22
mental handicap in surviving infants. to 25 µW/cm2/nm.2 Because phototherapy
On the other hand, in the aggressive pho- in this study, and in almost all infants of
totherapy group, there was a 5% increase in this birth weight, is used in a prophylactic
mode (with the goal of preventing fur- the development of bilirubin encepha-
ther elevation of the TSB level), it is quite lopathy than are nonhemolyzing infants
likely that lower irradiance levels could be with similar bilirubin levels, although
equally effective and perhaps less harmful. the reasons for this are not clear. In Rh
In view of the observed increase in mortal- hemolytic disease, phototherapy should
ity it seems prudent, at least in infants with be used early, as soon as there is evidence
birth weights of less than 750 g, to initiate of a rapidly increasing bilirubin level. The
phototherapy at lower irradiance levels and AAP guidelines (Figs. 13-12 and 13-13)
to increase these levels, or to increase the provide for earlier institution of photo-
surface area of the infant exposed to phototherapy and exchange transfusion in the
therapy, only if the TSB level continues to presence of isoimmunization.11 Recent
rise. studies have confirmed the wisdom of this
Should all NICUs adopt prophylactic approach.66,79 In infants with TSB concen-
phototherapy from birth for extremely low- trations of less than 25 mg/dL, the presence
birth-weight infants? This question cannot of isoimmunization (a positive DAT result)
be answered with confidence, but in many significantly increases the risk of a low IQ
units, phototherapy is initiated in infants score. The use of intravenous γ-globulin
of less than 1000 g when the TSB level (IVIG) has been shown to reduce the need
reaches 5 mg/dL. Because the TSB level at for exchange transfusions in both Rh and
the start of phototherapy in the aggressive ABO hemolytic disease,112 although a
group in the NICHD study was 4.8 mg/dL, recent randomized controlled trial involv-
it is likely that this approach will achieve ing several affected infants with Rh dis-
similar outcomes. ease did not show any benefit from IVIG
administration, and a Cochrane review
INFANTS WITH ELEVATED DIRECT- concluded that the routine use of IVIG
REACTING OR CONJUGATED BILIRUBIN cannot currently be recommended.113,114
LEVELS Tin-mesoporphyrin will decrease TSB lev-
There are no good data to guide the clinician els in infants with Coombs-positive ABO
in dealing with the occasional infant who incompatibility and in G6PD deficiency
has a high TSB level as well as a significant (see “Pharmacologic Treatment”).115
elevation in direct-reacting bilirubin. Kernic-
terus has been described in infants with TSB INFANTS WITH HYDROPS FETALIS
levels of more than 20 mg/dL (340 µmol/L) The pathogenesis of hydrops fetalis is not
but in whom, because of significant eleva- fully understood. In the fetal sheep model,
tions in direct bilirubin levels, the indirect acute severe anemia leads to hydrops asso-
bilirubin levels were well below 20 mg/dL ciated with increased venous pressure and
(340 µmol/L).109,110 Elevated direct bilirubin placental edema, whereas the same degree
levels may decrease the infant’s albumin- of anemia produced over a longer period
binding capacity. The magnetic resonance does not. Thus, high-output failure result-
image shown in Figure 13-10 was obtained ing from anemia is probably not the pri-
from an infant with Rh erythroblastosis feta- mary mechanism for hydrops. Profound
lis in whom a TSB level of 45.2 mg/dL (773 extramedullary hematopoiesis occurs in
µmol/L) developed, of which 31.6 mg/dL the fetus with erythroblastosis fetalis, and
(514 µmol) was direct reacting.110 It is com- this leads to both portal hypertension and
monly recommended that the direct biliru- disruption of normal liver function. It is
bin concentration not be subtracted from likely that these are the primary mecha-
the total bilirubin level unless it exceeds nisms responsible for the development
50% of the TSB concentration.11 This seems of hydrops in isoimmune hemolytic dis-
reasonable but would not have benefitted ease. Infants with hydrops are commonly
the aforementioned infant with Rh eryth- hypoxic and severely anemic, and they
roblastosis.110 It has been suggested, but not demand immediate treatment. Exchange
confirmed, that infants with bronze baby transfusion of 50 mL/kg of packed cells
syndrome are at an increased risk of devel- soon after birth increases the hematocrit
oping bilirubin encephalopathy.111 to about 40%. Phlebotomy should not
be performed routinely on these infants
INFANTS WITH HEMOLYTIC DISEASE because they are usually normovolemic
Infants with hemolytic disease are gener- and may even be hypovolemic, and their
ally considered to be at a greater risk for blood volume should not be manipulated
without appropriate measurements of cen- ultraviolet (UV) radiation, and UV light

tral venous and arterial blood pressures. is never used for phototherapy. A small
To measure central venous pressure accu- amount of UV light is emitted by fluores-
rately, the umbilical venous catheter must cent tubes, but this UV light is of longer
enter the inferior vena cava via the ductus wavelengths (>320 nm) than those that
venosus. If the catheter is in a portal vein cause erythema, and in any case, almost all
or the umbilical vein, the pressures so mea- UV light produced is absorbed by the glass
sured are meaningless and preclude inter- wall of the fluorescent tube and by the
pretation of the infant’s circulatory status. Plexiglas cover of the phototherapy unit.
In addition, before therapeutic decisions Light-emitting diodes do not emit UV light.
are made based on measurements of cen-
tral venous pressure, acidosis, hypercar- IRRADIANCE
bia, hypoxia, and anemia (all of which can There is a direct relationship between the
affect the measured central venous pres- efficacy of phototherapy and the irradiance
sure) must be corrected. Serum glucose lev- used (Fig. 13-14), and irradiance is inversely
els must be monitored carefully, because related to the distance between the light
hypoglycemia is common. source and the infant (Fig. 13-15). The
irradiance in a certain wavelength band is
PHOTOTHERAPY called the spectral irradiance and is expressed
Phototherapy works in much the same as µW/cm2/nm (see Table 13-6). As shown
way as do drugs: the absorption of photons in Figure 13-15, there is a strong inverse
of light by bilirubin molecules in the skin relationship between the light intensity
produces a therapeutic effect similar to the (measured as spectral irradiance) and the dis-
binding of drug molecules to a receptor. tance from the light source. Thus, the closer
Whereas drug doses are conveniently mea- the phototherapy lamp is to the infant, the
sured in units of weight, photon doses are more effective it is. Note that halogen or
more difficult to measure and are expressed tungsten lamps cannot be put close to the
in less familiar terms. Table 13-6 defines the infant because of the risk of burn.
radiometric quantities used in assessing the
dose of phototherapy, and Table 13-7 lists SPECTRAL POWER
the major factors that influence the dose, The spectral power is the product of the
and therefore the efficacy, of phototherapy. skin surface irradiance and the spectral irra-
diance across this surface area. Calculations
LIGHT SPECTRUM of spectral power permit comparisons of the
Bilirubin absorbs light most strongly in the dose of phototherapy received by infants
blue region of the spectrum near 460 nm, using different phototherapy systems.
and the penetration of tissue by light
increases markedly with increasing wave- MECHANISM OF ACTION
length.116 The optical properties of bilirubin The conversion of bilirubin to photoisomers
and skin determine the light wavelengths during phototherapy probably does not take
that most effectively lower bilirubin level; place in skin cells but most likely takes place
these are wavelengths that are predomi- in bilirubin bound to albumin in the blood
nately in the blue-green spectrum.116 Note vessels or in the interstitial space. Although
that none of the light systems used in pho- it is not known exactly where phototherapy
totherapy emit any significant amount of takes place, a biological response to light
Table 13-6. Radiometric Quantities Used
Quantity Dimensions Usual Units of Measure

Irradiance (radiant power incident on a surface per W/m2 W/cm2
unit area of the surface)
Spectral irradiance (irradiance in a certain wavelength W/m2/nm µW/cm2/nm
band) (or W/m2)
Spectral power (average spectral irradiance across a W/m mW/nm
surface area)
From Maisels MJ: Why use homeopathic doses of phototherapy? Pediatrics 98:283–287. Copyright 1996
by the American Academy of Pediatrics.
Table 13-7. Factors That Affect the Dose and Efficacy of Phototherapy
Technical
Factor erminology
T Rationale Clinical Application
Type of light Spectrum of light Blue-green spectrum is Use special blue fluorescent tubes or
source (nanometers) most effective at lowering light-emitting diodes or another light source
total serum bilirubin (TSB); with output in blue-green spectrum for
light at this wavelength intensive PT.
penetrates skin well and
is absorbed strongly by
bilirubin.
Distance of light Spectral irradiance ↑ Irradiance leads to ↑ rate If special blue fluorescent tubes are used,
source from (a function of both of decline in TSB. Standard bring tubes as close as possible to infant
patient distance and light PT units deliver 8-10 µW/ to increase irradiance. (Do not do this with
source) delivered to cm2/nm; intensive PT halogen lamps because of danger of burn.)
surface of infant delivers ≥30 µW/cm2/nm. Positioning special blue tubes 10-15 cm
above infant will produce an irradiance of at
least 35 µW/cm2/nm.
Surface area Spectral power (a ↑ Surface area exposed For intensive PT, expose maximum surface
exposed function of spectral leads to ↑ rate of decline area of infant to PT. Place lights above and
irradiance and in TSB. below* or around† the infant. For maximum
surface area) exposure, line sides of bassinet, warmer bed,
or incubator with aluminum foil.
Cause of PT is likely to be less When hemolysis is present, start PT at a
jaundice effective if jaundice is lower TSB level and use intensive PT. Failure
caused by hemolysis or if of PT suggests that hemolysis is the cause of
cholestasis is present (direct the jaundice. When direct bilirubin is elevated,
bilirubin is increased). watch for bronze baby syndrome or blistering.
TSB level at The higher the TSB, the Use intensive PT for higher TSB levels.
start of PT more rapid the decline in Anticipate a more rapid decrease in TSB
TSB with PT. when TSB >20 mg/dL.
From Maisels MJ, Watchko JF: Treatment of hyperbilirubinemia. In Buonocore G, Bracci R, Weindling M:
Neonatology: a practical approach to neonatal diseases, Milan, 2009, Springer-Verlag.
*Commercially available sources for light below include special blue fluorescent tubes available in
the Olympic Bili-Bassinet (Natus Medical, San Carlos, Calif.), BiliSoft fiberoptic LED mattress (GE
Healthcare, Wauwatosa, Wisc.), NeoBLUE Cozy mattress (Natus Medical).
†The Mediprema Cradle 360 (Mediprema, Tours Cedex, France) provides 360-degree exposure to special
blue fluorescent light.

PT, Phototherapy.
can occur only if the light is absorbed by a

photoreceptor molecule.
Percent decrease of serum bilirubin
60 Phototherapy detoxifies bilirubin by con-

55
50 verting it to photoproducts that are more
45 lipophilic than bilirubin and can bypass
40 the conjugating system of the liver and be
in first 24 hr
35 excreted without further metabolism.116

30
25 Absorption of light by dermal and subcu-
20 taneous bilirubin induces a fraction of the
15 pigment to undergo several photochemical
10
5 reactions that occur at very different rates.
0 These reactions generate yellow stereoiso-
0 5 10 15 20 25 30 35 40 45 50 mers of bilirubin and colorless derivatives of
Average spectral irradiance 425-475 nm (µW/cm2/nm)
lower molecular weight.
Figure 13-14. Relationship between average spectral
irradiance and decrease in serum bilirubin concentration. BILIRUBIN PHOTOCHEMISTRY
Full-term infants with nonhemolytic hyperbilirubinemia
During phototherapy, bilirubin absorbs
were exposed to special blue light (Phillips TL52/20W) of
different intensities. Spectral irradiance was measured as
light, and photochemical reactions occur.116
the average of readings at the head, trunk, and knees. The relative contributions of the various reac-
(From Maisels MJ: Why use homeopathic doses of tions to the overall elimination of bilirubin
phototherapy? Pediatrics 98:283, 1996. Copyright 1996 are unknown, although in vitro and in vivo
by the American Academy of Pediatrics.) studies suggest that photoisomerization is
DOSE-RESPONSE RELATIONSHIP
70
Figure 13-14 shows that there is a clear rela-
at 425-475 nm(µW/cm2/nm)
Average spectral irradiance
60
tionship between the dose of phototherapy
50 and the decline in the TSB level, and Table
40 13-7 lists the factors that determine the
dose. The initial TSB level is also an impor-
30
tant factor that influences the rate of decline
20 of serum bilirubin level, with the rate being
10 proportional to the initial bilirubin con-
centration. Because configurational isomers
0
5 10 15
20 25 30 35 40 45 formed during light treatment revert to nat-
Distance (cm) ural unconjugated bilirubin in the intestine
Figure 13-15. Effect of light source and distance from the after hepatic excretion, reabsorption of nat-
light source to the infant on average spectral irradiance. ural bilirubin occurs via the enterohepatic
Measurements were made across the 425- to 475-nm circulation and contributes to the bilirubin
band using a commercial radiometer (Olympic Bilimeter load to be cleared by the liver. Both of these
Mark II). The phototherapy unit was fitted with eight 24-inch phenomena account for the fact that light
fluorescent tubes. ▪, Special blue, General Electric 20-W treatment is most effective during the first
F20T12/BB tube; ◆, blue, General Electric 20-W F20T12/B
24 hours of therapy, after which the efficacy
blue tube; ▲, daylight blue, four General Electric 20-W
F20T12/D blue tubes and four Sylvania 20-W F20T12/D
decreases.
daylight tubes; •, daylight, Sylvania 20-W F20T12/D
daylight tube. Curves were plotted using linear curve fitting TYPES OF LIGHT
(True Epistat, Epistat Services, Richardson, Tex.). The best
fit is described by the equation y = AeBX. (From Maisels Fluorescent Tubes
MJ: Why use homeopathic doses of phototherapy? Daylight, white, and blue fluorescent tubes
Pediatrics 98:283, 1996. Copyright 1996 by the are widely used fluorescent light sources,
American Academy of Pediatrics.) but they are less effective than special
blue fluorescent tubes, which provide sig-
nificantly more irradiance in the blue spec-
trum (see Fig. 13-15). Special blue tubes
more important than photodegradation. are labeled F20T12/BB (General Electric,
Bilirubin elimination depends on the rates Westinghouse) or TL52/20W (Phillips).
of formation as well as the rates of clearance These are different from regular blue tubes
of the photoproducts. Photoisomerization (F20T12/B), which provide only slightly
occurs rapidly during phototherapy, and more irradiance than daylight or white
isomers appear in the blood long before the tubes (see Fig. 13-15). Compact special blue
level of plasma bilirubin begins to decline. fluorescent bulbs (Osram 18W) are also
The radiometric quantities used and the effective and are cheaper than standard flu-
important factors that influence the dose orescent bulbs.117 Systems have been devel-
and efficacy of phototherapy are listed in oped that provide special blue fluorescent
Table 13-7. light above and below the infant as well as
a 360-degree configuration (see footnote to
CLINICAL USE AND EFFICACY Table 13-7).
Phototherapy is an effective mechanism
for the prevention and treatment of hyper- Halogen Lamps
bilirubinemia and dramatically reduces the High-pressure mercury vapor halide lamps
need for exchange transfusion. There are provide reasonably good output in the blue
more than 50 published controlled trials range and have the advantage of being much
confirming the efficacy of phototherapy.48 more compact than lamps containing stan-
Some idea of the magnitude of the effect of dard fluorescent tubes. An important disad-
phototherapy can be gauged from the fol- vantage, however, is that, unlike fluorescent
lowing: when phototherapy was not used, lamps, they cannot be brought close to the
36% of infants with birth weights of less infant (to increase the irradiance) without
than 1500 g required an exchange trans- incurring the risk of a burn. Furthermore,
fusion. In the recent NICHD Neonatal the surface area covered by most halogen
Research Network study, 5 of 1974 infants lamps is small, and the spectral power is,
(0.25%) with birth weights of 1000 g or less therefore, less than that produced by a bank
required an exchange transfusion.2 of fluorescent lamps.
Fiberoptic Systems in low-birth-weight infants or infants in the

Fiberoptic phototherapy systems contain a NICU, the special blue fluorescent lights can
tungsten-halogen bulb that delivers light be placed between the radiant warmer and
via a fiberoptic cable to be emitted by the the warmer bed. In either case, the light
sides and ends of the fibers inside a plastic should be no further than 10 to 15 cm from
pad. These systems provide a convenient the infant. At this distance, special blue
way of delivering phototherapy above and fluorescent tubes provide an average spec-
below the infant simultaneously. But the tral irradiance of 40 to 50 µW/cm2/nm (see
original fiberoptic pads covered only a small Fig. 13-15). This configuration does not pro-
surface area, which significantly reduced the duce significant warming of naked full-term
spectral power achieved. New designs that infants, and if slight warming does occur,
combine an LED light source with fiberoptic the lamps can be elevated slightly. Halogen
pads have overcome this problem (see foot- phototherapy lamps cannot be positioned
note to Table 13-7). closer to the infant than recommended by
the manufacturers without incurring the risk
Light-Emitting Diodes of burn.
The use of high-intensity gallium nitride LED lights are also effective for intensive
light-emitting diodes (LEDs) permits higher phototherapy.118 Their only potential dis-
irradiance to be delivered in the spectrum of advantage is that they produce almost no
choice (e.g., blue, blue-green) with minimal heat, so that most naked infants will need
heat generation. to be placed in an incubator or under a radi-
An LED unit is a low-weight, low-voltage, ant warmer.
low-power, portable device that provides The use of fiberoptic or LED-fiberoptic
an effective means of delivering intensive pads has made it easy to increase the surface
phototherapy.118 An LED light source and a area of the infant exposed to phototherapy,
fiberoptic pad have recently been combined and this type of “double phototherapy” is
to create pads that are much larger than the approximately twice as effective as single
original fiberoptic pads and have a high irra- phototherapy in low-birth-weight infants
diance (GE Healthcare, Wauwatosa, Wisc.) and almost 50% better in full-term infants.
(see footnote to Table 13-7). The better response of low-birth-weight
infants is likely the result of the fact that,
EFFECTIVE USE OF PHOTOTHERAPY at similar levels of irradiance, the fiberoptic
pad covers more of a small infant than of
Term and Late Preterm Infants a large one. With the newer LED-fiberoptic
In the NICU, phototherapy is used primarily pads this difference might disappear.
as a prophylactic measure to prevent slowly Using these techniques, a decline of
increasing serum bilirubin concentrations 30% to 40% in TSB concentrations can be
from reaching levels that might require an achieved within 24 hours.119
exchange transfusion. In the days when full-
term infants remained in the hospital for 3 Low-Birth-Weight Infants
to 5 days, phototherapy was also commonly Use of phototherapy in low-birth-weight
used to treat modestly jaundiced infants. infants is described earlier (see “Treatment:
Currently, full-term and late pre-term infants Low-Birth-Weight Infants”).
who need phototherapy are often those who
have left the hospital and are readmitted on MEASUREMENT OF PHOTOTHERAPY
days 4 to 7 for treatment of severe hyperbili- DOSE
rubinemia. Such infants need a therapeutic Because phototherapy is a drug, like all
dose of phototherapy (sometimes termed drugs the dose should be measured to
intensive phototherapy) to diminish the biliru- ensure that a therapeutic level is being
bin level as soon as possible.11 One effective achieved and that excessive levels of irradi-
way of delivering intensive phototherapy ance are not being used when they are not
is to use special blue fluorescent tubes and required. The radiometric quantity most
to bring them as close as possible to the commonly reported in the literature is the
infant (see Fig. 13-15). To do this, a term or spectral irradiance (see Table 13-6). In the
late preterm infant must be in a bassinet, nursery, spectral irradiance can be measured
not an incubator (the top of the incubator by using commercially available spectrora-
prevents the light from being brought suffi- diometers. These instruments take a single
ciently close to the infant). When necessary measurement across a band of wavelengths,
typically 425 to 475 or 400 to 480 nm, and dehydrated. In such infants it makes more
provide a readout in microwatts per square sense to provide both supplemental calo-
centimeter per nanometer. Unfortunately, ries and fluids using a milk-based formula,
there is no standardized method for report- because formula inhibits the enterohepatic
ing phototherapy doses in the clinical litera- circulation of bilirubin and helps to lower
ture, so it is difficult to compare published the bilirubin level.
studies on the efficacy of phototherapy. In
addition, different radiometers and spec- BIOLOGICAL EFFECTS AND
troradiometers produce markedly different COMPLICATIONS
results when measuring irradiance from Even though phototherapy has been used on
the same phototherapy system.108 Thus it millions of infants for more than 30 years,
is important to use the spectroradiometer reports of significant toxicity are exception-
recommended by the manufacturer for use ally rare. Bilirubin is a photosensitizer and,
with a given phototherapy system. in some circumstances, can act as a photo-
The measured irradiance varies widely dynamic agent in the presence of light and
depending on where the measurement is produce damage. In infants with congenital
taken. Irradiance measured below the center erythropoietic porphyria, phototherapy pro-
of the light source is much greater than that duces severe blistering and photosensitivity,
measured at the periphery, but the recom- and congenital porphyria is an absolute con-
mendations issued by the AAP and given in traindication to the use of phototherapy. All
this chapter refer to irradiance levels measured of the affected infants had significant direct
directly below the center of the light source.11 hyperbilirubinemia and elevated plasma
In the past, it was not thought necessary porphyrin levels. Significant accumulation
to measure spectral irradiance on a daily of coproporphyrin has also been described in
basis, but there is no longer any reason why infants with bronze baby syndrome, which
this should not be done. It is recommended occurs exclusively in phototherapy-exposed
that irradiance from all phototherapy units infants who also have cholestasis. In bronze
be measured at least daily and documented baby syndrome, dark grayish brown discol-
in the medical record, as should the type of oration develops in the skin, serum, and
phototherapy system being used and the urine in infants with cholestatic jaundice
surface area of the infant being exposed. who are exposed to phototherapy.121 The
pathogenesis of this syndrome is not fully
Intermittent versus Continuous Therapy understood. If phototherapy is necessary, an
Because light exposure increases bilirubin elevated direct-reacting bilirubin level is not
excretion (compared with darkness), contin- a contraindication to its use, even if bronz-
uous phototherapy should be more efficient ing results.
than intermittent phototherapy. However, Complications associated with the use of
clinical studies comparing these two meth- fiberoptic phototherapy blankets have been
ods have produced conflicting results.120 If reported in extremely premature infants
bilirubin levels are very high, intensive pho- (≤25 weeks’ gestation) who had conditions
totherapy should be administered continu- that might reduce skin integrity, such as
ously until a satisfactory decline in the TSB birth trauma, hypotension, poor perfusion
level has occurred. On the other hand, in of the skin, or bacterial contamination of the
most circumstances, phototherapy does not incubator or bed, and have included exten-
need to be continuous. It should certainly sive erythematous denuded areas of skin
be interrupted during feeding or parental resembling a partial-thickness burn as well
visits, and eye patches must be removed to as purplish red necrotizing lesions.122,123 It is
allow appropriate parent-infant contact. important to note that the skin of extremely
premature infants is remarkably fragile.
HYDRATION Because light can be toxic to the retina,
Because some of the lumirubin produced the eyes of infants receiving phototherapy
during phototherapy is excreted in urine, should be protected with appropriate eye
maintaining adequate hydration and a good patches.
urine output helps to improve the efficacy Conventional phototherapy can pro-
of phototherapy. However, supplementa- duce an acute change in the infant’s ther-
tion (with dextrose water) is not neces- mal environment, leading to an increase in
sary for an infant receiving phototherapy peripheral blood flow and insensible water
unless there is evidence that the infant is loss.124 This issue has not been studied for
LED lights, but because of their relatively performing exchange transfusions as well
low heat output, they should be much less as the technique for and complications
likely to cause insensible water loss. In term of the procedure has been provided else-
infants who are nursing or feeding ade- where.125,126
quately, additional intravenous fluids are As discussed previously, very few ex
usually not required. change transfusions are currently being
Phototherapy decreases the expected done. The prevention of Rh hemolytic
postprandial increase in blood flow velocity disease with Rh immunoglobulin and the
in the superior mesenteric artery and might effective use of phototherapy has led to
also increase cerebral blood flow velocity in a dramatic decline in the number of ex-
preterm infants of 32 weeks’ gestation or change transfusions performed.2 As fewer
less. Phototherapy also increases the likeli- of these procedures are done, it is likely
hood of a patent ductus arteriosus in very that the risks and complications will in-
low-birth-weight infants. crease. A list of potential complications is
In a recent randomized, controlled study provided in Box 13-6. An overall mortality
there was a 5% increase in mortality in rate of 0.3 in 100 procedures has been re-
infants with birth weights of 501 to 750 g in ported, but in term and near-term infants
the “aggressive phototherapy” group2 (see who are relatively well, the risk of death
“Treatment: Low-Birth-Weight Infants” dis- is low.127 Jackson reported a 15-year expe-
cussed earlier). rience of exchange transfusion (1980 to
A 6-year follow-up of children in the 1995) in 106 infants.128 Eighty-one infants
NICHD cooperative phototherapy study were healthy, and there were no deaths in
showed no differences between the photo- these infants, although severe necrotizing
therapy and control groups in any aspect of enterocolitis requiring surgery did develop
growth or developmental outcome.86 in one child. There were 25 sick infants, of
whom 3 (12%) experienced serious com-
EXCHANGE TRANSFUSION plications from the exchange transfusion
Exchange transfusion removes bilirubin- and 2 (8%) died. There were three addi-
laden blood from the circulation and tional deaths that were considered “pos-
replaces it with donor blood (usually packed sibly” to be the result of the exchange
red blood cells reconstituted with plasma). transfusion. Thus, the total number of
In addition to removing bilirubin, when deaths in sick infants, possibly as the re-
used in the treatment of immune-mediated sult of the exchange, was 5 of 25 (20%).
hemolytic disease, it also accomplishes the Adverse events associated with exchange
following goals: transfusions were reviewed at two perina-
• Removal of antibody-coated red blood tal centers in Cleveland, Ohio, between
cells 1992 and 2002.127 Over a 10.5-year period,
• Correction of anemia only 67 infants were identified and had ex-
• Removal of maternal antibody change transfusions for hyperbilirubine-
• Removal of other potential toxic byprod- mia—an average of about three exchange
ucts of the hemolytic process transfusions per year in each institution.
A double-volume exchange transfusion The gestational ages ranged from less than
(approximately 170 mL/kg) removes about 32 weeks (n = 15) to term (n = 22). Adverse
85% of the infant’s red blood cells and events occurred in 74% of the exchanges,
110% of the circulating bilirubin (extra- with thrombocytopenia (44%), hypocalce-
vascular bilirubin enters the blood during mia (20%), and metabolic acidosis (24%)
the exchange), but because at least 50% of being the most common. There were only
the infant’s bilirubin is in the extravascular two serious adverse events, both in infants
compartment, only 25% of the total body who had other preexisting, serious neona-
bilirubin is removed.125 Postexchange bili- tal morbidities. The one infant who died
rubin levels are about 60% of preexchange was a critically ill 25-week gestation infant
levels, and the reequilibration that occurs with a birth weight of 731 g. The investi-
between the vascular and extravascular gators also found that exchange transfu-
bilirubin compartments produces a rapid sions performed using umbilical venous
rebound of serum bilirubin levels (within and arterial catheters were significantly
30 minutes) to 70% to 80% of preexchange more likely to be associated with adverse
levels. A detailed description of the basic events than those done through the um-
indications for, and contraindications to, bilical vein alone or via other routes.127
Potential Complications given to mothers and infants, can lower

Box 13-6. TSB levels in the first week of life. However,
of Exchange Transfusion
because of concerns about long-term toxic-
Cardiovascular ity, it is rarely used.
Arrhythmias
Cardiac arrest DECREASING BILIRUBIN PRODUCTION
Volume overload The metalloporphyrins are inhibitors of
Embolization with air or clots heme oxygenase, the enzyme necessary
Thrombosis for the conversion of heme to biliverdin,
Vasospasm one of the first steps in the formation of
Hematologic bilirubin from hemoglobin. In a series of
Sickling (donor blood) controlled clinical trials, the use of tin-
Thrombocytopenia mesoporphyrin was shown to be effective
Bleeding (overheparinization of donor blood) in reducing TSB levels and the requirement
Graft-versus-host disease for phototherapy in full-term and preterm
Mechanical or thermal injury to donor cells infants as well as in infants with G6PD defi-
Gastrointestinal ciency.130-133 The only side effect seen has
Necrotizing enterocolitis been a transient, non–dose-dependent ery-
thema that disappeared without sequelae
Biochemical in infants who received phototherapy after
Hyperkalemia administration of tin-mesoporphyrin.133 A
Hypernatremia multicenter randomized controlled trial of
Hypocalcemia tin-mesoporphyrin is currently in progress
Hypomagnesemia in the United States.
Acidosis Controlled trials have confirmed that the
Hypoglycemia administration of IVIG to infants with Rh
Infectious and ABO hemolytic disease significantly
Bacteremia reduces the need for exchange transfu-
Virus infection (hepatitis, cytomegalovirus sion.85,112,134 The dosages usually range
infection) from 500 mg/kg given over 2 hours soon
Malaria after birth to 800 mg/kg given daily for 3
Miscellaneous days. The mechanism of action of IVIG is
Hypothermia unknown, but it is possible that it might
Perforation of umbilical vein alter the course of hemolytic disease by
Drug loss blocking Fc receptors and thus inhibiting
Apnea hemolysis. A recent observational study
suggests an association between the use of
From Watchko JF: Exchange transfusion in the man- IVIG in term and late preterm infants with
agement of neonatal hyperbilirubinemia. In Maisels Rh and ABO hemolytic disease and the diag-
MJ, Watchko JF, editors: Neonatal jaundice, London, nosis of necrotizing enterocolitis.135
2000, Harwood Academic Publishers, pp 169–176.
BINDING OF BILIRUBIN TO DETERGENTS
Ursodeoxycholic acid, a bile salt, has been
used to treat cholestatic jaundice and, under
Exchange transfusion also carries the usual some circumstances, could be beneficial in
risk of infection associated with any blood ameliorating indirect hyperbilirubinemia as
transfusion, although this risk is currently well.60 The mechanism for this is not fully
very low. understood, although bile salts might cap-
ture unconjugated bilirubin in the intesti-
PHARMACOLOGIC TREATMENT nal lumen and decrease the enterohepatic
For a recent detailed review of this topic circulation.129
please see Cuperus et al.129
ACCELERATION OF NORMAL METABOLIC

PATHWAYS FOR BILIRUBIN CLEARANCE
Phenobarbital induces conjugation and
excretion and increases bile flow and, when
CASE 1 foil to further optimize the surface area of the infant

A 37 ⁄7-week gestation male infant is born follow-
2 exposed to phototherapy. Typing and cross matching
ing an uncomplicated pregnancy and delivery. He is for blood for exchange transfusion must be performed
breast fed by his mother and appears to be nursing immediately, because the cause of this extreme hy-
adequately. At age 40 hours, a physical examina- perbilirubinemia is unknown, and if a subsequent
tion reveals no jaundice and the TcB concentration is TSB level remains the same or even increases de-
6.7 mg/dL (low-risk zone). He is discharged home at spite appropriate phototherapy, an exchange trans-
the age of 42 hours, and the mother is instructed to fusion should be performed immediately. Because it
bring him back to the pediatrician’s office in 10 days. is essential to know which way the bilirubin level is
On the morning of the sixth day, he is brought to the moving, a repeat TSB level should be obtained within
office because the mother has noticed that he was 2 to 3 hours and certainly no later than 4 hours. In ad-
increasingly jaundiced over the previous 2 days and dition, the baby should be given formula in an attempt
had nursed poorly. He had refused the breast com- to reduce the enterohepatic circulation. Because the
pletely for the past 12 hours, was lethargic, and had rate of decline of the TSB level with phototherapy is
a weight loss of 14% of his birth weight. On closer directly related to the initial TSB level (the higher the
questioning, the mother acknowledges that he had level, the more rapid the decline), a decrease of at
never nursed very well. Upon examination, the infant least 2 to 3 mg/dL (and often more) can be expected
appears extremely jaundiced but is otherwise alert in the first 4 hours. In addition to limiting the entero-
and responsive and had no posturing or arching of hepatic circulation, formula gives needed calories as
hid back. A stat serum bilirubin level is 29.4 mg/dL well as additional fluid. Because the structural isomer
(50 µmol/L) and he is admitted to the hospital. The lumirubin is excreted in the urine, maintaining a good
attending pediatrician asks the resident to start pho- urine output helps to lower the TSB level more rapidly.
totherapy and requests that a repeat bilirubin level
be obtained in 8 hours. The infant is placed under Does this infant have ABO hemolytic
daylight phototherapy lamps that produce an irradi- disease?
ance of 9 µW/cm2/nm in the blue spectrum (420 to It is hard to be sure. He was not at all jaundiced at
480 nm). The resident asks about sending blood for age 40 hours, and although there is A-O incompat-
typing and cross matching for a possible exchange ibility with a positive DAT result, if this were truly ABO
transfusion, and the attending pediatrician responds, hemolytic disease, clinical jaundice should have
“Unless we find evidence of hemolytic disease, this been seen within the first 24 hours and certainly by
sounds like typical breast milk jaundice, and these 36 hours. It is quite likely that this infant has a com-
babies never get into trouble. But let’s get a type and bination of increased bilirubin production from ABO
Coombs anyway.” The resident complies. The baby’s incompatibility together with breast-feeding–associ-
blood type is A Rh-positive with a weakly positive re- ated hyperbilirubinemia related to a low caloric intake
sult on direct Coombs test. The mother’s blood type and exaggeration of the enterohepatic circulation.
is group O Rh-positive. A major error in the care of this infant was schedul-
ing a follow-up visit at age 10 days in a newborn dis-
D o y o u a g re e w i t h t h e a t t e n d i n g charged at age 42 hours. As emphasized earlier, such
pediatrician’s orders? infants should always be seen within 2 days of dis-
There are several problems with the way this baby is charge, particularly if the baby is breast fed and young-
being treated. The attending pediatrician’s assertion er than 38 weeks’ gestation as was the case here.
that these infants “never get into trouble” is not true.
Kernicterus is well described in apparently healthy What other tests should be ordered for this
term (≥37 weeks’ gestation) and late preterm (34 to infant?
366⁄7 weeks’ gestation) breast-fed newborns. A bili In addition to the blood typing and Coombs test, a
rubin level of 29.4 mg/dL (503 µmol/L) is a medical complete blood count with smear, reticulocyte count,
emergency and demands immediate and intensive and G6PD determination should be performed.
phototherapy. Under these circumstances, standard Measurement of serum albumin level would be help-
phototherapy lights are inadequate, and intensive ful. In selected infants with very low serum albumin
phototherapy must be used. A phototherapy source levels and therefore less ability to bind bilirubin, earlier
that delivers light in the 460- to 490-nm blue region exchange transfusion might be considered.
of the spectrum and that can deliver an irradiance of
at least 30 µW/cm2/nm should be used, and lights How could this extreme hyperbilirubinemia
should be placed above and below the infant (see Ta- have been prevented?
ble 13-12 for a list of commercially available sources). Follow-up of this infant within 2 days of discharge
The sides of the bassinet can be lined with aluminum would likely have identified an infant who was be-
coming progressively jaundiced. A TSB level would syndrome). There is a strong association between
have been obtained, the mother would have been prolonged indirect hyperbilirubinemia in breast-fed
counseled to improve breast feeding efforts, and, if infants and the (TA) [UGT1A1*28] dinucleotide vari-
necessary, phototherapy would have followed. ant allele within the A(TA)nTAA repeat element of the
UGT1A1 TATAA box promoter3, which differs from
the more prevalent wild-type A(TA) TAA promoter. In-
dividuals with Gilbert syndrome are homozygous for
CASE 2 the UGT1A1*28 allele.
A healthy full-term female infant is brought to the
pediatrician’s office at age 3 weeks. The baby is be-
ing breast fed, has had an excellent weight gain, and
has perfectly normal examination results except that CASE 3
she is slightly jaundiced.
A 40-week gestation African American female breast-
fed infant, birth weight 3400 g, was discharged
What questions should be asked of the home at 36 hours of age with no evidence of jaun-
mother? dice and a predischarge TcB value of 7.6 mg/dL (low
The most important information needed is the color intermediate risk zone). The mother is a 26-year-old
of the baby’s stool and urine. If the urine is pale yellow O Rh-positive, antibody screen–negative, multipa-
and nearly colorless and the stool is a normal brown- rous woman who breast fed her two previous chil-
ish color, the likelihood of cholestatic jaundice is slim. dren. The infant was seen in the pediatrician’s office
2 days after discharge and during that visit was noted
The mother reports that the baby’s stools to show marked signs of jaundice, including scleral
and urine are normal. What should be icterus. The mother reported that her daughter had
done? fed poorly that morning and has been less active.
For any infant who is jaundiced at 3 weeks of age or A TSB concentration is 24.7 mg/dL. The infant is di-
older a total and direct-bilirubin level must be mea rectly admitted to a local NICU for further evaluation,
sured to rule out cholestatic jaundice and the pos- and intensive phototherapy is started on arrival. The
sibility of extrahepatic biliary atresia. infant’s admission weight is 3200 g and she is noted
to be lethargic but otherwise neurologically intact. On
The TSB level is 8.2 mg/dL and the direct admission, the TSB level is 28.8 mg/dL, and the in-
bilirubin level 0.5 mg/dL. Do you need to fant’s blood type is O Rh-positive and the DAT result
do anything else? is negative. The hemoglobin and hematocrit are 14
Although it is overwhelmingly likely that this baby has g/dL and 42%, respectively; the reticulocyte count
breast milk jaundice, any baby with prolonged indi- is 2%; and red blood cell morphology on smear is
rect hyperbilirubinemia should undergo an evaluation unremarkable.
of thyroid function, because hypothyroidism is one
cause of prolonged indirect hyperbilirubinemia. This What is the most likely explanation for this
can easily be accomplished without further testing infant’s extreme hyperbilirubinemia?
by referring to the hospital chart (or the state labora- Of the major risk factors for subsequent severe hy-
tory results) and confirming that the metabolic screen perbilirubinemia, only breast milk feeding is evident.
was done and that the thyroid function was normal. However, by report the infant had been feeding well
until the morning of admission and the infant’s weight
The mother comes back when the baby is has declined only approximately 6% from birth. The
10 weeks old and the baby is still jaundiced. blood type and DAT result rule out an immune-
The TSB level is 7.5 mg/dL (130 µmol/L) mediated hemolytic process. The TSB level is rising
and the direct bilirubin level is 0.4 mg/dL (7 quickly, and an alternative cause must be sought.
µmol/L). What should the mother be told? The most likely cause of this infant’s extreme hy-
Indirect hyperbilirubinemia up to age 12 weeks is well perbilirubinemia is G6PD deficiency. Although the
within the limits of the breast milk jaundice syndrome; disorder is X-linked and is more prevalent in male in-
reassure the mother that she need not be concerned. fants, homozygous and heterozygous females may
be affected. The prevalence of G6PD deficiency in
Are there additional questions that should African American females is 4.1%. The absence of
be asked of the mother? overt anemia, reticulocytosis, and abnormal red cell
Ask the mother whether there is any history of mild, morphology on smear do not exclude this diagnosis.
unconjugated hyperbilirubinemia in her family (Gilbert
What would you anticipate the The pediatric resident states that the
TSB trajectory to be in response to infant is most likely a homozygous
phototherapy? G6PD-deficient female given the infant’s
Although hyperbilirubinemia in the context of G6PD hyperbilirubinemia course. The attending
deficiency is often responsive to intensive photo- neonatologist is not so sure.
therapy, one cannot be assured of this. The marked The results of the quantitative G6PD enzyme assay is
increase in TSB from 24.7 mg/dL to 28.8 mg/dL in 7.6 IU/g hemoglobin (normal: 7.0 to 20.5 IU/g hemo-
the period between the drawing of the bilirubin sam- globin) and the infant is heterozygous for the G6PD
ple at the office visit and the measurement of TSB A mutation. Female neonates heterozygous for the
on NICU admission suggests active hemolysis, which G6PD mutations represent a unique at-risk group.
may not be responsive to phototherapy alone. Ap- X inactivation results in a subpopulation of G6PD-
propriately, a blood sample is sent to the blood bank deficient red blood cells in every female heterozygote;
on NICU admission for typing and cross matching of that is, each heterozygous female is a mosaic with
blood for a possible double-volume exchange trans- two red blood cell populations including one that is
fusion. Indeed, a repeat TSB measurement 3 hours G6PD deficient. A heterozygous female may be re-
after admission is 31.2 mg/dL despite intensive pho- ported as enzymatically normal yet harbor a sizable
totherapy, and the infant undergoes a double-volume population of G6PD-deficient, potentially hemolyz-
exchange transfusion. A G6PD assay and genotyp- able red blood cells that represent a substantial res-
ing are performed on the first aliquot of the infant’s ervoir of bilirubin. When this pool undergoes acute
blood removed during the double-volume exchange hemolysis, hazardous hyperbilirubinemia can evolve
transfusion. rapidly, as seen in this infant. There is no reliable bio-
chemical assay to detect G6PD heterozygotes; only
After the exchange transfusion, the TSB DNA analysis can provide this information. No appar-
level is 21.2 mg/dL, but the infant is noted ent trigger for hemolysis (e.g., naphthalene in moth-
to have posturing, both retrocollis and balls, sepsis) was identified as is frequently the case.
opisthotonos. What should be done? It should be noted that in the presence of acute
The infant should undergo a second double-volume hemolysis, the G6PD level can be normal, even in
exchange transfusion. The presence of advanced homozygotes, because older red blood cells are de-
clinical signs of acute bilirubin encephalopathy is an stroyed and the remaining younger cells have higher
indication for immediate exchange transfusion irre- levels of G6PD. In such a case, if G6PD deficiency
spective of the TSB level. is suspected, the G6PD level should be measured
Prompt institution of the second double-volume again in 2 to 3 months. In a homozygous G6PD-defi-
exchange transfusion is associated with a further cient infant, the G6PD level will then be low.
decrease in TSB to 16.7 mg/dL and resolution of
bilirubin encephalopathy signs. Magnetic resonance REFERENCES
imaging results and auditory brain stem response be-
fore discharge are both normal.
The reference list for this chapter can be found
online at www.expertconsult.com
14
Infections in the
Neonate
Jill E. Baley and Ethan G. Leonard
EPIDEMIOLOGY, RISK FACTORS, GBS to cause EOS in very low-birth-weight

AND PRESENTATION premature infants.2,3 Although GBS and
The fetus and the newborn are extremely enteric bacilli cause the preponderance of
susceptible to infections. This susceptibility EOS, a third pathogen, Listeria monocyto-
stems from maternal risk factors, obstetrical genes, can cause EOS. Unlike GBS and the
complications, the postnatal environment, gram-negative pathogens, which usually
and the immature host defenses of the new- are acquired through asymptomatic mater-
born. Neonatal sepsis is defined as a systemic nal colonization, L. monocytogenes generally
inflammatory response syndrome second- causes a flulike or gastrointestinal illness
ary to infection. The age of onset of sep- in the mother. This organism is mostly
sis reflects the likely mode of acquisition, acquired from animal products: unpasteur-
microbiologic features, mortality rate, and ized milk, cheese, delicatessen meats, and
presentation of the infection. Meningitis is hot dogs. The importance of this organ-
usually a sequela of sepsis. The incidence of ism will become clear in the discussion of
neonatal sepsis ranges from 1 to 8 cases per empiric antibiotic therapy.
1000 live births, whereas meningitis may Late-onset sepsis is defined as the infec-
occur in 1 of every 6 septic infants.1 Epide- tions that occur beyond the first week of life
miologically, neonatal sepsis is divided into but before 30 days of life. Very late-onset sep-
the following categories: early-onset sepsis, sis occurs beyond 30 days of life. Although
late-onset sepsis, and very late-onset sepsis. obstetrical complications may be identified,
Early-onset sepsis (EOS) is a systemic, these are not typical. Late-onset disease is
multiorgan disease that presents in the first more likely to reflect infection with gram-
week of life and usually on the first day of positive organisms acquired in the nursery:
life. Infection is most often acquired before coagulase-positive staphylococci, Staphy-
delivery. Obstetrical complications contrib- lococcus aureus, and enterococci. Very late-
ute to the development of infection and onset disease includes infections caused by
include rupture of membranes prematurely GBS, gram-negative bacilli, and Streptococcus
(before onset of labor) or a prolonged period pneumoniae.
(>18 hours) before delivery, chorioamnio The high incidence of gram-positive
nitis, maternal fever, maternal urinary tract infection in the hospitalized infant reflects
infection, and infant prematurity or low the combination of usually lower gesta-
birth weight. These infants have a fulminant tional age and low-birth-weight, and the
onset of respiratory symptoms, usually due consequent need for the insertion of cen-
to pneumonia; shock or poor perfusion; and tral venous catheters for supportive care.3
temperature instability. Mortality may be as Although many of these infants will mani-
high as 30% to 50%. The microbiologic fea- fest poor feeding, temperature instability,
tures of EOS reflect maternal genitourinary and lethargy, they are more likely to have
and gastrointestinal colonization. Before localized disease: urinary tract infection,
the adoption of intrapartum antibiotic pro- osteoarthritis, or soft tissue infection. Men-
phylaxis (IAP) against group B Streptococcus ingitis is common. Presentation may be
(GBS), this pathogen caused the overwhelm- slowly progressive or fulminant. Mortality
ing majority of EOS. Today, GBS still causes is lower than with EOS but may still be 20%
most cases of EOS; however, enteric bacilli to 40%.
such as Escherichia coli have become more The widespread use of IAP in the United
prevalent in term infants and are as likely as States has been shown to have decreased
346
CHAPTER 14 Infections in the Neonate 347
the incidence of EOS by 70%, to 0.44 cases as blood, urine, or cerebrospinal fluid (CSF).
per 1000 live births, an incidence equiva- Although many indirect indices of infection
lent to that of late-onset sepsis.4 Of impor- have been identified and studied, includ-
tance is that the improved survival of very ing total white blood cell count, absolute
low-birth-weight infants has put them at neutrophil count, C-reactive protein level,
increased risk of systemic nosocomial infec- procalcitonin level, and levels of a variety of
tion. In a multicenter trial of prophylactic inflammatory cytokines, these tests are non-
intravenous immunoglobulin administra- specific and are not adequately sensitive to
tion involving more than 2400 very low- confirm or exclude systemic infection.
birth-weight infants, 16% of the infants In any infant with suspected EOS cultures
developed sepsis at a median age of 17 days. of blood should be drawn and, if the infant
Compared with the infants who did not is in hemodynamically stable condition, spi-
develop sepsis, these infants not only had nal fluid should be obtained, and the infant
increased morbidity, but their mortality should be started on intravenous antibiot-
rose from 9% to 21% (not always directly ics. The need for lumbar puncture in the
due to sepsis) and their average length of first 24 to 72 hours of life has been a topic
hospital stay increased from 58 to 98 days.5 of some controversy.9 Data suggesting that
The most important risk factors for the lumbar puncture is unnecessary in these
development of neonatal sepsis are low infants comes primarily from retrospective
birth weight and prematurity. Sepsis con- studies of asymptomatic infants. The poor
versely is also the most common cause of correlation between the results of neonatal
death in infants under 1500 g.6 The inci- blood cultures and CSF cultures underscores
dence of sepsis is inversely proportional to the need for lumbar puncture. Several stud-
the gestational age or birth weight of the ies report that bacterial meningitis would be
infant. Other risk factors include immature missed in approximately one third of neo-
immune function, exposure to invasive pro- nates on the basis of blood culture results
cedures, hypoxia, metabolic acidosis, hypo- alone.10,11 Antibiotic regimens should cover
thermia, and low socioeconomic status—all GBS, gram-negative bacilli, and L. monocy-
factors associated with low birth weight and togenes. The most commonly used regimens
prematurity. In a multicenter survey of GBS are ampicillin and cefotaxime or ampicillin
disease carried out by the Centers for Disease and gentamicin. Both regimens are quite
Control and Prevention (CDC), 13.5 cases effective against GBS. Unfortunately, E. coli
per 1000 live births were diagnosed among has increasingly become resistant to ampi-
black infants compared with 4.5 cases cillin. In many institutions, more than half
among 1000 white infants, and EOS was of the E. coli isolates are resistant to ampi-
twice as common among black infants as cillin. A search of the Cochrane database
among white infants.7 Although males have for evidence suggesting that one regimen
a higher incidence of sepsis, once respiratory is superior to another does not yield a con-
distress syndrome is accounted for, they are clusion.12 Regardless of the regimen used,
not at a significantly higher risk of sepsis, ampicillin should be included, because the
contrary to the results of older studies.1,8 cephalosporins have no activity against L.
It is generally felt that sepsis is more com- monocytogenes, and gentamicin monother-
mon among the firstborn of twins. Infants apy would be ineffective.
with galactosemia are more likely to become The data for empirical therapy in late-
infected with gram-negative organisms, in and very late-onset disease are not defini-
particular E. coli. The administration of iron tively in favor of any one regimen.13 Given
for anemia appears to increase risk because the prevalence of staphylococcal species,
iron may be a growth factor for a number many clinicians would include vancomy-
of bacteria. Finally, the widespread use of cin in the empiric treatment of a hospital-
broad-spectrum antibiotics may cause a shift ized neonate with signs of sepsis beyond
in the nursery to a higher prevalence of resis- the seventh day of life. If the infant is being
tant bacteria that are also more invasive. admitted from the community, the regimen
should include coverage for GBS, E. coli, and
EVALUATION AND MANAGEMENT S. pneumoniae. Commonly cited guidelines
OF NEONATAL SEPSIS for the evaluation of febrile children without
Definitive diagnosis of bacterial infection a focus of infection who are between 30 and
is predicated on the recovery of a patho- 60 days of life include obtaining blood and
gen from a normally sterile body site such urine samples for culture and performing a
348 CHAPTER 14 Infections in the Neonate
lumbar puncture before administration of bacteriuria or who had previously delivered

antibiotics. an infant with EOGBS was to receive IAP.
In addition to the administration of IAP,
GROUP B STREPTOCOCCUS INFECTION the guidelines provided for the evaluation
Streptococcus agalactiae, or group B Strepto- of the infant after delivery. These strategies
coccus (GBS), is the most common cause of reduced the incidence to 0.6 cases per 1000
vertically transmitted neonatal sepsis, a sig- live births in 1998.19,20 Ongoing active sur-
nificant cause of maternal bacteriuria and veillance of GBS demonstrated that the
endometritis, and a major cause of serious screening-based approach was superior to the
bacterial infection in infants up to 3 months risk-based approach in preventing EOGBS.21
of age. Nine serotypes of GBS have been iden- In 2002 the CDC published revised guide-
tified on the basis of differing polysaccharide lines that promoted the universal screening
capsules: Ia, Ib, II, and III through VIII. Tradi- of all pregnant women between 35 and 37
tionally, neonatal disease is considered early weeks’ gestation using rectovaginal cultures
onset (EOGBS) if it occurs in the first 7 days and recommended that all women with posi-
of life and late onset if it occurs from 8 days tive culture results receive IAP.19 The guide-
through 3 months of life. Epidemiologically, lines also recommended IAP for mothers who
the serotypes responsible for neonatal disease had any history of GBS bacteriuria during the
shifted significantly in the 1990s. Type Ia, pregnancy, who had suspected amnionitis,
type III, and type V cause 35% to 40%; 25% or who had previously delivered an infant
to 30%; and 15% of cases of EOGBS, repec- with EOGBS. These guidelines also clarified
tively.14-16 Type III still causes the majority of the antibiotic dosages for IAP, alternatives for
late-onset disease and neonatal meningitis.17 mothers with penicillin allergy, and the man-
Antibodies against specific serotypes of GBS agement of an exposed newborn (Fig. 14-1).
are protective but not cross-reactive. As of 2003, the incidence of EOGBS was
Although GBS can cross the placenta, down to 0.3 cases per 1000 live births.22
the primary mode of transmission is after Although effective, the screening-based
rupture of membranes and during passage approach incurs the costs of testing, IAP,
through the birth canal. Approximately 20% and management of the exposed infant.
to 40% of women are colonized in their geni- Although, to date, no studies have shown an
tal tract, but the primary reservoir of GBS is association between penicillin and ampicillin
the lower gastrointestinal tract. High genital IAP and the emergence of antibiotic resistance
inoculum at delivery increases the likelihood in other bacteria, this risk remains a concern.
of transmission and the consequent rate of An immunization-based strategy targeting
EOGBS. Half of infants born to colonized pregnant women has the potential to pre-
women will themselves be colonized with vent EOGBS, late-onset disease, and some
GBS. Before the use of IAP targeted against maternal disease and to be more cost effec-
GBS, the incidence of EOGBS ranged from 1 tive. A multivalent protein conjugate vaccine
to 3 cases per 1000 live births. By definition, has proved effective in a murine model, and
EOGBS presents in the first 6 days of life, and several human trials of individual serotype
close to 90% of cases present within 24 hours conjugate vaccines have shown promise.23-26
of life. The vast majority of these infants For documented GBS infection, penicil-
demonstrate systemic illness by 12 hours. lin is the drug of choice and is the most
In 1986 Boyer and Gotoff published the narrow-spectrum agent. Ampicillin is an
first randomized controlled trial showing acceptable alternative agent. No penicillin
the effectiveness of IAP in reducing neona- resistance has been reported to date. The
tal colonization and EOGBS.18 In 1996 the dosages and intervals depend on the post-
CDC published the first set of guidelines gestational age of the infant. The duration
for the prevention of perinatal GBS disease. of therapy is 10 days for bacteremia without
The guidelines endorsed two approaches a focus, 14 days for uncomplicated menin-
to IAP: (1) women with vaginal or rectal gitis, and up to 4 weeks for septic arthritis,
cultures positive for GBS should receive endocarditis, or ventriculitis.27
IAP; or (2) women with any of the follow-
ing risk factors—delivery before 37 weeks’ COAGULASE-NEGATIVE
gestation, membrane rupture 18 hours or STAPHYLOCOCCUS INFECTION
longer before delivery, or maternal fever of For several decades, coagulase-negative
38° C or higher—should receive IAP. In addi- staphylococci have been the most common
tion, any woman who had a history of GBS cause of nosocomial blood stream infections
Maternal IAP for GBS? Maternal antibiotics for

suspected amnionitis?
Yes
Yes
Signs of neonatal sepsis?
Complete blood cell count
with differential, blood
Yes culture, lumbar puncture, and,
if respiratory symptoms, a
No chest radiograph.
Empiric antibiotic therapy.
Yes
Gestational age <35 wk? Complete blood cell count,
blood culture, and observe
No ≥48 hr if sepsis suspected
Duration of IAP before Yes
delivery <4 hr?
No
No evaluation
No therapy
Observe ≥48 hr*
*A healthy appearing infant >38 weeks’ gestation whose mother received greater than 4
hours of IAP before delivery may be discharged after 24 hours if other discharge criteria
are met and family is able to comply with instructions for home observation.
Figure 14-1. Algorithm for management of neonates exposed to intrapartum antibiotic prophylaxis (IAP). GBS, Group B
Streptococcus.
in the neonatal intensive care unit and are Neonatal infections with coagulase-
responsible for the majority of cases of late- negative staphylococci typically present
onset sepsis in preterm neonates. Infections without localizing signs with fever, new-
with these gram-positive bacteria are most onset respiratory distress, or a deterioration
often associated with indwelling central in respiratory status. Other common non-
venous catheters. These bacteria are part specific signs of coagulase-negative staphy-
of normal human skin flora. Staphylococcus lococcus sepsis include apnea, bradycardia,
epidermidis is the most common species of poikilothermia, poor perfusion, poor feeding,
coagulase-negative staphylococci recovered irritability, and lethargy. Indolent infection
from human skin and mucous membranes. is more common than fulminant disease,
Most infants are colonized within the first with mortality generally under 15%. Coagu-
week of life from passage through the birth lase-negative staphylococci infections, how-
canal and repeated exposure from colonized ever, are a major source of morbidity leading
caregivers. to increased antibiotic exposure, length of
The major virulence factor for coagu- stay, and hospital costs.
lase-negative staphylococci is its ability to Treatment of coagulase-negative staphylo-
adhere to plastic and other foreign bodies cocci often requires the use of vancomycin.
by producing a biofilm. The biofilm consists More than 80% of strains acquired in the hos-
of multiple layers of bacteria surrounded pital are resistant to β-lactam antibiotics.28
by an exopolysaccharide matrix or slime. Resistance is typically attributable to altered
This biofilm protects the bacteria from penicillin-binding proteins and β-lactamase
host phagocytic cells and interferes with production. Unfortunately, these types of
the ability of many antimicrobial agents to resistance can be inducible and therefore may
effectively eliminate infection. This affin- not be detected by routine microdilutional
ity for plastic foreign bodies explains the methods. If a strain is reported as penicil-
high recovery rate of these organisms from lin sensitive, consultation with the hospital
infected catheters, ventricular shunts, endo- microbiologist is recommended to confirm
tracheal tubes, and artificial vascular grafts testing for inducible resistance. More than
and cardiac valves. 50% of coagulase-negative staphylococci
are resistant to clindamycin, trimethoprim- a systematic review of the use of systemic

sulfamethoxazole, gentamicin, and cipro- antibiotics to reduce morbidity and mortal-
floxacin. Coagulase-negative staphylococci ity in neonates with central venous cathe-
isolated from hospitalized patients show ters. Results are not yet available.
varying rates of resistance to the tetracyclines,
chloramphenicol, rifampin, and newer-gen- STAPHYLOCOCCUS AUREUS INFECTION
eration quinolone antibiotics. Some S. epider- Staphylococcus aureus is a gram-positive
midis isolates have been recovered that show bacteria that is morphologically indistin-
resistance to vancomycin; however, these guishable from the coagulase-negative
species have been susceptible to the newer staphylococci by light microscopy. S. aureus
agents for gram-positive organisms: line- is part of normal skin flora. This organism
zolid, quinupristin-dalfopristin, and dapto- causes a much wider and potentially more
mycin.29,30 Pharmacokinetic data and clinical invasive spectrum of disease than that
experience with these agents in neonates are caused by coagulase-negative species. This
limited, and these drugs should be used only pathogen is a common cause of superficial
in consultation with a physician with exper- pustular disease and localized cellulitis, and
tise in infectious diseases. is the most frequent cause of surgical site
The most effective management of coagu- infection in infants and adult patients. The
lase-negative staphylococci infections is the production of numerous toxins, enzymes,
combination of systemic antimicrobial ther- and binding proteins facilitates its ability
apy and, whenever possible, the removal to establish aggressive, life-threatening pyo-
of the foreign body. When a foreign body genic infection. Small-inoculum coloniza-
cannot be feasibly removed, the combination or infection can produce catastrophic,
tion of vancomycin with rifampin, and/or toxin-mediated disease such as scalded skin
an aminoglycoside, may be used. In the case syndrome or toxic shock.
of ventricular shunt infections, antibiotics Over the last two decades, S. aureus has
may be administered both systemically and shown an increasing resistance to β-lactam
intraventricularly. If an attempt is made to antibiotics, as documented by methicillin
manage an infection without foreign body susceptibility testing36; these methicillin-
removal, consultation with an infectious resistant strains (MRSA) are resistant to all
disease expert would be advised to deter- penicillins, penicillin–β-lactamase inhibitor
mine the best antimicrobial agents and combination drugs, cephalosporins, and car-
duration of therapy. bapenems. Most hospital-acquired strains
Although many groups have proposed are resistant to clindamycin. Until recently,
different strategies to prevent neonatal these resistant strains were not inherently
catheter infections, few studies have yielded more virulent. Unfortunately, however,
promising results. Several groups have stud- over the last several years community MRSA
ied the use of prophylactic antibiotics in strains have acquired an additional viru-
neonates with indwelling catheters. The lence factor, Panton-Valentine leukocidin.
Cochrane Neonatal Group found no evi- This factor has contributed to a significant
dence to support this practice for neonates increase in invasive, pyogenic infection by
with umbilical arterial or venous cathe- MRSA. Several outbreaks in preterm and term
ters,31,32 nor did they find evidence to sup- neonates, as well as nosocomial transmis-
port routine use of vancomycin in preterm sion from caregivers, equipment, and toys
infants to prevent nosocomial sepsis.33 The in neonatal intensive care units, have been
use of a vancomycin-heparin lock solu- reported.37-41 In an ill, hospitalized neonate
tion to prevent nosocomial blood stream who develops suspected or documented
infection showed promise in a small ran- infection with gram-positive cocci, vanco-
domized, controlled, double-blinded study mycin should be included in the empiri-
in critically ill neonates with peripherally cal antibiotic regimen. As discussed earlier,
inserted central venous catheters34; how- blood stream infections caused by coagulase-
ever, larger studies are needed. The use of negative species are much more prevalent
antibiotic- or silver-impregnated catheters than bacteremias from S. aureus; however,
has not been studied in neonates. In 2002, many clinicians would elect to start vanco-
the CDC recommended against the rou- mycin for any gram-positive blood stream
tine use of antimicrobial prophylaxis for infection in a hospitalized neonate because
patients with central venous catheters.35 In of the high rate of resistance to β-lactam
2006, the Cochrane Neonatal Group began antibiotics in the coagulase-negative strains
and the potential consequences of not treat- than among term infants and occurs in up
ing MRSA. Other drugs are available with to 25% of these infants in the first week of
activity against MRSA, including older life.48 One fourth of intubated infants dem-
drugs like tetracyclines and trimethoprim- onstrate respiratory colonization.
sulfamethoxazole, but these drugs are typi- A large number of predisposing factors
cally avoided in neonates. Several newer have influenced the rate of dissemination.
drugs—quinupristin-dalfopristin, linezolid, One of the primary factors is the prolonged
and daptomycin—have activity against and frequent use of broad-spectrum antibi-
MRSA. MRSA infections in neonates should otics that suppress the growth of bacteria in
be managed by an individual with expertise the gastrointestinal tract and allow candi-
in the pharmacodynamics and pharmacoki- dal overgrowth. Eventually, penetration of
netics of these drugs. the epithelial barrier leads to disseminated
disease. Mucosal penetration and dissemi-
CANDIDIASIS nation are more likely the denser the colo-
The survival of fragile, very low-birth-weight nization, and C. albicans has been shown
neonates has led to increased infections due to adhere to the mucosa of the preterm
to candidiasis in the nursery. Candida spe- infant better than to that of the term infant.
cies are responsible for 2.4% of early-onset In particular, the use of third-generation
infections in newborns but, more impor- cephalosporins seems to increase the risk
tantly, they cause 10% to 12% of late-onset of gastrointestinal colonization and subse-
infections. Overall, infections with these quent candidemia.46,49 Dense colonization
fungi are among the three most common of the gastrointestinal tract increases the
infections in the neonatal intensive care chances of translocation of the yeast across
unit.6,42,43 the mucosa. Intestinal ischemia, necrotizing
Although Candida albicans once caused enterocolitis, and spontaneous perforation
75% of invasive candidal infections, infec- of the intestine, common in the preterm
tions involving non-albicans species are infant, are all highly associated with can-
now becoming more common, approach- didemia. Delayed enteral feeding has also
ing 40% to 45% of infections. The incidence been associated with infection.49 The use
of Candida parapsilosis infection, unique of histamine 2 blockers raises the pH of the
to the newborn, has risen more than ten- stomach and increases colonization, par-
fold, and this species now causes 25% of ticularly of C. parapsilosis.50 Abdominal and
fungal infections in the newborn. Also of cardiac surgeries are greater risks in term
note, the incidence of Candida tropicalis infants. In a similar fashion, candidal organ-
and Candida glabrata infection has nearly isms readily penetrate the relatively poor
doubled during the same time period.44,45 barrier provided by the immature skin of
The reported mortality attributable to C. the preterm infant, and that skin also read-
albicans infection varies widely but may be ily breaks down during ordinary care. Colo-
as high as 20% to 40%.46,47 The mortality nized infants are more likely to be delivered
from C. parapsilosis is certainly significant vaginally than by cesarian section.48,51 The
but tends to be lower than that attributable use of topical petrolatum for skin care of
to C. albicans. extremely low-birth-weight infants may
Vertical transmission from mother increase the risk. Catheters, as well as all
to infant usually occurs during passage other indwelling tubes (endotracheal, chest,
through the birth canal, especially in the urinary, ventriculoperitoneal), may become
presence of vaginitis. This is most often seen infected. The longer the duration of an
with C. albicans and C. glabrata. Congeni- indwelling catheter, particularly if used for
tal infections may rarely be seen and have total parenteral nutrition or infusion of
been attributed both to ascending infection intravenous lipids, the greater the risk is to
from the vagina and transplacental infec- the infant.50 Immature immune defenses
tion. C. parapsilosis, however, is frequently provide yet another set of risk factors. Neu-
transmitted horizontally and is the most trophils ingest and kill Candida intracellu-
common fungal organism isolated from larly, but neutropenia is also common in
the hands of health care workers. This fun- very low-birth-weight infants. Theophyl-
gus is not commonly found in the geni- line, frequently used in preterm infants,
tourinary tracts of mothers. Colonization may inhibit the candidacidal activity of
appears to occur more readily among very neutrophils. Steroids inhibit the immune
low and extremely low-birth-weight infants response, induce hyperglycemia, and, in the
mouse, increase the adherence of the yeast treatment, averages 7 days. Most infants
to the intestinal mucosa. have several positive blood culture results,
Congenital candidiasis is extremely rare. and 10% experience candidemia for longer
In the term infant, infection results in an than 14 days.49,54 Infants have a multitude
erythematous, macular eruption that then of signs and symptoms including, in order of
becomes pustular and desquamates.52 These frequency, respiratory deterioration, apnea
same skin infections become burnlike in the and bradycardia, hyperglycemia, a necrotiz-
preterm infant and then develop either a ing enterocolitis–like picture without pneu-
branlike or sheetlike desquamation, becom- matosis, skin involvement, temperature
ing superficial erosions. Intrauterine infec- instability, and hypotension.55 Meningitis,
tion is highly associated with the presence once reported in half of infants with sys-
of genital tract foreign bodies, in particular, temic candidiasis, now occurs in only 5%
cerclage, but have not been associated with to 9%,49,56 probably due to more aggressive
maternal diabetes or urinary tract infections. diagnosis and treatment. Roughly half of
The diagnosis in the newborn can be made infants with meningitis will have negative
with skin scrapings and blood and cerebro- blood culture results and half will have nor-
spinal fluid cultures. In the term infant with mal CSF parameters.52,56 Endophthalmitis,
only cutaneous infection, survival is the once seen in half of infants, again is now
rule. These infants do not require treatment, relatively uncommon, occurring in fewer
although many will administer topical ther- than 1%.57,58 Prognosis is excellent if the
apy to relieve symptoms and to decrease the infection is treated. However, fungal sepsis
mass of organisms the infant has to clear. in extremely low-birth-weight infants may
In contrast, in the preterm infant weighing be associated with increased frequency of
less than 1500 g, or in any infant with respi- threshold retinopathy of prematurity.59,60
ratory symptoms signifying aspiration and Endocarditis, which may be the source of
pneumonia, mortality is the rule unless sys- infected thromboemboli, is associated with
temic treatment is begun. the presence of central venous catheters.
Mucocutaneous infection (thrush or a The prognosis for osteoarthritis or osteomy-
monilial diaper rash) is the most likely infec- elitis is also good with treatment. Cutaneous
tion after birth, seen in 4% to 6% of new- manifestations may include a generalized
borns and occurring as early as 4 to 5 days erythema or subcutaneous abscesses. Infants
after birth but peaking at 3 to 4 months. may be neutropenic or have an extreme
Thrush manifests as white, curdlike, pseu- leukocytosis. Continued thrombocytope-
domembranous plaques on the oropharynx nia is often an indication of ongoing dis-
or posterior pharynx, whereas the diaper ease. Pneumonitis presents with respiratory
dermatitis produces an erythematous, scaly deterioration and a bronchopulmonary
lesion with satellite papules or pustules in the dysplasia–like picture on chest radiograph.
intertriginous areas. The latter may be repeti- Other infants may develop abdominal dis-
tively reinfected by a gastrointestinal tract tension, guaiac-positive stools, and feeding
reservoir. Therapy in those areas is local. Oral intolerance but no pneumatosis intestinalis.
nystatin may be given to treat the thrush. A few will have hepatic abscesses, diarrhea,
Gentian violet works as efficaciously, but or perforation. Mortality is extremely high
its propensity to stain makes it less popular. in those with candidal peritonitis. Urinary
For the skin lesions, topical nystatin alone tract involvement is found in over half of
works well, although occasionally it should infants with systemic candidiasis and ranges
be combined with oral nystatin to reduce the from a bladder infection to renal abscesses
gastrointestinal tract reservoir and to prevent or renal papillary necrosis to a mycetoma
spillage onto the groin. Once the rash starts or fungal ball in the renal pelvis, possibly
spreading beyond the usual area in the dia- resulting in a flank mass. Disease of the uri-
per, systemic therapy must begin. nary tract may be entirely silent or present
Invasive candidiasis is a leading cause of with hypertension or acute renal failure with
morbidity and mortality in infants of less oliguria or anuria. Mortality is usually in the
than 1000 g. Incidence in neonatal centers range of 20% to 50%, but death or disabil-
ranges from 2% to 28%.53 Systemic disease ity ensues in as many as 73% of extremely
in these infants, unlike in adults, results in low-birth-weight infants.49 Compared with
multiple foci of infection. Onset is delayed, age-matched controls, there is a higher
usually occurring at several weeks of life, incidence of periventricular leukomalacia,
and the duration of candidemia, even with chronic lung disease, severe retinopathy of
prematurity, and adverse neurologic out- Treatment of maternal candidal infections

come at 2 years corrected age.61 may limit vertical transmission to the neo-
Candidal species grow readily in cul- nate. Prevention of horizontal transmis-
tures of blood or urine or specimens from sion is more difficult. Hand washing does
other normally sterile sites, and yeast or not reduce the recovery of C. albicans from
hyphae can be seen on urinalysis. Given the medical workers’ hands.67 Removal of artifi-
propensity for dissemination, the patient cial fingernails may help. Careful attention
should undergo ultrasonography of the to central lines is of benefit, as is attention
kidneys, echocardiography, and a retinal to limiting exposure to drugs that increase
examination. Fungal stains of skin scrapings the risk of disease. No consensus has been
can be helpful. A complete blood count and reached on the use of fluconazole prophy-
C-reactive protein level may give indirect laxis. Some studies have shown a decrease
evidence of infection. A lumbar puncture, in the incidence of colonization, invasive
together with culture, gram staining and disease, or mortality.68-72 Finally, concern
cytologic analysis, is imperative. Overall, it is remains regarding the risk of isolates devel-
important to have a high index of suspicion. oping resistance. A recent metaanalysis
Immediate consideration should also be of three trials involving over 1600 infants
given to the removal of possibly contami- found a decrease in the risk of invasive
nated medical devices, particularly central fungal infection in very low-birth-weight
intravascular catheters. Amphotericin B has infants with oral-topical antifungal prophy-
been the standard for antifungal therapy laxis but warned about the major method-
for years, but many other agents have been ologic weaknesses in trials to date.73 Also,
introduced, and few data are available to one recent trial comparing fluconazole and
indicate the advantages of one drug over nystatin oral prophylaxis had to be halted
another, let alone safety, efficacy, dosages, early due to a significant increase in deaths
or duration of treatment. CSF penetration of not related to fungal infections among the
amphotericin B, while better than in adults, nystatin-treated infants.74 Reports do exist
is highly variable. This has led a few to sug- of increased resistance among infants with
gest the use of 5-fluorocytosine or flucon- C. parapsilosis infection, a rising form of
azole, both of which have good penetration candidiasis.75,76
of the CSF, in combination with amphoteri-
cin B. Others have successfully treated men- CONGENITAL CYTOMEGALOVIRUS
ingitis with amphotericin B alone. There INFECTION
are three lipid formulations approved by Cytomegalovirus (CMV) infection is the
the U.S. Food and Drug Administration for most frequent congenital infection in
use in adults: amphotericin B lipid complex humans. The virus is endemic and world-
(ABLC), amphotericin B colloidal disper- wide and has no seasonal pattern of infec-
sion (ABCD), and liposomal amphotericin tion. Typically, after a primary infection,
B (AmBisome). Because higher dosages may virus is shed for weeks to even years before
be used without toxicity, these preparations becoming latent. Periodic episodes of viral
may be appropriate for the infant with renal shedding occur. The virus consists of three
disease or severe nephrotoxicity.62-64 A few major components: an inner icosahedral or
studies have shown fluconazole to be effi- 20-sided capsid containing double-stranded
cacious in the treatment of invasive disease DNA that is similar to that of herpes sim-
in neonates, equivalent to treatment with plex virus; an amorphous layer consisting of
amphotericin B.65,66 Unfortunately, half viral proteins and RNA; and an outer enve-
of Candida glabrata and Candida krusei iso- lope. The virus does not code for thymidine
lates are resistant to fluconazole. Flucon kinase, which renders acyclovir ineffective.
azole monotherapy is only recommended Infection with CMV largely depends
in neonates after identification of the fungal on socioeconomic status, which reflects
organism and determination of its suscepti- crowding. It also increases with parity and
bility. Caspofungin is fungicidal against all number of sexual partners. Finally, sero-
candidal species. However, there are only positivity is much higher among African
case reports of its use in neonates, and it American and Asian women. Seropositiv-
cannot be recommended at this time. ity occurs in 0.5% to 2.0% of infants in the
Prevention is clearly the best treatment United States and Western Europe and rises
for neonatal systemic candidiasis, yet this to 50% to 85% among young women, but
is also the area of greatest controversy. it is much more prevalent in developing
countries and among lower socioeconomic 10% to 15% of them are still at risk of later
groups, where seropositivity may be as high developmental abnormalities, which appear
as 90%. At childbearing age, 2% of women of within the first years of life. Among asymp-
middle to upper socioeconomic status sero- tomatic infants, 7.2% will ultimately have
convert yearly, compared with 6% of those of hearing loss.80 Half of these neonates will
lower socioeconomic groups.77 Transplacental have bilateral, progressive disease. This pro-
transmission of CMV from mother to infant gressive loss, however, may be missed by
is typical in congenital infection. A primary routine nursery screening. A much lower risk
maternal infection results in transplacental (2%) is that of chorioretinitis, which is also
infection in 30% to 40% of infants, with usually delayed in onset. A similar number of
10% to 15% of them developing symptom- children may also develop neurologic abnor-
atic infection. The later in the pregnancy malities, including microcephaly, neuromus-
the seroconversion occurs, the more likely cular motor defects, and mental retardation,
it will result in neonatal infection: 75% of or defects in tooth enamel. Cytomegalic
infants are infected in the third trimester. inclusion disease is seen in only 5% to 10%
However, the later in the pregnancy the of infected newborns and usually occurs as
infection occurs, the less likely the infection a result of primary infection in the mother
will be significant in the infant. Recurrent around the time of conception (Table
infections in the mother may also occur as 14-1).81 Mortality, which may reach 20%
a result either of reactivation or reinfection to 30%, results from liver failure, bleed-
with a different strain.78 In either instance, ing, disseminated intravascular coagulation
transplacental infection still occurs in 1% of (DIC), and secondary bacterial infection.
infants, but fewer than 1% of the infections Some deaths may occur after the neona-
are symptomatic. Polymerase chain reac- tal period as a result of the complications
tion (PCR) methodology can detect CMV of severe neurologic handicap. One half
excretion in breast milk in 70% to 90% of of symptomatic infants have intrauterine
women, particularly when the whey por- growth restriction and one third are prema-
tion is tested, and perinatal transmission turely born. Microcephaly may also be seen
occurs to 40% to 60% of infants.79 Excretion in half of the infants, along with intracra-
occurs among these infected infants from nial calcifications. Hepatomegaly, and even
3 weeks to 3 months after birth. Also, trans- more frequently splenomegaly, are among
mission appears to occur readily among the most common findings in newborns.
young children, and day care is responsible Two thirds of the infants develop jaundice,
for transmission rates of over 50%, which which often persists and becomes increas-
most likely reflects contamination from ingly due to a rise in the direct component,
saliva on toys and hands. Seroconversion and most infants have some rise in liver
may be as high as 15% to 45% among par- enzyme levels. Petechiae and even purpura
ents of children attending day care and 11% are found in over half. Thrombocytopenia,
among women working in day care centers, due to suppression of the megakaryocytes in
so that subsequent pregnancies account the bone marrow, may be severe (one third
for nearly one fourth of symptomatic con- have platelet counts of <10,000). There may
genital infections in the United States. In also be a Coombs-negative hemolytic ane-
contrast, studies of seroconversion among mia. Diffuse interstitial pneumonitis is rare
health care workers do not show any risk of (<1%) and is more commonly seen in peri-
nosocomial transmission greater than the natally acquired disease. A peculiar defect
risk of acquiring the infection in the com- of the enamel of the primary teeth may be
munity. Yet nosocomial transmission to the seen in infants. This yellow, soft enamel
infant may occur in the nursery, most likely wears away early, leaving the teeth suscep-
via contaminated hands or fomites. Finally, tible to rampant caries. Male infants may
infants may be infected as a result of blood also have inguinal hernias. Both the defect
transfusion or exchange transfusion. These in dental enamel and the hernias appear
cases may be largely prevented by using to be teratogenic in nature. A few infants
seronegative donors, leukocyte filtration, have manifested necrotizing enterocolitis.
or frozen, deglycerolized packed red blood Sensorineural hearing loss is found in over
cells. one third of the infants and, as in asympto
Nearly 90% of congenital infections are matic infants, may be unilateral or bilateral,
asymptomatic and the infants are neither profound, and progressive. Chorioretinitis,
growth restricted nor premature, although optic atrophy, and strabismus may be found
Sequelae in Children with Congenital Cytomegalovirus Infection According

Table 14-1.
to Type of Maternal Infection
Type of Maternal Infection
Primary Recurrent
Sequela % (No.) % (No.) P value
Sensorineural hearing loss 15 (18/120) 5.4 (3/56) 0.05
Bilateral hearing loss 8.3 (10/120) 0 (0/56) 0.02
Speech threshold >60 dB* 7.5 (9/120) 0 (0/56) 0.03
IQ <70 13.2 (9/68) 0 (0/32) 0.03
Chorioretinitis† 6.3 (7/112) 1.9 (1/54) 0.20
Other neurologic sequelae‡ 6.4 (8/125) 1.6 (1/64) 0.13
Microcephaly 4.8 (6/125) 1.6 (1/64) 0.25
Seizures 4.8 (6/125) 0 (0/64) 0.08
Paresis or paralysis 0.8 (1/125) 0 (0/64) 0.66
Death§ 2.4 (3/125) 0 (0/64) 0.29
Any sequela 24.8 (31/125) 7.8 (5/64) 0.003
From Fowler K, Stagno S, Pass RF, et al: The outcome of congenital cytomegalovirus infection in relation
to maternal antibody status, N Engl J Med 326:663, 1992.
*For the ear with better hearing.
†Three of the seven children with chorioretinitis (43%) in the primary infection group had visual
impairment.
‡Four of the eight children (50%) had more than one abnormality.
§After the newborn period.
in 22%, and the retinitis is more likely to have indicated little long-term developmen-
present at the macula than in adults.82 The tal effect in infected infants.
outcome is grim, with 90% of infants devel- Viral isolation in tissue culture, usually
oping at least one neurologic abnormality. from urine or saliva, remains the most sen-
Although microcephaly is a strong predic- sitive and specific test for diagnosis in the
tor of intellectual impairment, intracranial infant. To differentiate congenital infection
calcifications on computerized tomographic in the neonate from perinatal infection, virus
images indicate a risk as high as 90% and are must be isolated in the first 2 weeks after
often accompanied by progressive, severe, birth. With hyperimmune sera or monoclo-
bilateral hearing loss, optic atrophy, and nal antibodies, detection may occur within
neuromuscular abnormalities. Ultrasonog- 24 hours. Because immunoglobulin (Ig) G
raphy may accurately demonstrate calcifi- is transplacentally transferred, its detection
cations, but magnetic resonance imaging is not helpful without paired sera, and the
may provide additional findings, such as measurement of serum IgM is associated
polymicrogyri, hippocampal dysplasia, and with many false negatives. However, PCR
cerebellar hypoplasia.83 amplification for detection of viral DNA
A perinatal infection may develop in an has been found to be extremely sensitive
infant after passage through the birth canal for diagnosis in a large range of tissues and
or from breast milk. In the term infant this secretions, particularly blood and saliva.84 A
is usually asymptomatic with little effect new technique is the use of nested PCR to
on developmental outcome, although such detect viral DNA in dried blood spots that
infants may develop a diffuse interstitial are obtained for metabolic tests after birth.85
pneumonitis. Few require hospitalization These blood spots may be used in screening
and mortality is low. Among preterm infants or can be tested later to determine whether
there is more risk. Transfusion of packed red symptoms such as hearing loss are a result
blood cells may result in a sepsis-like pic- of congenital infection. Once the blood is
ture with pneumonia, hepatosplenomegaly, dried it is no longer infectious. The samples
thrombocytopenia, and neutropenia, and can be shipped easily and stored for years.
the mortality may reach 50%. More recently Maternal and prenatal diagnosis is more
there has been considerable concern regard- complicated. The mother is usually asymp-
ing breast feeding of preterm infants by tomatic, so infection is not suspected
seropositive mothers,79 but most studies clinically. Screening thus becomes more
important. The detection of IgG does not be initiated in the first month of life, and
define whether the mother has a primary the infants need to be closely monitored for
infection or a recurrent one. The same is toxicity, particularly neutropenia.
true of isolation of the virus. IgM responses
are variable and may be detected for HERPES SIMPLEX
16 weeks or longer after infection. An IgG Neonatal herpes simplex virus (HSV) disease
avidity assay, based on the determination has really only been recognized in the last
that antibody is of low avidity in the first 70 years. This double-stranded DNA virus
months of infection, is particularly effec- consists of a dense viral DNA core sur-
tive as a negative predictor up to 21 weeks rounded by an icosahedral protein capsid,
of pregnancy, but is less so later. However, which is further surrounded by an amor-
the most important factor is whether or phous layer of proteins and an envelope.
not the fetus is infected and whether or not The herpesviruses are known for their abil-
that infection is symptomatic. Cordocen- ity to enter a latent state after the primary
tesis for fetal blood testing will miss many infection from which an active recurrence
infected fetuses. IgM appears only after may arise, despite the presence of humoral
20 weeks’ gestation and is only detected and cellular immunity. There are two anti-
in half of cases. Viral DNA can be detected genic types: HSV-1 is usually found above
but the test has a low sensitivity. The stan- the waist, whereas HSV-2 is found below
dard assay has now become quantitative the waist and is the most common source
PCR on amniotic fluid.86 Ultrasonographic of genital and neonatal herpes. Infections
abnormalities may be associated with, but with either type are usually asympto
are not diagnostic of, infection and many matic. HSV-1 may cause gingivostomatitis
are transient. These include microcephaly, in young children and a sore throat or a
intracranial calcifications or cysts, intrauter- mononucleosis-like infection in an adult.
ine growth restriction, oligohydramnios As with other herpesviruses, seropreva-
or polyhydramnios, pericardial or pleural lence is related to socioeconomic status.
effusions, hepatic lesions, and hyperechoic More than three quarters of lower socio-
abdominal masses. economic populations have antibody to
Because disease is often present for a HSV-1 in their first decade, as opposed to
prolonged period in the fetus and already only one third of those of upper middle
has deleterious effects, treatment becomes socioeconomic groups. HSV-2 is respon-
problematic. Clearly the best treatment is sible for 80% of genital infections and is
prevention of fetal infection. Vaccines are usually transmitted by sexual intercourse;
being explored but are not currently avail- thus it most often appears after the second
able. Recently, hyperimmune globulin was decade and is found in 20% to 25% of indi-
given to 31 women with primary infec- viduals. African Americans have a higher
tions in pregnancy and the infant of only rate of infection than whites. Higher rates
one (3%) had disease at birth, developing are also seen in women, who have an 80%
handicaps by 2 years of age.87 In contrast, risk of infection after a single contact with
the rate of disease was 50% among the an infected male. From 1988 to 1994 in
infants of 14 women who did not receive the United States, the prevalence of HSV-2
the hyperimmune globulin. Placental thick- infection was 21%, which represented a
ness, which increases in primary infection, significant increase over prior years. In the
declined after treatment as well.88 Passive most recent surveys, from 1999 to 2004,
protection after birth is unlikely to be of the seroprevalence of HSV-2 dropped to
benefit. In a randomized, controlled trial 17%.91 Of note, HSV-1 is now responsible
of intravenous ganciclovir in 100 infants for a larger proportion of both genital and
with central nervous system (CNS) disease, neonatal disease. HSV-1 genital infections
the therapy prevented worsening of hearing are less likely to recur than HSV-2 genital
loss at 6 months and 1 year of age.89 Fewer infections and are usually less severe. Both
developmental delays at 6 and 12 months HSV-1 and HSV-2 are found worldwide,
of age, as measured by Denver develop- and the only reservoir is in humans. Infec-
mental tests, were also seen among infants tion occurs year round and is not seasonal.
receiving intravenous ganciclovir therapy Host defenses begin in 7 to 10 days, with
than among control infants.90 Treatment humoral immunity appearing 2 to 6 weeks
of congenital CMV in infants with CNS later, although this does not prevent recur-
disease should be considered but needs to rences.
Transmission to the neonate most com- with active cervical lesions. For this reason,
monly occurs from exposure of the infant many experts recommended that infants
to contaminated maternal secretions in the of such mothers be delivered via cesarian
birth canal at delivery. Maternal infection is section—before rupture of membranes, if
classified as primary if it is the initial infec- possible, but at least before 6 hours after
tion with either HSV-1 or HSV-2 and there rupture.93 Cesarian section reduces the risk
are no preexisting antibodies to either type. of fetal infection from 7.7% to 1.2%,94 but
A recurrent infection occurs in an indi- does not eliminate the risk entirely. In the
vidual with latent infection, whereas an United States it is estimated that infection
initial nonprimary infection occurs in an occurs in 1 in 1500 deliveries, resulting in
individual with preexisting antibodies to 2200 infected newborns per year.
the other HSV type. All three types of infec- Intrauterine infection is rare and may
tion are likely to be asymptomatic. Many result from either ascending infection from
infections believed to be new infections the birth canal or transplacental infection.
in pregnant women are actually reactiva- It may also occur in either primary or recur-
tions of previously acquired asymptomatic rent maternal infection. These infants are
infections. Infection does not appear to be severely affected and have a combination of
associated with an increase in spontaneous skin vesicles and scarring, hydranencephaly
abortion or premature rupture of mem- or microcephaly, and keratoconjunctivitis.
branes. Cervical shedding of virus has been Antiviral therapy is futile.
demonstrated in 0.56% of women with The third route of transmission is post-
symptomatic infections and in 0.66% of natal acquisition. Virus may be obtained
women with asymptomatic infections. Fre- by breast feeding from an infected breast or
quent cervical cultures have failed to detect being kissed by a family member who has
which mothers will be shedding virus at the orolabial herpes, usually HSV-1. Nosocomial
time of delivery. It is important to note that infection in the nursery is also possible. Pro-
over 75% of infected neonates are born to spective hospital studies have demonstrated
women who have no history or symptoms that as many as one third of employees
of HSV infection, nor do their sexual part- have a history of nongenital herpes and
ners. Acquisition of HSV-1 or HSV-2 occurs that twice that many have asymptomatic
in 2% of susceptible pregnant women and shedding. It remains controversial whether
is evenly distributed throughout the preg- individuals with labial lesions should be
nancy.92 There is up to a 60% risk of neona- removed from the nursery. Currently they
tal infection when the mother is shedding are asked to use face masks and to perform
virus at the time of delivery secondary to careful hand washing. Individuals with her-
a primary infection.92 The risk falls to 30% petic whitlow (finger lesions) should not be
if the mother is shedding virus at deliv- providing direct patient care.
ery due to an initial nonprimary infection In stark contrast to the case of congeni-
and to 2% if the mother is shedding virus tal infection of the newborn with CMV,
due to reactivation of infection acquired another herpesvirus, asymptomatic infec-
either before pregnancy or during an ear- tions with either HSV-1 or HSV-2 are rare.
lier trimester. This is primarily due to the Neonatal disease has been classified, for
larger quantity and duration of viral shed- purposes of describing outcome, into local-
ding from the cervix during a primary ized skin, eye, and mouth (SEM) disease;
infection. However, some protection is encephalitis with or without skin, eye, or
afforded by preexisting neutralizing trans- mouth involvement (CNS); and dissemi-
placental antibodies, so that the infants at nated disease, with or without CNS involve-
highest risk are the ones who are infected ment. The National Institute of Allergy and
at birth or after birth and who are born Infectious Diseases Collaborative Antiviral
before transplacental transfer of antibod- Study Group reported that 34% of neonates
ies. Type-specific maternal antibody test- had SEM disease at presentation, 34% had
ing may be useful in determining the risk CNS disease, and 32% had disseminated
of infection of the neonate.93 The use of disease.95 Common presenting signs and
invasive monitoring provides a site for viral symptoms include lethargy, temperature
entry into the fetus, and this site is often instability, conjunctivitis, pneumonia, hep-
the location of initial lesions. An additional atitis, and DIC. Skin lesions are the most
risk factor is rupture of membranes longer suggestive of HSV infections, but fewer than
than 6 hours before delivery in a mother 30% of infants ever develop such lesions.
Likewise, seizures, focal or generalized, and first but rises significantly over time. Com-
encephalitis are very indicative. puted tomography may show localized or
Symptoms of SEM disease usually appear multifocal areas of hemorrhage, edema,
at 7 to 10 days of life. The most easily recog- and infarct. An electroencephalogram may
nized skin lesion is the vesicle, which may also help in determining the extent of dis-
progress to clusters of vesicles or join with ease. Brain stem disease results in the death
other vesicles to form bullae. Although lim- of half of untreated infants.96 The progno-
ited to the skin at first, the lesions tend to sis of survivors is poor and includes severe
progress to more serious disease; this was psychomotor retardation, blindness, micro-
particularly true before the advent of acy- cephaly, chorioretinitis, and spasticity. Even
clovir therapy. They are most commonly with antiviral therapy, only 17.5% of infants
found on the head of the infant, especially infected with HSV-2 and 75% of infants
if there was a scalp monitor, but may also be infected with HSV-1 have a normal out-
found on the trunk or extremities. Lesions come at one year of age.97
in the mouth presumably are caused by Most infants with disseminated HSV dis-
swallowed contaminated amniotic fluid ease are born to mothers with primary infec-
and maternal secretions. Keratoconjuncti- tion and lack transplacental antibody. The
vitis, chorioretinitis, and cataracts may also resulting viremia in the infant spreads the
develop. Even with antiviral therapy, infants disease to all organs, usually in the first week
tend to have recurrent skin lesions over sev- of life but also in the first 24 hours. Adre-
eral years and some may develop cataracts. nal hemorrhage and shock with fulminant
Long-term neurologic impairment has also hepatitis may be prominent. There may be
been seen in these infants, probably due a sepsis-like picture with metabolic acidosis,
to unrecognized CNS disease. This group respiratory distress, DIC, direct hyperbiliru-
may experience quadriplegia, microcephaly, binemia, thrombocytopenia, neutropenia,
and blindness between 6 and 12 months of elevated hepatic enzyme levels, and seizures.
age.95 Before the acyclovir era, 30% of these A vesicular rash is usually not present at
infants progressed to more invasive disease onset, and one third of infants never develop
and had neurologic sequelae. With acyclo- vesicles. Meningoencephalitis develops in
vir therapy, all infants with HSV-1 infection the majority of infants. Others may develop
and 95% of those with HSV-2 SEM disease an interstitial or hemorrhagic pneumonia
had normal neurologic examination find- or necrotizing enterocolitis with pneumato-
ings at 12 months of age.96,97 sis intestinalis. These infants have the high-
Isolated CNS disease in the newborn est mortality—more than 80% if untreated,
probably represents retrograde axonal often secondary to DIC or pneumonia—but
transport of the virus in infants who have survivors may have a better neurologic out-
acquired transplacental neutralizing anti- come. Although HSV-1 and HSV-2 infection
body, which possibly has not allowed hema- are clinically indistinguishable in dissemi-
togenous spread of the virus.95 In these nated disease, a normal neurologic outcome
infants the infection becomes apparent at is more common after antiviral therapy in
a slightly older age, after the first week of infants infected with HSV-2 (41%) than in
life—often in the second or third week, but infants infected with HSV-1 (23%).97
even as late as 6 weeks of life. Nonspecific It is extremely important to have a high
signs may include temperature instability, index of suspicion for HSV. Enteroviral sep-
lethargy, irritability, and poor feeding. HSV sis is the major differential. Viral isolation
encephalitis should always be considered in by culture remains the standard. Swab speci-
the presence of focal or generalized seizures, mens for viral isolation should be taken from
especially if they are refractory to treatment; all skin lesions, the nasopharynx, urine,
a bulging fontanelle; tremors; pyramidal stool, and conjunctivae. Isolation of the
tract signs; and focal neurologic deficits. virus from the skin or nasopharynx in the
Skin lesions or vesicles frequently are not first 24 hours of life may represent transient
found at presentation. The CSF may be nor- contamination from birth, so swab speci-
mal initially or show only subtle abnormali- mens should be taken at 24 hours of life in
ties. Many infants will have a bloody tap infants born vaginally to mothers with geni-
due to CNS hemorrhage. Most commonly tal lesions or known shedding. Viral typing
the CSF glucose concentration is low and is important for prediction of survival and
there is a mononuclear pleocytosis. The neurologic outcome. Analysis as well as viral
protein content may show little elevation at culture of the CSF is required. The sensitivity
and specificity of PCR for viral antigen in and audiologic assessments in addition to
the CSF is high. Skin lesions should also be neurodevelopmental testing.
examined by either immunofluorescence or Recurrent skin lesions can also be a source
PCR testing. The evaluation should include of infection. Exclusion from day care is not
an ophthalmologic examination, brain imag- necessary, however, if the lesions are cov-
ing, electroencephalography, and audiologic ered to prevent direct contact with others.
testing. A complete blood count, measure- Reducing transmission of HSV to neo-
ment of hepatic enzyme levels, blood gas nates is the ideal, but most women shed
analysis, and coagulation studies should also virus asymptomatically. Delivery by cesar-
be performed for these infants. ian section may be beneficial in the presence
Intravenous acyclovir is the treatment of maternal genital lesions or symptoms but
of choice for newborns. Infants should is not indicated in the absence of lesions,
be isolated to prevent nosocomial spread. because the risk of transmission to the
Oral therapy is not acceptable. Acyclovir is exposed infant in recurrent infection is less
a competitive inhibitor of HSV DNA poly- than 3%. A primary maternal infection dur-
merase and terminates DNA chain elon- ing pregnancy should be treated. Valacyclo-
gation. It is activated by HSV thymidine vir is now commonly being administered to
kinase. All infants with HSV disease should pregnant women with a history of recurrent
be treated with 60 mg/kg/day acyclovir genital HSV, beginning at 36 weeks’ gesta-
in three divided doses. Infants with SEM tion. Metaanalysis indicates that treatment
disease may be treated for 14 days, but all reduces the risk of HSV recurrences and viral
infants with either CNS or disseminated shedding at delivery and the need for cesar-
disease require 21 days of therapy.98 PCR ean section.101 It is not known if this ther-
assessment of the CSF at the end of treat- apy also reduces the incidence of neonatal
ment of encephalitis or meningitis can be herpetic disease, and its use may give the cli-
used to determine the need for continued nician a false sense of security.102 The long-
therapy in infants whose PCR results remain term risk to the fetus, particularly the fetal
positive.99 Adequate hydration is important kidney, is not known, although the acyclo-
to prevent nephrotoxicity. Ocular anti- vir and valacyclovir pregnancy registry has
viral therapy should be used in the pres- not shown any increase in the rate of birth
ence of ophthalmic infection, but topical defects or change in their pattern in infants
treatment is not necessary for skin lesions born to treated women, compared with
because intravenous acyclovir adequately those born to the general population of
penetrates these lesions. There is no indi- pregnant women. The rise of resistant virus
cation that hyperimmune globulin is of in these treated women is also of concern.
benefit. Acyclovir resistance is rare in the
non–human immunodeficiency virus– HUMAN IMMUNODEFICIENCY VIRUS
infected newborn. INFECTION
As discussed, prognosis depends on both In the early 1980s, acquired immunodefi-
the viral antigen type and the location of ciency syndrome (AIDS) was first described
the infection (SEM disease only, localized in infants and children. Children younger
CNS infection, or disseminated disease). Fur- than 13 years infected with human immu-
ther improvements in outcome will require nodeficiency virus (HIV) account for fewer
earlier recognition and treatment of infec- than 1% of the total number of infected
tion, but this has not occurred since acyclo- people in the United States. More than 90%
vir has become available.96 Poor prognostic of these cases resulted from vertical trans-
signs at the initiation of therapy include mission from infected mothers. Since 1992,
prematurity, coma, DIC, and pneumoni- the CDC reports a 90% decrease in new
tis.96 There is also an association between infection in children younger than 13 years
the frequency of recurrence of skin lesions of age. Only 166 new cases in this age group
and the development of late sequelae. A were reported in 2005.103 As will be dis-
6-month trial of oral acyclovir suppression cussed, this nadir was achieved by improved
did eliminate the recurrence of skin lesions prenatal screening, management of preg-
in 81% of treated infants, whereas only nant mothers, and postpartum prophylaxis.
54% of untreated infants escaped recur- HIV is an RNA retrovirus of the genus
rence,97,100 but whether this will improve Lentivirus. The virus primarily targets CD4+
the long-term outcome is not known. Serial lymphocytes, where it incorporates itself as
evaluations should include ophthalmologic a provirus into the host cells’ genome and is
replicated as part of normal host cell DNA HIV-infected mothers, blood should be sent
replication. Infection is therefore lifelong. for either HIV DNA PCR testing or HIV RNA
Even with the use of potent combination PCR assay during the first 48 hours of life. If
antiretroviral therapy and reduction in HIV results are positive, a second sample should
RNA serum levels below detectability, latent be sent for PCR assay to confirm the diag-
virus has been demonstrated in periph- nosis. Once infection has been established,
eral blood monocytes. In active infection, HIV RNA PCR testing is used to monitor the
virus can be isolated from a variety of cells, efficacy of therapy, because this test reports
organs, and bodily fluids; however, epide- back a quantitative result or viral load in
miologic studies have only demonstrated copies per milliliter. There are several ways
infectivity from blood, breast milk, cervical to rule out infection. A negative result on
secretions, and semen. two PCR samples obtained after 1 month
Neonatal infection is generally clinically and 4 months of life rules out infection. Two
silent. Infants may have nonspecific physical negative antibody test results separated by
examination findings of hepatosplenomeg- 1 month obtained after 6 months of life or a
aly or lymphadenopathy. Oral candidiasis single negative antibody test result after 12
in a neonate does not arouse suspicion for to 18 months of life excludes infection.106
pathologic T-cell dysfunction. Refractory, As noted earlier, interruption of vertical
recurrent oral candidiasis, encephalopathy, transmission has greatly reduced the num-
developmental delay, poor growth, chronic ber of infected children in the United States.
diarrhea, and parotitis are relatively com- Currently, the CDC recommends universal
mon findings in infected infants during screening of all pregnant women in the first
the first year of life; again, none of these trimester with repeat testing in the third tri-
symptoms is particularly specific for HIV mester for women felt to be at high risk of
infection. Before the improvement in iden- infection. In 1994, the Pediatric AIDS Clini-
tification of infected mothers, use of highly cal Trials Group Protocol 076 trial demon-
active antiretroviral therapy (HAART), and strated a 67% reduction in perinatal HIV
initiation of appropriate postnatal prophy- transmission with use of a zidovudine regi-
laxis for viral and opportunistic infections, men for mother and infants.107
pneumonia caused by Pneumocystis jiroveci Numerous subsequent studies have
(formerly Pneumocystis carinii) accounted looked at a variety of simple and complex
for the majority of AIDS-defining illness in regimens testing different antiretroviral
the first year of life, with a peak incidence agents, timing, and duration, and have
between ages 3 and 6 months.104 Many examined their efficacy and side effects in
infants, however, do not have AIDS-defin- pregnant women and their offspring. The
ing opportunistic infection, but rather may routine use of HAART starting in 1996 has
experience recurrent serious bacterial infec- enabled physicians to greatly suppress viral
tions, including pneumonia, septic arthritis, burden in infected patients. Several stud-
bacteremia, or meningitis. Although a sin- ies have demonstrated the benefit of viral
gle occurrence of these infections does not suppression in mothers in preventing ver-
raise suspicion about immunodeficiency, tical transmission to their infants.108 The
their recurrence should alert the clinician CDC currently recommends that pregnant
to evaluate the infant’s immune system. In women receive HAART, containing zidovu-
general, the likelihood of serious bacterial dine if possible, if they require it for their
infection or opportunistic infection corre- own health or if they have HIV RNA levels
lates inversely with infants’ CD4+ counts; of more than 1000 copies/mL.109 There is no
without HAART, these counts begin to absolute viral threshold that reduces the risk
decline around 3 months of age.105 of transmission to zero, and therefore the
Diagnosis of HIV infection in infants can CDC urges consideration of this regimen
be made in several ways. Serologic testing for pregnant women even if they have HIV
is not diagnostic in a neonate, because a RNA levels of less than 1000 copies/mL. Sev-
positive result on an enzyme immunoassay eral studies have shown that elective cesar-
may simply reflect maternal serologic status ean delivery in HIV-infected women who
due to passive transplacental transfer of IgG have not received HAART and who have not
antibody. Antibody tests may yield false- begun labor or had rupture of membranes
negative results if the mother was infected reduces the rate of vertical transmission by
late in pregnancy and had not yet under- 50%.110,111 The role of cesarean section in
gone seroconversion. In infants born to women receiving HAART who have RNA
viral loads of less than 1000 copies/mL is age and has CD4+ counts appropriate for
controversial, and therefore cesarean sec- age. The need for chemoprophylaxis against
tion is not recommended for those women. infection with other opportunistic agents,
Breast feeding has been a major vehicle of including Mycobacterium avium-intracellulare
vertical transmission. Studies estimate that complex, Toxoplasma gondii, and various
between 15% and 40% of vertical transmis- herpesviruses, will be determined by the
sion worldwide occurs through breast milk. patients’ CD4+ counts and clinical condi-
Since 1985, the CDC has recommended tions. A discussion of specific HAART regi-
that women with HIV avoid breast feed- mens is beyond the scope of this chapter.
ing if they have access to safe, affordable HAART has dramatically increased the life
formula112; the World Health Organization expectancy of infants and children with
made a similar recommendation in 2000.109 HIV infection. In the absence of a cure,
Any infant born to an infected mother HIV-infected children may require lifelong
should receive antiretroviral therapy as therapy with drugs that have been associ-
soon as possible after delivery. Antiretrovi- ated with premature coronary artery dis-
ral therapy administered beyond 48 hours ease, insulin resistance, and bone fragility.
of life is not likely to impact the rate of The personal and societal costs of prolonged
vertical transmission. The therapeutic regi- HAART therapy emphasize the importance
men should be determined with the help of of HIV prevention.
a pediatric infectious disease specialist and
should take into account the mother’s viral GONOCOCCAL INFECTION
load and CD4+ count, mode of delivery, and Neisseria gonorrhoeae is frequently asymp-
antiretroviral exposure. Exposed infants tomatic in women and may therefore be
generally receive antiviral therapy for 4 to unknowingly transmitted to neonates.
6 weeks unless infection is confirmed. For all Endocervical screening samples should be
exposed infants chemoprophylaxis against sent for mothers in the first trimester of
P. jiroveci, most commonly trimethoprim- pregnancy, and for women at high risk, a
sulfamethoxazole, should be initiated at second culture should be performed late in
4 to 6 weeks of life. Prophylaxis should be the third trimester. Gonococcal infection,
continued until HIV infection is excluded. whether or not overt clinical symptoms are
The likelihood of vertical transmission can present, may cause vaginitis, cervicitis, sal-
be reduced to less than 1% with the aggres- pingitis, and pelvic inflammatory disease.
sive use of HAART to reduce maternal viral These conditions may result in neonatal
loads below the limits of detection and the morbidity and mortality directly by infec-
use of neonatal antiretroviral prophylaxis. tion of the neonate or indirectly by precipi-
In the most recent guidelines for testing of tation of preterm labor with its consequent
pregnant mothers and neonates, the CDC complications.
recommends that women in labor whose The most common manifestation of neo-
HIV status is unknown be offered rapid natal infection is ophthalmia neonatorum, a
antibody testing. If the results are positive, severe bacterial ocular infection. Before the
the woman should be offered antiretroviral routine use of silver nitrate, tetracycline, or
therapy and cesarean section without wait- erythromycin topical eye preparations, an
ing for confirmatory test results.113 This infant born to a mother with N. gonorrhoeae
aggressive approach reflects clinical consen- endocervical infection had approximately a
sus that the risk of exposing an uninfected 30% chance of developing ocular disease. A
mother or child to antiretroviral therapy premature infant or an infant born a pro-
and/or surgery is outweighed by the abil- longed period after membrane rupture has
ity to prevent vertical transmission of this an even greater risk of developing infection.
incurable infection. Infants with docu- Signs of infection typically manifest by 48
mented HIV infection should be evaluated to 96 hours of life but may occur within
and treated by an experienced pediatric hours. Classically, the infant has bilateral
infectious disease physician who can moni- lid edema, chemosis, and purulent drain-
tor response to therapy as well as medication age. Without treatment the infection can
toxicities. Current guidelines suggest that all result in permanent corneal damage and
children younger than 1 year of age receive panophthalmitis with vision loss.
HAART regardless of viral load or immune Rarely, disseminated infection with N. gon-
status. Pneumocystis prophylaxis should be orrhoeae occurs in neonates secondary to bac-
continued until the infant is 12 months of teremia. The majority of systemically infected
infants in the United States are born to moth- Any infant with documented gonococcal
ers who were inadequately screened and who disease should also be evaluated for other
have asymptomatic infection. The most com- common sexually transmitted diseases:
mon presentation of disseminated neonatal syphilis, Chlamydia trachomatis infection,
N. gonorrhoeae infection is pyogenic polyar- HIV infection, and hepatitis B.
thritis. The infant may have a pseudoparaly-
sis of the affected limb. Even in disseminated CHLAMYDIA TRACHOMATIS INFECTION
disease, meningitis has rarely been reported. Chlamydia trachomatis is an obligate intra-
Interestingly, the hallmark skin manifesta- cellular bacterium. C. trachomatis infection
tions of disseminated N. gonorrhoeae infection is the most common reportable sexually
seen in adults are not common in bacteremic transmitted disease in the United States.
infants. Localized cellulitis at breaks in the The high prevalence of maternal infection
skin, such as pH probe sites, does occur. In coupled with the lack of efficacy of the
the United States, most systemically infected topical agents recommended as univer-
infants do not have ocular disease because of sal ocular prophylaxis for neonates makes
the universal use of topical prophylaxis. The C. trachomatis the most common cause of
diagnosis of infection at any site is best made ophthalmia neonatorum. A few of the 18
by Gram staining and culture of purulent reported serovars are responsible for the
material on appropriate media. majority of genital infections in women
Prevention of neonatal infection is and, consequently, in neonates. Transmis-
accomplished through appropriate maternal sion is primarily from infected genital secre-
screening, treatment of infected pregnant tions but has been reported in infants born
mothers, and universal ophthalmic pro- via cesarean section to mothers with intact
phylaxis. Pregnant women found to have membranes. Infants born to mothers with
N. gonorrhoeae infection should be treated untreated infection have a 50% likelihood
according to current CDC guidelines. Uni- of acquiring infection, with the nasophar-
versal ophthalmic prophylaxis effectively ynx being the most frequently colonized
prevents ocular disease in over 95% of site. Once infected, infants have between
infants born to infected mothers; however, a 25% and 50% chance of developing con-
as noted, the topical therapy does not pre- junctivitis and between a 5% and 20%
vent systemic illness. Infants born to moth- chance of developing pneumonia.
ers with known N. gonorrhoeae infection Conjunctivitis typically appears within
should receive standard ocular prophylaxis a few days to weeks after birth, but the
and a single dose of 125 mg of intravenous timing of infection cannot reliably distin-
or intramuscular ceftriaxone. In preterm or guish C. trachomatis infection from gono-
low-birth-weight infants, the dose should be coccal disease. The symptoms tend to be
25 mg to 50 mg/kg with a maximum dose similar to, although milder than, those
of 125 mg. seen in gonococcal disease: lid edema, ery-
For any infant with suspected infection, thema, and purulent exudate. Treatment
cultures should be performed on blood results in resolution of symptoms within
and CSF as well as samples from any exu- 1 to 2 weeks without permanent sequelae.
date—ocular, skin abscess, or articular. Most No treatment or inadequate therapy can
infants should be hospitalized to ensure result in symptoms for up to a year with
evaluation and therapy. Gonococcal oph- the potential for conjunctival scarring or
thalmia neonatorum should be treated with micropannus formation. Diagnosis is con-
a single dose of intravenous or intramus- firmed by culture of cells from conjunc-
cular ceftriaxone at 25 to 50 mg/kg up to tival specimens. The test depends on the
a maximum dose of 125 mg. In addition, collection of epithelial cells, because C. tra-
infants should receive frequent eye irriga- chomatis is an intracellular pathogen. Con-
tion with saline until the discharge has sultation with the hospital microbiologist
resolved. Topical therapy alone is insuf- or infectious disease expert to determine
ficient to treat established infection and the most appropriate collection methods
is unnecessary with systemic therapy. In and culture media is recommended. Stain-
infants with bacteremia or septic arthritis, ing will reveal intracytoplasmic inclusion
ceftriaxone or cefotaxime therapy should be in more than 90% of neonatal ocular speci-
administered for 7 days. If cultures of CSF mens with confirmation of C. trachomatis
give positive results, the duration of therapy infection by species-specific monoclonal
should be 10 to 14 days.114 antibody staining.
Pneumonia caused by C. trachomatis typi- infants will require a second course of anti-
cally presents from the late neonatal period biotics. In infants younger than 6 weeks of
through the first 4 months of life with a age, erythromycin therapy has been associ-
mild to moderate respiratory illness charac- ated with hypertrophic pyloric stenosis. The
terized by persistent staccato cough, tachyp American Academy of Pediatrics continues
nea, and nasal congestion without fever. to recommend that neonates with chlamyd-
Physical examination often demonstrates ial disease be treated with erythromycin
tachypnea and rales but no wheeze. Half of pending further studies of other potentially
infants with C. trachomatis pneumonia have effective agents and further delineation of
evidence of conjunctivitis. Classically, chest the association between erythromycin and
radiography demonstrates bilateral intersti- pyloric stenosis.115 If neonates are treated
tial infiltrates with hyperinflation. Diagno- with erythromycin, the physician should
sis of C. trachomatis pneumonia is largely inform the parents of this association and
clinical. Although in many affected infants its warning signs.
cultures of nasopharyngeal specimens will Disease prevention targets screening of all
be positive for the organism, the absence of pregnant women, with treatment of those
a positive culture finding in samples from infected and documentation of cure. Despite
this site does not eliminate the possibility of the high likelihood of neonatal infection for
C. trachomatis as the responsible pathogen. infants born to untreated or inadequately
Elevation of C. trachomatis–specific IgM to treated mothers, the routine use of systemic
a titer of 1:32 or higher is diagnostic, but erythromycin therapy for exposed infants
this assay is not always readily or rapidly is not recommended given the association
available. Interestingly, IgM levels do not with the drug and hypertrophic pyloric ste-
typically increase in infected infants with nosis. C. trachomatis disease, as discussed,
isolated ocular disease. is generally not associated with significant
Infants with chlamydial conjunctivi- morbidity or mortality. Infants should be
tis should be treated with oral erythromy- observed for clinical signs of infection and
cin base or ethylsuccinate, 50 mg/kg/day treated if such signs are present.
divided into four doses for 14 days. Azithro-
mycin and clarithromycin are likely to be SYPHILIS
effective; however, not enough data exist After World War II, the number of cases of
about the proper dosing and duration of acquired and, consequently, of congeni-
therapy to allow them to be recommended tal syphilis declined steadily until the late
for neonatal ocular disease at this time. 1980s and early 1990s, when an epidemic
Pneumonia may be treated with erythromy- occurred. This epidemic coincided with an
cin in the same manner as ocular disease or increase in the incidence of HIV infection,
may be treated with azithromycin 20 mg/ crack cocaine use, and the poverty rate. By
kg/day for 5 days. Outside of the period 1998, aggressive public health measures led
immediately after birth, sulfonamides may to a decline in congenital syphilis cases to
be used if the infant cannot tolerate eryth- the current record low level of fewer than
romycin therapy. Up to 20% of treated 500 cases per year (Fig. 14-2).116
P and S rate (per 100,000 population)
20 7.5
CS cases (in thousands)
16 6.0
12 4.5
P and S
8 syphilis 3.0
4 1.5
Congenital
syphilis
0 0.0
1970 1975 1980 1985 1990 1995 2000
Figure 14-2. Reported cases of congenital syphilis (CS) in infants younger than 1 year of age and rates of primary (P) and
secondary (S) syphilis among women in the United States, 1970 to 2004.
The causative organism, Treponema palli- include frontal bossing, saber shins, and
dum, can cross the placenta at any time during saddle nose deformity. Dental abnormali-
pregnancy and during any stage of maternal ties include abnormal molars and notched,
disease. Among newly infected women, 40% small central incisors classically described as
of pregnancies result in stillbirth, spontane- Hutchinson teeth. Interstitial keratitis pres-
ous abortion, or perinatal death. Women ents as unilateral or bilateral photophobia
with untreated primary or secondary syphi- with lacrimation that occurs after the fifth
lis have a 60% to 90% chance of transmitting year of life. The symptoms are followed
infection to the fetus. Women with early within weeks to months by vascular opacifi-
latent and late latent infection have a 40% cation of the cornea and consequent blind-
and 8% chance of transmission, respectively. ness. Eighth nerve involvement can present
By definition, congenital syphilis is a at any age with vertigo, progressive hear-
hematogenously spread infection and there- ing loss, and ultimately permanent deaf-
fore lacks a primary stage. More than half ness. The high proportion of asymptomatic
of infected newborns are asymptomatic at infected neonates and the devastating con-
birth. Historically, infection that is detected sequences of late-onset disease underscore
before a child is 2 years old is referred to the importance of screening all women in
as early disease, and infection discovered early pregnancy. All 50 states require sero-
after 2 years of age is classified as late dis- logic testing of women at the beginning of
ease. Early-onset disease typically manifests prenatal care.
before an infant is 3 months old. The definitive diagnosis of syphilis is
When symptomatic, infected infants made by darkfield microscopic identifica-
manifest multiorgan involvement consis- tion of spirochetes in exudate or tissue or
tent with their hematogenously dissemi- direct fluorescent antibody testing of such
nated infection. Neurologic symptoms are material. These tests can be performed on
usually absent even when the CSF is mark- the placenta or umbilical cord. Unfortu-
edly abnormal. The CSF shows signs of nately, neither procedure is particularly
elevated protein or pleocytosis in 50% of sensitive or practical. Serologic screening is
symptomatic infants and in up to 10% of generally performed using nontreponemal
asymptomatic infants. Some infants may tests: the rapid plasma reagin (RPR) test and
have pseudoparalysis of an extremity sec- the Venereal Disease Research Laboratory
ondary to bony involvement. Long bone (VDRL) test. These tests detect IgG and IgM
radiographs show abnormalities in 95% of to lipoidal antigen from T. pallidum. These
symptomatic infants and 20% of asymp- tests, however, are not specific enough to
tomatic infants.117 The chronic, erosive rhi- make a definitive diagnosis. False-positive
norrhea of syphilis, “snuffles,” is no longer results can be seen in pregnancy, intrave-
commonly seen. If present, the nasal dis- nous drug use, a variety of connective tissue
charge is highly infectious. Highly symp- diseases, and viral infection. Nontrepone-
tomatic infants may present with respiratory mal antibodies generally appear within 8
distress and pulmonary infiltrates referred weeks of infection and are seen in 100% of
to as pneumonia alba. Nearly all sympto patients with secondary or latent syphilis.
matic infants have hepatomegaly with ele- False-negative results can occur if specimens
vations in serum alkaline phosphatase level. are drawn too early after infection or if anti-
Generalized lymphadenopathy is also com- body concentrations are extremely high and
mon. Many symptomatic infants develop cause a prozone effect. Titer testing can use
an erythematous, maculopapular rash that serial dilution to provide useful quantitative
becomes coppery and frequently involves data about a patient’s response to therapy.
their palms and soles. Infants, unlike chil- The same nontreponemal test should be
dren and adults with skin involvement, used to follow a patient’s titer. The titers
may develop vesicles or bullous lesions, typically show a fourfold decrease within
known as pemphigus syphiliticus, that tend 6 months of successful therapy for primary
to rupture and contain numerous infectious or secondary infection and antibodies are
organisms. Leukocytosis, anemia, or throm- undetectable after a year. Unfortunately,
bocytopenia is present in the majority of most untreated patients, including those
symptomatic infants. with congenital infection, will become sero-
Late-onset disease presents in children negative by nontreponemal testing within
older than 2 years of age. Bony malforma- 2 years. Only the VDRL test has been
tions secondary to chronic osteomyelitis approved for detecting spinal fluid infection.
Treponemal tests—the fluorescent trepo- evaluation including CSF testing, and radio-
nemal antibody absorption test (FTA-ABS) graphic findings are normal and appropriate
and the microhemagglutination assay– follow-up is expected, some experts would
Treponema pallidum (MHA-TP)—are more treat with a single intramuscular dose of
specific for T. pallidum and should be per- benzathine penicillin.
formed to confirm a diagnosis of syphilis in The American Academy of Pediatrics rec-
patients with positive results on nontrepo- ommends that exposed infants undergo
nemal tests. These tests are qualitative, and nontreponemal serologic follow-up test-
results remain positive for life. They are ing at 2 to 4 months, 6 months, and
therefore not used to ascertain the treat- 12 months after treatment or until the titers
ment status or clinical response of a patient. decline fourfold or are nonreactive. The
An infant born to a mother with a history titers should be nonreactive by 6 months in
of syphilis or serologic evidence of syphilis infants who have been adequately treated
should undergo the same test of nontrepo- or who were uninfected but had transpla-
nemal antibodies as the mother so that centally acquired maternal antibody. Per-
titers can be compared. If the mother’s titer sistently positive titers or increasing titers
has increased fourfold, if the infant’s titer is warrant complete evaluation and 10 days
four times higher than the mother’s titer, or of intravenous penicillin G therapy. Neo-
if the infant has signs or symptoms of infec- nates with positive results on VDRL tests of
tion, further evaluation is warranted. Cord CSF or uninterpretable CSF results should
blood is not reliable for serologic diagno- have repeat examinations of their CSF every
sis. Further evaluation should also be initi- 6 months until negative.119
ated if documentation of maternal therapy
is unavailable, if insufficient serologic fol-
low-up is available to assess adequacy of CASE 1
therapy, if syphilis during pregnancy was An infant is born vaginally at 39 weeks to a mother
treated with a nonpenicillin regimen,118 or with known gonococcal and chlamydial cervicitis. The
if syphilis during pregnancy was treated less mother’s HIV status, hepatitis B status, and VDRL
than 1 month before delivery. In any infant status are unknown. The baby receives 0.5% eryth-
with signs and symptoms of infection, non- romycin ocular ointment and intramuscular vitamin K.
treponemal titers four times higher than
those of the mother, or positive results on Which of the following is(are) true?
body fluid testing by darkfield microscopy
a. The infant has a 30% chance of developing oph-
or fluorescent examination, CSF should
thalmia neonatorum from N. gonorrhoeae and a
be sent for VDRL testing, cell count, and
25% chance of developing it from C. trachomatis.
measurement of protein concentration. In
b. The infant should receive a 25 to 50 mg/kg dose
addition, asymptomatic infants born to
of intramuscular ceftriaxone.
inadequately treated mothers should have
c. The infant should receive oral erythromycin thera-
their CSF examined even if their nontrepo-
py for 2 weeks.
nemal titers are the same as or less than four
d. The infant should be given hepatitis B vaccine
times higher than the mother’s titer.
and hepatitis B immunoglobulin (HBIG) within
Any infant with evidence of infection,
12 hours of birth.
positive results on placental or umbilical
The correct answer is b.
cord testing by darkfield microscopy or flu-
orescent technique, a fourfold higher non-
Standard ocular prophylaxis with 0.5% erythro-
treponemal titer than the mother, or positive
mycin, 1% tetracycline, or 1% silver nitrate is more
VDRL results for CSF should be treated with
than 95% effective in preventing gonococcal ophthal-
parenteral penicillin G for 10 days. If infec-
mia neonatorum. In the absence of prophylaxis, the
tion cannot be excluded, the evaluation can-
neonate would have approximately a 30% likelihood
not be completely performed, or follow-up
of developing gonococcal disease. This prophylaxis,
is not ensured, the infant should be treated
however, is ineffective in preventing chlamydial dis-
for 10 days. A negative CSF VDRL result
ease. Approximately 50% of infants born to mothers
does not exclude congenital neurosyphi-
with Chlamydia infection will have nasopharyngeal
lis; pleocytosis and elevated protein level
infection; half of these infected children will go on to
should be considered signs of infection. In
develop ophthalmia neonatorum. Infants born to a
the case of an asymptomatic infant born to
mother known to be infected with N. gonorrhoeae
an inadequately treated mother, if physical
should receive standard ocular prophylaxis as well as
examination findings, results of laboratory
a single dose of intramuscular ceftriaxone at 25 to Gram staining of a sample from a lesion

50 mg/kg to a maximum dose of 125 mg. This therapy gives a negative result. A direct fluorescent
effectively prevents gonococcal ophthalmia neonato- antibody test is positive for HSV-2. Which
rum and disseminated gonococcal disease. Chlamy- of the following is(are) true?
dia does not cause disseminated infection. Although a. The infant should undergo lumbar puncture.
10% of infants born to mothers with chlamydial in- b. The infant should be admitted to the hospital for
fection will develop pneumonia, Chlamydia does at least 2 weeks of intravenous acyclovir therapy.
not disseminate or cause acute, vision-threatening c. This patient will likely show an elevation of
ophthalmic disease. The association between neo- transaminase levels.
natal erythromycin exposure and hypertrophic pyloric d. If a lumbar puncture is performed and the results
stenosis combined with the relatively indolent con- are negative, the infant can be managed with oral
sequences of chlamydial infection preclude the pre- therapy.
scription of erythromycin as a prophylactic. In cases The correct answers are a, b, and d.
of documented chlamydial infection, the benefits of
erythromycin outweigh the risks. Neonatal HSV infection is classically divided into
Although hepatitis B is readily transmitted vertically, three clinical presentations. The most severe and ear-
the vaccine is fairly effective in preventing disease. The liest to present is disseminated disease. This usually
infant should receive the vaccine within 12 hours of manifests in the first week of life with systemic illness
birth while the mother is tested for hepatitis B surface and multiorgan involvement, and carries a high mor-
antigen. If she is found to be positive for the antigen, tality. The majority of these patients have significant
the infant then should receive HBIG. In addition, the hepatitis. The next most serious presentation is that
mother should be tested for syphilis and HIV infection. of meningoencephalitis. This presentation typically oc-
curs around 3 weeks of age and has clinical manifesta-
tions that can be as subtle as fever without a focus or
CASE 2 as obvious as severe alterations in mental status and
A 3-week-old male infant is brought to the emergen- seizures. The gold standard for making this diagnosis
cy department with vesicular lesions on his thigh and has become PCR testing of the CSF. HSV infection is
abdomen. The vesicles appear to contain cloudy fluid clearly in the differential diagnosis of any neonate with
and are surrounded by an erythematous base. The an “aseptic” meningitis. The patient in this case de-
infant is afebrile and otherwise well appearing. scription has the most indolent type of neonatal HSV—
SEM disease. The patient should undergo a lumbar
Which of the following is(are) true? puncture, because a positive PCR result on the CSF
would have prognostic implications and would extend
a. The vesicles should be unroofed to obtain speci-
the duration of therapy. Even if they have a well ap-
mens for viral and bacterial culture.
pearance, if they are not treated systemically, infants
b. The absence of a maternal history of genital HSV
with this presentation develop disseminated disease
infection makes this cause unlikely.
70% of the time. Acyclovir should be administered
c. Mothers with active, recurrent genital herpes
intravenously for 2 weeks because of its exceedingly
pose the highest risk of vertical transmission.
poor oral bioavailability. The dosing and efficacy of
d. Exudate from the lesions is inadequate to test for
newer, more bioavailable antiviral agents for treatment
HSV.
of these infants have not been adequately studied.
The correct answers are a and d.
The differential diagnosis for vesicular lesions in-

cludes bacterial impetigo and HSV or varicella-zoster
virus infection. If these lesions are prominent in the
CASE 3
diaper area, C. albicans is also a possibility. Some The mother of a 42-day-old, 32-week gestation pre-
60% to 80% of infants with neonatal HSV infection term infant asks you about the appropriate timing
are born to mothers without a clinical history of HSV of immunizations and the need for prophylaxis for
disease. Although mothers with active, recurrent HSV respiratory syncytial virus (RSV) infection. The infant
infection give birth to the majority of infected infants, currently weighs 2700 g and after going home will
the risk of transmission to the infant is greatest in a continue to receive supplemental oxygen via nasal
mother with a first-episode primary infection. The lat- cannula for chronic lung disease.
ter situation implies a mother without any protective
antibodies to HSV. Both culture and antigen testing Which of the following is(are) true?
for HSV rely on the recovery of cells. The base of the a. The infant should receive the same immuniza-
vesicle should be scraped for diagnosis. tions as any 6-week-old infant.
b. The infant should receive a single 0.25-mL dose REFERENCES

of influenza vaccine in January and a second The reference list for this chapter can be found
0.25-mL dose a month later. online at www.expertconsult.com.
c. Whether treatment with monoclonal RSV anti-
body (palivizumab) is needed in infants such as
this 32-week gestation premature infant is con-
troversial.
d. The immunizations should be given when the in-
fant reaches a corrected age of 6 weeks.
The correct answer is a.
Inactivated polio, conjugate pneumococcal, Hae-

mophilus influenza B, and DTaP (diphtheria, tetanus,
and acellular pertussis) vaccines are all safe and im-
munogenic in this population. The infant should be
immunized as any other infant. If the infant has not
already received the first dose hepatitis B vaccine, it
would be appropriately given at this point. If an infant
weighing less than 2000 g received the first dose of
hepatitis B at birth because of maternal risk factors,
that dose would not be counted toward the three dos-
es necessary to complete the series. The first counted
dose can be given anytime after 4 weeks of age.
Inactivated influenza vaccine should not be ad-
ministered before 6 months of life. The first time it is
to be administered to a child younger than 3 years,
the doses would be split up as described in the case
description.
Although controversy exists about the need for
palivizumab in a healthy infant born after 32 weeks’
gestation, consensus exists that infants younger than
2 years of age with chronic lung disease of prematu-
rity who require therapy within 6 months of the start
of RSV season should receive antibody prophylaxis
for at least the first season.
The Heart
Christina M. Phelps, Philip T. Thrush,
and Clifford L. Cua
15
Congenital heart disease is the most com- environment), radiographic findings, and
mon cause of infant death in the United results of electrocardiography, echocardiog-
States.1 In most children, serious heart raphy, and occasionally additional imaging
disease presents during the first month such as cardiac computerized axial tomog-
of life. Thus, care for newborns demands raphy (CAT), magnetic resonance imaging
an awareness of the prevalence of cardiac (MRI), or invasive cardiac catheterization
defects and the ability to screen appropri- allows the physician to delineate the spe-
ately to differentiate infants with cardiac cific congenital cardiac defect. When a neo-
disease from other critically ill newborns. nate suspected of having congenital heart
In 2000, the prevalence of congenital heart disease is being examined, it is important
disease found by a population study in to frame physical and laboratory findings
Quebec was 11.89 per 1000 among chil- within the context of the transition from
dren and 5.78 per 1000 in the general fetal to neonatal circulation. This chapter
population. By contrast, the prevalence considers the physiology and pathophysiol-
of severe congenital heart disease was ogy of the fetal and neonatal cardiovascu-
1.45 per 1000 children and accounted for lar systems in newborns with and without
12% of all congenital cardiac lesions in heart disease.
children.2 Advances in fetal and neonatal
ultrasonographic screening allow identifi- PHYSIOLOGY AND
cation of an increasing number of children PATHOPHYSIOLOGY
with congenital heart disease and, more
importantly, appropriate counseling for FETAL AND PERSOENS NEONATAL
their parents. As many as 60% of newborns CIRCULATIONS
admitted to large pediatric cardiac inten- Newborns undergo dramatic changes in
sive care units have an established diag- the pulmonary and systemic circulations
nosis at the time of birth. Although some following birth. In the fetus, oxygen-rich
studies indicate an important benefit of blood from the placenta reaches the right
fetal diagnosis in terms of morbidity and atrium via the umbilical vein and shunts
mortality, the unintended result is that in preferentially across the foramen ovale to
some centers postnatal acute presentations the left ventricle, providing increased oxy-
of congenital heart disease are becoming gen content to the myocardium and brain
more rare, and this may be detrimental by (Fig. 15-1). A smaller portion of the highly
assuaging fears of congenital heart disease oxygenated blood passes from the right
in symptomatic newborns and thus caus- atrium to the right ventricle and bypasses
ing delay in care and potentially increased the lungs via the ductus arteriosus to flow
morbidity and mortality. In a large study to the lower body. Because of this parallel
of neonates in the United Kingdom, up circulation, individual organs may receive
to 25% of children with congenital heart blood from both ventricles, and thus the
disease were not diagnosed until after dis- output of the fetal heart is expressed as com-
charge from the newborn nursery, and mis- bined ventricular output (CVO). Advances
diagnosis was found to occur in up to 7 per in fetal ultrasonographic techniques have
100,000 live births in the United States.3,4 enabled a more accurate determination of
Careful evaluation of the history, physi- human fetal blood flow than was previously
cal examination findings, laboratory data available using fetal lamb studies. In the
(including the response of upper and lower normal human fetus, CVO has been docu-
body blood gas concentrations and arterial mented by echocardiographic studies to be
oxygen saturation in an enriched oxygen 450 mL/kg/min.5
368
CHAPTER 15 The Heart 369
Approximately 45% (200 mL/kg/min) of the foramen ovale into the left atrium.
this blood perfuses the placenta for oxygen Oxygenated blood crossing the foramen
uptake and returns via the umbilical veins. ovale comprises 76% of the left ventricular
Approximately one half of umbilical venous output and 33% of combined cardiac out-
return enters the inferior vena cava directly put supplying the cerebral and myocardial
through the ductus venosus, thereby circulations.6 Thus, the streaming of blood
bypassing the hepatic microcirculation; the from the inferior vena cava to the left heart
remainder passes primarily through the left increases the efficiency of oxygen delivery
lobe of the liver and enters the inferior vena to the most actively metabolizing area of
cava via the left hepatic vein. Although the fetus, the brain. Venous drainage from
venous returns from the lower body, duc- the right hepatic veins and the abdominal
tus venosus, and hepatic veins all pass inferior vena cava tends to stream prefer-
into the thoracic inferior vena cava, these entially to the right atrium and right ven-
streams do not mix completely. There is tricle. Similarly, desaturated superior vena
preferential streaming via the inferior vena caval return from the cerebral circulation is
cava into various cardiac chambers, with preferentially directed to the right ventricle
blood from the ductus venosus and left through the tricuspid valve. The right ven-
hepatic veins passing preferentially across tricle ejects much of this relatively undersat-
urated blood via the ductus arteriosus back
to the placenta. The remainder of the right
ventricular output passes into the pulmo-
AAo nary vascular bed. The proportion of CVO
DA to the lungs increases throughout gestation
MPT by 60% from 20 to 38 weeks, with pulmo-
PA
nary blood flow accounting for 11% of the
CVO.6,7 Thus, although the circulations are
not completely separated, each ventricle
RV LV
primarily performs its postnatal function—
the left ventricle delivers blood for oxygen
SVC utilization, the right for oxygen uptake.
RA
LA The left and right ventricles do not eject
similar volumes in the fetus. The right ven-
tricle has been shown to be dominant in
fetal lamb studies, ejecting almost twice the
blood volume ejected by the left ventricle.
In human fetuses, the stroke volume of the
LHV right ventricle is approximately 28% greater
than that of the left ventricle.5 Left ven-
DV
RHV tricular output is distributed mainly in the
upper body, including the brain (approxi-
PS mately 20% of CVO) and the myocardium
(3%); the remainder (about 10%) crosses the
aortic isthmus to the lower body.
PV DAo In the fetus, the ductus arteriosus is part
UV of a specialized system of oxygen-sensitive
organs and tissues in the body. Blood flow
across the ductus arteriosus is 78% of the
IVC P right ventricular cardiac output and 46% of
the CVO.6 In comparison with the aorta and
the pulmonary arteries, it is thicker walled,
with a medial layer composed of longitudi-
Figure 15-1. Diagrammatic representation of normal fetal nal and spiral layers of smooth muscle fibers
circulation. AAo, Ascending aorta; DA, ductus arteriosus;
within concentric layers of elastic tissue
DAo, descending aorta; DV, ductus venosus; IVC, inferior
vena cava; LA, left atrium; LHV, left hepatic vein; LV, left
and an intimal layer of smooth muscle and
ventricle; MPT, main pulmonary trunk; P, placenta; PA, endothelial cells.8-10 Continued patency of
pulmonary artery; PS, portal system; PV, portal vein; RA, the ductus arteriosus throughout gestation is
right atrium; RHV, right hepatic vein; RV, right ventricle; controlled by the relatively low fetal oxygen
SVC, superior vena cava; UV, umbilical vein. tension and the inhibition of procontractile
370 CHAPTER 15 The Heart
mechanisms by vasodilators.11,12 The vaso- with congenital diaphragmatic hernia and

dilators primarily responsible for ductal twin-twin transfusion syndrome (TITS).17-20
patency include prostaglandin and prosta- From a cardiac standpoint, fetal echocar-
cyclin, which interact directly with ductal diography can accurately diagnose most
prostanoid receptors, and to a lesser extent forms of congenital heart defects and track
carbon monoxide and nitric oxide.13,14 their evolution in utero (Fig. 15-2). This
may improve postnatal morbidity and mor-
Fetal Echocardiography tality, especially in newborns with ductal-
The increased availability and use of fetal dependent cardiac defects. 21,22 The level
echocardiography has significant clinical of parental psychological stress, however,
implications postnatally. All echocardio- appears to be related to the severity of the
graphic techniques (see the later section on cardiac defect and not to a prenatal versus
echocardiography of the newborn) can be postnatal diagnosis.23 Another recent use
used to produce a fetal echocardiogram. A of fetal echocardiography is in conjunction
fetal study is usually performed between 18 with interventional techniques.24 Interven-
and 22 weeks’ gestation for optimal imag- tions have been reported in fetuses with
ing. Studies can be carried out earlier in ges- hypoplastic left heart syndrome and restric-
tation but may need to be repeated to clarify tive atrial septa,25 severe aortic stenosis,26,27
the diagnosis or follow disease progression. and pulmonary stenosis or atresia.28 Fetal
A fetal study can be prompted by either echocardiography is essential for assisting
maternal or fetal indications (Box 15-1).15 in these procedures.
Not only can fetal echocardiography be
used to diagnose cardiac anatomic defects, Fetal Heart Failure
but analysis of fetal blood flow patterns in The parallel nature of the fetal circulation
the ductus venosus, umbilical artery, and makes it uniquely equipped to tolerate most
umbilical vein can provide information on structural abnormalities of the heart that
the overall cardiovascular well-being of the are life threatening after birth. Even in cases
fetus.16 Fetal echocardiography may also of significant obstruction and falling unilat-
have prognostic implications in infants eral ventricular output, the unaffected side
of the heart is able to increase its output
and fetal blood flow is redistributed so that
Indications for Fetal the unaffected ventricle can produce most,
Box 15-1. if not all, of the cardiac output.29 As a result,
Echocardiography
cardiac shunts, pulmonary overcirculation,
Maternal indications Fetal indications and anatomic causes of systemic hypoper-
Family history of Abnormal obstetrical fusion generally do not become noteworthy
congenital heart ultrasound screen until the infant is born. There are a limited
disease Extracardiac
Metabolic disorders abnormality
Exposure to teratogens Chromosomal
Exposure to prosta- abnormality
glandin synthase Arrhythmia
inhibitors Hydrops
Rubella infection Increased
Autoimmune disease first-trimester
(systemic lupus ery- nuchal translu-
RV
thematosus, Sjögren cency
syndrome, etc.) Multiple gestation LV RA
Familial inherited and suspicion of
disorders (Marfan twin-twin transfu- LA
syndrome, Noonan sion syndrome
syndrome, etc.)
In vitro fertilization
From Rychik J, Ayres N, Cuneo B, et al: American

Society of Echocardiography guidelines and stan-
dards for performance of the fetal echocardiogram, Figure 15-2. Fetal echocardiogram of an infant with a
J Am Soc Echocardiogr 17:803, 2004. hypoplastic left heart. LA, Left atrium; LV, left ventricle; RA,
right atrium; RV, right ventricle.
number of cardiovascular causes of fetal dis- aggressive intervention, survival of infants

tress that may result in the development of with AV block associated with structural
hydrops, including arrhythmias, myocar- heart disease is particularly dismal, with a
dial disease, severe atrioventricular (AV) or 75% to 90% incidence of fetal or neonatal
semilunar valve insufficiency, and prema- demise.36
ture constriction of the ductus arteriosus Structural heart disease is the most com-
with a restrictive atrial septum. All of these mon cause of fetal heart failure and may
conditions share a final common pathway lead to significant mortality without inter-
of elevated ventricular end-diastolic pres- vention. Some fetuses with severe semilunar
sure, increased atrial and central venous valve stenosis are candidates for an attempt
pressure, and movement of fluid from the at intrauterine valvuloplasty to stabilize the
capillary bed into fetal tissue.29 patient’s condition and ideally improve
Sustained tachyarrhythmias (over 200 long-term surgical options.26,27 Early deliv-
beats per minute) or bradycardia associ- ery with immediate intervention is often the
ated with congenital heart disease are not best management strategy for fetuses who
well tolerated. Tachyarrhythmias may be show symptoms associated with specific
controlled by administering antiarrhyth- structural heart defects such as ductus arte-
mic medications to the mother, including riosus restriction, Ebstein anomaly of the
digoxin, β-blockers, sotalol, flecainide, and tricuspid valve, or tricuspid valve dysplasia
amiodarone. Digoxin is a first-line therapy with significant tricuspid insufficiency.36
for short ventriculoatrial supraventricular
tachycardia and atrial flutter in the absence Circulatory Changes After Birth
of hydrops and is associated with an 80% By the end of the third trimester, the fetal
to 85% success rate in the treatment of fetal pulmonary circulation begins to demon-
supraventricular tachycardia and a 60% to strate vasoreactivity and responsiveness to
65% success rate for atrial flutter.30 Sotalol is maternal hyperoxygenation.39 The onset
another first-line therapy with a 72% conver- of breathing produces a dramatic increase
sion rate.31 Arrhythmia control is likely to be in pulmonary blood flow (from 11% of
successful if treatment is initiated before the the CVO to a full cardiac output) and a
development of hydrops. Successful treat- decrease in pulmonary vascular resistance.
ment of supraventricular tachyarrhythmias With the onset of ventilation, air replaces
in the presence of hydrops is more complex intraalveolar fluid and local oxygen concen-
and typically requires the use of at least two tration increases markedly, both of which
medications and a longer therapeutic course. may directly dilate the pulmonary vascular
Incessant fetal supraventricular tachycardia smooth muscle or cause the release of vaso-
warrants an attempt at conversion with dilating substances. Bradykinin, a potent
intraumbilical administration of antiar- pulmonary vasodilator, is released when the
rhythmic medications. Even with successful lungs are exposed to oxygen; bradykinin, in
treatment, there is an 8% to 30% reported turn, stimulates endothelial cell production
risk of fetal or neonatal mortality.32-35 of nitric oxide, a potent vasodilator. Pros-
Fetal bradycardia may be associated tacyclin (prostaglandin I2), a pulmonary
with significant intrauterine mortality. AV vasodilator derived from the metabolism of
block is caused by maternal autoantibod- arachidonic acid, is released when the lung
ies in approximately 45% to 48% of cases is mechanically ventilated (not necessarily
and can present as early as 18 weeks’ ges- oxygenated) or exposed to other vasoactive
tation.36,37 There have been reports of suc- substances such as bradykinin or angioten-
cessful treatment of early low-grade heart sin II. Inhibiting prostaglandin production
block, with improvement in outcomes, by by administering a cyclooxygenase inhibi-
administration of fluorinated steroids to the tor (such as indomethacin) attenuates the
mother.37,38 β-Sympathomimetic agents, normal ventilation-induced decline in pul-
intravenous immunoglobulins, and direct monary vascular resistance, which further
fetal pacing are also being used as therapies supports the role of these vasoactive sub-
for autoimmune-mediated fetal AV heart stances in the establishment of a normal pul-
block. Another 45% to 48% of fetal AV monary circulation after birth. The increase
block is associated with structural heart dis- in pulmonary blood flow greatly alters the
ease (most commonly left atrial isomerism venous return to the left atrium and con-
and congenitally corrected transposition of sequently the left ventricular preload. Left
the great arteries). Unfortunately, even with ventricular cardiac output increases from an
estimated 179 mL/min/kg to approximately of prostaglandins. Constriction and closure

240 mL/min/kg within the first 2 hours after after birth reflect removal of the stimuli
birth due to increased stroke volume.40 As that maintain relaxation and the addition
the ductus arteriosus closes and the left- of factors that produce active constriction.
to-right shunt diminishes, left ventricular Circulating prostaglandin E2 (PGE2) con-
output falls to approximately 190 mL/min/ centrations in the fetus are high because of
kg.40 the very low pulmonary blood flow. With
The initial dramatic decrease in pulmo- clamping of the placenta, the source of
nary vascular resistance is secondary to prostaglandin E2 is removed. With inspira-
relaxation of the resistance vessels. There tion, there is a dramatic increase in pulmo-
is then a slow, progressive decline over the nary blood flow and an abrupt increase in
next 2 to 6 weeks of life as these pulmonary oxygen tension that inhibits ductal smooth
arterioles remodel from their fetal pattern, muscle voltage-dependent potassium chan-
in which a large amount of smooth muscle nels and results in an influx of calcium
is present in the medial layer, to the adult and ductal constriction.12 In addition, the
pattern, with very little muscle in the media. remaining prostaglandin E2 (is almost com-
The development of the “physiologic ane- pletely metabolized as it passes through the
mia” that normally occurs during this time pulmonary circulation, which results in a
decreases the viscosity of the blood perfus- rapid decrease in serum levels of prostaglan-
ing the lungs, which decreases shear stress din E2 and allows active constriction of the
and also contributes to the overall decrease ductus arteriosus to be unopposed. The duc-
in pulmonary vascular resistance. tus arteriosus constricts rapidly; in mature
infants, functional closure generally occurs
Closure of the Foramen Ovale within 10 to 15 hours after birth. Perma-
Functional closure of the foramen ovale nent closure by intimal cushion formation,
occurs after the placenta is removed from intimal proliferation, fibrosis, and thrombo-
the circulation. With clamping of the umbil- sis may take several weeks.41
ical cord, blood flow through the inferior
vena cava to both atria decreases dramati- MYOCARDIAL PERFORMANCE
cally. Initiation of breathing increases blood AND CARDIAC OUTPUT
flow through the pulmonary bed to the left Fetal myocardium differs from neonatal
atrium. These changes result in a left atrial and adult myocardium in several impor-
pressure that now exceeds the right atrial tant ways. The primary fuel for fetal myo-
pressure, which causes the valvelike flap of cardium is almost exclusively glucose in
the foramen ovale to close. Although func- contrast to the adult heart, which can use
tional closure of the foramen ovale occurs fatty acids as a significant energy source. In
in most infants, anatomic closure is not addition, especially early in gestation, the
always complete. As a result any action that fetal heart grows by hyperplasia of the myo-
raises right atrial pressure to the point that cardial cells in contrast with the newborn
it equals or exceeds left atrial pressure can heart, in which the myocardium grows by
result in a right-to-left shunt across the fora- hypertrophy. Fetal myocardium also func-
men ovale. Likewise, in conditions that have tions distinctly by developing less active
large left-to-right shunts, such as a large tension for a given stretch than does adult
patent ductus arteriosus (PDA) or ventricu- myocardium and therefore has less ability
lar septal defect (VSD), the left atrium may to contract. Thus, ventricular output can be
become dilated, which results in stretching increased only modestly by volume loading
of the atrial septum and incompetence of and only at relatively low atrial pressures;
the foramen ovale and a left-to-right shunt. unlike in the adult, output increases only
In many adults, despite the events leading to slightly at levels more than 2 to 4 mm Hg
functional foramen closure, a probe-patent above baseline. Inotropic stimulation of the
foramen may persist. fetal myocardium also increases cardiac out-
put relatively little. This inability to respond
Closure of the Ductus Arteriosus to changes in preload and in the inotropic
Closure of the ductus arteriosus is a more state is related in part to immaturity of
complex phenomenon. The media of the muscle structure. Early in gestation, there
ductus arteriosus contains smooth muscle are relatively fewer contractile elements,
in a spiral configuration that is maintained an immature sarcoplasmic reticulum with
in a relaxed state, primarily by the action lower affinity for calcium binding and a
some what chaotic overall arrangement of SVC PV

fibers with considerable interstitial tissue. –
62% 95% 5
Toward term, more contractile elements are
present, and these are more mature and are IVC 67%
arranged in a more orderly fashion. Another
factor limiting fetal myocardial performance
is incomplete sympathetic innervation, which –
3 65% 95%
–
5
limits response to inotropic stimulation. The
fetus is best able to increase ventricular out- RA LA
put by increasing its heart rate. There is a
linear relationship between ventricular out- RV LV
put and heart rate up to about 250 beats 30/3 65% 95% 70/5
per minute; thereafter, ventricular output
reaches a plateau and even starts to decline.
As heart rate goes below the normal range,
ventricular output decreases dramatically
because of the limited ability to increase
stroke volume. As a result the fetal myo- — —
30/16 20 65% 95% 70/50 57
cardium is operating under a high-volume
load and responds poorly to any increase MPA Ao
in ventricular afterload. Although adrener-
gic support can be supplied either by cir-
culating catecholamines or through neural Figure 15-3. Representative blood oxygen saturation (%)
pathways, the overall quantitative response and pressure (mm Hg) in various cardiac chambers and
may be less than in the adult. The control of vessels in the normal newborn infant. Ao, Aorta; IVC,
cardiac rate and the distribution of cardiac inferior vena cava; LA, left atrium; LV, left ventricle; MPA,
main pulmonary artery; PV, pulmonary vein; RA, right
output are the major mechanisms for main-
atrium; RV, right ventricle; SVC, superior vena cava.
tenance of circulatory function.
As discussed previously, the left ven-
tricular cardiac output increases dramati-
cally within the first 2 hours after birth and that on the left side of the heart is 92% to
remains elevated for several weeks before 95%. The oxygen saturations may be used to
decreasing to approximately 190 mL/min/ determine the direction of shunting within
kg.40 Because of the high resting values in the heart or great vessels. For example, an
the period immediately after birth, ventric- increased saturation in the right atrium sug-
ular output can be increased only modestly gests a left-to-right shunt at the atrial level;
by volume loading or inotropic stimula- a decreased saturation in the left atrium in a
tion with dopamine and dobutamine. The neonate with otherwise healthy lungs indi-
neonatal myocardium remains sensitive to cates a right-to-left shunt at the atrial level.
the administration of the calcium ion and
responds positively to the lusitropic effects Physical Factors That Control Blood Flow
of milrinone. After the initial newborn Flow (Q) through a vascular bed is governed
period, resting values decrease progressively, by the resistance to flow (R) and the pressure
and ventricular output can be increased decrease across the bed (ΔP) (Ohm’s law).
much more effectively. ΔP
Q=
Normal Physiologic Data in the Newborn R
The normal physiologic values in the heart Furthermore, by application of Poiseuille’s
and great vessels are shown in Figure 15-3. law, resistance to flow is directly related
Pulmonary arterial pressures in the newborn to the viscosity of the blood and inversely
are variable but generally decrease to half of related to the cross-sectional area of the bed
systemic pressure within 8 to 12 hours and (radius).
to one third of systemic pressure within a An appreciation of the general relation-
day or so. Over the next 4 weeks, there is ship of pressure, resistance, and flow is
a further slow, progressive decline to adult important in understanding the pathophys-
levels. iology and natural history of various con-
The oxygen saturation on the right side genital heart defects.
of the heart is approximately 60% to 70%; Blood flows where resistance is least.
Vascular resistance is calculated from the RV LV

formula
ΔP RVP = LVP
Q= PVR < SVR
R Qp > Qs
L – R Shunt
For the systemic circulation, the ΔP (pres-
sure decrease) is systemic arterial pres- PA Ao
sure (SAP) minus systemic venous pressure
(SVP); for the pulmonary circulation, the ΔP A PVR SVR
is pulmonary arterial pressure (PAP) minus
pulmonary venous pressure (PVP).
Pulmonary vascular resistance (PVR) RV LV
= PAP − PVP RVP = LVP

Pulmonary ﬂow PVR = SVR
Qp = Qs
Systemic vascular resistance (SVR) O Shunt
= SAP − SVP
Systemic ﬂow PA Ao
If the pressure decrease is measured in mil-

limeters of mercury and the flow is measured B PVR SVR
in liters per minute per square meter, then the
calculated vascular resistance is considered in
resistance units. One resistance (or Wood) unit RV LV
is equal to 80 dyne • sec/cm5. The maximum RVP = LVP
normal PVR is 2.5 to 3 units, and the maxi- PVR > SVR
Qp < Qs
mum normal SVR is 15 to 20 units. R – L Shunt
Peripheral vascular resistance is not the
only type of resistance that will affect flow.
For example, a narrowed valve provides PA Ao
more resistance to blood flow than does a
wide open valve; a small VSD provides more C PVR SVR
resistance to blood flow than does a large Figure 15-4. Diagrammatic representation of intracardiac
VSD; and a thick, noncompliant ventricular shunting patterns as related to outflow resistances of the
chamber provides more resistance to blood two sides of the heart. Ao, Aorta; L, left; LV, left ventricle;
flow than does a thinner, more compliant LVP, left ventricular pressure; PA, pulmonary artery; PVR,
ventricular chamber. pulmonary vascular resistance; Qp, pulmonary blood flow;
If two similar cardiac chambers or arter- Qs, systemic blood flow; R, right; RV, right ventricle; RVP,
ies (one left-sided or systemic and the other right ventricular pressure; SVR, systemic vascular resistance.
right-sided or pulmonary) communicate
with each other and the opening between shunt is present (Fig. 15-4, A). Because the
them is so large that there is little or no flows and shunting pattern depend on the
resistance to blood flow, the defect is con- relationship of the downstream pulmonary
sidered nonrestrictive. The pressures on each and systemic vascular resistances, these are
side of the opening are fully transmitted called dependent shunts. When the two resis-
and approximately equal. If the opening is tances are equal, no shunt occurs (see Fig.
small (restrictive), there is resistance to blood 15-4, B). When resistance to outflow of the
flow, and the pressures are not fully trans- right ventricle exceeds that of the left ven-
mitted. In the presence of a nonrestrictive tricle (see Fig. 15-4, C)—as might occur with
defect, the resistances to outflow (down- the development of pulmonary vascular
stream resistance) from each of the two disease or, more commonly, when there is
communicating chambers determine the an associated pulmonic stenosis (tetralogy
direction of blood flow. For example, with a of Fallot)—right-to-left shunting is present.
large VSD in which ventricular pressures are When there is a communication between the
equal, pulmonary vascular resistance is usu- two sides of the heart at different anatomic
ally lower than systemic vascular resistance, levels (e.g., arteriovenous malformation,
and pulmonary blood flow is greater than left ventricular–right atrial communica-
systemic blood flow; that is, a left-to-right tion), the pressure difference between the
two chambers or vessels, rather than down- blood exceeds 5 g/dL (saturation equal to or
stream resistance, dictates the magnitude of below 85% in patients with a normal hemo-
the shunt; these are called obligatory shunts. globin level). If the lungs are functioning
For example, in a left ventricular–right atrial normally, the level of systemic arterial blood
shunt, blood shunts continuously through oxygen saturation depends entirely on the
the defect because the left ventricular pres- effective pulmonary blood flow—that is, the
sure is always higher than right atrial pres- amount of blood oxygenated by the lungs
sure, regardless of the distal pulmonary and that subsequently passes into the systemic
systemic vascular resistances. arterial circulation. Neonates frequently
It is customary to relate the cardiac out- experience acrocyanosis that is unrelated to
puts and pressures in each side of the heart. heart disease. The best method of assessing
Thus, if there is three times as much flow for central cyanosis in an infant is to look
into the pulmonary artery as into the aorta, at the tongue. Other diagnostic procedures
there is a 3 to 1 pulmonary-to-systemic are needed to determine the cause of the
flow ratio. If the pressure in the pulmonary cyanosis. Comparing arterial blood oxygen
artery is 60 mm Hg and that in the aorta saturation or Po2 above and below the duc-
is 90 mm Hg, pulmonary hypertension is at tus arteriosus may be beneficial. In addition,
two thirds of the systemic level. the “hyperoxia” test, or ventilation with a
high inspired oxygen concentration, is fre-
PHYSICAL EXAMINATION quently considered a valuable diagnostic
It is imperative to perform a complete phys- tool. An increase of more than 50 mm Hg
ical examination of all neonates and to (and often much higher) in systemic arte-
monitor for ongoing changes suggestive of rial Po2 is seen in infants with primary pul-
pathologic conditions. Some studies have monary problems (especially because high
begun to advocate using pulse oximetry to levels of oxygen tend to dilate the pulmo-
screen all newborns. In 2009 the American nary arterioles and decrease the pulmonary
Academy of Pediatrics and the American arterial pressures). A Pao2 of less than 100
Heart Association issued a scientific state- mm Hg in an enriched oxygen environ-
ment regarding the usefulness of pulse ment indicates congenital heart disease
oximetry in clinical practice. The statement until proven otherwise and should prompt
authors concluded that additional studies an echocardiographic examination and the
were needed before the use of pulse oxim- initiation of prostaglandin E2 therapy. Fre-
etry in all newborns could be recommended quently the practicalities adhere less to the
as a standard of care.42 In an infant who is textbook: a significant increase in systemic
not transitioning in a normal fashion, how- arterial blood oxygen tension or saturation
ever, pulse oximetry may be used in concert can occur in cyanotic heart disease as long
with physical examination findings to sug- as effective pulmonary blood flow is reason-
gest the need for supplementary testing. able. Therefore, a Pao2 of 100 to 250 mm Hg
The neonate with congenital heart disease may be suggestive of congenital heart dis-
must be differentiated from infants with ease and warrants additional investigation.
other acute illnesses. Likewise, an infant A Pao2 above 250 mm Hg makes life-threat-
with known heart disease remains suscepti- ening cyanotic heart disease less likely. If a
ble to other disease processes, including bac- hyperoxia test is performed, direct oxygen
terial sepsis, anemia, and pulmonary disease. measurements should be made simultane-
Acutely ill infants may have several simul- ously in the upper and lower body to exag-
taneous working diagnoses while caregivers gerate any potential difference and thus
are stabilizing their physiologic condition. help to delineate the presence of a right-
In these instances, some additional factors to-left ductal shunt. The measurement of
may suggest cardiac abnormalities. Dysmor- upper and lower body saturation during
phic or syndromic features in any neonate crying can also help to exaggerate potential
should prompt the clinician to pay particu- differences due to ductal shunting.
lar attention to the cardiovascular system as
the infant transitions to postnatal life. RESPIRATORY DISTRESS
Most infants with mild arterial oxygen
CYANOSIS desaturation are tachypneic because of che-
Central cyanosis indicates a reduced arterial moreceptor stimulation but show little or
blood oxygen saturation and is generally no respiratory distress. Congenital heart dis-
visible when reduced hemoglobin in the ease that presents with respiratory distress
is very difficult to diagnose in infants: their been reported in up to 60% of healthy new-
symptoms are usually more insidious and borns.46 Several recent studies have dem-
less dramatic than cyanosis, the differential onstrated a higher incidence of congenital
diagnosis is broader, and the yield of heart heart disease in infants with murmurs in
disease is much less, which lowers one’s the neonatal period. In a study of 7204
index of suspicion. When a physician sees consecutively examined newborn infants,
a newborn lying in a crib, blue and com- fewer than 1% of the neonates were found
fortable, the diagnosis is almost always car- to have cardiac murmurs. All neonates with
diac disease; when the infant is acyanotic, cardiac murmurs were referred for echocar-
tachypneic, and showing retractions, it is diography, and an underlying cardiac mal-
usually not. Infants with respiratory distress formation was diagnosed in 54% of them.47
usually have modest degrees of systemic A retrospective review of 20,323 live births
blood oxygen desaturation, depending on over a 3-year period in a hospital in Israel
the type of circulatory derangement and the found 170 newborns with an isolated find-
severity of pulmonary edema. The respira- ing of a heart murmur who were referred
tory distress is related to decreased lung for echocardiography. Of those infants, 147
compliance in these patients, and intersti- (86%) were found to have structural heart
tial fluid is usually present. Thus, even with defects, including isolated VSD (37%), PDA
a normal separation of circulations, some (23%), and combined VSD and PDA (7%);
degree of hypoxemia is present. abnormalities creating left-to-right shunts
comprised 66% of the diagnoses.48 Thus,
CARDIAC EXAMINATION although any murmur noted in the neona-
tal period should prompt the practitioner
Palpation to be suspicious of congenital heart disease,
The cardiac impulse should be palpated. certain murmurs are nearly diagnostic. An
Obvious cardiac malposition in the right S4 gallop is always abnormal.
chest should be documented and warrants
additional evaluation. The right ventricular ABDOMINAL EXAMINATION
impulse is dominant in a newborn. Hepatomegaly is a nonspecific finding
that may be indicative of increased central
Auscultation venous pressures. It can be associated with
Heart sounds in most newborns with sig- cardiac lesions that volume-load the right
nificant congenital heart disease are abnor- side of the heart (such as a systemic arte-
mal. The rapid heart rates of most neonates riovenous malformation, anomalous pul-
can make this determination difficult even monary venous return, or right-sided valve
for the experienced practitioner. Multiple insufficiency as seen with Ebstein anomaly
studies have assessed the skill of pediatric and absent pulmonary valve syndrome).
cardiologists and general pediatricians in Hepatomegaly may also be associated with
detecting heart disease in inpatient neo- low-output states such as myocarditis, car-
natal settings and have found sensitivity diomyopathy, and tachyarrhythmias.
rates of 80% to 83% for congenital heart
disease.43-45 A single second sound after PERIPHERAL EXAMINATION
the first 12 hours may indicate pulmonary It is imperative to palpate femoral and radial
atresia or transposition of the great arteries. pulses in all newborns. Bounding pulses are
The presence of a pulmonary systolic ejec- typically associated with a widened pulse
tion click may be normal in the first hours, pressure and may be found in congenital
but after that any systolic ejection click is abnormalities with increased diastolic pul-
abnormal, indicating an abnormal pulmo- monary blood flow. Diminished femoral
nary or aortic valve, an enlarged pulmonary pulses or brachial-femoral delay may be
artery or aorta, or truncus arteriosus. If the associated with coarctation of the aorta,
infant has pulmonary disease without con- hypoplastic left heart syndrome, or an inter-
genital heart disease and has a narrowly rupted aortic arch. Inability to palpate pulses
split or single second sound, then a high in all extremities should prompt the exam-
pulmonary vascular resistance is expected. iner to palpate the right carotid or temporal
Although systolic murmurs are more eas- artery. If these pulses remain intact, the diag-
ily distinguished than the first and second nosis would include an aberrant subclavian
heart sounds, they are common during artery in addition to aortic arch obstruction.
the neonatal period and have historically If all pulses are severely diminished, the
obstruction to blood flow is at the aortic A complete and standardized approach is

valve or within the left ventricle. Dimin- needed for the initial echocardiographic eval-
ished femoral pulses should prompt the cli- uation of the neonate. In the usual examina-
nician to initiate therapy with prostaglandin tion the probe is placed just to the left of the
infusion while awaiting confirmatory imag- sternum to obtain parasternal long (Fig. 15-5)
ing or transfer to another center. and short axial images (Fig. 15-6), at the apex
of the heart to obtain an apical four-chamber
IMAGING OF THE NEONATE view (Fig. 15-7), under the xiphoid process to
Accurately diagnosing the anatomy and obtain subcostal coronal (Fig. 15-8) and sagit-
physiology of the cardiac defect is a corner- tal images (Fig. 15-9), and in the suprasternal
stone of pediatric cardiology. To accomplish notch to obtain suprasternal long (Fig. 15-10)
these goals, multiple imaging modalities are and short axial views (Fig. 15-11). More views
available. Currently, the most frequently may be obtained depending on the complex-
used techniques for imaging the newborn ity of the anatomy. If the heart is displaced
are echocardiography, CAT scans, MRI, and as in the case of dextrocardia or congenital
cardiac catheterization. The decision to diaphragmatic hernia, adjustments of probe
perform one or more of these studies will position are required. Numerous sweeps with
depend on the history, clinical examination application of M-mode, two-dimensional
findings, and clinical course of the patient. analysis, Doppler, and color Doppler allow
With the use of these imaging techniques, for an inclusive examination that will give
a complete assessment of the cardiac defect anatomic, physiologic, and functional data.
can be obtained to aid in achieving an opti- For a complete review the reader is referred
mal outcome. to recent textbooks on echocardiography in
pediatric heart disease.49,50
ECHOCARDIOGRAPHY
Echocardiography remains the main imag-
ing technique in pediatric cardiology.6
An echocardiogram is likely the first and Indications for Initial Echocar-
possibly the only cardiac image that will Box 15-2. diographic Examination of the
be obtained to rule in or rule out a car- Neonate
diac abnormality (Box 15-2). Most clinical Syndromes
and surgical decisions can be made purely Trisomy 13
from the echocardiographic examination. Trisomy 18
Advantages of echocardiography include its Trisomy 21
portability, noninvasive nature, provision CHARGE association
of real-time information, and overall ease VACTERL association
of use. Disadvantages of echocardiography DiGeorge syndrome
include limitations in image quality in some Noonan syndrome
clinical circumstances and only fair ability Turner syndrome
to accurately diagnose certain complicated William syndrome
extracardiac vascular anomalies.
Nonsyndromes
Echocardiography is the application of
Congenital diaphragmatic hernia
ultrasound to obtain an image via reflected
Omphalocele
sound waves. Higher-frequency probes,
Midline abnormality workup
usually 5 MHz or higher, are used in the
Tracheoesophageal fistula
newborn since minimal penetration of the
sound wave into the patient is needed and Other
the shorter wavelengths allow clearer resolu- Unexplained hypoxemia
tion of the images. Scatter of the ultrasonic Abnormal findings on cardiac examination
wave, which inhibits image quality, usually Perinatal asphyxia
occurs between interfaces of material that Persistently positive blood culture results
have different densities. Bone and air, when Genetic abnormalities not otherwise specified
adjacent to soft tissue or fluid, produce sig-
nificant artifacts, whereas soft tissue next to CHARGE, Coloboma of the eye, heart disease, atre-
fluid produces minimal artifacts. For this sia choanae mental retardation, genital anomalies,
ear anomalies; VACTERL, vertebral anomalies, anal
reason, clinical conditions such as pneumo-
atresia, cardiac anomalies, tracheoesophageal fistula,
thorax or bronchopulmonary dysplasia may renal anomalies, limb anomalies.
reduce image quality.
RV
LV
PA
LA
RV RV
LV
LV AO
RA
LA
B C
Figure 15-5. Echocardiogram in the parasternal long axis view sweeping anterior (A) to posterior (C) through the heart. Ao,
Aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle.
RV
Ao PA
RA
LA
RV
RV
LV
MV
LV
B C
Figure 15-6. Echocardiogram in the parasternal short axis view sweeping from the base (A) to the apex (C) of the heart.
Ao, Aorta; LA, left atrium; LV, left ventricle; MV, mitral valve; PA, pulmonary artery; RA, right atrium; RV, right ventricle.
RA LA
Ao
RV LV
LA
RA LA
RA
CS
RV LV
RV LV
B C
Figure 15-7. Echocardiogram in the apical four-chamber view sweeping anterior (A) to posterior (C). Ao, Aorta; CS,
coronary sinus; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
Ao
LA
RA LV
LA LA
Ao LV
LV
RA
RA
RV
B C
Figure 15-8. Echocardiogram in the subcostal coronal view sweeping anterior (A) to posterior (C). Ao, Aorta; LA, left
atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
RVOT
LV
RV
DAo
SVC
AAo LA LA
RA IVC
RA
RV
B C
Figure 15-9. Echocardiogram in the subcostal sagittal view sweeping apex (A) to base (C). AAo, Ascending aorta; DAo,
descending aorta; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; RVOT, right
ventricular outflow tract; SVC, superior vena cava.
INNV Left
SVC
carotid
AAo Ao Left
subclavian
LA
RPA
A B
Figure 15-10. Echocardiogram in the suprasternal long axis view sweeping from the patient’s right (A) to left (B) side
assuming a left aortic arch. AAo, Ascending aorta; Ao, aorta; INNV, innominate vein; LA, left atrium; RPA, right pulmonary
artery; SVC, superior vena cava.
M-Mode Echocardiography chamber size. The image is usually obtained

M-mode echocardiography was one of the in the parasternal short-axis view at the
earliest techniques for evaluating cardiac level of the papillary muscle (see Fig. 15-6).
structures. A single line of interrogation is Shortening fraction is defined as follows:
obtained and plotted over time (Fig. 15-12). [(left ventricular end-diastolic dimension
Two-dimensional echocardiography has − left ventricular end-systolic dimension)/
largely replaced this modality, but M-mode left ventricular end-diastolic dimension].
is still used, mainly to calculate shortening The normal value is above 28%. M-mode
fraction and measure wall thickness and echocardiography has long been used to
PA Ao
Ao
RPA
RPA LPA
RPV LA LPV
A B
Figure 15-11. Echocardiogram in the suprasternal short axis view sweeping superior (A) to inferior (B). Ao, Aorta; LA, left
atrium; LPA, left pulmonary artery; LPV, left pulmonary vein; PA, pulmonary artery; RPA, right pulmonary artery; RPV, right
pulmonary vein.
Two-Dimensional Echocardiography
As stated earlier, two-dimensional echocar-
diography incorporating numerous views is
the most common way that a cardiac ana-
tomic diagnosis is made. Systolic function
can also be qualitatively and quantitatively
assessed. Tracing the left ventricular cham-
ber in end systole and end diastole can give
an estimate of ventricular volume, and thus
an ejection fraction can be calculated simi-
larly to shortening fraction. In general, an
ejection fraction above 50% is considered
normal. Not only does two-dimensional
Figure 15-12. M-mode analysis through the left ventricle
echocardiography support anatomic diag-
with a normal shortening fraction of 39%. nosis and functional analysis, but secondary
changes to chamber sizes may give physi-
ologic clues. For example, a PDA may be
estimate cardiac function, but it has limita- large by dimensions, but if left-sided struc-
tions, including the fact that only a single tures are not enlarged, there may be mini-
plane is used to estimate global function mal left-to-right shunting, possibly because
and thus regional wall abnormalities may of PPHN or insufficient passage of time for
be missed. In addition, it is fairly preload these changes to be noted.
dependent and does not measure intrinsic
myocardial contractility per se. Using short- Three-Dimensional Echocardiography
ening fraction to define ventricular function The ability to perform real-time three-
also assumes normal electrical conduction dimensional imaging is a relatively new
and a circular shape of the left ventricle. advancement in technology. The benefit of
Conduction abnormalities or flattening of this technology is that it can improve visu-
the interventricular septum that may occur alization of spatial relationships between
with increased right ventricular volumes structures instead of requiring mental con-
due to shunts or elevated right ventricu- struction of an image from two-dimensional
lar pressures due to persistent pulmonary views (Fig. 15-13). Although three-dimen-
hypertension of the newborn (PPHN) may sional imaging continues to improve, its
invalidate these measurements. Normative practical uses for imaging the newborn are
data are available for wall thickness and minimal at this time.
chamber sizes and are usually referenced to
a z score. The z score is simply a normalized Doppler Echocardiography
value expressed as the number of standard Use of the Doppler principle allows one to
deviations from the mean, and if a z score is determine the direction and velocity of mov-
within ±2, it is considered normal. ing objects being interrogated. Currently,
measurement of blood flow velocity and width of the regurgitant jet. Stenotic areas are
direction is the main use for Doppler analy- also easily seen with color analysis because
sis, although measurement of myocardial the solid red or blue usually becomes multi-
velocity, termed tissue Doppler imaging, has color due to the abrupt increase in velocities
recently been introduced as another way that occurs in those areas (Fig. 15-15).
to quantify systolic and diastolic function. Pulse and continuous wave Doppler are
Color, pulsed wave, and continuous wave simply two technical ways to measure the
Doppler are the three main techniques used velocity of the object of interest. Pulse Dop-
for analysis. pler enables one to interrogate a specific
Color Doppler simply transforms the area and define the velocity at that point.
image of the interrogated area into colored The drawback is that high-velocity objects
pixels. By convention, shades of red signify cannot be measured accurately because
an object moving toward the transducer they will exceed the pulse Doppler capa-
and shades of blue indicate an object mov- bilities. Continuous wave Doppler can
ing away from the transducer. Color Doppler measure high-velocity objects because the
does not necessarily give quantitative infor- system is continuously measuring signals,
mation, but it is extremely helpful for identi- but it cannot pinpoint the area where the
fying minor defects such as a small muscular change of velocity occurs. This is impor-
VSD or PDA that might not easily be seen by tant, because the area where the change in
standard two-dimensional echocardiography velocity occurs is usually the site where a
(Fig. 15-14). Color analysis also aides in the stenosis is located. By convention, objects
qualification of regurgitant jets based on the moving away from the transducer have
velocities designated below a baseline and
objects with flow toward the transducer
have velocities designated above the base-
line. It must also be mentioned that the line
of interrogation should be as close as pos-
sible to parallel to the object of interest or
MV
else velocities, and thus also gradients, will
be underestimated.
Tissue Doppler imaging (TDI) is a newer
technique that measures the velocity of the
TV AoV myocardium via Doppler. The area inter-
rogated is usually the free wall at the level
of the AV valves. Three waves are usually
obtained via TDI: an e′ wave correspond-
ing to early ventricular relaxation, an a′
Figure 15-13. Three-dimensional echocardiographic wave corresponding to atrial contraction,
image of the cardiac valves. Av, Aortic valve; MV, mitral
and an s′ wave corresponding to ventricular
valve; TV, tricuspid valve.
systolic function (Fig. 15-16). The e′ and a′
.76
TArch
Coarctation -.76
MPA 4 4
RPA
RPA DAo
LPA PDA
105
Figure 15-14. Black and white rendition of an image of a Figure 15-15. Doppler echocardiogram showing a
small patent ductus arteriosus (PDA) obtained using color coarctation of the aorta as revealed by color flow aliasing
Doppler echocardiography. LPA, Left pulmonary artery; at the coarctation site. DAo, Descending aorta; RPA, right
MPA, main pulmonary artery; RPA, right pulmonary artery. pulmonary artery; TArch, transverse aortic arch.
waves quantify diastolic function, and the and deceleration of blood, and viscous forces.
s′ wave quantifies systolic function.51 This This formula can be simplified to
technique is less preload dependent and
therefore may be more useful than other Δ P = 4v2
previously described methods. TDI has assuming minimal proximal velocity, a dis-
already been used in patients with broncho- crete stenosis, and minimal viscosity. By
pulmonary dysplasia and congenital dia- using all three Doppler techniques and the
phragmatic hernia to assist in quantifying Bernoulli equation, the physiology can be
right ventricular function, and use of this thus determined (Fig. 15-17). For example, a
technique will likely continue to grow as left-to-right shunt is seen via color Doppler
more data become available.52-54 through a PDA with a peak velocity of 3.5 m/sec
Estimation of pressure gradients between by continuous wave Doppler. The pressure
two separate areas is obtained by measuring difference between the aorta and main pul-
the blood velocity across the site and using monary artery is 3.5 m/sec × 3.5 m/sec × 4
the Bernoulli equation: = 49 mm Hg. Furthermore, the right ven-
ΔP = ½ ρ (v2 − v1 ) + ρ f(dv / dt) ds + R(μ) tricular systolic pressure can be calculated
as aortic systolic pressure minus 49 mm Hg.
where ΔP is the pressure difference across the Similarly, if the tricuspid jet is 2.5 m/sec, the
stenotic area, ρ is the density of blood, v1 and pressure difference between the right atrium
v2 are the velocities proximal and distal to and right ventricle is 25 mm Hg. Assuming
the stenosis, R is the viscous resistance, and that a normal right atrial pressure is 5 mm
µ is the viscosity of the fluid. The three com- Hg, the right ventricular systolic pressure
ponents of the formula account for kinetic is approximately 30 mm Hg. Numerous
energy, loss of energy through acceleration calculations are thus performed to quan-
tify the physiology present. This equation
will underestimate the gradient if there is a
long-segment stenosis or if polycythemia is
.21
present because of the simplification. Con-
10
versely, if there is a significant proximal ste-
5 nosis in series, such as a stenotic aortic valve
s 15
-.21
and a coarctation, the proximal velocity
10 must be taken into account or else the distal
5 gradient will be overestimated. In general,
[cm/s] a velocity of 1 m/sec or less can be ignored.
-5
a -10 Strain and Strain Rate
-15 Strain (ε) is defined as the deformation of an
e
-20 object relative to its original length and is
90 expressed as a percentage. Strain rate is the
Figure 15-16. Tissue Doppler analysis of the left local rate of deformation or strain (ε) per unit
ventricular free wall at the level of the mitral valve annulus. of time and is expressed as inverse seconds.
AoV RV
AAo
LV
LA
A B
Figure 15-17. Color flow aliasing at the level of a stenotic aortic valve (A) with a peak velocity of 3 m/sec by continuous
wave Doppler echocardiography estimating a 36 mm Hg gradient (B). AAo, Ascending aorta; AoV, aortic valve; LA, left
atrium; LV, left ventricle; RV, right ventricle.
Figure 15-18. Strain analysis based on echocardiographic imaging in a patient with hypoplastic left heart syndrome.
These values can be obtained via TDI or via as little as 2.5 kg. Transesophageal echo-
speckle tracking technology using echocar- cardiography is most often performed in
diography. These parameters are probably neonates in conjunction with cardiac cath-
the least preload-dependent values obtained eterization or surgical intervention to give
via echocardiography and thus are theoreti- real-time information and aid in the inter-
cally the best values to quantify contractil- vention being performed (Fig. 15-19).58,59
ity and relaxation. This technique does not
use geometrical assumptions and therefore COMPUTERIZED AXIAL TOMOGRAPHY
is ideal for quantifying function in patients AND MAGNETIC RESONANCE IMAGING
with complex congenital anatomy (Fig. CAT or MRI scans may add additional infor-
15-18). Minimal data currently exist in pedi- mation that the echocardiogram cannot
atrics, especially for the premature neonate, provide. As noted earlier, complex extra-
but like TDI, this technique will probably cardiac abnormalities involving pulmonary
continue to gain acceptance over time.55-57 arteries, pulmonary veins, and the aortic
arch may not be well delineated by echo-
Transesophageal Echocardiography cardiography. Mixed total anomalous pul-
Transesophageal echocardiography is simply monary veins and tetralogy of Fallot with
the application of all the echocardiographic multiple aortopulmonary collaterals are just
techniques described earlier via a probe two examples of cardiac defects for which
inserted down the esophagus. It is rarely CAT and MRI are superior to echocardiogra-
indicated for newborns because most, if not phy for defining extracardiac abnormalities
all, of the desired images can be obtained (Figs. 15-20 and 21). In addition to anatomic
using transthoracic echocardiography. Fur- information, both modalities have the abil-
thermore, neonates would likely need to be ity to provide hemodynamic data, with MRI
intubated for this procedure to secure an air- being superior to CAT in that respect.
way. If the procedure is needed, probes are In general, MRI is preferable to CAT
currently available for neonates weighing because of the lack of radiation exposure.
FPS: 108.9
2 LA
RA
4 Ao
RV LV
6
Figure 15-19. Transesophageal echocardiogram in a

patient with an atrioventricular septal defect. Note the
common atrioventricular valve and the large central defect.
LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right
ventricle.
Since many children with complex cardiac

anatomy may undergo multiple imaging
and catheterization procedures over a life-
time, minimization of radiation exposure is
warranted. CAT customarily requires con-
trast, which is a relative contraindication Figure 15-20. Three-dimensional computerized axial
tomographic scan reconstruction for a patient with
in patients with renal insufficiency (Table
tetralogy of Fallot, pulmonary atresia, and multiple
15-1). Some concerns have also been raised aortopulmonary collaterals. This left posterior oblique view
regarding MRI and use of gadolinium con- shows multiple collateral vessels arising from the aorta and
trast in patients with renal insufficiency asso- supplying blood to the small pulmonary arteries. Ao, Aorta.
ciated with nephrogenic systemic fibrosis.60
Because of this concern, gadolinium is prob-
ably best not used in those patients until such as balloon atrial septostomy or valvu-
more data are available. CAT produces images loplasty.61 Disadvantages of catheterization
more quickly than MRI; thus in a patient in include its invasive nature and the radiation
unstable condition, CAT may be preferable and contrast exposure involved (see Table
to MRI. CAT scanning is also not as affected 15-1).
by artificial materials such as stents, coils, In summary, multiple imaging techniques
and so on, compared with MRI. As technol- are available for evaluation of the neonate
ogy advances, more devices have become with suspected heart disease. Echocardiog-
MRI compatible. It is essential that when- raphy will likely remain the main modal-
ever an patient may undergo MRI, screen- ity for the reasons stated earlier, but other
ing for device compatibility be performed techniques may give additive information
(www.mrisafe.com). Cardiac MRI may not depending on the clinical situation. Imag-
be readily available at some institutions, so ing technology will undoubtedly improve
the decision regarding type of imaging may over time, but the goal will always remain
be driven by practical considerations. the same: complete and accurate assessment
of anatomy, physiology, and function of
CARDIAC CATHETERIZATION the cardiac defect.
Like CAT and MRI studies, catheterization
procedures provide excellent images of DIAGNOSTIC GROUPS OF
extracardiac structures. Nonetheless, most CONGENITAL HEART DISEASE
anatomic, physiologic, and functional data The spectrum of neonatal congenital and
can be obtained via the imaging modalities acquired heart disease is conventionally
previously described. It would be extremely divided into broad categories based on pre-
rare to perform a catheterization procedure sentation, unifying pathologic features, and
purely for imaging purposes. Catheterization anticipated course. Practically, there can be
is reserved for neonates in whom pulmo- significant variation in the duration of neo-
nary vascular resistance measurements are natal transition, which impacts the observed
needed or when an intervention is required, physiology of a given lesion. Ideally, lesions
Table 15-1. Advantages and Disadvantages of Imaging Techniques
Cardiac
Echocardiography CAT MRI Catheterization
Portable Yes No No No
Noninvasive Yes Yes Yes No
Intracardiac structures +++ ++ +++ +
Hemodynamic assessment ++ + ++ +++
Extracardiac structures ++ +++ +++ +++
Contrast exposure No Yes No Yes
Radiation exposure No Yes No Yes
Interventional capability No No No Yes
CAT, Computerized axial tomography; MRI, magnetic resonance imaging. + to +++, The greater the
number of plus signs, the greater the advantage of the test.
can be classified by their primary presenting and truncus arteriosus, present with respi-
features: (1) cyanosis caused by obstruction ratory distress in infancy. Often these neo-
to pulmonary blood flow or poor mixing, (2) nates are asymptomatic immediately after
hypoperfusion and shock caused by obstruc- birth. As the pulmonary vascular resistance
tion to systemic blood flow, or (3) mild or falls, infants may begin to manifest signs of
no cyanosis with tachypnea and increased increased pulmonary blood flow, including
pulmonary blood flow. This section dis- tachypnea, tachycardia, diaphoresis, hepa-
cusses these types of presentation, the most tomegaly, and eventually failure to thrive.
common lesions in each, the diagnostic tests An exception to this situation is the preterm
necessary to distinguish among the lesions, infant, in whom there may be hemodynami-
subsequent therapy, and the differential cally significant left-to-right shunting within
diagnosis of noncardiac disease. a few days following delivery that contrib-
utes to earlier onset of symptoms. When the
MILD OR NO CYANOSIS WITH lung, particularly the pulmonary vascular
RESPIRATORY DISTRESS AND bed, is underdeveloped or damaged, such
INCREASED PULMONARY BLOOD FLOW as with diaphragmatic hernia, omphalocele,
Infants with a primary presentation of or chronic lung disease, a small shunt seems
tachypnea secondary to cardiac disease can much larger because of the reduced size of
be categorized into two major subgroups: the pulmonary vascular bed in these infants.
(1) those with pure left-to-right shunts, in The differential diagnosis of infants with
whom the shunt solely consists of pulmo- respiratory distress includes parenchymal
nary venous return being directed back to lung disease, an aspiration syndrome, dia-
the pulmonary arterial circulation, so that phragmatic hernia, pneumonia, and PPHN.
any arterial desaturation is secondary to The premature infant with resolving respira-
alveolar fluid or an intrapulmonary shunt; tory distress syndrome (RDS) who requires
and (2) those with bidirectional shunts increasing respiratory support may have
(complete mixing lesions), in whom sys- either an increasing ductal shunt or the
temic venous blood is also directed back onset of interstitial lung disease. Thus,
to the systemic arterial circulation, which several days of careful evaluation may be
directly causes some arterial desaturation. required before the presence of heart disease
Both groups may have elevated pulmonary is fully appreciated.
venous pressures or pulmonary blood flow
that causes interstitial edema, at which Ventricular Septal Defect
point respiratory distress becomes apparent. An isolated VSD accounts for between 30%
Some of the most common defects in con- and 40% of all congenital heart disease. The
genital heart disease, including simple left- majority of isolated VSDs are very small and
to-right shunt lesions (atrial and ventricular restrictive. In these infants, the resistance
septal defects, PDA, endocardial cushion to flow between the left and right ventricles
defect, arteriovenous malformations, and allows the pulmonary vessels to mature nor-
aortopulmonary window) as well as more mally into adult-type vessels. With a rapid
complex complete mixing lesions such as decrease in pulmonary vascular resistance,
anomalous pulmonary venous connection there is a corresponding decrease in right
ventricular pressure, and a left ventricular– animals is certainly less responsive to the
right ventricular pressure gradient will arise. constricting effects of oxygen. The relaxing
Therefore a left-to-right shunt can develop effects of prostaglandin E2 and prostacyclin
quickly, resulting in a loud (grade 3 to 4/6) are greater in the immature ductus arterio-
systolic murmur that is often present in the sus, and the metabolism of prostaglandin E2
newborn period. Despite the low pulmonary is not efficient. As a result, even the small
vascular resistance, the resistance to flow at circulating concentrations of prostaglan-
the VSD prevents large-volume left-to-right din E2 that may be present in the immature
shunting, which averts symptoms of conges- infant can cause the ductus arteriosus to
tive heart failure. Infants with this defect rarely remain in a partially relaxed state. The prin-
demonstrate pulmonary overcirculation. As a ciples discussed for VSD also apply to PDA.
result, most of these defects follow their natu- However, because there is length to the duc-
ral history and close spontaneously, and the tus arteriosus as well as caliber, resistance to
remainder rarely require surgical intervention flow is greater. A nonrestrictive PDA is less
because the defect and resulting additional common, so that systemic-level pulmonary
pulmonary blood flow do not contribute to hypertension is also less common.
the development of additional abnormalities. In a full-term infant with a PDA, the out-
In a large, nonrestrictive VSD (see Fig. come depends on the size of the channel.
15-4), the pressure in the right ventricle and With the gradual decrease in postnatal pul-
pulmonary artery is at systemic levels. If the monary vascular resistance, a left-to-right
thick-walled pulmonary vessels matured nor- shunt develops from aorta to pulmonary
mally, the vascular resistance would decrease artery, which produces excessive pulmonary
rapidly, and there would be a large left-to- blood flow, increased pulmonary venous
right shunt with left ventricular failure and return, and left atrial and ventricular dilata-
pulmonary edema. Such a series of events is tion. A small PDA produces only the typi-
unusual. In fact, when a large VSD is pres- cal continuous machinery murmur and full
ent, a heart murmur is not usually heard, pulses. A moderate to large PDA may pro-
even in the newborn period. The left-to-right duce signs of congestive heart failure as well
shunt does not develop rapidly, because the as a typical continuous murmur and wide
pulmonary resistance vessels remain heav- pulse pressure (bounding pulse), often in
ily muscular for a longer period than nor- the second month of life. In the healthy
mal and the decrease in pulmonary vascular term infant, only rarely does heart failure
resistance is delayed. The variation in pul- occur in the newborn period.
monary vascular resistance from one child to
the next is considerable. In some infants the Patent Ductus Arteriosus in Preterm Infants
resistance decreases considerably; in others, As noted earlier, preterm infants, and partic-
hardly at all. When there is a large defect, ularly very low-birth-weight infants, have a
the shunt is usually maximal by 2 to 3 weeks significantly increased incidence of persistent
of age, so that congestive heart failure, when PDA compared with their term peers. The
it occurs, is usually present by 4 weeks of age. PDA of the preterm infant warrants specific
discussion, because it may seriously com-
Patent Ductus Arteriosus plicate the management of RDS. Although
Persistent patency of the ductus arteriosus the left ventricle is capable of maintaining
beyond the first few days of life accounts for near-normal systemic blood flow even with
10% to 15% of all congenital heart defects. a large left-to-right shunt in the premature
Premature infants comprise the majority infant, the increased intravascular blood vol-
of patients with persistant patency of the ume and the associated increase in interstitial
ductus arteriosus. The proportion increases fluid aggravate the respiratory distress already
with lower gestational age and weight, with present. If left ventricular oxygen demand
upto 70% of infants born less than 28 weeks exceeds supply, the left ventricle may begin
of age demonstrating ductal patency.62 to fail, which raises pulmonary venous pres-
Patency of the ductus arteriosus may result sure and further increases interstitial fluid
from adverse events such as hypoxia or aci- production. In addition, pulmonary arterial
dosis in the newborn. Persistent patency pressures may be elevated because of the non-
of the ductus arteriosus occurs more fre- restrictive PDA itself or because of pulmonary
quently in premature infants than in full- venous hypertension, which may further
term infants. The exact mechanisms are not decrease lung compliance and exacerbate the
clear. The ductus arteriosus in premature pulmonary dysfunction. Thus, a PDA in the
presence of RDS may seriously affect pulmo- undergoing treatment for a hemodynami-
nary function by a variety of mechanisms. cally significant PDA as identified by these
The diagnosis of a PDA may be difficult markers have improved outcomes compared
in that tachycardia and an intermittent with peers whose PDAs are identified as sig-
systolic murmur may be the only ausculta- nificant by conventional methods.
tory findings. A wide pulse pressure is often Part of the challenge in identifying infants
present, as is increased precordial activity. with a significant PDA is that the manage-
Ventilator therapy and continuous positive ment approach to these infants remains
airway pressure may mask not only the clin- controversial. Constriction of the ductus
ical findings but also the radiographic find- arteriosus in premature infants has been
ings of a PDA. When the chest radiograph achieved by pharmacologic manipulation
shows a large heart and pulmonary venous using inhibitors of prostaglandin synthesis
congestion in the presence of signs of a PDA or by surgical ligation. Permanent closure
and a large liver, there is no problem in diag- of the ductus arteriosus requires both effec-
nosis. However, for many reasons, the heart tive muscular constriction to block luminal
may not be very large, and severe RDS may blood flow and anatomic remodeling to pre-
obscure radiographic findings of cardiomeg- vent later reopening. In the last few years,
aly and pulmonary edema. In the premature multiple investigators have looked for ways
infant with pulmonary disease, impaired to determine the appropriate treatment strat-
oxygen exchange in the lung may maintain egy for premature infants with a PDA. To
an elevated pulmonary vascular resistance, ascertain which patients require treatment,
which masks the presence of PDA. Improve- investigators must clearly show a morbidity
ment in the pulmonary disease permits the or mortality risk associated with a PDA in this
pulmonary resistance to fall, and signs of a patient group. Several observational studies
left-to-right ductal shunt to ensue. Thus, a have linked a ductus arteriosus in premature
PDA must be suspected in all infants with infants with increased risk of chronic lung dis-
severe RDS when the illness is protracted, ease, necrotizing enterocolitis, intraventricu-
blood gas concentrations suddenly deterio- lar hemorrhage, diminished regional cerebral
rate and require manipulation of ventila- oxygen saturation63,72 and overall poor
tion, or apneic episodes are intensified. Fluid neurodevelopmental outcome and mortal-
balance must be closely monitored, because ity.62,70-71 Both indomethacin and ibuprofen
excess fluid administration may exacerbate have been studied extensively over the last
the physiology of a PDA and induce con- decade and they have been determined to be
gestive heart failure. Infants must undergo equally effective in closing a PDA.59,68 How-
auscultation for murmurs several times ever, confounding the decision to close the
each day during the illness and should be duct are additional data from several studies
briefly removed from the ventilator to per- linking treatment with indomethacin to nec-
mit proper auscultation. Echocardiography rotizing enterocolitis, platelet dysfunction,
and Doppler imaging are diagnostic. Color and renal failure and ibuprofen to pulmo-
flow Doppler mapping can detect even a nary hypertension and hemorrhage.71,73-76
small, hemodynamically insignificant PDA. Although these risks may be acceptable to
In the past, a large left atrium-to-aortic physicians facing the significant morbidities
ratio, bulging of the atrial septum from left associated with intraventricular hemorrhage
to right indicating increased left atrial pres- or necrotizing enterocolitis, a Cochrane
sure, a dilated left ventricle, and the need for review demonstrated that administration of
severe fluid restriction and diuresis together indomethacin at less than 24 hours of life
with failure of aggressive ventilatory man- regardless of PDA status is associated with a
agement were considered sufficient to sug- reduction in the risk of severe intraventricular
gest that the ductus was hemodynamically hemorrhage but has no impact on mortality
significant. Recent studies have determined or severe developmental disability at 18 to 36
that conventional echocardiographic mark- months.77 As a result, several recent studies
ers do not predict outcome or neurodevel- have challenged the idea that premature neo-
opment at 2 years.45,63-65 As a result, several nates should receive prophylactic treatment.
studies have used biomarkers, including
troponin T, brain natriuretic peptide (BNP), Aortopulmonary Window
and N-terminal pro-BNP, to distinguish An aortopulmonary widow is a relatively
a hemodynamically significant PDA.66-69 uncommon communication between the
The question remains whether infants ascending aorta and the pulmonary trunk
differing from a truncus due to the pres- It occurs in 1% of cases of congenital heart
ence of two semilunar valves. The defect, disease and may be fatal by a mean age of
although variable in size, is very proximal 2.5 months if untreated.78,79 The patho-
and, unlike a PDA, does not have length; physiology is variable, but generally, as
thus flow is determined simply by the differ- pulmonary vascular resistance falls in the
ence in systemic and pulmonary resistances. first days of life, torrential pulmonary blood
As a result, a large left-to-right shunt may flow ensues, and the patient rapidly devel-
develop early in life. Classic cardiac examina- ops significant pulmonary overcirculation
tion findings include a systolic murmur with and symptoms of heart failure, including
middiastolic rumble secondary to increased tachypnea, failure to thrive, feeding diffi-
blood flow across the mitral valve. The elec- culties, and sweating. Due to the excessive
trocardiograph (ECG) typically demonstrates pulmonary blood flow, infants with truncus
left or biventricular hypertrophy. The classic arteriosus are only minimally cyanotic and
chest radiographic findings include cardiac frequently develop oxygen saturation levels
enlargement with prominence of pulmonary above 90%. If there is proximal pulmonary
artery and pulmonary vasculature. Due to the artery stenosis, the described clinical pre-
magnitude of the shunting that can occur, sentation may be delayed. In the newborn
these patients are often referred for surgical period, classic physical examination find-
repair at the time of diagnosis to avoid the ings include a hyperdynamic precordium, a
development of pulmonary vascular disease. left precordial bulge, a loud single S2 with
an early systolic ejection click, and a systolic
Combined Shunt Defects ejection murmur along the left sternal bor-
Although an isolated VSD, PDA, or atrial sep- der. If the truncal valve is insufficient, an
tal defect rarely causes symptoms of heart early diastolic decrescendo murmur may be
failure in the full-term newborn, combina- noted at left midsternal border accompanied
tions of these are more likely to do so. For by signs of heart failure immediately after
example, in a term infant with the clinical birth. As pulmonary blood flow increases,
features of VSD, if cardiac failure and respi- the patient develops a wide pulse pressure
ratory distress develop in the first week or and bounding pulses due to continuous dia-
two of life, an additional shunt or another stolic flow into the pulmonary arteries and
cardiac or vascular abnormality might be an apical rumble from increased flow across
present. In infants beyond the first few days the mitral valve. The ECG frequently dem-
of life, it is important to remember that onstrates right, left, or biventricular hyper-
the closing ductus arteriosus may unmask trophy and should be used to rule out the
another lesion such as a coarctation or arch unusual scenario of myocardial ischemia.
interruption that causes an infant in stable Medical management can be extremely
condition to abruptly become symptomatic. challenging if there is no obstruction to
pulmonary blood flow and is focused on
Complete Atrioventricular Septal Defect alleviating symptoms with diuresis, inotro-
(Endocardial Cushion Defect) pic support to augment cardiac output, and
Endocardial cushion defects are composed ventilatory support until the patient can
of atrial and ventricular septal defects as undergo definitive surgical repair. Mortality
well as a common atrioventricular valve in the first year of life may be higher than
orifice. In isolation these lesions are rarely 80% without repair.41 Thus early identifica-
associated with cardiac failure in the new- tion of neonates with truncus arteriosus can
born. Patients with signs of early failure be critical to their long-term survival.
may have a more complex lesion with asso-
ciated left-sided heart obstruction, valvular Total Anomalous Pulmonary Venous
insufficiency, or, less commonly, left ven- Return
tricular-to-right atrial shunting that causes In total anomalous pulmonary venous
an obligatory shunt (not dependent on pul- return (TAPVR), also known as total anoma-
monary vascular resistance). lous pulmonary venous connection, both sys-
temic and pulmonary venous flows return
Truncus Arteriosus to the right atrium, where they mix. There
Truncus arteriosus is characterized by a is an obligate right-to-left shunt across the
single arterial trunk that arises from the atrial septum that is the only preload to the
heart and gives rise to the aorta, the pul- left side of the heart and provides the sys-
monary arteries, and the coronary arteries. temic cardiac output. Oxygen saturations
in all cardiac chambers are identical and are with qR in V3R but may be without tall
determined by the relative amount of pul- spiked P waves. The chest radiograph dem-
monary blood flow. TAPVR types are clas- onstrates pulmonary venous obstruction
sified according to the manner in which with diffuse densities in a reticular pattern
blood from the confluence returns to the fanning out from the hilum and obscur-
heart: supracardiac (~50% of cases), cardiac ing the cardiac borders. The heart is not
(~25%), infradiaphragmatic (~15%), and enlarged. Infants with this defect must be
mixed (~10%). The location of the defect symptomatically supported until a cardiac
and the degree of obstruction dictates the surgeon is available. Most undergo surgical
presentation of an infant with TAPVR. repair within a few hours of diagnosis. All
The majority of infants with unobstructed children with very severe respiratory dis-
venous return have a dramatic increase in tress who are candidates for extracorporeal
pulmonary blood flow as vascular resistances support should undergo echocardiography
fall over the weeks after birth. As a result, it before initiation of support. The presenta-
is not uncommon for pulmonary blood flow tions of severe meconium lung disease and
to be three or more times that of the pre- severe obstruction in TAPVR are similar and
served systemic circulation. As a result oxy- easily confused. This form of TAPVR remains
gen saturation percentages are typically in one of the few cardiac surgical emergencies
the upper 80s and low 90s, and there is no in the newborn.
clinically apparent cyanosis. Instead, these The most severe form of anomalous
infants manifest tachypnea, poor feeding, venous return is complete atresia of the
repeated “respiratory infections,” failure to common pulmonary vein with no defini-
thrive, and clinical signs of heart failure. On tive egress of blood from the lungs. These
physical examination, there is a prominent infants become profoundly cyanotic imme-
right ventricular impulse, a widely split S2 diately after birth and have markedly
with an accentuated pulmonary component, diminished pulmonary blood flow. There
and an S3 gallop. There may be a systolic are no significant cardiac examination find-
murmur along the left upper sternal bor- ings, and the chest radiograph demonstrates
der reflective of increased pulmonary blood
flow across the pulmonic valve and relative
pulmonary stenosis. The ECG characteristi- SVC
cally demonstrates a tall, peaked P wave in
lead II, right axis deviation, and right ven- RUPV
tricular hypertrophy. The chest radiograph
shows signs of increased pulmonary blood
flow with enlarged right atrium and ventri-
cle, prominent pulmonary artery, and in the
case of supracardiac veins draining into the
left innominate vein, the “snowman sign”
created by the large supracardiac shadow.
In contrast, obstructed TAVPR (Fig.
15-21), which is more common in the infra-
diaphragmatic type, typically manifests
after the first 12 hours of life with rapid Verticle vein Pulmonary
progression of increased work of breathing, confluence
feeding failure, and cardiorespiratory col-
lapse. The differential diagnosis at the time Stenosis
of presentation often includes PPHN, RDS,
pneumonia, pulmonary lymphangiectasia,
meconium aspiration, and hypoplastic left
heart syndrome. Cardiovascular findings are
minimal. The right ventricular impulse is Figure 15-21. Three-dimensional computerized axial
tomographic scan reconstruction (posterior view) for a
not increased and S2 is normally split. There
patient with mixed total anomalous pulmonary venous
may be a soft blowing murmur in the pul- return. The right upper pulmonary vein (RUPV) drains into
monic area, but the remainder of the cardiac the superior vena cava (SVC), with the other veins draining
examination yields normal finding. Hepato- into a confluence, then down via a vertical vein into the
megaly is almost always present. The ECG hepatic veins. Note the narrowing in the vertical vein where
demonstrates right ventricular hypertrophy a stenosis is present.
severe venous obstruction. Most infants distress or meconium aspiration. An excep-

with atretic pulmonary veins die within a tion in the cardiac group is tricuspid insuffi-
few days of life. ciency resulting from myocardial ischemia,
in which a history of perinatal asphyxia is
Additional Defects common. Additional testing may be benefi-
Interference with inflow to the left ventricle, cial in differentiating pulmonary and car-
as in congenital mitral stenosis or cor triatri- diac abnormalities. Simultaneous upper and
atum, may lead to severe pulmonary venous lower extremity pulse oximetry measure-
congestion and respiratory distress but may ments can be diagnostic. If the oxygen satu-
not compromise systemic perfusion to any ration in the upper body is lower than that
major degree. Congenital mitral stenosis in the lower body, the infant most likely
may be related to parachute mitral valve has dextro-transposition with pulmonary
or double-orifice mitral valve with chordae hypertension or coarctation of the aorta. In
that are shortened and deformed and valve contrast, infants with PPHN have elevated
leaflets that are thickened and dysplastic. pulmonary vascular resistance, and the duc-
Infants are typically small with growth fail- tus arteriosus, if patent, shows right-to-left
ure and have wheezing and dyspnea. The ductal shunting with subsequent lowering
cardiac examination demonstrates a rum- of the blood oxygen saturation or Po2 in the
bling diastolic murmur with an opening descending aorta. Chest radiographs taken
snap. Chest radiograph demonstrates left in the first few days of life usually show
atrial enlargement and pulmonary venous normal heart size. Most cyanotic lesions are
congestion. Infants with cor triatriatum associated with either a diminutive pulmo-
have a similar presentation and in many nary artery (e.g., pulmonary atresia) or one
instances have been diagnosed as having that is transposed to the right; thus the nor-
chronic lung disease and have undergone mal pulmonary artery contour at the upper
treatment for many months before a con- left region of the cardiac silhouette is absent.
genital cardiac malformation is suspected. In addition, the aortic arch should be visual-
ized, because the aorta may descend to the
CYANOTIC HEART DISEASE right of the spine in right-sided obstruc-
Central cyanosis indicates reduced arterial tive lesions (especially if associated with
blood oxygen saturation and is generally DiGeorge syndrome). Finally, an attempt
visible when the level of reduced hemoglo- should be made to evaluate the pulmonary
bin in the blood exceeds 5 g/dL. The typical vascularity. Although assessment of pulmo-
picture of the infant with cyanotic heart dis- nary vascularity radiographically depends
ease is the development of cyanosis in the on the quality of the image and lung expan-
first few hours of life, which may be noted sion, if there are diminished markings on
initially only with crying or feeding, and the a good-quality radiograph with normally
absence of respiratory distress. As the ductus inflated lungs in the absence of PPHN, there
arteriosus begins to close, the cyanosis may is almost always heart disease.
become progressively more obvious. If the patient is not at a facility where
There are two major subgroups of lesions echocardiography can be performed, imme-
that feature cyanosis as the primary finding: diate transfer is mandatory. Stabilization
(1) lesions with obstruction to pulmonary before the transport is of utmost impor-
blood flow, and (2) lesions with normal or tance: metabolic requirements must be
increased pulmonary blood flow but with reduced to a minimum to provide adequate
separation of the pulmonary venous return substrate delivery, and if oxygen delivery is
from the systemic arterial circulation. In borderline (measured blood oxygen satura-
both subgroups, effective pulmonary blood tion is ≤80%, Po2 is ≤30 to 35 mm Hg, or
flow is low. The differential diagnosis of these metabolic acidosis is present), prostaglan-
infants includes mild pulmonary disease, din E1 infusion started at 0.05 µg/kg/min
PPHN, abnormalities of the central nervous and increased to 0.15 µg/kg/min should be
system, and methemoglobinemia. The ini- initiated. Prostaglandin E1 effectively dilates
tial evaluation usually directs the physician the ductus arteriosus to provide adequate
to strongly suspect cardiac disease. The his- pulmonary or systemic blood flow, and the
tory of the cyanotic infant with heart disease infant’s condition can then be stabilized
is generally benign, and the pregnancy and and carefully evaluated if a duct-dependent
delivery uneventful. In contrast, the infant lesion is present. It is appropriate to admin-
with PPHN often has a history of perinatal ister prostaglandin E1 to any infant in whom
the diagnosis of cyanotic congenital heart dis- of the right ventricle to generate sufficient
ease is strongly suspected, even before a complete force to eject blood into the pulmonary
evaluation is performed. Prostaglandin E1 has vessels. Newborns may have massive car-
well-defined side effects, such as apnea, jit- diomegaly, marked cyanosis, holosystolic
teriness or even frank seizures, hypotension murmurs, a gallop rhythm, hydrops, and
with peripheral vasodilatation, and a pos- pulmonary artery hypoplasia. The ECG will
sible increased risk of infection that should demonstrate right atrial hypertrophy, and
be expected by the treating physician. Fluid there may be associated Wolff-Parkinson-
administration may be necessary after ini- White syndrome (short PR interval and a
tiation of prostaglandin E1 treatment to delta wave). The chest radiograph frequently
maintain the arterial blood pressure if there demonstrates significant cardiomegaly, or
is significant systemic vasodilatation, and “wall-to-wall heart.” Infants with severe dis-
intubation may be necessary if significant ease will require prostaglandin to maintain
apnea occurs. pulmonary blood flow until pulmonary vas-
cular resistance has fallen and the adequacey
Abnormalities of the Tricuspid Valve of the right ventricle and pulmonary valve
Tricuspid atresia is a complete mixing lesion. can be assessed. Many cardiologists adopt a
Because of the atretic valve there is no out- “watch and wait” strategy with these infants
let from the right atrium except across the in an effort to avoid early surgical interven-
patent foramen ovale to the left atrium. tion and the associated mortality.
Blood flow reaches the right ventricle via
a VSD that is typically unrestrictive in the Abnormalities of the Right Ventricular
neonate. Tricuspid atresia may be associ- Outflow Tract
ated with normally related or transposed Tetralogy of Fallot is the signature lesion
great arteries, and saturations and blood associated with cyanosis due to decreased
flow depend on the relationship of the great pulmonary blood flow. The symptoms and
arteries, the size of the VSD, and the pres- presentation depend on the degree of sub-
ence or absence of semilunar valve stenosis. pulmonary or pulmonary valve obstruction.
If pulmonary blood flow is unobstructed, Infants with mild obstruction may manifest
patients may have tachypnea and early primarily symptoms of heart failure from the
heart failure with minimal to no cyanosis. large VSD. Other infants may have severe
The physical examination is significant for cyanosis on closure of the ductus arteriosus.
an increased left ventricular impulse (in “Tet spells” may be associated with vigor-
contrast to other cyanotic heart diseases ous crying—infants are initially hyperpneic
with increased right ventricular impulses). and restless with increasing cyanosis. The
Depending upon the anatomy, the second murmur becomes softer and may disappear
heart sound may be single (with atresia of entirely during a spell due to the lack of pul-
one of the great arteries), normal (in nor- monary blood flow. If untreated, the infant
mally related great arteries), or diminished may have a syncopal episode. Treatment for
(in transposed great arteries). A murmur an acute spell involves knee-to-chest posi-
may or may not be present depending upon tioning, oxygen supplementation, seda-
restriction of blood flow through the ventric- tion and/or analgesia, administration of
ular septal defect (holosystolic murmur) and β-blockers, and surgical repair to provide a
the semilunar valves (systolic ejection mur- consistent form of pulmonary blood flow.
mur) and a holosystolic murmur at the left In cases of absent pulmonary valve syn-
lower sternal border. The ECG may dem- drome, the hemodynamic pattern is similar
onstrate left axis deviation and right atrial to that in tetralogy of Fallot, but there is
enlargement. Echocardiography should be often severe respiratory distress. The mas-
performed and, in addition to confirming sively dilated pulmonary arteries that are
the diagnosis, will concentrate on assess- present in this syndrome compress the air-
ing the stability of the circulation in the ways and cause respiratory embarrassment.
absence of a PDA. Pulmonary atresia with a VSD is a more
Ebstein anomaly of the tricuspid valve severe form of tetralogy of Fallot that pre
is characterized by the downward displace- sents with severe cyanosis shortly after
ment of the valve leaflets into the right ven- birth. The infant with pulmonary atresia
tricular cavity. The severity of disease is often and VSD lacks the prominent pulmonary
dependent on the degree of displacement murmur present in tetralogy of Fallot. The
and the ability of the remaining portion S1 may be associated with an ejection click
secondary to a dilated aortic root. If the ovale and increased systemic oxygen deliv-
patient has additional pulmonary blood ery. Often this is sufficient to avoid acidosis
flow in the form of collateral vessels from and tissue oxygen debt. Frequently, how-
the descending aorta (which may be iden- ever, patients with TGA will undergo bal-
tified by continuous murmurs auscultated loon atrial septostomy either in the cardiac
over the patient’s back) the infant may have catheterization laboratory or at the bedside.
a stable form of pulmonary blood flow. All Clinically, the infant with TGA is likely to be
other infants require treatment with prosta- male and appear cyanotic but healthy, with
glandin E2. The ultimate surgical treatment a weight appropriate for gestational age.
depends on the presence or absence of the Auscultatory findings may be unremarkable
native pulmonary arteries and their size. except for a single loud S2. A nonspecific
Neonates with pulmonary atresia with an systolic murmur may be present. Reverse
intact ventricular septum have severe cya- differential cyanosis is rare but is indicative
nosis that progresses as the ductus arterio- of TGA with a PDA and an associated aortic
sus closes. The S2 is single and loud. Often arch abnormality or pulmonary hyperten-
there are no other murmurs (or a continu- sion. ECG findings may vary considerably,
ous murmur from the ductus). This defect with findings of the initial study often nor-
is dependent on the ductus for pulmonary mal for age. In the neonate with TGA and
blood flow. Due to the high-pressure right an intact ventricular septum, the chest
ventricle, there may be associated coronary radiograph may demonstrate a narrowed
artery abnormalities that affect whether sur- superior mediastinum with an egg-shaped
gical palliation via a single ventricle route cardiac silhouette (“egg on a string”), mild
or orthotopic heart transplantation is rec- cardiomegaly, and increased pulmonary
ommended. vascular markings. Surgical repair (arterial
switch operation) is often undertaken in
Transposition of the Great Arteries the first week of life, and most patients are
Infants with transposition of the great arter- expected to survive to adulthood and lead a
ies (TGA) show severe cyanosis immediately normal life.
after birth. Left untreated, these infants In summary, an infant with cyanosis
rapidly progress from cyanosis to tissue and little respiratory distress usually has
hypoxemia, acidosis, and, if the disorder is cardiac disease and requires prompt evalu-
unrecognized, death. Unlike infants with ation and stabilization. When the initial
other cyanotic congenital heart lesions, evaluation cannot exclude cardiac disease,
these infants have a normal volume of blood it is important to proceed with a complete
passing through the pulmonary bed. How- cardiovascular evaluation. With the dra-
ever, because the heart is arranged in paral- matic improvements in neonatal surgery
lel, infants with TGA have very low effective and the advent of prostaglandin E1 ther-
pulmonary blood flow (deoxygenated blood apy, infants with cyanotic heart disease
from the systemic circulation that reaches are now expected to survive to lead a more
the pulmonary bed) and effective systemic normal life.
blood flow (oxygenated blood that perfuses
the systemic bed). The degree of mixing SYSTEMIC HYPOPERFUSION
between the separate circulations depends The third common type of presentation
on the number and size of the anatomic of critical heart disease in the newborn is
connections. Blood may shunt at the atrial, shock due to hypoperfusion. Hypoperfusion
ventricular (if a VSD is present), or ductal is secondary to inadequate ejection of blood
level. The typical infant with TGA and an into the systemic arterial system, resulting
intact ventricular septum becomes progres- in hypotension and progressive metabolic
sively more hypoxemic as the ductus arterio- acidosis. This typically occurs as the duc-
sus closes secondary to inadequate mixing at tus arteriosus constricts in a patient with a
the foramen ovale. Frequently these infants ductal-dependent systemic circulation but
are given prostaglandin E1 until the atrial may also be found in infants with lesions
communication can be enlarged. Although in which the function of the left ventricle
it is unusual to have sufficient mixing at the is seriously impaired without underlying
ductal level, the increased pulmonary blood obstruction. The course may be rapidly pro-
flow provided by the PDA dilates the left gressive over the first few hours of life or
atrium, which allows a larger anatomic left- insidious in onset over the first few weeks.
to-right shunt across the stretched foramen Cardiac lesions in this category include
functional abnormalities of the left ventricle the foramen ovale, and, on rare occasions,
such as endocardial fibroelastosis, dilated aortic stenosis or hypoplastic left heart syn-
cardiomyopathy, hypertrophic cardiomy- drome. Maternal diabetes suggests diabetic
opathy, left ventricular noncompaction, left cardiomyopathy, and a familial history might
ventricular outflow tract obstruction, aortic suggest other forms of cardiomyopathy.
valve stenosis, interruption of the aortic The physical examination uniformly
arch, coarctation of the aorta, Shone com- shows a pale, tachypneic, and lethargic
plex, and hypoplastic left heart syndrome. infant. It is critical to differentiate sinus
Systemic hypoperfusion may also be caused tachycardia in a severely stressed infant
by arrhythmias that severely decrease car- from an underlying conduction distur-
diac output in the neonate. Hypoperfusion bance resulting in poor function. Some
syndromes often have associated findings, arrhythmias may be easily distinguished
including lethargy, a mottled appearance on telemetry, although a full 12-lead ECG
with pallor and poor pulses, and a degree should be obtained to confirm the diagnosis
of systemic arterial desaturation caused by and guide treatment. Peripheral pulses are
mixing of systemic and pulmonary venous decreased in low-output states, but a differ-
return, and most are associated with respira- ential pulse or blood pressure between the
tory distress secondary to elevated pulmo- upper and lower extremities can be diag-
nary venous pressures. nostic. In patients with obstruction along
The differential diagnosis of primary the aortic arch or descending aorta (i.e.,
noncardiac hypoperfusion is broad and interrupted aortic arch or coarctation of the
includes sepsis, adrenal insufficiency, ane- aorta), the lower limb pressures will be low
mia, hypovolemia, inborn errors of metabo- in the absence of a nonrestrictive ductus
lism, and neurologic instability. In practice, arteriosus. It is important to realize that the
all of these typically have a component of left subclavian artery frequently arises at the
poor cardiac function that improves as the origin of the coarctation and thus should
underlying disease is correctly diagnosed not be used to represent ascending aor-
and treated. While one works toward a uni- tic pressures in coarctation (Fig. 15-22, A).
fying diagnosis for a hypoperfused state, it Similarly, the right subclavian artery may
is important to consider conditions that are arise aberrantly from the descending aorta
most life-threatening if missed. The most fre- in 0.5% to 2% of the population,78 which
quent misdiagnosis in an infant with heart makes assessment of the ascending aorta
disease and hypoperfusion is sepsis. Because difficult. However, a difference in inten-
overwhelming infection is associated with sity between the carotid or temporal artery
high mortality, it is reasonable to perform pulse and the extremity pulses can be a clue
a workup for sepsis and even begin specific to this diagnosis. The precordial impulse is
therapy in any infant with signs of low out- often nonspecific, usually showing a right
put, but it is important to consider cardiac ventricular heave. The S2 is single in hypo-
disease as well. The most important decision plastic left heart syndrome, but because of
immediately following the diagnosis of left- the tachycardia in low-output states, it is
sided heart disease is to determine whether often difficult to appreciate a split sound
the left ventricle can sustain systemic car- in any of the lesions. Murmurs rarely help
diac output. If there is any question, the the diagnosis in this group: in the presence
infant should receive prostaglandin therapy of severe heart failure, most lesions are not
to ensure continued patency of the ductus associated with murmurs or have nonspe-
arteriosus until a more thorough assessment cific ones. Coarctation of the aorta in which
can be made. a VSD or subaortic stenosis is present is an
The history can help distinguish between exception, but critical aortic stenosis may be
cardiac and noncardiac disease and differen- associated with little or no murmur when
tiate among the specific cardiac lesions. In the left ventricular output is low. Rales are
general, the timing of presentation depends heard in most low-output states as a result
on the role of the ductus and the timing of elevated pulmonary venous pressures.
of its closure. There is sometimes a history Arterial blood gas values often indicate a
of perinatal problems. A history of recent metabolic acidosis at the time of diagnosis.
viral infection in the mother may be elicited Differential pulse oximetry measurements
in infants with myocarditis. Fetal hydrops between the right hand and foot may be
occurs in intrauterine supraventricular tachy- helpful. In coarctation or interruption of the
cardia, cardiomyopathy, premature closure of aorta, the saturation in the foot will be lower
SVC PV
–
50% 92% 9
IVC 45%
– –
4 52% 92% 9
RA LA
RV LV
65/4 58% 92% 75/9
—
92% 70/50 60
L.subclavian
PDA —
— 55/40 45
65/50 55 58% —
85% 45/37 40
MPA
Ao
A
B C
Figure 15-22. A, Representative blood oxygen saturation (%) and pressure (mm Hg) in an infant with coarctation of the
aorta. (See Fig. 15-3 for abbreviations.) B, Chest radiograph of an infant with coarctation of the aorta. C, Chest radiograph
of an infant with hypoplastic left heart syndrome. Chest radiographs usually cannot differentiate between left-sided
obstructive lesions.
if the ductus is patent because there will be an anomalous left coronary artery; endo-
right-to-left shunting from the pulmonary cardial fibroelastosis is characterized by
artery to the descending aorta. Conversely, prominent Q and R waves in the precordial
if the saturation is higher in the descending leads; there usually is marked right ven-
aorta, transposition with PPHN or transpo- tricular hypertrophy in coarctation of the
sition with interrupted arch should be con- aorta or critical aortic stenosis; ST-T wave
sidered. The chest radiographic study often abnormalities are present in myocarditis.
shows cardiomegaly and interstitial edema The echocardiogram is diagnostic in the
in both cardiac and noncardiac lesions once obstructive lesions; however, occasionally
there is severe heart failure and thus is not an isolated aortic coarctation can be masked
useful for diagnosis. The ECG is helpful in after the administration of prostaglandin
identifying several lesions. For example, E1, because the presence of a large PDA
left-sided forces are absent in hypoplas- decreases the flow through the area. Also, in
tic left heart syndrome; the regular rapid some patients, ductal tissue wraps around
heart rate of supraventricular tachycardia the aorta (so-called “ductal sling”), causing
is diagnostic (Fig. 15-23); there are signs of the obstruction when it contracts and the
an anterolateral ischemia or infarction in ductus closes. This area can be dilated by
Figure 15-23. Supraventricular tachycardia. Lead II standard electrocardiogram at a speed of 50 mm/sec. Heart rate is
300 beats per minute. No P waves are seen.
administration of prostaglandin E1, which EXTRASYSTOLES

makes diagnosis problematic in its pres- Premature atrial contractions (PACs) and pre-
ence. The echocardiogram is also useful in mature ventricular contractions (PVCs) are
assessing ventricular performance and the common findings in the fetal and newborn
response to therapeutic interventions. period, with PACs being the most common
Therapy must be prompt. Once deterio- arrhythmia seen in neonates. PACs can be
ration begins, it is usually rapidly progres- normally conducted, aberrantly conducted, or
sive. Initial measures must be directed at the blocked (Fig. 15-24). Distinguishing between
metabolic derangements: partial correction PACs and PVCs can prove difficult for various
of the metabolic acidosis; maintenance of reasons. The P wave can be superimposed on
adequate substrate, hemoglobin, and blood the preceding T wave, QRS prolongation can
volume; and prompt inotropic support with be subtle in the newborn, and aberrantly con-
rapidly acting agents such as dopamine or ducted PACs are common. Blocked PACs may
epinephrine. Prostaglandin E1 administra- mimic sinus bradycardia when atrial bigem-
tion is of utmost importance when obstruc- iny is present and the P waves are super-
tive lesions are considered; maintaining imposed on the antecedent T wave. These
ductal patency ensures that the lower body extrasystoles rarely produce symptoms and
will be perfused with blood ejected from become less frequent with time. In patients
the right ventricle through the pulmonary with central venous lines, it is important to
artery. The entire body can be perfused ensure that the catheter is not producing
by this route in critical aortic stenosis and right atrial mechanical irritation resulting in
hypoplastic left heart syndrome. In left ven- PACs. If this is the case, withdrawal of the
tricular obstructive lesions, the infant can be catheter from the right atrium should result
maintained on prostaglandin E1 before sur- in termination of the arrhythmia.
gery. If the diagnosis is in doubt, antibiotics
should be instituted after a sepsis workup, SINUS BRADYCARDIA, SINUS PAUSES,
and corticosteroids should be considered if AND JUNCTIONAL ESCAPE BEATS
adrenal insufficiency is a possibility. Sinus bradycardia, sinus pauses, and junc-
tional escape beats are very common find-
ARRHYTHMIAS IN THE NEONATE ings in neonates, reported in 19% to 90%
Neonatal arrhythmias are not infrequent, of infants.81 However, the true incidence of
but the clinical significance can vary greatly these findings is likely unknown, because
depending on the diagnosis, which can be almost all patients are asymptomatic and
difficult to make, especially the differen- only hospitalized infants are typically mon-
tiation of sinus tachycardia from tachyar- itored. These findings are usually transient
rhythmias. Neonatal arrhythmias occur and rarely symptomatic. In previous stud-
in 1% to 5% of newborns during the first ies, sinus bradycardia has been documented
10 days of life.80 Neonatal arrhythmias can by 24-hour Holter monitoring in healthy
be classified using various schemes, including neonates with rates as low as 42 beats per
bradycardia versus tachycardia and benign minute while asleep.81 However, others
versus nonbenign. No single scheme encom- have recommended defining sinus brady-
passes all aspects of arrhythmias, and often cardia on Holter monitoring in neonates
one must use an expanded classification sys- as 60 beats per minute while asleep and 80
tem. The following sections address the vari- beats per minute while awake.82,83 These
ous arrhythmias encountered in the neonate. findings are typically secondary to increased
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
V1
II
V5
Figure 15-24. Sinus rhythm with blocked premature atrial contractions in an asymptomatic 1-day-old infant. Sinus rhythm
precedes atrial trigeminy. Solid arrows indicate blocked premature atrial contractions.
autonomic tone and require no therapy or either with or without structural heart disease,
intervention. However, sinus bradycardia is rare and is most likely secondary to sodium
can be a manifestation of a more significant channelopathies.86 More often the disorder is
underlying medical condition, such as hypo- seen following cardiac catheterization proce-
thyroidism, hypoglycemia, hyperkalemia, dures, such as balloon atrial septostomy, or
hypercalcemia, increased intracerebral pres- cardiac surgery. These procedures can result
sure, or hypoxia.84 Sinus bradycardia can be in direct injury to the sinus node. Although
seen with airway obstruction, endotracheal surgery often results in permanent dysfunc-
intubation, and certain medications, espe- tion, cardiac catheterization procedure–asso-
cially sedatives. Finally, infants with long ciated sinus node dysfunction is frequently
QT syndrome have been shown to have sig- transient. Sinus node dysfunction can be
nificantly slower sinus rates, and thus any acquired, as seen in cardiomyopathy, various
neonate with sinus bradycardia should be inflammatory diseases (e.g., myocarditis), and
evaluated for long QT syndrome.85 genetic syndromes affecting the conduction
Treatment for sinus bradycardia is usually system, such as sodium channelopathies.
directed toward the underlying cause. How- Patients with sinus node dysfunction
ever, in symptomatic infants, temporary should be evaluated by 24-hour Holter mon-
chronotropic and inotropic support may itoring to assess degree of bradycardia, fre-
be warranted and can be achieved pharma- quency and duration of sinus pauses, average
cologically using various drugs, including heart rate, and associated atrial tachycardias.
isoproterenol, epinephrine, and atropine. Escape beats can arise from any cardiac focus,
Temporary pacing is rarely necessary, and including atrial, junctional, or ventricular,
efforts should remain focused on addressing during times of sinus pauses. Depending on
the underlying cause. the findings, these patients may benefit from
pacemaker implantation. Associated atrial
SINUS NODE DYSFUNCTION tachycardias should also be appropriately
Sinus node dysfunction can be secondary to treated with antiarrhythmic medications.
direct injury to the sinus node or intrinsic
sinus node disease. Sinus node dysfunction ATRIOVENTRICULAR BLOCK
often manifests as slow resting heart rate,
decreased heart rate variability, decreased First-Degree Atrioventricular Block
peak heart rate, and prolonged sinus pauses. First-degree AV block, also called first-degree
True congenital sinus node dysfunction, heart block, is defined as a PR interval longer
than the upper limit of normal for a patient’s block are similar to those of first-degree
age. The PR interval upper limit of normal is heart block. High-grade second-degree heart
160 msec in the first 24 hours of life and block has a variety of causes, only a hand-
140 msec at 1 month of age, although it is ful of which are seen in the neonatal period,
variable during the first month of life and including viral myocarditis, tuberous sclero-
continues to vary throughout childhood.87 sis, cardiac surgery, cerebral edema, and cer-
The PR interval can be prolonged because tain medications such as antiarrhythmics
of delay in conduction from the sinus and digoxin.89 High-degree second-degree
node through the atrium, from the atrium AV block may also be associated with con-
to depolarization of the bundle of His, or genital heart disease, typically AV septal
from depolarization from the bundle of His defects, levo-TGA, and left atrial isomer-
to initiation of ventricular depolarization. ism in patients with heterotaxy syndrome.
First-degree AV block is typically due to Recent publications have also reported
delayed conduction at the level of the AV high-grade AV block caused by mutations in
node. First-degree AV block may be associ- the cardiac transcription factors TBX5 and
ated with congenital heart disease or may be NKX2.5.90,91
secondary to an inflammatory process, such Therapy is not necessary for Mobitz type
as viral myocarditis. Various autoimmune I or asymptomatic Mobitz type II second-
inflammatory disorders, muscular dystro- degree heart block. The mainstay of therapy
phies, trauma, and pharmacologic therapies for patients with symptomatic high-grade
(including tricyclic antidepressants, cloni- heart block is pacemaker implantation,
dine, and digoxin) can cause a prolonged which is discussed in the following section
PR, but these causes are rare in neonates. on complete AV block.
First-degree AV is often considered a normal
variant and does not produce symptoms. Third-Degree or Complete Atrioventricular
No therapy is typically indicated. Block
Third-degree or complete AV block is char-
Second-Degree Atrioventricular Block acterized by a complete lack of conduction
(Type I and Type II) of atrial impulses to the ventricles (Fig.
Second-degree AV block is present when 15-25). The P-P intervals are typically con-
there is intermittent failure to conduct atrial stant on electrocardiogram, although they
impulses to the ventricular conduction sys- can display some variability due to respira-
tem. Second-degree AV block can be further tions and vagal tone. The R-R intervals are
subclassified into Mobitz type I (Wencke- fixed as well. In contrast to surgical com-
bach) and Mobitz type II block. Mobitz type plete heart block, congenital complete heart
I block is defined by progressive lengthen- block can display some variability in the
ing of the PR interval with eventual loss of escape rhythm depending on the physi-
conduction to the ventricle of 1 beat. The ologic conditions.
PR interval of the subsequent conducted Complete AV block occurs in approxi-
atrial impulse is always shorter than the mately 1 of every 20,000 pregnancies.92
PR interval of the last conducted ventricu- Causes of complete AV block are similar
lar beat. Mobitz type II block is defined to those for high-grade second-degree AV
by abrupt failure to conduct one or more block. However, in 91% of affected neonates,
atrial impulses to ventricles without preced- complete AV block is secondary to neona-
ing PR prolongation. This block typically tal lupus erythematosus.93 This is caused by
occurs below the AV node and can progress transplacental passage of maternal anti-Ro/
acutely to complete heart block.88 The pat- SSA and/or anti-La/SSB antibodies—auto-
tern of type II second-degree AV block can antibodies often seen in mothers with sys-
be regular and is described as 2:1, 3:1, and temic lupus erythematosus and Sjögren
so on. High-grade second-degree AV block syndrome. Although the mechanism is
is considered 3:1 or higher. This differs from not completely understood, the condition
complete heart block by the presence of R-R is thought to be the result of an immune-
interval variation or R-R intervals that are mediated inflammatory cascade leading to
multiples of the atrial cycle length. fetal myocardial fibrosis and thus complete
Type I second-degree AV block is often heart block. It is important to recognize that
considered a normal variant and can be the mother may be completely asymptom-
seen during periods of sleep in older chil- atic, and the birth of an affected neonate
dren. Causes of type I second-degree heart may be the initial sign of maternal systemic
I aVR V1 V4
II aVL V2 V5
* * *
III aVF V3 V6
II
Figure 15-25. Congenital complete atrioventricular block in an asymptomatic 3-week-old infant. Solid black arrows indicate
underlying atrial rate of 167 beats per minute. Asterisks denote narrow-complex junctional escape rhythm with a rate of 83
beats per minute.
lupus erythematosus. After the birth of an postoperative AV block may be transient

affected child, the risk of complete AV block or persistent. Older studies recommended
in subsequent children is up to 25%. waiting 10 to 14 days for return of AV con-
Although complete heart block is the duction, but more recent reports suggest
most concerning ECG finding in neonatal that AV conduction is unlikely to return
lupus erythematosus, these neonates and after 7 to 8 days. Current guidelines recom-
infants can display first- and second-degree mend delaying pacemaker implantation for
AV block as well. Fetuses can manifest heart 7 days from surgery to evaluate for return of
block as early as 16 to 18 weeks’ gestation, AV conduction.94
and first-degree heart block can rapidly prog- After delivery, all neonates with complete
ress to complete heart block. The fetus with heart block or known exposure to maternal
complete AV block can develop hydrops autoantibodies deserve ECG evaluation.
fetalis, and fetal mortality rate ranges from All patients with high-grade second-degree
15% to 30%.37 The mortality during the first AV block or complete AV block ultimately
year of life due to dilated cardiomyopathy is will require permanent pacemaker implan-
12% to 41%.38 Thus, efforts have focused on tation. Based on current guidelines from
early identification via fetal echocardiogra- the American College of Cardiology, the
phy to identify those infants with early, low- American Heart Association, and the North
grade heart block. Fluorinated steroids, such American Society for Pacing and Electro-
as betamethasone and dexamethasone, are physiology, current class I indications for
not metabolized by the placenta and have permanent pacing in neonates with con-
been shown to prevent progression of first- genital complete AV block include (1) con-
degree AV block to complete heart block in genital third-degree AV block with a wide
fetuses of mothers with anti-Ro/SSA and/or QRS escape rhythm, complex ventricular
anti-La/SSB antibodies.37,38 ectopy, or ventricular dysfunction; (2) con-
Although congenital complete heart genital third-degree AV block with a ven-
block is universally irreversible once present, tricular rate of less than 50 to 55 beats per
minute; and (3) congenital third-degree AV NARROW QRS COMPLEX TACHYCARDIA

block with congenital heart disease and
a ventricular rate of less than 70 beats per Sinus Tachycardia
minute. Class IIb indications for these neo- Sinus tachycardia is a normal variant in
nates include congenital third-degree AV neonates and children. In neonates, sinus
block in an asymptomatic neonate with an tachycardia can be difficult to differentiate
acceptable rate, narrow QRS complex, and from arrhythmias because of the ability of
normal function.94 the neonatal conduction system to conduct
normally at rates upwards of 230 beats per
PROLONGED QT minute. Therefore, it is imperative to differ-
A prolonged QT interval is generally consid- entiate sinus tachycardia from an arrhyth-
ered to be an interval longer than 460 msec. mia before any therapy is initiated. Sinus
However, it is important to correct the QT tachycardia is a sign of any condition that
interval for heart rate. This is termed the requires increased cardiac output. In the
corrected QT interval (QTc). It can be deter- newborn, such conditions may include pain,
mined by several formulas but is generally fever, infection, anemia, opiate withdrawal,
calculated using the Bazett formula hyperthyroidism, dehydration, and admin-
√ istration of certain drugs. Treatment should
QTc = QT interval / R − R interval
be directed toward the underlying cause.
where R-R interval is the R-R interval pre-
ceding the measured QT interval. Prolonged Supraventricular Tachycardias
QTc (≤470 msec) can occur after stressful Supraventricular tachycardia (SVT) is a gen-
delivery but usually resolves within 48 to eral term that encompasses multiple dis-
72 hours.89 Otherwise QTc prolongation tinct electrophysiologic tachyarrhythmias,
is typically either secondary to a genetic two of which are AV reentrant tachycardia
long QT syndrome or caused by medica- (AVRT) and AV nodal reentrant tachycardia
tion administration. The QTc can also be (AVNRT). The latter is uncommon in the
prolonged in the presence of hypocalcemia, neonatal period.
hypokalemia, and hypomagnesemia. There
are several forms of long QT syndrome, Atrioventricular Reentrant Tachycardia
including Jervell and Lange-Nielsen syn- AVRT is the most common cause of tachy-
drome, Romano-Ward syndrome, and long cardia in the newborn period and accounts
QT syndrome types 1 to 8. These have been for 50% of all pediatric cases of SVT. AVRT
mapped to multiple loci and can affect mul- is the most common abnormal SVT encoun-
tiple genes. All are inherited in an autoso- tered in the neonatal intensive care unit.
mal dominant pattern except for Jervell and AVRT is characterized by a sudden onset and
Lange-Nielsen syndrome, which is autoso- termination, typically normal QRS com-
mal recessive. A prolonged QTc places the plexes, and fixed cycle length (R-R interval).
neonate at risk for bradycardia, torsade de The P wave is usually identified following
pointes, ventricular tachycardia, and sud- the QRS complex but can be buried in the
den death. T wave. It usually has a retrograde mor-
Treatment is aimed at preventing arrhyth- phology (negative in leads II and aVF) (Fig.
mias associated with long QT syndromes. 15-26). When a bundle branch block is pres-
All electrolyte levels should be corrected as ent or when the accessory pathway is used as
necessary and any QTc-prolonging medi- the antegrade limb of the reentrant circuit,
cations discontinued if possible. A current the QRS can be prolonged. This is referred to
list of QTc-prolonging medications can be as supraventricular tachycardia with aberrancy
found at www.qtdrugs.org. Asynchronous and can be extremely difficult to distinguish
cardioversion and magnesium are useful for from ventricular tachycardia. There is typi-
treatment of torsade de pointes, although cally a 1:1 AV relationship. AVRT is usually
cardioversion may not prevent reinitiation seen in a structurally normal heart but can
of the arrhythmia. The mainstays of ther- be associated with Ebstein anomaly of the
apy for patients with long QT syndromes tricuspid valve, congenitally corrected TGA,
are β-blockers. Implantation of a cardiac and hypertrophic cardiomyopathy.
defibrillator is also warranted in patients The reentrant circuit requires two limbs—
at high risk and in those who develop tor- one is the AV node and the other typically
sade de pointes despite receiving β-blocker is a bypass tract with the ability to conduct
therapy. either antegrade or retrograde. The bundle
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
II
Figure 15-26. Atrioventricular reentrant tachycardia (supraventricular tachycardia) in a 4-week-old male. The infant had
manifestations of decreased cardiac output over the preceding 24 hours and showed mild left ventricular dysfunction by
echocardiogram. Note that the retrograde P waves are difficult to discern and are buried in the T waves.
of Kent in Wolff-Parkinson-White syndrome in hemodynamically stable condition, vagal

(WPW) is one such accessory pathway. maneuvers can be attempted. These can
“Concealed” pathways are accessory path- include applying ice to the face for 20 to 30
ways that have the ability to conduct only seconds to elicit the dive reflex, gagging the
in a retrograde manner. These accessory patient, or inserting a rectal thermometer.
pathways electrically link the atrial and ven- Application of pressure over the eyeball or
tricular tissue and can occur anywhere along the carotid sinus should be avoided because
the central fibrous body of the heart. AVRT the former can result in retinal detach-
is frequently triggered by a PAC or PVC. The ment and the latter can result in unilat-
accessory pathway is typically a source of eral occlusion of cerebral blood flow. All of
retrograde conduction, with the AV node these maneuvers increase vagal tone, which
serving as the antegrade limb. This is termed results in decreased AV node conduction. In
orthodromic reciprocating tachycardia. the event that these maneuvers are unsuc-
AVRT is typically well tolerated for short cessful, an intravenous bolus of adenosine
periods of time in the neonate. Neonates can be used to block AV node conduction.
may be relatively asymptomatic until pro- The initial dose of adenosine is 100 µg/kg
longed tachycardia results in decreased ven- and subsequent doses are 200 µg/kg and
tricular function. Symptoms can include 400 µg/kg. It is important to immediately
palpable tachycardia, irritability, tachypnea, follow the rapid intravenous bolus with
poor oral intake, diaphoresis with feeds, and an adequate saline flush to ensure that the
respiratory distress. When decreased ventric- medication reaches the central circulation
ular function is present, it usually resolves quickly given the short half-life of adeno
with adequate treatment of the arrhythmia. sine. This can be accomplished by inserting
AVRT can be terminated by a multitude of both syringes directly into the same hub or
mechanisms. In a patient with AVRT who is by using a three-way stopcock. A common
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
II
Figure 15-27. Wolff-Parkinson-White syndrome. The patient demonstrated preexcitation (solid black arrows) at baseline
after conversion to sinus rhythm following administration of adenosine.
cause of failure of adenosine to break SVT in neonates with WPW because it can
is inadequate administration. It is equally potentiate conduction down the accessory
important to record the rhythm throughout pathway by decreasing its refractoriness
the administration of adenosine. This allows and lead to ventricular arrhythmias.95-97 In
assessment of the underlying atrial rhythm cases in which digoxin and/or propranolol
as well as identification of the mechanism therapy is unsuccessful, flecainide, amio-
of reinitiation of arrhythmia if it were to darone, and sotalol have been used with
recur. If the initial dose of adenosine suc- success.98 As the antiarrhythmic properties
cessfully converts AVRT to sinus rhythm increase, so do the side effects, and addi-
but the arrhythmia recurs, additional doses tional monitoring is required. Calcium
of adenosine at escalating levels are unlikely channel blockers should be avoided in
to result in sustained sinus rhythm, and neonates because hemodynamic collapse
additional antiarrhythmic medication is after administration has been reported.
required. Tachycardia can also be termi- Only in extreme cases is intracardiac elec-
nated by overdrive atrial pacing. This can be trophysiologic study and accessory path-
accomplished by placing a transesophageal way ablation necessary. The prognosis for
pacing probe and pacing atrially at a rate neonates with AVRT is excellent, and most
10% higher than the SVT rate for approxi- do not require further treatment past 6 to
mately 20 seconds. In patients in hemody- 12 months of age.
namically unstable condition, synchronized Following conversion of SVT to normal
cardioversion should be immediately per- sinus rhythm, a baseline electrocardio-
formed to terminate the arrhythmia. gram should be obtained to assess for evi-
Multiple treatments are available for dence of ventricular preexcitation, which
AVRT. Current first-line therapies for AVRT is manifested on the electrocardiogram as a
include digoxin and β-blockers such as delta wave as in WPW (Fig. 15-27). This is
propranolol. Digoxin should be avoided important for initial medical management
decisions as outlined previously. The preva- paroxysmal and permanent forms.98,103 In

lence of WPW is 0.4 to 1 per 1000 in infants this type of tachycardia, there is no reen-
and children, and 60% of cases present before trant circuit. EAT is usually chronic and
2 months of age.99 Although patients who incessant. The tachycardia tends to “warm
manifest WPW during the neonatal period up” and “cool down” rather than showing
and infancy have a 60% to 90% chance of the abrupt onset and resolution of reentrant
resolution during the first year of life, one tachycardias. EAT typically manifests with
third will experience recurrence of symp- heart rates at or just above the upper limit of
toms during the first decade of life, typically normal for age. However, the resting heart
around 4 to 6 years of age.80 Patients dem- rate is often more elevated than expected,
onstrating WPW should undergo screening and the response to exercise is exaggerated.89
echocardiography to assess for associated EAT can be distinguished from sinus tachy-
congenital heart disease. cardia by abnormal P-wave morphology on
electrocardiogram. The permanent form can
Persistent Junctional Reciprocating frequently lead to congestive heart failure;
Tachycardia otherwise the symptoms can be very subtle,
Persistent junctional reciprocating tachycar- and the clinician must have a high degree of
dia (PJRT) is a relatively rare form of reentrant suspicion. Class Ic antiarrhythmics (propafe-
tachycardia. This is an incessant orthodromic none and flecainide) and class III antiar-
tachycardia with anterograde conduction rhythmics (sotalol, amiodarone) have been
over the AV node and retrograde conduction shown to provide effective rhythm control
via an accessory pathway with slow and dec- in multiple studies.104-106 When medica-
remental conduction.100,101 This arrhythmia tion fails, catheter ablation of the automatic
can present in utero, in the neonatal period, focus is a therapeutic option. The chance
during childhood, or during adulthood in of spontaneous resolution of EAT is 75% to
slower forms of PJRT. Over a long period 95% during the first year of life according
of time, the incessant tachycardia can lead to earlier reports.104,107 A more recent study
to tachycardia-induced cardiomyopathy, looked specifically at those patients diag-
although this is reversible with rate control. nosed with EAT before 3 years of age (range:
Infants with cardiomyopathy may come to 1 day to 2 years; median: 7 days) and found
attention due to symptoms of heart failure. that 78% of patients in this group experi-
During episodes of PJRT, the P wave is char- enced spontaneous resolution.108
acteristically inverted in the inferior leads but Chaotic atrial tachycardia is defined as an
may be normal during the brief periods of atrial tachycardia with at least three P-wave
sinus rhythm. These periods of sinus rhythm morphologies. The tachycardia rates vary
are typically no longer than a few beats. significantly with irregular P-P intervals.
Because of the risk of tachycardia-induced car- Chaotic atrial tachycardia is not typically
diomyopathy, aggressive therapy should be related to congenital heart disease. How-
initiated for PJRT. β-Blockers have been used ever, it has been frequently associated with
with some success but may be inadequate. respiratory illness, especially bronchiolitis
Success rates of 80% have been reported caused by respiratory syncytial virus.77,109
for the use of amiodarone and verapamil to As with EAT, prolonged arrhythmia can
achieve arrhythmia suppression.102 PJRT may result in decreased cardiac function. Treat-
also resolve spontaneously, although not as ment options are similar to those for EAT.
frequently as does AVRT. Vaksmann et al
observed resolution in 22% of their cohort Atrial Flutter
and in 25% of patients younger than 1 year Atrial flutter is uncommon in the neonatal
of age. Unfortunately, the range for resolu- period and accounts for approximately 3%
tion of tachycardia was 2 months to 16 years of neonatal arrhythmias.110,111 It is caused
with a median of 5.4 years.102 by a macro-reentry circuit within the atrial
muscle. Atrial flutter is characterized by
Ectopic Atrial Tachycardia and Chaotic Atrial regular, rapid atrial tachycardia with saw-
Tachycardia tooth flutter waves (Fig. 15-28). These are
Ectopic atrial tachycardia (EAT) is a primary typically best appreciated in the inferior
atrial tachycardia resulting from localized leads and tend to have atrial rates of 300
automatic foci located in the atria. EAT to 600 bpm. AV block is typically present
accounts for 5% to 20% of cases of SVT in with a 2:1 block, and thus the R-R interval
pediatric patients and can be present in is an integer of the atrial rate. However, the
conduction can vary. In the neonatal pre- neonates. Because atrial flutter is a self-lim-
sentation, atrial flutter is typically not asso- ited process with a low risk of recurrence
ciated with congenital heart disease, but once sinus rhythm has been established, no
it was seen in conjunction with an atrial further antiarrhythmic medication may be
septal defect in one study.112 As with other necessary following initial cardioversion.
tachyarrhythmias, neonates in atrial flutter
for prolonged periods can show depressed Junctional Ectopic Tachycardia
ventricular function. Spontaneous conver- Junctional ectopic tachycardia (JET) is an un
sion to normal sinus rhythm is common common narrow-complex automatic tachy
in infants with atrial flutter, occurring in cardia originating in or near the AV node
almost 25% of patients. For those who fail that is typically seen in the early postopera-
to convert to sinus rhythm, direct-current tive period in infants and children with con-
(DC) cardioversion and transesophageal genital heart disease. However, a congenital
pacing are effective in reestablishing sinus form of JET can also been encountered in
rhythm. Previously, digoxin was the anti- patients who have had no prior surgery.
arrhythmic medication of choice, but its JET is characterized by a narrow-complex
efficacy has been debated because of the tachycardia with rates typically 180 to 240
widely variable time between initiation of beats per minute with AV dissociation and
digoxin therapy and conversion to sinus a slower atrial rate.89 Appropriately timed
rhythm.112-114 Given the likelihood of spon- atrial beats conduct normally through
taneous conversion, it is reasonable to mon- the AV node, and this can be an impor-
itor an asymptomatic infant for a period of tant clue to the diagnosis. Transesophageal
several hours, but cardioversion should be atrial electrocardiography may be necessary
the treatment of choice in symptomatic to confirm the diagnosis. In patients with
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
II
Figure 15-28. Atrial flutter with 2:1 atrioventricular conduction in a 1-day-old infant. Note the sawtooth flutter wave pattern,
most evident in the rhythm strip, at a rate of approximately 380 beats per minute and a ventricular rate of approximately 190
beats per minute.
postoperative JET, the atrial electrocardio- beats that occur at a rate more than 20%
gram can often be obtained from temporary above that of the preceding sinus rhythm
atrial pacing wires. Congenital JET can pres- (Fig. 15-29). VT is a wide-QRS complex
ent at any age, but when it presents in in- tachycardia, but it is important to distin-
fancy it can be associated with up to 35% guish VT from aberrantly conducted SVT,
mortality according to one study.115 Oth- whether caused by rate or antegrade con-
ers, however, have reported lower mortality duction down an accessory pathway such
rates of 0% to 4%.116,117 The cause of con- as in WPW. VT can be distinguished by
genital JET is poorly understood, but post- the presence of fusion beats, AV dissocia-
operative JET is thought to be secondary to tion, and morphology similar to that of
surgical trauma. The hemodynamic signifi- PVCs. Unfortunately, neonates and infants
cance of JET warrants aggressive therapy. tend to have 1:1 retrograde conduction.
JET is refractory to overdrive pacing, DC This means that AV dissociation may not
cardioversion, and adenosine administra- be seen in VT in this population. VT can
tion. Class III antiarrhythmics, particularly be monomorphic (a single morphology)
amiodarone, have been relatively success- or polymorphic (more than one morphol-
ful in controlling the rhythm. Additional ogy), such as torsade de pointes. It can also
management should focus on withdrawal of be nonsustained, lasting between 3 and 30
inotropic agents when possible and modest beats, or sustained, lasting longer than 30
cooling. A recent study demonstrated that beats. VT can progress to ventricular fibril-
therapeutic hypothermia resulted in a sig- lation if left untreated.
nificant decrease in JET rate and subsequent The presence of VT requires a thorough
restoration of AV synchrony, either by rees- evaluation for possible causes. These can
tablishing sinus rhythm or by allowing suc- include myocarditis, cardiomyopathy, tumors
cessful atrial pacing above the JET rate.118 In (including hamartoma and rhabdomyoma),
patients with persistent JET or failure of ami- myocardial infarction (secondary to anoma-
odarone therapy, it is reasonable to pursue lous origin of the left coronary artery from
either radiofrequency ablation or cryoabla- the pulmonary artery, maternal cocaine use,
tion of the automatic focus. Both modalities or thromboembolism), electrolyte abnormal-
have similar success rates (82% to 85%) and ities, metabolic abnormalities, drug intoxica-
recurrence rates (13% to 14%).117 These pro- tion, and long QT syndrome, to name a few.
cedures may lead to inadvertent high-grade Initial evaluation should consist of electrocar-
second-degree or complete heart block that diography, echocardiography, and possibly
necessitates pacemaker implantation. cardiac MRI to aid in the diagnosis of cardiac
tumors not seen by echocardiography.
WIDE QRS COMPLEX TACHYCARDIA The morphology of VT can also be a clue
to the underlying diagnosis. Polymorphic
Accelerated Idiopathic Ventricular Rhythm VT tends to occur in myocarditis and myo-
Accelerated idiopathic ventricular rhythm is cardial infarctions. Incessant VT, defined
a benign arrhythmia occasionally seen in the as VT occurring for more than 10% of a
neonatal period. It is characterized by wide- 24-hour period, is often associated with
complex tachycardia with rates no higher myocarditis and hamartoma.119
than 20% of the preceding sinus rate. Most In patients with sustained VT and hemo-
of these rhythms are less than 200 beats per dynamic compromise, synchronized DC
minute. The QRS is prolonged above the cardioversion is the treatment of choice.
upper limit of normal for age and gener- In patients who remain in hemodynami-
ally has a left bundle branch morphology. cally stable condition, initial management
Fusion beats are commonly seen at the onset may consist of intravenous administration
and termination of the accelerated ventricu- of either procainamide or lidocaine, but
lar rhythm because the rate is similar to the pharmacologic therapy is typically initi-
sinus rate. There is no association with con- ated after conversion to sinus rhythm. In
genital heart disease, and the arrhythmia patients with asymptomatic, nonsustained
results in no hemodynamic compromise. No VT, no underlying cause, and a structurally
further evaluation or therapy is necessary. normal heart, spontaneous resolution is
expected, and therefore therapy may not be
Ventricular Tachycardia indicated once conversion to sinus rhythm
Ventricular tachycardia (VT) is defined is achieved.120 For sustained VT, incessant
as three or more consecutive ventricular VT, or rapidly conducting nonsustained VT,
I aVR V1 V4
II aVL V2 V5
III aVF V3 V6
II
Figure 15-29. Ventricular tachycardia with a rate of 140 beats per minute. Note the change in QRS morphology compared
with the sinus beats.
class I, II, and III antiarrhythmic drugs have and results of the cardiac examination
been used with varying success. Implanta- should be used in conjunction with heart
tion of a cardioverter-defibrillator is typi- size, respiratory pattern, and other findings
cally not indicated in the neonatal period. to point toward a diagnosis.
1. Heart sounds are usually abnormal in
SUMMARY OF NEONATAL ARRHYTHMIAS newborns with a serious congenital heart
Arrhythmias are a common problem in disease. A single S2 after the first 12 hours
the neonatal period. Although AVRT is the often indicates heart disease, although
most common arrhythmia encountered, with rapid heart rates this can be difficult
most other forms of SVT and VT are rare. to verify. A well-split S2 is always abnor-
The electrocardiogram remains crucial for mal and suggests TAPVR. The presence of
accurate diagnosis and proper therapeutic a pulmonary systolic ejection click may
intervention. Echocardiographic evaluation be normal in the first hours, but after
is warranted in all neonates with arrhyth- that any systolic ejection click is abnor-
mias, but most arrhythmias are not associ- mal, indicating an abnormal pulmonary
ated with congenital heart disease. Finally, or aortic valve, an enlarged pulmonary
although some neonatal arrhythmias, such artery or aorta, or truncus arteriosus. If
as PJRT and incessant VT, can be recalcitrant the infant has pulmonary disease without
to treat, most are responsive to antiarrhyth- congenital heart disease and has a nar-
mic medications and are “outgrown” during rowly split or single S2, then a high pul-
the first year of life. monary vascular resistance is expected.
2. Visible central cyanosis in the early
PRACTICAL HINTS newborn period usually indicates a very
All of the following hints should be used in low arterial oxygen tension. Even when
conjunction with additional data to make a the clinical judgment is that of only
diagnosis of cardiac disease. The adequacy of questionable cyanosis, the arterial Po2
systemic perfusion, arterial oxygen tension, may be very low.
3. Peripheral cyanosis (acrocyanosis) is infants. The pulse may be palpable even

normal and must be differentiated from with significant coarctation of the aorta
central cyanosis. A suspicion of hypox- while the ductus arteriosus is open, dis-
emia must be verified by arterial blood appearing when the ductus arteriosus
gas determinations. closes. Observation of diminished or
4. Measurement of systemic arterial blood absent femoral pulses by any examiner
gas concentrations while the infant requires additional investigation.
breathes room air and while supplemen- 9. A high index of suspicion is required
tal oxygen is administered may be help- to diagnose congenital heart disease
ful in differentiating pulmonary from early. Careful history taking, physical
cardiac cyanosis. A Pao2 of less than examination, and laboratory studies—
100 mm Hg in an enriched oxygen envi- including chest radiographs, ECG, and
ronment indicates congenital heart dis- blood gas or oximetric studies in an
ease until proven otherwise and is an enriched oxygen environment—often
indication for echocardiography and the help to establish the diagnosis. However,
initiation of prostaglandin E2 therapy. two-dimensional echocardiography per-
A Pao2 of 100 to 250 mm Hg is sugges- mits accurate and definitive diagnosis,
tive of congenital heart disease and war- accomplished without delay.
rants additional investigation. A Pao2 10. Life-threatening congenital heart dis-
above 250 mm Hg makes life-threaten- ease is sooner or later associated with
ing cyanotic heart disease less likely. In respiratory distress or frank cyanosis, or
questionable cases, hypoxemia without both.
significant hypercapnia (CO2 retention) 11. The presence of a large liver usually
tends to suggest primary cardiac disease. indicates systemic venous congestion
However, pulmonary venous congestion but does not necessarily point to con-
may result in considerable CO2 retention. gestive heart failure. Many conditions
5. Blood gas concentrations determined in the neonatal period can produce an
from heel-stick specimens do not pro- enlarged liver.
vide accurate measures of the arterial 12. On occasion, in the presence of RDS
Po2. However, the error is always on the and a PDA, congestive heart failure may
low side, so that in cyanotic congenital be diagnosed without cardiomegaly.
heart disease, a reasonably high Po2 on
a heel-stick sample is reassuring.
6. Transcutaneous Po2 or oximetric mea- CASE 1
surements are inaccurate at low levels On the day of discharge, the physical examination
and in the presence of hypoperfusion. findings for a full-term baby are significant for a harsh
They are valuable for monitoring trends murmur at the lower left sternal border. The exami-
or comparing upper and lower body nation before this was unremarkable. The child is
oxygenation. acyanotic, and the murmur is typical of a VSD with
7. Oximetric measurements may be ben- left-to-right shunt.
eficial in determining the type of con-
genital heart disease. Measurements Is a VSD possible? Why?
should be taken simultaneously in the A VSD is possible. The left ventricular pressure is not
right upper and either lower extrem- transmitted to the right side through the small restrictive
ity. Cyanosis-desaturation that is equal VSD. Therefore, nothing impedes the normal decrease
in the upper and lower extremities can in pulmonary vascular resistance. As the pulmonary
indicate right-sided heart obstruction vascular resistance decreases, the right ventricular
or TAPVR. Cyanosis-desaturation that is pressure decreases as it would normally. Therefore,
worse in the lower extremity indicates there is a large pressure gradient between the ventri-
left-sided heart obstruction or suprasys- cles, and an early left-to-right shunt is possible.
temic pulmonary artery pressures in the
face of a PDA. Cyanosis-desaturation Is the defect likely to be small or large?
that is worse in the upper extremity is The shunt rarely becomes large because of the high
diagnostic for dextro-TGA with elevated resistance to flow through the small defect. The major
pulmonary vascular resistance or coarc- key to suspecting that the defect is small is the early
tation until proven otherwise. onset of the loud, typical murmur. Also, large defects
8. Femoral or pedal pulses must be carefully should not produce a murmur because the pressure
and repeatedly palpated in all newborn
equalizes between the right and left ventricle when a relative pulmonary stenosis at the left upper sternal
large VSD is present. border caused by increased flow across either valve.
The degree of atrial-level shunting is determined by
Is eventual congestive heart failure likely? the ventricular compliance, so in a patient on the first
Heart failure is not likely when the left-to-right shunt day of life, there is likely minimal shunting because the
is small. right ventricle is still relatively stiff and noncompliant.
If the defect was larger, what symptoms Echocardiography confirms a balanced

would the infant manifest and how would complete AVSD with moderate-sized atrial
it best initially be managed? and ventricular septal defect components.
In the setting of a moderate to large defect that per- As this infant grows, how will the infant’s
mits significant left-to-right shunting, infants manifest heart disease manifest?
several symptoms. Due to the increased pulmonary Manifestations will depend on the right-sided pres-
blood flow, these patients are tachypneic, although sures. If the pulmonary pressures remain elevated,
they rarely display respiratory distress at rest, and the infant will be unlikely to develop overcirculation
their oxygen saturation is usually 99% to 100% un- and will remain relatively balanced. The infant may be
less they have significant pulmonary flow to produce mildly cyanotic at baseline due to bidirectional shunt-
interstitial edema. They may have minimal to mild re- ing at the ventricular level or may become more cy-
tractions. The liver may be felt below the right costal anotic with transient increases in the right-sided pres-
margin. During feedings, these infants may become sure, such as during crying. If pulmonary pressures
more tachypneic or diaphoretic, or develop respira- and right-sided pressures fall, the patient is likely to
tory distress. Because of increased energy demands, develop VSD-type physiology with increased pulmo-
they may also demonstrate poor weight gain. nary circulation. In this situation, the patient would
manifest symptoms similar to those discussed in
Case 1 and may require anticongestive therapy.
CASE 2
A 40-year-old mother has just delivered a term infant
boy. She had little prenatal care and no prenatal test- CASE 3
ing or ultrasonography. The infant does well and goes A 36-week gestation infant is born to a 20-year-old
to the newborn nursery. On examination, the infant is primigravid mother. The mother received minimal
found to have multiple features consistent with trisomy prenatal care. The mother’s labor was prolonged
21. The cardiac examination is unremarkable, but be- with rupture of membranes 18 hours before delivery.
cause occasional PACs are noted on a monitor, an There is meconium in the fluid, and the infant under-
ECG is obtained. This ECG shows normal sinus rhythm goes suctioning for meconium aspiration following
with occasional PACs and a leftward/northwest axis. vaginal delivery. He is intubated due to respiratory
distress and taken to the neonatal intensive care unit
Given the findings described, does this for further management, where oxygen saturation
infant have congenital heart disease? measured on his right hand is 75%. An oxygen satu-
Yes. The finding of a leftward or northwest axis on ration probe on his left foot reads 90%.
ECG is very suspicious for an AV septal (endocardial
cushion) defect. The PACs are insignificant and are a What is the difference between differential
common finding in the neonatal period. cyanosis and reverse differential cyanosis?
Differential cyanosis is present when the preduc-
Assuming the infant has a complete tal oxygen saturation is higher than the postduc-
atrioventricular septal defect (AVSD), does tal oxygen saturation. Reverse differential cyanosis
the lack of a murmur surprise you? is present when the preductal oxygen saturation is
No. In this clinical situation, the pulmonary pressures lower than the postductal oxygen saturation. A PDA
have not fallen, and thus there may be minimal shunt- is necessary for either form.
ing at the level of the VSD component. In patients with
trisomy 21, this fall in pulmonary pressures can be What form of differential cyanosis does this
delayed or may not occur. Murmurs are not typically patient have and what clinical situations
heard due to shunting through the atrial septal defect, result in this finding?
but in the setting of a large left-to-right shunt at the The patient has reverse differential cyanosis. This
atrial level, there may be a diastolic rumble associated type of cyanosis can be seen in TGA with either a
with relative tricuspid stenosis at the lower left sternal significant coarctation or interrupted aortic arch. Ob-
border or a systolic ejection murmur associated with taining oxygen saturation measurements from the left
upper extremity can be helpful in determining the site is indicative of critical aortic stenosis with duct-de-
of either coarctation or interruption. Reverse differen- pendent systemic blood supply.
tial cyanosis can also occur in TGA with supersys-
temic pulmonary pressures that result in right-to-left What are the effects of aortic valve
shunting across the PDA. stenosis in utero on the left ventricle?
Aortic valve stenosis results in increased left ventricular
How can these three distinct entities best pressure and left ventricular hypertrophy. Increased left
be identified? ventricular hypertrophy results in decreased left ven-
In the neonatal period, echocardiography should be tricular compliance, which may lead to decreased flow
sufficient to determine the presence of coarctation or through the left side of the heart if severe enough. If
interruption. Pulmonary pressures can accurately be flow through the left side of the heart is too restricted,
estimated and flow across the PDA can be determined it can affect the development of “downstream” struc-
by color in color flow Doppler echocardiography. tures, including left ventricular chamber size, aortic
valve annulus size, and the size of the ascending aorta.
What clinical scenarios can result in
differential cyanosis (not reverse)? Explain the cardiac collapse when this
Normally related great arteries with a hypoplastic aor- patient was taken to the pediatrician.
tic arch, severe coarctation, or interruption can result The findings this infant exhibited are characteristic of
in differential cyanosis. Also PPHN with normally re- a patient whose left ventricle is unable to handle the
lated great arteries can result in differential cyanosis. entire cardiac output. In this situation, the infant is de-
pendent upon the PDA for systemic circulation. The
What should be the initial management symptoms of circulatory collapse can occur abruptly
of this patient with reverse differential as the ductus closes. Inadequate systemic circula-
cyanosis? tion results in poor peripheral pulses. The respiratory
A common theme in all cases of reverse differential symptoms are secondary to pulmonary venous con-
cyanosis is the presence of TGA. Initial management gestion. Tachycardia is a manifestation of the infant’s
should include initiation of prostaglandin E1 infusion attempt to increase cardiac output (cardiac output =
to maintain ductal patency. Additional management stroke volume × heart rate).
may include balloon atrial septostomy to insure ad-
equate mixing before surgical repair or supplemental In a patient such as this with severe aortic
oxygen or inhaled nitric oxide to help with manage- stenosis, what would one expect to see on
ment of PPHN if appropriate. the ECG?
Patients with aortic valve stenosis typically demon-
strate voltage changes that meet the criteria for left
CASE 4 ventricular hypertrophy, although approximately one
third of patients with severe aortic stenosis may have
A 38-week gestation girl was born to a 30-year-old
a normal ECG. However, the findings of left ventricu-
mother via cesarean section. Pregnancy was uncom-
lar hypertrophy, ST depression, and T-wave inversion
plicated. A grade 3/6 systolic ejection murmur heard
are fairly specific for severe aortic stenosis.
best at the mid-left sternal border and right sternal
border was noted on examination while the infant
What initial steps should be taken to
was in the nursery. Because the infant was feeding
stabilize this patient’s condition?
well, she was discharged home at 2 days of age on
Friday with instructions for follow-up with the pediatri- This patient is clearly duct dependent, and prostaglan-
cian on Monday. She did well through the weekend, din E1 infusion should be initiated immediately to restore
feeding every 3 hours, but on Monday morning she systemic circulation. Metabolic acid-base derange-
became more irritable, pale, and tachypneic. She was ments must be managed, and the hemoglobin level
taken immediately to her pediatrician who noted poor should be optimized. Echocardiography is essential
pulses, tachycardia, respiratory distress, hepatomeg to accurately establish the diagnosis and identify any
aly, a hyperdynamic right ventricular impulse, and a associated lesions. This is also important to determine
similar ejection murmur. The infant was subsequently whether the patient may need a two-ventricle repair.
transferred to the emergency department of a tertiary
care pediatric hospital.
Can a diagnosis be suggested? REFERENCES

The location of the murmur in the nursery raises suspi- The reference list for this chapter can be found
cion of aortic stenosis. The progression of symptoms online at www.expertconsult.com.
The Kidney
David N. Kenagy and Beth A. Vogt
Advances in neonatology, perinatology,

16
The lower portion of the S-shaped structure
and molecular genetics have defined new becomes associated with a tuft of capillaries
disease processes and raised new questions and forms the glomerulus; the upper portion
in the field of nephrology. For example, the forms the tubular elements of the nephron.
advent of prenatal ultrasonography has cre- The complex process of kidney devel-
ated questions about the prenatal manage- opment appears to be under the control of
ment of urinary tract anomalies. The use growth factors, a series of key regulatory
of invasive vascular catheters has led to a genes, and renal innvervation.1-3 A number of
new set of complications, including renal genes that control DNA transcription are cru-
artery and aortic thrombosis associated with cial in the control of cellular events in renal
umbilical artery catheterization. The admin- development.2 For example, mutation of the
istration of loop diuretics and steroids to transcription factor gene PAX 2, which is nor-
infants with bronchopulmonary dyspla- mally expressed in developing renal tissue, is
sia has led to neonatal nephrocalcinosis. associated with a syndrome characterized by
Simultaneously, genetic similarities among vesicoureteral reflux, hypoplastic kidneys,
children whose conditions were formerly reduced calyces, and optic nerve colobomas.4
considered phenotypically distinct are rede- Mutations in another transcriptional factor
fining congenital anomalies of the kidneys gene, WT-1, results in renal agenesis, which
and urinary tract. suggests that this gene product may be cru-
This chapter reviews the anatomic and cial for outgrowth of the ureteric bud.5
functional development of the kidney, out-
lines the recommended approach to evalu- FUNCTIONAL DEVELOPMENT
ation of the neonate with suspected renal During intrauterine life, the kidneys play a
disease, and comments on the more com- minor role in regulating fetal salt and water
mon nephrologic and urologic problems balance, because this function is main-
seen in preterm and term neonates. tained primarily by the placenta. The pri-
mary function of the kidneys prenatally is
ANATOMIC DEVELOPMENT to produce large amounts of hypotonic or
The definitive mammalian kidney, the isotonic urine to provide adequate amniotic
metanephros, starts developing at 5 weeks’ fluid. After birth, a progressive maturation
gestation and begins to produce urine by in renal function begins that appears to
10 to 12 weeks’ gestation. Development of parallel the neonate’s metabolic needs for
the metanephros occurs through a series of growth and development. In general, matu-
interactions between the metanephric blas- ration of most renal functions is complete
tema and the ureteric bud. The ureteric bud by 2 years of age (Table 16-1).
progressively branches and grows, eventu-
ally forming the ureter, renal pelvis, and RENAL BLOOD FLOW
intrarenal collecting system. Both absolute renal blood flow and the per-
At the same time, mesenchymal cells of centage of cardiac output directed to the
the metanephric blastema are induced by the kidneys increases steadily with advancing
advancing ureteric bud to differentiate into gestational age (see Table 16-1). Renal blood
epithelial cells that eventually become the flow in the human fetus and term infant are
glomeruli and renal tubules. Foci of meta- estimated to be as low as 4% and 6% of the
nephric blastema cells interact with the sur- cardiac output, respectively. The relatively
rounding extracellular matrix and condense low renal blood flow of the neonate is related
adjacent to the branching ureteric bud to form to high renal vascular resistance caused by
comma-shaped bodies, which then elongate increased levels of renin, angiotensin, aldos
to form S-shaped tubular structures (Fig. 16-1). terone, endothelin, and catecholamines.
410
CHAPTER 16 The Kidney 411
A B C
Ureteric
bud tips
Ureteric Stroma
bud
Condensed
Renal vesicle
mesenchyme
D Proximal
tubule
Efferent Collecting
Collecting arteriole duct
duct
Afferent
Distal arteriole Distal
tubule tubule
Proximal Podocytes Thick

Glomerulus
tubule ascending
Parietal
Endothelial glomerular limb
cells epithelium
Henle loop
S-shaped body Nephron

Figure 16-1. Stages of nephrogenesis. A, Induction of the metanephric mesenchyme by the ureteric bud promotes
aggregation of condensed mesenchyme around the tip of the ureteric bud. B, Polarized renal vesicles as the mesenchyme
transitions to epithelium. C, Fusion of renal vesicles occurs with the collecting ducts. D, A cleft forms in the renal vesicle,
giving rise to the comma-shaped body with formation of a second proximal cleft, the S-Shaped body forms. Invasion of
the proximal cleft by angioblasts leads to formation of the glomerulus. (Redrawn from Dressler GR: The cellular basis of
kidney development, Annu Rev Cell Dev Biol 22:509–529, 2006.)
Postnatally, there is a sharp increase in renal is achieved, and the rate further increases to
blood flow, which reaches 8% to 10% of car- 21 mL/min/1.73 m2 at term (see Table 16-1).
diac output at 1 week of life and achieves The GFR continues to increase postnatally,
adult values of 20% to 25% of cardiac out- achieving adult values of 118 mL/min/1.73 m2
put at 2 years of age. This dramatic increase by age 2 years. In preterm infants born before
in renal blood flow is related to decreasing 34 weeks’ gestation, the GFR remains stable
renal vascular resistance and increasing car- until the conceptual age (gestational age plus
diac output and perfusion pressure. postnatal age) exceeds 34 weeks, at which
In addition to the increase in overall time the GFR begins to increase. Although
renal blood flow, there is a marked change adult values for GFR are attained by 2 years
in distribution of blood flow within the of life in term infants, achievement of adult
neonatal kidney in the postnatal period. GFR is delayed in preterm infants, especially
Because of a preferential decrease in vascu- in very low-birth-weight infants and infants
lar resistance in the outer cortex, there is with nephrocalcinosis.6
a pronounced increase in superficial renal Several factors are responsible for the
cortical blood flow. postnatal increase in GFR. The increase in
GFR during the initial weeks of postnatal
GLOMERULAR FILTRATION RATE life is primarily due to an increase in glo-
Glomerular filtration rate (GFR) in the fetal merular perfusion pressure.7 Subsequent
kidney increases with gestational age. By 32 increases in GFR during the first 2 years of
to 34 weeks, a GFR of 14 mL/min/1.73 m2 life are primarily due to increases in renal
412 CHAPTER 16 The Kidney
Table 16-1. Normal Values for Renal Function
Glomerular Maximal Urine Serum Fractional

iltration Rate
F Renal Blood Flow Osmolality Creatinine Excretion of
Age (mL/min/1.73 m2) (mL/min/1.73 m2) (mOsm/kg) (mg/dL) Sodium (%)
Newborn
32-34 wk 14 ± 3 40 ± 6 480 1.3 2-5
gestation
Full Term 21 ± 4 88 ± 4 800 1.1 <1
1-2 wk 50 ± 10 220 ± 40 900 0.4 <1
6 mo–1 yr 77 ± 14 352 ± 73 1200 0.2 <1
1-3 yr 96 ± 22 540 ± 118 1400 0.4 <1
Adult 118 ± 18 620 ± 92 1400 0.8-1.5 <1
Adapted from Avner ED, Ellis D, Ichikawa I, et al: Normal neonates and maturational development of
homeostatic mechanism. In Ichikawa I, editor: Pediatric textbook of fluids and electrolytes, Baltimore,
1990, Williams & Wilkins.
Table 16-2. Change in Body Water with Maturation

% Body Weight
Age Extracellular Fluid Intracellular Fluid Total Body Fluid

Gestational
14 wk 65 27 92
28 wk 55 25 80
40 wk 45 30 75
Postnatal
14 wk 25 40 65
Adapted from Sulyok E: Postnatal adaptation. In Holliday MA, Barratt TM, Avner ED, editors: Pediatric
nephrology, Baltimore, 1994, Williams & Wilkins.
blood flow and maturation of superficial therapy is required. If insensible fluid losses
cortical nephrons, which lead to an increase are overestimated during the prediuretic
in glomerular filtration surface area. phase, excess fluid intake may result in dilu-
During the first week of postnatal life, tional hyponatremia. On the other hand,
an infant’s GFR passes through three dis- a deficiency in fluid intake during this
tinct phases to maintain fluid and electro- phase may lead to volume contraction and
lyte homeostasis. The initial 24 hours of hypernatremia. During the diuretic phase,
life (prediuretic phase) is characterized by a hypernatremia may develop as a result of
transitory increase in GFR at 2 to 4 hours excessive urinary fluid losses.
of life followed by a return to low baseline
GFR and minimal urine output regardless FLUID COMPARTMENTS
of salt and water intake. This phase may The change in distribution of intracellular
extend up to 36 hours of life in the preterm fluid (ICF) and extracellular fluid (ECF) in the
infant, with delay in onset of the transitory fetus and newborn infant is summarized in
increase in GFR. During the second and Table 16-2. In the healthy term infant, ECF
third days of life (diuretic phase), the GFR volume decreases and ICF volume increases
increases rapidly, and the infant experiences in the first few days of life.8 In the preterm
diuresis and natriuresis regardless of salt and infant, total body water decreases, primarily
water intake. By the fourth to fifth day of as a result of ECF losses in the first week of
life (postdiuretic phase), the GFR decreases life, a process that is delayed in infants with
slightly, then continues to increase slowly respiratory distress syndrome. The change
with maturation, with salt and water excre- in ICF during the first week of life is vari-
tion varying according to intake. able and may be dependent on total energy
Importantly, the duration and timing of intake and corresponding change in body
these phases differ among infants, so that weight during this period. For example,
individualization of fluid and electrolyte in preterm infants with more than a 10%
5.0 4 to 5 mEq/kg/day of sodium may be neces-

4.0 Respiratory morbidity sary in preterm infants to offset high renal
3.0
Transient or absent sodium losses during the first few weeks of
2.0 Persistent life.
Percent fractional sodium excretion
Healthy term neonates have basal sodium

1.0 handling similar to that of adults, as demon-
strated by an FENa of less than 1.0%, although
0.4
a transient increase in FENa occurs during the
second and third days of life (diuretic phase).
Urinary sodium losses may be increased in
0.2
certain conditions, including renal dysplasia,
hypoxia, respiratory distress, hyperbilirubi-
0.1 nemia, acute tubular necrosis (ATN), polycy-
0.06 themia, increased fluid and salt intake, and
0.04
the use of theophylline or diuretics.7 Phar-
macologic agents such as dopamine, labet-
alol, propranolol, captopril, and enalaprilat
0.02
that influence adrenergic neural pathways
0 10 20 30 40 50 60 70 in the kidney and the renin-angiotensin axis
Age (days) may also increase urinary sodium losses in
Figure 16-2. Fractional excretion of sodium in neonates the neonate.
born at 28 to 33 weeks of gestation during the first 2 The mechanisms responsible for increased
months of life. (From Ross B, Cowett RM, Oh W: Renal urinary sodium losses in the preterm infant
functions of low birth weight infants during the first two are multifactorial. Glomerulotubular imbal-
months of life, Pediatr Res 11:1162, 1997.)
ance, which occurs when GFR exceeds the
reabsorptive capacity of the renal tubules,
occurs because of the preponderance of
loss in body weight during the first week of glomeruli compared with tubular structures,
life, there is a decrease in ECF without an renal tubular immaturity, large extracellular
increase in ICF. volume, and reduced oxygen availability.11
Capillary filtration between the intravas- Decreased renal nerve activity may also
cular and interstitial fluid compartments is contribute; studies in fetal and newborn
higher in the neonatal period than it is later sheep demonstrate an inverse relationship
in life, which leads to a relatively large inter- between renal nerve stimulation and urine
stitial fluid compartment. This phenom- sodium excretion.11 Finally, fetal and post-
enon may be due to a number of factors, natal kidneys exhibit diminished respon-
including increased hydrostatic pressure, siveness to aldosterone compared with adult
decreased intravascular osmotic pressure, kidneys, which results in the attenuation of
and increased levels of atrial natriuretic fac- sodium reabsorption.12
tor, vasopressin, and cortisol.9 The relatively
large interstitial fluid compartment enables URINARY CONCENTRATION AND
the neonate to better tolerate hemorrhage DILUTION
because the large volumes of interstitial As noted in Table 16-1, renal concentrat-
fluid can shift into the intravascular space, ing capacity is low at birth and progres-
but it may also lead to reduced ability to sively increases following delivery from 800
excrete a free water load. mOsm/kg H2O in the first 2 weeks of life to
adult values of 1400 mOsm/kg H2O between
SODIUM HANDLING 1 and 3 years of age.13 This improvement in
Renal sodium losses are inversely propor- ability to excrete a concentrated urine is due
tional to gestational age, and the fractional to increased urea generation, improved end-
excretion of sodium (FENa) may be as high as organ responsiveness to vasopressin, and
5% to 6% in infants born at 28 weeks’ gesta- anatomic maturation of the renal medulla
tion (Fig. 16-2). As a result, preterm infants and its vasculature.
younger than 35 weeks’ gestation may dis- The ability of the neonatal kidney to
play negative sodium balance and hypona- excrete a water load is somewhat limited in
tremia during the initial 2 to 3 weeks of life comparison with that of the adult kidney.
due to high renal sodium losses and ineffi- For example, term and premature newborns
cient intestinal sodium absorption.10 Up to can dilute their urine to an osmolality of
70 metabolic acidosis may develop as a result

60 of stress during birth and disturbances in
cardiopulmonary adaptation. Late meta-
Number of infants
50 bolic acidosis, on the other hand, may

40 develop during the first week of life and is
1 SD 1 SD
most pronounced in the second and third
30
2 SD 2 SD weeks of life. This type of acidosis is due
20 to an imbalance between net acid input,
10
primarily from dietary protein intake and
bone mineralization, and renal capacity for
// net acid excretion. Late metabolic acidosis
10.5 12.5 14.5 16.5 18.5 20.5 22.5 24.5 26.5 28.5 30.5
may result in poor weight gain or skeletal
Total bicarbonate (mmol/L)
growth. Late metabolic acidosis usually
Figure 16-3. Frequency distribution of serum total resolves spontaneously by the end of the
bicarbonate level in low-birth-weight neonates during the
first month of life as a result of the rapid
first month of life. (From Schwartz GJ, Haycock GB, Chir
B, et al: Late metabolic acidosis: a reassessment of
postnatal increase in the renal capacity for
the definition, J Pediatr 95:102, 1979.) net acid excretion.
An important consequence of chronic
metabolic acidosis in the newborn is
50 mOsm/kg and 70 mOsm/kg, respectively, enhanced urinary calcium losses, negative
whereas adults can dilute their urine to 30 calcium balance, and bone demineraliza-
mOsm.13 This inability to maximally dilute tion, which may contribute to the phe-
the urine is due to reduced GFR as well as nomenon of osteopenia of prematurity.
to decreased activity of transporters in the The mechanism for this process is multi-
early distal tubule (diluting segment), which factorial. Acidosis causes release of calcium
are most prominent in the preterm infant.14 from bones directly and via parathyroid
hormone secretion. Acidosis also inhibits
ACID-BASE BALANCE intestinal calcium absorption and impairs
The range of normal serum bicarbonate levels 1α-hydroxylation of 25-hydroxyvitamin D.
is lower than that of adults, and infants main- Finally, acidosis increases urinary flow rate
tain a mild metabolic acidosis (Fig. 16-3). and urinary calcium excretion.16 Therefore,
This limitation in acid-base homeostasis seen persistent metabolic acidosis should be cor-
in neonates, particularly preterm infants, is rected with sodium bicarbonate, with a goal
related to immaturity of both proximal and of achieving a serum bicarbonate level of 17
distal tubular function. to 18 mEq/L.
The proximal tubular bicarbonate thresh-
old, defined as the steady-state serum CALCIUM AND PHOSPHORUS BALANCE
bicarbonate level above which significant Within 24 to 48 hours after birth, the serum
amounts of bicarbonate appear in the calcium concentration decreases, a phenom-
urine, is much lower in neonates than in enon that is most pronounced in preterm
adults, which leads to incomplete bicar- infants.17 Although the exact mechanism
bonate reabsorption. The cause of the low of neonatal hypocalcemia is unknown, it
proximal tubular bicarbonate threshold is appears to be due to suppressed parathyroid
unknown. Studies in the fetal lamb have hormone secretion and elevated plasma
demonstrated that renal tubular reabsorp- phosphate concentration. In most neo-
tion of bicarbonate is inversely proportional nates, the ionized calcium level remains
to ECF volume.15 Therefore, expanded ECF above a physiologically acceptable concen-
compartment characteristic of the preterm tration and the infant experiences no clini-
and term infant may be related to the low cal symptoms. Symptomatic hypocalcemia
renal bicarbonate threshold and low plasma may occur, however, in neonates stressed by
bicarbonate concentration. Limited dis- illness or in the presence of aggressive fluid
tal tubular excretion of titratable acid and administration, diuresis, and sodium sup-
incomplete development of tubular ammo- plementation, all of which increase urinary
nia production also contribute to the rela- calcium losses.
tive metabolic acidosis of the newborn. The normal serum phosphorus level in
Newborn infants may display two forms the newborn ranges from 4.5 to 9.5 mg/
of acidosis. In the first 24 hours of life, an dL, whereas adult values are 3.0 to 4.5 mg/
early type of combined respiratory and dL. The higher serum phosphorus level in
the newborn is due to enhanced dietary PHYSICAL EXAMINATION

phosphorus intake, particularly in infants Evaluation of blood pressure and volume
fed cow’s milk formulas; lower GFR; and status is critical in the newborn with sus-
higher tubular reabsorption of phospho- pected renal disease. Hypertension may be
rus. Tubular reabsorption of phosphorus present in infants with autosomal reces-
is lower, however, in preterm infants and sive polycystic kidney disease, acute renal
increases progressively during gestation failure, or renovascular or aortic throm-
as a result of maturation of renal tubular bosis. Hypotension, on the other hand, in
function. The phosphorus losses seen in addition to cardiovascular disorders, may
premature infants cause relative phospho- suggest volume depletion, hemorrhage, or
rus deficiency, which may result in inad- sepsis, all of which may lead to acute renal
equate bone mineralization. For premature failure. Edema may be seen in acute renal
infants, therefore, greater attention must failure, in hydrops fetalis, or with massive
be given to nutritional supplies of phos- urinary protein losses associated with con-
phorus and calcium in enteral and paren- genital nephrotic syndrome. Ascites may
teral formulations. be seen in acute renal failure with volume
overload, congenital nephrotic syndrome,
EVALUATION or urinary tract obstruction with rupture.
The evaluation of an infant with suspected Special attention should be paid to the
renal disease must be comprehensive and abdominal examination. In the neonate,
begins with a careful history taking and thor- the lower pole of both kidneys should
ough physical examination. Selected labora- be easily palpable because of the neo-
tory studies may be useful in determining nate’s reduced abdominal muscle tone.
the cause and severity of renal dysfunction. An abdominal mass present in a newborn
Limited radiologic evaluation may be useful should be assumed to involve the urinary
in clarifying renal anatomy and detecting tract until proven otherwise, because the
complications of vascular catheters. majority of neonatal abdominal masses are
genitourinary in origin.25 The most com-
HISTORY mon renal cause of an abdominal mass is
Results of prenatal ultrasonography should hydronephrosis, followed by multicystic
be carefully reviewed with particular atten- dysplastic kidney. Less common causes of
tion to kidney size, echogenicity, malforma- an abdominal mass are polycystic kidney
tions, amniotic fluid volume, and bladder disease, renal vein thrombosis, ectopic or
size and shape.18 The presence of unilateral fused kidneys, renal hematoma or abscess,
or bilateral small or enlarged kidneys, renal and renal tumors. The newborn bladder
cysts, hydronephrosis, bladder enlargement, should be able to be percussed just above
or oligohydramnios may suggest significant the symphysis pubis and, if it is enlarged,
renal or urologic abnormalities. lower urinary tract obstruction should be
The causes of congenital renal disease are suspected. A palpable prostate in a male
multifactorial but may include exposure to newborn is always abnormal and suggests
teratogens.19 The antenatal history should posterior urethral valves. The abdomen
be reviewed, with particular attention given should be examined for absence or laxity of
to medications, toxins, or unusual exposures the abdominal muscles, which may suggest
during the pregnancy. Congenital renal Eagle-Barrett (prune-belly) syndrome.
anomalies have been described in infants A number of anomalies should alert the
with antenatal exposure to angiotensin- physician to the possibility of underly-
converting enzyme inhibitors,20,21 angio- ing renal defects, including abnormal ears,
tensin receptor blockers, 21 nonsteroidal aniridia, microcephaly, meningomyelocele,
antiinflammatory drugs,19,22 gentamicin, pectus excavatum, hemihypertrophy, per-
corticosteroids, 23 calcineurin inhibitors,19 sistent urachus, bladder or cloacal exstro-
and cocaine.24 phy, abnormality of the external genitalia,
Review of the family medical history cryptorchidism, imperforate anus, and limb
should include information on any prior deformities. A single umbilical artery
fetal or neonatal deaths. Although there should raise suspicion of renal disease. In
is no hereditary cause for most congenital one study, 7% of otherwise normal infants
renal anomalies, there is a clear genetic basis with a single umbilical artery were found
for certain diseases such as polycystic kid- to have significant persistent renal anom-
ney disease and nephronophthisis. alies.26 The utility of screening all infants
with a single umbilical artery, however, symptoms of renal disease. Failure to void
remains controversial. for longer than 48 hours should prompt
further investigation, including kidney
and bladder ultrasonography to rule out
urinary tract anomalies.
EDITORIAL COMMENT: The question of whether to
Evaluation of the urine is a vital part of
perform further investigation in well infants with an
the examination of any neonate suspected
isolated single umbilical artery is both controversial
of having a urinary tract abnormality. Col-
and clinically relevant, with the incidence of single
lection of an adequate, uncontaminated
umbilical artery approximating 0.3% of newborns.
specimen is difficult in the neonate. A spec-
Some reviews recommend that all infants with a sin-
imen collected by cleaning the perineum
gle umbilical artery undergo routine screening with
and applying a sterile adhesive plastic bag
ultrasonography with or without micturating cystoure-
enables analysis of urinary protein or elec-
thrography.27 Deshpande et al28 looked at 137 con-
trolytes. Tests for heme and cultures may
secutively examined infants born with a single umbili-
give erroneous results. For cultures, blad-
cal artery in a 6-year period. Of those infants, 122 with
der catheterization produces a reliable
an isolated single umbilical artery underwent renal
specimen but may be technically difficult
ultrasonography and only 2 infants (1.6%; 95% con-
in preterm infants. Suprapubic bladder
fidence interval: 0.20 to 5.5) had clinically significant
aspiration has been considered the collec-
renal anomalies. The authors of that study concluded
tion method of choice in infants without
that postnatal renal ultrasonography was not routinely
intraabdominal abnormalities or bleeding
warranted in infants with an isolated single umbilical
disorders, although anecdotal evidence
artery.
suggests that few clinicians opt for that
approach.
Analysis of the urine should include
A constellation of physical findings inspection, measurement of specific gravity,
called the Potter sequence may be seen in urinary dipstick testing, and microscopic
infants with bilateral renal agenesis. Lack analysis. The urine of newborns is usually
of fetal renal function results in severe oli- clear and nearly colorless. Cloudiness may
gohydramnios, which causes fetal defor- be caused by either urinary tract infection or
mation by uterine wall compression. the presence of crystals. A yellow-brown to
The characteristic facial features include deep olive-green color may indicate increas-
wide-set eyes, depressed nasal bridge, ing amounts of conjugated bilirubin. Por-
beaked nose, receding chin, and posteri- phyrins, certain drugs such as phenytoin,
orly rotated, low-set ears. Other associated bacteria, and urate crystals may stain the
anomalies include a small, compressed diaper pink and be confused with bleed-
chest wall and arthrogryposis. The con- ing. Brown urine suggests bleeding from
dition is uniformly fatal. “Potter-like” the upper urinary tract, hemoglobinuria, or
features may be noted in infants with in myoglobinuria.
utero urinary tract obstruction or chronic Urinary specific gravity may be measured
amniotic fluid leakage. In this group of using a clinical refractometer or a urinary
infants, pulmonary and renal function are dipstick. The specific gravity of neonatal
generally not as severely impaired and the urine is usually very low (<1.004) but may
prognosis is less grim. In infants with sig- be factitiously elevated by high-molecular-
nificant renal defects, pneumothorax or weight solutes such as contrast agents, glu-
pneumomediastinum are common clinical cose or other reducing substances, or large
associations related to varying degrees of amounts of protein. Gouyon and Houchan
pulmonary hypoplasia. showed that dipstick estimation of urinary
specific gravity was an unreliable test of uri-
URINALYSIS nary concentrating ability in the neonate
Twenty-five percent of male infants and and suggested that urinary osmolarity is a
7% of female infants void at the time more reliable measure of the kidney’s con-
of delivery. Although 98% of full-term centrating and diluting ability.30
infants void in the first 30 hours of life,29 Urine dipstick evaluation can detect the
a delay in urination for up to 48 hours presence of heme-containing compounds
should not be a cause for immediate con- (red blood cells, myoglobin, and hemo-
cern in the absence of a palpable blad- globin), protein, and glucose. White blood
der, abdominal mass, or other signs or cell products such as leukocyte esterase and
nitrite may also be detected by urine dip- abscess, perinephric abscess), obstruction
stick and should raise suspicion of urinary (hydronephrosis, hydroureter), and blad-
tract infection, which should prompt the der morphology.
clinician to order a urine culture. Micro- Voiding cystourethrography is the pro-
scopic urinalysis should be performed if the cedure of choice to evaluate the urethra
urinary dipstick result is abnormal and is and bladder and to ascertain the presence
useful in detecting the presence of red blood or absence of vesicoureteral reflux. This
cells, casts, white blood cells, bacteria, and study involves urinary catheterization and
crystals. instillation of radiopaque dye into the
infant’s bladder. A voiding cystourethro-
LABORATORY EVALUATION gram should be considered in all infants
Clinical evaluation of neonatal renal func- with urinary tract obstruction, renal dys-
tion begins with measurement of serum plasia or anomaly, or documented urinary
creatinine level. As discussed previously, tract infection.
normal values for serum creatinine vary Other radiologic tests may occasionally be
with gestational age and postnatal age (see used for diagnostic purposes in the neonate.
Table 16-1). The serum creatinine level is A technetium 99m (99mTc) MAG-3 (mercap-
relatively high at birth, with normal values toacetyltriglycine) or 99mTc DTPA (diethyl-
up to 1.1 mg/dL in term babies and 1.3 mg/ ene triamine pentaacetic acid) diuretic renal
dL in preterm infants, but decreases to a scan may be helpful in confirming urinary
mean value of 0.4 mg/dL within the first 2 tract obstruction in an infant with hydrone-
weeks of life.13 In general, each doubling of phrosis or hydroureter on ultrasonography.
the serum creatinine level represents a 50% A renal scan using 99mTc DMSA (dimercapto-
reduction in GFR; for example, an increase succinic acid) or 99mTc glucoheptonate may
in creatinine concentration from 0.4 mg/ help to identify renal scarring related to prior
dL to 0.8 mg/dL reflects a 50% reduction pyelonephritis or umbilical artery catheter–
in GFR. The Schwartz formula, which esti- related embolic phenomenon. Computerized
mates GFR using serum creatinine level tomography may be helpful in evaluating
and body length, has been applied to nor- suspected renal abscess, mass, or nephro-
mal preterm and term infants. Recently, lithiasis.
the methodology for measuring serum cre-
atinine has changed from the Jaffe method SPECIFIC PROBLEMS
to one involving the plasma disappearance
of iohexol. This has led to a revision of the HEMATURIA AND PROTEINURIA
Schwartz formula for children aged 1 to 16
years.31 The new formula, which has not yet
been studied in term or preterm infants, is
At 16 hours of age, a 4300-g 41-week infant born to
as follows:
a mother with gestational diabetes develops macro-
0.413 × Height scopic hematuria. Physical examination reveals a list-
Estimated GFR = less, pale infant with a large left flank mass. Urinalysis
(Cr)
demonstrates hematuria (4+) with more than 250
red blood cells/mm.32 Laboratory findings include a
where GFR is expressed in milliliters per
hematocrit of 36%, a platelet count of 75,000/mm3,
minute per 1.73 m2; height is expressed
and a serum creatinine concentration of 1.0 mg/dL.
in centimeters; and creatinine (Cr) con-
Renal ultrasonography shows an enlarged left kidney
centration is expressed in milligrams per
with impaired venous flow by Doppler study, consis
deciliter.
tent with renal vein thrombosis.
RADIOLOGIC EVALUATION The infant is treated conservatively with hydra-
tion and careful observation of fluid balance and
Renal ultrasonography is the initial procedure
renal function. Within 48 hours, the macroscopic
of choice in infants with suspected renal dis-
hematuria resolves and renal function remains sta-
ease.25 Renal ultrasonography offers a non-
ble. Serial ultrasound examinations reveal gradual
invasive anatomic evaluation of the urinary
resolution of the thrombosis over the next 7 days,
tract without the use of contrast agents or
with improvement in renal venous blood flow. At
radiation exposure. Renal ultrasonography
6 months of age, the infant’s serum creatinine con-
can demonstrate kidney size and morphol-
centration is 0.4 mg/dL and renal ultrasound find-
ogy, presence of nephrocalcinosis or neph-
ings are normal.
rolithiasis, complications of infection (renal
Hematuria may be suspected by urinary ACUTE KIDNEY INJURY

dipstick testing (microscopic) or visual
examination (macroscopic or gross). Con-
firmation of hematuria requires micro- A 2300-g female infant is delivered after a 36-week
scopic examination showing at least 5 red uncomplicated pregnancy. Fetal decelerations were
blood cells per high-power field. A posi- noted before delivery, and a tight nuchal cord is
tive urinary dipstick result with negative present. Apgar scores are 1 at 1 minute and 4 at 5
findings on microscopic examination for minutes. The infant is resuscitated using intubation,
red blood cells suggests myoglobinuria or compressions, and epinephrine. Arterial blood gas
hemoglobinuria. Myoglobinuria may be analysis shows a pH of 7.10, Pco2 of 54 mm Hg,
seen in infants with inherited metabolic and Po2 of 93 mm Hg. Initial laboratory work reveals
myopathies, infectious myositis, and rhab- normal electrolyte levels and a serum creatinine con-
domyolysis related to prolonged seizure centration of 0.9 mg/dL.
activity, corticosteroid use, or direct muscle Over the next 3 days, the infant becomes oligur
trauma. Hemoglobinuria may be present in ic, and laboratory results are as follows: Na, 127
erythroblastosis fetalis and other forms of mmol/L; K, 6.5 mmol/L; Cl, 106 mmol/L; HCO3, 15
hemolytic disease. mmol/L; blood urea nitrogen, 18 mg/dL; and cre-
The most frequent cause of hematu- atinine, 2.0 mg/dL. Urinalysis shows hematuria (2+)
ria in the neonate is ATN following birth and proteinuria (1+). Renal ultrasonography shows
asphyxia, exposure to nephrotoxic drugs, hyperechoic parenchyma without evidence of renal
or sepsis. Another important cause of hema- dysplasia or obstruction. Peritoneal dialysis is initi-
turia is renal vein thrombosis, which must ated for supportive treatment of presumed ATN. Af-
be considered in infants of diabetic moth- ter 10 days, dialysis is discontinued as the infant’s
ers and in infants with cyanotic congeni- renal function recovers. The infant is discharged
tal heart disease, polycythemia, or marked home at 21 days of age with a serum creatinine
dehydration. Other causes of hematuria concentration of 1.0 mg/dL. Follow-up laboratory
are urinary tract infection, blood dyscra- work 6 weeks later shows the serum creatinine level
sias, bladder hemangioma, renal tumor, to be 0.5 mg/dL.
nephrolithiasis, congenital urinary tract
malformations, and cortical necrosis. Glo-
merulonephritis, which represents a com-
mon cause of hematuria in childhood and
adolescence, is extremely uncommon in the Acute kidney injury (AKI) is character-
neonatal population. ized by a sudden impairment in renal func-
Proteinuria is defined as a urinary dipstick tion that leads to an inability of the kidneys
reading of 1+ (30 mg/dL) or higher with a to excrete nitrogenous wastes. Both the
specific gravity of 1.015 or less, or a reading of clinical care of infants and studies of AKI
2+ (100 mg/dL) or higher with a specific grav- are complicated by the difficulty of defin-
ity of more than 1.015. False-positive dipstick ing the condition. A consensus definition of
readings for protein may result from very AKI based on biomarkers is a serum creati-
concentrated urine, alkaline urine, infection, nine level of more than 1.5 mg/dL.34 Cre-
and detergents. Average quantitative protein atinine, however, is a metabolic product of
excretion declines with increasing gestational muscle. Normal levels reflect maternal levels
age, from 182 mg/m2 per 24 hours in prema- initially and fall as the infant’s production
ture infants to 145 mg/m2 per 24 hours in and excretion find their own steady state.
full-term infants to 108 mg/m2 per 24 hours Clinically, oliguric AKI is characterized by
in infants 2 to 12 months of age.33 a urine flow rate of less than 0.5 to 1 mL/
Common causes of neonatal proteinuria kg/hr, whereas in nonoliguric AKI, urine
include ATN, fever, dehydration, cardiac flow rate is maintained at a higher level.
failure, high-dose penicillin therapy, and This measure of renal function is unreliable
contrast agent administration. Persistent when diuretics have been administered. A
massive proteinuria and edema in a neonate prospective study of 229 infants found the
should prompt consideration of congenital incidence of AKI to be 18% among very low-
nephrotic syndrome, an autosomal reces- birth-weight infants.35 The causes of neona-
sive disorder characterized by proteinuria, tal AKI are multiple and can be divided into
failure to thrive, large placenta, and chronic prerenal, renal, and postrenal categories
renal dysfunction. (Box 16-1).
Causes of Acute Renal Failure and who required mechanical ventilation and blood
Box 16-1.
in the Neonate pressure support in addition to umbilical artery cath-
eterization were most likely to manifest AKI. The next
Prerenal
steps are to identify early and reliable markers of AKI,
Dehydration
intervene appropriately, and improve outcomes. These
Hemorrhage
infants all need long-term follow-up to monitor their re-
Sepsis
nal function and watch for the onset of hypertension.
Necrotizing enterocolitis
Congestive heart failure
Drugs: angiotensin-converting enzyme inhibi- Prerenal Acute Kidney Injury
tors, nonsteroidal antiinflammatory agents, Prerenal (functional) AKI is the most com-
amphotericin, tolazoline mon type of AKI in the neonate and
Intrinsic accounts for up to 85% of neonatal AKI.37
Acute tubular necrosis Prerenal AKI is characterized by inadequate
Renal dysplasia renal perfusion, which, if promptly treated,
Polycystic kidney disease is followed by improvement in renal func-
Renal vein thrombosis tion and urine output. If glomerulotubular
Uric acid nephropathy injury occurs as a consequence of inadequate
Transient acute renal insufficiency of the renal perfusion, the constellation of clini-
newborn cal and laboratory findings constitute AKI.
The most common causes of prerenal AKI
Postrenal
are hypotension (dehydration, hemorrhage,
Posterior urethral valves
septic shock, necrotizing enterocolitis) and
Bilateral ureteropelvic junction obstruction
renal hypoperfusion (patent ductus arterio-
Bilateral ureterovesical junction obstruction
sus, congestive heart failure, asphyxia) as
Neurogenic bladder
well as medications that reduce renal blood
Obstructive nephrolithiasis
flow, such as nonsteroidal antiinflammatory
drugs (indomethacin) and angiotensin-con-
verting enzyme inhibitors (enalaprilat).
EDITORIAL COMMENT: Acute kidney injury (AKI) is
a common clinical problem in neonatal intensive care
Intrinsic Acute Kidney Injury
units and is usually associated with a contributing
ATN is one of the most common manifesta-
condition such as hypovolemia, hypotension, or hy-
tions of intrinsic AKI in neonates. Causes of
poxia, often due to sepsis, asphyxia, and heart failure.
ATN include perinatal asphyxia, sepsis, car-
Attention has been focused on biomarkers for AKI that
diac surgery, prolonged prerenal state, and
might enable early recognition and prompt interven-
administration of nephrotoxic drugs (indo-
tions to limit renal injury. The level of neutrophil ge-
methacin and aminoglycoside antibiotics).
latinase–associated lipocalin (NGAL), and specifically
The pathophysiology of ATN is complex
urinary NGAL (UNGAL), predicts renal failure sooner
and appears to involve renal tubular cellular
than serum creatinine level, and the immunoassay can
injury, alterations in adhesion molecules,
be done as quickly as creatinine determination.36
and changes in renal hemodynamics. Cellu-
Neonatologists tend to focus on the lung, brain,
lar injury results from decreased adenosine
and gastrointestinal tract, giving little attention to the
triphosphate (ATP), increased intracellular
kidney. This needs to change. In the first prospective
calcium influx, and the destructive action
epidemiologic study addressing AKI in preterm infants
of phospholipases, free radicals, and prote-
with a birth weight of less than 1500 g, 18% of 229 in-
ases. Alterations in cellular adhesion mol-
fants manifested AKI when a creatinine-based definition
ecules lead to sloughing of injured tubular
was used.37 However, because the investigators did not
epithelial cells and subsequent luminal
measure serum creatinine concentration in every infant
obstruction. Increased endothelin as well as
every day, this number may be an underestimate. Fur-
decreased prostaglandins and nitric oxide
thermore, AKI is a serious condition, and there is an in-
activity result in markedly decreased renal
dependent association between AKI and mortality when
blood flow.
analyzed both by gestational age and by birth weight.
Other less common causes of intrinsic
Most infants who developed AKI were extremely pre-
renal failure in the newborn include renal
mature and developed AKI within the first week of life.
dysplasia, autosomal recessive polycystic
Sicker babies whose condition was depressed at birth
kidney disease, and renal vein thrombo-
sis. Uric acid nephropathy may represent
an underrecognized cause of AKI in the Neonates with an FENa of more than 2.5% to
neonatal population and may occur when 3.0% generally have intrinsic AKI, whereas
uric acid crystals precipitate in the lumen those with an FENa of less than 1.0% have
of the nephron following hypoxia, hemo- prerenal AKI. Prematurity, however, is asso-
lysis, rhabdomyolysis, or cardiac surgery. ciated with immaturity of Na+,K+-ATPase,
Finally, neonatal transient renal failure is a which results in a higher FENa under nor-
poorly understood, rapidly reversible syn- mal circumstances. As mentioned earlier,
drome characterized by oliguric AKI and the ability of creatinine concentration to
hyperechogenic renal medullary pyramids assess glomerular filtration is limited. New
on ultrasonography.38 This syndrome has biomarkers that are not affected by muscle
been reported in otherwise healthy full- mass are emerging but have not yet been
term infants with sluggish feeding and is validated in this population. Of these,
thought to be related to deposition of uric neutrophil gelatinase-associated lipocalin
acid crystals and/or Tamm-Horsfall protein (NGAL), kidney injury molecule 1, and cys-
in the renal tubular collecting system. tatin C have been studied in AKI following
cardiac surgery.39
Postrenal Acute Kidney Injury Renal ultrasonography is helpful in the
Postrenal (obstructive) AKI is caused by identification of congenital renal disease
bilateral obstruction of the urinary tract and urinary tract obstruction. Voiding cys-
and can be reversed by relief of the obstruc- tourethrography should be performed in
tion. Obstructive AKI in the neonate may neonates with suspected posterior urethral
be related to a variety of congenital urinary valves, vesicoureteral reflux, or bladder
tract conditions, including posterior urethral abnormality.
valves, bilateral ureteropelvic or ureterovesi-
cal junction obstruction, obstructive neph- Medical Management
rolithiasis, or neurogenic bladder. Extrinsic If the neonate is oliguric, a urinary catheter
compression of the ureters or bladder by a should be placed to rule out lower urinary
congenital tumor such as a sacrococcygeal tract obstruction. If there is no improve-
teratoma and intrinsic obstruction by renal ment in urine output after bladder drain-
calculi or fungus balls are rare causes of age is established, a fluid challenge of 10 to
obstructive AKI. 20 mL/kg should be administered over 1 to
2 hours to rule out prerenal AKI. A lack of
Evaluation of the Neonate with Acute improvement in urine output and serum
Kidney Injury creatinine concentration after adequate
For neonates with AKI a careful history drainage of the urinary tract and volume
should be taken that focuses on prenatal resuscitation suggests intrinsic AKI, and flu-
ultrasonographic abnormalities, perinatal ids should be restricted to insensible losses
asphyxia, systemic illness, administration of (500 mL/m2) plus urine output and other
potentially nephrotoxic drugs, and family losses. Daily weights and careful intake and
history of renal disease. Physical examina- output measurements are optimal to follow
tion should focus on the abdomen, genitalia, volume status.
and a search for other congenital anomalies The goal of medical management of
or signs of Potter sequence. Levels of elec- established intrinsic AKI is to provide sup-
trolytes (including acid-base status), blood portive care until there is spontaneous
urea nitrogen, creatinine, calcium, phos- improvement in the infant’s renal function.
phorus, and uric acid should be monitored Nephrotoxic drugs should be discontinued
at least daily and more frequently if signifi- to reduce the risk of additional renal injury.
cant metabolic abnormalities are present. Medications should be adjusted by dose and
Urine should be sent for urinalysis, urine interval according to the degree of renal dys-
culture, and urine sodium and creatinine function. Potassium and phosphorus should
determination. Calculation of FENa may be be restricted in neonates with hyperkalemia
helpful in differentiating prerenal AKI from or hyperphosphatemia. Metabolic acidosis
intrinsic AKI. This calculation is a sensitive may require treatment with intravenous or
measure of tubular injury. oral sodium bicarbonate. Loop and thiazide
diuretics may prove helpful in augmenting
[Naurine ] × [Crplasma ] urinary flow rate. The role of low-dose dopa-
FENa = × 100 % mine in neonatal AKI management remains
[Naplasma ] × [Crurine ] unproven.
Renal Replacement Therapy primarily by diffusion. The chief advantage

Renal replacement therapy (RRT) refers to all of CRRT is that it allows continuous control
technologies that substitute for the work of of fluid removal, which makes this modal-
native kidneys. RRT should be considered if ity especially useful in the neonate with
maximal medical management fails to main- hemodynamic instability. The main disad-
tain acceptable fluid and electrolyte status. vantages are the need to achieve and main-
The two purposes of RRT are ultrafiltration tain central vascular access and the need for
(removal of water) and dialysis (removal of continuous anticoagulation. Limiting fac-
solutes). Indications for initiation of RRT tors are the size of catheter that the child
include hyperkalemia, hyponatremia, aci- can tolerate and the ability to obtain flow
dosis, hypocalcemia, hyperphosphatemia, through the catheter without occlusion by
symptomatic volume overload, uremic thrombi.
symptoms, and inability to provide ade- Acute hemodialysis is a less commonly
quate nutrition (Box 16-2). employed, but technically feasible, mode of
Peritoneal dialysis is the most commonly RRT in the neonatal population. Hemodial-
employed renal replacement modality in ysis involves intermittent 3- to 4-hour treat-
the neonatal population, because it is less ments in which fluids and solutes are rapidly
technically difficult and does not require removed from the infant using an extracor-
vascular access or anticoagulation. In this poreal dialyzer with rapid countercurrent
procedure, hyperosmolar dialysate is repeat- dialysate flow. The chief advantage of hemo-
edly infused into and drained out of the dialysis is the ability to rapidly remove sol-
peritoneal cavity via a catheter, accomplish- utes or fluid, a characteristic that makes this
ing both ultrafiltration and dialysis (Fig. modality the therapy of choice in neonatal
16-4). Cycle length, dwell volume, and the hyperammonemia, although CRRT has also
osmolar concentration of the dialysate can been used successfully in the management
be varied to accomplish the goals of ther- of inborn errors of metabolism. Critically
apy. Relative contraindications to peritoneal
dialysis include recent abdominal surgery,
necrotizing enterocolitis, pleuroperitoneal
leak, and ventriculoperitoneal shunt.
Continuous renal replacement therapy
(CRRT) is becoming a more practical option
for RRT in children who are in hemody-
namically unstable condition.40 In this pro-
cedure, the neonate’s blood is continuously
circulated through an extracorporeal circuit
containing a highly permeable hemofilter.
An ultrafiltrate of plasma is removed, and
a smaller volume of fluid is returned to the
patient. This smaller volume is a physiologic
replacement fluid. The two CRRT modalities
are continuous venovenous hemofiltration
(CVVH) and continuous venovenous hemo-
dialysis (CVVHD). CVVH removes solute by
convection, whereas CVVHD removes solute
Box 16-2. Indications for Dialysis

Hyperkalemia
Hyponatremia
Acidosis
Hypocalcemia
Hyperphosphatemia
Volume overload Figure 16-4. Critically ill infant with acute renal failure
Uremic symptoms undergoing treatment with peritoneal dialysis. (Courtesy
Inability to provide adequate nutrition Julie H. Corder, PNP, Rainbow Babies and Children’s
Hospital, Cleveland.)
ill neonates may experience hemodynamic HYPERTENSION

instability and osmolar shifts with the rapid
solute and fluid movement associated with
intermittent hemodialysis. A 4500-g term male infant develops respiratory dis-
tress and clinical features consistent with pulmonary
Prognosis hypertension of the newborn. Blood pressure is
The prognosis for neonates with AKI is vari- 70/40 mm Hg. Mechanical ventilation is initiated and
able. In general, infants with prerenal AKI an umbilical artery catheter is placed to the level of
who receive prompt treatment for renal T8. On day 7 of life, the blood pressure is noted to be
hypoperfusion have an excellent prognosis. 116/78 mm Hg.
The outcome for infants with postrenal AKI Serum electrolyte levels are normal and creatinine
related to congenital urinary tract obstruc- concentration is 0.7 mg/dL. Ultrasonography reveals
tion depends on the degree of associated an irregularly shaped thrombus measuring 1.5 cm in
renal dysplasia. Infants with intrinsic AKI length in the abdominal aorta, partially occluding the
have the poorest prognosis. right renal artery. The infant is initially given sodium ni-
Survival differs, depending on the cause troprusside and furosemide to control blood pressure
of AKI. Blowey et al reported that neonates and is later converted to oral captopril. At 6 months
with renal structural anomalies had a 17% of age, the child’s creatinine level is 0.4 mg/dL and
mortality rate, whereas those with ATN a renal ultrasound examination reveals that the right
had a 55% mortality rate.41 After adjust- kidney is slightly smaller than the left kidney. By 12
ment for potential confounders, very months of age, the infant is successfully weaned off
low-birth-weight infants with AKI have a all antihypertensive therapy.
higher chance of death, with an adjusted
hazard ratio of 2.4 (95% confidence inter-
val: 0.95 to 6.04).35
Kidney survival may be improving. In Many factors influence blood pressure
Blowey et al’s 1993 study of 23 infants in neonates, including gestational age,
who received peritoneal dialysis in the first weight, postconceptual age, anxiety, pain,
month of life, at 1 year 30% were receiving and level of wakefulness. For example,
dialysis, 9% had chronic kidney disease, in term infants, systolic blood pressure is
and 26% had made a full renal recovery; approximately 6 mm Hg higher in awake
35% died in the neonatal period.41 In infants than in asleep infants and may
2003, decreased GFR was reported in 45% increase by 25% with abdominal palpa-
of extremely low-birth-weight infants who tion, crying, or pain.44 The gold standard
sustained neonatal AKI.42 In 2009, Mor- for blood pressure measurement is intra-
tazavi et al reported that 76% of Iranian arterial analysis of the waveform. Upper
infants who had developed AKI were dis- extremity pressures may be overestimated
charged with normal kidney function and by this technique in older children, but
3% with diminished kidney function.43 in neonates, the umbilical and peripheral
In this population renal disease was due arterial values correlate well.45 Automated
to intrinsic AKI in 52%, prerenal AKI in oscillometric methods are easy to use, but
42%, and postrenal AKI in 5%. Perinatal accuracy varies among devices. There is a
asphyxia was present in 30% of the neo- greater likelihood of an elevated pressure
nates, sepsis in 29%, respiratory distress when measured by oscillometric devices
syndrome in 25%, dehydration in 24%, than when obtained by direct methods.45
and heart failure in 21%. Eight-five percent Nwankwo et al suggested a protocol (Box
of patients had more than one contribut- 16-3) for standardizing pressure measure-
ing condition.43 Risk factors for the devel- ment using oscillometric devices that has
opment of long-term impairment of GFR been embraced by other experts in pediat-
include multisystem failure, hypotension, ric hypertension.46
need for pressors, hemodynamic instabil- Hypertension occurs in only 0.2% to 3%
ity, need for mechanical ventilation, and of neonates.45 Zubrow et al collected data
need for dialysis. Therefore, high-risk neo- that show normal neonatal blood pressures
nates who appear to have recovered from according to birth weight, gestational age,
acute renal failure should be followed care- and postconceptual age.47 Normal blood
fully over time, because they may be at risk pressures on day 1 of life for newborn
for late development of chronic kidney infants as a function of birth weight are pre-
disease. sented in Figure 16-5.47
Protocol for Blood Pressure After birth, the blood pressure in prema-
Box 16-3. Measurement Using an ture infants increases quickly, so that the
Oscillometric Device normal value in a 10-week-old baby born at
28 weeks is not comparable to that of a new-
Wait at least 1.5 hours after a meal or medical born baby born at 38 weeks.47 Dionne et al
intervention. published a table of values (Table 16-3) that
Place infant in prone or supine position. is better suited to evaluating blood pressure
Use appropriately sized blood pressure cuff. according to postconceptual age.45 Hyper-
Place cuff on right upper arm. tension in children is defined as blood pres-
Leave infant undisturbed for 15 minutes after sure elevation above the 95th percentile for
cuff placement. peers of similar age, size, and gender. Dionne
Ensure that infant is asleep or in quiet awake et al recommend that drug treatment begin
state. when pressures consistently exceed the 99th
Take three successive blood pressure read- percentile. For older infants found to be
ings at 2-minute intervals. hypertensive following discharge from the
neonatal intensive care unit, data generated
by the Second Task Force on Hypertension,
shown in Figure 16-6, are useful.48
Causes of Neonatal Hypertension

Upper 95% CL Causes of hypertension in the neonate are
90
Systolic blood pressure (mm Hg)
listed in Box 16-4. Renovascular hyperten-

80
sion is a frequent cause of neonatal hyper-
70 tension and accounts for up to 90% of cases
60 for which a discrete cause is identified. The
50 most common cause of renovascular hyper-
Lower 95% CL
40 tension is renal artery thromboembolism
30 related to umbilical artery catheterization,
20 although congenital renal artery stenosis
10 and renal vein thrombosis may also occur.
0 // Hypertension may also be seen in infants
with hypervolemia related to oliguric acute
5
00
25
50
75
00
2. 5
50
75
00
25
3. 0
75
00
renal failure. A small proportion of neo-

.7
5
1.
1.
1.
1.
2.
2.
2.
3.
3.
3.
4.
natal hypertension is related to structural

A Birth weight (kg) renal disease, including autosomal reces-
sive polycystic kidney disease and obstruc-
tive uropathy. Conditions associated with
Diastolic blood pressure (mm Hg)
70 hypertension include bronchopulmonary

Upper 95% CL dysplasia, patent ductus arteriosus, intraven-
60
tricular hemorrhage, indwelling umbilical
50
artery catheter, antenatal steroid therapy,
40
maternal hypertension, coarctation of the
30
aorta, medications, endocrine disorders,
20 Lower 95% CL abdominal wall closure, and extracorporeal
10 membrane oxygenation.45,49
0 //
Clinical Presentation
25
1. 0
75
2. 0
25
2. 0
75
4. 5
1. 5
1. 0
1. 5
50
00
00
5
7
.7
0
2
The clinical presentation of hypertension in

3.
2.
2.
3.
3.
3.
B Birth weight (kg) the neonate is variable. Although some babies

may be asymptomatic, nonspecific symp-
Figure 16-5. Linear relationship between mean systolic
toms such as poor feeding, irritability, and
(A) and diastolic (B) blood pressure and birth weight on
day 1 of life. CL, Confidence limit. (From Zubrow AB,
lethargy are common. Significant cardiopul-
Hulman S: Determinants of blood pressure in infants monary symptoms may be present, includ-
admitted to neonatal intensive care units: a prospective ing tachypnea, cyanosis, impaired perfusion,
multicenter study. Philadelphia Neonatal Blood Pressure vasomotor instability, congestive heart fail-
Study Group, J Perinatol 15:470, 1995.) ure, cardiomegaly, or hepatosplenomegaly.
Neurologic symptoms such as lethargy,
coma, tremors, hypertonicity, hypotonicity,
Table 16-3. Blood Pressure Values in Infants from 26 to 44 Weeks’ Postconceptual Age
Postconceptual Age 50th Percentile 95th Percentile 99th Percentile

44 wk
SBP 88 105 110
MAP 63 80 85
42 wk
SBP 85 98 102
MAP 62 76 81
40 wk
SBP 80 95 100
MAP 60 75 80
38 wk
SBP 77 92 97
MAP 59 74 79
36 wk
SBP 72 87 92
MAP 57 72 71
34 wk
SBP 70 85 90
MAP 50 65 70
32 wk
SBP 68 83 88
MAP 48 62 69
30 wk
SBP 65 80 85
MAP 48 65 68
28 wk
SBP 60 75 80
MAP 45 58 63
26 wk
SBP 55 72 77
MAP 38 57 63
From Dionne JM, Abitbol CL, Flynn JT: Hypertension in infancy: diagnosis, management and outcome,
Pediatr Nephrol 27(1):17, 2012.
MAP, Mean arterial pressure; SBP, systolic blood pressure.
opisthotonos, asymmetric reflexes, hemi- finding of unequal kidney size (>1.5 cm

paresis, seizures, and apnea may also occur. difference) should raise suspicion of renal
Hypertensive retinopathy is uncommon in artery disease. Echocardiography should
neonates with hypertension and resolves be performed to diagnose aortic coarcta-
with control of blood pressure. Renal effects tion and evaluate left ventricular mass
of hypertension may include acute renal fail- and function. Thyroid function studies
ure and sodium wasting related to pressure and urinary studies for catecholamines,
natriuresis. 17-hydroxysteroids, and 17-ketosteroids
should be reserved for the rare instances in
Evaluation of the Neonate with which results of the aforementioned stud-
Hypertension ies are normal.
Evaluation of the hypertensive newborn
begins with a careful history taking and Management of the Neonate with
physical examination. Initial laboratory Hypertension
studies should include urinalysis, serum Neonates with signs and symptoms of a
electrolyte levels, blood urea nitrogen level, hypertensive emergency such as cardiopul-
serum creatinine concentration, and serum monary failure, acute neurologic dysfunc-
calcium level. Ultrasonography of the kid- tion, or renal insufficiency require immediate
neys with Doppler flow study of the aorta treatment with intravenous medication. The
and renal arteries should be performed to goal of therapy is a prompt decrease in blood
rule out a renal artery or aortic thrombus pressure to minimize injury to the brain,
or urinary tract structural anomalies. A heart, and kidneys. Blood pressures should
115 115
95th 110 95th
Systolic BP (mm Hg)
Systolic BP (mm Hg)

110
105 90th 105 90th
100 75th 100 75th
95 95
90 50th 90 50th
85 85
80 80
75 75
70 70
65 65
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
Months Months
75 75
95th
Diastolic BP (mm Hg)

95th
70 90th 70
90th
65 65
75th
75th
60 60
50th
55 55 50th
50 50
45 45
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
Months Months
90th percentile 90th percentile
Systolic BP 87 101 106 106 106 105 105 105 105 105 105 105 105 Systolic BP 76 98 101 104 105 106 106 106 106 106 106 105 105
Diastolic BP 68 65 63 63 63 65 66 67 68 68 69 69 69 Diastolic BP 68 65 64 64 65 65 66 66 67 67 67 67 67
Height (cm) 51 59 63 66 68 70 72 73 74 76 77 78 80 Height (cm) 54 55 56 58 61 63 66 68 70 72 74 75 77
Weight (kg) 4 4 5 5 6 7 8 9 9 10 10 11 11 Weight (kg) 4 4 4 5 5 6 7 8 9 9 10 10 11
A B
Figure 16-6. Age-specific percentiles for blood pressure (BP) in boys (A) and girls (B) from birth to 12 months of age. (From
Report of the Second Task Force on Blood Pressure Control in Children—1987. National Heart, Lung, and Blood
Institute, Bethesda, Md, Pediatrics 79:1, 1987.)
Box 16-4. Causes of Neonatal Hypertension not be lowered below the 95th percentile
until 24 to 48 hours after initiation of ther-
Renovascular disease apy to avoid cerebral and optic disc ischemia.
• Renal artery thrombosis Antihypertensive medications used in
• Renal artery stenosis the neonate are listed in Table 16-4. Sodium
Congenital renal malformations nitroprusside is commonly administered as
• Polycystic kidney disease an intravenous infusion to treat hyperten-
• Hydronephrosis sive emergencies. Alternative intravenous
Renal parenchymal disease infusions include nicardipine, esmolol,
• Acute tubular necrosis and labetalol. Enalaprilat, an intravenous
Coarctation of the aorta angiotensin-converting enzyme inhibitor,
Other is effective in reducing blood pressure but
• Endocrine disorders must be used with extreme caution because
• Bronchopulmonary dysplasia it may cause prolonged hypotension and
• Drug exposure: cocaine, methadone, acute renal failure.50
corticosteroids, aminophylline Oral antihypertensive agents are useful
• Abdominal wall closure in infants with less severe, asymptomatic
• Extracorporeal membrane oxygenation hypertension or in those whose acute blood
pressure elevation has been controlled with
intravenous agents and who are ready to
transition to long-term therapy. Captopril
has a long history of use in neonates.51 The
risk of renal injury or failure has contributed
Table 16-4. Antihypertensive Medications
Drug Dose Route Dosing Interval Action Comment

Sodium 0.5-10 µg/kg/min IV Continuous infusion Vasodilator Thiocyanate toxicity
nitroprusside can occur with pro-
longed use or in renal
failure.
Nicardipine 1-4 µg/kg/min IV Continuous infusion Calcium chan- May cause reflex
nel blocker tachycardia.
Esmolol 100-300 µg/kg/min IV Continuous infusion β-Blocker Very short acting; use
constant infusion only.
Labetalol 0.25-3 mg/kg/hr IV Continuous infusion α-, β-Blocker Heart failure and BPD
are relative contraindi-
cations.
0.20-1.0 mg/kg/dose IV Bolus q6h
Diazoxide 2-5 mg/kg/dose IV q12h Vasodilator Rapid IV bolus.
Hydralazine 0.15-0.6 mg/kg/dose IV bolus q4h Vasodilator Tachycardia is a
frequent side effect.
Enalaprilat 5-30 µg/kg/dose IV q8-24h ACE inhibitor May cause prolonged
hypotension and acute
renal failure.
Amlodipine 0.1-0.3 mg/kg/dose PO q12h Calcium chan- Longer acting than
nel blocker isradipine.
Captopril 0.1-0.5 mg/kg/dose PO q8-12h ACE inhibitor Drug of choice
(max 2 mg/kg/day) for most neonatal
hypertension; monitor
serum creatinine and
potassium.
Isradipine 0.05-0.15 mg/kg/dose PO q6h Calcium chan- Suspension may be
(max 0.8 mg/kg/day) nel blocker compounded.
Propranolol 0.5-1.0 mg/kg/dose PO q8h β-blocker May cause bradycar-
dia; avoid in infants
with BPD.
Furosemide 1-2 mg/kg/dose PO/IV q8-24h Loop diuretic Monitor electrolytes.
Chlorothia- 5-15 mg/kg/dose PO q12h Distal tubule Monitor electrolytes.
zide 1-4 mg/kg/dose diuretic
ACE, Angiotensin-converting enzyme; BPD, bronchopulmonary dysplasia; IV, intravenous; PO, oral.
to a greater interest in the use of calcium RENAL ARTERY THROMBOSIS

channel blockers.45 Hydralazine, a direct In the neonatal population, renal artery
vasodilator, is also effective in controlling thrombosis is most commonly associated
neonatal hypertension. Diuretics such as with an indwelling umbilical artery cath-
furosemide or hydrochlorothiazide may be eter. The incidence of thrombus formation
effective adjunctive agents in infants with in the aorta in the presence of umbilical
volume overload. artery catheters ranges from 26% when
The long-term prognosis for children evaluated by ultrasonography to 95%
with neonatal hypertension is excellent, when determined by aortography.53,54 Risk
particularly for those with hypertension factors for complications from umbilical
related to an umbilical artery catheter. Of artery catheters include maternal diabetes,
17 children described by Friedman and Hus- sepsis, dehydration, birth trauma, perina-
tead with hypertension diagnosed either tal asphyxia, patent ductus arteriosus, and
in the nursery or by 18 weeks of age after cocaine exposure. Although 30% to 40%
discharge, no children were receiving anti- of infants with arterial thrombosis may
hypertensive medication at 24 months of be asymptomatic, hypertension occurs in
age.52 Children with hypertension related approximately 25% of patients and may be
to other causes, including polycystic kid- associated with hematuria, oliguria, renal
ney disease, coarctation of the aorta, renal failure, congestive heart failure, or lower
artery stenosis, or renal vein thrombosis extremity ischemia.
may have persistent hypertension through- Ultrasonography of the kidneys with
out childhood. Doppler flow study of the aorta and renal
arteries is the diagnostic study of choice

administration to treat her lung disease. Urinalysis
when renal artery thromboembolism is
revealed hematuria (1+) with 10 to 15 red blood cells
suspected. In patients with suspected renal
per high-power field. Urine culture yielded no growth.
artery thromboembolism in whom renal
Spot urine calcium-to-creatinine ratio was elevated
ultrasound and Doppler findings are nor-
at 1.65. Loop diuretics were discontinued and chlo-
mal, confirmation with renal radionuclide
rothiazide initiated to reduce urinary calcium excre-
imaging using either MAG-3 or DTPA may
tion. Corticosteroids were tapered and discontinued
be required. Aortography may be necessary
over the next 2 months. Urine calcium-to-creatinine
even in the presence of normal ultrasound
ratio decreased to 0.8 and serial ultrasound examina-
findings in a sick child with lower extrem-
tions showed gradual resolution of nephrocalcinosis.
ity vascular insufficiency, congestive heart
When the infant was 8 months of age, chlorothiazide
failure, or acute renal failure.
was discontinued, and at 1 year of age a follow-up
The primary treatment for hypertension
renal ultrasound study yielded normal findings.
associated with arterial thromboembolism
is removal of the umbilical artery catheter
and institution of antihypertensive therapy. Renal medullary calcifications in the prema-
Heparinization and fibrinolytic therapy are ture infant were first described in 1982 by
reserved for patients at high risk of complete Hufnagle et al.57 Since then, nephrocalcino-
occlusion or those with oliguric acute renal sis has become a well-known complication in
failure, congestive heart failure, or severe the neonatal population, occurring in 27%
lower extremity ischemia. In these situa- to 65% of hospitalized premature infants.58
tions, successful use of systemic or intra Infants with nephrocalcinosis may present
thrombic urokinase or streptokinase has with microscopic or gross hematuria, granu-
been reported.55 Aortic thrombectomy may lar material in the diaper, acute renal failure
be necessary in patients in whom antico- related to ureteral obstruction, or urinary
agulants and fibrinolytic agents are ineffec- tract infection. Nephrocalcinosis may also
tive, but spontaneous recanalization of an be discovered incidentally on abdominal
aortic clot with development of collateral ultrasound examination.
circulation around permanently occluded The majority of infants with nephrocal-
renal arteries has been described.56 cinosis have had exposure to loop diuretics
Although children with renovascular for management of bronchopulmonary dys-
hypertension secondary to renal artery plasia. Furosemide and other loop diuretics
thromboembolism from umbilical artery enhance urinary calcium excretion, which
catheters do not typically require antihy- predisposes to deposition of calcium oxalate
pertensive medications beyond 24 months crystals in the renal interstitium. However,
of age, several long-term issues exist. In a nephrocalcinosis has also been reported
report of 12 children studied at a mean fol- in infants with no prior exposure to loop
low-up of almost 6 years, Adelman noted diuretics. Other factors that may contribute
that 5 of 11 patients displayed unilateral to the development of neonatal nephrocal-
renal atrophy on ultrasonography or intra- cinosis include fluid restriction; treatment
venous pyelography despite having normal with corticosteroids or xanthine deriva-
creatinine clearances.32 Furthermore, follow- tives, which have a hypercalciuric effect;
up radionuclide scans continued to show decreased urinary concentration of stone
abnormal findings in all patients studied, inhibitors such as citrate and magnesium;
even in patients without renal atrophy on hyperuricosuria; increased oxalate excretion
ultrasonography. The long-term significance related to parenteral hyperalimentation;
of these findings in terms of the likelihood of and familial history of nephrolithiasis.59,60
chronic hypertension or renal insufficiency In infants with nephrocalcinosis or nephro-
with prolonged follow-up is unknown. lithiasis, use of agents that increase urinary
calcium excretion, such as loop diuretics
NEPHROCALCINOSIS and corticosteroids, should be minimized or
eliminated if possible. A high urinary flow
A 5-month-old infant with bronchopulmonary dys-
rate should be maintained to reduce the
plasia who had been born prematurely at 25 weeks
probability of urinary crystallization. Oral
was incidentally noted to have medullary nephrocal-
calcium supplements should be discon-
cinosis on an abdominal ultrasound study. She had
tinued, and metabolic acidosis, if present,
required long-term loop diuretic and corticosteroid
should be treated with bicarbonate, because
chronic acidosis enhances urinary calcium
excretion. Thiazide diuretics such as chlo- Molecular genetic research reveals that
rothiazide may be effective in reducing uri- shared genetic defects are associated with
nary calcium excretion,57 although serum phenotypes that were previously consid-
calcium levels should be monitored closely ered to be distinctly different conditions.
to avoid hypercalcemia. This finding has led to wider use of the term
The long-term consequences of neona- congenital anomalies of the kidney and urinary
tal nephrocalcinosis are not clearly defined. tract (CAKUT) for a spectrum of renal mal-
In approximately 50% of affected infants, formations. CAKUT refers to conditions as
nephrocalcinosis spontaneously resolves diverse as hypoplasia, hydronephrosis, ure-
within 5 to 6 months of discontinuation of terocele, vesicoureteral reflux, and posterior
diuretics without identifiable adverse conse- urethral valves. CAKUT occurs in 1 in 500
quences.61 However, infants with nephrocal- live births.63
cinosis may have diminished renal growth
and impairment of renal function, although Renal Agenesis
the degree to which nephrocalcinosis causes Unilateral renal agenesis occurs in 1 in 500
these sequelae remains uncertain. to 1 in 3200 individuals, whereas bilateral
renal agenesis occurs in 1 in 4000 to 1 in
EDITORIAL COMMENT: Kist-van Holthe et al 62 10,000 live births.64 Renal agenesis occurs
looked at the long-term effects of nephrocalcino- when the ureteric bud fails to induce
sis in a prospective study in which they followed a proper differentiation of the metanephric
number of preterm infants (<32 weeks’ gestation) blastema, an event that may be related to
with and without nephrocalcinosis. They found that both a genetic defect and environmental
even 71⁄2 years later children who had had neonatal factors.63
nephrocalcinosis showed increased rates of (mild) Renal agenesis may be seen in infants with
chronic renal insufficiency. In addition, the investi- VACTERL association (vertebral defects, imper-
gators found that prematurity itself was associated forate anus, cardiac defects, tracheoesopha-
with small kidneys, high blood pressure, and (distal) geal fistula, radial and renal anomalies, limb
tubular dysfunction. Thus it becomes imperative to anomalies), caudal regression syndrome,
provide long-term follow-up of blood pressure and branchio-oto-renal syndrome, and multiple
renal function in preterm infants, especially those chromosomal defects,64 but it may also be
with nephrocalcinosis. seen in otherwise healthy infants. Because
contralateral urinary tract abnormalities,
including vesicoureteral reflux, ureteropelvic
CONGENITAL RENAL DISEASE junction obstruction, renal dysplasia, and
ureterocele, occur in up to 90% of individuals
A 2100-g male infant was delivered at 32 weeks after
with unilateral renal agenesis,65 a thorough
oligohydramnios had been noted in the third trimes-
evaluation of the urinary tract including
ter. Apgar score was 8 at 1 minute and 9 at 5 min-
voiding cystourethrography is warranted in
utes. Physical examination yielded normal findings,
all patients.
including absence of abdominal masses. The infant
fed poorly and showed decreased activity. Labora-
Renal Dysplasia
tory evaluation revealed a rising serum creatinine lev-
Renal dysplasia is characterized by abnor-
el, which reached 4.5 mg/dL on day 6 of life. Renal
mal fetal renal development that leads to
ultrasonography demonstrated absence of the right
replacement of the renal parenchyma by
kidney and a small, hyperechoic left kidney with sev-
cartilage and disorganized epithelial struc-
eral small cortical cysts. Results of voiding cystoure-
tures. The pathogenesis of renal dysplasia
thrography were normal.
may involve mutations in developmental
The infant’s diagnosis was chronic kidney disease
genes, altered interaction of the ureteric
due to right renal agenesis and left renal dysplasia.
bud with extracellular matrix, abnormalities
A peritoneal dialysis catheter was placed and dialy-
of renal growth factors, and urinary tract
sis initiated. The infant’s parents were trained by the
obstruction.66
nephrology team to perform home dialysis, supply
Renal dysplasia is frequently present in
supplemental nasogastric feedings, and administer
infants with obstructive uropathy and a
multiple medications for management of chronic kid-
variety of congenital disorders, including
ney disease. The infant continued on home peritoneal
Eagle-Barrett syndrome (prune-belly syn-
dialysis until 2 years of age, when he received a do-
drome); VACTERL association; branchio-
nor kidney from his mother.
oto-renal syndrome; CHARGE syndrome
(coloboma of iris, choroid, or retina, heart
defects, atresia of the choanae, restricted recessive polycystic kidney disease (ARPKD)
growth and development, genital anomalies may present in the neonatal period.
or hypogonadism, ear anomalies or deaf- ADPKD has an incidence of 1 in 200 to 1
ness); trisomy 13, 18, and 21; and Jeune syn- in 1000 and is the most common inherited
drome. The function of dysplastic kidneys is renal disease.68 Mutations in the PKD1 and
variable, and infants with bilateral dysplasia PDK2 genes may trigger ADPKD by alter-
may exhibit signs of renal insufficiency as ing a multimeric protein complex that
early as the first few days of life. Concen- plays an important regulatory role in kid-
trating and acidification defects may also ney development. The clinical presenta-
be present, whereas hematuria, proteinuria, tion of ADPKD in the neonatal period may
and hypertension are unusual findings. Pro- vary from a severe form with significant
gressive renal insufficiency generally devel- renal failure to asymptomatic renal cysts
ops in children with bilateral renal dysplasia detected by ultrasonography.
during childhood and adolescence. ARPKD is a much less common disor-
der, with an incidence of 1 in 20,000.69 The
Multicystic Dysplastic Kidney majority of cases present in infancy. Pre-
Multicystic dysplastic kidney (MCDK) repre- natal ultrasonography may show oligohy-
sents the most severe form of renal dysplasia, dramnios and bilaterally large, hyperechoic
in which the kidney consists of a grapelike kidneys. Characteristic clinical findings in
cluster of cysts devoid of normal renal archi- the neonate include palpable abdominal
tecture and function. MCDK is the most masses, severe hypertension, pulmonary
common unilateral abdominal mass in the hypoplasia, congenital hepatic fibrosis, and
neonatal period, although with the advent renal insufficiency. Primary management
of prenatal ultrasonography, the majority concerns include control of hypertension,
of cases are identified prenatally. The inci- management of renal insufficiency, and
dence of MCDK is estimated at 1 in 4000 live provision of ventilatory support.
births.67 MCDK usually occurs as a sporadic
event, although it may be seen in conjunc- HYDRONEPHROSIS
tion with VACTERL association, branchio-
oto-renal syndrome, Williams syndrome, At 20 weeks’ gestation, screening ultrasonography
Beckwith-Wiedemann syndrome, trisomy reveals moderate bilateral hydronephrosis in a male
18, or 49,XXXXX syndrome. The pathophys- fetus. Serial ultrasound studies show persistence of
iology is incompletely understood but may the hydronephrosis, development of hydroureters,
involve failure of the ureteric bud to inte- and a large bladder with a thickened wall. The infant
grate properly into the metanephros during is delivered at 35 weeks’ gestation. A bladder cathe-
development. Because contralateral urinary ter is placed immediately to secure adequate bladder
tract abnormalities (reflux, obstruction, dys- drainage. Renal ultrasonography shows moderate
plasia) are present in up to 50% of patients bilateral hydronephrosis and hydroureter, a trabecu-
with unilateral MCDK, a careful evaluation lated bladder, and a dilated proximal urethra. Voiding
of the urinary tract including voiding cysto- cystourethrography confirms the diagnosis of poste-
urethrography is warranted in all patients. rior urethral valves as well as the presence of bilateral
The majority of infants with unilateral grade III vesicoureteral reflux.
MCDKs have an excellent prognosis, because The infant undergoes primary valve ablation to
the MCDK generally involutes spontane- relieve the urinary tract obstruction. Antibiotic proph-
ously over time, whereas the contralateral ylaxis is administered to prevent urinary tract infec-
kidney grows larger than expected as a result tion. Serum creatinine concentration is 1.4 mg/dL
of compensatory hypertrophy.67 In view of at hospital discharge and 0.9 mg/dL at 6 months of
the small but real risk of hypertension and age, which suggests chronic kidney disease.
malignancy, children must be followed
carefully with serial ultrasound studies and
blood pressure monitoring. Some clinicians
offer the option of surgical removal of a uni- The advent of prenatal ultrasonography has
lateral MCDK if the MCDK fails to involute, led to detection of hydronephrosis in 0.45%
increases in size, or causes any symptoms. to 4% of all pregnancies.70,71 Hydronephro-
sis is defined as dilatation of the upper uri-
Polycystic Kidney Disease nary tract. Prenatal hydronephrosis may
Both autosomal dominant polycystic be associated with a wide spectrum of con-
kidney disease (ADPKD) and autosomal ditions ranging in severity from urethral
atresia with expected fetal demise to tran- reflux. Definitive treatment involves surgi-
sient physiologic dilatation of the collecting cal repair.
system with expected complete spontaneous
resolution.72 The Society for Fetal Urology Ureterovesical Junction Obstruction
uses a grading scale ranging from grade 0 Ureterovesical junction obstruction is the
(absent) to grade 4 (most severe) for fetuses second most common cause of congeni-
of more than 20 weeks’ gestation. Measure- tal hydronephrosis and is characterized by
ment of the anterior-posterior diameter of hydronephrosis with associated ureteral
the renal pelvis offers an alternative means dilatation. This disorder may be related to
to judge the severity of neonatal hydrone- underdevelopment of the distal ureter or
phrosis.73,74 There is no firm consensus on the presence of a ureterocele. Diagnosis is
which system is more clinically relevant. confirmed by radionuclide scan and voiding
Unilateral hydronephrosis with a normal cystourethrogram. Ureterovesical junction
contralateral kidney does not compromise obstruction is usually not associated with
fetal or neonatal survival. Bilateral hydro- other congenital malformations. Many cli-
nephrosis, however, carries greater risk. nicians advocate antibiotic prophylaxis to
Unilateral hydronephrosis accompanied by prevent urinary tract infection, although this
contralateral renal dysplasia may have a less practice remains somewhat controversial in
favorable outcome. The finding of oligohy- cases of ureterovesical junction obstruction
dramnios may be an early indicator of such without associated reflux. Definitive treat-
a pathologic condition. ment involves surgical repair.
Neonates with hydronephrosis identi-
fied on prenatal ultrasonography should Posterior Urethral Valves
undergo postnatal ultrasonography within Posterior urethral valves are the most com-
the first week of life. Because the degree mon cause of infravesicular urinary tract
of hydronephrosis may be underestimated obstruction, with an incidence of 1 in 5000
(as a result of the newborn’s low GFR), to 1 in 8000 males. Prenatal ultrasonog-
a second ultrasound study is necessary raphy may show hydronephrosis, dilated
within several weeks. In infants with only ureters, thickened trabeculated bladder,
low-grade hydronephrosis on prenatal dilated proximal urethra, and oligohydram-
ultrasonography, postnatal ultrasonogra- nios. Antenatal presentation may include a
phy may be postponed until 2 weeks of palpable, distended bladder; poor urinary
age if the infant is otherwise well. Further stream; and signs and symptoms of renal
evaluation, including voiding cystoure- and pulmonary insufficiency. Voiding cys-
thrography and radionuclide renal scan- tourethrography is diagnostic for posterior
ning, should be coordinated by a pediatric urethral valves and may reveal associated
nephrologist or urologist.71 In 48% of cases vesicoureteral reflux in 30% of patients.
of antenatal hydronephrosis, no cause is Treatment is centered on securing ade-
identified.70 quate drainage of the urinary tract, initially
by placement of a urinary catheter and later
Ureteropelvic Junction Obstruction by primary ablation of the valves, vesicos-
Ureteropelvic junction obstruction is a com- tomy, or upper tract diversion. The long-
mon cause of congenital hydronephrosis term outcome for infants with posterior
and may be the result of incomplete recan- urethral valves depends on the degree of
alization of the proximal ureter, abnor- associated renal dysplasia. As many as 30%
mal development of ureteral musculature, of boys with posterior urethral valves whose
abnormal peristalsis, ureteral valves, or symptoms manifest in infancy are at risk for
polyps. Ureteropelvic junction obstruction progressive renal insufficiency in childhood
is more common in male infants and may or adolescence.
be associated with other congenital anom-
alies, syndromes, or genitourinary mal- Eagle-Barrett Syndrome
formations. Diagnosis is confirmed by an Eagle-Barrett syndrome, formerly known
obstructive pattern on a diuretic-enhanced as prune-belly syndrome, is characterized by
radionuclide scan. Many clinicians advo- deficiency of abdominal wall musculature,
cate antibiotic prophylaxis to prevent uri- a dilated nonobstructed urinary tract, and
nary tract infection, although this practice bilateral cryptorchidism. The estimated inci-
remains somewhat controversial in cases of dence is 1 in 35,000 to 1 in 50,000 live births,
ureteropelvic junction obstruction without with more than 95% of cases occurring in
males. Two current theories of pathogenesis urination. Vesicoureteral reflux appears to

include in utero urinary tract obstruction have a genetic component, because the inci-
and a specific mesodermal injury between dence of reflux is at least 30% in first-degree
the fourth and tenth weeks of gestation. relatives. Of infants and children evaluated
The most common urinary tract abnormal- for their first urinary tract infection, at least
ities in infants with Eagle-Barrett syndrome one third have vesicoureteral reflux on void-
are renal dysplasia or agenesis, vesicoureteral ing cystourethrography.
reflux, and a large-capacity, poorly contrac- Primary vesicoureteral reflux tends to
tile bladder. Cardiac, pulmonary, gastroin- resolve over time as the intravesical seg-
testinal, and orthopedic anomalies occur ment of the ureter elongates during growth,
in a large percentage of patients with Eagle- with the greatest rate of spontaneous reso-
Barrett syndrome. Treatment in the neona- lution in patients with the lowest grades of
tal period involves optimization of urinary reflux. Conservative management involves
tract drainage, management of renal insuffi- administration of daily oral antibiotic pro-
ciency, and antibiotic prophylaxis if vesico- phylaxis to prevent urinary tract infection.
ureteral reflux is present. Management later Surgical repair is considered in children
in childhood may include surgical repair of with breakthrough urinary tract infections
reflux, orchiopexy, reconstruction of the or high-grade reflux. Newer minimally
abdominal wall, and renal transplantation. invasive methods to correct reflux, includ-
ing endoscopic injection of a dextrano-
Vesicoureteral Reflux mer and hyaluronic acid gel (Deflux), have
Vesicoureteral reflux, defined as retrograde recently been introduced. Long-term com-
propulsion of urine into the upper urinary plications of vesicoureteral reflux include
tract during bladder contraction, is another hypertension, renal scarring, and chronic
potential cause of hydronephrosis in the neo- kidney disease.
nate.75 The underlying pathophysiology of
vesicoureteral reflux is believed to be ectopic REFERENCES
insertion of the ureter into the bladder wall The reference list for this chapter can be found
resulting in a shorter intravesicular ureter, online at www.expertconsult.com.
which acts as an incompetent valve during
17
Hematologic
Problems
John Letterio, Sanjay P. Ahuja,
and Agne Petrosiute
RED BLOOD CELLS embryonic and adult erythropoiesis. KLF2 is

a positive regulator of the mouse and hu-
The great questions of the day are not decided man embryonic β-globin genes. KLF1 and
by speeches and majority votes but by blood KLF2 have highly homologous zinc finger
and iron. DNA-binding domains and have overlap-
ping roles in embryonic erythropoiesis.4
Otto von Bismarck, September 30, 1862 The ontogeny of fetal erythropoiesis has
been reviewed elsewhere.5
FETAL ERYTHROPOIESIS AND CHANGES Fetal erythropoiesis also occurs during
IN ERYTHROPOIESIS AFTER BIRTH chronic bone marrow failure and recovery
Rapid growth during fetal development from marrow suppression. Fetal erythrocytes
demands a brisk pace for red blood cell have hemoglobin F, with more G-γ than A-γ
production, and this capacity must expand chains, i antigen, large mean corpuscular
with the increase in blood volume, which volume, characteristic enzyme levels, low
is proportionate to the weight of the fetus. carbonic anhydrase, low hemoglobin A2,
Blood volumes average 80 mL/kg of fetal and short life span. Many of these fetal char-
body weight at term, but the ratio is larger acteristics are present in the red blood cells
in the preterm fetus (~90 mL/kg). The rapid of patients with temporary or chronic hema-
pace of erythropoiesis is reflected by a rise topoietic stress. Chronic fetal erythropoi-
in hematocrit throughout gestation (from a esis is seen in patients with constitutional
mean of 40% at 28 weeks of gestation to 50% aplastic anemia, such as Fanconi anemia
at term) and by high reticulocyte counts or Diamond-Blackfan anemia. Thus fetal
and the presence of circulating nucleated erythropoiesis occurs during hematopoietic
red blood cells at birth. stress, whether chronic or transient, if there
Hematopoiesis during mammalian em- is some marrow activity and may be due to
bryonic development proceeds from the expansion of fetal clones.6
yolk sac blood island to the aorta-gonad- Several endogenous proteins contribute
mesonephros region, the fetal liver, and to the changes in regulation of erythropoi-
subsequently the fetal bone marrow, and is esis after birth, with erythropoietin being
tightly regulated by the stromal cells in each the most recognized. Fetal erythropoiesis
of these unique areas that make up the he- is regulated by endogenous (fetal) erythro-
matopoietic niche1,2 (Fig. 17-1). Moreover, poietin produced in the liver, but in infancy
there are likely distinct myeloid-erythroid the main site of production converts to the
progenitors in the early yolk sac niche that kidneys. Although the rate of erythropoiesis
may exist transiently and contribute to the in the fetus is quite high, serum erythro-
unique regulation of the β-globin locus in poietin levels are low, and the erythropoi-
the mammalian embryo.3 The control of etin response to hypoxia in the fetus and
red blood cell production and progression neonate is reduced compared with that in
of fetal erythropoiesis from yolk sac to liver adults. After delivery erythropoietin lev-
(in utero) to bone marrow at birth is also els vary among species, which is probably
in part orchestrated by Kruppel-like factors related to the oxygen transport capacity
(KLFs) that control cell differentiation and of the hemoglobin mass. In all mammals,
embryonic development. KLF1 (erythroid hemoglobin level declines following birth
Kruppel-like factor) is essential during both and erythropoiesis nearly ceases, which
432
CHAPTER 17 Hematologic Problems 433
PROGENITORS PRECURSORS
Pre-T T cell
Lymphoid
stem cell
Pre-B B cell Plasmablast Plasma cell
Erythrocyte
E/mega BFU-E CFU-E Proerythroblast
Pluripotent CFU-mega Megakaryoblast Megakaryocyte

stem cell
Trilineage CFU-G Myeloblast Polymorphonuclear

myeloid leukocyte
stem cell CFU-G/M
(CFU-S)
Monocyte-
CFU-M Monoblast macrophage
CFU-Eo Eosinophiloblast Eosinophil

Figure 17-1. Overview of the cellular stages of hematopoiesis. The most primitive pluripotent stem cell is shown at the
far left. As hematopoietic progenitor cells differentiate, they become committed to a single lineage. This diagram does not
emphasize the large increase in the number of cells (amplification) that occurs in the progenitor and precursor compartments.
BFU, Burst-forming unit; CFU, colony-forming unit; E, erythrocyte; Eo, eosinophil; G, granulocyte; M, macrophage; mega,
megakaryocyte; S, stem cell. (From Lipton JW, Nathan DG: The anatomy and physiology of hematopoiesis. In Nathan DG,
Oski FA, editors: Hematology of infancy and childhood, ed 3, Philadelphia, 1987, Saunders.)
gives rise to “early anemia.” Except in Recent studies indicate that human fetal and
humans, erythropoietin levels increase pro- infant growth is stimulated by GH, IGF-I,
portionally with the fall in hemoglobin, but and IGF-II. Erythropoietin, GH, and IGFs
there is a discrepancy between the curves are expressed early in fetal life. IGF-I levels
for serum immunoreactive erythropoietin are low in the fetus and increase slowly fol-
and for erythropoiesis-stimulating factors. lowing birth except in preterm infants, in
The latter include other stimulatory factors whom the levels decline. The physiology of
in addition to erythropoietin. These other erythropoietin during mammalian develop-
factors work in concert with erythropoietin ment has been reviewed elsewhere.7
to control erythropoiesis and probably con- The low level of erythroid production
tribute to enhanced erythropoiesis during noted earlier persists for over a month
periods of rapid growth, which is unlikely following birth, during which time the
to be attributable to the same molecular hematocrit gradually declines. Late in the
controls that enhance erythropoiesis dur- second or third month of life, the hemato-
ing periods of stress or hypoxia. For exam- crit approaches 30%. This is commensurate
ple, it is known that erythropoietin acts in with a rise in serum erythropoietin levels,
concert with general growth-promoting which prompts a resumption of erythro-
factors, particularly growth hormone (GH) poiesis and leads to a rise in red blood cell
and the insulin-like growth factors (IGF-I mass. This rise in red blood cell mass keeps
and IGF-II). The erythropoietin and GH/ pace with rapid overall growth and blood
IGF systems are both activated by hypoxia volume, and the hematocrit rises relatively
and share similar receptors and pathways. little as a consequence.
434 CHAPTER 17 Hematologic Problems
Erythropoietin and Neuroprotection placenta). If the umbilical cord is not clamped

in the Neonate quickly, a major shift in blood can lead to sig-
One other aspect of the erythropoietin sys- nificant effects on blood volume, hematocrit,
tem that is important to the fetus and new- and hemoglobin concentration during the
born deserves mention here. Erythropoietin first days of life. Infants exposed to a signifi-
is a pleiotropic neuroprotective cytokine, cant delay in umbilical cord clamping may
and recent studies have shed light on the experience excessive placental transfusion,
biological basis of its efficacy in the dam- with attendant decreases in plasma volume,
aged developing brain. Coordinated expres- increased hematocrit, and elevated blood vis-
sion of erythropoietin ligand and receptor cosity. Regardless of the extent of placental
expression occur during central nervous transfusion, postnatal adjustments of blood
system development to promote neural cell volume and hematocrit begin within 15 min-
survival. Studies of fetal hypoxia-ischemia in utes after birth and continue for several hours.
rat models have demonstrated that prenatal A controlled trial has suggested that delayed
third-trimester global hypoxia-ischemia dis- cord clamping in very preterm infants may
rupts the developmentally regulated expres- reduce the incidence of intraventricular hem-
sion of neural cell erythropoietin signaling orrhage and late-onset sepsis.13
and predisposes neural cells to death. Fur-
thermore, exposure of the neonate to exoge-
EDITORIAL COMMENT: Delayed cord clamping
nous sources of recombinant erythropoietin
has continued to show benefits and little, if any, risk
can restore the mismatch of erythropoietin
in preterm infants.14,15 The benefits of delayed cord
ligand and receptor levels and enhance
clamping in preterm infants include increased blood
neural cell survival. The data generated by
volume,15,16 improved circulatory and respiratory func-
these studies suggest the potential utility of
tion, reduced need for blood transfusion, improved
neonatal recombinant erythropoietin when
cerebral oxygenation, and reduced intraventricular
administered in the days immediately after
hemorrhage and sepsis.13 The cord blood of extremely
a global prenatal hypoxic-ischemic insult as
preterm infants is a rich source of hematopoietic
a means to rescue neural cells and present a
progenitor cells such as hematopoietic stem cells,
novel clinically relevant paradigm in which
endothelial cell precursors, mesenchymal progeni-
the benefits of erythropoietin in the context
tors, and stem cells of multipotent-pluripotent line-
of a stress are linked to the induction of sig-
age; hence the merit of delayed cord clamping has
naling pathways in both erythroid and non-
been magnified. Tolosa et al referred to this aspect of
erythroid lineages.8,9
delayed cord clamping as “realizing mankind’s first
PLACENTAL TRANSFUSION AND stem cell transfer” and proposed that “it should be
DISTRIBUTION OF BLOOD AT BIRTH encouraged in normal births.”17 The extra endowment
of progenitor cells resulting from delayed cord clamp-
The effect of early and late umbilical cord
ing has the potential to both increase red blood cell
clamping on neonatal hematocrit has been
production and boost host immune defenses through
well studied.10 Delayed cord clamping has
production of leukocytes.
been shown to be associated with a higher
There has been a shift in thinking to explore milk-
hematocrit in very low-birth-weight infants,
ing of the umbilical cord as an alternative to delayed
which suggests effective placental transfu-
cord clamping, which may provide the same benefits
sion.11 Several analyses have confirmed that
without the need to delay resuscitation.
delaying cord clamping (by at least 30 sec-
onds) increases average blood volume across
the full range of gestational ages studied.12
On average, the infant will gain roughly PROPERTIES OF FETAL HEMOGLOBIN
14 mL/kg of blood during this first 30 sec- AND THE SWITCH TO ADULT
onds, which leads to a blood volume of 89 HEMOGLOBIN
mL/kg. This process has been termed placen- The different types of human hemoglo-
tal transfusion. It occurs due to the continued bin consist of various combinations of the
circulation of blood through the umbilical embryonic, fetal, and adult hemoglobin
arteries and veins, and leads to a net shift subunits that are present at distinct times
of blood from the placenta to the newborn during development. This orderly tran-
infant. At birth, the partition of blood vol- sition from one form of hemoglobin to
ume between the infant and the fetal placen- another represents a major paradigm of
tal vasculature is nearly 2:1 (75 mL/kg body developmental biology but remains poorly
weight in the infant and 40 mL/kg in the understood. Studies have pointed to a
competition between subunits for more deliver it to the tissues. This function is reg-
favorable partners with stronger subunit ulated and/or made efficient by endogenous
interactions, so that the protein products of heterotropic effectors.
gene expression can themselves play a role Hb A is the major oxygen-binding tetra-
in the developmental process due to their meric protein found in the blood. It is one of
intrinsic properties.18 Fetal hemoglobin, or the best-recognized proteins in the human
Hb F (two α-globin chains and two γ-globin body because of its uniquely bright red color,
chains, [α2γ2]), is the main hemoglobin syn- and its color changes in diseases such as ane-
thesized up to birth, at which point it makes mia, hypoxia, and cyanide and carbon mon-
up more than 80% of the hemoglobin in cir- oxide poisoning. Hemoglobin has drawn
culating red blood cells. However, Hb F sub- the attention of physicians and physiolo-
sequently declines, and adult hemoglobin, gists since ancient times. Modern quantita-
Hb A (α2β2), becomes predominant. tive analysis of the structure and function
The main reason for this shift is the tran- of hemoglobin started in the late 1800s and
sition from synthesis of mainly γ chains dur- early 1900s. Important observations of the
ing fetal development to mainly β chains hemoglobin allostery have been attributed
during late gestation, with a concomitant to Christian Bohr (who reported in 1903
gradual shift from Hb F to Hb A beginning that its oxygen-binding process was sigmoi-
at 34 weeks’ gestation. Several studies have dal or cooperative) and to Bohr, Hasselbalch,
indicated that expression of the Hb F sub- and Krogh, who reported in 1904 that the
unit γ-globin might also be regulated post- position of the oxygen-binding curve of the
transcriptionally. One recently identified blood was sensitive to changes in Pco2 (and
mechanism for posttranscription regulation H+ or pH), known as the Bohr effect. These
of gene expression is through the produc- observations regarding the allosteric behav-
tion of micro-RNAs. These micro-RNAs are iors of hemoglobin are reviewed elsewhere.20
approximately 22 nucleotides in length It is widely recognized that the most
and can specifically target messenger RNAs important functional difference between Hb F
(mRNAs) for selected genes, thus acting as and Hb A is their different oxygen-binding
disease modifiers as well as molecules that properties. The higher oxygen affinity of Hb
control gene expression during develop- F is an advantage to the fetus because of the
ment and in response to environmental site of oxygen uptake, the placenta, where
stimuli. A study comparing micro-RNA the umbilical venous Po2 is just 35 to 40 mm
expression in reticulocytes from cord blood Hg, and represents the highest Po2 in all the
and adult blood revealed several micro- fetal circulation. Because the oxygen dissoci-
RNAs that were preferentially expressed in ation curve is “shifted” to the left (because of
adults, among them micro-RNA-96, which higher affinity), there is a capacity to main-
appears to directly suppress γ-globin expres- tain a higher O2 content, but this capacity
sion and thus contributes to control of Hb is no longer needed after birth because the
F production and its suppression during the lungs provide an environment with a sig-
switch to postnatal erythropoiesis.19 nificantly higher oxygen tension (typically
Although new hemoglobin produced dur- above 75 mm Hg) in the pulmonary capil-
ing postnatal life is essentially all Hb A, there laries. More importantly, the persistence
are exceptions to this rule. Perhaps the most of Hb F is a disadvantage to the newborn
well known is the persistence of Hb F in because the release of oxygen in the capil-
patients with sickle cell disease and the con- lary bed depends on a much lower Po2 for
tribution of Hb F to amelioration of disease efficient oxygen delivery and maintenance
severity in these individuals (see later discus- of tissue metabolism, which is in contrast
sion). Hb F expression can be increased dur- to the dynamics of O2 release by Hb A. This
ing periods of stress erythropoiesis, and in difference has been shown in clinical inves-
the infant recovering from anemia of prema- tigations to influence morbidity in new-
turity, there is a transient phase in the recov- borns with cardiopulmonary disease. Studies
ery of erythropoiesis during which Hb F is evaluating the impact of exchange transfu-
the predominant hemoglobin synthesized. sion in extremely premature infants demon-
strated a link between improved survival and
Functional Differences of Specific substantial replacement of Hb F by Hb A,
Hemoglobins despite the absence of a significant change in
The major physiologic function of hemo- hematocrit. This effect is often achieved as a
globin is to bind oxygen in the lungs and consequence of frequent phlebotomies and
multiple small transfusions of packed red death. Under these conditions, if the source
blood cells in very low-birth-weight infants. of toxicity can be eliminated, methemoglo-
bin levels will return to normal. Disorders
Hemoglobinopathies of oxidized hemoglobin are relatively easily
Globin gene mutations are a rare but impor- diagnosed and in most cases, except when
tant cause of cyanosis. Crowley et al iden- congenitally defective Hb M is present, can
tified a missense mutation in the fetal G be treated successfully.22
γ-globin gene (HBG2) in a father and daugh-
ter with transient neonatal cyanosis and ANEMIA
anemia. This newly recognized mutation Neonatal anemia is a condition with a
modifies the ligand-binding pocket of fetal diverse etiologic spectrum. To reach an
hemoglobin. The mechanisms described accurate diagnosis, the pediatrician must
include a diminutive effect of the relatively have some knowledge of the more com-
large side chain of methionine on both the mon causes of low hemoglobin concentra-
affinity of oxygen for binding to the mutant tions and hematocrit in the neonate. Proper
hemoglobin subunit and the rate at which it history taking, physical examination, and
does so. In addition, the mutant methionine interpretation of diagnostic test results can
is converted to aspartic acid posttranslation- narrow the focus and aid in establishing
ally, probably through oxidative mecha- an accurate diagnosis and in directing the
nisms. The presence of this polar amino acid appropriate therapeutic interventions.23
in the heme pocket is predicted to enhance
hemoglobin denaturation, causing anemia.21 HEMORRHAGIC ANEMIAS
Hemorrhagic anemia in a newborn is often
Methemoglobinemia heralded by some features of the history or
Methemoglobinemia arises from the produc- clinical findings that allow time to antici-
tion of nonfunctional hemoglobin contain- pate and prepare for treatment of the infant.
ing oxidized Fe3+, which results in reduced The fetus may lose blood through a variety
oxygen supply to the tissues and manifests of routes. Hemorrhage commonly occurs
as cyanosis in the patient. It can develop by through the placenta into the mother’s cir-
three distinct mechanisms: genetic mutation culation and may be detected most readily
resulting in the presence of abnormal hemo- through a Kleihauer-Betke test performed on
globin, a deficiency of the methemoglobin the mother’s blood. For monozygotic twins,
reductase enzyme, and toxin-induced oxida- there is an additional risk that one fetus may
tion of hemoglobin. The normal hemoglo- hemorrhage through the placental vascular
bin fold forms a pocket to bind heme and anastomosis into the other twin (see the sec-
stabilize the complex of heme with molecu- tion on twin-to-twin transfusion syndrome
lar oxygen. This process prevents spontane- later in this chapter). The fetus may also
ous oxidation of the Fe2+ ion chelated by the bleed through the placenta into the birth
heme pyrroles and the globin histidines. In canal. In many cases of placental abruption,
the abnormal M forms of hemoglobin (Hb M) the vaginal blood contains a mixture of fetal
amino acid substitution in or near the heme and maternal blood. The fetus may lose a
pocket creates a propensity to form methe- large volume of blood into the fetal placen-
moglobin instead of oxyhemoglobin in the tal circulation at the time of birth (see also
presence of molecular oxygen. Under nor- Chapter 2). All of the latter circumstances
mal conditions, hemoglobin is continually have the same effect as hemorrhage. Some of
oxidized, but significant accumulation of these mechanisms, such as placental abrup-
methemoglobin is prevented by the action tion and trapping of blood in the placenta
of a group of methemoglobin reductase by cord compression, also produce asphyxia,
enzymes. In the autosomal recessive form and the coexistence of asphyxia with hypo-
of methemoglobinemia, there is a deficiency volemia complicates both the assessment and
of one of these reductase enzymes, which the management of the infant. Even though
allows accumulation of oxidized Fe3+ in most newborn babies with asphyxia are not
methemoglobin. Oxidizing drugs and other hypovolemic, there is a subset of infants who
toxic chemicals may greatly enhance the have lost blood volume around the time of
normal spontaneous rate of methemoglo- delivery and most also experienced asphyxia.
bin production. If levels of methemoglobin Before delivery, internal hemorrhage
exceed 70% of total hemoglobin, vascu- may occur, with the most common type
lar collapse occurs resulting in coma and being intraventricular hemorrhage. The true
incidence of intracranial hemorrhage is not When approaching the treatment of hem-

certain, but in cases of alloimmune thrombo- orrhagic anemia presenting in the newborn
cytopenia in which there is severe thrombo- period, one needs first to consider any atten-
cytopenia, intracranial hemorrhage may be dant cardiorespiratory effects of blood loss
seen in as many as 20% of cases. Administra- that are present. Because of the capacity for
tion of intravenous gammaglobulin (IVIG) rapid transport of fluid across the placenta
and/or corticosteroids to the mother during and a limitless reservoir for volume replace-
a subsequent pregnancy with an affected ment, a hemorrhage that occurs sufficiently
fetus is widely practiced to increase the fetal far in advance of delivery will likely manifest
platelet count and thus avoid intracranial only the consequences of decreased oxygen-
hemorrhage (see later discussion).24 Inter- carrying capacity from the anemia. This
nal hemorrhage can also result from trauma capacity for rapid replacement of volume
around the time of delivery. Important com- loss via the placenta is an important safety
mon types of hemorrhage secondary to birth- net for the fetus, who might not otherwise
related trauma are subgaleal hematomas, tolerate intermittent hypoxemia during the
hepatic subcapsular and mediastinal hemato- contractions associated with labor. For any
mas, intracerebral and cerebellar hemorrhage, infant known to have chronic in utero ane-
and hematomas in fractured limbs. Adrenal mia, volume expansion must be approached
hemorrhage is more common in neonates carefully. The infant in this situation is
than in children or adults. The incidence of often anemic but has normal intravascular
detected cases ranges from 1.7 to 2.1 per 1000 volume. Consequently, additional volume
births. Because adrenal bleeding may remain may lead to heart failure secondary to vol-
asymptomatic, the real incidence is probably ume overload. For symptomatic infants with
higher. In published series, the most common chronic anemia, partial exchange transfu-
clinical feature in infants with adrenal hem- sion with packed red blood cells can be per-
orrhage was jaundice, which was observed in formed to achieve a desired hematocrit and
67.6% of cases in at least one series. Thus, it avoid volume fluctuation and severe volume
has been suggested that in cases of hyperbili- shifts. The amount to be exchanged depends
rubinemia of unknown cause, adrenal hem- on both the baby’s blood, the severity of the
orrhage must be kept in mind.25 anemia, and the hematocrit of the packed red
For hemorrhages that are associated with blood cells, but an exchange of between 30
birth trauma, the occurrence is highest in and 50 mL/kg body weight may be required.
difficult term deliveries, particularly in When hemorrhage occurs acutely during
infants who are large for gestational age and delivery, the hematocrit will not fully reflect
require multiple applications of vacuum to the degree of blood loss because there has
assist delivery. Splenic rupture is uncommon been little hemodilution. In this situation,
but may lead to catastrophic intraabdomi- one will need to aggressively manage shock,
nal hemorrhage in infants with hemophilia paying close attention to the hemodynamic
and in babies in whom intrauterine spleno- and cardiorespiratory parameters. Measures
megaly develops as a result of erythroblasto- of metabolic acidosis, capillary filling time,
sis or other causes. Extensive trauma to the and both arterial and/or central venous pres-
perineum in babies born through breech sures are important to monitor, because they
deliveries can lead to hypovolemia and ane- will guide the approach and extent of fluid
mia, and these symptoms are typically exag- resuscitation. Almost invariably, newborn
gerated in the preterm infant. babies with hypovolemic shock will have
In the newborn the clinical presentation experienced some degree of asphyxia, the
and symptoms associated with fetal hem- manifestations of which will influence the
orrhage are directly related to the interval assessment of shock. Thus, one must con-
between hemorrhage and delivery, as well as sider this to be an important variable, and
to the extent of hemorrhage. When the bleed it needs rapid attention, so that the treat-
occurs only shortly before birth, there is little ment of shock must not delay correction
time for hemodilution; thus these babies will of asphyxia. Acute situations may include
not be anemic initially and will show few if placenta previa, vasa previa, abruption, or
any signs that would indicate hypovolemia blood loss from the cut umbilical cord. In
or anemia. The hematocrit will fall during such cases, immediate volume replacement
the first hour after delivery, but a rise in retic- with blood is preferable because this rapidly
ulocyte count will not typically be seen until enhances oxygen delivery to tissues, which
the anemia has been present for several days. is not the case when crystalloid solutions are
used. Anticipation of the need for resuscita- the transfusion may be highly variable. It
tion is a key factor, so recognition of mater- may begin as early as the second trimes-
nal vaginal bleeding should be a signal to ter and therefore be long-standing at the
anticipate for the need for transfusion. time of delivery. In the most severe cases
Most labor and delivery units have type O in which the transfusion is of long dura-
Rh-negative uncrossed red blood cells avail- tion, the donor is substantially anemic and
able.26 The classic approach to shock in the exhibits significantly increased erythropoi-
newborn is to transfuse 10 mL/kg of blood esis that can even be present in the dermis
over 5 to 10 minutes and to repeat infusions (“blueberry muffin baby”); the donor also
until there are signs of adequate circulation. becomes progressively small for gestational
age and develops oligohydramnios. Simul-
Twin-to-Twin Transfusion Syndrome taneously, the recipient twin continues to
Twin-to-twin transfusion syndrome (TTTS) grow normally and becomes polycythemic;
is a complication that may occur in mono- in extreme cases, this progresses to polyhy-
chorionic twins which may originate in dramnios and potentially to hydrops fetalis.
either imbalance or abnormality of the sin- If the growth-restricted twin dies in utero,
gle placenta serving two twins. It is a serious the risk exists for embolization through vas-
complication in 10% to 20% of monozy- cular anastomoses to the surviving twin as
gous twin gestations with an overall inci- a consequence of intravascular coagulation
dence (i.e., including those in which it is in the dying twin. Embolization in the sur-
not a serious complication) of 4% to 35% viving twin will have major consequences,
in the United States.27 The diagnosis is well often affecting vital organs including the
established in overt clinical forms through brain, gastrointestinal tract, and kidneys.
the association of polyuric polyhydramnios Postpartum management of liveborn twins
and oliguric oligohydramnios. TTTS is a affected by this syndrome will be quite
progressive disease in which sudden deterio- complicated, even when the pediatrician is
ration in clinical status can occur, leading to prepared well in advance of delivery. The
the death of a twin. Up to 30% of survivors polycythemic twin will need reduction of
have abnormal neurologic development as the hematocrit, whereas the treatment of
a result of the combination of profound the anemic donor is more straightforward.
antenatal insult and complications of severe If either of the newborn twins demonstrates
prematurity. Newer treatment options have evidence of cardiomyopathy, the infant
improved the outcomes.27 would be intolerant of blood volume shifts
TTTS results from an unbalanced blood and may be particularly sensitive to blood
supply through placental anastomoses in volume expansion, in which instance a par-
monochorionic twins. These anastomo- tial exchange transfusion is again the pre-
ses may be arterial to arterial, but arterial to ferred approach.
venous are believed to be responsible for a The best treatment in cases of TTTS pre-
majority of the cases presenting clinically. senting before 26 weeks of gestation is
TTTS induces growth restriction, renal tubu- fetoscopic laser ablation of the intertwin
lar dysgenesis, and oliguria in the donor and anastomoses on the chorionic plate.29-31
visceromegaly and polyuria in the recipient.
Studies have shown a potentially important
role of the renin-angiotensin system with EDITORIAL COMMENT: In twin-to-twin transfusion
upregulation in the donor twin, whereas in syndrome (TTTS) the likelihood of perinatal survival of
recipients, renin expression was virtually at least one twin was not found to vary with severity
absent, possibly because it was downregulated as classified by Quintero stage (stage I, 92%; stage II,
by hypervolemia.28 In the donor, congestion 93%; stage III, 88%; stage IV, 92%).32 However, dual
and hemorrhagic infarction were accompa- twin survival did vary by stage (stage I, 79%; stage II,
nied by severe glomerular and arterial lesions 76%; stage III, 59%; stage IV, 68%; P < .01), pri
resembling those observed in polycythemia- marily because stage III TTTS was associated with de-
or hypertension-induced microangiopathy. creased donor twin survival. Sequential selective laser
Thus, fetal hypertension in the recipient twin photocoagulation of communicating vessels in preg-
in TTTS might be partly mediated by the nancies with TTTS was associated with higher dual
transfer through the placental vascular shunts survival and donor twin survival rates compared with
of circulating renin produced by the donor. a nonsequential technique. Overall survival of one or
The degree of transfusion from one both twins was 91% and dual twin survival was 72%.
twin to the other and the time course of
NONHEMORRHAGIC ANEMIAS phototherapy alone and ultimately requires

Hyperbilirubinemia is far more common exchange transfusion. For patients with Rh
and more severe in neonates with hemolytic sensitization and intrapartum asphyxia,
anemia than in older children. The bilirubin correction of anemia is essential to mini-
level may increase rapidly in the first hours mize cardiorespiratory distress and is thus
after birth, so identification of the underly- an important part of resuscitation in this
ing cause is extremely important. To diag- group of patients. The most extreme cases of
nose the cause of hemolysis, it is essential to Rh sensitization are associated with hydrops
obtain good information about any family fetalis in utero. Antenatal therapies have
history of anemia or neonatal jaundice, and been implemented to prevent this severe
without exception, both the baby and a blood manifestation of alloimmunization, includ-
smear should be examined. Clues to the ing intrauterine transfusions. Treated infants
appropriate diagnostic tests are often present are born with only mild to moderate ane-
in these smears, suggested by morphologic mia, with all of their red blood cells derived
abnormalities of the red blood cells. It is from the intrauterine transfusions. In these
standard to perform a direct antiglobulin test infants, the DAT finding may often be nega-
(DAT, or direct Coombs test), because the tive, but the result of the indirect antiglobu-
majority of hemolytic episodes are a conse- lin test is strongly positive. Quite frequently,
quence of maternal antibodies that cross the the consequence of intrauterine transfusion
placenta in late gestation and then react with is that the newborn will have no reticulo-
paternal antigen expressed on the infant’s cytosis despite moderate anemia, and with
erythrocytes. These maternal immunoglob- the majority of the infant’s red blood cells
ulin G (IgG) alloantibodies against pater- derived from intrauterine transfusions with
nal antigen are responsible for most cases Rh-negative blood, there is no hemolysis. It
of hemolytic disease of the newborn. If the is imperative that these infants be watched
DAT result is negative but hyperbilirubine- closely over the first several months, because
mia persists and the hematocrit is declining, a late episode of hemolysis and anemia may
a more thorough evaluation is required. This arise when the donor erythrocytes eventually
typically does not include a bone marrow decline in number. As erythropoiesis begins
examination, which is reserved for cases in to accelerate, these infants produce their own
which anemia is not associated with hemo- Rh-positive blood cells, which are susceptible
lysis and in which there is evidence suggest- to attack by residual maternal antibodies.
ing a primary disorder of erythropoiesis. In such infants, the DAT result may remain
strongly positive for months and they will
Hemolytic Anemias require supplemental folic acid to keep pace
Maternal Antibodies with the demands of increased erythropoiesis.
Fetal-neonatal alloimmune disease is the
most common cause of severe hemolytic EDITORIAL COMMENT: It is truly remarkable that after
anemia in an otherwise healthy newborn. Of the discovery of the blood groups in the 1940s, the
these disorders, Rh disease remains the most virtual elimination of erythroblastosis with anti-D globu-
common cause of severe anemia. Anemia lin took a mere 30 years, and this is one of the more
varies from mild to severe, the DAT result is notable accomplishments in modern medicine. Anti-
strongly positive, and the reticulocyte count D, a polyclonal immunoglobulin G, is purified from the
is almost uniformly elevated. Antenatal plasma of D-alloimmunized individuals. It is routinely
assessment is an important aspect of good and effectively used to prevent hemolytic disease of the
management and should include maternal fetus and newborn caused by the antibody response to
screening and frequent surveillance of fetal the D antigen on fetal red blood cells. This therapy has
well-being. In sensitized pregnancies, vigi- effectively reduced the number of cases of Rh isoim-
lance in pursuing these evaluations is essen- munization from 13% to less than 1% and the mortality
tial if one is to define the appropriate time rate from one in four to fewer than 5%. The residual
for intervention with premature delivery or cases are few and far between and have been attribut-
intrauterine transfusions. ed mainly to failed maternal prophylaxis caused by im-
proper timing or dosage of immunoglobulin anti-D ther-
Hyperbilirubinemia apy and by immunization during pregnancy resulting
Hyperbilirubinemia is a problem in the major- from an early occult fetomaternal hemorrhage (at <28
ity of cases of Rh disease, and in patients with weeks’ gestation). With erythroblastosis, the late-onset
the most severe degree of hemolysis, the ele- anemia may be either hemolytic or hyporegenerative.
vated bilirubin level cannot be managed by
Alloimmune Disease anemia. The peripheral blood smear of

Alloimmune disease may also occur as a patients with ABO incompatibility shows
consequence of other blood group incom- microspherocytes, and in most cases, the
patibilities (anti-c, anti-e, and anti-C in the mother is type O, whereas the baby is either
Rh system and anti-Kell). In alloimmune type A or type B. The elevation in serum bili-
anemia of the newborn, the level of hemo- rubin concentration typically resolves within
lysis caused by the presence of antibodies 1 to 2 weeks, and it is rare for this form of
to antigens of the Kell blood group system alloimmune hemolytic disease to result in a
is less than that caused by antibodies to drop in hemoglobin level or hematocrit suf-
the D antigen of the Rh blood group sys- ficient to require transfusion in the absence
tem, and the numbers of reticulocytes and of other complicating factors such as infec-
normoblasts in the baby’s circulation are tion. Clinical disease rarely occurs in group
inappropriately low for the degree of ane- A mothers with group B babies or in group B
mia. These findings suggest that sensitiza- mothers with group A babies.
tion to Kell antigens results in suppression
of fetal erythropoiesis as well as hemolysis. Congenital Infections
Vaughan et al compared the ex vivo growth Congenital infections may be associated
of Kell-positive and Kell-negative hema- with hemolytic anemias and have most
topoietic progenitor cells from cord blood often been observed in the setting of TORCH
in the presence of human monoclonal infections (toxoplasmosis, rubella, cytomeg-
anti-Kell and anti-D antibodies and serum alovirus infections, herpes simplex) as well
from women with anti-Kell antibodies.33 as syphilis.34,35 The association of hemolytic
The growth of Kell-positive erythroid pro- anemia with cytomegalovirus infection is
genitor cells (erythroid burst-forming units well described, and cytomegalovirus infec-
and colony-forming units) from cord blood tion has been documented as a cause of auto-
was markedly inhibited by monoclonal immune hemolytic anemia in the setting of
IgG and IgM anti-Kell antibodies in a dose- vertically acquired neonatal infection with
dependent fashion (range of concentra- human immunodeficiency virus (HIV).36
tions: 0.2% to 20%), but monoclonal anti-D Parvovirus B19 has an affinity for erythroid
antibodies had no effect. The growth of progenitors and produces severe erythroid
these types of cells from Kell-negative cord hypoplasia, with severe infection during
blood was not affected by either type of fetal development resulting in hydrops fe
antibody. Neither monoclonal anti-Kell talis or congenital anemia. Diagnosis is based
antibodies nor monoclonal anti-D antibod- on examination of bone marrow and viro-
ies inhibited the growth of granulocyte or logic studies. Much is known of the patho-
megakaryocyte progenitor cells from cord physiology of the virus, and studies are in
blood. Serum from 22 women with anti- progress to develop a vaccine to prevent
Kell antibodies inhibited the growth of this widespread infection. Bacterial infec-
Kell-positive erythroid burst-forming units tions can precipitate a hemolytic episode,
and colony-forming units but not of Kell- particularly in individuals with glucose-6-
negative erythroid burst-forming units and phosphate dehydrogenase deficiency, and
colony-forming units (P <.001 for the differ- thus this diagnosis should be considered in
ence between groups). The maternal anti- the setting of sepsis and severe hemolysis in
Kell antibodies had no inhibitory effects on the neonate.37
granulocyte-macrophage or megakaryocyte
progenitor cells from cord blood. These Enzymopathies
data indicate that anti-Kell antibodies spe- Specific erythrocyte glycolytic enzyme
cifically inhibit the growth of Kell-positive defects can be the cause of hemolytic syn-
erythroid burst-forming units and colony- dromes in the neonate. Two of the most
forming units, a finding that supports the commonly observed enzymopathies are
hypothesis that these antibodies cause fetal described in the following sections.
anemia by suppressing erythropoiesis at the
progenitor cell level. Glucose-6-Phosphate Dehydrogenase
A third form of alloimmune disease is Deficiency
caused by ABO incompatibility. This is per- Glucose-6-phosphate dehydrogenase (G6PD)
haps one of the most frequent causes of deficiency is the most common human
hyperbilirubinemia in the newborn but is enzyme defect and is present in more than
rarely responsible for a significant hemolytic 400 million people worldwide.38 As with
sickle cell disease, the global distribution The diagnosis of G6PD-deficient hemo-
of G6PD is remarkably similar to that of lytic anemia should be suspected in male
malaria, which lends support to the hypoth- infants with evidence of acute hemolytic
esis that these red blood cell disorders confer anemia and a negative result on Coombs
protection against malaria. G6PD deficiency test/DAT. Because the reticulocyte has
is an X-linked genetic defect caused by muta- higher levels of G6PD, screening tests for
tions in the G6PD gene, which lead to func- G6PD activity performed on the heels of
tional variants with many biochemical and a hemolytic episode are less reliable and
clinical phenotypes. Significant deficiency should be repeated 2 to 3 months after an
occurs almost exclusively in males. About acute hemolytic episode in conjunction
140 mutations have been described; most with family studies.
are single-base changes leading to amino
acid substitutions. The most common Pyruvate Kinase Deficiency
G6PD mutation in North America is the Pyruvate kinase deficiency is a rare cause
G6PD-A variant, present in approximately of neonatal hemolytic jaundice, with a
10% of African Americans. Term infants prevalence estimated at 1 case per 20,000
are rarely symptomatic. The most frequent live births in the United States, but with a
clinical manifestations of G6PD deficiency higher prevalence in the Amish communi-
are neonatal jaundice and acute hemolytic ties in Pennsylvania and Ohio. One report
anemia, which are usually triggered by an described four neonates with pyruvate kinase
exogenous agent. Jaundice in the neonate deficiency born in a small community of
with G6PD deficiency may occur without individuals practicing polygamy.40 All four
any known oxidant exposure. In contrast had early, severe hemolytic jaundice. Pyru-
to G6PD-A, G6PD-Canton, a variant com- vate kinase deficiency should be considered
mon in South China, is commonly associ- in neonates with early hemolytic, Coombs
ated with significant neonatal jaundice. test–negative, nonspherocytic jaundice, par-
Some G6PD variants cause chronic hemo- ticularly in communities with considerable
lysis, which leads to congenital nonsphero- consanguinity. Such cases should be recog-
cytic hemolytic anemia. The most effective nized early and managed aggressively to pre-
management of G6PD deficiency is to vent kernicterus. (See also Chapter 13.)
prevent hemolysis by avoiding oxidative
stress. DEFECTS OF THE RED BLOOD
Glucose-6-phosphate dehydrogenase is CELL MEMBRANE
the rate-limiting enzyme in the hexose Inherited abnormalities of one of the pro-
monophosphate shunt pathway. This teins of the red blood cell membrane may
pathway is principally important for the be associated with neonatal hemolysis and
production of reduced glutathione, and jaundice. Hereditary spherocytosis is an
this antioxidant has a vital role in protect- autosomal dominant condition and the
ing the red blood cell membrane from oxi- most common of this class of disorders.
dant damage. G6PD deficiency is common Most cases of spherocytosis result from
worldwide, with certain molecular vari- decreased production of spectrin. Heredi-
ants associated with neonatal hemolysis tary spherocytosis, including the very mild
and hyperbilirubinemia. A case recently or subclinical forms, is the most common
reported in the literature described a novel cause of nonimmune hemolytic anemia
missense mutation in a white neonate with among people of Northern European ances-
chronic nonspherocytic hemolytic anemia try, with a prevalence of approximately
caused by a class I G6PD deficiency.39 The 1 in 2000. However, very mild forms of
missense mutation in exon eight of the the disease may be much more common.
G6PD gene (c.827C>T p.Pro276Leu) was Hereditary spherocytosis is inherited in
associated with severe elevation in serum a dominant fashion in 75% of cases; the
bilirubin level, which peaked on day 5 at 24 remaining are truly recessive cases and de
mg/dL with a conjugated bilirubin level of novo mutations.41 A negative family his-
17 mg/dL. Jaundice resolved within 4 weeks. tory does not rule out the diagnosis, because
A detailed work-up failed to reveal other new mutations are quite common. Diag-
specific factors contributing to cholestasis. nosis may be aided by the evaluation of a
Severe hemolytic disease of the newborn peripheral blood smear in infants suspected
may cause cholestasis, even in the absence of one of these disorders of the red blood
of associated primary hepatobiliary disease. cell membrane.
OTHER CONGENITAL ANEMIAS pursuing this diagnosis. Blackfan-Diamond

anemia may result in severe fetal anemia
Congenital Dyserythropoietic Anemias requiring transfusion. Although autosomal
Congenital dyserythropoietic anemias (CDAs) dominant inheritance of Blackfan-Diamond
are rare hereditary disorders characterized syndrome is considered uncommon, it has
by ineffective erythropoiesis and by distinct been described44; the onset of anemia char-
morphologic abnormalities of erythroblasts acteristically occurs within the first year of
in the bone marrow. Although historically life, with 10% of cases presenting at birth.
these disorders have been largely diagnosed Affected infants exhibit variable degrees
through identification of characteristic mor- of anemia, with normal circulating white
phologic aberrations, the recent discovery blood cell and platelet counts. Hydrops fe
of underlying etiologic genetic abnormali- talis has been reported in rare cases. Among
ties has established the usefulness of molec- women with this disorder, a percentage are
ular diagnostic approaches that might serve at risk for having an infant with substantial
as rapid tools for the identification of these anemia in both the fetal and perinatal peri-
conditions. The first CDA partly accounted ods. Because the penetrance of the disorder
for genetically has been CDA I, for which is variable, pregnant women with a his-
the responsible gene CDAN1, encoding tory of Blackfan-Diamond anemia should
codanin-1, was discovered in 2002. Genetic be considered at risk. Recommendations
defects linked to CDA II (SEC23B) and a for the prenatal management of Blackfan-
previously unrecognized CDA (KLF1) have Diamond syndrome include prepregnancy
been identified. SEC23B encodes SEC23B, counseling for parents with Blackfan-Dia-
which is a component of the coated ves- mond syndrome, detailed and serial fetal
icles transiting from the endoplasmic ultrasound and echocardiographic stud-
reticulum to the cis compartment of the ies, cordocentesis if there are signs of ane-
Golgi apparatus. KLF1 encodes the ery- mia, consideration of in utero transfusion,
throid transcription factor KLF1 (Kruppel- and planned early delivery if the fetus is
like factor 1), and the recently identified affected.44
mutation leads to major ultrastructural
abnormalities, the persistence of embryonic Fanconi Anemia
and fetal hemoglobins, and the absence of Fanconi anemia is a rare chromosomal
some red blood cell membrane proteins. instability disorder associated with a variety
The current understanding of the vari- of developmental abnormalities, bone mar-
ous CDAs, including genotype-phenotype row failure, and predisposition to leukemia
relationships, has recently been reviewed and other cancers.45 The Fanconi anemia
elsewhere.42 gene family is a recently identified addi-
tion to the group of genes coding for the
Deficiencies of Red Blood Cell Production complex network of proteins that respond
Among the anemias that present in the new- to and repair certain types of DNA damage
born period, those resulting from inadequate in the human genome, but little is known
production are rare but, when present, may about the regulation of this novel group of
point to one of the rare congenital disorders genes at the DNA level.46 A homozygous
affecting red blood cell production. These missense mutation in the RAD51C gene has
congenital defects of erythropoiesis exhibit been described in a consanguineous fam-
a very low prevalence ranging from 4 to 7 ily with multiple severe congenital abnor-
per million live births and include Blackfan- malities characteristic of Fanconi anemia.47
Diamond anemia and Fanconi anemia, RAD51C is a member of the RAD51-like gene
which are described in the following sections. family involved in homologous recombina-
tion-mediated DNA repair. The mutation
Blackfan-Diamond Syndrome results in loss of RAD51 focus formation in
Blackfan-Diamond syndrome (also called response to DNA damage and in increased
congenital hypoplastic anemia) is the most cellular sensitivity to the DNA interstrand
common congenital disorder of red blood cross-linking agent mitomycin C and the
cell production in the neonate.43 Infants topoisomerase-I inhibitor camptothecin.
with Blackfan-Diamond syndrome are often Fanconi anemia generally affects children
small for gestational age and may have and results in bone marrow failure requiring
other anomalies (including renal abnor- blood or marrow transplantation for sur-
malities) that must be considered when vival. A unique feature of the condition is
the long waiting period, often many years, the production of Hb Bart’s. Hb Bart’s is com-
between genetic diagnosis and treatment, posed of tetrads of the γ-globin chain (γ4)
which presents a significant challenge to and exhibits a profoundly abnormal oxygen
the family and requires a strong, supportive dissociation curve reflecting the reduced
multidisciplinary approach to care.48 capacity to off-load oxygen at the tissue
capillary bed. The gene cluster, which codes
ANEMIA SECONDARY TO for and controls the production of these
HEMOGLOBINOPATHIES polypeptides, maps near the telomere of the
Hemoglobinopathies arise from mutations short arm of chromosome 16 within a G+C-
in the globin genes, with the most com- rich and early-replicating DNA region. The
mon hemoglobinopathies resulting from genes expressed during the embryonic stage
mutations in the β-globin gene. These are (ζ) or fetal and adult stage (α-2 and α-1) can
typically clinically silent at birth due to be modified by point mutations that affect
the persistence of Hb F but manifest as the either the processing-translation of mRNA
expression switches from γ- to β- chain pro- or make the polypeptide chains extremely
duction. unstable. Much more frequent are the dele-
tions of variable size (from approximately
Thalassemias 3 kilobases to more than 100 kilobases) that
Mutations in the β-globin gene that lead to remove one or both α genes in cis or even
a decrease in production are referred to as the whole gene cluster. Deletions of a single
β-thalassemias. The β-thalassemias result- gene are the result of unequal pairing dur-
ing from large structural deletions of the ing meiosis, followed by reciprocal recom-
β-globin gene cluster are a rare familial cause bination. These unequal crossovers, which
of microcytic anemia and hyperbilirubine- produce also α-gene triplications and qua-
mia.49 Although blood cell counts are nor- druplications, are made possible by the high
mal at birth, this disorder can be detected degree of homology of the two α genes and
by demonstrating the absence of Hb A on of their flanking sequences.
electrophoresis. In most states, umbilical The interaction of the different α-
cord blood is routinely screened to iden- thalassemia determinants results in three
tify infants with thalassemia and other phenotypes: α-thalassemic trait, clinically
hemoglobin disorders (including sickle cell silent and presenting with only limited
disease; see later discussion) before they alterations of hematologic parameters; Hb H
become symptomatic. disease, characterized by the development
α-Thalassemia is one of the most com- of a hemolytic anemia of variable degree;
mon human genetic disorders and is found and Hb Bart’s hydrops fetalis syndrome
extremely frequently in populations in (lethal), a consequence of compromised
Southeast Asia and southern China, and the oxygen delivery to tissues. The diagnosis of
expanding populations of Southeast Asian α-thalassemia caused by deletions is based
immigrants in the United States, Canada, on electrophoretic analysis of genomic
the United Kingdom, and Europe mean that DNA digested with restriction enzymes and
this disorder is no longer rare in these coun- hybridized with specific molecular probes.
tries.50,51 Couples in which both partners Recently, polymerase chain reaction (PCR)–
carry α0-thalassemia traits have a 25% risk of based strategies have replaced Southern blot
producing a fetus affected by homozygous analysis. Hemoglobin H disease, a muta-
α-thalassemia or hemoglobin Bart’s (Hb tion of three α-globin genes, is more severe
Bart’s) disease, with severe fetal anemia in than previously recognized. Anemia, hyper-
utero, hydrops fetalis, and stillbirth or early splenism, hemosiderosis, growth failure, and
neonatal death, as well as various maternal osteoporosis are commonly noted as the
morbidities. patient ages. Infants with one or two func-
The α-thalassemias present a different, tional α-globin genes have microcytosis at
greater challenge than β-thalassemia to birth (mean corpuscular volume is <95) and
the neonatologist and pediatrician. The an elevated percentage of Hb Bart’s on elec-
α-thalassemias are characterized by the trophoresis. α-Thalassemia major is usually
decrease or complete suppression of α-globin fatal in utero. Surviving newborns who did
polypeptide chains, with reduced or absent not undergo intrauterine transfusion often
synthesis of one to all four α-globin genes. have congenital anomalies and neurocog-
In the fetus, a complete deficiency of chain nitive injury. Serious maternal complica-
synthesis results in an absence of Hb F and tions often accompany pregnancy. Doppler
ultrasonography with intrauterine transfu- ventilatory assistance can often have more
sion ameliorates these complications. The than 5 mL of blood per day withdrawn for
high incidence in selected populations laboratory studies. At this rate, an 800-g
mandates population screening and prena- infant would lose his or her entire blood
tal diagnosis of couples at risk. Universal volume for laboratory studies in approxi-
newborn screening has been adopted in sev- mately 13 days. Large infants are less affected
eral regions with DNA confirmatory testing because of their greater blood volumes.
using the methods noted earlier.52,53 Rapid somatic growth of the preterm and
very low-birth-weight infant also contrib-
Sickle Cell Anemia utes substantially to anemia of prematurity.
Sickle cell disease (SCD) is caused by a single Very low-birth-weight infants will typically
point mutation in the β-globin gene that more than double their body weight and
causes the hydrophilic amino acid glutamic blood volume by the time they are ready for
acid to be replaced with the hydrophobic discharge from the nursery. In addition to
amino acid valine at the sixth position. the factors mentioned earlier, possibly the
SCD is an autosomal recessive genetic blood most significant contributing factor to this
disorder with incomplete dominance, char- process is the prolonged cessation of eryth-
acterized by red blood cells that assume ropoietin production. As noted previously,
an abnormal, rigid, sickle shape.54 Sick- reactivation of erythropoietin production in
ling decreases the cells’ flexibility and car- the infant kidney appears to be determined
ries a risk of various complications. The more by a biologic clock than by a response
introduction of newborn screening in the to stress. Indeed, there is no erythropoietin
United States has had a significant impact response to even severe anemia until the
on morbidity and mortality from SCD. His- infant reaches a corrected gestational age of
torically, the failure to achieve early iden- about 34 to 36 weeks. After this time, the
tification of SCD resulted in a high rate of erythropoietin system will respond when
mortality because of the susceptibility of the hematocrit declines into the range of
these patients to overwhelming infection, 25% to 30%. The reticulocyte count will typ-
particularly with encapsulated organisms. ically rise within 1 week after the increase in
Penicillin prophylaxis and the introduction erythropoietin production. Because transfu-
of the pneumococcal vaccine have had an sion during this critical period suppresses
additional impact on the risk of sepsis and the release of endogenous erythropoietin,
mortality in this population.55 Inheritance it can delay the recovery from anemia of
of the sickle gene with a thalassemia vari- prematurity, particularly in the seriously ill
ant, such as β-thalassemia, can alter the pre- preterm requiring multiple transfusions, in
sentation, in part by increasing the relative whom recovery may not be observed until
concentration of Hb S. an even later corrected gestational age.
Ultimately, it is the tissue oxygen tension
ANEMIA OF PREMATURITY that stimulates erythropoietin release, and
Anemia of prematurity is thought to be recipients of multiple transfusions in whom
principally a direct consequence of deliv- Hb F has largely been replaced by Hb A will
ery before placental iron transport and fetal be less likely to achieve a low enough tis-
erythropoiesis are complete and is exag- sue oxygenation to stimulate timely or early
gerated by various factors, including blood erythropoietin release.
losses associated with phlebotomy to obtain The treatment for anemia of prematu-
samples for laboratory testing, low plasma rity has evolved substantially. Because pla-
levels of erythropoietin due to both dimin- cental iron transport is incomplete in the
ished production and accelerated catabo- preterm infant, these babies require supple-
lism, rapid body growth and the need for mental iron to mount an effective erythroid
commensurate increases in red blood cell response. Iron stores are largely acquired
volume and mass, and disorders causing during the last month of intrauterine life,
red blood cell losses due to bleeding and/ thus term infants are born with large iron
or hemolysis. Blood losses resulting from stores. The combination of a lack of these
the phlebotomy required for frequent lab- iron stores and a rapid rate of growth (and
oratory studies can be a frequent cause of concomitant increase in blood volume)
anemia of prematurity, despite advances during the first 6 months of life place the
in blood conservation with microsampling preterm infant at significant risk of anemia
methods. The sick preterm infant receiving of prematurity. Most infants with a birth
weight of less than 1000 g are given multiple guidelines (hematocrit and hemoglobin levels, venti-
red blood cell transfusions within the first lation and oxygen needs, apneas and bradycardias,
few weeks of life. Red blood cell transfusions poor weight gain) that are relatively nonspecific.
have typically been the mainstay of therapy The need for transfusions can be reduced by limit-
for anemia of prematurity; recombinant ing phlebotomy losses, providing good nutrition, and
human erythropoietin (rHuEPO) is largely using standard guidelines for transfusion based on
unused because of the view that it fails to hemoglobin level or hematocrit. What those guidelines
substantially diminish red blood cell trans- should be is not clear. Analysis of data for the Prema-
fusion needs despite exerting substantial ture Infants in Need of Transfusion (PINT) trial, which
erythropoietic effects on neonatal marrow.56 compared management according to restrictive and
Multiple randomized, controlled trials liberal transfusion guidelines in infants weighing less
have shown that treatment of extremely pre- than 1000 g and used a composite primary outcome
term infants with rHuEPO during the period of death before home discharge or survival with either
when their endogenous erythropoietin sys- severe retinopathy, bronchopulmonary dysplasia, or
tem is inactive stimulates erythropoiesis, brain injury on cranial ultrasonography, revealed no
maintains a higher hematocrit, and reduces statistically significant differences between groups
the need for transfusions. Reticulocytosis in any secondary outcome.59 The investigators con-
appears about 1 week after the start of treat- cluded that in extremely low-birth-weight infants,
ment. The main population thought to ben- maintaining a higher hemoglobin level results in more
efit are those infants born before 30 weeks infants receiving transfusions but gives little evidence
of gestation, with the smallest, least mature of benefit. Data on the impact of transfusion practices
in this group exhibiting the greatest benefit. on long-term outcome are very limited and inconclu-
Treatment is usually started after the sive. Until further evidence surfaces, the tendency will
infant has tolerated the introduction of probably be to adopt more liberal indications for trans-
enteral feedings. Large multicenter trials fusion. Many centers continue to use the Shannon cri-
have demonstrated that administration of teria60 which call for transfusion in infants if any of the
rHuEPO plus iron supplementation can- following conditions are met: (1) a requirement for more
not prevent early transfusions, particularly than 35% inspired oxygen on continuous positive air-
in very low-birth-weight newborns and in way pressure (CPAP) or positive pressure ventilation
infants with severe neonatal diseases. How- with a mean airway pressure of more than 6 cm H2O;
ever, this approach may be effective in pre- (2) a requirement for less than 35% inspired oxygen
venting late transfusions. Doses of 100 U/ on CPAP or positive pressure ventilation with a mean
kg body weight given 5 days per week or airway pressure of less than 6 cm H2O, significant
250 U/kg given three times per week are apnea and bradycardia, tachycardia (>180 beats per
equally effective, and there is no evidence minute) or a respiratory rate of more than 80 breaths
that larger doses are more effective. Current per minute, weight gain of less than 10 g/day over
treatment of anemia of prematurity should 4 days, or sepsis; or (3) a hematocrit of less than 20%.
focus on efforts to minimize factors that Valieva et al modified these criteria to be more restric-
reduce erythrocyte mass (phlebotomies, tive because of concerns about complications in the
noninvasive procedures) and promote fac- transfused group.61 Their criteria include the following:
tors that increase it (placental transfusion, Hematocrit of less than 35% in the first week of life
adequate nutritional support).57 and in unstable condition*
Hematocrit of less than 28% in the first week of life
EDITORIAL COMMENT: Extremely low-birth-weight or in unstable condition*
preterm infants often develop anemia of prematurity Hematocrit of less than 20% if older than 1 week of
from frequent and excessive blood draws, a process age and in stable condition
referred to by Ed Bell as “gradual exsanguination.”58
*Instability is defined as an increased risk for poor oxygen
The hypoproliferative anemia is marked by inadequate delivery (e.g., prolonged oxygen desaturation episodes or
production of erythropoietin. Recombinant human hypotension requiring treatment).
erythropoietin (rHuEPO) has been available since
1990, but trials looking at reduction of red blood cell
transfusions with rHuEPO achieved limited success.
POLYCYTHEMIA
There has been a focus recently on autologous trans-
fusion, blood-sparing technologies, and limitation in
Several conditions are associated with poly-
the number of donors. Treatment of anemia of pre-
cythemia in utero. These include chronic
maturity includes red blood cell transfusions, which
hypoxia due to maternal toxemia and pla-
are given to preterm infants based on indications and
cental insufficiency, placental insufficiency
with postmaturity syndrome, pregnancy
at high altitudes, pregnancy in a diabetic carefully after this procedure, because it

woman, and trisomy 21. In most instances, will ultimately rise and if the HCTD is not
newborns who have clinically significant reached with the initial volume exchange, it
polycythemia have a preexisting high may rise again to a dangerous level.
hematocrit in utero due to one of the causes The greatest dilemma is that posed by the
listed previously, which is then exaggerated asymptomatic newborn with polycythemia.
by excessive placental transfusion at deliv- Although one might advocate observation,
ery. Conversely, early cord clamping and the reality that the first manifestations are
reduced placental transfusion can lead to a neurologic argues for early intervention and
normal hematocrit in an infant who devel- extremely close observation. Supporting
oped polycythemia in utero. early prophylactic exchange is the obser-
The complications of polycythemia are a vation that the incidence of neurologic
consequence of the rise in blood viscosity handicaps is increased in children who had
that occurs as the hematocrit rises, which untreated neonatal polycythemia.63 How-
compromises circulation to a variety of ever, the benefit of this approach for pre-
tissues and organs. The clinical manifes- venting neurologic complications remains
tations are distinct in each organ system. controversial.64
Skin manifestations include plethora and
delayed capillary filling. Renal symptoms ERYTHROCYTE TRANSFUSION
include proteinuria and hematuria, and in IN THE FETUS AND NEWBORN
extreme conditions, renal disease can be Packed red blood cell transfusions are often
indistinguishable from renal vein thrombo- administered to patients in the neonatal
sis. If the severity of polycythemia is poorly intensive care unit (NICU). Infants who
appreciated and early feeding is instituted, have significant cardiopulmonary disease
infants can develop necrotizing enterocoli- are transfused when they become anemic,
tis (NEC). The central nervous system mani- because it is thought that a higher oxygen-
festations of polycythemia may be mild, carrying capacity improves their tolerance
including poor feeding, irritability, and an of cardiorespiratory distress.65 Current
abnormal cry; more concerning cases are blood transfusion guidelines are useful in
those manifesting apnea, seizures, and cere- establishing parameters for transfusion, but
bral infarction.62 it is essential that physicians also modify
The diagnosis of polycythemia is not the application of these guidelines based
based solely on hematocrit, because there is on their own perceptions and assessments
no precise hematocrit at which symptoms in identifying patients in need of a packed
appear in all infants. This is partly due to red blood cell transfusion. In an evaluation
the fact that other factors affect viscosity in of the influence of caregiver perception and
addition to hematocrit. Although symptoms assessment on transfusion practices, neo-
are common when the venous hematocrit nates who underwent transfusion based on
exceeds 66%, serious signs of organ dys- caregivers’ perceptions rather than adher-
function develop in some infants with lower ence to strict guidelines were more likely to
hematocrits. It is essential that polycythe- be receiving noninvasive ventilatory sup-
mia be confirmed by measuring the venous port and were more symptomatic. Neonates
blood hematocrit, because capillary values who improved after transfusion had a lower
correlate poorly with the central venous pretransfusion hematocrit and were more
hematocrit (capillary hematocrits are gen- symptomatic compared with the group that
erally higher). The treatment for the neo- did not show clinical improvement. In this
nate with polycythemia is partial exchange study, tachycardia was the most sensitive
transfusion in which blood is replaced with predictor of benefit from packed red blood
a plasma substitute. Isotonic saline, plasma, cell transfusion.66
and a mixture of saline and albumin have Extremely low-birth-weight infants are
all been used with equal efficacy. The goal the most heavily transfused, yet the indi-
for the hematocrit is 50%. To achieve this cations for transfusion do continue to
through exchange, the following formula represent an area of controversy. A very
is typically used: V = [(HCT1 − HCTD) × important concept to which one should
body weight (kg) × 90 mL]/HCT1, where always adhere is that there is no single crit-
V = the exchange volume, HCT1 is the baby’s ical hematocrit that always requires trans-
hematocrit, and HCTD is the desired he fusion. In reality, there will be a range of
matocrit. The hematocrit must be monitored critical hematocrits at which transfusion
may be required even for an individual erythropoietic stage, myeloid progenitor cells
patient, and these different thresholds are can be found in the yolk sac during the third
values that are influenced by the sever- to fourth week of gestation.72 From the yolk
ity of illness. Several studies have sug- sac, these progenitor cells sequentially migrate
gested an association between red blood to the liver, thymus, and spleen and eventu-
cell transfusion and NEC in premature ally take up permanent residence in the bone
neonates.67,68 Withholding feeds during marrow at the eleventh to twelfth week of
transfusion has never been clearly demon- gestation. Hematopoietic stem cells with self-
strated to be beneficial but may have a pro- renewal capacity give rise to pluripotent pro-
tective effect against the development of genitors that progress to common lymphoid
NEC. In a retrospective case-control study or common myeloid progenitors.73,74 Com-
of premature low-birth-weight infants (<32 mon lymphoid progenitors differentiate into
weeks’ gestation and <2500 g) who devel- natural killer (NK) cells, B lymphocytes, T
oped NEC over a 6-year period (25 infants lymphocytes, and immature lymphoid den-
with NEC and 25 controls who never dritic cells. Common myeloid progenitors
developed NEC), more infants in the NEC differentiate into granulocytes (neutrophils,
group received transfusions in the 48 to eosinophils, and basophils), monocytes, and
72 hours preceding diagnosis (56% versus immature myeloid dendritic cells. Monocytes
20% within 48 hours [P = .019] and 64% give rise to tissue macrophages.73
versus 24% within 72 hours [P = .01]).68 The systems mediating innate immunity
The total number of transfusions and age have qualitative and quantitative deficien-
of red blood cells were not different in the cies that affect the newborn’s response to
two groups. The same investigators imple- infections. For example, neonatal neutro-
mented a policy of withholding feeds phils ingest and kill bacteria as efficiently
during transfusion, and this practice was as their adult counterparts, but adhesion
associated with a decrease in the incidence and subsequent migration of these cells to
of NEC from 5.3% to 1.3% (P = .047). These sites of infection are impaired. The migra-
data support the recognized association of tory defect of neonatal neutrophils is
NEC with the administration of red blood exacerbated by limited production of the
cell transfusions in the 48 to 72 hours pre- chemoattractant C5a and low generation
ceding presentation of NEC and provide a of C3b, which is necessary for opsoniza-
rationale for exercising caution in feeding tion and phagocytosis. Neutrophil stor-
around the time of packed red blood cell age pools are rapidly exhausted in the face
transfusions in the neonate. of serious infection, and the capacity to
The risk-to-benefit ratio of blood transfu- replenish those stores is limited in the neo-
sions for preterm infants will continue to be nate. Acquired immunity in the newborn is
defined by ongoing experience. Although affected by qualitative and quantitative defi-
use of a more restrictive transfusion thresh- ciencies in lymphoid lineage as well. Cell-
old for hemoglobin level or hematocrit, or mediated killing by NK and cytotoxic T cells
both, may decrease the number of blood is diminished, which leaves the newborn
transfusions in preterm infants, the impact vulnerable to certain viral and intracellular
of such an approach on long-term outcomes pathogens.73 The newborn infant produces
must be defined.69,70 primarily IgM, and little IgG and IgA, in
response to antigenic challenge. Neonatal
WHITE BLOOD CELLS T and B cells are predominately of a naive
But so long as you stimulate the phagocytes, phenotype. Since the lymphocyte matura-
what does it matter which particular sort of tion process is directed largely by cytokines
serum you use for the purpose? and the capacity of neonatal cells to pro-
duce key cytokines such as interleukin-4
George Bernard Shaw, and IFN-T interferon-gamma is limited, the
The Doctor’s Dilemma acquisition of adult-type functional capa-
bilities is delayed in vivo.
Mature white blood cells are derived from Despite encountering a pathogen-rich
pluripotent hematopoietic stem cells. In environment at the time of birth, most new-
early development, hematopoietic stem born infants, do not become ill. The rela-
cells emerge separately from the yolk sac, tive immunodeficiency of the neonate has
chorioallantoic placenta, and aorta-gonad- been viewed by some as an adaptive mecha-
mesonephros region.71 Following the initial nism to optimize survival by balancing the
conflicting immunologic requirements of Causes of Neutropenia in the

life in utero with those of the external envi- Box 17-1.
Neonate
ronment.
Increased neutrophil destruction or
NEUTROPHIL DISEASES utilization
Immune
NEUTROPENIA • Alloimmune/isoimmune neutropenia
The neutrophil counts in an infant vary by • Autoimmune neutropenia in the mother
birth weight and postpartum age. For term Nonimmune
and near-term infants, values published by • Maternal preeclampsia
Manroe et al are considered appropriate. An • Infection: bacterial, viral
absolute neutrophil count (ANC) of 1800 to • Periventricular hemorrhage
5500/µL is seen at birth, and ANC increases • Asphyxia
by threefold to fivefold over the next 12 to • Metabolic disorders
18 hours of life.75 By 24 hours of life, the Reduced neutrophil production
ANC begins to fall, decreasing steadily to Infants of hypertensive mothers
1800 to 7200/µL at 5 days, from then it Donors of twin-to-twin transfusion
falls to and remains at 1800 to 5400/µL Nutritional factors
through 28 days of age. Studies by Mouz- Kostmann disease (severe congenital
inho et al show that normal preterm very agranulocytosis)
low-birth-weight neonates have leukocyte Pure white cell aplasia
reference ranges that differ significantly Barth syndrome
from those of older neonates (neutrophil Reticular dysgenesis
counts have lower minimum values in the Hyperimmunoglobulin M syndrome
former group).76 Publications recommend Shwachman-Diamond syndrome
using the Mouzinho et al chart for infants Dyskeratosis congenita
of less than 1500 g birth weight and the Mixed causes
Manroe et al chart for larger infants (see also Drugs
Appendix C).75-78 Studies suggest that neo- TORCH infections (toxoplasmosis, rubella,
nates with neutrophil counts above 1000/ cytomegalovirus, herpes simplex)
µL are not likely to be at high risk of acquir-
ing a nosocomial infection. Counts below Excessive neutrophil margination
500/µL (particularly when they remain Pseudoneutropenia
below 500/µL for many days) are associ- Endotoxin-induced margination
ated with an increased risk for developing
a nosocomial infection. Persistent counts
between 500 and 1000/µL may pose some reticuloendothelial system, and the capacity
intermediate risk.77,78 of the infant’s marrow to compensate for the
shortened survival of antibody-coated neu-
Causes of Neonatal Neutropenia trophils.79,80 Antineutrophil antibodies have
Box 17-1 lists the most common causes of been found in as many as 20% of surveyed
neutropenia in newborns. In general, neutro- pregnant and postpartum women, but stud-
penia can be caused by either decreased neu- ies have documented ANN in 0.2% to 2%
trophil production or increased destruction. of consecutively sampled newborns.79-82 A
wide variety of antigenic targets have been
Neutropenia Secondary to Increased identified, including human neutrophil allo-
Neutrophil Destruction antigen (HNA) groups HNA-1, HNA-2, and
Alloimmune Neonatal Neutropenia HNA-3 as well as NC1, SH, SAR, LAN, LEA,
In alloimmune neonatal neutropenia (ANN) and CN1.79-83 The role of human leukocyte
the mother becomes immunized to a father’s antigen (HLA) is controversial.84 Despite all
neutrophil antigen that is expressed on the the available data, in nearly half of cases the
fetal neutrophils. Subsequently, IgG anti- antigens cannot be recognized.81,82 Symp-
bodies directed against fetal neutrophil anti- tomatic infants can manifest delayed sepa-
gen crosses the placenta and destroys the ration of the umbilical cord, skin infections,
fetal granulocytes. The severity of neutrope- otitis media, or pneumonia within the first
nia is influenced by the titer and subclass 2 weeks of life. Although most infections
of the maternal IgG neutrophil antibod- are mild, overwhelming sepsis is known to
ies, the phagocytic activity of the infant’s occur and is associated with a mortality rate
as high as 5% in infants with ANN. When rG-CSF is currently the first-line therapy
neutropenia is prolonged (>7 days), severe to achieve remission of the neutropenia.
(ANC of <500/µL), or associated with serious Treatment with IVIG is effective in less than
infections, ANN can be treated with subcu- 50% of cases and the benefit lasting less
taneous recombinant human granulocyte than 2 weeks. Steroids have limited effect in
colony-stimulating factor (rG-CSF). The use immune-mediated neutropenia.86
of growth factor in this setting is discussed
later in the chapter. Fortunately, in the Neonatal Autoimmune Neutropenia
majority of cases the disorder is self-limit- Neonatal autoimmune neutropenia is seen
ing and resolves over a period of weeks to a when mothers with autoimmune disease
few months as levels of the transplacentally transfer their neutrophil autoantibodies pas-
acquired maternal antibody diminish.79-82 sively to the fetus. Most often, the mother
and the infant are neutropenic. The infant’s
Autoimmune Neutropenia of Infancy neutropenia is transient and asymptomatic.
Autoimmune neutropenia of infancy (AIN) The recovery process takes a few weeks to
is a disorder caused by increased peripheral a few months and depends on the time it
destruction of neutrophils as a result of anti- takes to clear IgG antibodies.81,82
bodies in the infant’s blood that are directed
against the infant’s own neutrophils. It is Neutropenia in Neonates with Sepsis
analogous to immune thrombocytopenic Neonates have immature granulopoiesis.
purpura or autoimmune hemolytic anemia. This frequently results in neutropenia after
Primary AIN, which is not associated with sepsis, which is likely secondary to exhaus-
other diseases such as systemic lupus ery- tion of the storage and proliferative pools of
thematosus, is often observed in infants and the bone marrow. Neutropenic septic neo-
has an incidence of 1 in 100,000.80 A large nates have a higher mortality rate than non-
number of children with primary AIN show neutropenic septic neonates.91,92 Whether
the presence of antibodies specific to HNA- growth factor or granulocyte infusions
1a or HNA-1b. Less frequently, the antineu- should be used in such a setting remains
trophil autoantibodies recognize adhesion controversial (see later discussion). Neutro-
glycoproteins of the CD11/CD18 (HNA- penia commonly occurs in neonates who
4a, HNA-4b) complex, the CD35 molecule have NEC as well. In this instance, neu-
(CR1), and FcγRIIb.85,86 The origin of these tropenia results from increased use and/or
autoantibodies is not known. The mecha- destruction in tissues, margination due to
nism proposed include molecular mim- endotoxinemia, and increased mobilization
icry of microbial antigens, modification of neutrophils into the peritoneum.
of endogenous antigens as a result of drug
exposure, increased or otherwise abnormal Neutropenia Secondary to Decreased
expression of HLA antigens, or loss of sup- eutrophil Production
N
pressor activity against self-reactive lym- Severe Congenital Neutropenia
phocyte clones. There have been reported Severe congenital neutropenia is a geneti-
associations with parvovirus B19 infection cally heterogeneous bone marrow failure
and exposure to β-lactam antibiotics.87,88 syndrome characterized by maturation
AIN is usually diagnosed during the first few arrest of myelopoiesis at the promyelo-
months of life (3 to 8 months).85 cyte-myelocyte stage. Estimated frequency
Diagnosis of AIN in premature twins has is approximately 1 to 2 cases per million
been reported, which suggests that sensiti- with equal male-female distribution. Severe
zation can occur even in utero.89 Although congenital neutropenia follows an autoso-
there is significant neutropenia at presenta- mal dominant or autosomal recessive pat-
tion (500 to 1000/µL), the clinical course is tern of inheritance. About 60% of cases
usually benign with mild infections.85,86,90 are attributable to mutations in the gene
Severe infectious complications (pneumo- for neutrophil elastase (ELA2).93 Less com-
nia, sepsis, meningitis) are seen in about monly, mutations in HAX1, G6PC3, and
12% of these patients.80,86 AIN resolves other genes cause this disorder. From early
spontaneously by the age of 2 or 3 years in infancy, patients who have severe congeni-
95% of cases.85,86,90 Therefore most cases tal neutropenia experience bacterial infec-
require no specific therapy. The usefulness tions. Omphalitis, beginning directly after
of antibiotic prophylaxis must be assessed birth, may be the first symptom; however,
on a case-by-case basis. Administration of otitis media, pneumonitis and infections of
the upper respiratory tract, and abscesses Neutropenia in Neonates with Hypertensive
of the skin or liver are also common and Mothers
can lead to the diagnosis of severe congeni- Infants born to mothers who have preg-
tal neutropenia. Patients with the disorder nancy-induced hypertension (PIH) or
have severe chronic neutropenia with ANCs HELLP syndrome (hemolysis, elevated
continuously below 200/µL; in many cases, liver enzymes, and low platelet count) are
peripheral blood neutrophils are completely observed to have neutropenia in 40% to
absent. Peripheral monocytosis or eosino- 50% of cases, with the most severe neutro-
philia may be present. The bone marrow penia in the very low-birth-weight infants.78
usually shows a maturation arrest of neutro- This type of neutropenia is the result of
phil precursors at an early stage (promyelo- placental production of an inhibitor of
cyte-myelocyte level) with few cells of the myelopoiesis. It can be severe, with blood
neutrophilic series beyond the promyelo- neutrophil counts below 500/µL. With no
cyte stage. The use of rG-CSF remains first- specific treatment, this variety of neutrope-
line treatment for most patients with severe nia generally resolves in about 72 hours and
congenital neutropenia. Transplantation of almost always resolves by the fifth day after
hematopoietic cells from an HLA-identical birth. Whether a risk of sepsis is associated
sibling is beneficial for patients who are with neutropenia in infants born to moth-
refractory to rG-CSF therapy. Patients who ers with preeclampsia remains a topic of
have severe congenital neutropenia are at discussions.96,97
risk of leukemic transformation, and those
who develop myelodysplasia or leukemia Neutropenia in Donor Twins
should proceed urgently to hematopoietic Neutropenia occurs in the donor twin (the
stem cell transplantation.78,93 twin who becomes anemic) in twin-to-twin
transfusion. It is usually transient. Since
Shwachman-Diamond Syndrome the myelopoiesis shifts toward erythro-
Shwachman-Diamond syndrome is an poiesis, neutrophil production decreases,
autosomal recessive marrow failure syn- which results in neutropenia. No left shift
drome associated with exocrine pancreatic is present.
insufficiency and predisposition to leuke-
mia. Approximately 90% of patients meet- Neutropenia in Neonates with Rh Hemolytic
ing clinical criteria for the diagnosis of Disease
Shwachman-Diamond syndrome harbor The neutropenia in neonates with Rh hemo-
mutations in the SBDS gene (Shwachman- lytic disease is likely caused by a shift of
Bodian-Diamond syndrome) that maps to myelopoiesis toward erythropoiesis, which
the 7q11 centromeric region of chromo- diminishes neutrophil production. It is usu-
some 7.94,95 The initial symptoms typically ally transient.
are diarrhea and failure to thrive beginning
in early infancy, and it is truly rare for the Neutropenia Secondary to Mixed Causes
disease to present in the neonatal period. Drugs
Growth failure and metaphyseal chondro- Drugs can cause neutropenia through sup-
dysplasia associated with dwarfism are seen pressive effects on progenitors, changes in
in some patients. The most common hema- marrow extracellular matrix, development
tologic abnormality, affecting 88% to 100% of autoantibodies, and other mechanisms.78
of patients with Shwachman-Diamond Ganciclovir has been strongly associated
syndrome, is neutropenia. Patients with with neutropenia, and cessation of therapy
Shwachman-Diamond syndrome are sus- may be necessary.98 Other drugs used in the
ceptible to recurrent bacterial, viral, and NICU that have been implicated in causes
fungal infections; in particular, otitis media, of neutropenia include β-lactam antibiotics,
sinusitis, mouth sores, bronchopneumonia, thiazide diuretics, and ranitidine.88
septicemia, osteomyelitis, and skin infec-
tions.94 The illness may progress to bone Infection
marrow hypoplasia or dysplasia, leading to Intrauterine cytomegalovirus and rubella
moderate thrombocytopenia and anemia. virus infections can be associated with neu-
For treatment, rG-CSF has been used. The tropenia or pancytopenia. Neutropenia in
only definitive therapy for marrow failure, this instance is likely secondary to spleno-
myelodysplasia, or leukemia is hematopoi- megaly; however, there might be an ele-
etic cell transplantation.94,95 ment of decreased production as well.78,99
Pseudoneutropenia Management of Neonatal Neutropenia

Artifactual neutropenia has been described In ill neutropenic neonates, sepsis should
that is caused by ethylenediaminetetraace- always be suspected and antibiotic ther-
tic acid (EDTA)–induced neutrophil agglu- apy initiated promptly. If the neutropenia
tination in vitro. The condition can be is severe and prolonged, reverse isolation
diagnosed by the presence of neutrophil procedures might be useful. Accepted treat-
clumps on peripheral smears. ment options for symptomatic neonatal
neutropenia are discussed below.
EVALUATION OF THE NEONATE
WITH NEUTROPENIA Treatment
Neutropenia in the NICU requires little Recombinant Granulocyte and Granulocyte-
diagnostic evaluation if the cause is clear Macrophage Colony-Stimulating Factors
(e.g., NEC, sepsis, maternal PIH). However, The availability of recombinant myeloid
if neutropenia persists more than 3 to 5 growth factors has provided new strategies
days, particularly if the count is less than in the management of neonatal neutrope-
500/µL, additional evaluation is needed. nia. rG-CSF is structurally identical to the
Helpful findings on physical examination natural human G-CSF and increases the
include characteristic dysmorphic features number of circulating neutrophils by stimu-
such as skeletal dysplasia, radial or thumb lating the release of neutrophils from the
hypoplasia (congenital bone marrow failure bone marrow, inducing myeloid prolifera-
syndromes), hepatosplenomegaly (TORCH tion, and reducing neutrophil apoptosis.
syndrome, storage disorders), and skin or Both rG-CSF and recombinant granulo-
hair pigmentary abnormalities (Chédiak- cyte-macrophage colony-stimulating factor
Higashi syndrome). A complete blood (rGM-CSF) have been administered as treat-
count, including microscopic examination ment for neonates with neutropenia with
of the peripheral blood smear to determine varying degrees of success. Calhoun et al have
neutrophil morphology, can be useful in outlined consistent approaches to procedures
identifying congenital neutropenia syn- and practices in neonatal hematology,100
dromes. The immature-to-total (I/T) neutro- including one for the use of rG-CSF.
phil ratio can be helpful in differentiating The decision regarding whether to
defects in production from destruction of administer rG-CSF to any given neutrope-
neutrophils. The I/T ratio can be calculated nic patient in the NICU must be individu-
as follows: alized with consideration of the risks and
benefits. The U.S. Food and Drug Adminis-
(Bands + Metamyelocytes + Myelocytes) / tration (FDA) has approved the use of rG-
(Segmented neutrophils + Bands + CSF as long-term treatment to reduce the
Metamyelocytes + Myelocytes) incidence and duration of sequelae of neu-
tropenia (e.g., fever, infections, oropharyn-
A normal or low I/T ratio in the presence geal ulcers) in symptomatic patients with
of severe neutropenia suggests that the neu- congenital neutropenia, cyclic neutrope-
tropenia is due to decreased production. nia, or idiopathic neutropenia. The variet-
A very high I/T ratio suggests increased ies of severe chronic neutropenia for which
neutrophil production, which implies rG-CSF administration has been best stud-
increased peripheral destruction or tissue ied are Kostmann syndrome, Shwachman-
recruitment of neutrophils.78 It is also use- Diamond syndrome, Barth syndrome, and
ful to obtain a complete blood count for cyclic hematopoiesis. At this time, it is not
the infant’s mother. If maternal blood neu- clear whether chronic idiopathic neutrope-
trophil concentration is normal, maternal nia or neonatal alloimmune neutropenia fit
neutrophil antigen typing and antineutro- under the FDA indication of severe chronic
phil antibody screening should be pursued neutropenia, because although these disor-
at a reference laboratory highly skilled in ders can be very severe, they are self-limited,
detection of neonatal alloimmune neutro- and the duration rarely exceeds 6 months.
penia. A bone marrow study is useful in Moreover, administration of rG-CSF to
patients with severe and prolonged neutro- patients with these latter neutropenic dis-
penia who were not born to mothers with orders has not been tested in randomized
PIH and in whom alloimmune and mater- placebo-controlled trials.100 However, these
nal autoimmune neutropenia have been patients generally derive considerable bene-
excluded.77 fit from rG-CSF treatment.101 In addition to
increasing circulating neutrophil numbers evidence suggests the need for a multi-
by stimulating the release of neutrophils center randomized clinical trial demon-
from the bone marrow, rG-CSF downregu- strating the clinical efficacy of rG-CSF
lates antigen expression, which makes the before this therapy can be universally rec-
neutrophils less vulnerable to circulating ommended in the NICU.111
antibodies. The majority of neonates with
either idiopathic or alloimmune forms of
neutropenia will respond to doses of 5 to EDITORIAL COMMENT: Neonates have a high risk
10 µg/kg given subcutaneously at intervals of sepsis if they are either neutropenic or have low
ranging from every day to less than once concentrations of immunoglobulin. Carr et al reported
per week, as needed, to bring the blood neu- that early postnatal prophylaxis with granulocyte-
trophil concentration to levels above 500 to macrophage colony-stimulating factor corrects neu-
1000/µL.100 It is recommended that rG-CSF tropenia but does not reduce sepsis or improve sur-
be used with caution in patients who have vival and short-term outcomes in extremely preterm
immune-mediated neutropenias caused by neonates.112 A metaanalysis that included this trial as
antibodies against HNA-2a (NB1), since it well as previously reported prophylactic trials showed
has been shown to increase the expression no survival benefit.110
of HNA-2a in healthy adult volunteers. In Although administration of granulocyte colony-
one case of a neonate who had ANN caused stimulating factor and granulocyte-macrophage
by anti–HNA-2a antibodies, the response colony-stimulating factor can raise white blood cell
was delayed and was achieved only with counts, this does not translate into fewer infections. Nor
an unusually high dose.102 rG-CSF has also is there conclusive evidence that in the face of proven
been used successfully in patients with neu- sepsis these cytokines effectively stimulate release of
tropenia caused by maternal PIH.103 neutrophils and improve outcome. The role of neu-
Several studies evaluated the role of rG- trophil transfusions and intravenous immunoglobulin
CSF therapy in septic neutropenic neo- for neutropenic septic babies is still being evaluated.
nates.104-108 These were followed by two
metaanalyses that examined the efficacy
and safety of treatment with hemopoi- Intravenous Immunoglobulin
etic colony-stimulating factors (rG-CSF or IVIG has been used with success in both
rGM-CSF) in newborn infants with sus- ANN and AIN, with a response rate of about
pected or proven systemic infection. In a 50%.80-82 However, because of the lack of a
metaanalysis by Bernstein et al,109 rG-CSF titratable dose-response effect and the possi-
recipients were found to have a lower mor- bility that IVIG may itself induce neutrope-
tality than did controls. However, when nia, this treatment has been used less often
the nonrandomized studies were excluded, than rG-CSF in patients who have immune
the analysis did not remain statistically neutropenia.80-82
adequate. More importantly, neutropenia
was not defined consistently in the stud- Granulocyte Transfusions
ies reviewed, and therefore the significant Current evidence does not show a clear ben-
reduction in mortality noted when rG-CSF eficial role for granulocyte transfusion in
was given to neonates with neutropenia neonates. Calhoun et al recommend using
requires further confirmation. A meta- granulocyte infusions for patients who have
analysis by Carr et al examined the effect early-onset sepsis and shock,100 are under-
of adjuvant G-CSF or GM-CSF treatment going mechanical ventilation and receiving
on 14- and 28-day overall mortality in infusions of pressors, have a blood neutro-
neonates with suspected or documented phil concentration well below 1000/µL with
sepsis.110 A combination of five studies a left shift, and have already received IVIG.
(n = 194) in the 28-day mortality analysis A systemic review by Mohan et al found
showed a reduction in all-cause mortality no significant difference in “all-cause mor-
in treated infants (relative risk: 0.51; 95% tality during hospital stay” in infants with
confidence interval [CI]: 0.27 to 0.98). sepsis and neutropenia who received granu-
When results from three studies (n = 97) locyte transfusions and those who received
that were limited to neutropenic infants placebo or no granulocyte transfusion.113
with systemic infection were analyzed, 14- Adequately powered multicenter trials of
and 28-day overall mortality was found granulocyte transfusion are needed to clar-
to be reduced by rG-CSF therapy (relative ify its role in the treatment of neonates with
risk: 0.34; 95% CI: 0.12 to 0.92). Current sepsis and neutropenia.
NEUTROPHILIA blood that can be taken from the neonate

Neutrophilia (defined as >7000 white blood for diagnostic studies.114 For all of these rea-
cells/µL in term infants and >13,000 white sons, it is difficult to identify the rare infant
blood cells/µL in premature infants) typi- in whom infection is due to an inherited
cally is a nonspecific response to a stressor.114 defect in neutrophil function.
The most common cause of neonatal neutro-
philia is infection (Box 17-2). Birth asphyxia EOSINOPHILIA
and other causes of acute or chronic hypoxia Eosinophilia (most frequently defined as
can induce the marrow to prematurely >700 eosinophils/µL115) is common in hos-
release immature myeloid and erythroid pitalized neonates of all gestational ages,
cells into the circulation. Nucleated eryth- but there are significant differences in pat-
rocytes are registered by electronic cell terns of incidence and severity based on
counters as leukocytes, so it is important gestational age, with increased incidence
to correct for the presence of nucleated red and greater severity of eosinophilia in the
blood cells when interpreting the white more immature infants.116,117 Eosinophilia
blood cell count. Neonatal granulocytosis in neonates has been attributed to a variety
caused by intrinsic disorders of the marrow of causes (Box 17-3).
is rare. Neonatal leukemia and the transient When evaluating the infant with eosino-
myeloproliferative disorder seen in infants philia, it is helpful to consider the potential
with trisomy 21 are usually associated with differences in etiology for those who are ill
large numbers of circulating immature versus those who are well.118 In the latter
myeloid cells and with hepatosplenomeg- group, infection should be strongly consid-
aly. The diagnosis is established by bone ered, especially if the complete blood count
marrow examination, which should include was obtained because of clinical suspicion of
cytogenetic analysis of unstimulated bone infection. An evaluation for sepsis is appropri-
marrow. ate if risk factors or predictors are present, such
NEUTROPHIL FUNCTIONAL DEFECTS

Neutrophil functional defects are uncom- Conditions Associated with
Box 17-3.
mon disorders that rarely present in the Eosinophilia in the Neonate
newborn. Because neonates have inherent Hematologic disorders
functional defects in their polymorphonu- • Hypereosinophilic syndrome
clear neutrophils and monocytes, and also • Eosinophilic leukemoid reaction
have a higher rate of infections than older • Eosinophilic leukemia
infants and children, the clinical manifesta- • Thrombocytopenia–absent radius
tions characteristic of dysfunctional phago- syndrome
cytosis may be obscured by the already • Congenital neutropenia with eosinophilia
higher infection rates in neonates. There- Infection
fore, it is necessary to have a relatively low • Bacterial
threshold for specific evaluation of these • Viral
conditions. Diagnostic evaluation may be • Fungal
difficult because of the limited volume of Necrotizing enterocolitis
Immune deficiency disorders
• Congenital immune deficiency syndromes
Conditions Associated with
Box 17-2. • Hyperimmunoglobulin E
Neutrophilia in the Neonate
Familial eosinophilia
Infection Establishment of an anabolic state
Birth asphyxia Drug reactions
Other causes of acute or chronic hypoxia (pneu • l-Tryptophan
mothorax, meconium aspiration) • Ceftriaxone
Hemolytic disease Congenital immunodeficiency syndromes
Seizures • Hyperimmunoglobulin E
Leukemoid reaction • Omenn syndrome
Neonatal leukemia and transient myeloprolif- Cow’s milk allergy
erative disorder Miscellaneous
Congenital anomalies (tetralogy of Fallot) • Congenital heart disease
Leukocyte adhesion deficiency • Chronic lung disease
as neutropenia, thrombocytopenia, coagula- phagocytic cells in LAD-1 and absence

tion dysfunction, hypotension, or respiratory of sialylated CD15 leukocyte antigens in
distress. An evaluation for NEC is appropri- LAD-2).114,120
ate if signs consistent with gastrointestinal
dysfunction are present. If the neonate with CHÉDIAK-HIGASHI SYNDROME
eosinophilia is well, close monitoring for 48 Chédiak-Higashi syndrome is a rare autoso-
hours is suggested. If the eosinophilia per- mal recessive disorder caused by mutations
sists, then a search for a specific cause of the in the LYST (or CHS1) gene. The Chédiak-
eosinophilia should be undertaken.118 Higashi syndrome gene affects the synthe-
sis and/or maintenance of storage-secretory
CHRONIC GRANULOMATOUS DISEASE granules in various types of cells. Lysosomes
Chronic granulomatous disease (CDG) is of leukocytes and fibroblasts, dense bodies
the most common inherited disorder of of platelets, azurophilic granules of neu-
leukocyte function. CDG has an X-linked trophils, and melanosomes of melanocytes
or autosomal recessive inheritance pattern are generally larger in size and irregular in
involving defects in genes encoding phox morphology. Che’diak–Higashi syndrome
proteins, which are the subunits of phago- manifests as recurrent pyogenic infections,
cyte reduced nicotinamide adenine dinucle- oculocutaneous albinism, and giant intra-
otide phosphate oxidase (NADPH oxidase). cellular granules in blood leukocytes.114,120
This results in failure to produce superox-
ide anion and downstream antimicrobial NEONATAL IMMUNE DEFICIENCIES
oxidant metabolites and to activate antimi- OF LYMPHOCYTE LINEAGE (T CELL,
crobial proteases. Affected patients are sus- B CELL, NATURAL KILLER CELL)
ceptible to severe, life-threatening bacterial It is important for neonatologists and pedia-
and fungal infections (such as pneumonia tricians to be able to differentiate between
caused by Aspergillus or liver abscess caused immune immaturity and a true primary
by Staphylococcus aureus) and excessive immunodeficiency that may present during
inflammation characterized by granuloma- the neonatal period. Failure to identify pri-
tous enteritis and genitourinary obstruction. mary immune deficiency properly can result
Early diagnosis of CGD and rapid treatment in delayed diagnosis and treatment, which in
of infections are critical. The diagnosis of turn can affect the outcome of the disease.
CGD requires demonstration of defective Examples of specific T-cell and B-cell disorders
NADPH oxidase activity in neutrophils. that are recognizable during early infancy are
The most common diagnostic assays are the presented in Table 17-1. Selected deficiencies
nitroblue tetrazolium dye reduction test (a are discussed in the following sections.
measure of superoxide anion release) and
flow cytometry evaluating dihydrorhoda- HUMORAL IMMUNE DEFICIENCIES
mine 123 (DHR) fluorescence (a measure of Antibody deficiencies are often unrecog-
intracellular hydrogen peroxide). Infection nized during the neonatal period because
prophylaxis and interferon-γ administra- of the protective effect of passively acquired
tions have significantly improved the natu- maternal antibodies. In premature neo-
ral history of CGD. Currently, the only cure nates, deficiency secondary to immaturity,
is allogeneic hematopoietic cell transplan- as opposed to primary antibody deficiency,
tation, although controversy remains as to makes the diagnosis even more difficult. As
which patients with CGD should receive a the levels of maternal antibodies decline,
transplant.119 humoral deficiency in the neonate becomes
apparent and can be diagnosed as early
LEUKOCYTE ADHESION DEFICIENCY as 6 months of age (earlier in the preterm
Leukocyte adhesion deficiency (LAD) exists infant).
in two forms. LAD-1 (Mac-1 deficiency)
is due to deficiency or dysfunction of leu- X-Linked Agammaglobulinemia
kocyte integrins, and LAD-2 is due to con- X-linked agammaglobulinemia is a defect
genital deficiency of selectin function. It is in B-cell development caused by mutations
a rare disorder that can present in the neo- in a cytoplasmic tyrosine kinase called Btk
natal period with severe infections, delayed that plays a pivotal role in B-cell develop-
separation of the umbilical stump, and leu- ment. Patients have a profound hypogam-
kocytosis. Diagnosis is made by flow cytom- maglobulinemia and markedly reduced
etry (absence of CD11b/CD18 on blood numbers or absence of B cells (no CD19- or
Table 17-1. Most Common Immune Deficiencies Encountered in Neonates
Type Disorder Clinical Features

Humoral immune deficiencies X-linked agammaglobulinemia Upper respiratory infections
Hyperimmunoglobulin M syndrome
Transient hypogammaglobulinemia
of infancy
Predominantly cellular immune Neonatal human immunodeficiency
deficiencies virus infection
Combined immune deficiencies Severe combined immunodeficiency
Omenn syndrome
Combined immune deficiency Wiskott-Aldrich syndrome Eczema, thrombocytopenia, recurrent
associated with other syndromes infections
DiGeorge syndrome Characteristic facial features, hypocal-
cemia, microdeletion of chromosome 22
Ataxia-telangiectasia Recurrent infections
CD20-bearing cells).121 Onset of recurrent maturation of immunoglobulin produc-

bacterial infections is seen in the first 24 tion in an infant as maternal antibodies
months of life. Overwhelming enteroviral disappear. This diagnosis encompasses cas-
sepsis and paralytic ileus following admin- es in which serum concentrations of one
istration of live polio vaccine have been or more of the three major immunoglobu-
observed in neonates with X-linked agam- lin classes is more than 2 standard devia-
maglobulinemia. Treatment is with immu- tions below normal for age in at least two
noglobulin replacement.121 specimens obtained during infancy and
the disorder lacks features consistent with
Hyperimmunoglobulin M Syndromes other forms of primary immunodeficiency.
Hyperimmunoglobulin M syndromes are a In transient hypogammaglobulinemia of
heterogeneous group of genetic disorders infancy, there is an extended period of hy-
causing primary immunodeficiency in which pogammaglobulinemia, which usually re-
defective immunoglobulin class switch solves by 30 to 40 months of life. Infants
recombination leads to deficiency of IgG, usually remain asymptomatic or develop
IgA, and IgE with preserved or elevated levels recurrent sinopulmonary infections, but
of IgM. The most common form of hyperim- severe or life-threatening infections are
munoglobulin M syndrome, accounting for rare.123
at least 70% of cases of class switch recombi-
nation defects, is caused by mutations in the PREDOMINANTLY CELLULAR
gene encoding the CD40 ligand (CD40LG). IMMUNE DEFICIENCIES
Clinical problems occur early in life with a Neonatal HIV infection is discussed in
median age at diagnosis of younger than Chapter 14.
12 months. Two thirds of infants have neu-
tropenia with associated perirectal abscesses COMBINED IMMUNE DEFICIENCIES
and oral ulcers. Patients have increased T-cell and combined immune deficiencies
susceptibility to Pneumocystis and other commonly manifest initially during the neo-
opportunistic organisms (e.g., chronic cryp- natal period (secondary to a lack of mater-
tosporidial infection leading to persistent nally acquired immunity and a vital T-cell
diarrhea and failure to thrive). The mainstay role in immune response). Patients expe-
of treatment for these forms of hyperimmu- rience severe infections including oppor-
noglobulin M syndrome is immunoglobulin tunistic infections (Pneumocystis jiroveci
replacement therapy.122 [Pneumocystis carinii] pneumonia, infection
with Mycobacterium species, fungal infec-
Transient Hypogammaglobulinemia tions), viral infections, and graft-versus-host
of Infancy disease (caused by either maternally derived
Transient hypogammaglobulinemia of in- T cells or transfusions with nonirradiated
fancy is a common and heterogeneous blood products). Some combined immuno-
immune deficiency with indistinct patho- deficiencies present as a part of a syndrome
physiology presenting with a delay in that also includes altered function of other
organ systems (Wiskott-Aldrich syndrome, goal. As a potential screening tool, a test of

DiGeorge syndrome, etc.). T-cell receptor gene excision circles (TRECs)
was chosen by some researchers. This test
Severe Combined Immunodeficiency is performed on DNA from the dried blood
Severe combined immunodeficiency (SCID) spots collected for screening newborns.
designates a genetically heterogeneous It can identify any infant with profound
group of syndromes that have in common T-cell lymphopenia and not just infants
a profound disturbance of both T and B with SCID. In a study by Routes et al,126
cells. At least 15 different molecular defects TREC assay by real-time quantitative PCR
have now been identified, all of which was performed on newborn screening cards
lead to early death in the absence of ther- for newborn infants. Seventeen of 64,397
apy.124,125 The affected genes encode cell infants older than 37 weeks’ gestation
surface receptors and other activation sig- screened using the TREC assay (approxi-
naling molecules (IL2RG, JAK3, IL7R, CD45, mately 0.026%) had TREC values below the
CD3 components, FOXN1), T-cell and cutoff limit (<25 TRECs/µL blood). Eleven
B-cell antigen receptor gene recombinases infants subsequently underwent a confirma-
(RAG1, RAG2, Artemis, DNA ligase 4), and tory flow cytometry screening test, which
purine pathway enzymes (adenosine deami- confirmed the presence of T-cell lymphope-
nase, purine nucleoside phosphorylase).125 nia in 8 infants. The ongoing trials of SCID
Typical symptoms of SCID are noted from screening will need to answer questions on
birth and include recurrent severe infec- optimal screening protocols and the costs of
tions, chronic diarrhea, and failure to treatment and screening that would provide
thrive. However, infants may appear nor- appropriate information for policy makers
mal at birth and have no family history of deciding among competing health care pri-
immunodeficiency. Therefore, infants with orities.127
severe T-cell deficiencies may not be identi-
fied until life-threatening infections occur. Omenn Syndrome
Physical examination may reveal thrush Omenn syndrome is an autosomal recessive
and absence of lymphoid tissue. Hypogam- combined immunodeficiency characterized
maglobulinemia is often present, and T cells by infiltration of the skin and gastrointesti-
are often absent. B-cell and NK cell pattern nal tract by activated oligoclonal T lympho-
varies, which results in various SCID pheno- cytes. In contrast with other forms of SCID,
types.120 the total number of circulating T lympho-
Hematopoietic stem cell transplanta- cytes in Omenn syndrome is normal and
tion and enzyme replacement (in the case they show activated phenotype. However,
of adenosine deaminase deficiency) have their proliferative response to in vitro stimu-
made this previously fatal set of diseases lation by mitogens and antigens is markedly
treatable.125 decreased. In contrast, B cells are usually
If the diagnosis is made early in the first undetectable both in peripheral blood and
months of life before the onset of seri- in lymphoid tissues, and hypogamma-
ous infections, the long-term prognosis globulinemia results. A remarkable hypere-
for infants with SCID may be markedly osinophilia and increased IgE serum levels
improved (better survival, less morbidity, are observed. T-cell repertoire in Omenn
and lower treatment costs than when SCID syndrome is highly restricted as well.128
is recognized only after the onset of serious The most common causes of Omenn syn-
infections). Administration of attenuated drome are hypomorphic mutations of the
vaccines that are recommended in early recombination-activating genes. Mutations
infancy and that can cause serious infection of the Artemis (DCLRE1), IL7RA, RMRP,
in infants with T-cell lymphopenia should IL2RG, and CHD7 genes may also result
be avoided. in the Omenn syndrome phenotype.129
Molecular identification of SCID gene Patients with Omenn syndrome develop
mutations now enables early diagnosis in early-onset, generalized, exudative erythro-
affected families. Infants with SCID identi- dermia associated with lymphadenopathy,
fied because of a family history can undergo and hepatosplenomegaly. The loss of pro-
prenatal mutation diagnosis and be treated tein through the skin (and often also due
early in life.125 to chronic diarrhea) results in hypoprotein-
Universal newborn screening for SCID emia and generalized edema. In addition,
has become an important public health alopecia is a frequent finding. Many of the
clinical features of Omenn syndrome are insulin-resistant diabetes, and clinical and
reminiscent of acute graft-versus-host dis- cellular radiosensitivity (higher incidence of
ease. Because of their unique susceptibility malignancies). The gene that is mutated in
to severe infections, patients with Omenn ataxia-telangiectasia (ATM) has been local-
syndrome inevitably die early in life unless ized to chromosome band 11q22-23.131
treated with hematopoietic stem cell trans- Immunodeficiency is seen in approxi-
plantation.128 mately 70% of patients with ataxia-telangi-
ectasia. T- and B-cell numbers are normal.
COMBINED IMMUNE DEFICIENCIES T cells bearing the γ-δ form of the T-cell
ASSOCIATED WITH OTHER SYNDROMES receptor constitute up to 50% of T cells
(normal: 1% to 5%), and T-cell function is
Wiskott-Aldrich Syndrome impaired. A varying degree of humoral defi-
Wiskott-Aldrich syndrome is discussed later ciency (IgA, IgG) is common. Patients usu-
in the section on thrombocytopenia caused ally have bronchopulmonary infections at
by reduced platelet production. presentation.131
DiGeorge Syndrome NEONATAL THROMBOCYTOPENIA

DiGeorge syndrome is caused by a hemizy- Neonatal thrombocytopenia is the most
gous deletion of chromosome band 22q11.2. common hematologic problem in the neo-
It is extremely common, with nearly 1 in nate. A normal platelet count in healthy
3000 children affected.130 Patients display newborn infants irrespective of gestational
characteristic facies (hypertelorism, short age is considered to be 150 × 109/L and
philtrum, low-set ears), cardiac defects, para- above.132-136 Some 1% to 5% of newborns
thyroid hormone deficiency, and immune show thrombocytopenia at birth, and 0.1%
deficiency. Approximately 20% of patients to 0.5% have severe thrombocytopenia
have no evidence of diminished T-cell num- (<50 × 109 platelets/L). In contrast, 22% to
bers, and fewer than 1% have true thymic 35% of all infants admitted to the NICU
aplasia requiring transplantation.130 Based develop thrombocytopenia, the rate of which
on clinical and immunologic profiles, par- increases as gestation age decreases.134 Chris-
tial and complete DiGeorge syndrome have tensen et al observed that 73% of extremely
been distinguished. In the complete form of low-birth-weight neonates had one or more
DiGeorge syndrome, the thymus is absent. platelet counts below 150 × 109/L, and 38%
Therefore, T cells are absent or markedly of them had a severely low count.137
decreased in number, and B cells (although Causes of thrombocytopenia can be clas-
present) make little antibody. Complete sified into those leading to increased platelet
DiGeorge syndrome is usually fatal unless destruction (including consumption), those
treated with thymus transplantation.130 In resulting in decreased platelet production,
partial DiGeorge syndrome, T-cell numbers and those involving both.138 Box 17-4 lists
correlate with the amount of thymus tissue the most common causes of thrombocyto-
present. T-cell proliferative responses, as penia in neonates.
well as immunoglobulin levels, are usually Classification can also be based on whether
normal. However, IgA deficiency, impaired the thrombocytopenia was caused by mater-
responses to vaccines, and frank hypogam- nal factors or not.138 Cause can be predicted
maglobulinemia have been described. Clini- by the timing of the onset of thrombocy-
cal studies show that most patients do not topenia and its natural history.132-134 For
demonstrate a susceptibility to opportunis- instance, thrombocytopenia presenting dur-
tic infections.130 ing fetal life is most commonly caused by an
alloimmune reaction, congenital infection,
Ataxia-Telangiectasia or aneuploidy, whereas thrombocytopenia
Ataxia-telangiectasia is an autosomal representing within 72 hours of birth (early-
cessive disorder that is characterized by onset neonatal thrombocytopenia) mostly
early-onset progressive cerebellar ataxia, affects preterm neonates born after preg-
oculocutaneous telangiectasia, immunode- nancies characterized by impaired placen-
ficiency, and lymphoid tumors.120,131 Vari- tal function and/or fetal hypoxia. Neonatal
ous other abnormalities are also associated alloimmune or autoimmune thrombocyto-
with this disorder, including the absence penia is common as well. Finally, thrombo-
or rudimentary appearance of a thymus, cytopenia presenting in infants in the NICU
progressive apraxia of eye movements, after the first 72 hours of life (late-onset
Causes of Thrombocytopenia HPAs have been identified, although feto-

Box 17-4. maternal incompatibility between only
in the Neonate
3 (HPA-1a, HPA-5b, and HPA-15b) cause
Increased platelet destruction or 95% of cases in white populations. Feto-
consumption maternal incompatibility for HPA-1a is the
Alloimmune neonatal thrombocytopenia most common and is responsible for 75%
Autoimmune neonatal thrombocytopenia of cases in whites.139 In NAIT the mother is
Sepsis HPA-1a negative and the father is HPA-1a
Birth trauma positive, as is the fetus. When the mother
Acidosis/hypoxia is exposed to fetal platelets, anti–HPA-1a
Disseminated intravascular coagulation antibodies are generated. These antibod-
Thrombosis ies traverse the placenta via the neonatal
Kasabach-Merritt syndrome Fc receptor, as does all maternal IgG, and
Malignancies (leukemia, etc.) cause fetal thrombocytopenia.140 Because of
Cyanotic heart disease its frequency and severity, NAIT is the most
Decreased platelet production important cause of severe fetal-neonatal
Thrombocytopenia–absent radius syndrome thrombocytopenia.
Congenital amegakaryocytic thrombocytopenia HPA-1a incompatibility occurs in 1 in
Amegakaryocytic thrombocytopenia and 350 pregnancies, although thrombocyto-
radioulnar synostosis penia develops in only 1 in 1000 to 1 in
X-linked macrothrombocytopenia due to 1500 pregnancies. The ability of an HPA-
GATA1 mutation 1a–negative woman to form anti–HPA-1a
Fanconi anemia is class II restricted and is controlled by
Wiskott-Aldrich syndrome the HLA-DRB3*0101 allele, so that HLA-
Bernard-Soulier syndrome DRB3*0101-positive women are 140 times
MYH9-related thrombocytopenias more likely to make anti–HPA-1a than HLA-
Chromosomal abnormalities DRB3*0101-negative women.141 NAIT is
Preeclampsia usually suspected in neonates with bleed-
Mixed causes ing or severe, unexplained, and/or isolated
Maternal medications postnatal thrombocytopenia. Three criteria
Intrauterine growth restriction distinguish cases of NAIT from other causes
TORCH infections (toxoplasmosis, rubella, of unexplained thrombocytopenia142:
cytomegalovirus, herpes simplex) 1. Severe thrombocytopenia (platelet count
Rh disease of <50 × 109/L)
2. Intracranial hemorrhage (ICH) associ-
ated with one or more of the following:
neonatal thrombocytopenia) almost always • Apgar score at 1 min of more than 5
results from late-onset sepsis or NEC.132-134 • Birth weight of more than 2200 g
When the cause is being sought, the gesta- • Documented antenatal or postnatal
tional age of the infant is important as well. bleeding
In one study of extremely low-birth-weight 3. No additional nonhemorrhagic neonatal
infants, more than 60% of cases of throm- medical problems
bocytopenia were due to infection, dissemi- Thrombocytopenia is often extremely
nated intravascular coagulation, or NEC, severe (platelet count of <20 × 109/L) and
and 10% were not explained.137 begins early in gestation. It may result in
Despite our growing knowledge of neona- major bleeding, particularly ICH. Although
tal thrombocytopenia, the cause cannot be the incidence of ICH is difficult to ascer-
identified in a significant number of patients. tain precisely, large series report ICH in
10% to 20% of pregnancies in which NAIT
THROMBOCYTOPENIA DUE TO is present.134 It is reported that 80% of ICH
INCREASED PLATELET DESTRUCTION events associated with NAIT occur in utero,
with 14% occurring before 20 weeks and a
Neonatal Alloimmune Thrombocytopenia further 28% occurring before 30 weeks.143
Neonatal alloimmune thrombocytopenia Overall, two thirds of infants with NAIT-
(NAIT) is the platelet equivalent of Rh dis- associated ICH develop neurodevelop-
ease. Human platelet antigens (HPAs) are mental problems, approximately half of
uniquely expressed on platelets, and 16 which are severe (e.g., severe cerebral palsy
and/or sensory impairment).139 The course even asymptomatic ICH, the target platelet
of NAIT in otherwise well neonates is vari- count is higher—more than 100 × 109/L—
able, with thrombocytopenia resolving in and management of the next affected preg-
most cases within 1 week without long- nancy will be more intensive and start
term sequelae. earlier. NAIT often resolves within 2 to 4
Considerable advances have been made weeks.140,145
in the clinical and laboratory diagnosis of Another important aspect of NAIT care
NAIT, and its postnatal and antenatal man- is antenatal management of subsequent
agement. Detailed laboratory investigations pregnancies. If the previously affected sib-
are required to confirmation the diagnosis ling had an ICH, the next affected fetus will
and should be performed by an experienced have early, severe thrombocytopenia and
reference laboratory. in utero ICH unless effective treatment is
Current consensus is that screening provided.140 Radder et al performed a litera-
should be performed for HPA-1, HPA-3, and ture search for ICH cases in untreated NAIT
HPA-5 in all cases of potential NAIT and pregnancies.146 The recurrence rate of ICH
for HPA-4 as well if the patient is of Asian in the subsequent offspring of women with
descent. HPA-9 and HPA-15 are the next a history of NAIT with ICH was 72% (CI:
most commonly involved in antigen incom- 46% to 98%) when fetal deaths were not
patibilities. For testing to confirm NAIT, included and 79% (CI: 61% to 97%) when
analysis must reveal both a platelet antigen they were included. The risk of ICH after a
incompatibility between the parents and previous occurrence of NAIT without ICH
a maternal antibody directed against that was estimated to be 7% (CI: 0.5% to 13%).
antigen. The lack of laboratory parameters predic-
Because of the morbidity and mortality tive of severe disease remains one of the
associated with NAIT, this disorder requires major barriers to optimizing antenatal man-
expert management with close collabora- agement of NAIT and is an important area
tion between fetal medicine specialists, for future research.145 Antenatal treatment
hematologists, and neonatologists. intensity depends on the occurrence of ICH
The mainstay of postnatal management and severity of thrombocytopenia in the
of affected neonates is prompt random- previous sibling. Maternally administered
donor platelet transfusion.144 If promptly therapy (maternal IVIG, steroids) should
available, matched (antigen-negative) plate- be the first-line approach in all cases. This
lets are preferred. The latter are platelets recommendation is based on data describ-
from donors negative for HPA-1a or HPA- ing the effectiveness and safety of mater-
5b (which are compatible in >90% of NAIT nal treatment in contrast to the toxicity of
cases, can be given in larger increments, serial administration of fetal bovine serum
and have a longer half-life). Concentrated to deliver weekly fetal platelet transfusions.
maternal platelets can also be used; how- Different centers currently have different
ever, their processing takes at least 12 to 48 strategies based on their own experience
hours. and results of published studies.141,145
Platelet transfusion is recommended in
well term neonates if the count is less than Neonatal Autoimmune Thrombocytopenia
30 × 109/L unless an ICH is diagnosed, in Neonatal autoimmune thrombocytopenia
which case a threshold of 100 × 109/L is is mediated by the transplacental passage of
used. A higher count, for example 50 × maternal antiplatelet antibodies. Unlike in
109/L, may be selected in cases of prematu- NAIT, in this case the antibody responsible
rity, birth asphyxia, or another condition binds both maternal and fetal platelets and
predisposing to ICH.140 causes thrombocytopenia in the mother
IVIG can also be infused (effective in and the neonate.138 In most instances, the
at least 75% of cases).145 The IVIG dose is underlying maternal disease is idiopathic
1 g/kg/day for 1 to 3 days depending on thrombocytopenic purpura, but other dis-
response. Some centers administer steroids orders (e.g., systemic lupus erythematosus)
with IVIG.140 However, with these therapies, can also produce this syndrome. Mater-
platelet count increase is slow (requiring nal platelet autoantibodies occur in 1 to
about 48 to 72 hours), and therefore platelet 2 in 1000 pregnancies; however, they are
transfusion may still be needed. Head ultra- much less likely to cause a clinical prob-
sonography is mandatory for a thrombocy- lem than NAIT. Thrombocytopenia occurs
topenic neonate. If NAIT is complicated by in only 10% of neonates whose mothers
have autoantibodies, and the incidence of Usually it is severe, but it is exacerbated

ICH is 1% or less. Maternal disease sever- in some cases by the development of DIC.
ity and/or platelet count during pregnancy Review of the blood film often, although not
and the occurrence of severe thrombocyto- always, reveals red blood cell fragmentation,
penia in a previous neonate are the most which can help in the diagnosis of difficult
useful indicators of the likelihood that cases. When treatment is required, admin-
significant fetal and neonatal thrombocy- istration of steroids followed by interferon
topenia will complicate the current preg- and/or vincristine is effective in over 50%
nancy.135,147,148 The platelet count should of cases, although the mortality is 20% to
be determined at birth for all neonates of 30%.149
mothers with autoimmune disease. In neo-
nates with normal platelet counts (>150 Necrotizing Enterocolitis
× 109/L), no further action is necessary. NEC frequently causes thrombocytopenia
In those with thrombocytopenia, a plate- in neonates. In fact, probably 80% to 90%
let count should be repeated after 2 to 3 of patients with NEC develop thrombocy-
days, because platelet counts are often at topenia (platelet count of <150 × 109/L) as
a nadir at this time before rising sponta- part of the presentation, and many have
neously by day 7 in most cases.134 In a platelets counts in the range of 30 to 60 ×
small number of cases thrombocytope- 109/L. Platelet destruction seems to be the
nia may persist for several weeks. In this primary mechanism.135
situation, when the thrombocytopenia
is severe (platelet count of <30 × 109/L), Thrombosis
treatment with IVIG (2 g/kg over 2 to Thrombosis can cause thrombocytopenia
5 days) may be useful. in a neonate when platelet uptake in the
thrombus is more rapid than platelet pro-
Disseminated Intravascular Coagulation duction. If thrombocytopenia is severe it
Disseminated intravascular coagulation can be treated by platelet transfusions until
(DIC) complicates several disease pro- the underlying cause of the platelet destruc-
cesses (bacterial or viral sepsis, respiratory tion is removed.132,135
distress syndrome, meconium aspiration,
asphyxia). Thrombocytopenia is a consis- THROMBOCYTOPENIA DUE TO
tent and very early finding in neonates with DECREASED PLATELET PRODUCTION
DIC.135 Prolonged prothrombin times and
partial thromboplastin times, increased lev- Bernard-Soulier Syndrome
els of fibrin degradation products, increased Bernard-Soulier syndrome is an autosomal
d-dimer levels, and depletion of fibrinogen recessive disorder caused by qualitative
are other abnormal laboratory findings usu- or quantitative defects in the glycopro-
ally seen in neonates with DIC. Successful tein Ib-IX-V complex. Bernard-Soulier syn-
treatment of neonatal DIC depends on the drome may present in the neonatal period,
diagnosis and treatment of the underly- although bleeding is not usually severe in
ing disorder. Treatment of the hemostatic neonates. A diagnosis of Bernard-Soulier
abnormalities in neonates with DIC is not syndrome is suggested when there is mild to
clearly established and depends on the clini- moderate thrombocytopenia together with
cal manifestations.135 Exchange transfusions giant platelets. Treatment by platelet trans-
complement administration of platelets and fusion is effective but should be reserved for
fresh frozen plasma. cases of life-threatening hemorrhage.150
Kasabach-Merritt Syndrome Wiskott-Aldrich Syndrome

Kasabach-Merritt syndrome typically pre Wiskott-Aldrich syndrome, caused by muta-
sents in the neonatal period with profound tions in the Wiskott-Aldrich syndrome
thrombocytopenia together with micro- gene, is a complex and diverse disorder
angiopathic anemia, DIC, and an enlarg- with X-linked inheritance.115 Affected boys
ing vascular lesion. Hemangiomas are exhibit microthrombocytopenia with hem-
usually cutaneous, but in 20% there is vis- orrhagic diathesis in early childhood and
ceral involvement (e.g., in the liver). Throm- variable degrees of eczema, combined immu-
bocytopenia in Kasabach-Merritt syndrome nodeficiency, and increased risk of autoim-
is mainly due to the trapping of platelets munity and lymphoid malignancies. The
on the endothelium of the hemangioma. numbers of T and B lymphocytes decline
over the years, and in vitro proliferation of T cerebellar vermis and corpus callosum, may
lymphocytes to specific antigens is reduced. be present. Symptomatic allergy to cow’s
IgA and IgE serum levels are often increased, milk is present in 47% of individuals with
which reflects immune dysregulation. Unless TAR syndrome. Treatment is based on provi-
hematologic and immune reconstitution sion of platelet support when needed.152,153
by hematopoietic stem cell transplantation
or gene therapy is achieved, patients with Congenital Amegakaryocytic
classic Wiskott-Aldrich syndrome tend to Thrombocytopenia
develop autoimmune disorders and lym- Congenital amegakaryocytic thrombocy-
phoma or other malignancies that lead to topenia (CAMT) is an autosomal recessive
an early death.115 disorder caused by mutations in the throm-
bopoietin receptor c-Mpl. It presents at birth
Fanconi Anemia with severe thrombocytopenia (platelet
Fanconi anemia is an autosomal recessive count of <50 × 109/L) with platelets that are
disease characterized by aplastic anemia of normal size and granularity. Importantly,
and congenital abnormalities (absent radii, phenotypic findings in CAMT are usually
absent or malformed thumbs, microcephaly, limited to those related to thrombocytope-
hypogonadism, hypertelorism, gastrointesti- nia, including cutaneous and intracranial
nal malformations, renal-ureteral malforma- hemorrhages before or after birth. Several
tions, café au lait spots). Hypersensitivity to patients have been described with clinical
DNA cross-linking agents like diepoxybutane features of CAMT who also exhibited growth
is often used as a diagnostic test. At birth, the or developmental delay, strabismus, or cen-
blood count is usually normal, and macrocyto- tral nervous system abnormalities, includ-
sis is often the first detected abnormality. This ing cerebellar malformations and cortical
is typically followed by thrombocytopenia dysplasia.153-155 Reduction or absence of
and anemia that progresses to pancytopenia. megakaryocytes is seen in the bone marrow
The majority of patients develop progres- with evolution of hypocellular or aplastic
sive bone marrow failure or acute myelog- bone marrows later in the course. Measure-
enous leukemia, of which are diagnosed with ment of plasma thrombopoietin levels is
peak frequencies at the age of 7 and 10 to a useful diagnostic assay in the evaluation
15 years, respectively.151 Of subjects regis- of congenital thrombocytopenia; however,
tered between 1982 and 1992 in the Inter- this assay is not widely available.154 In chil-
national Fanconi Anemia Registry, several dren in whom the diagnosis is suspected
showed hematologic abnormalities during based on clinical findings, CAMT can be
the neonatal period. confirmed by identification of homozygous
or compound heterozygous mutations in
Thrombocytopenia–Absent Radius the thrombopoietin receptor c-Mpl. Sup-
Syndrome portive care for patients with CAMT consists
Thrombocytopenia–absent radius (TAR) syn- primarily of platelet transfusions. Currently,
drome is characterized by bilateral absence of the only definitive treatment available for
the radii with the presence of both thumbs the long-term management of patients with
and thrombocytopenia. Thrombocytopenia CAMT is hematopoietic stem cell transplan-
may be congenital or may develop within tation.153-155
the first few weeks to months of life. Patients
usually show severe symptomatic throm- Amegakaryocytic Thrombocytopenia
bocytopenia in the first week of life with and Radioulnar Synostosis
increased mortality due to ICH when the Amegakaryocytic thrombocytopenia and
platelet count is less than 20 × 109/L. With radioulnar synostosis is an autosomal domi-
increasing age, the recurrence of thrombo- nant disorder associated with HOXA11
cytopenic episodes decreases, and platelet mutation with features that include con-
count can improve to near-normal levels. genital amegakaryocytic thrombocytope-
Leukocytosis and eosinophilia may precede nia, aplastic anemia, proximal radioulnar
thrombocytopenia. Typically, patients have synostosis, clinodactyly, syndactyly, hip
bilateral aplasia of the radii, but abnormali- dysplasia, and sensorineural hearing loss.156
ties involving the lower extremities have also Symptomatic thrombocytopenia with bruis-
been described. Unlike in Fanconi anemia, ing and bleeding is present from birth,
thumbs are present bilaterally. Cardiac and necessitating ultimate correction by stem
facial anomalies, as well as hypoplasia of the cell transplantation.157
MYH9-Related Inherited Therefore, an extensive evaluation of mild

Thrombocytopenia to moderate thrombocytopenia in neonates
MYH9-related inherited thrombocytopenia with Down syndrome is not suggested.
(MYH9-related disease) is one of the most
frequent forms of inherited thrombocytope- Pregnancy-Induced Hypertension
nia. It is transmitted in an autosomal domi- PIH is a common cause of thrombocyto-
nant fashion and derives from mutations penia in neonates, but the pathogenesis of
of MYH9, the gene for the heavy chain of the condition is unclear. Possibly, it is the
nonmuscle myosin IIA. Patients have con- kinetic result of decreased platelet produc-
genital macrothrombocytopenia with mild tion. Of all infants born to women with
bleeding tendency and may develop kidney PIH, preterm babies are at highest risk of
dysfunction, deafness, and cataracts later in developing thrombocytopenia. The throm-
life. The term MYH9-related disease encom- bocytopenia presents at birth or in the first
passes four autosomal dominant thrombo- few days of life, reaches a nadir on days 2 to
cytopenias that were previously described 4, and resolves by day 7 to 10.135
as distinct disorders: namely, May-Hegglin
anomaly, Sebastian syndrome, Fechtner THROMBOCYTOPENIA DUE TO MIXED
syndrome, and Epstein syndrome. Throm- CAUSES
bocytopenia is usually mild and derives
from complex defects of megakaryocyte Infection
maturation and platelet formation. Usually Intrauterine cytomegalovirus infection and
the presence of giant platelets in peripheral rubella can be associated with neutrope-
blood raises the suspicion of MYH9-related nia or pancytopenia. Thrombocytopenia
disease, and a simple immunofluorescence is most likely secondary to splenomegaly;
test showing the distribution of nonmuscle however, an element of decreased produc-
myosin heavy chain IIA within neutrophils tion might be associated as well.99
on blood films confirms the diagnosis. Char-
acteristic Döhle-like bodies are identified in Intrauterine Growth Restriction
the cytoplasm of neutrophil granulocytes in Thrombocytopenia is particularly common
42% to 84% of patients.158 in preterm infants who are small for gesta-
tional age, but it is relatively uncommon in
X-Linked Macrothrombocytopenia term infants who are small for gestational
X-linked macrothrombocytopenia caused age. The cause of the thrombocytopenia is
by mutation in GATA1 is a recently described not known. The pathogenesis may involve
isolated X-linked macrothrombocytopenia accelerated platelet removal from the blood
without anemia (but with some dyserythro- or decreased platelet production related to a
poietic features). In this disorder, immature failure to compensate by increasing produc-
platelets are released into the circulation tion of thrombopoietin.135
that have hyperplastic endoplasmic reticu-
lum and a disturbed glycoprotein Ib-V-IX EVALUATION OF THE NEONATE
complex with weakened function. The dis- WITH THROMBOCYTOPENIA
order may present with severe thrombocyto- The first step in evaluating a neonate with
penia and profound bleeding at birth.159,160 thrombocytopenia is to classify the throm-
bocytopenia into one of the categories
Chromosomal Abnormalities discussed previously. This involves con-
Infants with chromosomal abnormali- sideration of the infant’s age (early versus
ties (trisomies of chromosomes 13, 18, or late thrombocytopenia), the severity of the
21; Turner syndrome) can have neonatal thrombocytopenia, the presence of dysmor-
thrombocytopenia in addition to the char- phic features, the clinical condition (sick
acteristic physical features of these disorders. versus not sick), and the medications used.
Although historically trisomy 21 has been In determining the cause of thrombocyto-
associated mostly with other hematologic penia in an affected neonate, it is important
disorders, such as polycythemia, transient first to consider conditions that could be
myeloproliferative disorder, and acute leu- life threatening (e.g., infections, DIC, NEC,
kemia, isolated neonatal thrombocytopenia thrombosis) or that have significant impli-
is a frequent finding. The thrombocytope- cations for further pregnancies (e.g., alloim-
nia is usually mild to moderate and tran- mune or autoimmune thrombocytopenia,
sient, with resolution at 2 to 3 weeks of life. genetic disorders). If any of these entities
is suspected, appropriate diagnostic testing 50 × 109/L should be reserved for patients

should be conducted promptly (e.g., bacte- with active major bleeding, such as new or
rial or viral cultures, assays for antiplatelet extending intraventricular hemorrhage or
antibodies, chromosome analysis). Once pulmonary, gastrointestinal, or renal hem-
these conditions have been ruled out, other orrhage.134,161
causes of thrombocytopenia (generally Infants who are being treated with medi-
more benign) should be considered. Several cations known to induce platelet dysfunc-
tests have been used for indirect evaluation tion (e.g., indomethacin, aspirin, or nitric
of the mechanisms causing thrombocy- oxide) should probably be maintained at
topenia. Two of them (mean platelet vol- higher platelet counts than neonates who
ume and time between transfusions) are are not receiving such medications. The
easily available to the clinician caring for a same applies to neonates receiving antico-
thrombocytopenic neonate. A high mean agulants (heparin or low-molecular-weight
platelet volume usually suggests increased heparin) or thrombolytic agents (e.g., tissue
platelet production, presumably as a com- plasminogen activator), whose risk of bleed-
pensation for accelerated platelet destruc- ing is significantly higher in the presence of
tion. In cases in which the cause is clearly thrombocytopenia.100 As discussed earlier,
defined, no further evaluation is necessary special consideration should be given to the
unless the thrombocytopenia is especially transfusion of HPA-1b–negative platelets, or
severe or more prolonged than is expected platelets obtained from the mother, to neo-
given the cause identified. A bone marrow nates with alloimmune thrombocytopenia.
evaluation may be warranted in a patient
with prolonged and severe thrombocyto- COAGULATION SYSTEM IN THE
penia of unclear cause despite extensive NEONATE
evaluation.135 The human hemostatic system starts devel-
oping in utero and continues to develop well
PLATELET TRANSFUSION GUIDELINES into childhood. This system can be thought
Until data from controlled trials become of as having discrete fluid phase (circulat-
available, decisions about platelet transfu- ing proteins), cellular (platelets), and vas-
sion in neonates will be based on consen- cular (vessel wall) compartments. Although
sus guidelines.100 Patients qualifying for a this approach is useful in classifying spe-
platelet transfusion should receive 10 to 15 cific disorders, the component parts of the
mL/kg of cytomegalovirus-negative standard hemostatic system are functionally and
platelet suspension, prepared from a fresh biochemically interrelated. The functional
unit of whole blood or by platelet pheresis. levels of many of the procoagulants, coagu-
This amount should be sufficient to increase lation inhibitors, and fibrinolytic compo-
the platelet count of a thrombocytopenic nents in the neonate differ from the those
infant by approximately 100 × 109/L. No in the adult. The component functions
volume-reducing processing is routinely rec- reach adult levels by 6 months of age. The
ommended because of the risk of platelet pioneering work of Dr. Maureen Andrew in
loss, clumping, and dysfunction due to the the 1980s elucidated the unique aspects of
additional handling.100 the neonatal and fetal coagulation system
The decision to administer a prophylactic (Fig. 17-2). The term developmental hemosta-
platelet transfusion should be made on the sis was used for the first time to describe her
basis of many factors, including the platelet work. Even though neonates have different
count, the mechanism responsible for the functional levels of all the coagulation com-
thrombocytopenia, the medications admin- ponents compared with adults, they rarely
istered, and the condition of the patient. have problems with bleeding or thrombo-
Usually such decisions are institution- sis. The differences in prothrombotic and
driven, “best-guess” estimates. For patients antithrombotic components are uniquely
in the first week of life at greatest risk of balanced in the neonate, which creates a
hemorrhage (e.g., extremely preterm neo- normal physiologic state. Table 17-2 pre
nates in unstable condition), administration sents the reference ranges for coagulation
of prophylactic platelet transfusions at trig- test values for healthy full-term neonates
ger thresholds of up to 50 × 109/L is gener- and healthy preterm babies.
ally considered to represent acceptable and A number of bleeding and clotting dis-
safe clinical practice. Platelet transfusions in orders can present in the neonatal period.
neonates with platelet counts of more than The following sections briefly review the
INTRINSIC SYSTEM
Contact Factors
XII XIIa
EXTRINSIC SYSTEM
XI XIa
IX IXa Tissue Thromboplastin
VIII VIIIa VIIa VII

X Xa X
V Va + Xa + Platelet phospholipid
Prothrombin (II) Thrombin (IIa)
Fibrin
Fibrinogen (I)
monomer
Figure 17-2. Overview of the coagulant proteins of the intrinsic system (upper left) and extrinsic system (upper right),
which both feed into the common pathway (bottom).
Table 17-2. Normal Values for Coagulation Tests in Healthy Full-Term and Premature Infants
Coagulation Test Full-Term Infant Premature Infant Older Child

Platelets (per µL) 150,000-400,000 150,000-400,000 150,000-400,000
Prothrombin time (sec) 10.1-15.9 10.6-16.2 10.6-11.4
Partial thromboplastin time (sec) 31.3-54.5 27.5-79.4 24-36
Thrombin clotting time (sec) 19-28.3 19.2-30.4 19.8-31.2
Fibrinogen (mg/dL) 167-399 150-373 170-405
Fibrin degradation products (µg/mL) <10 <10 <10
Factor VIII (U/mL) 0.50-1.78 0.50-2.13 0.59-1.42
Factor IX (U/mL) 0.15-0.91 0.19-0.65 0.47-1.04
von Willebrand factor (U/ml) 0.50-2.87 0.78-2.10 0.60-1.20
Adapted from Cantor AB: Developmental hemostasis: relevance to newborns and infants. In Orkin
SH, Fisher D, Look AT, et al, editors: Nathan and Oski’s hematology of infancy and childhood, ed 7,
Philadelphia, 2009, Saunders.
presentation, work-up, and initial manage- Next, history taking for the infant should
ment of common inherited bleeding and focus on confirming administration of vita-
clotting disorders. min K. A detailed family history focusing
on the types and severity of any bleeding
INITIAL LABORATORY EVALUATION OF symptoms, as well as the sex of the affected
THE NEONATE WITH BLEEDING members, gives valuable information on the
About 15% to 30% of patients with inherited type and inheritance pattern of a possible
bleeding disorders have bleeding symptoms bleeding disorder. However, a third of new
in the neonatal period.162 Evaluation of a cases of severe hemophilia represent new
bleeding neonate always begins with taking mutations, and therefore no family history
a detailed maternal and family history. It is of such disorders is present.
important to obtain details about the moth- Examination of the neonate should
er’s state of health during pregnancy and quickly differentiate between a well-
labor, including infections, maternal auto- appearing baby and a sick one. A sick
immune disease, and platelet count. Other infant may have medical conditions con-
details about the labor and delivery itself, tributing to hemorrhage. Findings of birth
such as prolonged time between rupture trauma, evidence of bruises and petechiae,
of membranes and delivery, fetal distress, and presence of flank masses suggestive of
and chorioamnionitis are also important. renal vein thrombosis should be sought.
Hepatosplenomegaly in a sick neonate may of the APTT. The sensitivity and reproduc-
suggest disseminated intrauterine infec- ibility of the APTT, unlike those of the PT,
tion. The most common cause of bleeding depend strongly on the specific reagents
in healthy infants is thrombocytopenia sec- used. With most reagents, the APTT is not
ondary to transplacental passage of a mater- prolonged unless the factor VIII level is less
nal antiplatelet antibody, sepsis, vitamin K than 35% (0.35 U/mL). Deficiencies of fac-
deficiency, or congenital coagulation factor tor XII, prekallikrein, and high-molecular-
deficiencies. In an otherwise well infant, weight kininogen result in prolongation of
bleeding from a circumcision site, oozing APTT but no clinical bleeding symptoms.
from the umbilicus, bleeding into the scalp, Isolated prolongation of the APTT in the
large cephalhematomas, or ICH may point neonate is likely due to deficiency of factor
to coagulation factor deficiencies such as VIII, IX, or XI, if contamination with hepa-
hemophilia or von Willebrand disease, or rin is ruled out. For a child with mild bleed-
disorders of platelet numbers such as NAIT. ing, if hemophilia is suspected, factor VIII
NAIT is the most common cause of severe and IX assays must be performed regardless
thrombocytopenia in a well infant, occur- of the APTT value. The APTT is somewhat
ring in approximately 1 in 1000 to 2000 less sensitive to vitamin K deficiency than
births. A detailed description of the causes the PT. The TT measures the thrombin-
and investigation of thrombocytopenic induced conversion of fibrinogen to fibrin
bleeding can be found elsewhere in this and hence is useful for investigating the
chapter. clotting function of fibrinogen in a variety
Blood volume in a neonate is low, and of fibrinogen disorders.
hence a small blood loss, even for investi- A number of pitfalls exist in performing
gative blood draws, can have major conse- and interpreting tests such as the PT and
quences. Judicious use of laboratory tests for APTT. Extreme caution must be taken when
screening for underlying bleeding disorders sending blood for coagulation testing. The
requires partnership with an experienced blood sample must be from free-flowing
hematologist specializing in coagulation blood without any air bubbles present. Par-
disorders. If the history and physical exami- ticular attention should be paid to ensuring
nation are not suggestive of a specific dis- the 1:10 ratio of the anticoagulant sodium
order, a panel of screening tests should be citrate to plasma by filling the tube up to
ordered. These include a complete blood the appropriate mark. Specialized microcol-
count with review of the peripheral smear, lection tubes (1 mL) must be available in
including platelet number and morphol- the neonatal unit to avoid wastage. Draw-
ogy; prothrombin time (PT); activated ing blood from an indwelling catheter is
partial thromboplastin time (APTT); and strongly discouraged because it often results
thrombin time (TT). The results must be in contamination of the sample with hepa-
compared with the expected normal ranges rin and other fluids, which leads to spurious
based on the gestational age of the infant prolongation of clotting times. In neonates
as mentioned previously. References ranges with polycythemia (hematocrit of >55%),
for PT and APTT in healthy term newborns the amount of citrate should be reduced to
and preterm infants are given in Table 17-2. maintain the 1:10 ratio of citrate to plasma.
The PT and APTT measure the overall func- This is particularly important in neonates
tion of proteins in the coagulation cascade. with cyanotic congenital heart disease, who
The PT measures the activities of factors I have very high hematocrit values. If the sam-
(fibrinogen), II (prothrombin), V, VII, and ple is suspected of being contaminated with
X. PT is generally prolonged when the func- heparin, measuring TT and reptilase time
tional activities of one of these factors goes helps to differentiate between prolongation
below 30%. The most common cause of iso- of APTT due to heparin and prolongation
lated prolongation of PT is factor VII defi- due to other causes. A 1:1 mixing study of
ciency. The APTT measures the functional the sample with prolonged APTT can also be
activities of the factors in the intrinsic arm performed by adding normal plasma to the
of the coagulation cascade: namely, VIII, IX, specimen. If the prolonged APTT corrects,
XI, XII, prekallikrein, and high-molecular- the cause is not heparin contamination.
weight kininogen. It also measures the func- Other coagulation tests include closure
tional activities of factors I (fibrinogen), II time measured by platelet function ana-
(prothrombin), and V. Deficiency of any lyzer, platelet aggregation test, urea clot sol-
of these factors results in the prolongation ubility, and other coagulation factor assays.
These tests are not useful as screening tests The bleeding manifestation is usually in the
in the neonate and should not be performed form of oozing from the umbilicus, bleeding
unless there is a strong suspicion of a spe- from circumcision and puncture sites, ICH,
cific disorder. These tests are described in and gastrointestinal hemorrhage. Causes
the discussions of the individual bleeding include poor placental transfer of vitamin K,
disorders to which they are relevant. marginal vitamin K content in breast milk
Bleeding in a neonate with thrombocy- (<20 µg/L), inadequate milk intake, and a
topenia is discussed in a different section of sterile gut. Vitamin K deficiency bleeding
this chapter. (VKDB) rarely occurs in formula-fed infants
because commercially available formulas
BLEEDING IN NEONATES WITH are supplemented with vitamin K. In the
NORMAL PLATELET COUNTS absence of vitamin K prophylaxis, the inci-
The disorders considered in the differential dence of VKDB ranges from 0.25% to 1.7%.
diagnosis of bleeding in a neonate with a The incidence depends on the population
normal platelet count can be broadly clas- studied, the supplemental formula used,
sified based on whether the infant appears and the prevalence of breast feeding in the
well or sick. These various disorders are dis- community. Early HDN develops in the first
cussed in the following sections. The clini- 24 hours of life and is linked to maternal
cal and laboratory features of these disorders use of specific medications that interfere
are summarized in Table 17-3. with vitamin K stores or function, such as
some anticonvulsants. Bleeding can be in
HEMORRHAGIC DISEASE OF THE the form of ICH, gastrointestinal bleed-
NEWBORN (VITAMIN K DEFICIENCY) ing, or cephalhematomas. Late HDN occurs
Hemorrhagic disease of the newborn (HDN) between weeks 2 and 8 of life and is linked
is defined as hemorrhage from multiple sites to disorders that compromise ongoing vita-
on days 1 to 5 in an otherwise healthy infant. min K supply, such as cystic fibrosis, α1-
It was first described by Townsend163 in 1894. antitrypsin deficiency, biliary atresia, and
Vitamin K acts on the precursors of factors II, celiac disease. Infants with these disorders
VII, IX, and X (vitamin K–dependent factors) are at risk of development of late vitamin K
to generate active procoagulants. Its biochem- deficiency weeks to months after receiving
ical function involves creating calcium-bind- parenteral vitamin K at birth.
ing sites in these proteins by carboxylating Results of screening laboratory tests reveal
specific glutamic acid residues. Levels of the a normal platelet count and an abnormal
vitamin K–dependent factors are physiologi- PT and APTT. The PT is often markedly pro-
cally low in newborns.164 It is a common longed compared with the APTT. Levels of
practice to routinely administer parenteral fibrinogen and fibrin degradation products
vitamin K after birth. Therefore, HDN is a rare as well as TT are normal. Other tests that
condition. can aid in the diagnosis are specific factor
The clinical manifestations of HDN can be assays, measurement of the levels of decar-
of three different types based on the timing boxylated forms of vitamin K–dependent
and type of bleeding complications. Classic factors, assay of protein induced by vitamin
HDN is defined as bleeding on days 2 to 7 of K antagonists, and direct measurement of
life in breast-fed, healthy, full-term infants. vitamin K levels.
Table 17-3. Conditions Associated with Bleeding and Normal Platelet Count
Diagnosis Appearance PT APTT Other Useful Tests

Hemorrhagic disease Well ↑ ↑ Fibrinogen; fibrin degradation products
of the newborn
Hepatic disease Sick ↑ ↑ Albumin; fibrinogen; fibrin degradation
products; liver function tests
von Willebrand disease* Well Normal Normal or ↑ Bleeding time (see text)
Hemophilia Well Normal ↑ Mixing tests; factor VIII and IX assays
Factor XIII deficiency Well Normal Normal Urea clot solubility
Disorders of platelet function* Well Normal Normal Bleeding time, platelet aggregometry
*Some patients with these disorders show mild to moderate thrombocytopenia (see text for details).
APTT, Activated partial thromboplastin time; PT, prothrombin time.
All newborns suspected of having HDN levels in newborns and may be a useful
should be treated with vitamin K immedi- marker. The diagnosis is also supported by
ately pending the results of laboratory tests. a low serum albumin level and by abnormal
For hemorrhages that are not life threaten- results on liver function studies. Secondary
ing, parenteral vitamin K can be used to rap- effects of liver disease on platelet number
idly correct the bleeding diathesis. Vitamin and function also occur in newborns. Sec-
K works within a few hours because it gener- ondary vitamin K deficiency may occur as
ates active procoagulants from the precur- a result of impaired absorption from the
sors with no requirement for new protein small intestine, particularly in infants with
synthesis. Infants with VKDB should be intrahepatic and extrahepatic biliary atresia.
given vitamin K either subcutaneously or Supplemental vitamin K should be adminis-
intravenously, depending on the situation. tered to these infants. Severe bleeding is best
Vitamin K should not be given intramus- treated by infusion of fresh frozen plasma.
cularly to infants with VKDB because large Cryoprecipitate is indicated for patients
hematomas may form at the site of the with severely reduced fibrinogen levels.
injection. Intravenous vitamin K should be Patients with clinical bleeding may benefit
administered slowly and a test dose should temporarily from replacement of coagula-
be given, because it may induce an anaphy- tion proteins using fresh frozen plasma,
lactoid reaction. For infants with major or cryoprecipitate, or exchange transfusion.
life-threatening hemorrhage, fresh frozen Without recovery of hepatic function, how-
plasma should be administered to stop ever, replacement therapy is futile. Hence,
bleeding and increase levels of vitamin the overall goal should be to identify and
K–dependent proteins. Prothrombin com- reverse the underlying condition.
plex concentrates, if available, can also be
used to treat life-threatening hemorrhages. HEREDITARY COAGULATION
A number of special considerations apply FACTOR DEFICIENCIES
to the high-risk newborn. Vitamin K pro- A number of hereditary coagulation fac-
duction by bacteria in the gut is reduced by tor deficiencies can present in the neonatal
illnesses which require that enteral feedings period. Deficiencies of factors VIII and IX are
be delayed or interrupted. Treatment with common and have an X-linked inheritance
broad-spectrum antibiotics also decreases pattern, whereas deficiencies of factors II,
vitamin K synthesis. For these reasons, it V, VII, XI, and XII, prekallikrein, and high-
is highly recommended that vitamin K be molecular-weight kininogen are autoso-
administered weekly to infants who are mally inherited disorders and are rare, with
not breast fed and to those who are being consanguinity present in many affected
treated with parenteral antibiotics. families. Rarely, combined deficiencies of
factors II, VII, and IX and/or factors V and
LIVER DISEASE VIII present in the neonatal period.165 Only
Coagulopathy associated with liver disease the common inherited coagulation factor
in newborns is a result of failure of the deficiencies such as the hemophilias and
hepatic synthetic function. There is gener- von Willebrand disease are described here.
alized impairment of hepatic synthesis of A detailed discussion of the rarer forms of
proteins, including the coagulation pro- coagulation factor deficiencies can be found
teins. In a newborn, the problem may be elsewhere.120
exacerbated, because of the already existing
physiologic immaturity of the coagulation The Hemophilias
system. Common causes of liver dysfunc- Hemophilia A and hemophilia B are X-linked
tion in newborns are total parenteral nutri- bleeding disorders caused by congenital defi-
tion, hypoxia, shock, fetal hydrops, and ciencies of proteins in the intrinsic coagu-
viral hepatitis. Rarely, genetic diseases such lation cascade. Hemophilia A (or classic
as α1-antitrypsin deficiency, galactosemia, hemophilia) is due to a deficiency of factor
and tyrosinemia are responsible for the liver VIII and accounts for 85% of cases. Hemo-
impairment. philia B (Christmas disease) results from
Laboratory abnormalities induced by absent or decreased factor IX activity and is
acute liver disease include prolongation responsible for the remaining 15% of cases.
of the PT and low plasma concentrations Hemophilia A and hemophilia B are clini-
of several coagulation proteins, including cally indistinguishable. The percentage of
fibrinogen. Fibrinogen is present at adult factor VIII or IX coagulant activity is used
to classify the hemophilias as severe (<1%), either by a continuous infusion of 8 to 10

moderate (1% to 5%), or mild (5% to 15%). U/hr or by boluses of 50 U/kg every 8 hours.
Severe factor VIII deficiency is the most com- Infants with hemophilia B who have severe
mon inherited bleeding disorder manifesting bleeding are given a bolus of 100 to 120 U/kg
in the neonatal period. Although a positive of factor IX concentrate followed either by a
family history is helpful in making the diag- continuous infusion starting at 5 U/kg/hr or
nosis, new mutations account for about one by bolus doses given every 12 hours. Lower
third of all cases of factor VIII deficiency. The dosages are recommended for less severe
bleeding symptoms in infants with hemo- bleeding.166 The presence of inhibitors is
philia range from mild to catastrophic. Large rare in neonates. The duration of replace-
cohort studies have shown that approxi- ment therapy is based on the location and
mately 10% of children with hemophilia extent of the bleeding and on the clinical
have clinical symptoms in the neonatal response of the patient. Less severe hemor-
period. Approximately 50% of patients with rhages (such as those that typically follow
severe hemophilia bleed excessively fol- circumcision) often resolve after application
lowing circumcision. Other cases present of pressure to the wound or may require a
with severe visceral or intracranial hemor- single bolus dose of 10 to 25 U/kg of factor
rhage after difficult vaginal deliveries. These VIII concentrate or 15 to 30 U/kg of factor
infants may be acutely ill from hypovolemia IX concentrate. Replacement therapy is not
or local hemorrhage into vital organs. indicated for infants with hemophilia who
The only abnormality in laboratory test are not bleeding unless they require surgery.
results is prolongation of the APTT (to >100 Cryoprecipitate contains factor VIII but not
seconds in severe cases). The PT and the factor IX and can therefore be used to treat
platelet count are normal. Specific assays bleeding complications in hemophilia A.
for factors VIII and IX quickly confirm the One unit of cryoprecipitate per 5 kg of body
diagnosis, but these are not available in all weight increases the factor VIII level by
laboratories. When hemophilia is suspected about 40%. The Medical and Scientific Advi-
in a male infant with a prolonged APTT and sory Committee of the National Hemophilia
factor assays are not immediately available, Foundation recommends against the use
other studies are helpful. The PTT should be of cryoprecipitate because it is not a virally
repeated using a 50:50 mix of patient and inactivated product. Recommended dosages
normal plasma. In hemophilia, the PTT of factor concentrates and cryoprecipitate
corrects to normal. Even small clinical lab- are presented in Table 17-4.
oratories often have a stock of factor VIII–
deficient plasma. If the PTT corrects with von Willebrand Disease
normal plasma, the mixing study is repeated Although von Willebrand Disease (VWD) is
with this factor VIII–deficient plasma. If probably the most common inherited bleed-
the PTT corrects to normal, hemophilia A ing disorder, it is rarely diagnosed in the
is excluded and hemophilia B is the likely nursery. von Willebrand factor is the prod-
diagnosis. If the PTT does not correct to nor- uct of an autosomal gene, and the common
mal, factor VIII deficiency is the presump- form of VWD is transmitted as a dominant
tive diagnosis. condition. von Willebrand factor plays a
Recombinant concentrates of factor VIII central role in hemostasis by promoting
or factor IX (produced in vitro using recom- platelet adherence to the vascular endothe-
binant DNA technology) have been the lium, a reaction mediated through a specific
mainstay for treating bleeding in patients receptor on the platelet called glycoprotein
with hemophilia. In the early 1980s, use of Ib. von Willebrand factor is stored in plate-
lyophilized concentrates was associated with let granules and is also released from the
a high incidence of transfusion-transmitted endothelial cell lining of the injured vessel.
HIV infection. Routine heating of factor von Willebrand factor circulates as high-,
concentrates in the manufacturing process intermediate-, and low-molecular-weight
has apparently eliminated this problem. complexes called multimers. In addition to
The dose of factor VIII or IX used to treat playing a role in platelet adherence, von
hemorrhagic complications depends on the Willebrand factor associates with and stabi-
severity of the bleeding. Life-threatening lizes factor VIII. This, in turn, delivers fac-
hemorrhages in infants with hemophilia tor VIII to sites of vascular injury. Although
A should be treated with an initial dose of there is extraordinary clinical heterogene-
factor VIII concentrate of 50 U/kg followed ity in the common, autosomal dominant
Table 17-4. Products Used in the Treatment of Neonatal Coagulopathies
Product Contents Usual Dose Indications

Fresh frozen plasma All factors 10-20 mL/kg Disseminated intravascular
coagulation (DIC), protein C
deficiency, liver disease
Cryoprecipitate Factor VIII, factor XIII, 1 bag (~250 mg fibrinogen, Factor XIII deficiency, DIC, liver
von Willebrand factor, 80-120 U factor VIII) disease, factor VIII deficiency,
fibrinogen von Willebrand disease
Factor VIII concentrates Factor VIII 25-50 U/kg Factor VIII deficiency
Factor IX concentrates Factor IX 50-120 U/kg Factor IX deficiency
Vitamin K 1-2 mg Vitamin K deficiency
Platelet concentrates Platelets 1-2 U/5 kg Thrombocytopenic bleeding
type of VWD, hemorrhage typically occurs circumcision site, and umbilical cord separa-
in the skin and mucosal surfaces. Screening tion. Because these disorders are uncommon
tests usually reveal a normal PT and plate- and are often inherited as autosomal recessive
let count, although some patients have mild conditions, a history of consanguinity is espe-
thrombocytopenia. The APTT is either nor- cially important. The PT and APTT values are
mal or mildly prolonged depending on the normal. In some disorders (e.g., gray platelet
amount of factor VIII activity. Plasma con- syndrome, Bernard-Soulier syndrome), there
centrations of von Willebrand factor are is mild thrombocytopenia and the plate-
increased in neonates. Therefore, labora- lets are morphologically abnormal. Careful
tory testing of affected adults in the family examination of the blood smear is therefore
is a good initial step in evaluating infants mandatory whenever an inherited disorder of
suspected of having VWD. The results may platelet function is suspected. In certain dis-
be used to determine the best test (or tests) eases (e.g., Glanzmann thrombasthenia), both
for the infant. However, even this approach the platelet count and platelet appearance are
has pitfalls, particularly because pregnancy normal. A hallmark of inherited disorders of
markedly alters VWF levels, which renders platelet function is marked prolongation of
evaluation of the mother unreliable. Some the bleeding time. Studies of platelet aggrega-
plasma-derived factor VIII concentrates are tion in response to various stimuli, antibody
manufactured so that they also contain von staining for antigens expressed on the surface
Willebrand factor. These products are an of the platelets, electron microscopy, and
excellent treatment for bleeding complica- molecular analysis are all useful in selected
tions in neonates with VWD. Cryoprecipi- cases. Transfusions of platelet concentrates
tate is another effective therapy for treating are given for severe bleeding.
hemorrhage in infants with a family history
of VWD. Circumcision should not be per- THROMBOSIS
formed if a parent has VWD. In the absence Despite prolongation of the PT and APTT
of significant bleeding, laboratory work-up of well beyond the normal adult range, many
infants with a family history of VWD should experts in neonatal hematology believe
be deferred until after 6 months of age. that neonates are better viewed as being in
The autosomal recessive form of VWD a “hypercoagulable” state. Indeed, throm-
(type III VWD) is a much rarer and more botic complications are more common in
severe condition. Affected infants have a the neonatal period than at any other time
severe bleeding disorder caused by a com- during the first two decades of life and
bination of profoundly abnormal platelet are receiving increased attention as more
function and low factor VIII levels, and they high-risk patients survive invasive medical
require regular treatment with an appropri- interventions. Why newborns experience a
ate von Willebrand factor–containing con- relatively high incidence of thrombosis is
centrate. unknown; however, increased blood viscos-
ity resulting from a high hematocrit at birth
DISORDERS OF PLATELET FUNCTION may play an important role. Polycythemia
Inherited disorders of platelet function are may partially account for why infants of
rare. In general, they present with petechiae, diabetic mothers are at high risk of throm-
purpura, and bleeding from puncture sites, a bosis. In addition, the levels of protein C,
a vitamin K–dependent serine protease, are arteriography in severe cases.170 Contrast-

low at birth. Preterm infants with respira- enhanced angiography is considered the
tory distress syndrome have very low lev- gold standard for diagnosis of arterial
els of antithrombin, increasing their risk of thrombosis. The sensitivity and specificity
thromboembolic complications. of Doppler ultrasonography for diagnosis of
Although thrombosis is a serious compli- venous and arterial thrombosis is unknown.
cation in high-risk infants, this problem has Management of severe thrombosis should
received relatively limited attention until be individualized. Systemic heparinization,
recently. Investigators at McMaster Univer- treatment with fibrinolytic agents, and
sity estimated that the incidence of clini- thrombectomy have all been used.167,170 In
cally apparent thrombotic episodes was 2.4 infants without evidence of major vessel
per 1000 admissions to the NICU based on obstruction, catheter removal is often fol-
a multicenter survey of 97 cases.167 Ninety lowed by resolution of symptoms.
percent of cases in their series were associ-
ated with the use of indwelling catheters. RENAL VEIN THROMBOSIS
Twenty-one infants had renal vein throm- Renal vein thrombosis in infants occurs
bosis, 39 had right atrial thrombosis or other most commonly (80% of cases) in the first
major venous thromboses, and 33 had arte- month and usually in the first week of life.
rial thrombosis. Because severe thrombosis There is no sex predilection and the left and
is relatively uncommon in neonates, almost right sides are equally affected. About 24%
no data from controlled trials are available of infants have bilateral renal vein throm-
addressing the efficacy of thrombolytic or bosis. The clinical triad of flank mass, hema-
anticoagulant therapies. turia, and mild thrombocytopenia (average
platelet counts of 100 × 109/L) is the classical
THROMBOSIS ASSOCIATED WITH presentation of renal vein thrombosis in the
INDWELLING CATHETERS neonatal period. Proteinuria and impaired
Thromboembolic complications are clearly kidney function are also seen. If the inferior
an important risk associated with the use of vena cava is involved, cold, cyanotic, and
venous and arterial catheters. Autopsy stud- edematous lower limbs can be noted. Dop-
ies reveal that 20% to 65% of infants who pler ultrasonography is the test of choice
die with an umbilical venous catheter have for diagnosis. Treatment depends on the
an associated thrombus. Use of appropriate extent and severity of involvement. Sup-
technique and proper placement of umbili- portive care alone is sufficient for unilateral
cal venous catheters are crucial to prevention renal vein thrombosis with no uremia or
of a thrombus and its possible complica- extension into the inferior vena cava. How-
tions, such as portal vein thrombosis with ever, heparin therapy is usually indicated
portal hypertension, splenomegaly, gastric in infants with unilateral renal vein throm-
and esophageal varices, and hepatic necro- bosis with inferior vena cava extension or
sis. The incidence of asymptomatic clot for- bilateral renal vein thrombosis, because the
mation in the aorta is also high. A number risk of pulmonary embolism and renal fail-
of studies have shown that continuous infu- ure increases. In cases of bilateral renal vein
sion of heparin at a rate of 0.5 to 3.5 U/kg/hr thrombosis with evidence of renal failure,
improves catheter patency, reduces the rate thrombolytic therapy must be considered.
of thrombus formation, and decreases the More than 85% of children survive with
incidence of hypertension.168 It is uncertain adequate renal function. Long-term mor-
whether higher dosages of heparin provide bidity data are lacking, however.
any additional benefit, and the evidence
linking heparin use to intraventricular hem- PROTEIN C DEFICIENCY
orrhage is weak.169 Damping of the arterial Severe protein C deficiency is a reces-
pressure wave tracing is a frequent early sive disorder associated with catastrophic
sign of catheter thrombosis. Blanching or thrombosis and necrosis of dependent tis-
cyanosis of a “downstream” anatomic area sues, consumption of coagulation factors,
suggests obstruction. The involved segment and DIC.171 A history of consanguinity or
may include only the tip of a toe, or it may thrombotic disease in multiple adult rela-
encompass an entire extremity or even half tives may be elicited. Infants with severe
of the body. protein C deficiency are severely ill with
Ultrasonography is a useful, noninva- purpura fulminans—diffuse tissue infarction
sive initial test and may be followed by with secondary hemorrhage, particularly in
the skin. The PT and PTT are prolonged, thrombosis often occurs in the context of
the platelet count and fibrinogen level are systemic infection. A constellation of hema-
reduced, and the level of fibrin degrada- turia, abdominal mass, and thrombocytope-
tion products is elevated. An important nia is observed in many infants with renal
diagnostic clue that helps distinguish pro- vein thrombosis. Although the PT, APTT,
tein C deficiency from DIC is its propensity and platelet count all should be measured,
to be associated with prominent areas of the values of these indicators are frequently
segmental tissue infarction. Although the unremarkable in infants with thrombosis.
diagnosis is strongly supported by the dem- The mother should be screened for the pres-
onstration of profoundly reduced levels of ence of antiphospholipid antibodies (lupus
protein C, Manco-Johnson et al observed anticoagulant), because these may be associ-
transient reductions in some infants that ated with neonatal thrombosis. In addition,
later improved.172 Their data emphasize the studies should be performed to exclude
importance of parental blood studies and hereditary conditions, including factor V
serial testing to confirm the diagnosis. Treat- Leiden mutation, prothrombin gene muta-
ment may initially include exchange trans- tion, and deficiencies of antithrombin III,
fusions, infusions of fresh frozen plasma at protein C, and protein S. With the excep-
10 to 20 mL/kg every 6 to 12 hours to raise tion of DNA analysis for factor V Leiden
the protein C level and replenish consumed mutation and prothrombin gene mutation,
coagulation factors, and heparinization.173 all of these tests may be unreliable in the
A protein C concentrate (Ceprotin) has been setting of acute thrombosis. For this reason,
approved by the FDA for use in the treat- it is suggested that parents be screened ini-
ment of congenital protein C deficiency. tially with follow-up testing of the infant as
The dose of Ceprotin for acute thrombotic indicated. Although contrast angiography
episodes and short-term prophylaxis is 100 is the most definitive modality for demon-
to 120 IU/kg in neonates with subsequent strating thrombi, Doppler ultrasonography
doses of 60 to 80 IU/kg every 6 hours and is preferred by most clinicians because it can
maintenance doses of 45 to 60 IU/kg every be performed at the bedside.176 Prospective
6 to 12 hours.174 Warfarin is preferred for studies have not been reported comparing
long-term management, with a target inter- the sensitivity of contrast angiography and
national normalized ratio of 2.5 to 4.5.173 Doppler ultrasonography in infants with
thrombosis. It is imperative to use imag-
FACTOR V LEIDEN ing studies to evaluate clinically significant
A missense mutation in the factor V gene was thrombotic events, because this aids in
first associated with resistance to the action therapeutic decision making and provides
of activated protein C in adults with venous a baseline for clinical follow-up. Infants
thrombosis. This allele encodes a molecule should not be exposed to the risks of sys-
called factor V Leiden that is relatively insen- temic anticoagulant therapy unless throm-
sitive to inactivation by protein C and is bosis is well documented.
most prevalent in northern European popu-
lations. Individuals who are heterozygous ANTICOAGULANT AND FIBRINOLYTIC
for the factor V Leiden mutation show a THERAPY
five- to ten-fold increase in the incidence The paucity of data from controlled studies
of venous thrombosis as young adults, and and the clinical heterogeneity seen in new-
homozygotes are at very high risk. Pediatric borns with thrombosis preclude definitive
patients with thrombosis have been shown recommendations regarding which infants
to have a higher than expected incidence of are likely to benefit from anticoagulant and
factor V Leiden mutation.175 fibrinolytic treatment and which agents,
doses, and schedule should be used. The fol-
EVALUATION OF INFANTS lowing discussion describes the guidelines
WITH THROMBOSIS and therapeutic agents for such therapy.
In general, thrombosis appears to be both The Children’s Thrombophilia Network
underdiagnosed and undertreated in neo- (800-NO-CLOTS) offers telephone advice on
nates. Symptoms and signs are highly management of infants and children with
variable and depend on the location and thrombosis. Although this service is very
severity of the thrombotic process. Not helpful, its optimal use is in combination
only do a high percentage of infants with with on-site pediatric hematology consul-
thrombosis have indwelling catheters, but tation. To exclude ICH and hemorrhagic
infarction, it is essential that central ner- Warfarin is a competitive inhibitor of

vous system imaging be performed before vitamin K and therefore depresses the levels
systemic anticoagulant or thrombolytic of active procoagulant factors II, VII, IX, and
therapy is administered in the NICU. X and of the anticoagulant proteins C and
Heparin is the mainstay of anticoagu- S. Warfarin is not an appropriate treatment
lant therapy for infants with acute throm- for acute thrombosis, but warfarin admin-
bosis. McDonald and Hathaway studied istration may be instituted later and used
the use of continuous heparin infusions as long-term therapy in some infants with
in 15 infants with significant thrombo- ongoing hypercoagulable disorders. There
sis.177 They achieved plasma heparin levels is little published experience in the use of
in the therapeutic range at dosages of 16 warfarin in neonates, and dosing is prob-
to 27 U/kg/hr and found that infants who lematic given the rapid growth and dietary
had large thrombi showed the most rapid changes that occur during the first few
clearance. Because of the very wide range of months of life.
normal APTT values, the authors followed The fibrinolytic agents urokinase and tis-
micro whole blood clotting times to moni- sue plasminogen activator (TPA) are used
tor heparin effects. The recommendation is in the acute management of certain types
that heparin therapy begin with a loading of vascular occlusion in adults.180 TPA is the
dose of 50 U/kg followed by a continuous most commonly used thrombolytic agent in
infusion at 20 U/kg/hr. Heparin treatment neonates. The administration of TPA to 23
should be continued for at least 7 days in neonates with venous thrombosis, most of
infants with significant thrombosis. whom were treated for renal vein, atrial, or
The advantages of low-molecular-weight vena cava thrombosis, resulted in complete
heparin (LMWH) products include a longer clot lysis in 56%, partial lysis in 35%, and
plasma half-life than standard heparin, no lysis in 9%. Major hemorrhagic compli-
which permits subcutaneous dosing, and cations occurred in three infants (13%), two
less variability in anticoagulant effects in of whom had ICH. Both infants experienc-
different patients. Given the difficulties ing ICH were thrombocytopenic.181-183 An
in administering and monitoring heparin absolute contraindication to the use of TPA
therapy in neonates, LMWH drugs appear in neonates is the presence of ICH or active
to offer considerable theoretic advantages bleeding from any site. A platelet count
over standard heparin in managing throm- above 100,000/µL and fibrinogen level
bosis in the NICU. There are important dif- above 100 mg/dL is highly recommended
ferences in the biochemical mechanisms during TPA therapy. Laboratory responses
of action of standard heparin and LMWH include a decrease in the fibrinogen level
(enoxaparin sodium [Lovenox]). In particu- and an increase in the d-dimer level. A
lar, although heparin markedly accelerates hematologist with experience in the man-
the rate of thrombin inactivation through agement of neonatal thrombosis should be
its ability to form a stable ternary com- consulted when fibrinolytic treatment is
plex that includes antithrombin III and considered.
thrombin, the major anticoagulant effect
of LMWH occurs through antithrombin
III–mediated destruction of activated fac- CASE 1
tor X. The APTT is therefore not a useful You are called to evaluate a 2-day-old full-term male
test for measuring the anticoagulant effects infant who was noted to have continued oozing from
of LMWH, which can be monitored by fol- the circumcision site. The nurse provides results for
lowing anti-factor Xa levels. Studies have a complete blood count and coagulation studies,
begun to elucidate optimal dosing for neo- which reveal a normal platelet count of 220 x 109/L, a
nates. In a series that included 7 infants PT of 12.9 seconds (normal for age), and an APTT of
and 18 older children, Massicotte et al 72 seconds (prolonged).
found that infants required higher doses
of enoxaparin per kilogram to achieve What is your initial approach?
therapeutic anti–factor Xa levels than older The first goal is to determine whether the baby is a
children.178 In a much larger study examin- well-appearing or sick-appearing infant. In a sick-
ing 147 courses of enoxaparin in pediatric appearing infant, DIC or sepsis can cause bleeding.
patients, the same group reported clinical Usually the platelet count is abnormally low in such
resolution of thromboembolic events in cases. If the baby appears ill, a sepsis work-up
84% of patients.179
should be performed and parenteral antibiotic ther- What should be done now?
apy should be initiated. The platelet count, as men- The baby’s diagnosis is severe hemophilia A with a
tioned earlier, is normal in this case. Investigation of factor VIII level of less than 1%. Infusion of recom-
bleeding in a well-appearing infant always includes binant factor VIII concentrate at a dose of 50 U/kg will
obtaining a detailed family and maternal history. raise the plasma factor VIII level by 100% and stop
Maternal infection, prolonged period between rup- the bleeding from the circumcision site. The baby
ture of the placental membranes and delivery, and may need additional smaller doses of the recom-
maternal idiopathic thrombocytopenic purpura all binant factor over the next day or two if the oozing
predispose to bleeding in the neonate. A detailed from the circumcision site continues.
family history should focus on the type and sever- The mother should be checked to determine if she
ity of bleeding in family members with particular is a carrier of hemophilia by measuring factor levels
emphasis on the sex of the family members affect- and possibly performing genetic mutation analysis. If
ed. This information gives important clues to the the mother is a carrier of hemophilia A, there is a 25%
inheritance pattern of the bleeding disorders under chance that a male child in subsequent pregnancies
investigation. If only male members on the maternal will be affected. If the mother is not a carrier, the baby
side are affected, the diagnosis is most likely one is deemed to have a new mutation that caused he-
of the hemophilias. If both sexes are affected in the mophilia.
family, one should think of VWD, keeping in mind
the autosomal inheritance pattern. Finally, admin-
istration of vitamin K should be confirmed in any
neonate with bleeding symptoms. Although physi-
cal examination may not contribute much to the CASE 2
diagnosis of a bleeding disorder, it is required for You are called to evaluate a 12-hour-old infant who
completeness. was noted to have a petechial rash soon after delivery.
The baby appears well except for bleeding from A complete blood count is obtained, which reveals a
the circumcision site. The remainder of the physical platelet count of 8 x 109/L.
examination is unremarkable. Family history is nega-
tive for any bleeding symptoms in any of the family What is your initial approach?
members. The baby should be examined. The first goal is
to determine whether there is clinical evidence of
What should be done next? severe pathology (i.e., does the baby look sick?).
About 15% to 30% of patients with an inherited Thrombocytopenic bleeding may be the first sign of
bleeding disorder come to medical attention in the sepsis or NEC. Maternal fever, rupture of the pla-
neonatal period. Moreover, 30% of cases of newly cental membranes a prolonged time before deliv-
diagnosed hemophilia are caused by a new muta- ery, and premature birth all predispose to invasive
tion in patients with no family history of bleeding. In infection. If the baby appears ill, a sepsis work-
a case such as this, an isolated prolongation of the up should be performed and parenteral antibiotic
APTT is suggestive of hemophilia. Ideally, factor VIII therapy should be initiated. Physical examination
and IX assays will be performed to quickly confirm may disclose other abnormalities that suggest the
the diagnosis. However, factor assays are not avail- correct diagnosis. Babies with thrombocytopenia
able in all centers and at all times. The APTT test caused by congenital viral infections often show
should be repeated using a 50:50 mix of patient and microcephaly and hepatosplenomegaly. Radial and
normal plasma. In hemophilia, the APTT corrects to ulnar aplasia or hypoplasia suggests a primary
normal. Even small clinical laboratories often have defect in platelet production (e.g., Fanconi anemia
a stock of factor VIII–deficient plasma. If the APTT or TAR syndrome).
corrects when the specimen is mixed with normal The baby weighs 3450 g and vaginal delivery was
plasma, the mixing study is repeated with the factor uncomplicated. She appears well except for scat-
VIII–deficient plasma. If the APTT corrects to nor- tered petechiae and bruising from heel-stick and
mal, hemophilia A is excluded and hemophilia B is venipuncture sites. The remaining results of the com-
the likely diagnosis. If the APTT does not correct plete blood count are unremarkable (white blood cell
to normal, factor VIII deficiency is the presumptive count: 10,000/µL with a normal differential; hemo-
diagnosis. globin level: 17.2 g/dL).
The baby’s APTT corrected to normal when a
50:50 mix of patient and normal plasma was tested. What should be done next?
The APTT did not correct to normal when factor VIII– Factitious thrombocytopenia should always be con-
deficient plasma was used, which confirms a diagno- sidered, but it is unlikely in this case because of the
sis of factor VIII deficiency, or hemophilia A. presence of clinical signs. The blood smear should
be examined for normal-appearing red and white What do you tell them?
blood cells and for giant platelets, which, if present, The risk of severe neonatal hemorrhage in subse-
suggest an increased rate of peripheral platelet de- quent pregnancies is high. The mother should be
struction with the marrow attempting to compensate followed as a “high-risk” patient. If the previously
by releasing young platelets into the circulation. The affected sibling had an ICH, the next affected fetus
mother’s platelet count should be checked and she will have early, severe thrombocytopenia and in utero
should be questioned regarding medication use and ICH unless effective treatment is instituted. Recent
any history of idiopathic thrombocytopenia purpura, data indicate that the administration of IVIG to the
lupus, or other collagen-vascular disorder. Maternal mother before delivery decreases the incidence of
thrombocytopenia is an important clue that suggests neonatal thrombocytopenia.
transplacental transmission of maternal antiplatelet
IgG autoantibodies. This is a common cause of neo-
natal thrombocytopenia in babies who appear well.
The baby’s blood smear reveals giant platelets
and marked thrombocytopenia, but findings are oth- CASE 3
erwise normal. The mother’s platelet count is normal You are asked to evaluate a newborn who appears
and there is no history suggesting maternal autoim- pale shortly after birth and reportedly has a low blood
mune disease. capillary venous hematocrit.
What is the most likely diagnosis and what What is your initial approach?
should be done? An important first step is to obtain an accurate his-
The most likely diagnosis is neonatal alloimmune tory of both the prenatal course and the delivery. This
thrombocytopenia (NAIT). Detailed laboratory inves- should be accompanied by a thorough examination
tigations are required for confirmation of the diag- of the newborn that looks for signs of bleeding as well
nosis and should be performed by an experienced as for organomegaly (increased size of the liver and
reference laboratory. Current consensus is that spleen, in particular).
both parents should be screened for HPA-1, HPA- You learn that this baby boy was born at 39 weeks’
3, and HPA-5 in all cases of potential NAIT and for gestation and weighs 3700 g. All routine prenatal
HPA-4 as well if the patient is of Asian descent. screening yielded negative results, and the prenatal
HPA-9 and HPA-15 are the next most commonly course was uneventful. The mother is a 28-year-old
involved in antigen incompatibilities. For testing to white female, now gravida 3 para 3, who failed to
confirm NAIT, results must reveal both a platelet report for the majority of her routine visits to her obste-
antigen incompatibility between the parents and trician leading up to this delivery. Her other two children
maternal antibody directed against that antigen. were also term deliveries, and there was no report of
The baby’s platelet count should be measured at problems in the newborn period. You are told that the
least daily for the first few days of life, and she should mother is group O, Rh- negative, that her antibody
be observed for signs of active hemorrhage. screen results are negative, and that she did not
While discussing the probable diagnosis with the receive anti-Rh globulin. The delivery was reportedly
parents, you are called urgently to the nursery be- without complications, and the baby had Apgar scores
cause the baby has developed worsening petechiae of 8 and 9 with normal vital sign values at birth. A
and gross hematuria. Her vital sign values are stable. venous specimen obtained by heel stick at 25 minutes
of age showed a hematocrit of 37%, and the test was
What should be done next? repeated because of the increase in pallor. Examination
The baby now has evidence of significant active shows no petechiae, bruising, or evidence of bleed-
hemorrhage and should receive a random-donor ing, and no splenomegaly or hepatomegaly.
platelet transfusion promptly. If readily available,
matched (antigen-negative) platelets are preferred. What should be done next?
The latter are platelets from donors negative for HPA- A thorough review of the available laboratory results
1. They can be given in larger increments and have is necessary to determine the appropriate tests and
a longer half-life. Concentrated washed irradiated the next steps needed to confirm the diagnosis.
maternal platelets can be used as well; however, their A hematocrit of venous blood obtained at 45 min-
processing takes at least 12 to 48 hours. utes was 30%.
The baby’s platelet count increases and she stops
bleeding after she is transfused with HPA-1–negative What do you consider in your differential
platelets. The mother is HPA-1 negative. The parents diagnosis and what should be done?
are interested in having other children and are con- A decline in the hematocrit in the newborn period
cerned about the risk of recurrence. should raise a concern for hemolytic disease. An
important consideration is Rh disease, given the this case is the low reticulocyte count. This provides
maternal blood type and the mother’s failure to follow a clue that the anemia has an onset and cause
up with her obstetrician during the latter part of ges- that are more acute in nature and could indeed be
tation. ABO incompatibility and isoimmune disease caused by blood loss, despite the lack of any physi-
should also be considered. The quickest way to de- cal evidence on examination of the baby.
termine whether these might be a real concern is to
perform a DAT (Coombs test), the results of which What do you tell the physician requesting
will invariably be strongly positive in Rh disease. The the consultation?
absence of organomegaly in this instance argues The most likely cause, and greatest concern, is that
against this possibility; however, it cannot be ruled transplacental blood loss occurred. This would place
out on the basis of examination alone, and accurate the mother at significant risk of being sensitized to the
diagnosis will depend on the results of blood typing Rh(D) antigen. This risk is further heightened because
on both mother and infant. she did not receive hyperimmune anti-Rh globulin
You request the tests mentioned. The results of during pregnancy, but in the setting of a significant
the direct antiglobulin test are negative, the baby’s bleed even the standard dose may fail to provide suf-
blood type is group O, Rh(D)-positive. The reticu- ficient protection from sensitization of the mother to
locyte count is 138,000/µL, (4%), and the platelet the Rh(D) antigen. In this case, because the moth-
count is 300 x 109/L, with a normal white blood cell er and infant share the blood group antigen O, the
count and differential. mother’s risk of becoming sensitized to D antigen is
even greater.184,185 You should instruct the obstetri-
What is the diagnosis? What should be cian to order a Kleihauer-Betke test on the mother’s
done? blood immediately to look for fetal cells. If increased
For the reasons discussed earlier (negative result numbers of fetal cells are present, a larger dose of
on DAT, absence of splenomegaly, lack of elevated hyperimmune globulin must be given to the mother.
reticulocyte count), this is not a case of Rh disease. One can establish an estimated blood loss based on
It is also clearly not ABO incompatibility, because the baby’s blood volume and hematocrit at birth.
mother and infant are both blood group O. The
negative DAT result also rules out other isoimmune
disorders. One could consider G6PD deficiency be- REFERENCES
cause this is a male infant, but G6PD deficiency is The reference list for this chapter can be found
most common in the African American population, online at www.expertconsult.com.
which makes it less likely in this instance. A hint in
18
Brain Disorders
of the Fetus
and Neonate
Mark S. Scher
A physician’s knowledge of prenatal brain STAGES OF PRENATAL BRAIN

development in the context of maternal- DEVELOPMENT
placental health and disease greatly enhances Maturation of the brain is defined through
the neurologic assessment of the newborn.1 descriptions of sequential and overlapping
Although acute neurologic signs after birth developmental processes, beginning with
should be investigated aggressively for peri- conception and involving continual interac-
partum or neonatal causes, pathologic pro- tions of the gene environment. Beginning
cesses may also occur during prenatal life during gestation and following trimester-
that subsequently modify neonatal brain specific stages of development of the embryo
functions. Any discussion of the neurologic and fetus, anatomic, biochemical, and phys-
evaluation of the newborn, therefore, must iologic processes occur: neural induction
take into account historical and physical followed by neuronogenesis, programmed
examination findings that integrate intra- cell death and neuroblast migration, for-
uterine and extrauterine periods, during mation of axons and dendrites, continuous
which inherited and acquired components energy generation to provide membrane
may synergistically alter fetal brain develop- excitability, synaptogenesis, neurotransmit-
ment in ways specific to gestational matu- ter biosynthesis, and myelination of axons.
rity. The evaluation of the neonate must These prenatal time periods are fundamental
consider familial, maternal, fetal, placental, for brain development. However, postnatal
and environmental factors to better deter- processes of programmed cell death, con-
mine the developmental niche of the fetus tinued synaptogenesis, and neurotransmit-
or neonate when stress or disease favorably ter maturation highlight important brain
or unfavorably alters structure and function maturational events needed for continued
because of time-sensitive strengths or vul- preservation of appropriate structure and
nerabilities. function.2 Regional differences in the rate of
This chapter begins with a discussion maturation of the nervous system also must
of prenatal brain development, followed be recognized. Different brain structures do
by three sections that each highlight a dif- not express equivalent function at specific
ferent perspective on accurate neurologic times during the development of the fetus,
diagnosis: consideration of fetal neurologic premature infant, and full-term neonate.
consultations in the context of prenatal Table 18-1 summarizes the major prenatal
organ development and disease risk, serial developmental sequences in brain matu-
and systematic bedside examinations, and ration that occur in the cerebrum and cer-
laboratory investigations of the newborn, ebellum and lists representative disorders
with emphasis on classic components of at each stage. Both volume and gyral-sulcal
neurologic assessment. Finally, selected complexity increase during prenatal devel-
neurologic conditions are described that opment, with prominent changes in the last
underscore the importance of integrating 3 months of gestation (Fig. 18-1)3 reflecting
historical and examination findings in the major molecular and histologic maturational
evaluation of brain disorders of the fetus changes during the formation of maturing
and neonate. cortical-subcortical cellular connections.
476
CHAPTER 18 Brain Disorders of the Fetus and Neonate 477
Table 18-1. Major Stages of Central Nervous System Development
Peak Time of Major Morphologic Major Morphologic Main Corresponding

Stage Occurrence Events in Cerebrum Events in Cerebellum Disorders*
Uterine 1 wk
implantation
Separation of 2 wk Formation of neural plate Enterogenous cysts and
three layers fistulae
Dorsal 3-4 wk Formation of neural tube, Paired alar plates Anencephaly,
induction neural crest, and derivatives encephalocele,
Neurulation Closure of anterior (day 24) craniorachischisis, spina
and posterior (day 29) bifida, meningocele
neuropores
Caudal 4-7 wk Canalization and regressive Rhombic lips (day 35), Diastematomyelia,
neural tube differentiation of cord cerebellar plates Dandy-Walker syn-
formation drome, cerebellar
hypoplasia
Ventral 5-6 wk Forebrain and face (cranial Fusion of cerebellar Holoprosencephaly,
induction neural crest) plates median cleft face
Cleavage of prosencephalon syndrome
into cerebral vesicles (day 33)
Optic placodes (day 26),
olfactory placodes
Diencephalon
Neuronal 8-16 wk Cellular proliferation in ven- Migration of Purkinje Microcephaly,
and glial tricular and subventricular cells (9-10 wk) Migration megalencephaly
proliferation zone (interkinetic migration) of external granular layer
Early differentiation of (10-11 wk)
neuroblasts and glioblasts
Migration 12-20 wk Radial migration and acces- Elaboration of the Lissencephaly-
sory pathways (e.g., corpus dendritic tree of Purkinje pachygyria (types I and
gangliothalamicum) cells (16-25 wk) II), Zellweger syndrome,
Formation of corpus glial heterotopia, micro-
callosum gyria (some forms),
agenesis of corpus
callosum
Organization† 24 wk to Late migration (to 5 mo) Monolayer of Purkinje Minor cortical
postnatal Alignment, orientation, and cells (16-28 wk) Migra- dysplasias, dendritic
layering of cortical neurons tion of granules to form and synaptic abnormali-
Synaptogenesis internal granular layer (to ties, microgyria (some
Glial proliferation- postnatal life) forms)
differentiation well into
postnatal life
Myelination 24 wk to 2 yr Dysmyelination, clastic
postnatally insults
Adapted from Aicardi J, Bax M, Gillberg C, et al: Diseases of the nervous system in childhood, ed 2, New
York, 1998, MacKeith Press.
*Disorders do not necessarily correspond to abnormal development. They may also result from
secondary destruction or disorganization.
†Programmed cellular death takes place throughout the second half of pregnancy and the first year of
extrauterine life.
FETAL NEUROLOGIC is first documented. Alternatively, medical

CONSULTATIONS conditions during the antepartum or intra-
The pediatric neurologist can fulfill a use- partum periods can predispose the fetus or
ful role as a subspecialty consultant for the neonate to express brain dysfunction at a
fetus with a suspected brain disorder, given later period, with either de novo or com-
that neurologic disease may occur before the pounded brain injury. The pediatric neu-
intrapartum period, either from a primary rologist must therefore consider maternal,
brain disease or secondarily from systemic placental, and fetal diseases on which a neo-
diseases. Brain disorders detected in the natal encephalopathy may be superimposed
neonatal period may also reflect fetal brain (Box 18-1). This section describes how the
damage that occurred before dysfunction neurologist uses an integrative approach to
478 CHAPTER 18 Brain Disorders of the Fetus and Neonate
25 days 35 days 40 days 50 days 100 days
5 months 6 months 7 months
8 months 9 months
Figure 18-1. Gyral development

in the human brain from 25 days
to 9 months. Note the prominent
increase in volume and gyral
complexity in the last 3 months of
gestation. (From Cowan WM: The
development of the brain, Sci Am
241:113, 1997.)
fetal neurology, emphasizing perspectives well as a variety of biochemical investi-

from other subspecialties such as maternal- gations. The most commonly performed
fetal medicine, pathology, and neonatology, tests are α-fetoprotein level and screening
as well as additional pediatric subspecialties. studies for specific chromosomopathies
Evaluation of future strategies for either or neural tube defects.7-9 (See Chapter 2.)
fetal or neonatal brain resuscitation will 2. Chorionic villous sampling can be under-
need to consider the developmental context taken at 8 weeks’ gestation or beyond,
in which a suspected brain injury occurred with specimens used for chromosomal
during the antepartum, intrapartum, or studies by direct examination or culture
neonatal period.4 as well as for biochemical analysis.
3. Fetal blood sampling guided by ultra-
TOOLS FOR FETAL NEUROLOGIC sonography can be performed from 18
DIAGNOSIS weeks’ gestation onward to clarify ambig-
Diagnostic techniques for evaluation of the uous amniocentesis or chorionic villous
fetus have improved over the past several sampling results and diagnose fetal infec-
decades, providing morphologic, biochemi- tions, isoimmunization, or other hema-
cal, and physiologic diagnoses. Many medi- tologic problems.
cal conditions can be better documented 4. Ultrasound examination using trans-
during the prenatal period. vaginal probes can detect structural
Indications for the use of these tests are abnormalities as early as the embryonic
enumerated in both obstetric and pediatric period, but abdominal probes are rou-
guidelines (Box 18-2).5,6 Most of the follow- tinely used at 15 to 20 weeks’ gestation
ing investigative tools are invasive and have and the examination can be repeated
specific indications. as required. Evaluation of fetal matu-
1. Amniocentesis is usually performed at 16 rity and the assessment of intrauterine
weeks’ gestational age or earlier if neces- growth are powerful measures for the
sary. Fluid can be used for karyotyping as antenatal diagnosis of many neurologic
Main Causes of Fetal Indications for the Use

Box 18-2.
Box 18-1. Encephalopathies of Prenatal Diagnostic Tests
of Circulatory Origin
General risk factors*
Lesions related to maternal pathologic Maternal age 35 years or older at time of
conditions expected delivery†
Systemic diseases
Specific risk factors
• Maternal anemia
Previous child with malformation or
• Toxemia with chronic hypertension
chromosomal abnormality
• Renal diseases
History of stillbirth or neonatal death
• Repeated seizures during second tri-
Structural abnormality in mother or father
mester of pregnancy
(e.g., neural tube defect)
• Severe hypoxia
Balanced chromosomal translocation in one
Maternal trauma
parent
• Direct trauma to abdomen
Family history of inherited disease in first-
• Maternal accidents
degree relatives
Gas intoxication
Maternal diabetes mellitus, phenylketonuria,
• Carbon monoxide intoxication
exposure to teratogens, or some infectious
• Butane intoxication
diseases
Lesions related to fetal conditions
Risk factors specific to certain ethnic
Twin gestation (especially with one macerated
groups
twin)
Tay-Sachs disease (screening in Ashkenazi
Prenatal arterial occlusions
Jews of Eastern European origin)
Blood dyscrasias
Sickle cell disease (screening in African and
• Hemolytic disease with or without fetal-
African American blacks)
maternal blood group incompatibility
Thalassemia (screening in some Mediterranean
• Thrombocytopenia (genetic, isoimmune,
and some Asian populations)
or of infective origin)
Nonimmune hydrops fetalis Modified from D’Alton ME, DeCherney AH: Prenatal
Lesions related to placental or cord diagnosis, N Engl J Med 328:114, 1993, with
abnormalities permission.
Fetomaternal hemorrhage *Mostly for chromosomal anomalies.
†Risk of Down syndrome increases significantly after
Chronic placental insufficiency with fetal
35 years. Other chromosomal abnormalities are also
distress
increasingly common after this age with double or
Placental abruption
triple the overall risk.
Cord knotting
Adapted from Larroche JC: Fetal encephalopathies

of circulatory origin, Biol Neonate 50:61, 1986. Doppler-visualized placental and umbili-
cal blood flow adds valuable information
regarding fetal stress secondary to utero-
and nonneurologic fetal conditions. placental insufficiency.12,13
Table 18-2 lists selected brain malforma- 5. Fetal neuroimaging provides additional
tions that can be diagnosed antenatally anatomic information for the clinician
by ultrasonography. Newer techniques regarding normal and abnormal struc-
using three- and four-dimensional ultra- ture. Magnetic resonance imaging (MRI)
sonography can show cerebral and non- technology provides greater detail regard-
cerebral anatomic structures in greater ing gray and white matter structures, and
detail.10 Although abnormal fetal ultra- can now detect anatomic correlates of
sonographic findings might be discov- pathophysiologic mechanisms related
ered fortuitously, previous pregnancy to asphyxia and/or inflammation that
complications or current medical dif- affect water diffusion and lead to edema
ficulties during early pregnancy usually (e.g., diffusion-weighted imaging).14-17
prompt the proactive performance of 6. Biochemical, cytogenetic, and molecular
one or more studies. In routine practice, biological techniques can assess for spe-
the sensitivity of ultrasonography is not cific enzymes or other biochemical prod-
uniformly satisfactory, but reliability has ucts that bear a relationship to specific
improved (Fig. 18-2).11 The addition of genetic conditions. Techniques of DNA
Major Malformations That Can consequences of hematologic disorders.

Table 18-2. Be Diagnosed Antenatally by Withdrawal of fluid from body cavities
Ultrasonography (e.g., pleural, peritoneal), catheterization
of the bladder, and, in rare situations,
Earliest fetal surgery for hydrocephalus can be
Gestational ercentage
P considered.
Age at Which Diagnosed
Diagnosis Is by THE CONSULTATION PROCESS
Diagnosis Possible* (wk) 20-24 wk†
Advances in neuroscience at the bench and
Anencephaly 12-16 100 bedside throughout the last several decades
Encephalocele 12-20 75-100 have refocused attention on the fetal origins
Meningomyelocele 14-32 60-95 of neonatal brain diseases. Discussions of
Hydrocephalus 20-36 25 the causes for fetal and neonatal brain injury
Microcephaly‡ 18-36 25 have been reviewed. Stevenson et al high-
Callosal agenesis 20 Probably high
light maternal, placental, and fetal factors
Lissencephaly 20 Occasional
reports that may contribute to encephalopathy and
subsequent functional impairments in the
Adapted from Aicardi J, Bax M, Gillberg C, et al: Diseases newborn.22 A consensus report by a multi-
of the nervous system in childhood, ed 2, New York, 1998, disciplinary task force reviewed medical lit-
MacKeith Press, with permission.
*Associated malformations are often the most obvious erature regarding neonatal encephalopathy
and can lead to discovery of central nervous system and cerebral palsy, emphasizing antepar-
abnormalities.
†Frequency estimates using best technique available in 1990. tum and intrapartum factors that need to be
‡This group includes cases of lissencephaly, true genetic considered in determining the pathogenesis
microcephaly, and microcephaly caused by early destructive and pathophysiology of neonatal brain dis-
lesions.
orders.23 Pediatric neurologists who provide
either fetal or neonatal consultations need
to consider antepartum and intrapartum
analysis make possible prenatal diagnosis factors when offering recommendations for
of specific inherited biochemical abnor- brain resuscitation to either the perinatolo-
malities, detection of mutant genes, and gist or neonatologist, as novel therapeutic
linkage studies with fragment-length opportunities are made available.
polymorphisms or other DNA markers
for a specific familial condition.18 Initiation of Fetal Neurologic Consultations
7. Techniques are available to assess for A physician’s formulation of a medical dif-
physiologic fetal well-being versus dis- ferential diagnosis always begins with fact
tress. In utero surveillance of physio- finding and incorporates relevant historic
logic functions of the fetus can also be information into the diagnostic fabric of the
achieved using fetal ultrasonography. patient’s medical presentation.24 Although
Specific fetal activities that can be moni- the investigation begins with the history of
tored include gross body movements, the present illness, consideration of medi-
eye movements, sucking movements, cal and family histories may augment the
heart rate patterns, and respiratory pat- physician’s understanding of the present
terns, and quantitative determination abnormal medical condition. These gen-
of amniotic fluid volume is possible.19 eral guidelines can be applied to fetal neu-
Components can be combined to calcu- rologic consultations. The information
late a fetal biophysical score, which may obtained regarding the preconception and
reflect fetal physiologic well-being. Early pregnancy health of the mother, fetal well-
or midgestation assessments are contro- being, and placental function must always
versial; during the last trimester, studies include details of acquired environmental
of fetal behaviors may help document stresses and adverse family medical histories
altered functional brain maturation by to allow the physician to unravel the diag-
defining dysfunctional fetal organization nostic puzzle.
of different behaviors.20 The pediatric neurologist will be called
8. Intrauterine fetal therapies involve direct upon to offer opinions on fetal neuro-
intervention on the fetus by a variety of logic issues as part of the interdisciplinary
techniques to treat specific conditions.5,21 fetal consultation team. Such input may
For instance, fetal exchange transfusion be requested at any time during the moth-
is used to treat the anemia and secondary er’s pregnancy. This multispecialty team
v t
c c m
t
v
A B C
D E
Figure 18-2. Standard planes for viewing cerebral structures. A, Thalamic view at 20 menstrual weeks showing thalamus-
hypothalamus complex (t), ambient cistern (solid arrow), insula (open arrow), tips of the anterior frontal horns of the
lateral ventricles (v), and cavum septi pellucidi (c). B, Ventricular view at 18 weeks. The ventricle measurement is indicated
(arrowheads). The tips of the anterior frontal horns (arrows) and cavum septi pellucidi (c) are visible. C, Cerebellar view at 18
menstrual weeks. The cerebellar hemispheres (arrows) and cisterna magna (m) are indicated. D, Coronal view at 19 weeks
through the coronal suture showing anterior frontal horns (black arrows) and large nerve trunks; the fornices (white arrows)
are clearly visible below the cavum septi pellucidi (c). E, Midsagittal view through the metopic suture at 19 weeks showing the
normal corpus callosum (arrows) containing the cavum septi pellucidi in its arc below the corpus callosum. (From Rumack
CM, Wilson SR, Charboneau JW, et al, editors: Diagnostic ultrasound, ed 4, St Louis, 2011, Mosby, Figure 34-2.)
(sometimes referred to as the fetal board) gen- predicted from prenatal imaging in the
erally holds regular meetings, coordinated absence of polyhydramnios. Cranial nerve
by maternal-fetal specialists, to discuss case deficits evident on postnatal examinations
histories of maternal-fetal pairs. The pedi- will drastically alter the neurologist’s prog-
atric neurologist can provide an important nostic assessment.
perspective to this multidisciplinary group Fetal neurologic consultations can also be
regarding neurologic diagnoses, while also initiated because of the presence of systemic
considering input from the perinatologist, maternal or fetal disease entities. Hyperten-
neonatologist, and other subspecialists. The sive disorders or autoimmune disorders in
pediatric neurologist can clarify findings the mother during pregnancy, for example,
that may suggest normal variation of the predispose some fetal patients to throm-
brain rather than a disease entity and pro- bophilia, and thrombo-occlusive disease
vide experienced views regarding long-term occurs in the brains of some children.25-27
prognosis. Careful serial documentation of brain struc-
The neurologist provides a balanced tures and cerebrovascular integrity around
perspective on a neurologic diagnosis that the circle of Willis by fetal ultrasonography
is based on the structural and functional needs to be performed to detect possible
expressions of a brain disease or anomaly. blood flow compromise with parenchy-
Although structural brain anomalies, such mal brain injury. Systemic fetal diagnoses
as myelomeningocele, can be detected by such as hydrops fetalis, for example, raise
ultrasonography, anticipation of postna- suspicion of cerebrovascular compromise
tal bulbar dysfunction cannot always be of the fetal brain because of reductions in
end-diastolic placental flow documented by cardiac and other organ system anomalies
ultrasonographic Doppler studies.28 in addition to those in the central nervous
Information regarding the structural- system (CNS) in a percentage of children.29
functional expression of fetal brain disor-
ders must be communicated by the pediatric Diagnostic Process of Fetal Neurologic
neurologist not only to other subspecialists Consultations
on the fetal board but also to the primary Fetal Considerations: CNS-Specific
care physician in family practice or pediat- Anomalies
rics who will oversee the general health care Care of fetal patients with primary CNS
of the child after birth. Finally, the child anomalies requires input from the neuro-
neurologist has the opportunity to establish logic consultant. Estimates are that 50% of
an early relationship (during the prenatal all cases presented to a multidisciplinary fetal
period) with the family of a child with a board involve primary CNS anomalies.30 An
brain disorder, which will facilitate continu- opinion may also be requested from the
ity of care after the birth both in the neona- pediatric neurosurgery service, since surgical
tal unit and the outpatient service. intervention after birth may be considered
for hydrocephalus or myelodysplasia. Even if
Timing of Fetal Neurologic Consultations the CNS anomaly is the starting point for the
On occasion, preconceptional consultations multidisciplinary term, a brain anomaly may
will be requested when the medical diag- be a surrogate marker for non-CNS abnor-
noses of the parents or other siblings with malities or genetic syndromes. For example,
neurologic disorders may affect the decision the presence of holoprosencephaly may
making of parents who wish to conceive suggest triploidy of chromosomes 13 to 15
additional children. More likely, the pediat- or 18, non-CNS organ anomalies (e.g., car-
ric neurologist begins the consultation dur- diac lesions), or cholesterol dysmetabolism
ing the second or third trimester, depending associated with underdeveloped genitalia
on prenatal diagnostic findings supple- (Smith-Lemli-Opitz syndrome).31
mented by other information, after referral Structural abnormalities in the brain can
by the high-risk perinatal service. This con- be detected by prenatal imaging (See Table
sultation may include a review of the results 18-2) and represent a spectrum of disor-
of abdominal imaging, Doppler flow studies ders that involve different parts of the CNS,
showing placental perfusion, nonstress tests with implications for involvement of mul-
to assess state stability in the fetus, and cyto- tiple organ systems.24 Knowledge of prena-
genetic testing interpreted by maternal-fetal tal brain development provides perspective
specialists and geneticists. Given the greater regarding timing, pathogenesis, and patho-
diagnostic accuracy of genetic screening physiology of congenital or acquired brain
tests or transvaginal imaging performed dur- lesions. The pediatric neurologist, however,
ing the first trimester, brain disorders may may not always accurately predict postnatal
be detected during the embryonic period of developmental trajectories during fetal con-
development (i.e., sooner than 56 days after sultations. Continuity of care for children
conception). At the other extreme, consulta- with neurologic disorders provides an accu-
tions may be initiated only after birth when rate long-term perspective on functional
neurologic problems are first detected or plasticity at successively older ages.
suspected. An example of a more nonspecific, and
The grave prognostic implications of consequently problematic, prenatal imaging
triploidy of chromosomes 13 to 15 or 18, finding is fetal ventriculomegaly. At the ini-
for example, may be pointed out by the tial ultrasonographic study, documentation
geneticist or maternal-fetal specialist, who of enlarged ventricles does not allow immedi-
will ask the neurologist to discuss the low ate insight into whether a progressive process
chances for survival and poor quality of representing hydrocephalus exists or com-
life because of associated brain anomalies pensatory fetal ventriculomegaly has arisen
such as the holoprosencephaly syndromes. because of a failure of adequate brain growth
Cardiologists and nephrologists may iden- with resultant enlargement of the ventricular
tify anomalies in these organ systems that and cisternal spaces. Hydrocephalus in utero
carry associated risks to the nervous system. requires serial ultrasonographic evaluations
The deletion syndrome involving the short to document progressively decreasing cor-
arm of chromosome 22 (velocardiofacial tical thickness and progressively increas-
syndrome), for instance, is associated with ing ventricular size. Only after 24 weeks’
L ∗
A B
Figure 18-3. Nonneurologic findings on fetal ultrasound images that may suggest brain disease. A, Unilateral cleft lip
(arrow). L, Lip; N, nose. B, Sagittal view of the fetal trunk. Pleural effusion (asterisk) surrounds the fetal lung. Fetal ascites is
present (arrow). (From Sanders RC: Structural fetal abnormalities, St Louis, 1996, Mosby.)
gestation do changes in the occipital-frontal (Fig. 18-4), whereas acquired lesions from
circumference reliably indicate progressive intravascular occlusive events generally occur
ventriculomegaly suggesting hydrocepha- later during the second half of pregnancy
lus. Ventriculomegaly is also a nonspecific (e.g., encephalomalacia from stroke syn-
anatomic finding that can be a marker for dromes associated with maternal preeclamp-
associated nervous system anomalies such as sia or fetal thrombotic vasculopathy of the
myelomeningocele, Dandy-Walker malfor- placenta). Thrombophilia predisposes the
mation, Chiari malformation, and a variety fetus to intravascular occlusive events within
of genetic syndromes (Fig. 18-3).32 Fetal MRI either the arterial or venous circulation of the
may delineate CNS anomalies better than brain. Fetal stroke occurs in approximately
fetal ultrasonography. 1 in 4000 live births and can be associated
Ultrasonographic detection of other major with multiple maternal, placental, and fetal
body anomalies as well as cytogenetic and diseases.33-37
serologic findings from amniocentesis may
suggest syndromic, chromosomal, and infec- Fetal Circulatory and Vascular Disorders
tious disorders associated with ventriculo- Bothing ischemic and hemorrhagic cerebro-
megaly. The perinatal team must develop vascular lesions can result from circulatory
the best delivery strategy and postnatal treat- disorders of the mother, fetus, or placenta.
ment of the infant with suspected progres- The consequences of intrauterine circula-
sive ventriculomegaly. tory and vascular disorders related to systemic
A second nonspecific ultrasonographic diseases of the mother, including maternal
finding that may suggest a variety of CNS anemia, hypertensive disorders of pregnancy,
anomalies is the intracranial cystic lesion. and uncontrolled maternal seizures leading to
Usually detected during the second or third severe hypoxia, may present only after birth
trimester, these lesions can arise from mul- in the immediately neonatal period. Direct
tiple causes ranging from congenital to trauma to the mother’s abdomen, indirect
acquired conditions.24 When such intracra- consequences of maternal accidents, and gas
nial lesions have been detected by transab- intoxication by carbon monoxide or butane
dominal ultrasonography, fetal MRI studies poisoning are other examples of maternal
should be performed to more definitively pathologic conditions that promote fetal vas-
visualize intracranial lesions and surround- cular brain injury. Vascular lesions related to
ing brain structures. One must always fetal conditions include vascular disruptions
distinguish destructive from congenital associated with multiple gestation, particu-
lesions. A cystic lesion is more likely to be larly when one macerated twin is present (Fig.
congenital if it occurs during the first half 18-5); prenatal arterial occlusions caused by
of pregnancy (e.g., encephaloclastic lesions altered angiogenesis; blood dyscrasias due to
such as schizencephaly or arachnoid cysts) hemolytic disease or thrombocytopenia; and
A B
Figure 18-4. Congenital cytomegalovirus infection in a 5-day-old newborn evident on two computed tomographic scans.
A, Periventricular and diffuse cerebral calcifications and ventriculomegaly. B, Cerebellar hypoplasia and large cisterna magna
(arrows). (From Volpe J: Neurology of the newborn, ed 3, Philadelphia, 1995, Saunders, p 680.)
destructive (encephaloclastic) lesions caused

by ischemia or hemorrhage. For example,
schizencephaly may be the result of faulty
vascular supply to the developing neocortex
before the seventieth day of gestation, which
leads to a “true porencephaly” with an epen-
dymal lined cleft or tract between the intra-
ventricular and subarachnoid spaces.
In general, the migration of neocortical
cells, angiogenesis of the blood vessels, and
gliogenesis of supportive cellular elements
occur in an overlapping manner. There-
fore, it may be difficult to predict precisely
Figure 18-5. Multicystic encephalomalacia in the brain of a the specific brain injury because of the
monozygotic twin whose stillborn co-twin was macerated. unknown timing of the insult or insults
Note honeycomb appearance of subcortical white matter on
that precede or follow critical stages of
postmortem examination. (From Aicardi J, Bax M, Gillberg
C, et al: Diseases of the nervous system in childhood,
brain maturation. Circulatory disturbances
ed 2, New York, 1998, MacKeith Press, p 15.) generally damage the periventricular white
matter of the preterm infant. Ischemic or
hemorrhagic injuries in the preterm brain
hydrops fetalis with hematologic, infectious, tend to occur between 26 and 34 weeks’
or other congenital causes. Finally, placental gestation, whether they occur prenatally in
or cord anomalies, including fetal-maternal the fetal brain or postnatally in the preterm
hemorrhage, chronic placental insufficiency infant’s brain. On the other hand, cortical,
with fetal distress, placental abruption, true subcortical, and basal ganglia regions are
cord knots, and long or short cords may con- more susceptible to injury after 34 weeks’
tribute to vascular compromise in the fetus in gestation in either the near-term or term
either the antepartum or intrapartum period infant, because of the more advanced mat-
(see Box 18-1). uration of brain vasculature. These vascu-
Circulatory disturbances affect the fetal lar lesions may also be produced before or
brain differently depending on the stage of after birth, depending on the timing of the
brain development. Brain injuries before the insult after 36 weeks’ gestation. This topic
seventieth day in utero result in abnormal is discussed in greater detail in the section
migratory patterns of neuronal groups within on asphyxia.
the white matter or neocortex without major Clinical manifestations of fetal circulatory
cavitation, whereas later injuries result in and vascular disorders may be difficult to
detect, either before or after birth. The pres-

ence of unexpected alterations in fetal move-
ments, as perceived by the mother or with
abdominal ultrasonography, may be a help-
ful sign, but such alternations are observed
largely through serendipity. Fetal growth
restriction, hydrops fetalis, and hydramnios
are examples of other, more obvious suspi-
cious features. Multiple gestation pregnancies
and maternal trauma can also be associated
with circulatory abnormalities in the fetal
brain. However, vascular lesions may result
even in the absence of documented mater-
nal, fetal, or placental disorders.
After birth, specific clinical and laboratory Figure 18-6. Microscopic sample of intervillous region at
findings may suggest in utero brain injury 2Ox HxE stain. Chronic placental infarction superimposed
on a more recent retroplacental hemorrhage.
related to circulatory disturbances. Marked
neonatal anemia, microcephaly at birth,
marked rigidity or spasticity, or isolated
seizures in the absence of post–hypoxic- the anterior chamber of the eye may docu-
ischemic brain disorder raise suspicions of ment an anterior chamber (i.e., embryo-
antepartum disorders. Early neuroimaging toxon) anomaly associated with peroxisomal
(computed tomography [CT] or MRI) within diseases, or colobomata of the iris or retina,
48 hours after birth should distinguish an which represent a nonspecific arrest in ocu-
acute from a chronic brain lesion. Specific lar development caused by either metabolic
types of CT or MRI images (e.g., inversion- and genetic or developmental disorders.
recovery sequences or diffusion-weighted Association with nonimmune hydrops or
views) may distinguish acute stages of cel- intrauterine growth restriction may also
lular edema with transmembrane diffusion be a clue to the diagnosis. Careful inspec-
of intercellular and intracellular fluid con- tion of placental specimens may document
tents38,39 (whatever the cause, but presum- destructive lesions, vascular lesions, con-
ably after a recently occurring pathogenetic genital anomalies, or storage material that
process such as asphyxia, infection, trauma) reflects the timing or cause of disease states
from gliotic scarring, irregular ventricular (Fig. 18-6).
borders, ventriculomegaly, or brain mal-
development, which imply a remote brain Fetal Considerations: Non-CNS Anomalies
injury. The fetus with brain disorders may initially
show abnormalities of other organs. Impor-
Inherited Metabolic and Neurodegenerative tant diagnostic clues for the fetal or neuro-
Diseases of Fetal Onset logic consultant are provided by a variety of
Although it may be difficult to definitively systemic fetal conditions, as suggested by
identify children with metabolic or neuro- Table 18-3. Regardless of which organ system
degenerative disorders during fetal life, cer- is the starting point for a multidisciplinary
tain clues can raise concerns before or after medical discussion, associations with the
birth.40 Specific disease entities may pres- nervous system must be considered, because
ent in the neonatal period with hypotonia, non-CNS anomalies may be surrogate mark-
decreased levels of arousal, or intractable ers for CNS disease. Seventy-eight percent of
neonatal seizures inappropriate to events fetal neurologic consultations provided to
around birth. Decreased arousal or coma 166 maternal-fetal pairs involved systemic
after formula feedings may suggest a bio- disease conditions, with or without CNS
chemical disorder involving carbohydrate, anomalies.30 For example, children with
protein, or fat metabolism. A constellation the midgut anomaly omphalocele can have
of minor brain or somatic anomalies may associated neural tube defects.41
heighten the physician’s clinical suspicions. Generalized systemic medical conditions
Limb contractures, an underdeveloped tho- also predispose the fetal brain to harmful
rax, or decreased muscle mass, for instance, effects. For example, multiple gestation preg-
may suggest congenital neuromuscular dis- nancies may result in twin-to-twin transfu-
eases. Careful ophthalmologic evaluation of sion syndrome, which is seen in 5% to 15%
Table 18-3. Nonneurologic Findings Associated with Neurologic Diagnoses

Nonneurologic Finding Neurologic Diagnosis
Cardiac rhabdomyoma Tuberous sclerosis
Hypoplastic left heart syndrome Brain malformations (e.g., microgyria, agenesis of corpus callosum)
Multicystic dysplastic kidney Brain malformations with specific genetic syndromes vs. destructive brain lesions
Diaphragmatic hernia Brain malformations (e.g., cerebellar hypoplasia)
Polyhydramnios Brain malformations with genetic syndromes or destructive brain lesions
Hydrops fetalis Congenital syndromes (e.g., Turner syndrome) or destructive brain lesions, usually
of vascular or infectious origin (e.g., asphyxia, parvovirus infection, metabolic
disorders)
Cleft lip and palate Midline brain malformations (e.g., holoprosencephaly)
Arthrogryposis Neuromuscular disease or destructive brain lesions (e.g., congenital muscular
dystrophies)
Multiple gestation pregnancy Destructive brain lesions of white or gray matter (e.g., periventricular leukomalacia)
Omphalocele/gastroschisis Neural tube defects
of all twin pregnancies,42,43 with the most hematologic disorders, diaphragmatic hernia,
severe form occurring in 1% of monocho- gastrointestinal problems, maternal diabetes,
rionic gestations. Twin-to-twin transfusion placental-cord diseases, congenital infections,
syndrome has hematologic consequences and inborn errors of metabolism.
that lead to overperfusion or underper- Hydrops fetalis is an important patho-
fusion of the siblings. Polycythemia and logic condition that may predispose the
hydrops fetalis are two possible complica- child to fetal or neonatal encephalopathies.
tions, and these conditions predispose the Cerebral injury and genetic or metabolic
unborn child to cerebrovascular injury from diseases of the brain may present in general
hypoperfusion caused by either hypervis- as hydrops fetalis on fetal ultrasonography.
cosity or ischemia, possibly with accompa- Fetal brain vasculopathies may manifest as
nying thrombophilia. Significant growth stroke syndromes or intracranial hemor-
discrepancy with growth restriction in the rhage in patients with hydrops fetalis. Neo-
donor twin may result. End-diastolic vol- natal encephalopathies expressed after birth
ume, as determined by Doppler flow ultra- in neonates with hydrops fetalis may also
sonography, may become compromised, reflect remote fetal brain injury, usually
with loss of placental flow to one or both from hypoperfusion or thrombo-occlusive
twins. If one twin dies in utero, the surviv- disease that occurred during the third tri-
ing fetus will have a significantly increased mester due to hydrops fetalis.
risk of cerebrovascular injuries and may later
exhibit cerebral palsy. Associated placen- Infectious Diseases
tal abnormalities also have been described Both the embryo (<8 weeks’ gestation) and
in children who experienced brain injury fetus (>8 weeks’ gestation) are vulnerable to
manifesting as motor deficits.44,45 a number of infectious agents. Infections
Another systemic presentation of fetal dis- during the first and early second trimesters
ease with adverse consequences to the brain result in congenital malformations more
is hydrops fetalis. The diagnosis of hydrops commonly than in destructive lesions. Later
fetalis requires documentation of fluid accu- infections during the third trimester gener-
mulation in serous cavities and edema of the ally result in destructive changes in the brain.
soft tissues of the fetus, which can be docu- The inflammatory response provoked by
mented by transabdominal ultrasonography infectious agents leads to glial scarring of the
(Fig. 18-3) (see also Chapter 2). Most clinical brain, usually after 26 to 28 weeks’ gestation.
series include isolated fetal ascites in the defi- The brain may appear markedly atro-
nition of hydrops fetalis, with an incidence phic, with calcification of neurotic areas, as
of approximately 1 in 2500. The causes of documented by CT scans of the head after
most cases of hydrops fetalis remain non- birth (see also Chapter 14). Major destruc-
specific, involving maternal, fetal, or placen- tive lesions may also be noted on fetal sono-
tal disorders. Associated conditions include grams or neonatal neuroimaging scans (see
congenital heart disease, triploidy, Turner Fig. 18-4). The most common infections
syndrome, cystic hygroma, twin pregnancies, that can affect fetal brain integrity and
development are those caused by cytomega- circulations, specific exogenous or endoge-

lovirus, rubella virus, herpes simplex virus, nous toxins may nonetheless reach the fetus
Toxoplasma gondii, Treponema pallidum, and to produce malformations or destructive dis-
human immunodeficiency virus (HIV). turbances, depending on the timing of the
Clinical manifestations in the neonate of toxin exposure. Examples of such exogenous
fetal infectious disease may include organo- agents are therapeutic agents, industrial pol-
megaly, intrauterine growth restriction, lutants, and recreational substances. Some of
jaundice, microcephaly, intracranial calci- the main agents producing neurologic injury
fication, osseous lesions, encephalitis, and are listed in Table 18-4, which also describes
chorioretinitis, particularly with cytomega- the various patterns of damage that may
lovirus infection.46,47 Specifically for rubella, occur. An example of endogenous toxicity
any combination of brain, eye, heart, or ear is maternal diabetes mellitus. All forms of
involvement is possible, and some infants diabetes may produce problems for the fetus
may show irritability, lethargy, and hypo- and neonate. Careful control of maternal
tonia at birth, whereas others experience diabetes can prevent most major congenital
only hearing loss, depending on when the malformations of the brain and spinal cord,
fetus was infected. Infants with herpes sim- yet developmental and destructive insults
plex infections may be acutely ill during the can result during fetal life, during parturi-
period immediately after delivery or may tion, or after birth, including immaturity of
become symptomatic over the first several brain development, sacral agenesis, intracra-
weeks of life.48,49 Intractable seizures and nial venous thromboses from hyperviscos-
coma may also highlight their neonatal clin- ity-polycythemia syndrome, and peripheral
ical course. Congenital toxoplasmosis can nerve injury from shoulder dystocia caused
take a severe neonatal form that includes by impaction of a hypotonic-macrosomic
hepatosplenomegaly, fever, and purpura. fetus against the pelvic inlet during delivery.
Ventricular dilatation may exist in utero, as Postnatal polycythemia, hypoglycemia, and
documented by fetal ultrasonography, and hypocalcemia all may result in neonatal sei-
chorioretinitis is a common feature seen on zures or coma, or both.
retinal examination in the newborn period.
The clinical presentation of an infant with Immunologic and Blood Disorders in the Fetus
congenital syphilis also includes hepato- Blood type incompatibility has classically
splenomegaly, retinitis, and osteochondri- been associated with erythroblastosis fetalis
tis, but these may appear only after several and can be prevented by isoimmunization
months of life, along with irritability, vom- and the administration of globulins. Blood
iting, cranial nerve deficits, and chronic dyscrasias of either an immune or a nonim-
hydrocephalus. HIV infection can be trans- mune origin can also contribute to hydrops
mitted as early as 15 weeks’ gestation; most fetalis; the association of hydrops fetalis
HIV-infected neonates are asymptomatic with cerebrovascular lesions in the fetus was
with positive serologic results for up to sev- described earlier. Nonimmune hydrops feta-
eral years.50 Diagnosis in the neonatal period lis may occur after infection with parvovirus
is generally difficult. However, some infants B19 or as a result of various inherited meta-
receive a large viral load in utero and may bolic disorders, cardiac diseases, or chromo-
be born prematurely with microcephaly and somal diseases such as Turner syndrome.
calcification of the basal ganglia. Fetal-maternal and twin-to-twin transfusion
Less common viruses that also affect the syndromes are also frequently implicated in
brain but have no consistent pattern of fetal fetal brain disease, which usually results from
injury include influenza virus, measles virus, ischemic or hemorrhagic injuries caused by
hepatitis virus, variola virus, and enterovi- venous stasis (i.e., hyperviscosity-polycy-
ruses and adenoviruses. Infection with one themia syndrome) or arterial ischemia (i.e.,
virus, parvovirus B19, has been associated anemia). Intrauterine thrombocytopenia
with nonimmune hydrops fetalis and may resulting from isoimmunization against fetal
indirectly affect fetal brain integrity by caus- platelets or idiopathic causes may produce
ing uteroplacental insufficiency leading to fetal brain damage.51,52 The inflammatory
vasculopathies. process has been implicated in cerebral palsy.
Exogenous and Endogenous Toxic Disorders Intrauterine Growth Restriction

Although the placenta is usually an effec- Fetal growth restriction increases the risk of
tive barrier between maternal and fetal neurologic problems. Intrauterine growth
Main Substances That Can Be Transmitted from Mother to Fetus

Table 18-4.
and Produce Neurologic Damage
Category Pattern of Damage
THERAPEUTIC AGENTS
Antiepileptic drugs (phenytoin, barbiturates, Fetal growth restriction, small head, dysmorphism of face and fin-
carbamazepine, diones, sodium valproate) gers, clefts, congenital heart disease, and other defects
Benzodiazepines Poorly defined
Warfarin and other Coumarin derivatives Punctate chondrodystrophy, deafness
Vitamin A Hydrocephalus, ear, and heart anomalies (uncertain)
Retinoic acid, isotretinoin Central nervous system migration disorder
INDUSTRIAL POLLUTANTS
Methylmercury Abnormal neuronal migration, deranged cortical organization
Polychlorinated biphenyls (PCBs) Microcephaly, large fontanelles, behavioral disturbances
Carbon monoxide Hypoxic-ischemic lesions
RECREATIONAL SUBSTANCES
Alcohol Fetal growth restriction, facial dysmorphism, brain malformations
with excess neuronal migration, and other central nervous system
defects
Narcotics (heroin, codeine, methadone) Virtually all such substances may produce fetal growth restriction,
Other street drugs (amphetamines, and narcotics may produce withdrawal symptoms in neonates. In
pyribenzamine, phencyclidine) addition, cocaine can induce placental abruption and fetal death and
Cocaine may be responsible for skull and brain malformations and vascular
damage with infarcts or hemorrhage.
Toluene and other inhalants Microcephaly, minor craniofacial anomalies, limb anomalies
Tobacco Fetal growth restriction, possible effects on cognitive development
restriction is defined in various ways, usu- restriction and brain injury should be con-
ally as somatic growth that is less than the sidered in the context of other historical
2nd percentile or at least 2 standard devia- and physical examination factors.
tions less than the mean for gestational
age (see also Chapter 5). Symmetric growth Maternal-Placental Considerations
restriction and asymmetric growth restric- Fetal neurologic consultations can be ini-
tion imply different time courses for a dis- tiated because of maternal disorders such
ease state. A fetus with early gestational as diabetes mellitus, pregnancy-induced
disorders from chromosomal or syndromic hypertension, or specific organ diseases.
conditions is more likely to demonstrate A woman’s history of miscarriages in
balanced growth restriction (i.e., both head early pregnancy may suggest genetic or
and somatic growth compromised). Asym- acquired risks to the fetus resulting from
metric growth restriction occurs during inherited forms of thrombophilia or recur-
the last trimester in response to acquired ring infection. Thrombo-occlusive disease
deficits, which tend to spare head growth. (e.g., stroke, heart disease) at younger
Infants who are small for gestational age ages in family members also suggests the
as a compensatory response to stress in possibility of these disease entities in the
utero may escape subsequent neurologic mother.
sequelae, whereas other infants with intra- Placental anomalies also suggest increased
uterine growth restriction may experience risks to the fetus. An abnormally large or
brain injury. However, a subset of infants small placenta, anomalies of the umbili-
with more subtle reductions in somatic cal cord, and structural anomalies to the
dimensions (i.e., lower ponderal index) placenta may adversely affect fetal well-
may have more pervasive disorders or dis- being. Velamentous insertion of the cord,
eases that occur closer to parturition. The for example, puts the child at risk for later
fetus with intrauterine growth restriction exsanguination if umbilical vessels sepa-
exhibits malformations or dysmorphic syn- rate during the delivery process. Vascular
dromes at a much higher rate than the gen- changes within maternal or fetal placental
eral population (5% to 15%). Therefore, the vascular beds, such as chorioangiosis, mater-
possible association of intrauterine growth nal floor infarction, and fetal thrombotic
vasculopathy, imply hypoperfusion of the the fetus to intrapartum distress and neona-
fetus.53,54 tal depression with hypotonia immediately
after birth and during delivery room stabili-
Consultations during the Peripartum zation. The rapid expression of hypertonic-
and Neonatal Periods ity, sometimes with cortical thumbs, in an
Knowledge of adverse events around the initially neurologically depressed neonate
puerperal period is important to the pediat- who rapidly returns to wakefulness after vig-
ric neurologist who later participates in neu- orous resuscitation usually suggests chronic
rointensive neonatal consultation.55 The fetal neurologic disorder.
mother’s report of the quality and quan- By contrast, after an intrapartum asphyx-
tity of fetal movements before the onset of ial stress as documented by severe meta-
labor, as well as specific information from bolic acidosis at birth (pH of <7.00), a
fetal surveillance close to and during labor, depressed 10-minute Apgar score (<3), sus-
need to be considered. Abnormal findings tained hypotonia, and unresponsiveness
on nonstress tests and biophysical profiles with seizures throughout the next 3 to 7
may provide important clues to fetal dis- days suggest an evolving hypoxic ischemic
tress during the period preceding or during encephalopathy.23 These general encepha-
parturition. Accurate information regarding lopathic features consisting of a depressed
the length of labor and delivery and any sensorium and hypotonia (with or without
associated complications must be provided seizures), however, may also be expressed
for the neurologist’s consideration. Fetal by infants with fetal (i.e., antepartum)
heart rate patterns, scalp and cord pH val- brain injury that is superimposed on neona-
ues, Apgar scores, and the degree of neonatal brain dysfunction after a stressful labor
tal resuscitative efforts can help characterize and delivery.22-24 It may be impossible in a
an evolving neonatal brain disorder in the particular infant to differentiate neonatal
context of adverse conditions before and encephalopathy from preexisting antepar-
during labor and delivery. Fetal distress, as tum brain injury that occurred only hours
reflected by fetal heart rate abnormalities, to a few days before the start of active labor.
uncommonly indicates intrapartum brain A presumption of fetal brain injury might
injury and instead usually reflects ante- be supported by the presence of preexisting
partum causes.56,57 For the individual neo- maternal disease, chronic placental-cord
nate, however, severe and abrupt changes abnormalities, specific persistent neuroim-
in markers of fetal well-being, such as scalp aging findings, or neuropathologic find-
pH or fetal heart rate, denote risks for acute ings on postmortem examination.59,60
brain injury. Intrapartum asphyxial stress certainly can
During the period immediately after add further brain injury to previous dam-
birth, the neurologist must be cognizant of age in some infants. Newer neuroimaging
the infant’s extrauterine adaptation follow- techniques using diffusion-weighted MRI
ing the stresses of labor and delivery. Altered and magnetic resonance spectroscopy may
arousal, altered muscle tone, and seizures are help establish the timing of injury that
the three principal clinical components of occurred closer to events during labor and
an evolving encephalopathy and sometimes delivery.14,61-63
occur after a stressful experience during par- The pediatric neurologist must unify all
turition.24 However, the infant’s initial met- pertinent data from the antepartum, peri-
abolic acidosis, neonatal depression, and partum, and neonatal periods to arrive at the
hypotonia may not evolve into a persistently most accurate interpretation of the neonatal
altered state of depressed arousal, hypoto- neurologic examination findings. Compari-
nia, and seizures.58 Rapid resolution of met- sons between prenatal brain images (obtained
abolic acidosis and improvement in Apgar via abdominal ultrasonography or fetal MRI)
scores without the need for resuscitation and postnatal images are essential. Diffusion-
indicate that a neonatal encephalopathy is weighted MRI images may help identify any
less likely to develop. Specific examination acute or subacute cerebral edema. Although
findings may preferentially reflect fetal brain fetal MRI provides better resolution of brain
disorders even in the encephalopathic new- structures than abdominal ultrasonogra-
born. Intrauterine growth restriction, joint phy, continued brain development in utero
contractures, and hydrops fetalis are exam- may mislead the neurologist, who conse-
ples of clinical findings that suggest longer- quently offers inaccurate or incomplete
standing fetal diseases, which predispose anatomic diagnoses after birth. The postnatal
evaluation of the infant must be incorporated Basic Elements of the Neonatal

into the neurologic consultation. Phenotypic Box 18-3.
Neurologic Examination
features of either genetic or acquired medical
conditions may not have been appreciated Level of alertness
during fetal life. Cranial nerves
Neurointensive care recommendations • Olfaction (I)
by the pediatric neurologist will involve rec- • Vision (II)
ommendations for neuroimaging studies, • Optic fundi (II)
neurophysiologic testing with electroen- • Pupils (III)
cephalography or evoked potentials, as well • Extraocular movements (III, IV, VI)
as biochemical studies to investigate meta- • Facial sensation and masticatory power (V)
bolic disturbances. Pathologic examination • Facial motility (VII)
of the placenta and umbilical cord during • Audition (VIII)
the first day of life are essential to provide • Sucking and swallowing (V, VII, IX, X, XII)
additional information on the etiology and • Sternocleidomastoid function (XI)
timing of a fetal or neonatal brain disorder. • Tongue function (XII)
All recommendations will be integrated • Taste (VII, IX)
with those of the neonatal team. Motor function
• Tone and posture
APPROACH TO NEUROLOGIC • Motility and power
EXAMINATION OF THE NEWBORN • Tendon reflexes and plantar response
Although the nervous system of the new- • Primary neonatal reflexes
born is structurally and functionally imma- Moro reflex
ture, general strategies for performing a Palmar grasp
neurologic examination should parallel Tonic neck response
the bedside approach used with the older Sensory function
infant and child.1,64,65 Neuronal networks
in the neonatal brain with limited dendritic Adapted from Volpe JJ: Neurology of the newborn,
and synaptic interconnections, as well as ed 3, Philadelphia, 1995, Saunders, p 95.
immature myelination patterns, contribute
to the expression of immature neurologic
function. Clinical neurologic signs there- the clinician’s diagnostic and prognostic
fore reflect subcortical structures to a larger abilities. Abnormalities found on neuro-
extent and cortical function to a more lim- logic examination reflect the moment-to-
ited extent. Judicious coordination of care- moment functional integrity of the infant
ful neurologic clinical examination and and may have little bearing on the location
neurobehavioral state assessment, with elec- or extent of brain damage that occurred
troencephalographic (EEG) and polygraphic during fetal or neonatal life; this becomes
analyses, can provide better assessment of more demonstrable only at older ages.
brain function.
To reinforce the discussion in the previ- ESTIMATION OF GESTATIONAL AGE
ous section concerning fetal brain develop- Estimation of the maturity of an infant is
ment and the unique susceptibilities of the crucial to understanding the neurodevel-
fetal brain to maldevelopment or injury, the opmental niche in which the infant is situ-
present discussion of the clinical evaluation ated when an examination is performed.
of the newborn explores how the newborn’s Responses to the neonatal neurologic exam-
clinical repertoire reflects prenatal, peripar- ination change with the infant’s matura-
tum, and postnatal disease processes. tional level. Disease entities also express
Systematic neonatal examination tech- different characteristics in newborns who
niques must be followed in a sequential and are born appropriate for gestational age
repetitive fashion, emphasizing specific lev- compared with those who are small for ges-
els of the neuraxis (Box 18-3). The preterm tational age. Finally, specific types of insults
infant has a more limited clinical repertoire to the brain have varying impact on differ-
because of greater immaturity; yet, serial ent parts of the nervous system, depending
examinations can optimize the validity of on the child’s gestational maturity.1
normal or suspicious findings. Knowledge The most useful historical data for esti-
of the evolution of signs and symptoms over mating gestational age, especially in pre-
the early postnatal period can contribute to term infants, is the date of the mother’s last
menstrual period. Techniques for estimat-

ing gestational maturity by clinical exami-
nation are based on careful anthropometric
measurements such as body weight, length,
and head circumference, as well as observa-
tions of external characteristics such as body
hair, skin texture, skin creases, and areola
size. Ponderal index and body mass index
reference curves for large neonatal popula-
tions identify more pervasive expressions
of growth restriction not detected using
standard growth curves.66 Laboratory evalu-
ations also provide estimates of maturity;
these include radiographic studies of bone
growth, neurophysiologic measures of EEG
or nerve conduction velocities,67 and neu-
roimaging descriptions of sulcal, gyral, and
myelination features.68
CHARACTERISTICS OF THE HEAD

Examination of the head focuses on four
areas: skin characteristics, head circumfer-
ence, shape of the head, and rate of head
growth.
The skin should be carefully inspected for
the presence of (1) dimples or tracts, which
can be associated with brain malformations; Figure 18-7. Angiomata characteristic of Sturge-Weber
(2) subcutaneous masses that reflect trauma, syndrome in a newborn.
tumors, or encephaloceles; and (3) cutane-
ous lesions, which may be associated with
specific congenital vascular abnormalities or
neurocutaneous syndromes, such as Sturge- Metopic
Weber syndrome, linear sebaceous nevus
syndrome, or incontinentia pigmenti.
Description of skin lesions may help diag-
nose a medical condition with important Coronal
manifestations in the brain. For instance,
the port wine stain of Sturge-Weber syn-
drome can be associated with abnormalities
in choroidal vessels in the eye and menin- Squamosal
ges, which may result in glaucoma and cor-
tical lesions. Skin lesions may evolve with
maturation. For example, pale macular Sagittal
lesions present in Sturge-Weber syndrome
become more deeply stained red or purple
Lambdoidal
with age (Fig. 18-7).69
Head circumference should be considered
Figure 18-8. Cranial sutures in the skull of the newborn.
as a surrogate measure of brain and cerebro-
spinal fluid (CSF) volumes. Generalized or
localized scalp edema affects the accuracy of from acquired or congenital processes.
the head circumference measurement. True Molding of the skull may be caused by a dif-
macrocephaly or microcephaly can be esti- ficult vaginal descent and extraction. Scalp
mated by determining whether the child’s edema, cephalohematomas, or subgaleal
head size is larger than the 97th percentile hematomas may have occurred. Knowledge
or smaller than the 3rd percentile, respec- of all cranial sutures is necessary (Fig. 18-8).
tively. Craniosynostosis (premature closure of a
The shape of the head also requires care- cranial suture) may be a congenital cause
ful inspection. Skull deformities may result of a malformed shape. Sagittal synostosis is
Table 18-5. Major Features of Neonatal Behavioral States in Term Infants
Eyes Open Respiration Regular Gross Movements Vocalization

State 1 − + − −
State 2 − − ± −
State 3 + + − −
State 4 + − + −
State 5 ± − + +
Adapted from Volpe JJ: Neurology of the newborn, ed 3, Philadelphia, 1995, Saunders, with permission.
Data from Pryds O, Greisen G, Lou H, et al: Heterogeneity of cerebral vasoreactivity in preterm infants
supported by mechanical ventilation, J Pediatr 115:638, 1989.
−, Absent; +, present; ±, present or absent.
the most common type, leading to an elon- dysplasias. Underdevelopment of the man-
gated shape with a high forehead. Different dibular structures suggests congenital syn-
head shapes result from closure of coronal, dromes such as Pierre Robin sequence.
metopic, or lambdoidal sutures; several
sutures may also be fused. Genetic disor- LEVELS OF ALERTNESS
ders or endocrinologic syndromes such as As with a patient at any older age, the for-
Treacher Collins syndrome and congenital mal neurologic examination of the new-
hypothyroidism can be associated with cra- born should include an assessment of the
niosynostosis. level of alertness. Terms such as state or vigi-
Finally, the rate of head growth is lance have been used in defining criteria for
extremely important to note on serial exami- level of alertness, and these criteria usually
nations. Appropriate postnatal growth rates describe the two initial states of quiet (state
are difficult to define, but certain generalities 1) and active (state 2) sleep, followed by pro-
should be considered. Modest head shrink- gressively increased levels of arousal from
age, reflected by overriding sutures, can be an awake-sleep transition (state 3) through
seen during the first several days in the near- quiet wakefulness (state 4) and vigorous
term or term infant. Increases in head growth crying with wakefulness (state 5).72,73 The
by a mean of approximately 0.5 cm in the infant varies in levels of alertness depending
second week, 0.75 in the third week, and 1 on feeding or environmental stimuli, as well
cm per week thereafter, should be expected as disease states. Behavioral or polygraphic
for a healthy premature infant.70 The clini- criteria help define these state transitions
cian must recognize that a sick preterm infant (Table 18-5).74 Recent events in the nurs-
with systemic disease may require initial ery, such as exposure to painful procedures,
time for “catch-up” head growth, which may bathing, feeding, or medication administra-
exceed the expected rate. However, extremes tion, also affect the infant’s state of alert-
of growth arrest or excessive growth must ness. Scores on qualitative scales of arousal
be considered as part of a pathologic pro- and attention in the neonate and infant
cess (e.g., continued nutritional deprivation, have important prognostic implications.75
genetic influences, or progressive hydro- Abnormalities in levels of alertness are
cephalus). The possibility of a pathologic one of the more common neurologic defi-
condition should be considered in all infants cits noted in the newborn period. Such
with changes in head growth that are more abnormalities may be subtle, and their detec-
than 2 standard deviations above or below tion requires consideration of environmen-
the mean for all infants at that corrected age. tal influences as well as the maturity of the
Among newborns of extremely low gesta- infant. General categories of increased or
tional age, microcephaly at 2 years, but not decreased levels of arousal include hyperalert-
at birth, is associated with motor and cogni- ness, lethargy, stupor, and coma. The appear-
tive impairment at age 2 years.71 ance of the infant in a resting state, his or her
Comparison of relative head and face arousal response, and the quality and quan-
proportions may help elucidate genetic tity of motor responses allow the examiner to
or acquired syndromes or conditions. For estimate whether the infant should be con-
example, squaring of the forehead with sidered normally alert versus hyperalert and
frontal bossing may support a diagno- irritable or stuporous versus asleep. Exagger-
sis of hydrocephalus, rickets, or skeletal ated, diminished or absent arousal responses
and reduced motor responses are noted in gestation78; by 32 weeks, infants sustain
the infant who is abnormally hyperalert or prolonged eye closure as long as the light
lethargic. The distinction between stupor and source remains present. By 34 weeks of ges-
coma is also based on the quality and quan- tation, infants can track a large red object,
tity of motor responses relative to the infant’s and by 37 weeks, they can follow ambient
gestational maturity. After 28 weeks’ gesta- light. Optokinetic nystagmus elicited by
tional age, stimulation consistently results a rotating drum or striped cloth may be
in the infant’s waking for several minutes. seen after 36 weeks’ gestational age. Ana-
By 32 weeks’ gestational age, no stimula- tomic localization for visual fixation and
tion is needed for arousal. After 36 weeks’ following responses does not require the
gestational age, increased alertness is readily occipital cortex and may be subserved by
observed, and well-formed sleep-wake cycles subcortical structures such as the superior
are noted by term age.74 In general, the exam- colliculus of the midbrain and the pulvi-
iner should assume bilateral cortical dysfunc- nar, which link with the retina and optic
tion or subcortical disturbance of the reticular nerves.
activating system within the gray matter of It is far more difficult to study the visual
the diencephalon, midbrain, and upper pons abilities of acuity, color perception, contrast
if wakefulness cannot be achieved, even with sensitivity, and visual discrimination in the
vigorous stimulation. Diffuse or multifo- newborn. Estimations of these responses
cal disease processes, including those with can be obtained by careful observation of
infectious, vascular, dysgenetic, metabolic, or functional abilities using age-specific visual
toxic causes, can result in altered arousal. fixation devices.79 By 35 weeks’ gestational
age, newborns prefer complex patterns
CRANIAL NERVES with curved contours over straight lines.
There are 12 pairs of cranial nerves that are However, acuity, binocular visual acuity,
identified by their specific functions within and appreciation of depth perception vary
the cortex and brain stem. Cranial nerve widely in the newborn, and these rapidly
functions and abnormalities referable to a improve only during the first 3 to 4 post-
particular region of the brain are elaborated natal months.80 Therefore, the evalua-
in the following sections. tion of visual function may be hampered
by the difficulty of assessing these visual
Olfaction (I) functions at the bedside. Nonetheless,
Olfaction is often ignored in the neuro- infants with periventricular leukomalacia
logic evaluation of the neonate, but it involving parieto-occipital regions exhibit
may be affected by various disease condi- delayed visual acuity when studied later in
tions.76,77 A sensory stimulus such as a cot- infancy.81
ton pledget soaked with peppermint extract Funduscopic examination of cranial
elicits a consistent response in an infant nerve II is an extremely valuable aspect of
of 30 to 32 weeks’ gestational age, with a the neurologic assessment of the newborn.
sucking arousal or withdrawal response; Alterations in the color, depth of cup, and
more immature infants normally lack this circumference of the optic discs may reflect
response. Olfactory discrimination has been significant disease processes. Careful inspec-
demonstrated in the newborn, who prefers tion of the anterior chamber, retinal grounds,
odors from the mother, and rapid associa- and external eye structures by a pediatric
tive learning occurs within 48 hours. An ophthalmologist is essential. Corneal cloud-
absence of this response should be consid- ing, glaucoma, cataracts, colobomata, and
ered in infants in whom the olfactory bulbs chorioretinitis are examples of ophthalmo-
and tracts may not have developed, as is logic findings that have clinical importance
sometimes noted in disturbances of mid- for both acquired and genetic fetal disorders.
line brain development such as holopros- Indirect ophthalmologic evaluation by the
encephaly. This condition could be present pediatric ophthalmologist more fully exam-
in infants of diabetic mothers, who have a ines the fundus, particularly the posterior
higher risk of this type of brain anomaly. pole of the retinal surface. Major abnormali-
ties of the optic fundus during the newborn
Vision (II) period include colobomata, optic disc hypo-
Specific visual responses are subserved by plasia or atrophy (Fig. 18-9), retinal and
the second cranial nerves. Blinking to light preretinal hemorrhages, chorioretinitis, reti-
begins by approximately 25 to 26 weeks of nopathy of prematurity, and retinoblastoma.
A B
Figure 18-9. A, Coloboma of optic nerve, retina, and choroid. Yellow-white sclera is visible, and retinal vessels can be seen
coursing through the coloboma. There is malformation resulting from faulty closure of the fetal fissure within the first month
of gestation. B, Hypoplasia of the optic disc, which is half the normal size.
Congenital malformations associated with are reflected by changes in the overall size
optic disc hypoplasia usually occur early and symmetry of the pupils; bilateral cor-
during the first trimester of pregnancy (e.g., tical disease such as asphyxia and medica-
septo-optic dysplasia, agenesis of the corpus tion effects must be considered. Unilateral
callosum). As many as 50% of affected infants changes may imply autonomic dysfunc-
subsequently exhibit other neurologic disor- tion in central or peripheral nerve por-
ders. Atrophy suggests an acquired injury or tions of the pupillary pathways. These can
ongoing metabolic or degenerative process. be associated with brachial plexus injuries,
Retinal hemorrhages may suggest increased with herniation involving unilateral mass
ocular venous pressure, blood dyscrasias, or lesions (such as from infarction or intracra-
asphyxia, but they can also be present in nial hemorrhage), and with the mass effect
20% to 40% of all newborns. Chorioretini- of supratentorial brain structures along the
tis may suggest a congenital infection, and course of the third cranial nerve in which
retinopathy of prematurity is characterized the parasympathetic fibers are encased.1
by dilatation and tortuosity of vessels result-
ing from a variety of causes in premature Extraocular Movements (III, IV, and VI)
infants.82 The uncommon presentation of Attention must be directed to the infant’s
retinoblastoma or an embryotoxon would eye position, spontaneous eye movements,
be helpful in the diagnosis of a neoplasm or and movements elicited by oculovestibular
a genetic or metabolic disease, respectively. maneuvers (i.e., doll’s eye reflex) or ocu-
Retinoblastoma in neonates usually presents localoric testing (i.e., cold or warm water
with a white pupil and strabismus. Embryo- response). Three cranial nerves intercon-
toxon signifies an arrest in development nect within the brain stem to subserve these
within the anterior chamber, which requires functions, and the doll’s eye reflex can be
documentation with an indirect ophthal- observed in the infant as early as 25 weeks’
moscope. gestational age. The eyes normally move
conjugately in the direction opposite head
Pupils (II and III) movement, depending on the infant’s
Pupillary function is associated with both degree of prematurity.83 Caloric stimulation
the second and third cranial nerves and can be performed after 30 weeks, and spon-
appears by 30 weeks’ gestational age, with taneous roving eye movements are expected
consistent responses occurring between after 32 weeks.
30 and 32 weeks of gestation. Abnormali- Abnormalities in extraocular movements
ties in function of the pupillary pathways include dysconjugate gaze, skew or downward
deviation, and opsoclonus. These disorders Auditory (VIII)

of ocular motility can be seen in healthy A startle reaction or blink in response to
neonates84 and usually resolve over the loud sudden noise is present at 28 weeks’
first 6 months of life, but they may indicate gestational age. The lemniscal or auditory
persistent gaze palsies related to ocular stra- pathway that subserves this sensory func-
bismus or intracranial diseases in the brain tion is functionally active early in the third
stem or cortical visual pathways. Intermit- trimester of development.78 Auditory acuity,
tent abnormal eye movements may also be localization, and discrimination are pres-
associated with seizure abnormalities. Some ent in the neonate. Detection of significant
nonseizure pathologic processes associated hearing deficits may be quite important in
with abnormal eye movements are hydro- the examination of the neonate. Four cat-
cephalus, mass lesions, and genetic and egories of disorders causing nerve VIII dis-
metabolic diseases. turbances are familial forms of deafness,
bilirubin-induced injury to the auditory
Facial Sensation and Masticatory Power (V) pathway, congenital infections, and con-
The trigeminal nerve has both sensory and genital defects of the head and neck. Pre-
motor components. Facial sensation is best mature infants have a distinctly increased
assessed by eliciting facial grimaces to nox- incidence of significant hearing loss.1 The
ious stimuli. The three divisions of the tri- full-term infant may experience hearing loss
geminal nerve must be distinguished from from asphyxia-related causes that occur any
the first and second cervical root sensory time during the perinatal period; for exam-
distributions over the posterior scalp and ple, one specific pulmonary problem, persis-
neck, respectively. Masseter and pterygoid tent pulmonary hypertension of the newborn,
muscle strength also reflect fifth nerve may result in peripheral injury to nerve VIII.
motor function and may be affected if the Measurement of the brain stem auditory
neonate exhibits suck and swallow abnor- evoked response may more precisely local-
malities. Corneal reflexes are also subserved ize the site of the deficit to the peripheral
by the autonomic pathway in the fifth cra- nerve or auditory pathway.85
nial nerve, which becomes functional by
the twenty-fifth to twenty-sixth week of Sucking and Swallowing (V, VII, IX, X,
gestation. and XII)
Sucking involves coordinated action of
Facial Motility (VII) breathing, sucking, and swallowing, with
Facial nerve function involves the ampli- two coordinated phases that are linked in a
tude and symmetry of both spontaneous and synchronous action. The swallow response
sensation-elicited facial movements. Major has a voluntary phase followed by an invol-
causes of facial weakness in the neonatal untary phase, both of which physiologically
period arise at all levels of the neuraxis (i.e., improve with maturity. Although rooting
cerebral, nuclear, peripheral nerve, neuro- occurs as early as 28 weeks of gestation, the
muscular junction, and muscle). For example, synchronous action of swallowing does not
bilateral facial weakness may be secondary to appear until 30 to 34 weeks and is not coor-
severe hypoxic-ischemic encephalopathy, dinated with breathing until 37 weeks. Gag
but bilateral or unilateral facial weakness may reflexes subserved by cranial nerves IX and X
also be associated with brain stem hypoplasia are essential for the response of the posterior
or aplasia of the motor nuclear groups in a pharyngeal muscles, particularly to close the
disorder known as Möbius syndrome. Injury to larynx and prevent aspiration; the gag reflex
the facial nerve may also occur during labor appears at 28 weeks’ gestational age.86 Distur-
or delivery as a result of compression of the bances affecting suck and swallow functions
face against the maternal sacrum or forceps may originate throughout the neuraxis, rang-
compression. Finally, weakness at either the ing from the cerebral cortex through the brain
neuromuscular junction or the muscle may stem nuclear groups to peripheral nerve, neu-
be associated with congenital myasthenia, romuscular junction, and muscle levels.1
myopathies, or mitochondrial disorders.
Asymmetry of the infant’s face while cry- Sternocleidomastoid Function (XI)
ing may be associated with hypoplasia or The function of the sternocleidomastoid
absence of a specific muscle, the depressor muscle, which allows flexion and rotation
angularis oris, on the side of the face that of the neck and head, is mediated by cra-
does not depress. nial nerve XI. Disorders in this function are
usually related to a contracture or weakness a false sense of asymmetry in tone. Eighty

of the muscle, such as from fetal position- percent of infants spontaneously prefer
ing or trauma to the muscle. There are also right-sided head turning. Developmental
infants with congenital torticollis that reflects aspects of tone have been carefully docu-
congenital, musculoskeletal, and brain abnor- mented by earlier researchers; in general, a
malities referable to the cervicomedullary caudal to rostral progression in tone devel-
junction. Malformations during the embry- opment occurs with increasing gestational
onic or fetal periods can result in specific maturity. Minimal resistance is present at
anomalies. Careful inspection of the posterior 28 weeks of gestation. By 32 weeks, distinct
occiput of the skull, neck, and scapulae should flexor tone begins in the lower extremities.
be integrated into consideration of cranial By 36 weeks, flexor tone is prominent in the
nerve XI function. Associated anomalies such lower extremities and palpable in the upper
as a deep posterior occipital shelf, torticol- extremities. When an infant’s level of matu-
lis, or elevated and internally rotated scapu- rity is assessed, observations of tone and
lae may be markers for Chiari malformation, posture imply measurement or observation
Klippel-Feil syndrome, Sprengel deformity, of the angle of a limb around a joint, both at
syringobulbia, or basilar impression. rest and with gentle traction.87,88
The quantity, quality, and symmetry
Tongue Function (XII) of motility and muscular power are also
Tongue movements are usually best assessed important aspects of the motor examina-
by observing spontaneous tongue movements tion. The initial myoclonic movements
or the infant’s suck on the examiner’s finger- of the preterm infant evolve into larger-
tip. Abnormalities in tongue function usually amplitude, slower movements in the near-
involve neurons of the hypoglossal nerve or term and term infant. Also, as the infant
muscle. Atrophy or fasciculations may sug- matures, alternating rather than symmetric
gest a pathologic condition in the brain stem movements begin to be observed. By term,
nuclear group subserving tongue movement, an awake infant has the ability to momen-
ranging from congenital conditions (e.g., pro- tarily lift the head off the chest and hold it
gressive spinal muscular atrophy) to destruc- upright for several seconds while being sup-
tive processes (e.g., brain stem infarction). ported in a vertical position.78
The size of the tongue may imply syndromic
or metabolic disorders (e.g., macroglossia Deep Tendon Reflexes and Plantar
with hypothyroidism, Beckwith-Wiedemann Responses
syndrome, or specific lysosomal storage dis- Deep tendon reflexes are initially elicited
eases). The clinician should also consider that in the preterm infant after 32 to 34 weeks’
the tongue may appear enlarged because the gestational age. Pectoralis, biceps, brachio-
oral cavity is reduced in size due to hypogna- radialis, knee, and ankle reflexes should be
thism (e.g., Pierre Robin syndrome). assessed. Symmetric ankle clonus of 5 to
10 beats may be an acceptable finding in
MOTOR EXAMINATION a healthy full-term newborn. The plantar
Major features of the motor examination of response is usually extensor in the newborn;
the newborn involve descriptions of muscle therefore, it is assigned a pathologic signifi-
tone, posture of limbs, motility, muscular cance only if asymmetry is noted.
power, deep tendon reflexes, and plantar In general, abnormalities found on motor
responses. As with all aspects of the neuro- examination include altered muscle tone
logic examination, observations of motor with or without weakness, abnormalities in
function take into account gestational matu- deep tendon reflexes and plantar responses,
rity, level of alertness, and findings of serial and abnormal spontaneous movements.
examinations. Medications, feeding, disease A brief description of these abnormalities
states, and presence of noxious stimuli must follows.
also be considered, because they affect the One must always consider normal mat-
neonate’s motor responses. urational changes in motility, tone, and
reflexes before ascribing pathologic signifi-
Tone and Posture cance. Therefore, the presence of low tone
Tone is best assessed by passively manipu- or hypotonia—the most common motor
lating the limbs with the head in the mid- abnormality in neonates—must be con-
line. It is important to avoid head turning, sidered with respect to possible patterns of
which elicits a tonic neck reflex and gives muscle weakness that usually are present
Table 18-6. Main Causes of Generalized Hypotonia in the Newborn Infant
Site of Major Abnormality Disorder

Anterior horn cell Spinal muscular atrophy
Other anterior horn cell disease (in association with cerebellar atrophy)
Peripheral nerves or roots Congenital polyneuropathies (several types)
Muscle Congenital muscular dystrophy (several types, including Fukuyama
type and “occidental” types with and without merosin deficiency)
Congenital myotonic dystrophy
Congenital myopathies
Central core disease
Centronuclear myopathy
Nemaline myopathy
Congenital fiber-type disproportion
Other structural myopathies
Glycogen storage diseases types II and III
Mitochondrial myopathies (deficit in cytochrome c oxidase)
Types of mitochondrial myopathies
Severe type
Transient type
Neuromuscular junction Neonatal myasthenia (infants of myasthenic mothers)
Congenital myasthenia and myasthenic syndromes (several types)
Infantile botulism
Central nervous system Hypoxic-ischemic encephalopathy
Brain malformations (including trisomy 21)
Hemorrhagic and other brain damage
Drug intoxication
Mixed origin (mainly central nervous system) Zellweger syndrome and related peroxisomal disorders
Prader-Willi syndrome
Hypothyroidism
Connective tissue Marfan syndrome
abnormality Ehlers-Danlos syndrome
with low tone. Levels of the neuraxis that Hypertonia is a less common feature of
may be involved in hypotonia include focal neonatal neurologic disease, but it is one
or bilateral cerebral areas, brain stem, spinal that may have important significance.
cord, low motor neuron, nerve root, periph- Three forms of hypertonia can be expressed
eral nerve, neuromuscular junction, and by neonates as observed in older children
muscle (Table 18-6).1 Focal injury to the and adults.89 Spastic, rigid, and dystonic
cerebrum results in contralateral hemipare- forms of hypertonia may reflect acute or
sis. Parasagittal cerebral injury, usually from chronic processes, depending on the history
asphyxia, affects the border zone vascular of the present illness as well as examina-
regions over the cerebral convexities, which tion findings. Increased tone in the new-
results in weakness of the upper extremi- born period is commonly noted after acute
ties more than the lower extremities. Peri- illnesses such as mild acute postasphyxial
ventricular injury, primarily located in deep dysfunction, meningitis, or subarachnoid
white matter structures, largely affects tone hemorrhage. However, remote intrauterine
and strength in the lower extremities. Spi- damage from injury or malformation earlier
nal cord involvement usually spares the face in gestation may be expressed as hyperto-
and other functions of cranial nerves while nia. The chronic phase of bilirubin enceph-
involving sphincteric as well as motor and alopathy, prenatal substance exposure (e.g.,
sensory functions below the site of the spi- cocaine and amphetamines), and continu-
nal lesion. Other lower motor neuron effects ous muscle fiber activity (Isaac syndrome)
include primarily focal weakness situated in are other clinical conditions in the newborn
nerve roots or, more commonly, generalized that are also associated with hypertonic-
weakness localized to the peripheral nerve, ity. An unusual genetic or familial syn-
neuromuscular junction, or muscular levels. drome known as hyperexplexia may also be
expressed in an infant as increased muscle ble sequence of arm, leg, neck, and trunk movements.
tone, usually triggered by tactile stimuli. They wax and wane in intensity, force, and speed, and
Abnormalities in deep tendon reflexes they have a gradual beginning and end. If the nervous
and plantar responses also follow the gen- system is injured, general movements lose their com-
eral rule of localization at the site of neu- plex and variable character and become monotonous
rologic injury above or below the motor and poor.
neuron level. Preserved reflexes are seen So-called “fidgety” movements are small move-
with pathologic processes above the lower ments of the neck, trunk, and limbs that are of moder-
motor neuron unit, that is, lesions of the ate speed with variable acceleration and occur in all
cerebrum down to the anterior horn cell directions. Normally, they are the predominant move-
of the spinal cord. Diseases in the lower ment pattern in an awake infant at 3 to 5 months.
motor neuron unit, below the anterior horn Paucity of such movements may be seen in preterm
cell at the peripheral nerve, neuromuscular infants and are a bad prognostic sign.
junction, or muscle levels, result in absent Two specific abnormal general movement pat-
or diminished reflexes. Unlike in children terns reliably predict later cerebral palsy: (1) a per-
older than 1 year, plantar responses (i.e., sistent pattern of cramped-synchronized general
Babinski sign) are, in general, extensor and movements; the movements appear rigid and lack
therefore are clinically helpful only if they the normal smooth and fluent character, and limb and
are asymmetric. trunk muscles contract and relax almost simultane-
ously and (2) the absence of general movements of
Spontaneous Abnormal Movements fidgety character. The assessment of general move-
There are a variety of movement disorders ments is quick, noninvasive, even nonintrusive, and
that may suggest neurologic abnormalities: cost effective compared with other techniques such
tremulousness, myoclonus, dystonia, exces- as MRI, brain ultrasonography, and traditional neuro-
sive startle responses, fasciculations, and logic examination. A systematic review indicated that
complex movements all can be expressed by the qualitative assessment of general movements,
the neonate. Tremulousness is a common especially during the fidgety movements period, can
feature associated with a brain disorder after be used as a prognostic tool to identify infants with
asphyxial stress, metabolic disturbances neurodevelopmental disabilities.91,92
such as hypocalcemia and hypoglycemia,
or drug withdrawal. Fasciculations are asso
ciated with lower motor neuron disease,
particularly that involving anterior horn Primitive Fetal and Neonatal Reflexes
cells of the spinal cord. Excessive startle There are numerous primitive reflexes
reactions are noted with metabolic, genetic, whose assessment is a valuable aspect of
or familial disturbances, and myoclonus can the neonatal neurologic examination. Five
be seen in various diseases affecting mul- major responses to be elicited include the
tiple levels of the neuroaxis.90 One strik- Moro reflex, palmar and plantar grasp, tonic
ing movement disorder has been observed neck responses, placing reflex, and stepping
in preterm infants following severe bron- reflex.78
chopulmonary dysplasia at near-term or The Moro reflex appears between 28 and
term corrected age, as well as after bilirubin 32 weeks’ gestational age and is well estab-
encephalopathy. Athetotic, choreiform, and lished by 37 weeks; it is no longer active
dystonic movements have been described after 4 months of corrected age. The pal-
that reflect neuronal injury in the basal gan- mar grasp also appears at 28 weeks’ gesta-
glia or extrapyramidal pathways connected tional age, becomes well established by 32
to these midline gray matter structures. weeks, and disappears by 2 months of age.
These extrapyramidal movements can also The tonic neck reflex does not appear until
be expressed after asphyxial, inflammatory, 35 weeks’ gestational age and is well estab-
or traumatic injury to basal ganglia and lished at 1 month, but disappears by 5 to
associated pathways. 7 months. Placing and stepping reflexes are
usually elicited by 37 weeks’ gestational age
EDITORIAL COMMENT: Prechtl et al described gen-
and later become integrated with support-
eral movements that are part of the spontaneous
ing reflexes after 2 months of age.
movement repertoire and persist from early fetal life
Abnormal results on primitive reflex test-
onward until the end of the first half-year of life.20,73,74,88
ing usually involve reproducible asymmetry
General movements involve the whole body in a varia-
or the incomplete or exaggerated response
of a reflex. Asymmetry of any of the reflexes
may reflect a cortical, brain stem, plexus, or neuropathies. These infants characteristically
peripheral nerve disease. The complete rep- display irritability, lack the ability to express
ertoire of reflexes should be tested to ascer- tears, fail to maintain temperature, demon-
tain whether dysfunction of the upper or strate areflexia on tendon reflex testing, and
lower motor unit exists. lack fungiform papillae on the posterior part
of the tongue.
SENSORY EXAMINATION
Although sensory examination is an IMPORTANCE OF SERIAL NEONATAL
extremely important part of the newborn neu- NEUROLOGIC EXAMINATIONS
rologic examination, alerting and withdrawal Although the neurologic examination is
responses are the most practical expressions more limited in the newborn infant than
of both cortical and peripheral sensory abili- in older children and adults, it remains an
ties. Serial pinpricks over the medial aspect essential aspect of neurologic diagnosis in
of the extremity should result in a response the newborn, on which formulations of
that can be described in terms of latency, diagnostic and therapeutic strategies are
limb movement, facial reaction, localization, based. Examination findings documented
and habituation.1 A lower level of response shortly after birth should be compared with
as well as an exaggerated response should be later signs, since neurologic adaptation
noted. Some major generalizations provide occurs after a stressful delivery, a resusci-
guidance in evaluating abnormalities in the tative procedure, or the acute phase of an
sensory examination. Most illustrative are illness or injury. Also, the neurologic exami-
the sensory deficits in infants with brachial nation permits evaluation of functions that
plexus injuries, which occur in a segmental may be subcortical. Constellations of abnor-
manner depending on which portion of the mal neurologic findings persisting over time
plexus has been injured. A spinal cord injury are strong predictors of neurologic deficits
should be considered if an abrupt change in at older ages. Specific clinical abnormalities
sensory threshold can be appreciated over the predict the more commonly static motor
thorax, trunk, and legs. Genetic syndromes encephalopathies, collectively referred to as
involving the sensory system rarely present cerebral palsy. Various abnormalities of limb,
in the newborn period. One example of a neck, or trunk tone (Fig. 18-10); diminished
genetic disorder that encompasses periph- cry; weak or absent suck and swallow; the
eral sensory and autonomic nervous systems need for gavage or tube feeding; and dimin-
as well as higher cortical structures is Riley- ished levels of activity or arousal are asso-
Day syndrome, or familial dysautonomia. ciated with substantially increased risk of
Current classification systems place this dis- death or disability. Consideration of both
ease into the category of hereditary sensory clinical and laboratory findings provides the
Normal Response
Symmetrical braking
A B C
Imbalance of Tone
Favoring the extensor muscles

of the neck
A B C
Global Hypotonia
Rag doll
A B C
Raise To Sit Maneuver and Return Backward

Figure 18-10. Abnormalities of active tone in the neonate at term.
clinician with compelling bedside evidence of xanthochromia on careful examina-

of possible neurologic abnormalities. These tion of the supernatant after centrifugation,
same clinical findings may also reflect pro- particularly when accompanied by an ele-
gressive degenerative or metabolic disease vated CSF protein level, strongly suggests
that masquerades as asphyxial symptoms the possibility of an intracranial hemor-
and signs.93 rhage. The presence of nucleated red blood
cells in the spinal fluid as well as the periph-
eral blood may point to an intrauterine
ADDITIONAL EVALUATIONS OF THE pathologic process of longer duration than
NEWBORN INFANT the peripartum period. (See Appendix C.)
After maternal, fetal, and neonatal histories
are obtained and a careful bedside exami- DIAGNOSTIC IMAGING OF THE
nation is performed, neonatal neurologic NEONATAL BRAIN
assessment must then include judicious use Important tools have been developed to
of specialized studies that assess the struc- assist in the structural assessment of the
tural and functional integrity of the infant’s immature brain: cranial ultrasonography,
nervous system. Two diagnostic modalities CT, MRI, magnetic resonance spectros-
are tests of structure and tests of function. copy, and positron emission tomography.
Several important points should be kept in During the neonatal period, the clinical
mind. The early and repetitive use of spe- usefulness of positron emission tomogra-
cialized studies may not only shed light on phy is limited.
the severity of the encephalopathic state
but also elucidate aspects of cause and tim- Cranial Ultrasonography
ing during fetal life. Structural and func- Ultrasonography is a rapid, noninvasive,
tional studies are complementary and are cribside imaging technique that has been
therefore useful when combined with his- the method of choice for detecting and
torical and clinical data. Furthermore, serial following the evolution of specific brain
laboratory studies may provide insight into lesions. Excellent reviews are available for
the persistence or resolution of a pathologic consultation.1,14,39 Clinicians should be
process in the brain as a function of gesta- aware of the limits of visibility and accu-
tional age and the adaptation of brain func- racy in the images, which are confined pri-
tion to either stress or injury. marily to the periventricular regions and
ventricular space within the brain. Identi-
CEREBROSPINAL FLUID EXAMINATION fication of normal features, including the
Examination of the CSF is one important ventricular outline, choroid plexus, and
aspect of neurologic evaluation of the new- thalami, should initially be mastered (Fig.
born. The principal components of this 18-11, A). Visualization of the germinal
specific fluid examination include measure- matrix, intraventricular hemorrhage (see
ment of intracranial pressure, assessment of Fig. 18-11, B), periventricular echodensi-
the color of the spinal fluid (e.g., bloody or ties in the white matter (see Fig. 18-11, C),
xanthochromic), examination for turbidity and intraparenchymal echodensities are
(indicative of purulence), performance of the principal abnormalities. Normal ultra-
red and white blood cell counts and neu- sound examination results do not rule out
trophil differential count, measurement of the presence of cortical injury or malfor-
concentrations of protein and glucose, and mation. Brain lesions in intraparenchymal
testing for microorganisms as well as spe- subcortical or meningeal locations are not
cific metabolites. Normal values for preterm readily detected. Furthermore, visualiza-
and full-term neonates have been studied tion of posterior fossa structures is more
(See also Appendix C), but the following limited.
points should be kept in mind. The clinical
suspicion of meningitis should always be Computed Tomography
part of the general concern for clinical sep- CT of the neonatal brain continues to have
sis. The CSF might be infected despite the important applications in neonatal neurologic
absence of infection in the peripheral blood. assessment, despite the greater availability of
Values for blood cells, protein, and glucose MRI. Two conditions—acute hemorrhage and
in the CSF may be difficult to interpret, intracerebral calcifications—may be better
and clinical findings may need to be pref- visualized by CT than by MRI during the neo-
erentially considered. The documentation natal period (see Fig. 18-4). It is also somewhat
Figure 18-11. A, Normal lateral ventricle. A sagittal

view obtained through an open fontanelle clearly shows
Ant Post the frontal lobe (FL), lateral ventricle (LV), thalamus (Th),
temporal lobe (TL), and choroid plexus (CP). Ant, Anterior;
Post, posterior. B, Grade III intraventricular hemorrhage.
Longitudinal view through the left lateral ventricle shows
intraventricular hemorrhage and ventriculomegaly. C,
Periventricular leukomalacia. Longitudinal view through the
LV
right hemisphere demonstrates increased echogenicity
FL in the frontal-parietal region. (A, From Mettler FA Jr,
Th editor: Essentials of radiology, ed 2, Philadelphia, 2004,
Saunders, Figure 9-1; B and C, from Martin RJ,
Fanaroff AA, Walsh MC, editors: Fanaroff and Martin’s
CP
neonatal-perinatal medicine, ed 9, St Louis, 2011,
TL Mosby, Figures 37-45 and 37-47.)
A Magnetic Resonance Imaging

Even though the indications for MRI are
essentially the same as for CT in the new-
born, the higher resolution of MRI permits
more sensitive assessment of white and gray
matter structures; specific radiologic features
such as acute hemorrhage and calcifications
may not be as readily discernible as with CT.
Newer signal-processing techniques in MRI
provide better discrimination of regional
developmental changes in white and gray
matter structures, localization of pathologic
processes to specific regions such as the
basal ganglia, and detection of early cyto-
toxic changes with diffusion of water into
the extracellular space (Fig. 18-12). Identifi-
B cation of normal age-specific aspects of brain
development must first be mastered,94 par-
ticularly the process of myelination. T1- and
T2-weighted imaging (for increased and
decreased white matter signals, respectively),
as well as diffusion-weighted imaging, are
currently recommended. Morphometric mea-
surements provide quantitative estimates of
either developmental or destructive changes.
Newer research techniques using structural
MRI, functional MRI, and tractography will
provide additional insight into the pathogen-
esis and timing of insults.95-97
C Magnetic Resonance Spectroscopy
Magnetic resonance spectroscopy is a new
method for the measurement of energy
easier to obtain a CT scan than an MRI scan; metabolism; it can be sensitive in situations
however, the limited resolution of CT clearly in which impaired energy metabolism is
is a factor. Early ischemic injuries and more suspected (Fig. 18-13). This technique may
subtle malformations are generally not as well be particularly useful in detecting more
localized using CT. pervasive, less severe lesions that are more
A B C
Figure 18-12. Hypoxic-ischemic encephalopathy in a term infant demonstrated by magnetic resonance imaging. A, Intense
T2-weighted signal from basal ganglia on axial cuts. B, Extensive low T1-weighted signal from basal ganglia and thalami.
C, Multifocal cortical-subcortical damage in another infant. (From Aicardi J, Bax M, Gillberg C, et al: Diseases of the
nervous system in childhood, ed 2, New York, 1998, MacKeith Press.)
PME sleep state transitions and brain organization,

which have an important bearing on predict-
ing brain integrity. Serial measurements in
EEG-sleep studies document important mat-
Pi PDE ATP urational changes (Fig. 18-14), which can be
PCr analyzed visually by a specialist with expertise
γ α in interpreting such recordings or digitally
β by computerized systems that quantitate and
correlate data for multiple neuronal systems,
such as EEG power, cardiorespiratory regular-
ity, eye movements, and motility.99 Newer
analysis strategies that examine the complex-
ity of physiologic biosignals using nonlinear
algorithms such as correlation dimension will
offer greater appreciation of the maturation
10 5 0 -5 -10 -15 -20 -25 and organization of the brain.100
Parts per million Amplitude-integrated EEG has been
Day 32
Figure 18-13. Nuclear magnetic resonance Phosphorus
“rediscovered” as a bedside screening tool to
p137 spectrum for a normal infant showing individual assist in global hemispheric detection of sei-
peaks. ATP, Adenosine triphosphate; PCr, phosphocreatine; zures or brain dysfunction.101 Studies that
PDE, phosphodiesterase; Pi, inorganic phosphates; PME, compare amplitude-integrated EEG with
phosphomonoesterase. (From Volpe J: Neurology of the conventional EEG are needed to properly
newborn, ed 3, Philadelphia, 1995, Saunders.) integrate these tools into the ongoing care
of the sick neonate.102
localized and are not identified by ultraso- Evoked Potentials

nography or conventional MRI.98 Three types of short-latency sensory evoked
potentials can be useful for evaluation of
FUNCTIONAL BRAIN ASSESSMENTS the newborn. Brain stem auditory evoked
responses can objectively assess the func-
Electroencephalography tion of the auditory pathways in infants
EEG is an extremely sensitive technique suspected of abnormalities of the cranial
during the neonatal period for confirming nerve VIII or brain stem.103 Visual evoked
the clinical suspicion of neonatal seizures responses are useful to screen for major
as well as providing accurate information visual pathway disturbances.104 Somatosen-
regarding maturation of regional and hemi- sory evoked potentials can preferentially
spheric brain function.67 Combined EEG- monitor the motor pathways that may be
polysomnographic recordings can better assess involved in specific disease states.85
29 wk 4 D/O FP1-T3 38 wk 11 D/O

FP3-T3
T3 -O1 T3-O1
FP2-T4
FP4-T4
T4-O2
T4 -O2
FP1-C3
FP3-C3
C3-O1
C3 -O1
FP2-C4
FP4-C4
C4-O2
C4 -O2 T3-C3
T3 -C3 C3-Cz
C3 -Cz Cz-C4
Cz -C4 C4-T4
C4 -T4 Fz-Cz
Cz -Pz
Fz -Cz
T3-Cz
Cz -Pz
T4-Cz
T3 -Cz
EMG
T4 -Cz
LOC
EMG-A1
ROC
LOC-A1
RESP
ROC-A1 EKG 50 µV
RESP 1 SEC
EKG 50 µV
2 SECS
A B
Figure 18-14. A, Segment of an electroencephalogram (EEG) for a healthy 4-day-old preterm infant of 29 weeks’
gestational age demonstrating a discontinuous background with discrete regional patterns characteristic of this
postconceptual age. B, Segment of an EEG for a 38-week gestational age, 11-day-old female infant demonstrating normal
patterns, including prominent rhythmic theta and alpha activity at the midline (long arrow) and isolated sharp waves in the
right temporal region (small arrow).
Electromyography and Nerve Conduction and cord specimens can be extremely

Velocity Studies helpful in assessing the cause and timing
On rare occasions, electromyelography and of disease states in the newborn.44,45 The
nerve conduction velocity studies may be placental weight may not correlate with
helpful in the newborn nursery.105 These the weight of the infant; placental weights
methods are particularly applicable in above the 10th percentile for gestational
infants with suspected myopathic or motor age or below the 10th percentile for infant
neuron diseases before a muscle or nerve weight may suggest placental insuffi-
biopsy is considered. For instance, with the ciency. Body-to-placenta weight ratios are
simultaneous administration of neostig- sensitive markers of long-term stress in dis-
mine or edrophonium, electromyelography ease studies.106,107 Cord length as well as
may be used to diagnose congenital and cord abnormalities such as true knots and
neonatal forms of myasthenia gravis. Assess- anomalous development of the cord may
ment of peripheral nerve or nerve root func- also offer insights into fetal and neona-
tion using nerve conduction velocities can tal neurologic diseases. Abnormally short
grade the severity of a neurologic lesion at cords imply paucity of fetal movements,
the facial nerve, brachial plexus, or other whereas excessively long cords can be asso-
peripheral nerve location. ciated with an increased risk of cord entan-
glement and resultant occlusion before or
PLACENTAL EXAMINATION during parturition.
Incorporating information from the gross Microscopic evaluation of the placenta
and microscopic examinations of placental may reveal acute hemorrhage, villous edema,
or the presence of purulent material, which and (2) ischemia, or reduced perfusion of
possibly suggests acute or subacute patho- blood flow. The conventional method of
logic processes. Alterations in the size or identifying an asphyxial state is to perform
development of the placental cotyledons, blood gas analysis to document metabolic
more longstanding vascular changes with acidosis; specific values for Pco2, Po2, bicar-
or without infarction of the placenta, and bonate, and base excess must also be con-
deeply stained layers of the amnion and sidered. A greater degree of acidosis may
chorion with meconium within macro- imply increased production of lactate from
phages may be relevant to fetal or maternal incomplete catabolism of glucose (i.e., met-
disease processes. These pathologic features abolic acidosis), although hypercarbia from
have relevance to both the pathogenesis respiratory insufficiency may also explain
and timing of disorders that ultimately may an acidotic state (i.e., respiratory acido-
affect the fetal brain (see Fig. 18-6). sis), which is associated with less morbid-
ity. Metabolic acidosis eventually depletes
REPRESENTATIVE FETAL AND high-energy stores of phosphate, which
NEONATAL NEUROLOGIC DISEASES ultimately results in cellular dysfunction
The discussion in this section of selected because of inadequate energy production.
disease processes affecting the fetus and The initial stage of HIE is one of cellular
neonate reinforces the previous sections dysfunction. Two successive stages in the
pertaining to history taking, neurologic pathophysiologic process of HIE occur over
examination, and laboratory assessment. several hours, during which time excessive
The four disease topics covered illustrate the membrane depolarization and release of
overlapping nature of the neonatal clinical excitatory amino acid neurotransmitters
signs and symptoms that reflect the cause (e.g., glutamate) lead to calcium influx medi-
and timing of neurologic disease in the new- ated by N-methyl-d-aspartate (NMDA) and
born. Hypoxia-ischemia–induced brain dys- α-amino-3-hydroxy-5-methyl-4-isoxazole
function or injury, cerebrovascular lesions, propionic acid (AMPA) membrane recep-
and neonatal seizures are commonly over- tors.109 With an accumulation of cytosolic
lapping clinicopathologic entities in the calcium, intracellular activation of lipases,
newborn period (Table 18-7). The final topic proteases, and nucleases results in further
is hypotonia, which is another major clini- injury to essential cellular proteins. Free
cal sign that has an extensive differential radicals are also generated as a direct or
diagnosis and may occur in other infants indirect result of increased cytosolic cal-
in addition to those who experienced cium and nitric oxide. This entire cascade
asphyxia. ultimately produces membrane injury,
cytocellular disruption, and finally cell
HYPOXIC-ISCHEMIC ENCEPHALOPATHY disintegration. Several therapeutic options
Hypoxic-ischemic encephalopathy (HIE) are being considered that might abort this
occurs in 1.5 per 1000 live births and is the cytotoxic cascade, including use of calcium
single most important fetal or neonatal dis- channel blockers,110 excitatory amino acid
ease state.1 Yet in defining HIE, it is difficult antagonists (e.g., magnesium),111 inhibi-
to determine the role of events during the tors of nitric oxide synthesis, free radical
intrauterine or peripartum period that result scavengers,110 and agents that inhibit free
in neurologic dysfunction and to establish radical formation such as allopurinol. Mod-
the presence or timing of brain injury. Fetal erate hypothermia produced by either total
brain disorders that occur before labor and body cooling or direct brain cooling has
delivery may also cause or contribute to the proven to be beneficial.112-114
condition of an infant who manifests post
asphyxial encephalopathy syndrome after
birth. The clinician must also recognize
EDITORIAL COMMENT: PREDICTORS OF OUT-
that HIE reflects a neurologic condition of
COME: An Apgar score at 10 minutes provides useful
dysfunction with or without coincident or
prognostic data before other evaluations are available
subsequent damage. Scoring systems to aid
for infants with hypoxic-ischemic encephalopathy.115
in predicting death or disability are being
Death or moderate to severe disability is common,
continually reassessed.108
but not uniform, when the Apgar score is less than
The definition of asphyxia implies two
3; caution is needed before a specific time interval is
overlapping mechanisms: (1) hypoxia, or
adopted to guide duration of resuscitation.
reduced supply of oxygen in the blood;
Table 18-7. Clinical Features and Ultimate Outcome in Four Types of Perinatal Brain Damage
Gestational Acute Clinical
Age Timing Risk Situations Anatomic Findings Features Confirmed by Late Outcome
HYPOXIC-ISCHEMIC ENCEPHALOPATHY (SEVERE)
Full term or after Intrapartum or Acute birth asphyxia (pla-
Brain edema, massive cellular Major CNS depres- EEG findings: Severe sequelae in 50%
term immediately cental abruption, hemor-
necrosis (cortex, basal ganglia, sion, repeated critical and severe of survivors, with
postnatal rhage, cord compression,
brain stem), ± hemorrhage seizures (often interictal abnormalities microcephaly, multiple
CHAPTER 18 Brain Disorders of the Fetus and Neonate

mechanical injury)(intraventricular, subdural, or subtle in comatose Ultrasound and CT scan handicaps, ± epilepsy
Prolonged subacute intracerebral) child), ± brain stem findings: Motor handicap always
asphyxia (prenatal or signs (no sponta- edema ± hemor- more severe than
intrapartum) neous respiration, rhage within first cognitive handicap
Inadequate resuscitation no suck) week Less severe degree of
Usually systemic Cerebral necrosis of neuromotor, sensorial,
signs of acute various degrees intellectual, or behav-
hypoxia-ischemia and localization, but ioral deficit in others
(e.g., acute renal imaging findings often Normal or subnormal
tubular necrosis, normal acutely outcome possible
paralytic ileus)
HYPOXIC-ISCHEMIC ENCEPHALOPATHY (MODERATE OR MILD)
Same as above Same as above Same circumstances as Brain edema ± cellular In moderate cases, EEG findings: moderate Any type of permanent
above but less severe and damage ± subarachnoid CNS depression ± or no abnormalities deficit, including cere-
for shorter duration hemorrhage isolated seizures Ultrasound findings: bral palsy in about
In mild cases, usually normal 20% of moderate
hyperexcitability Purely clinical diagnosis cases
and tone based on signs within Normalization fast and
abnormalities (no first week of life complete in most mild
depression, no cases and about 50%
seizures) of moderate cases
Minimal brain dysfunc-
tion at school age in
about 30% of moder-
ate cases
PERIVENTRICULAR LEUKOMALACIA
Any age Any time Chronic fetal distress Ischemic necrosis of peri- CNS depression Ultrasound findings: Persisting neurologic
(prenatal or (± intrauterine growth ventricular white matter within first week periventricular leu- findings (including typical
postnatal) restriction) (centrum semiovale, corona Poor visual pursuit komalacia including spastic diplegia) ± sen-
Low CBF radiata, occipital and tem- and poor axial echogenicity sorial and intellectual
Acute hypotension (may be poral zones) tone at 40 wk cor- Organization within 1 deficit of various degrees
associated with apneic Coagulation necrosis in acute rected age mo: porencephalic
spell and bradycardia, stage ± hemorrhage cysts ± ventricular
cardiac arrest, or hemor- Cavitation and gliosis later enlargement caused
rhagic shock) Distribution often asym- by cerebral atrophy
Chorioamnionitis metric
505
Continued
506
Table 18-7. Clinical Features and Ultimate Outcome in Four Types of Perinatal Brain Damage—cont’d

Gestational Acute Clinical
Age Timing Risk Situations Anatomic Findings Features Confirmed by Late Outcome
INTRAVENTRICULAR HEMORRHAGE
Prematurity (<34 Postnatal (first Immaturity + respiratory Hemorrhage in germinal Major CNS depres- Ultrasound findings: Usually excellent in
wk) week of life) distress syndrome lead- matrix (grade I) sion ± seizure, resorption of blood in grades I and II
ing to hypoxia, hypercar- Intraventricular hemorrhage onset at birth or about 10 days Poor or very poor in
bia, unstable CBF without ventriculomegaly later Normalization in grades grade III, especially
Pneumothorax (grade II) Nonspecific and I and II when associated with
Intraventricular hemorrhage unexplained dete- Organization of periven- extensive periventric-
with ventriculomegaly rioration tricular leukomalacia ular leukomalacia
(grade III) Often silent often associated with Possible hydrocephalus
Hemorrhagic venous infarc- grade III within 1 mo (10%-30% risk)
tion (grade IV) (see earlier)
CEREBRAL INFARCTION (ARTERIAL TERRITORY)
Any age (fre- Mainly prenatal; Embolization in twin-to-twin Infarction of both white mat- Repeated focal CT scan within 48 hr of Improvement of neu-
quently full term) can occur transfusion, placental ter and cortex in arterial seizures within first birth: wedge-shaped romotor function in
intrapartum or abnormality distribution 3 days area of low attenu- first year, with mild
in first 24 hr Thrombophilia Contraction of affected area, No major depression ation with irregular residual hemiparesis
Thrombosis in disseminated multiple cystic degenera- Asymmetric findings margins; findings may (usually can walk
intravascular coagulation, tion in case of middle be normal if scan alone)
sepsis, maternal cocaine Middle cerebral artery most cerebral artery too soon after actual Mild mental deficit or
use common site (2 times more infarction none
Often no predisposing than other arteries) Rescanning a few No speech disorder,
factors Left hemisphere mainly (3 months later to evalu- usually
Low risk full term times more than right) ate loss of tissue Epilepsy uncommon
EEG findings: focal
seizures
CBF, Cerebral blood flow; CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram.
EDITORIAL COMMENT: Neonatal Hypothermia for other providers based in community hospitals play a
Hypoxic-Ischemic Encephalopathy: The neuropro- critical role in the initial assessment, recognition, and
tective effects of hypothermia reflect antagonism of stabilization of infants who may be candidates for
multiple cascades of events that contribute to brain therapeutic hypothermia.118
injury. A Cochrane review analyzed eight randomized
controlled trials that compared the use of therapeutic
hypothermia with standard care in 638 moderately or
Neuropathology
severely encephalopathic infants without recognizable
Two general forms of brain damage from HIE
major congenital anomalies.116 Therapeutic hypother-
have been described in experimental animal
mia resulted in a statistically significant and clinically
models. The acute total asphyxial model
important reduction in the combined outcomes of
usually leads to death because of circulatory
mortality or major neurodevelopmental disability to
collapse or the pattern of brain injury; these
18 months of age. Minor adverse effects of hypother-
immature animals are usually stillborn or
mia included a borderline significant increase in the
die shortly after birth. A small number may
need for inotrope support and a significant increase in
survive and have evidence of predominantly
thrombocytopenia.
brain stem and diencephalic damage. Sym-
Many important questions regarding the optimal
metric lesions within the brain stem, basal
therapeutic use of hypothermia remain to be an-
ganglia, and spinal cord structures are noted
swered. But independent metaanalyses of the pub-
on postmortem examination. MRI studies
lished trials now indicate a consistent, robust benefi-
have also documented this pattern of injury
cial effect of therapeutic hypothermia for moderate to
in neonates who die or experience severe
severe neonatal encephalopathy, with a mean number
sequelae after HIE (see Fig. 18-12).119
needed to treat of 6 to 8 to reduce disability and 14
A partial prolonged model of HIE-induced
to reduce mortality (Fig. 18-15).117 Despite significant
brain damage has also been described. In
reductions in cerebral palsy and fewer survivors with a
this model, brain lesions are more diffuse
mental and psychomotor developmental index of less
within the cortex, subcortical white matter,
than 70, almost half of the survivors are still neurologi-
and basal ganglia.
cally impaired. Complementary agents will have to be
Clinical settings in which these two
identified to further improve the outcome. Such trials
hypothetical forms of asphyxial situations
are in progress, as is long-term follow-up for the initial
can occur include the antepartum, intra-
trials.
partum, and neonatal periods. The follow-
In summary, for infants with hypoxic-ischemic en-
ing sections provide a brief discussion of
cephalopathy, moderate hypothermia is associated
the common brain lesions associated with
with a consistent reduction in death and neurologic
asphyxia.
impairment at 18 months. Hypoxic-ischemic encepha-
lopathy is often unanticipated and unavoidable, and
Periventricular Leukomalacia
may occur in any obstetric setting. Pediatricians and
The most commonly occurring lesion asso-
ciated with HIE in the preterm infant is
Hypothermia Normothermia
Study or
subgroup Events Total Events Total Risk ratio Weight Risk ratio
(95% CI) (%) (95% CI)
TOBY 74 163 86 162 39.0 0.86 (0.68 to 1.07)
NICHD 45 102 64 106 28.3 0.73 (0.56 to 0.95)
Cool Cap 59 116 73 118 32.7 0.82 (0.65 to 1.03)
Total (95% CI) 381 386 100.00 0.81 (0.71 to 0.93)
Total events 178 223
0.2 0.5 1 2 5
Favors Favors
hypothermia normothermia
Figure 18-15. Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on death
or disability (“events”). All infants randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel
fixed effects model was used to calculate risk ratios and 95% confidence intervals (CIs). Test for heterogeneity: χ2 = 0.82;
degrees of freedom = 2 (P = .66); I2 = 0%. Test for overall effect: Z = 3.03 (P = .002). Studies shown are the Total Body
Hypothermia (TOBY) trial,167 the National Institute of Child Health and Human Development (NICHD) trial,114 and the
CoolCap trial.112 (From Edwards AD, Brocklehurst P, Gunn AJ, et al: Neurological outcomes at 18 months of age
after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial
data, BMJ 340:C363, 2010.)
periventricular leukomalacia (PVL). PVL is of major intracerebral arteries is also more

characterized by symmetric bilateral lesions likely to be compromised in the brain of
that result from coagulation necrosis. The the term newborn, with injuries resulting
lesions are located adjacent to the external in these specific vascular regions within the
angles of the lateral ventricle, with or with- cortex.
out cavitation. Extensive lesions produce
multicystic encephalomalacia. The occur- Parasagittal Pattern of Injury
rence of PVL is directly related to the imma- A parasagittal pattern of injury can result
turity of the vascular supply to the central after HIE, contributing to a specific pat-
white matter of the preterm brain. Arterial tern of motor deficits in the proximal upper
end zones lack adequate collateral blood extremities, referable to the motor strip in
flow to the deep white matter. PVL is often each cerebral hemisphere. Although uncom-
associated with periventricular-intraven- mon, these lesions have been demonstrated
tricular hemorrhage.120 Many pathophysi- on neuroimaging studies.
ologic conditions may contribute to this
white matter necrosis, but usually it results Lesions of the Basal Ganglia
from either decreases in systemic blood pres- Lesions within the basal ganglia are another
sure or harmful effects of the inflammatory important type of brain injury that can
process. Systemic hypotension immediately result after HIE in the near-term or term
results in a decrease in cerebral blood flow, infant brain. Status marmoratus (a marble-
because the immature cerebral vasculature ized appearance of injury caused by patterns
reactivity in the premature brain causes of increased myelination in the caudate,
a pressure-passive state of brain hemody- putamen, and thalamus) has been classi-
namics.121 This physiologic immaturity of cally described by neuropathologists. These
the preterm infant brain is in contrast to deep gray matter structures possess a high
the mature cerebral blood flow response of concentration of excitatory neurotransmit-
the term infant, who can better maintain ters; consequently, these brain regions are
adequate cerebral perfusion over a wider vulnerable to the cytotoxic cascade that
range of systemic blood pressure values. results after release of the neurotransmitters
PVL may also result after the elaboration of into the extracellular space, which leads to
vasoactive cellular byproducts (e.g., inflam- further neuronal injury and death.
matory mediators) in response to infection
or inflammation.122 Such endotoxic agents Focal Cerebral Lesions
contribute to cerebrovascular occlusion Focal lesions in the brain may be caused by
and consequent ischemia-induced injury arterial infarction, usually within border
in combination with asphyxia. Release of zone territories between major cerebral arter-
inflammatory mediators may also occur ies. Thrombotic or embolic infarctions may
with infection, even in the absence of occur, which can convert from ischemic to
circulatory disturbances associated with hemorrhagic lesions.34,35,38
asphyxia. The final common pathway to
injury of immature neurons (pro-oligoden- Clinical and Neuroimaging Correlates of
drocytes) can be pathogenetic mechanisms Hypoxic-Ischemic Encephalopathy
causing asphyxia and/or infection.123 As described earlier, it is difficult for the
clinician to distinguish fetal distress that
Selective Neuronal Necrosis occurs because of events during labor and
In near-term and term infants who experi- delivery from brain injury that occurred dur-
ence HIE, cortical and basal ganglia injury ing the antepartum period.23 In some neo-
can occur, including subcortical white mat- nates, despite classic signs of intrauterine
ter lesions with selective or extensive gyral fetal distress, neither neurologic symptoms
involvement. Neuronal necrosis may be nor acute brain injury is noted after birth.
localized, multifocal, or diffuse and is gen- Infants who are asymptomatic at birth may
erally greater in the left hemisphere than have already sustained brain injury before
in the right.1 Cellular necrosis occurs with parturition. Even though fetal surveillance
reactive astrocytic gliosis and resultant lam- techniques detect the presence of fetal dis-
inar injury to the cortical mantle, which tress (as documented by electronic fetal
results in alterations in gyral thickness (ule- monitoring of the heart and fetal scalp pH
gyria) after destruction of layers of gray mat- monitoring) and, after birth, clinical signs
ter. End zone perfusion between territories of depressed arousal and muscle tone in the
neonate indicate an encephalopathy, these waveforms) or a burst suppression pattern.

expressions of dysfunction may be related The expression of continuous EEG rhythms
to a brain injury that occurred before fetal with age-appropriate patterns that sponta-
distress was first noted.124 neously change between active and quiet
Symptoms and signs of HIE are also differ- sleep states carries a more favorable progno-
ent in preterm and term infants. For the near- sis. Immature patterns on the EEG without
term or term infant, three general grades of amplitude-frequency suppression or burst
encephalopathy have been described.125 suppression patterns on the EEG may sug-
Stage I HIE syndrome is a mild form in which gest a more chronic in utero HIE process.67
the infant is hyperalert and tremulous during Neuroimaging techniques can document
the first 24 hours, with excessive responsive- the structural injury associated with HIE
ness to external stimulation. Muscle tone is as well as suggest the timing of the injury.
generally increased, and tendon reflexes are The ultrasonographic appearance of PVL in
hyperactive. Stage II, or moderate, HIE syn- preterm infants has been extensively stud-
drome is characterized by stupor or lethargy ied. Well-defined areas of echodensity along
lasting at least 24 to 48 hours. The infant can the lateral ventricle appear between 7 and
be aroused and then shows tremulousness, 14 days after a presumed asphyxial insult.122
but muscle tone is generally decreased after These echodensities generally disappear or
birth, although dystonic hypertonia may are replaced by small cysts over subsequent
be seen with tactile stimulation. Weakness weeks. More sophisticated neuroimaging
is noted in the shoulder and proximal arm techniques (e.g., CT and MRI) document
muscles. The clinical condition of the infant more details of neuroanatomy and patho-
may worsen or improve within 48 to 72 logic features.39,126 Cortical enhancement,
hours, and seizures may or may not occur. In particularly in the depths of the sulci and
stage III, or severe, HIE the infant is usually of lesions within the basal ganglia, indicates
stuporous or comatose, and seizures develop brain lesions associated with HIE in the
within the first 24 to 48 hours of life. Seizures near-term and term infant. Chronic changes
are difficult to distinguish from nonepilep- include calcifications. Other abnormalities
tic seizure-like events, as discussed later in such as focal ischemic lesions in the bor-
the section on neonatal seizures. In infants der zone between major cerebral arteries are
who are profoundly hypotonic, unrespon- more readily documented by either CT or
sive, and dependent on ventilatory support, MRI scans. Certain features on neuroimag-
cranial nerve abnormalities and other focal ing may suggest a more remote occurrence
motor abnormalities may be present, with a of a brain injury caused by an asphyxial
full, bulging fontanelle suggesting increased insult during the antepartum rather than
intracranial pressure. Such infants have the the peripartum period. Cerebral atrophy or
highest likelihood of neurologic sequelae or well-formed cystic cavitation at the time of
death. birth seen on ultrasound, CT, or MRI scans
The preterm infant with HIE, on the other signifies the process of liquefaction necrosis,
hand, may exhibit fewer clinical signs. The which requires 2 to 6 weeks during intrauter-
preterm infant with stage III HIE may appear ine life to appear. Irregularity of the ventricu-
ill based on respiratory distress, sepsis, or lar borders, white matter multicystic lesions,
other organ system problems, but the neuro- and the appearance of basal ganglia calcifi-
logic manifestations of HIE are more difficult cation or overall brain atrophy also suggest
to ascertain because the infant’s immaturity more chronic injuries. Therefore, despite the
hinders the clinical expression of neurologic clinical expression of HIE, brain injury may
function. Stages I and II HIE are much less have already resulted from clinically silent
well defined in preterm infants. events before the onset of fetal distress. This
possibility has obvious implications for the
Neurophysiologic and Neuroimaging choice of therapeutic interventions to treat
Correlates of Hypoxic-Ischemic HIE. The use of glutamate antagonists, for
Encephalopathy instance, may not be recommended in an
EEG can be useful in determining the pro- infant who has already experienced remote
gression of HIE and the findings may have intrauterine asphyxia. Conversely, those
strong prognostic significance. For mod- infants with well-documented intrapartum
erate to severe HIE, the EEG background or postnatal disorders may experience HIE
abnormalities include suppression of electri- brain injury, which may respond to thera-
cal activity (i.e., frequency and amplitude of peutic strategies for brain resuscitation.127
Table 18-8. Classification of Severity of Periventricular-Intraventricular Hemorrhage
Severity Staging of Papile et al (1978)129 Staging of Volpe (1995)1

Grade I Subependymal bleeding only Subependymal bleeding only, or <10% of
ventricular area filled with blood
Grade II <50% of ventricular area filled with blood; no 10%-50% of ventricular area filled with blood
ventricular dilation
Grade III >50% of ventricular area filled with blood; blood in >50% of ventricular area filled with blood;
white matter of centrum semiovale; ventricular dilation ventricular dilation
eventually is resorbed into the head of the

EDITORIAL COMMENT: Cerebral palsy is an um-
caudate. Hemorrhages within the subepen-
brella term encompassing a group of nonprogressive,
dymal region may be clinically silent, even
noncontagious motor conditions that cause physical
if ventricular dilatation occurs. Intraventric-
disability in human development chiefly in the various
ular hemorrhage results when venous sta-
areas of body movement. Most publications address
sis causes the ependymal lining to rupture,
the high rates and risk of cerebral palsy associated
with extravasation of blood that may extend
with preterm delivery. Nonetheless, numerically it is
into the ventricular space. The severity of
term and near-term infants who account for the major-
PIVH is graded based on the presence of
ity of cases of cerebral palsy despite their significantly
ventriculomegaly and amount of intraven-
lower risk. The risk of cerebral palsy is lowest at 40
tricular blood (see Fig. 18-11, B and Table
weeks, with the higher risks at 37 weeks and at 42
18-8).129 Although PIVH is a hemorrhagic
weeks or later.
event with leakage of blood due to rupture
of the thin endothelial lining of vessels
within the germinal matrix, the hemorrhage
originates because of venous stasis. More
CEREBROVASCULAR LESIONS OF THE severe venous stasis affects blood drainage
NEONATE more proximally within the terminal vein
Cerebrovascular lesions occur in both the pre- or the medullary veins of the deep white
term and full-term brain as a result of varying matter below the developing neocortex.
pathologic processes (e.g., asphyxia), infec- A hemorrhagic infarction may then result
tion, or blood disorders.34,35,38 Two manifes- and is graded as the most severe form of
tations of cerebrovascular disease processes intraventricular hemorrhage, documented
may occur: intracranial hemorrhage (ICH) as a parenchymal hemorrhage within a
and intracranial occlusive lesions. region of ischemia on neuroimaging or
The demographics of ICH have changed postmortem examination. Whereas a sym-
considerably over the past several decades. metric ischemic pattern of injury is noted
Two specific forms of ICH have decreased in with PVL, which is in an arterial distribu-
occurrence: subdural hemorrhage in term tion, the venous infarction associated with
infants and intraventricular hemorrhage in PIVH is asymmetric and may be extensive
preterm infants. In general, however, brain with accompanying ventriculomegaly.
injuries related to cerebrovascular lesions PIVH may subsequently give rise to
remain important structural correlates of hydrocephalus as a result of posthemor-
neurologic sequelae. rhagic adhesive arachnoiditis. Although
compensatory ventriculomegaly is expected
Periventricular-Intraventricular to occur during the first several weeks after
Hemorrhage hemorrhage, the time course for the estab-
Periventricular-intraventricular hemorrhage lishment of progressive hydrocephalus is
(PIVH) is the most frequent type of intracra- unknown. Both the initial hemorrhagic
nial hemorrhage in the neonate and over- venous infarction and progressive hydro-
whelmingly occurs in preterm infants (60% cephalus contribute to long-term neuro-
in infants weighing <1000 g compared with logic sequelae.
40% in larger infants).128 In preterm infants
PIVH originates primarily in the subepen- Periventricular Leukomalacia
dymal germinal matrix, a highly vascular PVL is an ischemic mechanism in the pre-
area that gives rise to neurons and glia dur- term brain that was described previously
ing brain maturation.1 The germinal matrix in the section on asphyxia. The tissue
destruction that follows an ischemic event Thalamic hemorrhage is an uncommon

caused by either asphyxia or inflamma- but potentially devastating form of intrapa-
tion130 results in gliosis with or without renchymal hemorrhage that is more com-
cavitation, usually limited to the white mat- monly seen in term infants.
ter region within the trigone of the white Primary subarachnoid hemorrhage is
matter, above the occipital horns, along the perhaps the most common form of intra-
optic radiations, or more anteriorly along cranial hemorrhage and occurs even after
the body and frontal horns of the lateral ven- seemingly nontraumatic deliveries.82 The
tricles. Twenty-five percent of children with true incidence of subarachnoid hemor-
PVL also experience PIVH; extensive forms rhage remains elusive because many infants
of PVL produce multicystic encephalomala- remain asymptomatic and the incidence of
cia. Unlike the asymmetric presentation in neurologic sequelae is generally low.
PIVH, PVL lesions are largely symmetric (see The field of neonatal neurology, and
Fig. 18-11, C). specifically its focus on the premature
infant, had its inception in neuropatho-
Other Intracranial Hemorrhages logic studies. Since then, the development
in the Neonate of advanced imaging techniques has guided
Other hemorrhagic events in the brain our developing understanding of the etiol-
occur less commonly. Subdural hemor- ogy and nature of neonatal brain injury.
rhage results from tentorial tears after rup- Brain injury in premature infants is of enor-
ture of the straight sinus, vein of Galen, or mous public health importance because of
small afferent veins. Subdural hemorrhages the large number of such infants who sur-
are mainly of traumatic origin in term vive with serious neurodevelopmental dis-
infants of higher birth weights. Posterior ability, including major cognitive deficits
fossae subdural hemorrhage may also occur and motor disability. Cognitive deficits
as a result of excessive head molding in the without major motor deficits are the most
vertex presentation or after excessive trac- common neurodevelopmental sequelae in
tion on the skull of the infant in a breech preterm infants, affecting 50% of infants
presentation.1,82 with a birth weight below 1000 g. This type
A third form of hemorrhage occurs within of brain injury is generally thought to con-
the cerebellar tissue within the posterior sist primarily of PVL, a distinctive form of
fossae, either after asphyxia or as a result of cerebral white matter injury. Important
mechanical trauma from occipital osteodia- new work using MRI and neuropathologic
stasis or traumatic cerebellar injury.131 techniques to study brain disease in survi-
vors of preterm birth shows that PVL is fre-
quently accompanied by neuronal-axonal
EDITORIAL COMMENT: Advances in imaging, in- disease affecting the cerebral white matter,
cluding cranial ultrasonography and magnetic reso- thalamus, basal ganglia, cerebral cortex,
nance imaging, have resulted in increased recognition brain stem, and cerebellum. This constella-
of cerebellar hemorrhage.132 The impact of cerebellar tion of PVL and neuronal-axonal disease is
hemorrhage is becoming apparent, and 40% of in- sufficiently distinctive to be termed enceph-
fants with such hemorrhage demonstrate neurologic alopathy of prematurity. Volpe’s thesis is that
abnormalities. Hemorrhage seen only on magnetic “the encephalopathy of prematurity is a
resonance imaging is associated with a much more fa- complex amalgam of primary destructive
vorable outcome than that visible on ultrasonography. disease and secondary maturational, devel-
Cerebellar injury in term infants is linked with a broad opmental and trophic disturbances.”135,136
spectrum of neurodevelopmental disabilities, particu-
larly in infants with large cerebellar lesions. Cerebellar NEONATAL SEIZURES
injury in preterm infants is associated with impaired Neonatal seizures remain one of the few neu-
growth of the uninjured contralateral cerebral hemi- rologic emergencies, and this condition may
sphere with significant impairment evident as early as indicate significant dysfunction or damage
term-equivalent age.133,134 to the immature nervous system both on
a remote and on an acute basis.4,94,137-141
Advances in neurophysiologic monitoring of
Other intraparenchymal hemorrhage within the high-risk infant have spurred the devel-
the cortex can occur in either term or pre- opment of an integrated classification of
term infants, usually in association with both clinical and electrographic criteria for
subarachnoid hemorrhage. diagnosis of seizures.142 Synchronized video
Extremely low-birth-weight infants with

clinical seizures are at increased risk of an
adverse neurodevelopmental outcome, inde-
pendent of multiple confounding factors.
Seizure Detection: Clinical versus

Electroencephalographic Criteria
Neonates are unable to sustain generalized
tonic followed by clonic seizures as observed
in older patients, although separately occur-
ring generalized tonic and clonic events do
appear, even in the same neonate. Most sei-
zures are brief and subtle, and consequently
Figure 18-16. Segment of a video electroencephalogram are expressed as clinical behaviors that are
for a 32-week gestational age, 5-day-old female with unusual to recognize. Five clinical categories
electroclinical seizures characterized by bitemporal of neonatal seizures have been described.1
electrographic discharges coincident with tonic posturing Several caveats should be mentioned before
to the left. these five clinical categories are reviewed.143
First, the clinician should be suspicious of
any abnormal repetitive stereotypic behav-
EEG-polygraphic techniques as well as com- ior that could represent a possible seizure.
puter-assisted analyses allow the clinician to Second, certain behaviors such as orbital
better characterize suspicious clinical behav- and buccolingual movements, tonic postur-
iors that may or may not be associated with ing, and myoclonus can be associated with
coincident surface-generated electrographic either normal neonatal sleep behaviors or
seizures (Fig. 18-16). Nonetheless, because nonepileptic pathologic behaviors. Third,
of the reliance on detecting suspicious clinical events may have only an incon-
clinical behaviors, recognition of neonatal sistent relationship to coincident electro-
seizures is still hampered by both overesti- graphic seizures.
mation and underestimation of their occur-
rence. Clinical criteria for suspected seizures Subtle or Fragmentary Seizures
may not easily distinguish seizure activity Subtle or fragmentary seizures constitute the
from either normal or pathologic nonepi- most frequently observed clinical group of
leptic behavior; coincident EEG is needed seizure-like phenomena and may be charac-
to best define the diagnosis. Subclinical EEG terized by repetitive facial activity, unusual
seizures may also occur that escape detec- bicycling or pedaling movements, momen-
tion by clinical observation alone. Con- tary fixation of gaze, or autonomic dysfunc-
versely, EEG criteria may not adequately tion. Specific autonomic signs such as apnea
recognize ictal patterns that originate from are rarely seen in isolation but usually occur
subcortical brain regions, but no universal in the context of other seizure phenomena
classification based on clinical criteria can in the same neonate. Even though these
distinguish subcortical seizures from nonep- clinical expressions appear unimpressive,
ileptic paroxysmal activity, although there they may reflect significant brain dysfunc-
is speculation regarding electroclinical dis- tion or injury. An inconsistent relationship
association. Certain clinically apparent sei- between specific subtle behaviors and EEG
zures originate in subcortical structures and seizures has been documented using syn-
only intermittently propagate to the corti- chronized video EEG-polygraphic record-
cal surface where EEG electrodes can readily ings, which emphasizes the need for further
record electrographic seizures. One prag- classification.144 It is generally considered
matic approach to the diagnosis and man- standard practice to require that suspicious
agement of neonatal seizures is therefore clinical behaviors occurring in close tem-
based on the documentation of seizures by poral proximity to EEG seizure patterns be
surface-recorded EEG studies. A therapeutic considered indicative of seizure.
end point for the use of antiepileptic medi-
cations can be more practically achieved Clonic Seizures
using EEG documentation, because clinical Clonic seizures are characterized by rhyth-
signs may be absent, minimal, or nonepilep- mic movements of muscle groups in a focal
tic in origin. or multifocal distribution. Rapid followed
by slow movement phases distinguish clonic information to the clinician regarding the
movements from the symmetric to-and-fro presence, severity, and persistence of an
movements of nonepileptic tremulousness encephalopathic state in the neonate.
or jitteriness.145,146 Whereas gentle flexion
of the extremity can suppress tremors, this is Interictal EEG Patterns. Background EEG
not possible with clonic seizure activity. The abnormalities have prognostic significance
clonic event may involve any muscle group for both preterm and full-term infants.149,150
of the face, limbs, or torso. Focal clonic sei- Such patterns include burst suppression,
zures may be associated with localized brain electrocerebral inactivity, low voltage invari-
injury, but they can also accompany gener- ant, and persistent multifocal sharp wave
alized cerebral disturbances.147,148 Following abnormalities (Fig. 18-17). Other interictal
seizures, newborns may also have a tran- EEG abnormalities, such as disparity in the
sient period of paresis or paralysis, called maturity of EEG and polygraphic activities,
Todd’s phenomenon. also have prognostic importance but require
greater skill in visual analysis to identify.67
Tonic Seizures
Tonic seizures are characterized by sustained Ictal EEG Patterns. Ictal EEG patterns in the
flexion or extension of either axial or appen- newborn are composed of repetitive wave-
dicular muscle groups, such as decerebra- forms of a certain minimum duration and
tion or dystonic posturing (see Fig. 18-16). similar morphology that evolve in response
Focal head or eye turning or tonic flexion or to frequency, amplitude, and electric field.
extension of an extremity exemplifies tonic The electroencephalographer can readily
seizures. Although some tonic behaviors are identify seizures that are at least 10 seconds
coincident with EEG seizures, there is a high in duration.151 Four categories of ictal pat-
false-positive correlation, with tonic behav- terns have traditionally been described:
ior occurring in the absence of concurrent focal ictal patterns with normal back-
electrical seizure activity. ground, focal ictal patterns with abnormal
background, focal monorhythmic periodic
Myoclonic Seizures patterns of various frequencies, and multi-
Myoclonic movements are rapid, isolated focal ictal patterns.
jerks involving the midline musculature or Neonatal encephalopathies should be
a single extremity either in a generalized or characterized in functional terms based on
multifocal fashion. Unlike the movements both interictal and ictal abnormalities and
in clonic seizures, which show fast and slow on severity and persistence over time.152
phases, myoclonic movements lack a two- The persistence of abnormal patterns in
phase movement. Healthy preterm and serial studies is more significantly corre-
term infants may demonstrate abundant lated with neurologic sequelae, although
myoclonic movements during either sleep EEG patterns rarely denote a particular dis-
or wakefulness.145,146 However, sick neo- ease state. Brain lesions documented on
nates may also exhibit myoclonus, which is neuroimaging or postmortem examination
either verified as seizure activity by EEG or may have had an electrographic signature
determined to be a manifestation of nonepi- on EEG studies on an acute, subacute, or
leptic abnormal motor activity.90 chronic basis. Therefore, EEG patterns must
be analyzed in the context of history, clini-
Electroencephalographic Seizure Criteria cal findings, laboratory information, and
EEG remains an invaluable tool for the assess- neuroimaging.
ment of both ictal and interictal cerebral
activity, as expressed on surface recordings. Clinical Correlates of Neonatal Seizures
Although an EEG finding is rarely pathog- Neonatal seizures are not disease specific
nomonic for a particular disease, important and may be caused by a number of medical
information about the presence and severity conditions. Establishing a specific reason
of a brain disorder with or without seizures for seizures in any infant is essential both
can be gained from careful visual interpreta- for treatment and for prediction of neuro-
tion.67 Major EEG background rhythm distur- logic outcome. Neonates with an encepha-
bances in the absence of seizures carry major lopathy or brain disorder may or may not
prognostic implications for compromised have seizures, and they commonly come
outcome. Specific interictal EEG abnormali- to attention because of a variety of distur-
ties on serial EEG recordings offer invaluable bances.67
42 wk 2 D/O
FP1-T3
T3 -O1
FP2-T4
T4 -O2
FP1-C3
C3 -O1
FP2-C4
C4 -O2
T3 -C3
C3 -Cz
Cz -C4
C4 -T4
Fz -Cz
Cz -Pz
T3 -Cz
T4 -Cz
EMG CHIN
LOC
ROC
RESP
EKG 50 µV
2 SECS
Figure 18-17. Segment of an electroencephalogram for a 42-week gestational age, 2-day-old male infant demonstrating
a burst suppression pattern with multifocal sharp waves and attenuation of activity in the right temporal and midline (T4 and
C2) region.
Asphyxia asphyxia in a newborn who may also experi-

Postasphyxial encephalopathy, the prin- ence seizures. Therefore, the events that lead
cipal disorder during which neonatal sei- to asphyxia must be considered in the con-
zures may occur, can also be accompanied text of the findings of the maternal, placen-
by hypoglycemia, hypocalcemia, cerebro- tal, and neonatal examinations, as well as
vascular accidents, or intraparenchymal the corroborative laboratory results. Adverse
hemorrhage. These latter conditions, indi- events during labor and delivery may reflect
vidually or in combination, can contribute longer-standing maternal, placental, or
to seizures. cord disorders that contribute to postnatal
Most neonates experience asphyxia either seizures, hypotonia, or coma. HIE, includ-
before or during parturition. In only 10% of ing neonatal seizures, develops in only 45%
affected neonates does asphyxia result from of infants who experience asphyxia at the
postnatal causes. Intrauterine factors lead- time of birth.122 Similarly, meconium stain-
ing to asphyxia before or during labor and ing of skin, placental tissue, or cord tissue
delivery compromise gas exchange or glu- can occur in asymptomatic infants with or
cose movement across the placenta. These without intrauterine insults. Distribution of
factors may be maternal (e.g., toxemia) or meconium-laden macrophages throughout
uteroplacental (e.g., placental abruption the placental amnion generally indicates
or cord compression) in origin. However, fetal distress in the antepartum period.153
other maternal conditions such as ante- Placental weights lower than the 10th or
partum trauma or infection not only are higher than the 90th percentile, altered
associated with acquired brain insults from placental villous morphology, lymphocytic
asphyxia but also may contribute to the for- infiltration, and erythroblastic prolifera-
mation of congenital malformations during tion in the villi indicate longer-term stress
early pregnancy, as detected by fetal ultra- to the fetus, whether or not seizures occur
sonography or cranial imaging of the infant during the period immediately after birth in
immediately after birth. Respiratory distress a neonate who is neurologically depressed.
syndrome, pulmonary hypertension of the In neonates with EEG-confirmed seizures,
newborn, and severe right-to-left cardiac the odds that antepartum placental lesions
shunts associated with congenital heart would be identified increased by a factor
disease are other major causes of postnatal of 12 as postconceptual age increased by
15 weeks.60 Other findings on neurologic and hypertensive encephalopathy. When

examination, such as hypertonia, joint isolated seizures occur in neonates with no
contractures without profoundly depressed accompanying encephalopathy, the cause
consciousness, seizures within the first can be timed to the antepartum period.156
hours after delivery, growth restriction, and
neuroimaging evidence of encephalomala- Infection
cia, separately or collectively point to the CNS infection acquired in utero or post-
antepartum period as the time when brain natally may give rise to neonatal seizures.
injury occurred. Congenital infections that are usually asso-
ciated with a severe encephalitis are also
Hypoglycemia accompanied by seizures and major inter-
Low blood glucose levels can result in sei- ictal EEG background disturbances. For
zures, either in association with asphyxia or instance, neonatal herpes encephalitis is
as a separate metabolic consequence of the associated with severe ictal and interic-
hypoglycemia. Infants of diabetic or tox- tal EEG pattern abnormalities consisting
emic mothers, those born as one of multiple of multifocal seizures as well as multifocal
gestation siblings, and, rarely, those with periodic discharges.49 Acquired in utero
metabolic diseases may also have hypogly- or postnatal bacterial infections caused by
cemia. (See Chapter 12.) Escherichia coli or group B streptococci may
result in neonatal seizures. Listeria monocy-
Hypocalcemia togenes and mycoplasma infections can also
Whereas hypoglycemia may be associated produce areas of lymphocytic infiltration
with seizures in neonates with asphyxia, and resultant encephalomalacia.
hypocalcemia may be seen in the context
of trauma, hemolytic disease, or metabolic Central Nervous System Malformations
disease. Hypomagnesemia may also occur Brain lesions that result from either genetic
in infants with hypocalcemia. Rarely, a or acquired defects during early fetal brain
form of hypocalcemia may be caused by development also contribute to neonatal
congenital hypoparathyroidism or may seizures (Fig. 18-18). Such lesions include
occur with delayed onset in an infant who microgyria, heterotopia, and lissencephaly.
received a high-phosphate infant formula. Other dysgenic CNS conditions such as
Congenital cardiac lesions have been found holoprosencephaly, schizencephaly, and
in some infants with seizures caused by congenital hydrocephalus may also be asso-
hypocalcemia or hypomagnesemia.154 (See ciated with neonatal seizures.
Chapter 12.)
Inborn Errors of Metabolism
Cerebrovascular Lesions Inherited biochemical defects are rare
Intracranial hemorrhage as well as ischemic causes of neonatal seizures.141 Peculiar body
cerebrovascular lesions can occur as a result odors, intractable seizures that occur later
of asphyxia, trauma, or infection, or in asso- in the newborn period, and persistently ele-
ciation with developmental or congenital vated lactate, pyruvate, ammonia, or amino
lesions. PIVH in the preterm infant who also acid levels in the blood may reflect inher-
has seizures has already been discussed.155 ited biochemical disorders rather than tran-
However, full-term infants with seizures sient postasphyxial insults. Neonates with
may also have intraventricular hemorrhage, metabolic disease may also have otherwise
usually arising within the choroid plexus or normal prenatal and delivery histories. The
thalamus. Intracranial hemorrhage at other emergence of food intolerance, increasing
sites (e.g., subdural space, subarachnoid lethargy, and late onset of seizures may be
space, or into the parenchyma) can also be the only indication of an inborn error of
associated with seizures that occur together metabolism. Certain conditions are respon-
with or independently of postasphyxial sive to supplementation or dietary altera-
encephalopathy. tion; for example, vitamin B6 dependency
Arterial and venous infarctions have is a rare form of metabolic disturbance
been noted in neonates with seizures.147,148 that can lead to intractable seizures which
Cerebral infarctions can occur during the are unresponsive to conventional antiepi-
antepartum, intrapartum, or neonatal peri- leptic medication.157 Glucose transporter
ods from diverse causes such as persistent deficiency syndromes are suspected when
pulmonary hypertension, polycythemia, CSF levels of glucose are low, and some
5 wk 1st DOL
FP3-T3
T3 -O1
FP4-T4
T4 -O2
FP3-C3
C3 -O1
FP4-C4
C4 -O2
T3 -C3
C3 -Cz
Cz -C4
C4 -T4
Fz -Cz
Cz -Pz
T3 -Cz
T4 -Cz
EMG CHIN
Pg1A1
Pg2A2 } OUTER
CANTHUS
RESP
EKG
Sen I-50 µv
7 P.S.15 mm/sec
A 2 sec
B
Figure 18-18. A, Segment of an electroencephalogram (EEG) for a 35-week gestational age, 1-day-old female infant with
periodic discharges at the midline (Cz). B, Computed tomographic scan documenting a lobar holoprosencephaly in the
same infant.
patients may respond to the ketogenic diet Major antiepileptic drug classes have been
regimen.158 used to treat neonatal seizures. Phenobarbi-
tal is the most commonly used antiepileptic
Neonatal Epileptic Syndromes medication, with a recommended loading
Few clinical situations involving neonatal dose of 20 mg/kg and a maintenance dosage
seizures represent a chronic epilepsy syn- of 3 to 5 mg/kg/day. Half-life of the drug is
drome. Most seizures in newborns reflect long, 40 to 200 hours.
transient disturbances that resolve over Phenytoin is the second most commonly
days (e.g., asphyxia, metabolic-toxic con- used medication for the treatment of sei-
ditions, infections). Rarely, a newborn has zures. A loading dose of phenytoin is 15 to
an ongoing epileptic condition that is inde- 20 mg/kg and a maintenance dosage is 4 to
pendent of, but perhaps is triggered by, 8 mg/kg/day. Maintenance doses may be
adverse events during fetal or neonatal life. given intravenously or orally; however, oral
A rare form of familial neonatal seizures has absorption can be erratic.160
been described with an autosomal domi- Some clinicians prefer to use benzodiaz-
nant inheritance pattern.159 The diagnosis epines for the acute treatment of seizures,
requires careful exclusion of acquired causes. particularly when phenobarbital or phenyt-
In two pedigrees the genetic defect for this oin is no longer effective. Lorazepam is one
condition was assigned to two genetic loci choice in this class of medication, and the
on chromosome 20. Although most new- recommended intravenous dose is 0.1 mg/
borns with the disorder respond promptly kg.160 Other benzodiazepines such as diaz-
to antiepileptic drug treatment and develop epam or midazolam, which vary in half-life,
in an age-appropriate manner, some chil- have also been used (Table 18-9). Benzodi-
dren experience delay at older ages. A defect azepines are not typically used for mainte-
in potassium-dependent channel kinetics nance therapy because of the potential for
has been described. tolerance and side effects.
Other rare epileptic states include pro- For refractory seizures, new agents are
gressive syndromes associated with severe available that have been used with some
myoclonic seizures and progressive devel- success as adjuvant therapy. Levetiracetam
opmental delay. These children have been is the most common of these new agents,
described as having an early infantile epilep- but its safety and efficacy data in neonates
tic encephalopathy (Ohtahara syndrome) are limited. The small studies that have
and usually have severe brain dysgenesis. been done suggest that it prevents neuro-
degeneration better than other agents. Dos-
Treatment of Neonatal Seizures ing begins at 10 mg/kg every 24 hours and
Before antiepileptic medications are admin- can be increased to a maximum of 60 mg/
istered, an acute rapid infusion of glucose or kg/day. Mild sedation is the only side effect
other electrolytes such as calcium or mag- that has been observed.161,162
nesium should be considered. Low magne- Free or unbound drug fractions have been
sium level and altered sodium metabolism suggested to affect the efficacy and poten-
are less common causes of neonatal seizures tial toxicity of antiepileptic drugs in pedi-
and do not require antiepileptic medica- atric populations, including the neonatal
tions.141 population. Binding of drugs can be altered
Questions persist with respect to when, significantly in neonates with seizures, par-
how, and for how long to administer antiep- ticularly in sick neonates with metabolic
ileptic medications to neonates who experi- dysfunction. Biochemical alterations may
ence seizures. Some believe that neonates cause toxic side effects by increasing the free
should undergo treatment only when the fraction of the drug, which readily affects
clinical signs of seizure are recognized and cardiovascular or respiratory function. Reg-
that brief electrographic seizures need not be ular monitoring of serum drug levels (free
treated. Others argue that this practice may and total) along with assessment of seizure
be potentially harmful because undetected control may improve the titration of anti-
repetitive or continuous electrographic sei- epileptic drugs.163
zures may adversely affect the metabolism The decision to maintain or discontinue
and cellular integrity of the immature brain. antiepileptic drug treatment is fraught
Consensus is lacking on the need for treat- with uncertainty.141 Practice varies widely,
ment when clinical seizure phenomena are with discontinuation of long-term therapy
minimal or absent.143 occurring from 1 week to 12 months after
518
Table 18-9. Treatment of Neonatal Seizures with Antiepileptic Medications
Phenobarbital Phenytoin Lorazepam Midazolam Diazepam Levetiracetam

Delivery route IV, IM, PO IV, PO IV IV IV IV, PO
Initial loading dose 20 mg/kg IV 15-20 mg/kg IV 0.1 mg/kg 0.15 mg/kg 0.1 mg/kg
Rate of administration Give IV dose over Give IV dose over 30 Slow push Slow push over at Give IV dose over 3-5 Give IV dose over 15
10-15 min min least 5 min min min
Max infusion rate of 0.5
mg/kg/min
Maintenance dosage 3-5 mg/kg every 24 hr 4-8 mg/kg every 24 hr Repeat dose prn Repeat dose prn Repeat dose prn 10-60 mg/kg/day
IV, IM or PO IV or PO based on response based on response based on response divided every 12-24 hr
Timing of first mainte- 12-24 hr after loading 12-24 hr after loading
nance dose
Therapeutic level 20-40 µg/mL Total drug concentra-
tion: first week 6-15 µg/
mL then 10-20 µg/mL
Serum half-life Varies from 40 to 200 18-60 hr, decreasing 40 hr 4-22 hr 50-95 hr 18 hr in neonates,
hr depending on age with age decreasing to 6 hr by 6
and duration of drug mo of age
usage
Possible adverse effects Sedation, respiratory Bradycardia, arrhyth- Respiratory depres- Respiratory depres- Respiratory depres- Sedation, irritability
depression (at serum mias, hypotension sion, myoclonic sion, hypotension, sion, hypotension
concentrations >60 during infusion jerking myoclonic jerking
µg/mL)
IM, Intramuscular; IV, intravenous; PO, by mouth; prn, as needed.

the last seizure. Because there is the poten-

tial for antiepileptic medications to damage
the developing nervous system, prompt dis-
continuation in the late neonatal period or
early infancy is recommended. This is espe-
cially true for infants who show no demon-
strable brain lesions on cranial imaging,
who exhibit appropriate findings on neuro-
logic examination, and who express normal
interictal EEG background patterns.1
Despite the urgent need to establish the
cause of a seizure, several unique aspects A
of neonatal seizures impede prompt diag-
nosis and treatment. There are a number
of etiologic possibilities for neonatal sei-
zures, and the efficacy of conventional
antiepileptic drugs in controlling seizures
remains controversial. Neonatal seizures
can reflect either acute or remote dis-
ease processes or can result from a series
of insults that began in the antepartum
period and extend to include events during
the intrapartum or postnatal periods. This B
knowledge of the acute or chronic causes
of neonatal seizures will alter the clini- Figure 18-19. A, Three-month-old infant with marked
cian’s choice of an antiepileptic treatment hypotonia resulting from neuromuscular disease. B,
Decerebrate posturing after severe asphyxia in a term
in the future. Neurorescue protective ther-
infant.
apy such as hypothermia can be helpful,
as can combinations of drugs that prevent
seizures from arising in immature neuronal manifestation of HIE (as discussed previ-
pathways that are injured, namely, pheno- ously) or of other acute forms of neonatal
barbital and levetiracetam. disease with metabolic or infectious causes.
Other cerebral causes of hypotonia are
HYPOTONIA congenital infections and genetic diseases,
Evaluation of tone in the neonate requires including inherited disorders of metabolism
considerable experience and perseverance by involving glucose, amino acids, fatty acids,
the clinician.164 The earlier section on clini- or peroxisomal pathways.
cal examination techniques discussed evalu- Peripheral causes of neonatal hypotonia
ation of the motor system and evaluation also usually result in greater degrees of weak-
of the infant with altered tone, principally ness, often including respiratory and swal-
hypotonia and, less commonly, hypertonia lowing difficulties. In cases of hypotonia
(Fig. 18-19). Clearly, the approach to the associated with anterior horn cell disease (i.e.,
diagnosis of hypotonia requires an under- progressive spinal muscular atrophy), infants
standing of the neuroanatomic locations are alert and their behavior is otherwise nor-
in the neuraxis that may be responsible for mal. In other clinical situations, such as neo-
producing low tone in the neonate. Such natal myotonic dystrophy or Prader-Willi
locations include the cerebrum, spinal cord, syndrome, there may be a mixture of central
peripheral nerve, and neuromuscular junc- and peripheral involvement in motor path-
tion or muscle (see Table 18-6). The clini- ways, causing hypotonia as well as other dis-
cal approach to hypotonia in the neonate is orders of cerebral or systemic function.120,165
summarized in Table 18-10. Most hypotonic Neonatal myasthenia gravis should be
neonates have disorders of the cerebrum. considered in neonates who are the offspring
In these situations, hypotonia is usually of myasthenic mothers and who have hypo-
not accompanied by profound weakness, tonia located at the neuromuscular junction.
and other signs of brain dysfunction such These infants exhibit cranial nerve deficits
as lethargy, swallowing difficulties, and such as facial diparesis, ptosis, and ophthal-
abnormal primitive reflexes are present. moplegia, as well as respiratory depression.166
Hypotonia can be one prominent clinical Exogenous causes of hypotonia include the
520
Table 18-10. Approach to Diagnosis of Hypotonia
Clinical Features Laboratory Aids
Eye Tongue Deep Electro- Muscle

Anatomic Pathogen- Move- Fascicula- Tendon Muscle myogra- Muscle Enzyme Neostig-

Site esis Alertness Cry ments tion Reflexes Bulk phy Biopsy (CPK)* mine
Cerebral Malforma- Poor Poor Occasion- No Normal or Normal Normal Normal Normal Negative
tion ally abnor- increased
Hemorrhage mal
Hypoxia-
ischemia
Metabolic
disorder
Infection
Drugs
Spinal cord Injury Good Normal Normal No Decreased Normal Normal Normal Normal Negative
or increased
Anterior Spinal Good Normal or Normal Yes Absent Decreased Neurogenic Neurogenic Normal Negative
horn cell muscular weak pattern group
atrophy†
(Werdnig-
Hoffmann
disease)
Neuro- Neonatal Good Weak Abnormal No Normal Normal ± Normal Normal Normal Negative
muscular myasthenia
junction gravis
Muscle Congenital Good Good Normal No Decreased Decreased Myopathic Myopathic Normal or Positive
myopathy or normal pattern change elevated
Myotonic
dystrophy‡
Glycogen
storage
disease
*CPK level is grossly elevated in Duchenne dystrophy, which does not usually manifest as hypotonia in neonates.
†Molecular diagnosis identifies survival motor neuron (SMN) gene deletions or mutations by analysis of blood, amniotic fluid, or tissue.
‡Molecular diagnosis of myotonic dystrophy identifies cytosine-thymine-guanine triplet repeat expansion.
CPK, Creatine phosphokinase.

administration of drugs to the mother, such A full-term infant who is clearly awake does not
as inappropriate systemic or local injections move below the neck except for fine myoclonic
of anesthetics that pass to the infant through movements of the fingers and toes, and shows
the placental circulation or are introduced fasciculations of the tongue. What study should
directly into the infant’s scalp at the time of the neonatologist request?
administration of paracervical or pudendal
blocks. These medications may cause a char- A specific serum-based genetic study to
acteristic syndrome of hypotonia, respira- diagnose spinal muscular atrophy should be
tory depression, and seizures during the first ordered.
day of life. Administration of magnesium or Anterior horn cell disease (i.e., spinal
aminoglycoside may result in transient neu- muscular atrophy, historically called Werd-
romuscular dysfunction leading to profound nig-Hoffmann disease) can be expeditiously
weakness and hypotonia. diagnosed by genetic analysis using a serum
Connective tissue abnormalities also may sample to document a deletional defect
be associated with low tone, particularly those on chromosome 7. This genetic study has
involving mesenchymal tissue, such as in Mar- largely replaced the more laborious and
fan syndrome and Ehlers-Danlos syndrome. indirect diagnostic investigations, includ-
Myopathies associated with either spe- ing electromyography and muscle biopsy,
cific muscular dystrophies or congenital which lack genetic specificity.
myopathies can present with neonatal Fasciculation is best evaluated with the
hypotonia and are generally accompanied tongue at rest.
by some degree of weakness or decrease in
muscle bulk. A mixture of lower and upper
motor neuron diseases is noted in certain True or False
congenital muscular dystrophies, as well as A newborn who is in neurologically depressed
in mitochondrial myopathies. condition at the time of birth with evidence of
fetal acidosis, low Apgar scores, and neonatal
seizures has always experienced asphyxia during
QUESTIONS the intrapartum period.
A full-term newborn whose mother had prema- Asphyxia in the neonate, as documented
ture rupture of membranes and a fever to 39° C by clinical and laboratory examination,
has a bulging fontanelle, seizures, and irritability. can have antepartum as well as intrapar-
Spinal fluid shows evidence of 100 white blood tum causes. Even though the infant may
cells µL and elevation of the CSF protein level to become symptomatic during a problematic
200 µg/dL. Is this evidence of intracranial hemor- labor and delivery that leads to asphyxia,
rhage, meningitis, or ganglioneuroma? the intrapartum period may not be the
time during which brain damage occurred.
The infant has an increased risk of infection Therefore, the statement is false.
because of premature rupture of membranes
in a mother with probable chorioamnionitis.
Careful examination of the placenta reveals True or False
lymphocytic infiltration, villous edema, and An elongated head shape in a preterm infant who
intravascular thrombin deposition. The CSF is a corrected age of 44 weeks suggests cranio-
findings are typical of meningitis. synostosis, and a neurosurgical referral should be
made immediately.
A growth-restricted newborn of 37 weeks’ gesta-
tion shows irritability, hypotonia, hepatospleno Even though craniosynostosis must be sus-
megaly, and chorioretinitis. Congenital infection is pected in a child with an abnormal head
suspected. Should the attending neonatologist ob- shape, premature infants commonly experi-
tain a cerebral CT scan rather than an MRI scan? ence inhibition of lateral head growth because
the head is turned to either side in contact
A CT scan better documents calcifications with the mattress. In most of these infants, no
associated with congenital infection, so CT is premature closure of the sagittal suture can
appropriate. An MRI study would otherwise be documented. The Back to Sleep campaign
be preferred for an infant suspected to have has dramatically decreased the incidence of
brain lesions that require higher resolution sudden infant death syndrome; however,
to document structural anomalies or injury. its sequela of deformational plagiocephaly
has today reached epidemic proportions.

CASE 1
Other factors associated with nonsynostotic
occipital plagiocephaly are multiple gesta- A 2300-g male infant was born at term to a 34-year-
tions and torticollis. Breast feeding, because old mother who had multiple urinary tract infections
of frequent positioning changes, has a pro- during pregnancy. The mother had a fever 24 hours
tective effect. Plagiocephaly, literally “skull before delivery and foul-smelling amniotic fluid was
asymmetry,” is seen characteristically with noted after artificial rupture of membranes. During
unilateral coronal or lambdoidal synostosis. labor, electronic fetal monitoring showed fetal dis-
Premature closure of a unilateral coronal tress as evidenced by minimal heart rate variability
suture, anterior plagiocephaly, occurs in 1 and transient bradycardic episodes to 100 beats per
in 10,000 live births and is characterized by minute on three occasions before delivery. The infant’s
flattening of the forehead and elevation of condition appeared depressed at birth and he had
the eyebrow on the affected side. Fortunately Apgar scores of 1, 3, and 8 at 1, 5, and 10 minutes
most clinicians have learned to clinically dis- of life. The cord pH was 7.12 and the base excess
tinguish deformational plagiocephaly, asso- was −11. After resuscitation the infant became irrita-
ciated with sleeping in the supine position, ble and hypertonic with back arching on stimulation.
from craniosynostosis, so that unnecessary The vernix of the infant was noted to be foul smelling.
surgical correction is prevented. Therefore,
the statement is false. Did the mother’s urinary tract infections
contribute to the infant’s neonatal
encephalopathy?
True or False Although the infant’s condition was depressed at birth,
A 37-week gestational age female neonate the degree of metabolic acidosis and the rapid re-
showed spontaneous lateral eye movements, sponse to resuscitative effort suggests that other rea-
buccolingual and orbital twitching, irregular sons should be considered for the infant’s subsequent
respirations, and low tone. This constellation neurologic abnormalities and irritability and hypertonia.
of signs occurred intermittently over a 15- to The mother’s frequent urinary tract infections, the foul-
20-minute period followed by cessation of smelling amniotic fluid on rupture of the membranes,
these movements, resumption of regular cardi- and the malodorous vernix of the infant all point to the
orespiratory rates, and increased muscle tone. probable occurrence of chorioamnionitis.
A concurrent EEG recording would most likely
have documented neonatal seizures during the What diagnostic steps are indicated?
period when the twitching and other signs oc- In the context of infection, the infant should be ag-
curred. gressively evaluated for a systemic and/or CNS in-
fection. The cellular blood count showed an elevated
These observations represent appropriate white cell count of 20,200/µL but there was no dif-
clinical phenomena associated with active ferential shift to the left. Culture was performed on
(rapid eye movement) sleep followed by all body fluids, including tracheal aspirate, blood, spi-
quiet (non–rapid eye movement) sleep in nal fluid, and urine, as well as on nasopharyngeal,
a near-term infant. The movements during skin, and throat specimens. Blood glucose, calcium,
rapid eye movement sleep may superficially potassium, and sodium levels were measured, and
resemble seizures but have no EEG correlate; blood gas analysis, chest radiography and urinalysis
therefore, the statement is false. were performed.
Results of all the aforementioned studies were
normal. The CSF was clear with two white blood cells
True or False per µL, both lymphocytes. The CSF glucose level was
A cranial ultrasound scan documents bilateral 90 mg/dL, blood glucose level was 110 mg/dL, and
echodensities surrounding the ventricular outline. the CSF protein level was 94 mg/dL. The Gram stain
In addition, the echodensity extends into the left of the spinal fluid was also negative for organisms.
brain substance with high-density signal within Histologic evaluation of the placenta documented
the ventricular space. The neuroimaging report severe chorioamnionitis and funisitis.
concludes that both intraventricular hemorrhage
and periventricular leukomalacia occurred in this Despite the negative culture results,
preterm infant. Is this possible? should this infant be presumptively treated
for infection?
These two forms of cerebrovascular lesions Definitely. This infant should be treated for bacterial
can occur in the same preterm infant. The meningitis given the clinical picture described. The
statement is true.
presence of hypertonia, particularly with dystonic and revealed a right hemispheric hypodensity in the
posturing on stimulation, may suggest abnormal distribution of the right middle cerebral artery. Sei-
function of the CNS, particularly if the fontanelle is zures continued until two antiepileptic medications
full and bulging. Infection may be present even in the were administered. A diffusion-weighted MRI scan
absence of positive culture results. The mother’s fre- was subsequently obtained 1 day after the onset of
quent urinary tract infections and clinical evidence of seizures and documented an abnormal area in the
chorioamnionitis supported by histologic examination right hemisphere in the distribution of the right mid-
of the placenta puts the infant at high risk of infection. dle cerebral artery. An echocardiogram, complete
Chorioamnionitis seldom causes systemic inflam- blood count, blood chemistry panel including co-
mation in the mother. However, ascending maternal agulation studies, CSF analysis, and drug screen all
infections frequently lead to a systemic fetal inflam- showed normal results.
matory reaction manifested by funisitis and elevated No subsequent seizures were noted, and the
levels of proinflammatory cytokines. The fetal inflam- infant was discharged on day 8 of life with normal
matory response is considered to be the counterpart results on neurologic examination. Subsequent eval-
of the systemic inflammatory response syndrome. uations by the pediatrician and consulting pediatric
Furthermore, antenatal exposure to inflammation neurologist indicated that head circumference re-
may masquerade as an asphyxial insult and puts the mained within the normal range, although the infant
extremely premature neonate at high risk of worsen- showed asymmetry of spontaneous movements,
ing pulmonary, neurologic, and other organ develop- which were decreased on the left compared with the
ment. Bronchopulmonary dysplasia is more common right. Reflexes as well as passive muscle tone were
following the fetal inflammatory reaction. Surprisingly, also increased on the left. After placement in a sitting
the presence of chorioamnionitis may be associated position, the infant lacked a lateral prop developmen-
with a lower rate of neonatal mortality in extremely tal reflex when leaned to the left. At 9 to 10 months of
premature newborns. age he had an asymmetric parachute reflex, with ab-
sence on the left. He continued to demonstrate delay
in meeting motor milestones. An MRI scan in the sec-
ond year of life documented a left porencephaly. He
CASE 2 is now 7 years of age and requires special education
A male infant was delivered at 37 weeks’ gesta- classes as well as preventative treatment for seizures,
tion by cesarean section to a 32-year-old gravida 2, which recurred at 4 years of age.
para 0 woman. She had a previous pregnancy that
spontaneously terminated at 3 months’ gestation. When did the brain injury occur?
The mother has a diagnosis of inflammatory bowel The specific cerebrovascular injury in this child fits
disease, specifically ulcerative colitis. Throughout within the diagnostic entity of stroke syndrome. His
pregnancy her inflammatory bowel disease was qui- stroke event was ischemic with no hemorrhagic com-
escent until shortly before delivery when she had a ponent. The event more likely than not occurred be-
clinical flare consisting of bloody diarrhea and fever. fore delivery. Given the mother’s inflammatory bowel
Although the evaluation for infection yielded nega- disease with an active phase of ulcerative colitis,
tive results, she was given broad-spectrum antibi- there is the possibility of an acquired thrombophilia
otics as well as sulfasalazine (Azulfidine) and ste that may have led to occlusion of the right middle
roids. Over the subsequent 4 to 5 days her clinical cerebral artery due to thrombosis on the fetal sur-
symptoms of inflammatory bowel disease resolved. face of the placenta. This possibility is supported by
After the sixth day of treatment she spontaneously placental findings showing a fetal thrombotic vascu-
went into labor. Fetal heart monitoring showed late lopathy. Despite evidence of transient fetal distress,
decelerations 1 hour before delivery, consisting of there was no depression at birth and no evidence of
bradycardia into the range of 90 to 100 beats per a neonatal encephalopathy at the time of delivery or
minute. Apgar scores were 7 at 1 minute and 9 at during the first 2 days of life until the onset of sei-
5 minutes. The infant required deep suctioning and zures. Seizures can occur following a symptom-free
supplemental oxygen for 3 minutes. He was ex- period after delivery in the absence of encephalopa-
amined and the findings were normal, and he was thy. After experiencing seizures, the infant required a
taken to a well-child nursery. He was observed and prompt evaluation for infection, intracranial hemor-
showed no problems until 2 days of age, when cya- rhage, and drug withdrawal, given the onset of the
nosis with apnea was noted in association with left seizures in the newborn period without preexisting or
arm clonic activity that could not be suppressed concurrent encephalopathic findings. Once results
by the extremities. An EEG was obtained, which of these evaluations were found to be negative, then
documented focal electrographic seizures coin- the possibility of a focal brain disorder secondary to
cident with the clonic activity. CT was performed stroke syndrome, as indicated by neuroimaging and
EEG studies, had to be pursued. Before the availabil- alopathies (i.e., cerebral palsy). Good documentation
ity of neuroimaging, children with stroke syndrome of clinical abnormalities is important to allow an early
were classically identified during infancy based on intervention strategy to be offered.
congenital hemiparesis, and such children are at high
risk of epilepsy as well as cognitive and behavioral Can stroke syndromes be prevented in the
deficits at older ages. fetus and neonate?
Women at increased risk of thrombophilia, including
Why were results of the initial neurologic those with known genetic or acquired risk factors for
examinations normal until 2 days of age? stroke syndromes, may be treated prophylactically
The infant lacked a brain disorder following a normal with low-dose aspirin or heparin. There are no guar-
delivery and before 2 days of age. The stroke event antees that this approach will be successful. There is
had occurred in utero if signs or symptoms were evidence that women with active inflammatory bowel
present in the first 2 days, then a more recent injury disease may develop thrombophilia, which can im-
would have reflected acute brain destruction, cerebral pact the fetus, as occurred in this case.
edema, and possible associated hemorrhage.
Could earlier intervention to address
Could the stroke syndrome have occurred developmental difficulties have made a
during the intrapartum period rather than difference?
during the antepartum period? Early intervention programs provide additional stim-
Although fetal distress was noted, no depression was ulation and prevent contractures from abnormal
observed at birth. Seizures then were noted at 2 days hypertonicity of the legs. Monitoring of developmen-
of age in the absence of any previous alterations in tal progress may provide an incentive for parents to
tone or arousal consistent with a neonatal encepha- supplement stimulation at an earlier time and on a
lopathy. The abnormality seen initially on the head CT more frequent basis. It is unclear whether this early
scan and then on the brain MRI scan suggested that interventional strategy lessens the risk of later learn-
the stroke occurred before the intrapartum period. The ing disabilities and behavioral problems.
lack of convincing signs of neonatal encephalopathy
placed the timing of this injury to days before delivery.
Why did the infant appear normal at the REFERENCES

time of discharge in the newborn period The reference list for this chapter can be found
only to show developmental delay at a online at www.expertconsult.com.
later time?
The immaturity of the brain during the early months
of life does not allow clinical expression of deficits in
children who later demonstrate static motor enceph-
19
The Outcome of
Neonatal Intensive
Care
Maureen Hack
Technical advances and improvements in When outcome results are evaluated,

perinatal care have been mainly responsible considerable variation is noted in the
for the improved survival of high-risk neo- results cited in different reports. One reason
nates (Fig. 19-1, Table 19-1, and Appendix is that selection of patients by birth weight
C). A major concern persists, however, that does not guarantee a homogeneous group,
neonatal intensive care results in an increase and populations studied in one center may
in the number of permanently handicapped differ considerably from those studied in
children. another center. There are several causes for
The initial follow-up studies of pre- these differences. One of the most impor-
term infants in the early 1970s described a tant factors is the pattern of referral to the
decrease in unfavorable neurodevelopmen- neonatal intensive care unit (NICU). Units
tal sequelae compared with the era before that receive admissions from numerous
neonatal intensive care. Despite the con- outlying hospitals have a selected popula-
tinued decrease in mortality rates, the inci- tion that may contain a disproportionate
dence of neurosensory and developmental number of the sickest babies or may include
handicaps initially remained constant in only those infants deemed well enough to
the 1980s; however, morbidity increased transport. In addition, patients treated in
in the 1990s following a further decrease an “inborn” unit have the advantage of
in mortality, which was associated with consistent and, presumably, good obstet-
antenatal steroid and surfactant therapies ric care coupled with the opportunity for
introduced in the early 1990s. These treat- immediate postnatal resuscitation and
ments resulted in the survival of high-risk management. Inadequate resuscitation at
infants who previously would have died. birth and prolonged hypoxia and acide-
Furthermore postnatal steroid therapy, mia, together with the cold stress associated
which was widely used to prevent or treat with transport that may be seen in referred
bronchopulmonary dysplasia, resulted in patients, influence not only the outcome in
higher rates of cerebral palsy.1-3 The abso- the period immediately after birth but also
lute number of both healthy and neurolog- the type and frequency of developmental
ically impaired children in the population sequelae. Other factors that may influence
thus increased in the 1990s.3 Additional outcome include (1) the socioeconomic
morbidity resulted from increased infec- profile of the parents, (2) the proportion of
tion, necrotizing enterocolitis, and poor infants with intrauterine growth restriction,
physical growth in infants of extremely (3) the incidence of extreme prematurity,
low birth weight (<1 kg) and short gesta- (4) a selective admission policy, (5) a selec-
tion (<26 weeks).3-5 tive treatment policy, and (6) changes in
Since 2000, the outcomes of children therapy during the study period.
with a birth weight of less than 1 kg have The major clinical outcomes that are
improved; this improvement has resulted important to preterm infants and their
from a significant decrease in nosocomial families are not only survival, but survival
infections and intraventricular hemorrhage, accompanied by normal long-term neurode-
together with a decrease in the use of post- velopment. These goals are not easily attain-
natal steroid therapy.6 able; however, the landscape has improved
525
526 CHAPTER 19 The Outcome of Neonatal Intensive Care
100
<1000 g
1000–1500 g
80
Percent 60
40
20
0
66–70 71–75 76–80 81–85 1992 1997 1999 2003
NICHD NICHD NICHD
OTA 1966–1985
Cleveland
Year of birth
Figure 19-1. Trends in Survival. Improvement in survival of low-birth-weight infants. (Data for 1966 to 1985 from
U.S. Congress, Office of Technology Assessment [OTA]: Neonatal intensive care for low-birthweight infants: cost and
effectiveness, Health Technology Case Study 38, Washington, DC, 1987, U.S. Congress; data for 1992, 1999, and
2003 from Stevenson DK, Wright LL, Lemons JA, et al: Very low birth weight outcomes of the National Institute
of Child Health and Human Development [NICHD] Neonatal Research Network, January 1993 through December
1994, Am J Obstet Gynecol 179:1632, 1998; and Fanaroff AA, Stoll BJ, Wright LL, et al; NICHD Neonatal Research
Network: Trends in neonatal morbidity and mortality for very low birthweight infants, Am J Obstet Gynecol 196[2]:147,
e1, 2007; data for 1997 from Rainbow Babies and Children’s Hospital, Cleveland.)
Table 19-1. Survival and Neurodevelopmental Impairment (NDI) according to Gestational Age
Gestational Age (wk) Survival (%) NDI (%) Survival Without NDI (%)
22 5 80 1
23 26 65 9
24 56 50 28
25 76 39 46
Adapted from Tyson JE, Parikh NA, Langer J, et al for the National Institute of Child Health and Human
Development Neonatal Research Network: Intensive care for extreme prematurity—moving beyond
gestational age, N Engl J Med 358:1672, 2008.
over the past two decades, and there are

now more intact survivors who attend main- EDITORIAL COMMENT: Follow-up of graduates from
stream schools and ultimately live indepen- the intensive care unit has shed the orphan role it had
dently. How to preserve brain function and for so long and is now a genuine and legitimate com-
permit normal brain development ex utero ponent of neonatology. Indeed, neurodevelopmental
remain enormous challenges. The period status on follow-up has become an integral part of the
between 20 and 32 weeks after conception is primary outcome measure in most prospective ran-
one of rapid brain growth and development. domized interventional trials involving both term and
Illness, hemorrhage, ischemia, metabolic preterm infants. Absence of harm and normal long-
disturbances such as hypoglycemia, hyper- term neurodevelopment are the desired outcome.
bilirubinemia, undernutrition, and infection
during this time may compromise neurode-
velopment. Indeed, events leading to the Measures of outcomes of neonatal care
premature birth such as chorioamnionitis include the rate of mortality before and
may have stimulated the release of cytokines after discharge from the neonatal inten-
that in turn injure the developing brain. sive care nursery, rate of rehospitalizations,
Scores of publications continue to demon- and incidence of chronic medical condi-
strate inferior intellect and function in the tions such as asthma and growth failure.
most immature babies compared with their Neurodevelopmental sequelae include sub-
term peers. normal and borderline cognitive (mental)
CHAPTER 19 The Outcome of Neonatal Intensive Care 527
Measures of Very Low-Birth- Factors Affecting Outcomes for

Box 19-1. Box 19-2.
Weight Outcome the Very Low-Birth-Weight Infant
Survival Birth weight <750 g or <26 weeks’ gestation
• To discharge Periventricular hemorrhage (grade III or IV)
• After discharge Periventricular leukomalacia or other echodense
Medical morbidity lesions
• Rehospitalization Persistent ventricular dilatation
• Chronic lung disease Neonatal seizures
• Growth failure Chronic lung disease
Neurodevelopmental outcome Neonatal meningitis
• Motor dysfunction (cerebral palsy) Subnormal head circumference
• Mental retardation Poverty or parental deprivation
• Seizures Congenital malformations
• Vision problems
• Hearing disorders
• Behavioral problems periventricular hemorrhage13,15; periventric-
• School-age outcomes ular leukomalacia16; bronchopulmonary dys-
Functional outcomes plasia, defined as an oxygen requirement at
• Health or illness 36 weeks’ postconceptional age; and severe
• Activity and skills of daily living intrauterine or neonatal growth failure, spe-
• Ambulation cifically a subnormal head circumference (≤2
• Need for technologic aids (gastric tube, standard deviations [SDs] from the mean) at
oxygen) discharge. Children born to mothers who
• Need for special services have a low educational level or live in pov-
Quality of life erty demonstrate the additional detrimental
Impact on family effects of the environment. Among term-born
Cost of care children, risk factors for later neurologic and
developmental sequelae also include perina-
tal asphyxia, neonatal seizures, an abnormal
function and neurosensory deficits such neurologic finding at discharge, and per-
as cerebral palsy, deafness, and blindness. sistent pulmonary hypertension requiring
These sequelae have traditionally been used prolonged ventilator therapy, nitric oxide
as outcome measures.7 Other outcomes therapy, or extracorporeal membrane oxy-
include functional abilities and the ability genation.17 Children born with multiple
to perform the activities of daily living.8-10 major malformations also constitute a group
Additional measures involve special health that generally has a poor developmental out-
care requirements such as the need for tech- come (Box 19-2).
nologic aids, frequent physician visits and
medications for chronic conditions, occu- IMPORTANCE OF FOLLOW-UP FOR
pational and physical therapy, and special HIGH-RISK INFANTS
education and counseling.8 Other measures Follow-up clinics should be an integral part
may include impact on the family, quality of every NICU. Specialized care for problems
of life,11 and cost of care. of growth, sequelae of bronchopulmonary
Regional outcome studies provide the dysplasia, and adaptation is best provided
most accurate data because they include all within the setting of a neonatal follow-up
infants born in a region rather than hospital- program. This care should initially be pro-
based results. Such studies have rarely been vided by the neonatal department and then
undertaken in the United States, although gradually transferred to developmental and
they have been performed in Canada, the educational specialists. The initial continu-
United Kingdom, and Australia.1 Results ity of care is important to the family, who
may also be reported from multigroup stud- will find reassurance in the fact that the
ies or randomized controlled trials of vari- same people who were responsible for the
ous therapies12-14 (Box 19-1). life-saving decisions early in the infant’s
The risk of neurodevelopmental problems life are continuing to assume responsibil-
increases as birth weight and gestational ity for the child’s adaptation into home life.
age decrease. Additional risk factors include There is also a moral obligation to main-
the occurrence of neonatal seizures; severe tain this contact. Furthermore, even if the
neonatologist does not continue the follow- usually resolves by the second year of life.
up for an extended period, he or she will Persistence of primitive reflexes beyond 4
benefit greatly by maintaining contact with months’ corrected age might be a sign of
the nursery graduates and recognizing the early cerebral palsy. Major neurologic hand-
sequelae of the early neonatal interventions. icap presents during the first 6 to 8 months
When growth and neurodevelopmental after term in about 10% of newborns in the
outcomes are assessed, it is important to cor- most high-risk categories; however, 90% of
rect the child’s age to account for the pre- high-risk newborns will be or become neu-
term birth. This should be done at least until rologically normal after the first year of life.
the child is 3 years of age. For extremely
immature infants (i.e., those born at 23 to PERSISTENT NEUROLOGIC SEQUELAE
25 weeks’ gestation), such age correction Major neurologic handicap can usually be
may be necessary until at least 5 years of age. defined during the latter part of the first year
of life or even earlier if severe. It is usually
MINOR TRANSIENT PROBLEMS classified as cerebral palsy (spastic diplegia,
The first few months after the neonate’s dis- spastic quadriplegia, or spastic hemiplegia
charge can be considered a period of con- or paresis); hydrocephalus (with or without
valescence for the infant and parents as accompanying cerebral palsy or sensory defi-
well. Many infants have minor problems cits); blindness (usually caused by retinopa-
specifically related to being born preterm, thy of prematurity); or deafness. Blindness
but these may seem major problems to their currently occurs very rarely because laser
parents. These problems include anemia of treatment or cryotherapy for severe retinopa-
prematurity, umbilical and inguinal hernias, thy of prematurity may prevent the progres-
relatively large, dolichocephalic, “preemie- sion of this disease. The developmental and
shaped” heads, and subtle behavioral dif- intellectual outcomes differ according to the
ferences. Most healthy preterm infants are severity of cerebral palsy. For example, chil-
discharged home at 36 to 37 weeks’ gesta- dren with spastic quadriplegia usually have
tional age (or when they weigh about 1.9 severe mental retardation, whereas children
kg). At this age they still tend to sleep most with spastic diplegia or hemiplegia may have
of the day, waking only for feedings; to feed relatively intact mental functioning. Men-
slowly and not always to demonstrate hun- tal functioning is not always measurable in
ger; to sometimes be jittery; and to have these children until after 2 to 3 years of age.
“preemie” vocalizations, which include
grunts and a relatively high-pitched cry.
EDITORIAL COMMENT: Cerebral palsy is an umbrella
TRANSIENT NEUROLOGIC ABNORMALITY term encompassing a group of nonprogressive, non-
There is a very high incidence of transient contagious motor conditions that cause physical dis-
neurologic abnormality during the first year ability in human development, chiefly in the various ar-
of life, ranging from 40% to 80% among eas of body movement. Most health care providers are
preterm infants. These include abnormali- familiar with the high rates and risk of cerebral palsy
ties of muscle tone such as hypotonia or in preterm infants. Nonetheless, numerically it is term
hypertonia. Such abnormalities present as and near-term infants who account for the majority of
poor head control at 40 weeks’ corrected age cases of cerebral palsy despite their significantly lower
(the expected term date), poor back support risk.
at 4 to 8 months, and sometimes a slight
increase in the tone of the upper extremi-
ties. Because there is normally some degree
of hypertonia during the first 3 months PHYSICAL SEQUELAE AND CHRONIC
after term, it is difficult to diagnose the DISEASE
early developing spasticity related to cere- Chronic diseases of prematurity, mainly
bral palsy. Children in whom cerebral palsy chronic lung disease (bronchopulmonary
later develops show hypotonia (poor head dysplasia), gradually resolve during infancy,
control and back support) initially and only although children with bronchopulmonary
later manifest spasticity of the extremities dysplasia have higher rates of recurrent
combined with truncal hypotonia. Spastic- respiratory infections and asthma during
ity during the first 3 to 4 months of life is childhood. Scars from various neonatal sur-
an indicator of poor prognosis. Mild hyper- gical procedures (tracheotomy, thoracocen-
tonia or hypotonia persisting at 8 months tesis, Broviac lines, shunt procedures) tend
to fade gradually and appear less significant ventilator and oxygen dependence, necrotiz-
as the child grows. There is, however, a high ing enterocolitis requiring surgery, and neu-
rate of rehospitalization, especially for those rologic impairment such as cerebral palsy.
children of extremely low birth weight who Neurologically impaired children may also
have bronchopulmonary dysplasia or neu- show failure to thrive after the neonatal dis-
rologic sequelae. Fifty percent of children charge. The genetic potential for growth as
with chronic lung disease may be hospital- measured by midparental height also plays
ized in the first year after discharge. Many a role in the potential for catch-up growth.18
hospitalizations that occur in winter have Use of increased-calorie formulas provid-
been due to respiratory syncytial virus infec- ing 22 calories per ounce and increased cal-
tions. These may be minimized with respira- cium might enhance growth during the first
tory syncytial virus immunization. Children few months after discharge home; however,
with neurologic sequelae such as cerebral there are no reported studies of the longer-
palsy or hydrocephalus also have a higher term effect of such formulas on growth to
rate of rehospitalization for shunt compli- the second year of life and thereafter.
cations, orthopedic correction of spasticity, Extremely low-birth-weight infants with
and eye surgery for strabismus. chronic lung disease (bronchopulmonary
dysplasia) who can feed orally may be dis-
PHYSICAL GROWTH charged home with oxygen supplementa-
Intrauterine and/or neonatal growth restriction when they are in stable condition. These
tion is present in many very low-birth-weight infants need close follow-up with pediatric
neonates who require intensive care and a pulmonary specialists or neonatologists with
prolonged hospitalization. For infants born expertise and interest in pulmonary follow-
at a size appropriate for gestational age, poor up care. As the infant is gradually weaned
neonatal growth is related to inadequate from oxygen, close attention needs to be
nutrition during the neonatal period, to paid to optimizing growth with the use of
increased caloric requirements associated increased-calorie formulas and to the grad-
with breathing in chronic lung disease, to ual weaning of any medications the child
poor feeding in neurologically impaired chil- might be receiving such as diuretics or anti-
dren, and to the lack of parental care or an reflux medication. Such children also require
optimal environment for growth in the nurs- respiratory syncytial virus immunization in
ery. As these conditions gradually resolve, winter.
and when an optimal home environment Most neurologic or physical problems
is provided, catch-up of growth may occur resolve or become permanent during the
during childhood. However, many of these first year of life. Furthermore, during the
infants still remain subnormal in weight and second year of life, the environmental
height in their third year. Growth attain- effects of parental education and social class
ment after discharge is a very good measure begin to influence the outcome measures.
of physical, neurologic, and environmental Clinical follow-up is essential for all high-
well-being. To promote optimal catch-up risk infants during this period. After the first
growth, neonatal nutrition needs to be maxi- year, the new problems that become evident
mized and sufficient calories provided during may include subtle motor, visuomotor, and
the recovery phase. This is especially impor- behavioral difficulties. These are best diag-
tant because catch-up of head circumference nosed and treated in an educational rather
in both appropriate for gestational age and than a medical setting.
small for gestational age infants may occur It is very important to pay attention to
during the first 6 to 12 months’ after term. the mother’s and father’s well-being, their
The prognosis for catch-up growth is support systems, and their ability to care
less optimal in infants born small for gesta- for the infant. Maternal depression is fairly
tional age after intrauterine growth failure, prevalent following the birth of preterm
because their initial period of growth failure and/or chronically ill infants.
occurred relatively early in gestation and
extended for a longer time during the criti- FOLLOW-UP—WHO, WHAT, HOW, AND
cal perinatal period of growth. WHEN
Predictors of poor catch-up growth include Infants at highest risk should be followed.
severe intrauterine growth failure, severe These include infants who had severe
neonatal complications including broncho- asphyxia complicated by seizures or signs
pulmonary dysplasia following prolonged of brain edema, periventricular or other
intracranial injury, meningitis, or multisys- have a Mental Development Index (MDI)

tem congenital malformations; infants who score of less than 70 at 18 to 24 months’
required ventilatory assistance; and those corrected age and do not have cerebral
born with very low birth weights (especially palsy may have higher IQ scores on testing
those weighing <1 kg) or at 23 to 25 weeks’ at school age, although they tend to have
gestation).19 poorer school functioning than children
Growth (weight, height, and head cir- who have a normal Mental Development
cumference), neurologic development, psy- Index score (>70) at 18 to 24 months of age.
chomotor development, ophthalmologic Beyond the age of 3 years, other tests may
status, vision, and hearing should all be be performed. These tests further validate
examined on a regular basis. the child’s mental abilities. Language may
also be measurable at this age. From 4 years
TIMING OF FOLLOW-UP VISITS of age, more subtle neurologic, visuomotor,
The initial follow-up visit should be 7 to and behavioral difficulties are measurable.
10 days after the neonatal discharge. This These difficulties affect school performance
is essential to evaluate how the infant is even in children who have normal intelli-
adapting to the home environment. This gence.19,21
visit usually occurs around the time of the
expected date of delivery. A clinic visit at NEUROSENSORY AND DEVELOPMENTAL
4 months’ corrected age is important to ASSESSMENT
document problems of inadequate catch-up Neurodevelopmental handicap is usually
growth and severe neurologic abnormality defined in children who have a neurologic
that might require intervention or physical abnormality or a developmental quotient or
therapy. IQ of less than 80. Some researchers include
Eight months’ corrected age is a good only a subnormal IQ (<70), whereas others
time to identify the presence of developing include all children with an IQ less than 1
cerebral palsy or other neurologic abnormal- SD from the norm (IQ of <85). Neurologic
ity. It is also an excellent time for the first abnormality is usually classified by neuro-
developmental assessment (preferably using logic diagnosis, which can include hypo-
the Bayley Scales of Infant Development). tonia or hypertonia, cerebral palsy (spastic
At this age, infants show very little outward diplegia or quadriplegia), hydrocephalus,
stranger anxiety and are most cooperative. blindness, or deafness.
Some physicians, however, prefer to per- The neurologic examination during
form the first developmental assessment at infancy is best based on changes in mus-
12 months of age. cle tone that occur during the first year of
The Bayley score attained at 8 to 12 life. The scale developed by Amiel-Tison
months’ corrected age tends to decrease measures the progressive increase in active
by the second year (partly as a function of muscle tone (head control, back support,
the test and partly because of the increased sitting, standing, and walking) together
effect of the environment) and is not of great with the concomitant decrease in passive
prognostic significance. However, low scores muscle tone that occurs during infancy.22
(<80) are predictive of poor later function- Furthermore, it documents visual and audi-
ing, as is cerebral palsy. By 18 to 24 months’ tory responses and some primitive reflexes.
corrected age, most transient neurologic This method gives a qualitative assessment
findings have resolved, and the neurologi- of neurologic integrity, which is defined
cally abnormal child may show adaptation as normal, suspect, or abnormal during
to neurologic sequelae. Furthermore, most the first year after term. The Amiel-Tison
of the potential catch-up growth has been method of evaluation extends into early
achieved, although catch-up growth may childhood.22
occur into the adolescent years. During the Short-term outcome studies of preterm
second year of life the mental scale of the infants who sustained a neonatal grade IV
Bayley scales provides some assessment of intraventricular hemorrhage (also known
the child’s cognitive performance, although as periventricular hemorrhagic infarction) have
these scales have very poor prognostic valid- reported a high rate of cerebral palsy rang-
ity for IQ measurement at school age.20 ing from 40% to 85%; however, there has
Cognitive function is not easily measured been no consensus regarding cognitive out-
before 1 year of age, because the test is based come, with normal cognition noted in 20%
mainly on motor function. Children who to 79%.23 Roze et al prospectively collected
a cohort of preterm infants with periventric- • The Wechsler scales (Wechsler Preschool
ular hemorrhagic infarction to determine and Primary Scale of Intelligence—Third
motor,24 cognitive, and behavioral outcome Edition for preschoolers and Wechsler
at school age and to identify cerebral risk Intelligence Scale for Children—Fourth
factors for adverse outcome. Of 38 infants, Edition for ages 6 to 16 years) yield verbal,
15 (39%) died. Twenty-one of the 23 sur- performance, and full-scale scores with
vivors were included in the follow-up. The means of 100.
investigators concluded that “the majority • The Kaufman Assessment Battery for Chil-
of surviving preterm children with periven- dren is used between the ages of 3 and
tricular hemorrhagic infarction had cerebral 10 years. Like the Stanford-Binet and
palsy with limited functional impairment Wechsler tests, it has a number of sub-
at school age. Intelligence was within 1 scales to assess various components of
SD of the norm of preterm children with- intelligence.
out lesions in 60% to 80% of the children. • The McCarthy Scales of Children’s Abilities
Verbal memory, in particular, was affected. provide measures of cognitive, perceptual-
Behavioral and executive function prob- performance, and quantitative abilities in
lems occurred slightly more than in preterm children between ages 2½ and 8 years as
infants without lesions. The functional well as a composite score (comparable to
outcome at school age of preterm children an IQ) and measures of motor and mem-
with periventricular hemorrhagic infarction ory functions. However, this test has not
is better than previously thought.” Papile been restandardized since 1972, and it is
notes, “Roze et al’s study points out one of likely that the norms are outdated.
the major shortcomings of infant neuro- • The Denver Developmental Screening Test is
developmental testing. Because successful used as a clinical screening tool in the first
completion of many test items relies heav- 6 years. It is not highly sensitive and fails
ily on motor function, the scores achieved to identify a significant number of at-risk
by preterm infants with motor impairment children. Because it is not a quantitative
such as cerebral palsy underestimate their assessment, it is rarely used for research to
true ability and may lead to an unduly pes- document outcomes in specific high-risk
simistic view regarding their ultimate out- populations.
come”.25
Visual Testing
Psychomotor Developmental Tests An ophthalmologic examination should
The Bayley Scales of Infant Development be performed on all high-risk infants
are the recognized standard for measur- before discharge. Infants younger than 30
ing infant development and may be used to 32 weeks’ gestation should have been
between early infancy and 42 months of age. followed with serial examinations in the
Separate motor and mental scales each yield nursery for signs of developing retinopathy
a developmental index with a mean of 100. of prematurity. Those who have residual
The scales were revised and restandardized findings at discharge or who have under-
in 1993 and more recently in 2006. In the gone laser therapy or cryotherapy should
first year, motor skills are weighted heavily, be followed by an ophthalmologist until
even in the mental scale, but by the second the abnormal findings resolve. All chil-
year, cognitive functions, including speech dren should undergo a repeat eye exami-
and behavior, may be more reliably mea- nation between 12 and 24 months of age.
sured. The 2006 edition of the test has three Infants of extremely low birth weight or
scales that measure cognitive, language, and gestational age who have had severe reti-
motor development as well as two scales that nopathy of prematurity might require cor-
measure social-emotional development and rection with glasses during infancy or early
adaptive behavior as reported by a parent. childhood.
In the preschool years and into adoles-
cence, the following tests are often used Hearing
both clinically and for research: Hearing should be screened before the
• The Stanford-Binet Intelligence Scale is used infant’s discharge from the NICU. This may
from age 2 years into the elementary be done by measuring base-of-brain evoked
school years. It provides a measure of responses or otoacoustic emissions. Hearing
intelligence that is highly correlated with should be reexamined between 12 and 24
school performance. months of age, because the most common
Table 19-2. Outcome Variables at 18 to 24 Months’ Corrected Age

Gestational Age (wk)
Birth Weight 501-800 g 23 24 25

Total followed (N) 1000 77 323 554
Severe disability 9%-37% 34% 22%-45% 12%-35%
Cerebral palsy 5%-37% 11%-15% 3%-20%
Subnormal cognitive 13%-47% 14%-39% 10%-30%
(Mental Development
Index of <70)
Blindness 2%-25% 0%-9% 3%-10%
Deafness 0%-7%
Adapted from Hack M, Fanaroff AA: Outcomes of children of extremely low birthweight and gestational
age in the 1990s, Semin Neonatol 5:89, 2000.
cause of hearing loss is upper respiratory made during the first year of life. Early
tract and middle ear infections, which may intervention and supportive psychologi-
occur during the first 2 years of life. cal help that can be facilitated by the
follow-up clinic are crucial.
EARLY INTERVENTION 6. Except when a severe neurologic or sen-
Early environmental enrichment with sory disorder persists, ultimate develop-
close attention to the family’s needs may ment depends on parental education,
improve the developmental outcome of all social class, the child’s genetic poten-
children, including infants with normal tial, and the environment. For children
birth weight as well as low birth weight and of extremely low birth weight and short
low gestational age, and especially of chil- gestation, neonatal risk factors tend to
dren in disadvantaged homes.26 Studies of predominate.3
early intervention have, however, shown a 7. The functional capacity attained is more
decrease in beneficial effects after discontin- important than the medical diagnosis of
uation of the intervention. Initial home vis- abnormality.
its during early childhood by experienced
nurses are also important for surveillance EARLY CHILDHOOD OUTCOMES
of the child’s growth and medical needs, A summary of some outcome variables for
for education concerning preterm behavior extremely immature and low-birth-weight
and development, and for support of the infants is presented in Table 19-2. The
mother. Such home visits can gradually be importance of early identification of devel-
phased out as the mother becomes more opmental deficits to plan and establish early
confident and when the child becomes appropriate interventions should be empha-
enrolled in an educational enrichment pro- sized. Developmental outcomes of children
gram, if available. are influenced by many risk factors, includ-
ing social, genetic, and biologic ones.
POINTS TO REMEMBER
1. Correct for gestational age (preterm
birth) until at least 3 years of age. EDITORIAL COMMENT: Hintz et al compared neu-
2. Do not emphasize to the parents the rodevelopmental outcomes at 18 to 22 months’ cor-
many abnormalities observed during the rected age for infants born with extremely low birth
3-month postdischarge period of conva- weight at an estimated gestational age of less than
lescence, because most are transient and 25 weeks during two periods: 1999 to 2001 (epoch
have little prognostic significance. 1) and 2002 to 2004 (epoch 2).27 Infant survival in
3. Be available, be honest, be optimistic. epoch 1 (35.4%) and epoch 2 (32.3%) was similar.
After the initial diagnosis of abnormality Cesarean delivery, surgery for patent ductus arterio-
is made, most children show improve- sus, and late sepsis were more common in epoch
ment, restitution, and growth. 2, but postnatal steroid use was dramatically re-
4. The majority of high-risk children do well. duced (63.5% in epoch 1 versus 32.8% in epoch 2;
5. In some cases, the diagnosis of cerebral P <.0001). Moderate to severe cerebral palsy was
palsy, hydrocephalus, or blindness is
iagnosed in 11% and the Mental Developmental

d gestation. Extremely preterm children who entered
Index was less than 70 in 50% of surviving infants compulsory education an academic year early be-
in epoch 1, whereas cerebral palsy in 15% and a cause of preterm birth had similar academic attain-
Mental Developmental Index of less than 70 in 59% ment but required more special educational needs
were noted in epoch 2. Hence, adverse outcomes support. The investigators concluded that survivors
were common in both epochs and were unchanged of extremely preterm birth remain at high risk of
between the two periods. learning impairments and poor academic attainment
in middle childhood. Papile noted, “The high preva-
lence of intellectual and learning difficulties suggests
that a disruption/delay of global brain development
SCHOOL-AGE OUTCOMES
rather than a specific lesion may be the underlying
At school age, children are required to con- cause”.25
form to formal learning in a classroom.
Many have difficulty in this regard because
of attention and other neuropsychologic
deficits, including poor memory, visuomo- Taylor et al reviewed the topic of math-
tor, and fine and gross motor function, and ematics deficiencies in children with very
difficulty with spatial concepts and execu- low birth weight or very preterm birth.30
tive function.28 Children who were born They noted that children with birth weights
preterm are often also shy and withdrawn of less than 1.5 kg and those with a gesta-
and have social difficulties as well as behav- tional age of less than 32 weeks have more
ioral problems, including attention-deficit/ mathematics disabilities or deficiencies and
hyperactivity disorder and symptoms of higher rates of mathematics learning disabil-
depression or anxiety. ities than normal-birth-weight, term-born
children. They commented, “mathematics
disabilities or deficiencies are found even in
EDITORIAL COMMENT: The EPICure study is an
children without global disorders in cogni-
ongoing longitudinal evaluation of extremely pre-
tion or neurosensory status even when IQ
mature infants born in the United Kingdom and the
is controlled, and they are associated with
Republic of Ireland between March and December
other learning problems and weaknesses
1995. The cohort consists of the 308 children who
in perceptual motor abilities and executive
were 20 to 25 weeks’ gestational age at birth and
function. Factors related to poorer mathe-
survived beyond the first year after birth. Johnson
matics outcomes include lower birth weight
et al assessed the academic attainment and special
and gestational age, neonatal complications,
educational needs in 219 (71%) of these children
and possible abnormalities in brain struc-
at 11 years of age and compared them with those
ture.” Little is known about mathematics
of 153 classmates born at term using standardized
disabilities or deficiencies. Thus, although
tests of cognitive ability and academic attainment
the outcomes have improved overall, there
and teacher reports of school performance and spe-
is no room for complacency. Understand-
cial educational needs.29 Extremely preterm children
ing the mechanisms of injury may help to
had significantly lower scores than classmates on
provide the solutions, because neuroplastic-
cognitive ability (−20 points; 95% confidence inter-
ity is known to permit the neonatal brain to
val [CI]: −23 to −17), reading (−18 points; 95% CI:
move a given function to a different loca-
−22 to −15), and mathematics (−27 points; 95% CI:
tion as a consequence of normal experience
−31 to −23). Twenty nine (13%) extremely preterm
or brain damage.
children attended special schools. Among extremely
YOUNG ADULT OUTCOMES
preterm children in mainstream schools, 105 (57%)
had special educational needs and 103 (55%) re-
The initial survivors of the early years of
quired special educational needs resource provision.
neonatal intensive care in the 1970s are
Teachers rated 50% of extremely preterm children
now adults. The results, to date, reveal that
as having below average attainment compared with
although these individuals may have a lower
5% of classmates. Overall 40% of the cohort has
IQ on formal testing and fewer attend college
moderate to severe cognitive impairment (>2 SD
than normal-birth-weight, term-born con-
from the mean) compared with 1.3% of classmates.
trols, they function fairly well and with few
Boys were twice as likely as girls to have a serious
exceptions are satisfied with their health-
impairment, but the prevalence was not significantly
related quality of life, which when studied
different for children born at 23, 24, and 25 weeks of
is similar to that of controls.31 Very low-
birth-weight young adults also demonstrate
less risk-taking behavior than normal-birth- and social interaction. Luu et al evaluated
weight controls, including alcohol use, executive and memory function in 337 ado-
drug abuse, and delinquent activities. Rates lescents born preterm compared with that in
of attention-deficit/hyperactivity disorder term-born controls at 16 years.32 After adoles-
tend to decrease during young adulthood, cents with neurosensory disabilities and those
although symptoms of depression and with- with an IQ of less than 70 were excluded,
drawal have been reported in women.31 adolescents born preterm, compared with
Overwhelming evidence is accumulating term controls, were found to show deficits in
that the neurodevelopmental consequences executive function on tasks of verbal fluency,
of extremely preterm birth extend far beyond inhibition, cognitive flexibility, planning
the confines of cerebral palsy (a static lesion) and organization, and working memory as
and intellectual delay. Problems in atten- well as verbal and visuospatial memory. The
tion, executive function, memory, spatial presence of these deficits was associated with
skills, fine and gross motor function, speech severe brain injury as detected by neonatal
and language, visual integration, and math- ultrasonography and lower maternal edu-
ematics, together with behavioral disorders, cational level. This implies that providing a
are common. Executive function refers to a more stimulating and enriched home envi-
collection of processes that are responsible ronment may be of some benefit in averting
for purposeful, goal-directed behavior, such executive function deficits.
as planning, setting goals, initiating, using
problem-solving strategies, and monitoring
thoughts and behavior. Executive function- REFERENCES
ing is important for a child’s intellectual The reference list for this chapter can be found
development, behavior, emotional control, online at www.expertconsult.com.
Ethical Issues
in the Perinatal
Period
Jonathan M. Fanaroff and
Lawrence J. Nelson
20
Despite great advances in perinatal medi- pressing questions and dominant myths
cine, not all newborns born alive can stay about forgoing treatment of newborns and
alive or survive without experiencing briefly explains why the myths should be
severe—perhaps even devastating—physical discarded by ethical and humane practi-
and mental problems. This is particularly tioners of neonatal medicine. These myths
true for extremely preterm infants (approxi- deserve attention because they are both
mately 24 to 27 weeks’ gestation), who widely held and dangerous to the interests
have a survival rate of approximately 75%.1 of infants, parents, and medicine. Unneces-
Thus, many extremely low-birth-weight sary legalism, improper disenfranchisement
infants can and do survive despite being of parents, simplistic reliance on a single
born much too soon, although they often popular standard of questionable meaning,
experience significant long-term problems and rejection of quality-of-life consider-
such as chronic lung disease, short gut syn- ations are still the deepest and most insidi-
drome, neurologic and cognitive abnormal- ous traps into which physicians and nurses
ities, poor growth, blindness, and chronic caring for newborns fall.
illness.2
In at least some of these cases, physi- THE CASE
cians, nurses, or parents raise questions Mark and Karla Miller filed a negligence lawsuit
about whether initial or continued aggres- against a hospital, Women’s Hospital of Texas, and
sive treatment is ethically correct, who the company that owns the hospital, Columbia/HCA
should make these decisions, and what Healthcare Corporation, following the premature
criteria they should use. These questions birth of their daughter, Sydney. She was born at 23
have been publicly asked and answered in weeks’ gestation and weighed 615 g. The parents
a variety of ways since 1973 when Duff and claimed that the hospital had “callously ignored the
Campbell acknowledged that they, their couple’s request not to artificially prolong the child’s
neonatal intensive care unit (NICU) staff, life at birth” and that resuscitating such an underde-
and the involved parents allowed some veloped baby amounted to “medical experimentation
infants to die because of their poor chances on humans.” They also accused the hospital of be-
of survival or of having a reasonable qual- ing motivated to impose treatment to collect the large
ity of life.3 No single standard of care exists revenues that would thereby be generated.
in this area, and indeed one commentator Mrs. Miller had developed chorioamnionitis, and
has noted that this area of bioethics remains she was hospitalized. “With her own life in potential
“as intractable today as it was 30 years ago, danger, she and her husband agreed with the doctor
when it began to be publicly discussed.”4 to induce labor.” They were notified about the “uncer-
Studies have shown what clinical experi- tain odds of survival in such a young pregnancy” and
ence and common sense posit: physicians’ the “baby’s unlikely prospects for survival so early in
practices regarding the use or withholding pregnancy.” After “much agonizing,” they decided to
of resuscitative therapy in the NICU are not have the baby delivered (following induction) but “to
consistent.5 let nature take its course.” According to the parents’
This chapter explores some answers to lawyer, they saw it as “God’s will” if the newborn had
these enduring and fundamental questions “not developed to the extent that it could survive
by presenting and commenting on an actual without artificial means”; they wanted no “special
case. In doing so, it considers the most
535
536 CHAPTER 20 Ethical Issues in the Perinatal Period
heroics” performed. The parents claimed they had rather than the hospital and that there was evidence
repeatedly requested that doctors not resuscitate the that indicated “arrogance” on the part of the hospital
newborn if she had not developed adequately to sus- and Columbia/HCA.
tain life on her own. Defense witnesses had testified that the care de-
Although the obstetrician and neonatologist livered to both the mother and infant met the applica-
agreed with the parents that comfort care was a ble standard of care and that “the newborn’s condi-
very reasonable option, the hospital administrator of tion was adequate enough to require them to try to
the NICU allegedly told the father that the hospital sustain life.” These witnesses also stated that deny-
had a policy requiring resuscitation of any infant that ing “proper care could subject the doctors to penal-
weighed more than 500 g, although she was never ties and sanctions, or even suit alleging negligence.”
able to produce a written policy to this effect. She The case generated considerable attention, and
also allegedly informed the father that “his only option one can read the large punitive damage award as
would be to take his wife to another hospital, which a clear signal by the jury that it supported the par-
he could not risk because of her condition.” When ents in this case and disapproved of the actions
the father said he would be in the delivery room and of the hospital. In the end, however, the Millers did
would stop physicians from performing resuscitation, not receive any compensation because the verdict
this administrator said police would be called to re- was overturned on appeal, with the Texas Supreme
move him from the premises. Court creating an “emergent circumstances” excep-
The hospital disputed the parents’ version of the tion whereby a physician in Texas may resuscitate
facts and claimed it had an ethical and legal obligation an infant in the delivery room without first obtaining
to keep the baby alive. It denied that treatment deci- parental consent.4 The sharp difference between
sions were related to financial considerations, that its the opinion of the jury and the reasoning of the court
administrator had made any threats or statement to raise a number of important ethical questions.
the father as he had alleged, and that it had any re-
This case report is based on four articles published in the
sponsibility for medical decisions that were made by Houston Chronicle on January 6, 1998 (Section A, p. 9),
the physicians and family involved. It claimed that the January 17, 1998 (Section A, p. 1), January 31, 1998
attending physicians had drafted a “birth plan” with (Section A, p. 29), and April 18, 1998 (Section A, p. 36).
the parents’ full consent and produced several con- Unless otherwise indicated, all direct quotes are taken from
these articles.
sent forms signed by the father for medical services.
Furthermore, the father allegedly never ques-
tioned the physician’s actions to keep the child alive
either in the delivery room or later. The hospital also DISCUSSION
asserted that the physicians honored the parents’
Is there a legal and ethical obligation to resusci-
decision not to restart the infant’s heart if she went
tate all newborns and continue providing treat-
into arrest. However, she had a heartbeat when born,
ment until a child is imminently dying?
although her “lungs and other vital organs” were not
working at birth, and received vigorous treatment.
Some, perhaps many, physicians and
Sydney was born with her eyelids fused shut and
nurses believe that no choice exists but to
is legally blind. She remained hospitalized for nearly
resuscitate every newborn infant in the
a year at a cost of about $1 million. She is severely
delivery room, no matter how small, and
brain damaged and requires extensive care, because
continue aggressive medical treatment in
she is almost totally incapacitated. Her mother ended
the NICU until he or she is headed inevita-
her career as an equities fund broker to care for her
bly and imminently toward death. Once the
daughter full time because the family could not afford
infant has shown itself to be close to death
the $200,000 annual cost of professional care.
despite aggressive medical management,
Eleven days after the start of the trial and after 2
then and only then can physicians and par-
days of deliberations, the jury returned a $42.9 mil-
ents choose to withhold or withdraw life-
lion verdict against the hospital and Columbia/HCA
sustaining treatment.
by a vote of 10 to 2: $29.4 million for the costs of the
First, it is incorrect to claim either that
child’s past and future medical care and $13.5 million
all infants are in fact resuscitated at birth or
in punitive damages. Pretrial interest of $22.4 million
that the standard of care requires that they
on the damages awarded made the total verdict
be resuscitated. In one cross-cultural study
worth $65.3 million. The parents’ lawyer stated that
of neonatal deaths, 29 of the 183 neona-
the key issue was “who will make the basic medi-
tal deaths (16%) occurred in infants who
cal decisions—families or medical specialists who do
received comfort care instead of cardiopul-
not have to live with the consequences.” One juror
monary resuscitation at delivery.6 Other
reported that he and other jurors believed the Millers
articles in the medical literature support
CHAPTER 20 Ethical Issues in the Perinatal Period 537
the position that resuscitation in the deliv- judgment that must inevitably be made
ery room is not professionally and ethically about forgoing treatment renders a paren-
required in all cases.5 In addition, the Neo- tal decision against initial resuscitation
natal Resuscitation Program, created jointly uninformed, poorly (if at all) justified, and
by the American Academy of Pediatrics and not prima facie morally binding on the
the American Heart Association, specifically health care providers. Even assuming the
recognizes that there are situations in which validity of this rationale, it still remains
it is ethical not to initiate resuscitation.7 true that after more clinical information
Second, it is false to claim on the mer- has been gathered and more deliberation
its that a strict ethical and legal obligation has occurred, the physicians, nurses, and
exists to resuscitate every newborn regard- hospital should then respect parental deci-
less of his or her condition, prognosis, or sions to forgo further treatment in appro-
parental desires about resuscitation. For priate cases.
example, if prenatal testing and ultraso- The father in the Miller case testified that
nography had unambiguously detected both the obstetrician and the neonatolo-
anencephaly, the parents had given their gist were bleak about the future prospects
informed consent to nontreatment, and for their child. The Millers were told that
this condition was clearly present at birth, the hospital had “never had such a prema-
no obligation to resuscitate such an infant ture infant live and that anything they did
would exist because of his or her permanent to sustain the infant’s life would be guess-
unconsciousness, the nature of the anom- work.” The Neonatal Resuscitation Program
aly, and the reasonableness of the parents’ explicitly recognizes that parents have the
determination of what they feel is in the primary role in determining what is in the
best interests of the child. best interests of their child. Their decision,
In other words, there may be cases in however, must be based on the best informa-
which enough can be known about a child’s tion available, which may not be obtainable
diagnosis and prognosis before birth that a until after delivery. In general, infants who
parental decision to decline aggressive resus- will die tend to declare themselves early,
citation is morally justified and within the although this period has grown increasingly
bounds of parental discretion. Such cases longer, from 2 to 3 days in the early 1990s
are likely to involve an infant with one of to 10 days in 2001.8 Waiting a few days to
the following diagnoses: confirmed gesta- reflect on forgoing treatment may generate
tional age of less than 23 weeks or a birth more clinical information and greater pre-
weight of less than 400 g, anencephaly, and dictability about the child’s diagnosis and
confirmed lethal genetic disorder or malfor- prognosis.
mation. Whatever the merits of this brief moral
On the other hand, an extremely prema- analysis, it is a myth that the law requires
ture infant can be born alive with no pre- all infants to receive aggressive resuscitation
natal indication of any specific anomaly or and treatment until they are imminently
disease, and his or her medical condition dying. The ultimate source of this myth is the
and prognosis might be so uncertain that so-called “Baby Doe” law, the Child Abuse
the attending physicians cannot honestly Amendments of 1984.9 These amendments
assess the particular child’s prospects for to the Child Abuse Prevention and Treat-
survival and outcome at birth. In this situ- ment Act (CAPTA)10 and the implement-
ation or a similar one, the physicians and ing regulations issued by the Department
nurses could conclude that they were under of Health and Human Services (DHHS)11
an ethical obligation to resuscitate the child constitute the Baby Doe laws that are cur-
initially because of uncertainty about his or rently in effect in the United States. These
her true diagnosis and prognosis. If this is laws require each state to establish certain
the case, however, they would also be obli- procedures for reporting alleged instances of
gated promptly to ascertain more accurately “medical neglect,” including the withhold-
the particular child’s medical condition and ing of “medically indicated treatment,” to
the prospects for a life not characterized by local child protective services and for inves-
excessive pain, burdensome interventions, or tigating such reports—if the state wishes
inability to consciously interact with others. to receive federal child abuse prevention
From this point of view, the absence grants. On their face, the DHHS regulations
of reasonably accurate medical informa- permit treatment to be forgone only in very
tion at birth needed to ground the value limited circumstances.
Many physicians are under the impres- Montalvo v Borkovec, a negligence suit was
sion that the Baby Doe law directly imposes brought by the parents of Emanuel Vila
on them certain duties to care for newborns against the obstetrician and neonatolo-
and that they will suffer federal penalties if gist for resuscitating him after he was born
they fail to do so. These laws, however, do at 23 weeks weighing 679 g.14 The parents
not apply directly to physicians or parents claimed that they were not sufficiently
of critically ill newborns; they only require informed of the risk of disability to Emanuel
states receiving federal funds to do certain and therefore the consent for his birth (via
things. The obligation of individual medi- cesarean section) and resuscitation was not
cal professionals to report instances of child informed. The Court of Appeals of Wis-
abuse or neglect, including medical neglect, consin, however, sharply disagreed that
arises out of the law of an individual state, informed consent was necessary:
not the federal Baby Doe law. The substan- First, requiring the informed consent
tive legal standards applicable to a determi- process here presumes that a right to decide
nation of whether a particular decision by a not to resuscitate the newly born child or
physician and parents to forgo life-sustain- to withhold life-sustaining medical care
ing treatment of a newborn as unacceptable actually existed. This premise is faulty.
are established by state law, not by the Baby The court went on to interpret CAPTA to
Doe law. mean that, under these circumstances, the
State law typically does not contain parents “did not have the right to withhold
explicit or detailed standards for deter- or withdraw immediate postnatal care from
mining when treatment is being improp- him.”14 As a state appellate court decision, it
erly withheld or withdrawn from a child. may not have much impact outside of Wis-
California, for example, requires physicians consin. Nevertheless, if similar reasoning is
and other licensed providers to report as adopted by the courts, it would effectively
child neglect parental refusals of “adequate remove decision making from the parent-
medical care,” but not when the parents physician dyad.
have made an “informed and appropriate Not only have legal cases addressed the
medical decision” after consulting with a issue, but legislation was passed in 2002 that
physician who has actually examined the has led to some confusion with respect to the
child.12 Because there is no statutory defi- treatment of extremely premature or disabled
nition of “informed and appropriate medi- infants. The Born-Alive Infants Protection
cal decision,” the practical meaning of the Act, Public Law No. 107-207, was passed by
term is left to clinicians, who must decide Congress in 2002. The law states that infants
whether an “inappropriate” medical deci- who are born alive, no matter what the cir-
sion has been made and consequently cumstances or stage of development, are “per-
whether they are going to make a report to sons who are entitled to the protections of the
child protective services. law.” The Neonatal Resuscitation Program
The legacy of the Baby Doe law has been Steering Committee does not believe that the
mixed. Shortly after its passage, one veteran law should “in any way affect the approach
clinician lamented that the Baby Doe law that physicians currently follow with respect
was “usually taken as a mandate to rescue to the extremely premature infant.”15 There
many infants by the application of avail- are concerns, however, that the law may
able technology, even though families and “potentially resurrect dormant governmen-
their health and other advisors often hold tal oversight of newborn-treatment decisions
that quality of life and other considerations, and thus may have influence over normative
including staggering costs and low benefits, neonatal practice.”16
clearly support a different choice.” Parents of extremely sick newborns such
He accused an influential portion of the as those in the Miller and Montalvo cases
medical profession of helping the federal often want no “special heroics” (a vague and
government to create “a law, which, chiefly ambiguous phrase that always needs spe-
on ideological or biological grounds, often cific interpretation and explanation) even at
mandates treatment that careful reflection birth because they are afraid that once the
by those most intimately involved finds physicians start to treat, they will refuse to
inappropriate.”13 stop until the child is literally a few minutes
In addition, at least one court has inter- or hours from death. Ultimately, however,
preted CAPTA to mean that resuscitation careful attention to the humane and com-
is required even for a 23-week infant. In passionate treatment of disabled and severely
ill newborns is the caregiver’s primary ethi- uncertainty of their diagnoses and progno-
cal duty. To the extent that excessive fear of ses and trying to explain this uncertainty to
legal liabilities in the past has led physicians parents.
to overtreat infants with very poor progno- Whatever its causes, routine disqualifi-
ses and thereby cause them (and others) suf- cation of parents from participating in the
fering with no corresponding benefit, or to medical treatment plans for their newborns
disenfranchise parents from giving informed is wrong. Parents have rather broad legal
consent to the treatment of their infants and moral authority to give or withhold
because “the law” has made the decision for their consent to treatment of their children,
them, we all have been done a profound dis- although this authority is certainly not
service, most especially the infants who are unlimited. The President’s Commission for
supposed to be the ones served by the physi- the Study of Ethical Problems in Medicine
cians who care for them. and Biomedical and Behavioral Research
rightly notes that there is a presumption,
Should physicians or hospitals, rather than par- strong but rebuttable, that parents are
ents, make decisions to forgo resuscitation or the appropriate decision makers for their
treatment of an extremely low-birth-weight new- infants. Traditional law concerning the
born? family, buttressed by the emerging constitu-
tional right of privacy, protects a substantial
Parents of severely ill newborns are fre- role for parental discretion for parents.19
quently disenfranchised, in whole or in part, Similarly, the U.S. Supreme Court has
from participating in the decisions pertain- affirmed that the “decision to provide or
ing to their child’s medical treatment. There withhold medically indicated treatment is,
are a number of reasons for this phenome- except in highly unusual circumstances,
non. First, as discussed earlier, physicians are made by the parents or legal guardian.”20
intimidated by what they often misunder- Parents have unique natural bonds of
stand to be the legal restrictions on forgoing love for and loyalty to a child. The child is
treatment of a newborn. In fairness, they also their flesh and blood and exists in a family
are probably genuinely puzzled about the they have created. Of course, not all parents
ethics of the matter. As a result, though, they treat their children properly, and they can
have serious trouble identifying the legal and make unacceptably poor decisions about
ethical boundaries of medical and parental treatment in some cases. Nevertheless, in
discretion in deciding to let a newborn die by the absence of strong evidence to the con-
forgoing life-sustaining treatment.17 Peremp- trary, one must assume that the parents are
torily ignoring parental requests to consider the proper decision makers. Furthermore,
forgoing treatment or adopting a policy of there is no assurance that strangers—be they
never forgoing treatment before a child’s physicians, nurses, judges, or lawyers—who
death is inevitable and imminent eliminates have no bonds of love or loyalty to a child,
the need to confront and practically resolve will make a better decision about treatment
the underlying ethical issue.18 than the parents.17
Second, at least some physicians simply Assuming it is true that the Millers had
consider themselves to be best qualified and repeatedly requested that physicians not
solely responsible for determining the medi- resuscitate their child if she had not devel-
cal fate of their infant patients. Indeed, in oped adequately to sustain her own life and
one survey of neonatologists only about one that the hospital (and presumably the attend-
third responded that parental preference ing physicians and nurses as well) “callously
would influence their decision on delivery disregarded the couple’s request,” then the
room resuscitation.5 health care providers improperly ignored
Third, many physicians and nurses the parents’ presumptive moral and legal
assume that parents of severely ill newborns authority to make medical decisions for their
are so influenced by anxiety, grief, and guilt child. Even if the providers conscientiously
that they could not possibly make good disagree with the parents, they have the
decisions about their child’s fate. They may obligation to express the factual and moral
even distrust the motives and character of grounds for their disagreement clearly and
any parent who wants anything other than plainly. More important, they are obliged
full, aggressive treatment. Finally, physi- to disclose whether and under what circum-
cians and nurses commonly experience seri- stances they will honor parental decisions
ous difficulty both coping with the inherent to refuse treatment. Even though ultimately
overturned, the jury’s verdict should serve except in very rare cases—there remains the
as a stern warning to physicians, nurses, question of what standards should be used
and hospitals that ignoring parental wishes, to make such decisions.
particularly in an arrogant and peremptory
manner, does not sit well with the public Is the “best interests of the child” the only stand-
and may carry legal consequences. ard that should be used in making decisions to
One important principle of pediatric forgo treatment of newborns and does it have a
ethics is that physicians, nurses, and other clear and generally accepted meaning?
clinicians do have independent ethical obli-
gations to the child. Clinicians are not just The “best interests of the child” constitutes
the tools of the parents’ wishes; they are the single most popular principle brought to
moral agents who bear responsibility for the bear on the controversial subject of forgoing
child as well. The medical team, together life-sustaining treatment of a child. Many
with the child’s parents, should be decid- commentators believe that the infant’s best
ing how best to care for a severely ill new- interests is the sole ethical criterion upon
born. Clinicians should provide parents which to base an ethically defensible deci-
with honest and accurate disclosure of both sion, although these same people disagree
the child’s medical diagnosis and prognosis on unavoidably related subjects such as
(with any attendant uncertainty) and their which infants should be treated, which con-
own carefully thought out recommendation ditions count as exceptions to the general
for a plan of action in light of relevant ethi- duty to preserve life, and whether parents,
cal, medical, and legal considerations. But physicians, and/or ethics committees ought
they may not simply ignore the parents. The to have a major role in the decision.21
jury’s verdict in the Miller case shows that Although the standard has remained a
members of the public will not automatically cornerstone of pediatric ethics, commenta-
defer to the clinicians or hospital and permit tors have long questioned its coherence and
them to act arrogantly toward parents who, adequacy as a substantive ethical principle.
quite literally, have to live with the conse- Over two decades ago Brody criticized the
quences of all the medical decisions that are best interests standard as trying not only
made on behalf of their children. to make a very complex matter simple, but
also magically to avoid abuse of parental
discretion in deciding against treatment (as
EDITORIAL COMMENT: Although in the Miller case occurred in the original Baby Doe of Bloom-
the parents did not wish resuscitation, often the par- ington case).22 Brody sees decisions to forgo
ents demand resuscitation against the advice of the treatment of newborns as inherently com-
physician. It is important to appreciate that parents plex in light of (1) the near impossibility of
are moving away from a tacit acceptance of physician having a reliable prognosis, (2) the medical
determination of lethality; they want more say, more and social differences between newborns
information, and more time. In addition, a powerful and adults, (3) the difficulty predicting
influence on parents’ decisions is being exerted by which medical interventions will help and
information on the Internet, which tends to engender which will hurt the child, and (4) the vast
an expectation that full resuscitation is a reasonable differences among families in adapting to
approach. This does not mean that parents have the the substantial changes that must occur in
only voice. Ceding authority for ethically troubling is- the life of a family with a severely ill new-
sues out of respect for parental autonomy can lead born. His analysis of the best interests stan-
to an ‘‘ethic of abdication’’ of professional obligation dard remains insightful and relevant even
to the newborn infant (and the parents). We do need to today and deserves careful consideration.
avoid characterizing these types of conflict as clashes Among other things, Brody’s criticism of
in abstract principles—between respect for parental the best interests standard rests upon the
autonomy and physician beneficence—and learn how following factors: (1) an infant’s interests
to harmonize these principles. are unknowable, (2) the best interests stan-
J. Hellmann, MBBCh, FRCPC, MHSc dard can yield results that seem inhumane,
and (3) the interests of persons other than
the infant deserve consideration at least in
Assuming, then, that decisions to forgo certain circumstances.
treatment of severely ill newborns ought to With respect to the first factor, Brody
be in the hands of the attending clinicians argues that once we move beyond basic
and of the child’s parents—and not the law needs such as food and shelter, we cannot
really know what is in someone’s interests In summary, despite its popularity and
without knowing a good deal about that frequent invocation, the best interests
person’s individual plans and desires about standard as traditionally understood is not
life. But a newborn has no such plans or necessarily either the best or the most intel-
desires. He offers the example of two neo- ligible one to use in making ethical decisions
natologists arguing over how aggressively to concerning newborns. Physicians, other cli-
treat an infant born with a high meningo- nicians, and parents should be considering
myelocele and hydrocephalus. One argues a complex set of factors when making deci-
that the infant’s best interests are served by sions about newborns and should be careful
early surgical intervention, noting the high in concluding just what the “best interests
probability of death or life with worse neu- of the infant” may mean in any given case.
rodevelopmental outcome without surgery.
She cites the occasional success story of an Is the present and future quality of an infant’s life
infant with an equally severe defect who relevant to a decision to forgo resuscitation or
turned out to have only mild cognitive and life-sustaining treatment of a premature or seri-
physical impairment. The other argues that ously ill newborn?
an early death is in the infant’s best interests
and points to the very high odds of major It is a myth that an infant’s quality of life
mental and physical handicap, plus the is utterly irrelevant to a decision to forgo
need for repeated, painful surgeries to treat treatment, although this claim is false only
the condition and its sequelae. Brody cor- in its extreme form. The appeal to quality of
rectly points out that what these physicians life can be both false and pernicious when
are really arguing about is what they think it is made in a manner that sanctions non-
ought to be done. The phrase “the infant’s treatment of children who are only mildly
best interests” is a rhetorical flourish that physically or intellectually impaired, or
does no useful work in the discussion. when it is taken to mean that the simple
Second, the best interests standard can presence of physical disability or mental
yield inhumane or unjust results because it retardation is a sufficient reason to deny
implies that whenever the benefits of treat- treatment. Denying medically needed treat-
ment outweigh burdens even to a slight ment to a child simply because the child has
degree, that fact alone fixes an obligation to Down syndrome (trisomy 21) or some form
treat—even if the benefits are minuscule or of spina bifida is a misuse of quality of life as
the burdens horrendous. He cites the case an ethically proper consideration in forgo-
of children so severely impaired as to be ing treatment.
unable to recognize other people or form The alleged complete irrelevance of
any human relationship, who can perceive quality-of-life considerations is false, how-
only primitive sensations such as light and ever, and moreover potentially inhumane,
color, but show no sign of suffering. Because when it is taken to mean that the life expec-
such children get some primitive pleasure tancy of a child, his or her level of physical
out of living and suffer little, a best interests and intellectual functioning, and the rela-
analysis would require that any newborn tive burdens and benefits of treatment make
with such a future have its life prolonged, no difference whatsoever when parents and
even by invasive or aggressive means. Brody clinicians decide to intervene medically.
claims that to save a child in order to let it The irrelevance of quality of life is typically
live such a life “may well do nothing of real, embedded in the application of a “medical
substantial benefit for the child.” benefit” standard, which holds that medical
Finally, Brody agrees with Strong23 that intervention must occur when it is likely,
the refusal to consider any interests other in the exercise of reasonable medical judg-
than the infant’s own is an arbitrary rather ment, to bring about its intended medical
than a principled ethical choice, although result. The use of such a medical benefit
this refusal is required by the best interests standard not only blindly falls into the trap
standard. In the many cases in which treat- of the technologic imperative (whatever can
ment will result in clear and substantial ben- be done, should be done), but also denies
efits to the infant, then its interests override that medicine is an enterprise devoted to
those of others. However, in other cases in benefitting an individual person whose life
which the benefit to the infant is less or more in the world cannot be reduced to the tech-
questionable, then the interests of the fam- nical “success” of an operation, a medicine,
ily ought to be factored into the decision. or a machine. Put differently, people are not
meant to be the passive objects of medical pain and burden of intervention and the
technology. lack of compensating benefit. At bottom,
Consider the generally accepted view medical procedures are “inhumane” and
that newborns with anencephaly should contraindicated only because of certain fea-
not receive any life-prolonging treatment tures pertaining directly to the infant’s qual-
other than basic supportive care. This view ity of life.
is usually justified on the basis that chil- Although quality of life may be relevant,
dren lacking a cerebral cortex are irrevers- physicians need to be extremely careful
ibly dying and should not have their agony about their own personal biases. Empiri-
prolonged. However, on closer analysis, cal studies of children with cerebral palsy
this justification is flawed in several ways. using self-reported quality-of-life question-
First, although it is true that such infants naires found that they had scores compa-
cannot live indefinitely, it is not true that rable to those of their peers without cerebral
their deaths are necessarily imminent. Most palsy.24 These results are similar to those of
anencephalic infants die quickly precisely other studies which have shown that neo-
because they do not receive any treatment, natal “survivors who subsequently develop
which is a human choice rather than a fact impairment may live happier lives than
of nature. Indeed, some babies with anen- doctors imagine.”25
cephaly have lived for several years. Thus, if In summary, virtually all medical inter-
we choose to, we could keep at least some of ventions have some risk attached: pain, side
these infants alive for quite some time. effects, complications, even death. As noted
Second, because anencephalic infants by the American Medical Association Code
are permanently unconscious, they experi- of Medical Ethics, determining what is in
ence neither agony nor pain nor anything the best interests of a seriously ill newborn
else during their lives. Deciding not to treat involves a number of difficult consider-
them aggressively does not truly spare them ations, including the following:
any unpleasantness. More honestly put, it • The chance that the therapy will succeed
is ethically proper not to resuscitate and • The risks involved in treatment and
treat such newborns aggressively precisely nontreatment
because they have no ability to survive • The degree to which the therapy, if suc-
indefinitely and no capability of experienc- cessful, will extend life
ing even primitive human interaction. In • The pain and discomfort associated with
other words, they have an unacceptably the therapy
poor quality of life. • The anticipated quality of life of the new-
Paradoxically, the Baby Doe law and born with and without treatment26
its implementing regulations contain an Although for many people, a life worth
express condemnation of quality-of-life con- living should hold at least some potential
siderations and yet also contain two excep- for interaction with others, this potential
tions to the general duty to preserve an does not have to be that for normal or near
infant’s life that rest upon quality of life. normal intelligence. In addition, physi-
The first exception approves of forgoing cians must be very careful not to under-
treatment when the infant is “chronically estimate the quality of someone’s life.
and irreversibly comatose.” Because some Quality of life is not an inherently dirty or
of these infants could live indefinitely and discriminatory concept, although it does
the exception does not depend upon their contain potential danger. But this is true of
imminent demise, the only justification left medicine itself: it can do great good, but it
for not treating them is their poor quality of can also cause bitter suffering and loss. We
life: unconscious infants have no potential should not abandon medicine because its
for human life as we understand it, and thus results are not always happy. Nor should
there is no ethical obligation to prolong we abandon the quest to determine what
their lives. is best for a newborn just because doing so
The second exception encompasses treat- is challenging.
ment that would be “virtually futile in
terms of the survival of the infant and the REFERENCES
treatment itself under such circumstances The reference list for this chapter can be found
would be inhumane.” Thus, treatment can online at www.expertconsult.com.
be withheld because the infant’s quality of
life would be seriously compromised by the
Drugs Used
A-1
for Emergency
and Cardiac
Indications
in Newborns
Jacquelyn McClary
Agent Dosage Comments

Adenosine (Adenocard) 50 μg/kg rapid IV (over 1-2 sec) followed Facial flushing, irritability, and
immediately by NS flush transient arrhythmias (asystole) may
Increase dose every 2 min by 50-μg/kg increments occur. Apnea in a premature infant
if no response; max dose 250 μg/kg has been reported. Monitor ECG
and blood pressure continuously
during administration.
Alprostadil Starting dose: 0.05-0.1 μg/kg/min continuous IV May cause apnea, fever,
(prostaglandin E1) infusion hypotension, and flushing.
Maintenance dose: after response observed titrate
down to lowest effective dose, which may be as
low as 0.01 μg/kg/min
Amiodarone Loading dose: 5 mg/kg IV over 30-60 min Monitor ECG and blood pressure
Maintenance dose: 7-15 μg/kg/min continuous continuously for bradycardia and
IV infusion hypotension. Administration into
central line preferred to minimize
risk of extravasation.
Atropine 0.01-0.03 mg/kg IV push or IM Low dosages may result in
Repeat every 10-15 min to max 0.04 mg/kg paradoxical bradycardia.
May be given via endotracheal tube
Calcium chloride 10% 35-70 mg/kg (0.35-0.7 mL/kg), 10-20 mg/kg Dilute with NS to a final
(27 mg elemental elemental calcium IV over 10-30 min concentration of 20 mg/mL. Stop
Ca2+ per mL) infusion if HR <100. Extravasation
may lead to tissue necrosis.
Calcium gluconate Emergency dose: 100-200 mg/kg (1-2 mL/kg), Dilute with NS to a final
10% (9.3 mg Ca2+ 10-20 mg/kg elemental calcium IV over 10-30 min concentration of 50 mg/mL. Stop
per mL) Maintenance dose in IV fluids: 200-800 mg/kg/day infusion if HR <100. Extravasation
(20-80 mg/kg/day elemental calcium) may lead to tissue necrosis.
Digoxin Loading dose (digitalization): divided into 3 doses Avoid hypokalemia,
over 24 hr given by slow IV push or PO hypomagnesemia, hypocalcemia,
PMA ≤29 wk: 15 μg/kg IV or 20 μg/kg PO and hypercalcemia. Assess renal
PMA 30-36 wk: 20 μg/kg IV or 25 μg/kg PO function. Monitor HR rate and
PMA 37-48 wk: 30 μg/kg IV or 40 μg/kg PO heart rhythm. Follow serum drug
PMA ≥49 wk: 40 μg/kg IV or 50 μg/kg PO concentrations with a target range
Maintenance dose: of 1-2 ng/mL.
PMA ≤29 wk: 4 μg/kg IV or 5 μg/kg PO q24h
PMA 30-36 wk: 5 μg/kg IV or 6 μg/kg PO q24h
PMA 37-48 wk: 4 μg/kg IV or 5 μg/kg PO q12h
PMA ≥49 wk: 5 μg/kg IV or 6 μg/kg PO q12h
Dobutamine 2-25 μg/kg/min continuous IV infusion Tachycardia may occur at high
dosages. Hypotension risk
increases in hypovolemic patients.
Tissue ischemia with extravasation;
inject phentolamine into affected
area as soon as possible.
Continued
543
544 APPENDIX A-1 Drugs Used for Emergency and Cardiac Indications in Newborns

Dopamine 2-20 μg/kg/min continuous IV infusion Pharmacologic effect is dose
“Renal dose”: 2-5 μg/kg/min dependent. Extravasation may lead
Cardiac stimulation: 5-15 μg/kg/min to necrosis; inject phentolamine
Vasoconstriction: >5 μg/kg/min into affected area as soon as
possible.
Epinephrine Emergency dose: 0.01-0.03 mg/kg (0.1-0.3 mL/kg Monitor HR and blood pressure
of 1:10,000 concentration) IV push; 0.1 mg/kg continuously. Infiltration may cause
ET followed by 1 mL NS tissue necrosis; inject phentolamine
Continuous IV infusion: 0.02-1 μg/kg/min into affected area as soon as
possible.
Esmolol (Brevibloc) Supraventricular tachycardia: 100 μg/kg/min Monitor ECG continuously.
continuous IV infusion; increase by 50-100 μg/ May cause hypotension at high
kg/min every 5 min; usual max 200 μg/kg/min dosages.
Postoperative hypertension: 50 μg/kg/min continu-
ous IV infusion; increase by 25-50 μg/kg/min
every 5 min; usual max 200 μg/kg/min
Hydralazine 0.1-0.5 mg/kg/dose IV or IM q6-8h; increase grad- Administration with a β-blocker
(Apresoline) ually to max 2 mg/kg/dose q6h may increase antihypertensive
0.25-1 mg/kg/dose PO q6-8h, or twice the IV dose effect and decrease the hydralazine
dose required.
Ibuprofen lysine First dose: 10 mg/kg IV over 15 min Monitor urine output and signs of
(NeoProfen) Second and third doses (starting 24 hr after first bleeding.
dose): 5 mg/kg IV over 15 min q24h
Indomethacin (Indocin) 3 doses given IV over 30 min q12-24h Monitor urine output, electrolytes,
Age at first dose determines dosing regimen: blood urea nitrogen, creatinine, and
<48 hr: 0.2/0.1/0.1 mg/kg platelet count. Monitor for signs of
2-7 days: 0.2/0.2/0.2 mg/kg bleeding.
>7 days: 0.2/0.25/0.25 mg/kg
Prolonged treatment option: 0.2 mg/kg q24h for
5-7 days
Isoproterenol (Isuprel) 0.05-0.5 μg/kg/min continuous IV infusion; max May cause arrhythmias and
dose 2 μg/kg/min hypoxemia. Correct acidosis prior
to starting therapy.
Lidocaine Bolus dose: 0.5-1.0 mg/kg IV push over 5 min; May cause CNS toxicity—monitor
may repeat every 10 min to a max of 5 mg/kg for seizures, apnea, respiratory
Continuous IV infusion: 10-50 μg/kg/min depression. High dosages may
cause bradycardia, heart block,
hypotension—monitor ECG, HR,
and blood pressure continuously.
Contraindicated in cardiac failure
and heart block.
Milrinone (Primacor) Loading dose: 50-75 μg/kg/min over 15-60 min Loading dose optional based
Continuous IV infusion: 0.25-0.75 μg/kg/min on status of patient. Correct
hypovolemia prior to initiation
of therapy. Blood pressure may
decrease 5%-9% after loading
dose and HR may increase
5%-10%.
Naloxone (Narcan) 0.1 mg/kg IV push repeated every 2-3 min until Not recommended as part of the
opioid effect reversed; may need to repeat doses initial resuscitation of newborns
every 20-60 min; may be given IM, SC, or ET, but with respiratory depression.
not recommended due to delayed onset of action
Neostigmine 0.04-0.08 mg/kg slow IV push (IM and SC adminis- Give in addition to atropine
(Prostigmin) tration have delayed onset of action) 0.02 mg/kg to reverse neuromuscu-
lar blockade.
Nicardipine (Cardene) 0.5 μg/kg/min continuous IV infusion; titrate up to Monitor blood pressure, HR, and
2 μg/kg/min heart rhythm continuously. May
take up to 2 days to see final effect
of dose.
Procainamide Bolus dose: 7-10 mg/kg IV over 1 hr Monitor for hypotension (increased
(Pronestyl) Continuous IV infusion: 20-80 μg/kg/min with rapid infusion), bradycardia,
arrhythmias. Monitor serum
levels, especially in patients with
hepatic or renal impairment, or
those receiving high dosages.
Monitor CBC for neutropenia,
thrombocytopenia regularly.
APPENDIX A-1 Drugs Used for Emergency and Cardiac Indications in Newborns 545

Propranolol (Inderal) 0.01 mg/kg/dose IV push over 10 min q6h; titrate Monitor ECG continuously during
up to max 0.15 mg/kg/dose q6h acute treatment of arrhythmias.
0.25 mg/kg/dose PO q6h; titrate up to max Monitor blood glucose for
3.5 mg/kg/dose q6h hypoglycemia. Monitor blood
pressure.
Sodium nitroprusside 0.25-0.5 μg/kg/min continuous IV infusion; titrate Monitor HR and intraarterial blood
(Nipride) up every 20 min. Usual maintenance dose is <2 pressure continuously.
μg/kg/min May produce severe hypoten-
Hypertensive crisis: doses up to 10 μg/kg/min can sion and cyanide/thiocyanate
be used for no longer than 10 min toxicity; increased risk of toxicity
with prolonged treatment, high
dosages, and renal or hepatic
impairment.
Protect drug from light.
CBC, Complete blood count; CNS, central nervous system; ECG, electrocardiogram; ET, endotracheal
tube; HR, heart rate; IM, intramuscular; IV, intravenous; max, maximum; NS, normal saline; PMA,
postmenstrual age; PO, by mouth; q, every; SC, subcutaneous.
Drug Dosing
Table
Jacquelyn McClary
A-2
Medication (Trade Important
Name)/Route of Adverse
Administration Mechanism of Action/Dosing Events Special Considerations
Acetaminophen Inhibits prostaglandin synthe- Liver toxicity in Rectal administration results
(Tylenol) sis in central nervous system. overdose (acute in prolonged, variable
PO/PR Peripherally blocks pain impulse or chronic) absorption.
generation. Elimination prolonged
Inhibits hypothalamic thermal in patients with liver
regulating center. dysfunction.
PO: 10-15 mg/kg q4-6h
PR: 15-20 mg/kg q6-8h
Acyclovir Inhibits DNA synthesis and viral Renal dysfunc- Maintain proper hydration,
(Zovirax) replication by incorporation into tion, neutropenia monitor renal function.
IV viral DNA. Consider prolonging dosing
interval in infants of <34 wk
IV: 20 mg/kg q8h
PMA or with significant renal
or hepatic impairment.
Adenosine Slows AV conduction, thereby Momentary Administer over 1-2 sec and as
(Adenocard) interrupting reentry pathway and complete heart close to IV insertion site as
IV restoring normal sinus rhythm. block after possible; follow immediately
administration with NS flush.
IV: 50 μg/kg initially; increase in
Bronchoconstric- Contraindicated in patients
50-μg/kg increments and repeat
tion in patients with second- or third-degree
every 2 min to max dose of
with reactive heart block.
250 μg/kg
airway disease Methylxanthines diminish
effect of adenosine and
therefore larger doses may
be needed.
Albuterol β2-agonist that relaxes bronchial Tachycardia, Oral administration may be
(Proventil, Ventolin) smooth muscle. hypokalemia associated with more systemic
PO/Neb/MDI with continuous adverse events.
Neb: 0.1-0.5 mg/kg q2-6h
administration
MDI: 1 actuation q2-6h
PO: 0.1-0.3 mg/kg/dose q6-8h
Alprostadil Prostaglandin E1 analog that pro- Hypotension, Apnea occurs in ~10%-12%
(prostaglandin E1) duces direct vasodilation of vascu- flushing, of neonates within first hour of
(Prostin VR) lar and ductus arteriosus smooth bradycardia, infusion.
IV muscle. fever, apnea
IV: 0.05-0.1 μg/kg/min via continuous
infusion; maintenance doses may
be as low as 0.01 μg/kg/min
Amikacin Inhibits bacterial protein synthesis by Nephrotoxic, Monitor serum concentrations.
(Amikin) inhibiting 50S ribosomal subunit. ototoxic, additive Therapeutic peak serum con-
IM/IV neuromuscular centration is 20 to 30 μg/mL.
PMA ≤29 wk:
blockade with Therapeutic trough serum con-
0-7 days old: 18 mg/kg q48h
neuromuscular centration is <10 μg/mL.
blocking agents Should not be concurrently
≥29 days old: 15 mg/kg q24h
administered in same IV
PMA 30-34 wk:
line with extended-spec-
trum penicillins (possible
≥8 days old: 15 mg/kg q24h
inactivation).
PMA ≥35 wk: 15 mg/kg q24h
Synergistic antibacterial
actions with penicillins and
other antibiotics.
546
APPENDIX A-2 Drug Dosing Table 547

Amiodarone Inhibits adrenergic stimulation, Hypotension, Hyperthyroidism or
(Cordarone, Pacerone) prolongs action potential and refrac- bradycardia, AV ypothyroidism may occur with
h
IV/PO tory period in myocardial tissue, block, pneumo- long-term use.
decreases AV conduction and sinus nitis, pulmonary
node function. fibrosis, liver
injury
IV: 5 mg/kg loading dose followed by
maintenance infusion of 7-15 μg/
kg/min
PO: 5-10 mg/kg q12h after 24-48 hr
of IV therapy
Ammonium chloride Increases acidity by increasing Metabolic acido- Use only as alternative supple-
IV/PO concentration of free hydrogen ions, sis, hyperchlo- ment after sodium and potas-
which combine with bicarbonate ion remia sium supplementation have
to form CO2 and water; net result is been optimized.
replacement of bicarbonate ions with
chloride ions.
IV/PO: 75-150 mg/kg/day divided
q6-8h
Amphotericin B Binds to fungal ergosterol, compro- Hypomagnese- Monitor renal function, electro-
(Amphocin, Fungi- mising fungal cell wall integrity. mia, hypokalemia lytes. Adjust dosing interval
zone) nephrotoxic- if serum creatinine increases
Amphotericin B: 1-1.5 mg/kg q24h
Amphotericin B lipid ity, fever, chills, >0.4 mg/dL from baseline.
over 2-6 hr
complex thrombocytopenia Less nephrotoxicity with lipid
Amphotericin B lipid complex:
(Abelcet) and liposome formulations.
5 mg/kg q24h over 2 hr
Amphotericin B lipo-
Amphotericin B liposome:
some
5-7 mg/kg q24h over 2 hr
(AmBisome)
IV
Ampicillin Inhibits bacterial cell wall synthesis CNS excitation For GBS bacteremia dosages
(Omnipen, Polycillin, by binding to specific penicillin-bind- or seizure activity may be increased to 200 mg/
Principen) ing proteins. Causes cell wall death with very large kg/day. For GBS meningitis
IM/IV resulting in bacteriocidal activity. doses dosages may be increased
to 300-400 mg/kg/day and
PMA ≤29 wk:
doses given at more frequent
0-28 days old: 25-50 mg/kg q12h
intervals.
>28 days old: 25-50 mg/kg q8h
PMA 30-36 wk:
PMA 37-44 wk:
PMA ≥45 wk: 25-50 mg/kg q6h
Atropine Competitively inhibits actions of ace- Tachycardia, Administer rapidly and
PO/IV/IM/ET tylcholine in secretory glands, smooth arrhythmias, undiluted. Small doses
muscle, and CNS. urinary retention, may result in paradoxical
decreased GI bradycardia.
PO: 0.02 mg/kg q4-6h; increase
motility
gradually to max 0.09 mg/kg/dose
IV/IM: 0.01-0.03 mg/kg over
1 min; may repeat every 10-15 min
(max dose 0.04 mg/kg)
ET: 0.01-0.03 mg/kg followed by
1 mL NS
Azithromycin Inhibits bacterial protein synthesis by Diarrhea, rash, Recommended PO dosing is
(Zithromax) binding to 50S ribosomal subunit. blood in stool for treatment of pertussis.
PO/IV IV dosing not well studied in
PO: 10 mg/kg q24h × 5 days
pediatric patients.
IV: 5-10 mg/kg q24h
Continued
548 APPENDIX A-2 Drug Dosing Table

Aztreonam Inhibits bacterial cell wall synthesis Hypoglycemia, Contains L-arginine—provide
(Azactam) and causes cell wall destruction by eosinophilia, adequate glucose to avoid
IM/IV binding to penicillin-binding proteins. elevated trans- hypoglycemia.
aminases
PMA ≤29 wk:
>28 days old: 30 mg/kg q8h
PMA 30-36 wk:
PMA 37-44 wk:
Beractant Modified bovine pulmonary surfactant Reflux of For IT administration only.
(Survanta) analog. Replaces deficient or ineffec- surfactant up Suspension should be at room
IT tive endogenous lung surfactant. ET, decreased temperature before admin-
oxygenation, istering. Do not artificially
IT: 4 mL/kg divided into 4 aliquots
bradycardia warm.
administered as soon as possible
Swirl suspension; do not shake
after birth; repeat up to 3 doses
or filter suspension. Continu-
within 48 hr of life if needed, no more
ously monitor heart rate and
frequently than q6h
oxygen saturation during
administration.
Bumetanide Inhibits chloride and sodium reab- Hypomagnese- Higher dosages required with
(Bumex) sorption in ascending loop of Henle mia, hyponatre- abnormal renal function or
PO/IM/IV and proximal renal tubule, causing mia, hypokalemia, congestive heart failure. May
increased excretion of water and metabolic hypo- displace bilirubin at high dos-
electrolytes. chloremic alka- ages or with long duration of
losis therapy.
PO/IM/IV: 0.005-0.1 mg/kg
<34 wk, 0-2 mo old: q24h
<34 wk, >2 mo old: q12h
≥34 wk, 0-1 mo old: q24h
≥34 wk, >1 mo old: q12h
Caffeine citrate Stimulates central inspiratory drive Tachycardia, Therapeutic trough serum
(Cafcit) and improves skeletal muscle con- cardiac dysrhyth- concentration range is 5-25 μg/
PO/IV traction. mias, insomnia, mL; toxicity is associated with
GI disturbances, serum concentrations of >40-
Loading dose: 20-25 mg/kg
gastroesophageal 50 μg/mL. Monitoring serum
Maintenance dose: 5-10 mg/kg q24h
reflux concentrations not typically
necessary at recommended
dosages.
Calfactant Natural surfactant extracted from calf Reflux of For IT administration only.
(Infasurf) lung. Replaces deficient or ineffective surfactant up Suspension should be at room
IT endogenous lung surfactant. ET, decreased temperature before admin-
oxygenation, istering. Do not artificially
IT: 3 mL/kg divided into 2 aliquots
bradycardia warm.
administered as soon as possible
after birth; repeat up to 3 doses if
needed, no more frequently than
q12h
administration.
Captopril Competitively inhibits angiotensin- Decreased cere- Monitor renal function. Onset
(Capoten) converting enzyme. bral or renal blood of action is 15 min and peak
PO flow, hyperka- effect is 30-90 min after dos-
Initial dose: 0.01-0.05 mg/kg q8-12h;
lemia ing.
adjust dose based on response
Max dose: 0.5 mg/kg q6-24h
Caspofungin Inhibits synthesis of essential cell wall Thrombophlebitis, Monitor electrolytes and
(Cancidas) component in susceptible fungi. hypercalcemia, hepatic transaminases.
IV hypokalemia,
IV: 25 mg/m2 q24h
increased liver
enzymes

Cefazolin Inhibits bacterial cell wall synthesis by Phlebitis, eosino- Poor CNS penetration. Often
(Ancef, Kefzol) binding to penicillin-binding proteins. philia used for perioperative infection
IM/IV prophylaxis.
PMA ≤29 wk:
PMA 30-36 wk:
PMA 37-44 wk:
Cefepime Inhibits bacterial cell wall synthesis by Eosinophilia, Widely distributed in body tis-
(Maxipime) binding to penicillin-binding proteins. elevated hepatic sues and fluids, including CNS.
IM/IV transaminases
Mild to moderate infections:
≤28 days old: 30 mg/kg q12h
Meningitis and severe infections:
50 mg/kg q12h
Cefotaxime Inhibits bacterial cell wall synthesis by Leukopenia, Widely distributed in CSF and
(Claforan) binding to penicillin-binding proteins. granulocytopenia, other tissues.
IM/IV eosinophilia
PMA ≤29 wk:
PMA 30-36 wk:
PMA 37-44 wk:
Cefoxitin Inhibits bacterial cell wall synthesis by Eosinophilia, Use often limited to skin,
(Mefoxin) binding to penicillin-binding proteins. elevated hepatic intraabdominal, and urinary
IM/IV transaminases tract infections.
PMA ≤29 wk:
PMA 30-36 wk:
PMA 37-44 wk:
PMA ≥45 wk: 25-33 mg/kg q6h
Ceftazidime Inhibits bacterial cell wall synthesis by Eosinophilia, Widely distributed in body
(Fortaz) binding to penicillin-binding proteins. elevated hepatic tissues and fluids. Synergistic
IM/IV transaminases with aminoglycosides.
PMA ≤29 wk:
PMA 30-36 wk:
PMA 37-44 wk:
Ceftriaxone Inhibits bacterial cell wall synthesis by Increased bleed- Displaces bilirubin from albumin
(Rocephin) binding to penicillin-binding proteins. ing time, leukope- binding sites—not recom-
IM/IV nia, eosinophilia, mended for use in neonates
Sepsis: 50 mg/kg q24h
transient gall with hyperbilirubinemia.
Meningitis: 100 mg/kg loading dose,
bladder precipita- Contraindicated with concur-
then 80 mg/kg q24h
tions rent administration of cal-
cium-containing solutions.
Continued

Chlorothiazide Inhibits Na reabsorption in distal renal Hypochloremic Synergistic effect with loop
(Diuril) tubules causing increased excre- metabolic alkalo- diuretics (e.g., furosemide) or
PO/IV tion of sodium, chloride, potassium, sis, fluid and elec- spironolactone. Monitor serum
bicarbonate, magnesium, phosphate, trolyte disorders, electrolytes closely.
calcium, and water. hyperglycemia
PO: 10-20 mg/kg q12h
IV: 2-10 mg/kg q12h
Cholecalciferol Vitamin D supplementation is used to Signs of toxicity Monitor 25-hydroxyvitamin D
(vitamin D3, stimulate or support skeletal growth. due to hypercal- concentrations, particularly
D-Vi-Sol) cemia (vomiting, in neonates receiving higher
Supplementation: 400 U q24h
PO nephrocalcinosis, dosages. Monitor calcium and
Vitamin D deficiency: 400-1000 U
arrhythmia) phosphorous levels.
q24h
Clindamycin Inhibits bacterial protein synthesis by Clostridium dif- Increase dosing interval in the
(Cleocin) reversibly binding to 50S ribosome ficile-associated presence of significant liver
PO/IM/IV subunit. diarrhea, pseu- dysfunction.
domembranous
PMA ≤29 wk:
colitis, phlebitis at
0-28 days old: 5-7.5 mg/kg q12h
site of injection
>28 days old: 5-7.5 mg/kg q8h
PMA 30-36 wk:
PMA 37-44 wk:
PMA ≥45 wk: 5-7.5 mg/kg q6h
Dexamethasone Decreases inflammation by suppress- Hypertension, For ventilator weaning, 10-day
(Decadron) ing proinflammatory mediators. hyperglycemia, GI DART trial protocol is
PO/IV/IM bleeding or per- commonly used.
Facilitation of ventilator weaning:
foration, growth Typically airway edema
0.01-0.075 mg/kg q12h
inhibition treatment limited to 3 doses.
Airway edema: 0.25-0.5 mg/kg q8h;
max dose 1 mg/kg/day
Diazoxide Inhibits insulin release from pancreas. Sodium and Alcohol content of oral suspen-
(Proglycem) fluid retention, sion is 7.25%; GI upset and
PO: 2-5 mg/kg q8h
PO pulmonary hyper- abdominal distension are
tension, cardiac common.
failure
Digoxin Reversibly binds to Na-K-Ca pump Atrial and ventric- Hypokalemia, hypomagnese-
(Lanoxin) and increases calcium influx within ular arrhythmias mia, hypermagnesemia, and
PO/IV myocardial cells, which results in hypercalcemia predispose
increase in force of myocardial con- patients to digoxin toxicity.
traction. Follow serum drug concentra-
tions with target range of
See Appendix A-1 for dosing.
1-2 ng/mL.
Dobutamine Reversibly binds to and stimulates Hypotension in Correct hypovolemia before
IV β1-adrenergic receptor, causing setting of hypovo- initiation of therapy if
increased contractility and heart rate. lemia, tachycar- possible.
dia, arrhythmias, Use phentolamine for
Continuous IV infusion:
phlebitis treatment of extravasation.
2-25 μg/kg/min
Dopamine Stimulates α- and β-adrenergic and Hypertension, Pharmacologic effect is dose
IV dopaminergic receptors, which tachycardia, dependent.
results in cardiac stimulation, phlebitis Use phentolamine for
increased renal blood flow, and treatment of extravasation.
vasoconstriction.
Continuous IV infusion: 2-20 μg/kg/
min
Dornase alfa Selectively cleaves DNA, which esaturation,
D Each single-dose ampule
(Pulmozyme) reduces mucous viscosity in airway ontains 2.5 mg/2.5 mL
c
Neb pulmonary secretions. obstruction dornase alfa.
Neb: 1.25-2.5 mL q12-24h

Enalapril (PO) Exerts blood pressure and cardiac Reflex tachy- Monitor renal function. Begin
(Vasotec) effects through competitive inhibition cardia, renal at low doses q24h and titrate
Enalaprilat (IV) of angiotensin-converting enzyme. dysfunction, up based on response.
hyperkalemia
PO: 0.04-0.15 mg/kg q6-24h
IV: 0.005-0.01 mg/kg q8-24h
Enoxaparin Potentiates antithrombin III activity Intracranial hem- Monitor Xa levels 4 hr after a
(Lovenox) and inactivates anticoagulation orrhage, GI bleed- dose; target range is 0.5-1
SC factor Xa. ing, hematoma at U/ml for treatment and
injection site 0.1-0.4 U/mL for prophylaxis.
Throm basis treatment:
Therapeutic dosages in preterm
Term: 1.7 mg/kg q12h
neonates are widely variable.
Preterm: 2 mg/kg q12h
Renally cleared; reduced
Prophylaxis: <3 months: 0.75 mg/kg
dosages required in renal
q12h ≥3 months: 0.5 mg/kg q12h
dysfunction.
Call 1-800-NOCLOTS for dos-
ing assistance.
Epinephrine Stimulates α- and β-adrenergic Hypertension, Correct acidosis before admin-
(Adrenalin) receptors, which results in cardiac tachycardia, istration if possible.
IV/ET stimulation and dilation of skeletal arrhythmias, Use phentolamine for
muscle vasculature. phlebitis, renal treatment of extravasation.
vascular ischemia
IV: 0.01-0.03 mg/kg/dose q3-5min
Continuous IV infusion: 0.02-1 μg/
kg/min
ET: 0.1 mg/kg followed by 1 mL NS
Epoetin alfa Synthetic analog of erythropoietin Neutropenia Subcutaneous route preferred.
(Epogen, Procrit) that stimulates erythropoiesis. Continue therapy until hemato-
IV/SC crit is ≥35% (usually 2-4 wk).
IV/SC: 400-500 U/kg 3 times per
Consider administration of iron if
week
iron stores are not adequate.
Erythromycin Inhibits bacterial protein synthesis by Bradycardia and Administer PO with feeds to
(Eryped, E.E.S.) reversibly binding to 50S ribosome hypotension dur- reduce GI side effects and
PO/IV subunit. ing IV administra- increase absorption.
tion, phlebitis,
PO erythromycin ethylsuccinate:
diarrhea, abdomi-
Infection: 10-12.5 mg/kg q6h
nal pain
Gastric motility: 10 mg/kg q6h ×
48 hr, then 4 mg/kg q6h
IV erythromycin lactobionate:
5-10 mg/kg q6h
Esmolol Competitively blocks response to β1- Hypotension, tis- Use phentolamine for
(Brevibloc) adrenergic stimulation with minimal sue necrosis treatment of extravasation.
IV effect on β2-adrenergic receptors.
Supraventricular tachycardia: 100
μg/kg/min continuous IV infusion;
increase by 50-100 μg/kg/min every
5 min to usual max 200 μg/kg/min
Postoperative hypertension: 50 μg/
kg/min continuous IV infusion;
increase by 25-50 μg/kg/min every
5 min to usual max 200 μg/kg/min
Famotidine Competitively inhibits histamine Late-onset Oral suspension contains
(Pepcid) receptors in gastric parietal cells, bacterial or fungal sodium benzoate.
PO/IV which results in inhibition of gastric sepsis
acid secretion.
PO: 0.5-1 mg/kg q24h
IV: 0.25-0.5 mg/kg q24h
Fentanyl Binds with opioid μ receptors in CNS Respiratory Dependence may occur with
(Sublimaze) to decrease pain. depression, chest long-term administration.
IV wall rigidity, uri- Effects reversed by naloxone.
IV push: 1-4 μg/kg q2-4h
nary retention Approximately 100 times more
Continuous IV infusion: 0.5-5 μg/kg/hr
potent than morphine.
Continued

Ferrous sulfate Repletes diminished iron stores and Constipation, Infants who have received mul-
(Fer-In-Sol) is incorporated into hemoglobin. discolored stool tiple recent blood transfusions
PO are at risk of iron overload—
Routine supplementation: 2-4 mg/kg/
typically no supplementation is
day divided q12-24h
required.
Patients receiving erythropoietin:
6 mg/kg/day divided q12-24h
Fluconazole Reversibly binds to fungal cyto- Increased liver Limited data for higher dos-
(Diflucan) chrome P-450, inhibiting sterol enzymes ages—consider using in
PO/IV C-14 α-demethylation and decreas- severe infection or if fungal
ing ergosterol synthesis, which strain has high minimum
ultimately inhibits cell membrane inhibitory concentration.
formation. Extend dosing interval in
setting of renal dysfunction.
Invasive candidiasis
Loading dose (IV/PO): 12-25 mg/kg
Maintenance dose (IV/PO):
PMA ≤29 wk:
PMA >30 wk:
Thrush
6 mg/kg PO × 1 dose, then 3 mg/kg
PO q24h
Flumazenil Antagonizes effect of Hypotension, Seizures most common
(Romazicon) benzodiazepines on GABA/ seizures in patients receiving
IV/IN/PR benzodiazepine receptors. benzodiazepines for long-term
sedation.
IV: 5-10 μg/kg over 15 sec; repeat
q45sec to max cumulative dose
of 50 μg/kg or 1 mg (whichever is
smaller)
IN: 20 μg/kg per nostril
PR: 15-30 μg/kg; repeat q15-20min
Fosphenytoin Phenytoin prodrug. Increases efflux Hypotension, May administer much more
(Cerebyx) or decreases influx of sodium ions venous irritation rapidly than phenytoin, up to
IV/IM across cell membranes in motor 1.5 mg/kg/min.
cortex, which results in neuronal Term infants >1 wk of age
membrane stabilization. may need higher dosages at
more frequent intervals
Dosing expressed in phenytoin
(8 mg PE/kg q8h).
equivalents (PE):
Displaces bilirubin from protein
Fosphenytoin 1 mg PE = phenytoin
binding sites.
1 mg
Target serum phenytoin levels
Loading dose: 15-20 mg PE/kg
are 6-20 μg/mL.
Maintenance dose: 4-8 mg
PE/kg q24h
Furosemide Inhibits chloride and sodium reab- Hypochlore- Has synergistic effect with
(Lasix) sorption in ascending loop of Henle mic alkalosis, proximal and distal tubule
PO/IV/IM and proximal renal tubule, which hyponatremia, inhibitors (e.g., thiazides).
causes increased excretion of water hypokalemia, Monitor electrolytes closely.
and electrolytes. hypercalciuria Risk of ototoxicity increased
and renal calculi, in neonates also receiving
IV: 1-2 mg/kg/dose q6-48h
ototoxicity aminoglycosides.
PO: 1-4 mg/kg/dose q6-48h
Ganciclovir Competes for incorporation into viral Thrombocyto- Treat acute infections for mini-
(Cytovene-IV) DNA and interferes with viral DNA penia, anemia, mum of 6 wk.
chain elongation, which results in neutropenia Monitor complete blood count
inhibition of viral replication. results 2-3 times per week
for first 3 wk, then weekly if
Acute infection: 6 mg/kg IV q12h
infant’s condition is stable.
Chronic suppression: 30-40 mg/kg
Cut dose in half for neutrope-
PO q8h
nia (<500 cells/mm3).
Discontinue if neutropenia
does not resolve.

Gentamicin Inhibits bacterial protein synthesis Nephrotoxic- Monitor serum trough con-
IV/IM by inhibiting 30S and 50S ribosomal ity, ototoxicity centration before third dose
subunits, which results in defective (increased risk if treating for >48 hr. Target
bacterial cell membrane. with concur- trough concentration is
rent use of other <1 μg/mL. Extend dosing
PMA <35 wk: 4 mg/kg q24h
nephrotoxic or interval if trough is >1 μg/mL.
ototoxic drugs) Should not be concurrently
administered in same IV line
with extended-spectrum
penicillin.
Glucagon Increases hepatic glycogenolysis Tachycardia, GI Rise in blood glucose lasts
IV/IM/SC and gluconeogenesis, which causes disturbances, about 2 hr.
increase in blood glucose. rebound hypogly-
cemia
0.2 mg/kg up to max dose of 1 mg;
repeat q20min prn
Heparin Potentiates action of antithrombin III, Hemorrhage, Effects reversible with
IV inactivates thrombin, inhibits conver- thrombocytopenia protamine.
sion of fibrinogen to fibrin. Monitor platelet levels closely.
Nontherapeutic doses added
Loading dose: 75 U/kg IV push
to TPN or IV fluids to main-
Maintenance dose: 28 U/kg/hr Con-
tain patency of lines
tinuous IV infusion—adjust based
(0.5-1 U/mL).
on APTT; target range dependent
on indication
Hyaluronidase Modifies permeability of connec- Erythema Administer as soon as possible
(Amphadase, Vitrase) tive tissue and increases distribution after extravasation.
SC and absorption of locally injected Not for use with extravasation
substances. of vasoactive agents.
SC: 150 U as 5 separate injections
around extravasation site
Hydralazine Produces direct vasodilation of arte- Agranulocytosis, If used with β-blocker expect
(Apresoline) rioles causing decreased systemic hypotension, reduction in hydralazine dose
PO/IV resistance. tachycardia required.
PO: 0.25-1 mg/kg q6-8h
IV: 0.1-0.5 mg/kg q6-8h gradually
increased to max of 2 mg/kg q6h
Hydrochlorothiazide Inhibits Na reabsorption in distal renal Hypochloremic Has synergistic effect with loop
(Microzide) tubules, which causes increased metabolic alkalo- diuretics (e.g., furosemide).
PO excretion of water and electrolytes. sis, hypokalemia, Administer with food to
hypouricemia, improve absorption.
PO: 1-2 mg/kg q12h
hyperglycemia
Hydrocortisone Corticosteroid that decreases inflam- Possible For ventilator weaning start at
(Solu-Cortef) mation by suppressing migration and aggravation of high dosages and wean over
PO/IV decreasing capillary permeability of fluid retention, 10 days.
proinflammatory mediators. pituitary-adrenal Taper stress dose and physi-
axis suppression, ologic dose based on patient
Stress dose: 20-30 mg/m2/day
hyperglycemia, response and condition.
divided q8-12h
hypertension,
Physiologic dose: 7-9 mg/m2/day
GI perforation
divided q8-12h
(increased risk
Facilitation of ventilator weaning:
if given with
0.2-2 mg/kg q12h
indomethacin)
Ibuprofen lysine Inhibits prostaglandin synthesis by GI perforation, Monitor urine output, BUN,
(NeoProfen) decreasing cyclooxygenase activity. renal impairment, and serum creatinine.
IV impaired platelet Verify adequate platelet count
Dose 1: 10 mg/kg
function before administration. Moni-
Doses 2 and 3 starting 24 hr after
tor for signs of bleeding.
dose 1: 5 mg/kg q24h
Continued

Imipenem/cilastatin Inhibits bacterial cell wall synthesis by Seizures in Cilastatin prevents renal
(Primaxin) binding to penicillin-binding proteins. patients with metabolism of imipenem, but
IV/IM meningitis or has no antibacterial activity.
IV/IM: 20-25 mg/kg q12h
renal dysfunction, IM route limited to mild to
increased platelet moderate infections.
count, eosino- Restricted to treatment of non-
philia, elevated CNS infections.
liver enzymes Clearance is directly related to
renal function.
Indomethacin Inhibits prostaglandin synthesis by Oliguria, anuria, Monitor urine output, BUN,
(Indocin) decreasing cyclooxygenase activity. GI perforation, and serum creatinine—
IV impaired plate- extend dosing interval if
Dose 1: 0.2 mg/kg followed by:
let function severe oliguria occurs.
Postnatal age <48 hr at time of
Verify adequate platelet count
dose 1: 0.1 mg/kg q12-24h for
before administration.
2 doses
Monitor for signs of bleeding.
Postnatal age 2-7 days at time of
dose 1: 0.2 mg/kg q12-24h for
2 doses
Postnatal age >7 days at time of
dose 1: 0.25 mg/kg q12-24h
for 2 doses
Insulin Regulates metabolism of Hypoglycemia Assess blood glucose every
(Humulin R) macronutrients and facilitates glucose and associated 15-30 min after starting infu-
IV/SC transport into muscle, adipose, and signs and symp- sion and after any changes.
other tissues. toms To avoid binding of insulin to
tubing, fill IV tubing with insu-
SC: 0.1-0.2 U/kg q6-12h
lin solution and wait 20 min
Continuous IV infusion:
before starting infusion.
0.01-0.1 U/kg/hr
Intravenous immune Concentrated form of immunoglobulin Hypotension, Monitor heart rate and blood
globulin (IVIG) G antibodies for replacement therapy. renal dysfunction, pressure during infusion. If
(Gamunex, Flebo- phlebitis infusion not well tolerated,
Standard dose: 500-750 mg/kg
gamma, Carimune NF) decrease in rate may be
Neonatal alloimmune thrombocytope-
IV warranted.
nia: 400-1000 mg/kg
In most cases a single dose is
sufficient, but doses may be
repeated every 24 hr.
Ipratropium Bronchodilator that blocks acetyl- Neonatal lung models suggest
(Atrovent) choline action in bronchial smooth better drug delivery with
Neb/MDI muscle. spacer and MDI than with
nebulizer.
MDI: 2-4 puffs q6-8h
Neb: 75-175 μg (0.4-0.9 mL) q6-8h
Iron dextran Replaces iron and allows for trans- Hypotension, Add to TPN solution and infuse
IV (IN Fed) portation of oxygen via hemoglobin. respiratory continuously if possible.
distress, delayed If intermittent infusion neces-
IV: 0.4-1 mg/kg q24h
fever or agitation sary, dilute each dose
(24-48 hr after (1-10 mg/mL) and administer
administration), over 1 hr. Longer infusion
phlebitis times can be used if intoler-
ance occurs.
Lamivudine Antiretroviral agent that inhibits Lactic acidosis, Used in combination with
(3TC, Epivir) reverse transcription via viral DNA elevated hepatic zidovudine for prevention
PO chain termination. enzymes of mother-to-child HIV
transmission.
PO: 2 mg/kg q12h
Consider consulting infectious
disease specialist for spe-
cific antiretroviral regimen
recommendations.
Monitor liver enzymes regularly
if long-term treatment
required.

Lansoprazole Inhibits proton pump and leads to Increased trans- Dosages up to 2 mg/kg/day
(Prevacid) decreased gastric acid secretion. aminases with have been used in refractory
PO prolonged therapy cases.
PO: 1 mg/kg q24h
Monitor liver function with
prolonged therapy.
Levetiracetam Exact mechanism unknown, but Sedation, irritabil- Second-line therapy for
(Keppra) activity may include blocking GABA- ity, GI distur- seizures refractory to
IV/PO ergic inhibitory transmission and bances, phlebitis phenobarbital or other
inhibiting voltage-dependent calcium antiepileptics.
channels.
IV/PO: 10 mg/kg q12-24h titrated up
every 1-2 wk to max of 30 mg/kg
q12h
Administer q24h in neonates and
q12h in infants
Levothyroxine Replacement therapy for thyroid hor- Tachycardia, Adjust PO dose in 12.5-μg
(Synthroid) mone involved in normal metabolism, fever, GI distur- increments and always
PO/IV growth, and synthesis. bances round up.
For oral doses crush tablet and
PO: 10-14 μg/kg q24h
suspend in small amount of
IV: 5-8 μg/kg q24h
sterile water, breast milk, or
formula and use immediately.
Do not use IV formulation for
PO administration.
Linezolid Inhibits initiation of bacterial protein Elevated transam- Limit use to infections caused
(Zyvox) synthesis by binding to 50S ribosome inases, diarrhea, by gram-positive organisms
PO/IV subunit. anemia, thrombo- that are refractory to treatment
cytopenia with vancomycin.
Preterm ≤1 wk of age:
PO/IV: 10 mg/kg q12h
Full term or preterm >1 wk of age:
PO/IV: 10 mg/kg q8h
Lorazepam Binds to GABA receptor, enhancing Hypotension, Injectable form contains benzyl
(Ativan) effects of GABA, which is the major respiratory alcohol, polyethylene glycol,
PO/IV/IM inhibitory neurotransmitter. depression, rhyth- and propylene glycol.
mic myoclonic Use limited to acute manage-
PO/IV/IM: 0.05-0.01 mg/kg repeated
jerking, phlebitis ment of seizures refractory
based on clinical response
to conventional therapy.
Meropenem Inhibits bacterial cell wall synthe- Thrombocytosis, Limit use to treatment of
(Merrem) sis by binding to penicillin-binding eosinophilia, severe infections resistant to
IV proteins. phlebitis other antibiotics; use of broad-
GA <32 wk: spectrum antibiotics increases
0-14 days old: 20 mg/kg q12h risk of fungal infection and
>14 days old: 20 mg/kg q8h pseudomembranous colitis.
GA ≥32 wk:
Methadone Binds to opiate receptors in CNS, Respiratory Start with lower doses at more
(Dolophine) altering perception of and response depression, frequent intervals and titrate
IV/PO to pain. abdominal disten- up as needed based on NAS
sion, delayed scores.
IV/PO: 0.05-0.2 mg/kg q6-24h
gastric emptying Wean doses 10%-20% per
week, adjusted based on
withdrawal symptoms.
Extend dosing interval first
until administration is every
12 hr, then wean dose.
Long elimination half-life
requires slow weaning.
Metoclopramide Dopamine receptor antagonist that Extrapyramidal Extrapyramidal symptoms
(Reglan) promotes gastric emptying and symptoms, dys- more likely at higher dosages
PO/IV accelerates intestinal transit time. tonic reactions or with prolonged use.
PO/IV: 0.033-0.1 mg/kg q8h
Continued

Metronidazole Breaks helical structure of DNA, GI disturbances,
(Flagyl) which results in inhibition of protein neutropenia,
PO/IV synthesis and cell death. thrombocytopenia
Loading dose: 15 mg/kg
Maintenance dose:
PMA ≤29 wk:
0-28 days old: 7.5 mg/kg q48h
>28 days old: 7.5 mg/kg q24h
PMA 30-36 wk:
PMA 37-44 wk:
PMA ≥45 wk:
7.5 mg/kg q8h
Micafungin Inhibits synthesis of essential cell wall Hypokalemia, Use higher dose (10 mg/kg)
(Mycamine) components of susceptible fungi, hypernatremia, for meningitis and neonates
IV which results in osmotic stress and thrombocytope- of <27 wk GA and <14 days
lysis of the fungal cell. nia, elevated liver of age.
enzymes
IV: 7-10 mg/kg q24h
Midazolam Binds to receptors for GABA, the Hypotension, Used most often for sedation,
(Versed) major inhibitory neurotransmitter, respiratory but can also be used for
PO/IV/IM/IN/SL which enhances effects of GABA. depression, refractory seizures.
myoclonus Prolonged or repeated use
IV push/IM: 0.05-0.15 mg/kg q2-4h
may have detrimental effects
prn
on neurodevelopmental
Continuous IV infusion: 0.01-0.06 mg/
outcomes.
kg/hr, titrated as needed
Respiratory depression more
IN/SL: 0.2 mg/kg
common when administered
PO: 0.25 mg/kg
with narcotics.
Preservative-free injection
available.
Milrinone Inhibits phosphodiesterase III, which Thrombocytope- Loading dose optional based
(Primacor) potentiates delivery of calcium to nia, arrhythmias, on status of patient.
IV the myocardium and results in a tachycardia, Correct hypovolemia before
positive inotropic effect. Also causes hypotension initiation.
relaxation of vascular muscle and Blood pressure may decrease
vasodilatation. 5%-9% after loading dose
and heart rate may increase
Loading dose: 50-75 μg/kg/min
5%-10%.
Continuous IV infusion: 0.25-0.75
μg/kg/min
Morphine Binds to opiate receptors in the CNS, Hypotension, Closely monitor respiratory
(Astramorph, Dura- altering perception of and response vasodilation, rate, blood pressure, heart
morph) to pain. flushing, pruritus, rate, oxygen saturation, and
PO/IV/IM/SC respiratory bowel sounds.
Analgesia
depression, Gl Metabolized to an active
IV/IM/SC: 0.05-0.2 mg/kg q4h prn
disturbances metabolite that is renally
Continuous IV infusion: 10-20 μg/kg/
excreted.
hr, titrated as needed
Effects reversed by naloxone.
PO: 0.15-0.3 mg/kg q4h prn (or 3
When used for NAS, wean
times IV dose)
10%-20% daily as tolerated.
NAS
PO: 0.03-0.1 mg/kg q3h, increase as
needed to control withdrawal

Nafcillin Inhibits bacterial cell wall synthesis by Extravasation, Increase dosing interval
IV/IM binding to penicillin-binding proteins. GI disturbances, in the presence of hepatic
acute interstitial dysfunction.
Sepsis: 25 mg/kg
nephritis
Meningitis: 50 mg/kg
PMA ≤29 wk:
0-28 days old: q12h
>28 days old: q8h
PMA 30-36 wk:
0-14 days old: q12h
>14 days old: q8h
PMA 37-44 wk:
0-7 days old: q12h
>7 days old: q8h
PMA ≥45 wk: q6h
Naloxone Competes and displaces narcotics at Half-life of naloxone may
(Narcan) narcotic receptor sites. be shorter than that of
IV/IM/SC opioids; therefore, repeating
IV/IM: 0.1 mg/kg q2-3min prn
doses every 1-2 hr may be
necessary.
May precipitate withdrawal
symptoms in neonates receiv-
ing long-term opioid therapy.
Neostigmine Inhibits hydrolysis of acetylcholine, Bradycardia, Use for reversal of nondepolariz-
(Prostigmin) which facilitates cholinergic activity. hypotension ing neuromuscular blockade.
IV/IM/SC Administer with 0.02 mg/kg
IV: 0.04-0.08 mg/kg
atropine to minimize
bradycardia.
Nevirapine Antiretroviral agent that inhibits GI disturbances, Used in combination with
(Viramune) reverse transcriptase and disrupts life eosinophilia, zidovudine for prevention
PO cycle of the virus. neutropenia, of mother-to-child HIV
hepatoxicity, transmission.
PO: 2 mg/kg × 1 dose as soon as
granulocytopenia Consider consulting infec-
possible after birth
tious disease specialist for
specific recommendations
on antiretroviral regimen and
treatment beyond 1 dose.
Nystatin Binds to sterols in fungal cell mem- Rash due to inac- Continue treatment for 3 days
(Nystop) branes and increases permeability, tive ingredients in after symptoms resolve.
PO, topical which allows leakage of cellular topical product
contents.
Topical: q6h
PO:
Preterm: 0.5 mL (50,000 U) to each
side of mouth q6h
Term: 1 mL (100,000 U) to each
side of mouth q6h
Omeprazole Inhibits proton pump, which results in Mild increase in Monitor liver function with
(Prilosec) decreased gastric acid secretion. transaminases prolonged therapy.
PO with prolonged
PO: 0.5-1.5 mg/kg q24h
therapy
Oxacillin Inhibits bacterial cell wall synthesis by Thrombocytope- Poor CSF penetration.
IV/IM binding to penicillin-binding proteins. nia, leukopenia, Consider extending dosing
eosinophilia, interval in the presence of
Sepsis: 25 mg/kg
neutropenia, poor renal function.
acute interstitial
PMA ≤29 wk:
nephritis, extrava-
0-28 days old: q12h
sation, elevated
>28 days old: q8h
liver enzymes
PMA 30-36 wk:
0-14 days old: q12h
>14 days old: q8h
PMA 37-44 wk:
0-7 days old: q12h
>7 days old: q8h
PMA ≥45 wk: q6h
Continued

Palivizumab Monoclonal antibody that neutralizes Swelling at injec- Immunoprophylaxis against
(Synagis) and inhibits respiratory syncytial virus tion site, fever, RSV infection in high-risk
IM (RSV). upper respiratory infants; not effective for
tract infection treatment of RSV disease.
IM: 15 mg/kg every month during
RSV season
Pancuronium Blocks acetylcholine from binding Tachycardia, Use with sedatives and analge-
(Pavulon) to motor end plate receptors, which changes in blood sics.
IV inhibits depolarization and causes pressure Provide eye lubrication.
neuromuscular blockade. Contains benzyl alcohol.
IV push: 0.04-0.15 mg/kg q1-2h
Papaverine Smooth muscle spasmolytic that Chronic hepatitis Prolongs patency of peripheral
IV produces generalized smooth muscle with long-term arterial catheter.
relaxation and vasodilation. therapy Use with caution in first days
of life in infants at risk of
Continuous IV infusion: 30 mg per
developing intracranial hem-
250 mL arterial catheter solution;
orrhage.
infuse at 1 mL/hr
Penicillin G Inhibits bacterial cell wall synthesis by Extravasation, Use only aqueous penicillin for
IV/IM binding to penicillin-binding proteins. cardiorespiratory IV administration.
arrest and death Use procaine or benzathine
Meningitis: 75,000-100,000 U/kg
if IM form given penicillin for IM
Bacteremia: 25,000-50,000 U/kg
IV administration.
PMA ≤29 wk:
Treat congenital syphilis for
0-28 days old: q12h
10 days.
>28 days old: q8h
PMA 30-36 wk:
0-14 days old: q12h
>14 days old: q8h
PMA 37-44 wk:
0-7 days old: q12h
>7 days old: q8h
PMA ≥45 wk: q6h
GBS or gonococcal bacteremia:
200,000 U/kg/day divided q6-8h
GBS or gonococcal meningitis:
500,000 U/kg/day divided q6-8h
Congenital syphilis: 50,000 U/kg IV
q12h for first 7 days, then q8h or
50,000 U/kg IM q24h
Phenobarbital Binds to GABA receptor and Extravasation, Begin maintenance dose 12-24
(Luminal) enhances GABA activity, which respiratory hr after loading dose.
PO/IV/IM results in depressed CNS activity. depression, seda- Avoid IM administration for
tion, elevated liver loading dose due to erratic
Loading dose: 20 mg/kg IV; repeat
enzymes absorption and slower onset
5-10 mg/kg prn to total 40 mg/kg
of action.
Maintenance dose: 3-5 mg/kg q24h
Target serum concentration
IV, IM, or PO
is 15-40 μg/mL; increased
sedation at concentrations
of >40 μg/mL and increased
respiratory depression at
concentrations of >60 μg/mL.
Phentolamine Blocks α-adrenergic receptors and Amount injected into extrava-
SC reverses vasoconstriction caused by sation site depends on size
extravasation. of infiltrate.
Use for extravasation of
SC: 1-5 mL of 0.5 mg/mL solution
vasoconstrictive agents
(dopamine, epinephrine,
etc.).

Phenytoin Stabilizes neuronal membranes and Bradycardia, Infuse slowly at maximum rate
(Dilantin) decreases seizure activity by alter- arrhythmia, and of 0.5 mg/kg/min.
PO/IV ing sodium ion transport across cell hypotension Do not administer IM.
membranes in the motor cortex. during infusion; Higher dosages (up to 8 mg/
extravasation; kg q8h) may be needed after
Loading dose: 15-20 mg/kg IV
rickets; nystag- 1 wk of age.
Maintenance dose: 4-8 mg/kg IV or
mus; gingivitis Target total serum
PO q24h
concentration is 6-15 μg/mL
in first few weeks of life, then
10-20 μg/mL.
Target free serum
concentration is 1-2 μg/mL.
Administer oral doses at same
time daily with regard to
meals.
Injectable form contains
alcohol and propylene glycol.
Piperacillin/tazobac- Inhibits bacterial cell wall synthesis by Eosinophilia, Limited CNS penetration; avoid
tam binding to penicillin-binding proteins. hyperbilirubine- use if meningitis suspected.
(Zosyn) Tazobactam binds to β-lactamases mia, elevated liver
IV and prevents degradation of enzymes
piperacillin.
IV: 50-100 mg/kg
PMA ≤29 wk:
0-28 days old: q12h
>28 days old: q8h
PMA 30-36 wk:
0-14 days old: q12h
>14 days old: q8h
PMA 37-44 wk:
0-7 days old: q12h
>7 days old: q8h
PMA ≥45 wk: q8h
Poractant alfa Natural surfactant extracted from por- Reflux of For IT administration only.
(Curosurf) cine lung. Replaces deficient or inef- surfactant up Suspension should be at
IT fective endogenous lung surfactant. ET, decreased room temperature before
oxygenation, administering. Do not artifi-
Initial dose: 2.5 mL/kg administered
bradycardia cially warm.
as soon as possible after birth
Repeat doses: 1.25 mL/kg q12h prn
× 2 doses
administration.
Propranolol Blocks stimulation of β1- and β2- Bradycardia, Rebound tachycardia occurs
(Inderal) adrenergic receptors, which results bronchospasm, with abrupt discontinuation.
PO/IV in decreased heart rate, myocardial hypoglycemia, Hypotension increased with
contractility, and blood pressure. hypotension underlying myocardial
dysfunction.
IV: 0.01 mg/kg q6h; increase prn to
max 0.15 mg/kg q6h
PO: 0.25 mg/kg q6h; increase prn to
max 3.5 mg/kg q6h
Protamine Combines with heparin to form com- Hypotension, Infusion rate should not
IV plex with no anticoagulant activity. bradycardia, exceed 5 mg/min.
bleeding Increased risk of bleeding and
Dose based on time since last hepa-
problems severe adverse reactions
rin dose:
with high dose, rapid
<30 min: 1 mg per 100 U heparin
administration, or repeated
received
doses.
30-60 min: 0.5-0.75 mg per 100 U
heparin received
60-120 min: 0.375-0.5 mg per 100 U
heparin received
>120 min: 0.25-0.375 mg per 100 U
heparin received
Max dose: 50 mg
Continued

Ranitidine Competitively inhibits histamine Thrombocyto- Oral solution contains 7.5%
(Zantac) receptors in gastric parietal cells, penia, bradycar- alcohol.
PO/IV which results in inhibition of gastric dia, late-onset
acid secretion. bacterial or fungal
sepsis
IV, term: 1.5 mg/kg q8h
IV, preterm: 0.5 mg/kg q12h
Continuous IV infusion: 0.04-
0.1 mg/kg/hr
PO: 2 mg/kg q8h
Rifampin Inhibits bacterial RNA synthesis Extravasation, Causes orange-red
(Rifadin) by binding to β subunit of DNA- elevated hepatic discoloration of urine,
PO/IV dependent RNA polymerase, thereby transaminases, sputum, tears, and other
inhibiting RNA transcription. thrombocytopenia bodily fluids.
Do not use as monotherapy
Treatment
due to quick development of
IV: 5-10 mg/kg q12h
resistance.
Prophylaxis
Meningococcus: 5 mg/kg PO q12h
× 2 days
Haemophilus influenzae type B:
10 mg/kg PO q24h × 4 days
Rocuronium Binds to cholinergic receptor sites Increased pul- Must be given with adequate
(Zemuron) and blocks neural transmission at monary vascular analgesia and sedation.
IV myoneural junction. resistance Primarily used before intuba-
tion due to rapid onset and
IV: 0.3-0.6 mg/kg over 5-10 sec
short duration of action.
Sildenafil Phosphodiesterase type-5 inhibitor Worsening Start therapy with lower
(Revatio) that causes vasodilation in the pul- oxygenation, dosages and titrate slowly
PO/IV monary vasculature. hypotension based on oxygenation and
blood pressure.
IV: 0.25-1 mg/kg q6-12h
Pharmacokinetics in neonates
PO: 0.5-2 mg/kg q6-12h
is not well defined.
Data for neonates are limited
and use is considered
experimental.
Sodium bicarbonate Dissociates to provide bicarbonate Tissue necrosis, Administer 1-2 mEq/kg over at
IV ion, which neutralizes hydrogen ion hypocalcemia, least 30 min.
and raises blood and urinary pH. hypokalemia, Maximum concentration used
hypernatremia in neonates is 0.5 mEq/mL
Usual dosage: 1-2 mEq/kg
(4.2%).
Based on base deficit:
Do not administer with
HCO3 needed (mEq) = HCO3
calcium- or phosphate-
deficit (mEq/L) × (0.3 × weight in kg)
containing solutions.
Administer ½ calculated dose then
Not recommended for use in
reassess
neonatal resuscitation.
Sotalol Blocks stimulation of β1- and β2- Arrhythmias Continuous cardiac monitoring
(Betapace) adrenergic receptors, which results (sinoatrial block, required for at least 3 days
PO in decreased heart rate and AV node AV block, torsade at maintenance dose.
conduction. Prolongs refractory de pointes, ven- High dosages increase risk
period of atrial muscle, ventricular tricular ectopic of torsade de pointes.
muscle, and AV accessory pathways. activity), hypoten-
sion, dyspnea
PO: 1 mg/kg q12h; increase every 3
days until stable rhythm maintained
to max dose of 4 mg/kg q12h
Spironolactone Competes for aldosterone receptors Hyperkalemia, GI Significantly less diuretic
(Aldactone) in distal renal tubules, increasing upset effect than thiazide and
PO sodium, chloride, and water excre- loop diuretics; use only
tion while conserving potassium and in combination with other
hydrogen ions. diuretics.
May help to decrease
PO: 1-3 mg/kg q24h
potassium losses secondary
to use of other diuretics.

Ticarcillin/clavulanate Inhibits bacterial cell wall synthesis Eosinophilia, Limited CNS penetration; avoid
(Timentin) by binding to penicillin-binding hyperbilirubine- use if meningitis suspected.
IV proteins. mia, hypernatre-
Clavulanic acid binds to β-lactamases mia, elevated liver
and prevents degradation of ticar- enzymes
cillin.
IV: 75-100 mg/kg
PMA ≤29 wk:
0-28 days old: q12h
>28 days old: q8h
PMA 30-36 wk:
0-14 days old: q12h
>14 days old: q8h
PMA 37-44 wk:
0-7 days old: q12h
>7 days old: q8h
PMA ≥45 wk: q6h
Tobramycin Inhibits bacterial protein synthesis Nephrotoxic- Monitor serum trough
IV/IM by inhibiting 30S and 50S ribosomal ity, ototoxicity concentration before third
subunits, which results in defective (increased risk dose if treating for >48 hr.
bacterial cell membrane. with concur- Target trough concentration
rent use of other is <1 μg/mL. Extend dosing
PMA <35 wk: 4 mg/kg q24h
nephrotoxic or interval if trough is >1 μg/mL.
ototoxic drugs) Should not be concurrently
administered in same IV line
with extended-spectrum
penicillin.
Ursodiol Reduces secretion of cholesterol from Abdominal pain, Administer with food.
(Actigall) liver and reabsorption of choles- constipation,
PO terol by intestines, which results in flatulence, nausea
decreased cholesterol in bile and bile and vomiting
stones.
Valganciclovir Rapidly metabolized to the active Thrombocytope- Treat acute infections for mini-
(Valcyte) component ganciclovir, which nia, neutropenia, mum of 6 wk.
PO competes for incorporation into viral anemia Hold dose for ANC of
DNA, interferes with viral DNA chain <500 cells/mm3 until ANC
elongation, and thus inhibits viral is >750 cells/mm3. If ANC
replication. falls again to <750 cells/
mm3 reduce dose by 50%. If
PO: 16 mg/kg q12h
ANC falls to <500 cells/mm3
discontinue drug.
Vancomycin Inhibits bacterial cell wall synthesis Nephrotoxicity Serum trough concentrations
(Vancocin) and alters bacterial cell membrane and ototoxicity correlate best with both
IV permeability. (increased with efficacy and toxicity.
aminoglycoside Target serum trough
therapy), phlebi- concentration is 5-15 μg/mL.
Bacteremia: 10 mg/kg
tis, neutropenia Concentrations up to 20 μg/mL
PMA ≤29 wk:
have been targeted in severe
0-14 days old: q18h
infections.
>14 days old: q12h
PMA 30-36 wk:
0-14 days old: q12h
>14 days old: q8h
PMA 37-44 wk:
0-7 days old: q12h
>7 days old: q8h
PMA ≥45 wk: q6h
Vecuronium Inhibits depolarization by blocking Bradycardia and Must be given with adequate
(Norcuron) acetylcholine from binding to motor hypotension sedation and analgesia.
IV end plate receptors. when used with Provide eye lubrication.
narcotics
IV push: 0.03-0.15 mg/kg q1-2h
Continuous IV infusion: 0.06-
0.1 mg/kg/hr
Continued

Vitamin A Retinol metabolites exhibit potent Signs and symp- Use in premature infants at
(Aquasol A) effects on gene expression and on toms of toxicity highest risk of developing
IM lung growth and development. include lethargy, chronic lung disease.
hepatomegaly,
IM: 5000 U 3 times per week × 4 wk
edema, bony
tenderness,
mucocutaneous
lesions
Vitamin K Promotes formation of clotting factors Pain and swelling Administer IV doses very
(Mephyton, phytona- II, VII, IX, and X in the liver. at IM injection site slowly, not to exceed
dione) 1 mg/min. Severe reactions
Prophylaxis of hemorrhagic disease
IM/IV have been reported very rarely
Term: 0.5-1 mg IM
in adults.
Preterm (<32 wk):
<1000 g: 0.3 mg/kg IM
≥1000 g: 0.5 mg IM
Treatment of hemorrhagic disease:
1-10 mg slow IV push
Treatment of clotting deficiency:
1-10 mg IM or IV push
Zidovudine (AZT) Phosphorylated to its active metabo- Anemia, neutro- Begin within 6-12 hr of birth and
(Retrovir) lite, which is incorporated into HIV penia, thrombo- continue for at least 6 wk.
IV/PO by reverse transcriptase; inhibits HIV cytopenia Consider consulting infectious
viral polymerases and DNA synthesis. disease specialist for spe-
cific antiretroviral regimen
IV: 1.5 mg/kg
recommendations.
PO: 2 mg/kg
PMA ≤29 wk:
0-28 days old: q12h
>28 days old: q8h
PMA 30-34 wk:
0-14 days old: q12h
>14 days old: q8h
PMA ≥35 wk: q6h
Adapted from Thomson Reuters Clinical Editorial Staff: NeoFax, Ann Arbor, Mich, 2011, Thomson
Reuters; and Taketomo CK, Hodding JH, Kraus DM: Pediatric dosage handbook, ed 17, Hudson, Ohio,
2010-2011, Lexi-Comp.
ANc, Absolute neutrophil count; APTT, activated partial thromboplastin time; AV, atrioventricular; BUN,
blood urea nitrogen; CNS, central nervous system; CSF, cerebrospinal fluid; DART, Dexamethasone—A
Randomized Trial (multicenter study of low-dose dexamethasone therapy); ET, endotracheal tube; GA,
gestational age; GABA, γ-aminobutyric acid; GBS, group B streptococcus; GI, gastrointestinal; HIV,
human immunodeficiency virus; IM, intramuscular; IN, intranasal; IT, intratracheal; IV, intravenous;
max, maximum; MDI, metered dose inhaler; NAS, neonatal abstinence syndrome; Neb, nebulizer; NS,
normal saline; PMA, postmenstrual age; PO, by mouth; PR, per rectum; prn, as needed; q, every; SC,
subcutaneous; SL, sublingual; TPN, total parenteral nutrition.
Drug Compatibility
Jacquelyn McClary and Leta Houston Hickey
B
Name Dosage Indications Side Effects Compatibility Considerations
Alprostadil Initial dose: Maintain Apnea, hypoten- Solution: D5W, NS Give through UAC
(prostaglan- 0.05-0.1 patency sion, hyperthermia, Y-site: TPN, heparin, only if absolutely
din E1) μg/kg/min of ductus seizures, diar- gentamicin, dopa- necessary and if flow
Maintenance arteriosus rhea, flushing, mine, dobutamine, is not interrupted by
dose: 0.01- bradycardia furosemide obtaining laboratory
0.1 μg/kg/ Incompatible: fat specimens.
min emulsion Requires constant, pat-
ent IV access.
Dobutamine 2-25 μg/kg/ Hypoper- Tachycardia at Solution: D5W, NS Correct hypovolemia
min fusion or high dosages, Y-site: TPN, fat prior to initiation of
hypotension arrhythmia, hyper- emulsion, alprosta- treatment.
related to tension, increased dil, dopamine, Monitor BP and HR
myocardial myocardial oxygen gentamicin, continuously.
dysfunction consumption, tis- morphine Pink discoloration is
sue ischemia with Incompatible: ampicil- not significant.
infiltration lin, sodium bicar-
bonate
Dopamine 2-20 μg/kg/ Hypotension Tissue slough- Solution: D5W, NS Use 1-5 mL of phentol-
min ing with infiltra- Y-site: TPN, fat amine 0.5 mg/mL for
tion, arrhythmias, emulsion, alprosta- extravasation.
increased dil, dobutamine, Monitor BP and HR
pulmonary artery gentamicin, heparin, continuously.
pressure morphine Check urine output and
Incompatible: peripheral perfusion
ampicillin, frequently.
indomethacin, Protect from light.
sodium bicarbonate Do not use if solution is
darker than slightly
yellow.
Epinephrine 0.02-1 μg/kg/ Asystole, Tachycardia, Solution: D5W, D10W, Never give through
min severe brad hypertension, NS UAC or other artery.
ycardia arrhythmias, trem- Y-site: TPN, heparin, Discard if brown or pink
ors, decreased gentamicin, dopa- color observed.
renal and splanch- mine, dobutamine Attempt to correct any
nic blood flow, Incompatible: acidosis before infu-
ischemia and fat emulsion, sion begins.
necrosis of tissue hyaluronidase, Protect from light.
if IV infiltration phenobarbital
occurs
Milrinone Loading dose: Low cardiac Decreased BP Solution: D5W, NS Correct hypovolemia
50-75 μg/kg output after loading Y-site: TPN, ampicillin, prior to initiation of
over 60 min dose, increased dopamine, genta- therapy.
(optional) HR, arrhythmias, micin, morphine, Monitor HR and BP
Maintenance thrombocytopenia sodium bicarbonate continuously.
dose: 0.25- Incompatible: fat Monitor fluid and
0.75 μg/kg/ emulsion, furose- electrolyte changes.
min mide Assess renal function
regularly.
Monitor platelets.
Continued
563
564 APPENDIX B Drug Compatibility
Name Dosage Indications Side Effects Compatibility Considerations

Sodium Initial dose: Hyper- Hypotension, Solution: D5W, NS Monitor BP and HR
nitro- 0.25-0.5 tension, decreased thyroid only continuously.
prusside μg/kg/min afterload function, possible Y-site: TPN, fat emul- Assess renal and
(Nipride) Maintenance reduction in cyanide or thiocya- sion, heparin, gen- hepatic function
dose: usu- refractory nate toxicity, local tamicin, morphine, daily.
ally <2 μg/ congestive tissue necrosis dopamine Follow cyanide and
kg/min heart failure Incompatible: ampicil- thiocyanate levels—
lin, hydralazine levels should be
<200 ng/mL and <50
μg/mL, respectively.
Administer via periph-
eral IV or central
venous catheter.
Protect from light with
opaque material.
Discard tubing after
24 hr.
Slight brownish color
is common and not
significant.
BP, Blood pressure; D5W, 5% dextrose in water; D10W, 10% dextrose in water; HR, heart rate; IV,
intravenous; NS, normal saline; TPN, total parenteral nutrition; UAC, umbilical artery catheter.
Normal Values
Mary Elaine Patrinos
C
565
566
CHEMISTRY VALUES
Table C-1. Blood Chemistry Values in Premature Infants during the First 7 Weeks of Life (Birth Weight 1500-1750 g)
APPENDIX C Normal Values

Age 1 Week Age 3 Weeks Age 5 Weeks Age 7 Weeks
Constituent Mean ± SD Range Mean ± SD Range Mean ± SD Range Mean ± SD Range

Na (mEq/L) 139.6 ± 3.2 133-146 136.3 ± 2.9 129-142 136.8 ± 2.5 133-148 137.2 ± 1.8 133-142
K (mEq/L) 5.6 ± 0.5 4.6-6.7 5.8 ± 0.6 4.5-7.1 5.5 ± 0.6 4.5-6.6 5.7 ± 0.5 4.6-7.1
Cl (mEq/L) 108.2 ± 3.7 100-117 108.3 ± 3.9 102-116 107.0 ± 3.5 100-115 107.0 ± 3.3 101-115
CO2 (mmol/L) 20.3 ± 2.8 13.8-27.1 18.4 ± 3.5 12.4-26.2 20.4 ± 3.4 12.5-26.1 20.6 ± 3.1 13.7-26.9
Ca (mg/dL) 9.2 ± 1.1 6.1-11.6 9.6 ± 0.5 8.1-11.0 9.4 ± 0.5 8.6-10.5 9.5 ± 0.7 8.6-10.8
P (mg/dL) 7.6 ± 1.1 5.4-10.9 7.5 ± 0.7 6.2-8.7 7.0 ± 0.6 5.6-7.9 6.8 ± 0.8 4.2-8.2
BUN (mg/dL) 9.3 ± 5.2 3.1-25.5 13.3 ± 7.8 2.1-31.4 13.3 ± 7.1 2.0-26.5 13.4 ± 6.7 2.5-30.5
Total protein (g/dL) 5.49 ± 0.42 4.40-6.26 5.38 ± 0.48 4.28-6.70 4.98 ± 0.50 4.14-6.90 4.93 ± 0.61 4.02-5.86
Albumin (g/dL) 3.85 ± 0.30 3.28-4.50 3.92 ± 0.42 3.16-5.26 3.73 ± 0.34 3.20-4.34 3.89 ± 0.53 3.40-4.60
Globulin (g/dL) 1.58 ± 0.33 0.88-2.20 1.44 ± 0.63 0.62-2.90 1.17 ± 0.49 0.48-1.48 1.12± 0.33 0.5-2.60
Hb (g/dL) 17.8 ± 2.7 11.4-24.8 14.7 ± 2.1 9.0-19.4 11.5 ± 2.0 7.2-18.6 10.0 ± 1.3 7.5-13.9
Adapted from Thomas J, Reichelderfer T: Premature infants: analysis of serum during the first seven weeks, Clin Chem 14:272, 1968.
BUN, Blood urea nitrogen; Hb, hemoglobin; SD, standard deviation.
APPENDIX C Normal Values 567
Table C-2. Measured Variables in Cord and Whole Venous Blood in Healthy Term Neonates
Cord Blood 2- to 4-Hour Blood
Mean ± SD Range Mean ± SD Range

pH 7.35 ± 0.05 7.19-7.42 7.36 ± 0.04 7.27-7.45
Pco2 (mm Hg) 40 ± 6 24.5-56.7 43 ± 7 30-65
Hct (%) 48 ± 5 37-60 57 ± 5 42-67
Hb (g/L) 1.65 ± 0.16 1.29-2.06 1.90 ± 0.22 0.88-2.3
Na+ (mmol/L) 138 ± 3 129-144 137 ± 3 130-142
K+ (mmol/L) 5.3 ± 1.3 3.4-9.9 5.2 ± 0.5 4.4-6.4
Cl− (mmol/L) 107 ± 4 100-121 111 ± 5 105-125
iCa (mmol/L) 1.15 ± 0.35 0.21-1.5 1.13 ± 0.08 0.9-1.3
iMg (mmol/L) 0.28 ± 0.06 0.09-0.39 0.30 ± 0.05 0.23-0.46
Glucose (mmol/L) 4.16 ± 1.05 0.16-6.66 3.50 ± 0.67 5.11-16.10
Glucose (mg/dL) 75 ± 19 2.9-120 63 ± 12 29-92
Lactate (mmol/L) 4.6 ± 1.9 1.1-9.6 3.9 ± 1.5 1.6-9.8
BUN (mmol/L) 2.14 ± 0.61 1.07-3.57 2.53 ± 0.71 1.43-4.28
BUN (mg/dL) 6.0 ± 1.7 3.0-10.0 7.1 ± 2.0 4-12
From Dollberg S, Bauer R, Lubetzky R, et al: A reappraisal of neonatal blood chemistry reference ranges
using the Nova M electrodes, Am J Perinatol 18:433, 2001.
BUN, Blood urea nitrogen; Hb, hemoglobin; Hct, hematocrit; iCa, ionized calcium; iMg, ionized
magnesium; SD, standard deviation.
Plasma Ammonia Levels in

Table C-3. Preterm Infants of ≤32 Weeks’
Gestational Age
Ammonia Level*
Age (days) μmol/L μg/dL

Birth 71 ± 26 121 ± 45†
1 69 ± 22 117 ± 37
3 60 ± 19 103 ± 33
7 42 ± 14 72 ± 24
14 42 ± 18 72 ± 30
21 43 ± 16 73 ± 28
28 42 ± 15 72 ± 25
Term infants at birth 45 ± 9 77 ± 16
Modified from Usmanii SS, Cavaliere T, Casatelli J, et al:
Plasma ammonia levels in very low birth weight preterm
infants, J Pediatr 123:798, 1993.
*Values represent mean ± 1 standard deviation unit.
†Plasma ammonia level declines significantly from birth to 7
days of age (P <.01).

568 APPENDIX C Normal Values
Table C-4. Liver Function Test Values
Test Age Value

Albumin (g/L) 0-5 days (<2.5 kg) 20-36
0-5 days (>2.5 kg) 26-36
1-30 days 26-43
31-182 days 28-46
183-365 days 28-48
Prothrombin time (sec) 1 day (30-36 wk of gestation) 10.6-16.2
5 days (30-36 wk of gestation) 10.0-15.3
1 day 11.6-14.4
5 days 10.9-13.9
30 days 10.6-13.1
90 days 10.8-13.1
180 days 11.5-13.1
Partial thromboplastin time (sec) 1 day (30-36 wk of gestation) 27.5-79.4
1 day 37.1-48.7
5 days 34.0-51.2
30 days 33.0-47.8
90 days 30.6-43.6
180 days 31.8-39.2
Ammonia (μmol/L) 1-90 days 42-144
3-11 mo 34-133
Aspartate aminotransferase (U/L) 0-5 days 35-140
1-3 yr 20-60
Alanine aminotransferase (U/L) 0-5 days 6-50
1-30 days 1-25
31-365 days 3-35
Alkaline phosphatase (U/L) 0-5 days 110-300
1-30 days 48-406
31-365 days 82-383
γ-Glutamyltransferase (U/L) 0-5 days 34-263
1-182 days 12-132
183-365 days 1-39
Adapted from Rosenthal P: Assessing liver function and hyperbilirubinemia in the newborn. National
Academy of Clinical Biochemistry, Clin Chem 43:228, 1997.
For full-term infants unless otherwise noted.
Table C-5. Plasma-Serum Amino Acid Levels in Premature and Term Newborns (μmol/L)
Newborn 16 Days to
Amino Acid Premature (First Day) (Before First Feeding) 4 Months
Taurine 105-255 101-181
Hydroxyproline 0-80 0
Aspartic acid 0-20 4-12 17-21
Threonine 155-275 196-238 141-213
Serine 195-345 129-197 104-158
Aspartate + Glutamate 655-1155 623-895
Proline 155-305 155-305 141-245
Glutamic acid 30-100 27-77
Glycine 185-735 274-412 178-248
Alanine 325-425 274-384 239-345
Valine 80-180 97-175 123-199
Cystine 55-75 49-75 33-51
Methionine 30-40 21-37 15-21
Isoleucine 20-60 31-47 31-47
Leucine 45-95 55-89 56-98
Tyrosine 20-220 53-85 33-75
Phenylalanine 70-110 64-92 45-65
Ornithine 70-110 66-116 37-61
Lysine 130-250 154-246 117-163
Histidine 30-70 61-93 64-92
Arginine 30-70 37-71 53-71
Tryptophan 15-45 15-45
Citrulline 8.5-23.7 10.8-21.1
Ethanolamine 13.4-10.5 32.7-72
α-Amino-n-butyric acid 0-29 8.7-20.4
From Behrman RE: Neonatal-perinatal medicine: diseases of the fetus and infant, ed 2, St Louis,
1977, Mosby, Appendix Table 20. Data from Dickinson JC, Rosenblum H, Hamilton PB: Ion exchange
chromatography of the free amino acids in the plasma of the newborn infant, Pediatrics 36:2, 1965; and
Dickinson JC, Rosenblum H, Hamilton PB: Ion exchange chromotography of the free amino acids in the
plasma of infants under 2,500 gm at birth, Pediatrics 45:606, 1970.
Reference Serum Amino Acid Reference Intervals for Urine

Concentrations That Have Been Amino Acid Excretion in
Table C-6. Table C-7.
Proposed as Standards for Untimed Samples (mmol per
Neonates (μmol/L) mol creatinine)
Term Infant Fed 1-12
Amino Acid Human Milk Cord Blood 0-1 Months Months
Isoleucine 26-93 21-76 Amino Acid (Mean) (Mean)
Leucine 53-169 47-120 Aspartic acid 9-57 (23) 10-69 (26)
Lysine 80-231 181-456 Glutamic acid 31-96 (54) 24-102 (50)
Methionine 22-50 8-42 α-Aminoadipic 7-96 (26) 7-110 (29)
Phenylalanine 22-71 24-87 acid
Threonine 34-168 108-327 Hydroxyproline 11-556 (100) 5-238 (34)
Tryptophan 18-101 19-98 Phosphoethanol- 13-167 (46) 12-216 (51)
Valine 88-222 98-276 amine
Alanine 125-647 186-494 Serine 48-509 (156) 34-329 (51)
Arginine 42-148 28-162 Asparagine 15-223 (58) 18-197 (59)
Aspartic acid 5-51 18 ± 17 Glycine 127-2042 (510) 133-894 (345)
Glutamic acid 24-243 92 ± 57 Glutamine 37-600 (148) 63-446 (168)
Glycine 77-376 123-312 β-Alanine 2-41 (8) 2-38 (8)
Histidine 34-119 42-136 Taurine* 12-1057 10-809
Proline 82-319 72-278 Histidine 23-676 (125) 69-392 (164)
Serine 0-326 57-174 Citrulline 1-18 (5) 2-46 (9)
Taurine 1-167 41-461 Threonine 9-337 (56) 12-145 (41)
Tyrosine 38-119 34-83 Alanine 34-358 (109) 27-313 (93)
Cystine 35-132 4-37 β-Aminoisobutyric 0-520 (14) 5-258 (36)
acid
Modified from Hanning RM, Zlotkin SH: Amino acid and Carnosine 3-184 (21) 8-160 (36)
protein needs of the neonate: effects of excess and
deficiency, Semin Perinatol 13:131, 1989. See also Moro G, Arginine 0-81 (10) 0-40 (5)
Minoli I, Boehm G, et al: Postprandial plasma amino acids Proline 3-257 (29) 2-90 (14)
in preterm infants: influence of the protein source, Acta 1-Methylhistidine 0-78 (7) 0-98 (7)
Paediatr 88:885, 1999.
3-Methylhistidine 5-85 (20) 10-95 (31)
Ethanolamine 33-253 (91) 57-221 (112)
Aminobutyric acid 1-43 (5) 1-58 (7)
Tyrosine 5-74 (19) 12-64 (28)
Valine 3-34 (10) 3-43 (11)
Methionine 2-24 (7) 2-18 (6)
Cystathionine 1-26 (6) 1-11 (4)
Cystine 5-109 (24) 2-42 (10)
Isoleucine 2-37 (8) 2-21 (6)
Leucine 4-84 (17) 4-72 (17)
Hydroxylysine 3-49 (11) 2-50 (9)
Phenylalanine 2-49 (9) 7-42 (17)
Tryptophan 1-46 (8) 3-37 (10)
Ornithine 2-37 (8) 2-19 (6)
Lysine 6-464 (54) 4-80 (18)
No. of subjects 20 (11/9) 30 (16/14)

(male/female)
Modified from Venta R: Year-long validation study and
reference values for urinary amino acids using a reverse-
phase HPLC method, Clin Chem 47:575, 2001.
*Observed ranges.
HEMATOLOGIC VALUES
Red Blood Cell Parameters of Infants with Very Low Birth Weight during the First 6 Weeks of Life Derived from Arterial
Table C-8.
or Venous but Not Capillary Blood Samples
Percentile
APPENDIX C
Day of Life No. of Infants 3 5 10 25 Median 75 90 95 97
Hemoglobin (g/dL) 3* 559 11.0 11.6 12.5 14.0 15.6 17.1 18.5 19.3 19.8
12-14 203 10.1 10.8 11.1 12.5 14.4 15.7 17.4 18.4 18.9
24-26 192 8.5 8.9 9.7 10.9 12.4 14.2 15.6 16.5 16.8
40-42 150 7.8 7.9 8.4 9.3 10.6 12.4 13.8 14.9 15.4
Hematocrit (%) 3 561 35 36 39 43 47 52 56 59 60
Normal Values
12-14 205 30 32 34 39 44 48 53 55 56
24-26 196 25 27 29 32 39 44 48 50 52
40-42 152 24 24 26 28 33 38 44 47 48
Red blood cells (1012/L) 3 364 3.2 3.3 3.5 3.8 4.2 4.6 4.9 5.1 5.3
12-14 196 2.9 3.0 3.2 3.5 4.1 4.6 5.2 5.5 5.6
24-26 188 2.6 2.6 2.8 3.2 3.8 4.4 4.8 5.2 5.3
40-42 148 2.5 2.5 2.6 3.0 3.4 4.1 4.6 4.8 4.9
Corrected reticulocytes (%) 3 283 0.6 0.7 1.9 4.2 7.1 12.0 20.0 24.1 27.8
12-14 139 0.3 0.3 0.5 0.8 1.7 2.7 5.7 7.3 9.6
24-26 140 0.2 0.3 0.5 0.8 1.5 2.6 4.7 6.4 8.6
40-42 114 0.3 0.4 0.6 1.0 1.8 3.4 5.6 8.3 9.5
From Obladen M, Diepold K, Maier RF; European Multicenter rhEPO Study Group: Venous and arterial hematologic profiles of very low birth weight infants, Pediatrics
106:709, 2000.
*On day 3, all infants are included regardless of the use of antenatal steroids and transfusions up to that time. Thereafter, infants who did not receive erythropoietin
were studied regardless of the use of antibiotics and steroids.
571
572
Reference Values for Nucleated Red Blood Cell (NRBC) Count from Umbilical Vein Sampling at Birth in 695 Newborns Divided

Table C-9.
into Four Groups According to Gestational Age
Birth Weight (g) Gestational Age (wk) NRBC*
No. of 25th-75th 25th-75th 25th-75th

Newborns Mean ± SD Percentiles Mean ± SD Percentiles Mean ± SD Median Percentiles
Group 1 120 954 ± 234 780-1105 26.7 ± 1 26-28 5643 ± 7228 2601 1147-7790
Group 2 128 1413 ± 398 1100-1720 30.4 ± 1 29-31 3328 ± 3577 1901 492-5970
Group 3 215 2189 ± 473 1940-2520 34.7 ± 1 34-36 1099 ± 1275 696 0-1672
Group 4 232 3201 ± 669 2905-3590 38.6 ± 1 38-40 442 ± 807 0 0-638
Adapted from Perrone S, Vezzosi P, Longini M, et al: Nucleated red blood cell count in term and preterm newborns: reference values at birth, Arch Dis Child Fetal
Neonatal Ed 90:F174, 2005.
*Absolute count (NRBCs/mm3).
SD, Standard deviation.
Table C-10. Hematologic Values in the First Weeks of Life Related to Gestational Maturity
MEAN CORPUSCULAR HEMOGLOBIN CONCENTRATION (%)*
3 days 1 Week 2 Weeks 3 Weeks 4 Weeks 6 Weeks 8 Weeks 10 Weeks
<1500 g, 32 32 32 33 33 33 33 32
28-32 wk
1500-2000 g, 32 32 32 33 33 33 33 32
32-36 wk
2000-2500 g, 32 32 33 33 33 33 33 33
36-40 wk
>2500 g, 32 33 33 33 33 33 33 33
Term
HEMOGLOBIN (g/dL)—MEAN (SD)
<1500 g, 17.5 (1.5) 15.5 (1.5) 13.5 (1.1) 11.5 (1.0) 10.0 (0.9) 8.5 (0.5) 8.5 (0.5) 9.0 (0.5)
28-32 wk
1500-2000 g, 19.0 (2.0) 16.5 (1.5) 14.5 (1.1) 13.0 (1.1) 12.0 (1.0) 9.5 (0.8) 9.5 (0.5) 9.5 (0.5)
32-36 wk
2000-2500 g, 19.0 (2.0) 16.5 (1.5) 15.0 (1.5) 14.0 (1.1) 12.5 (1.0) 10.5 (0.9) 10.5 (0.9) 11.0 (1.0)
36-40 wk
>2500 g, 19.0 (2.0) 17.0 (1.5) 15.5 (1.5) 14.0 (1.1) 12.5 (1.0) 11.0 (1.0) 11.5 (1.0) 12.0 (1.0)
Term
HEMATOCRIT (%)—MEAN (SD)
<1500 g, 54 (5) 48 (5) 42 (4) 35 (4) 30 (3) 25 (2) 25 (2) 28 (3)
28-32 wk
1500-2000 g, 59 (6) 51 (5) 44 (5) 39 (4) 36 (4) 28 (3) 28 (3) 29 (3)
32-36 wk
2000-2500 g, 59 (6) 51 (5) 45 (5) 43 (4) 37 (4) 31 (3) 31 (3) 33 (3)
36-40 wk
>2500 g, 59 (6) 51 (5) 46 (5) 43 (4) 37 (4) 33 (3) 34 (3) 36 (3)
Term
RETICULOCYTE COUNT (%)—MEAN (SD)
3 days 1 Week 2 Weeks 4 Weeks 6 Weeks 8 Weeks 10 Weeks
<1500 g 28-32 wk 8.0 (3.5) 3.0 (1.0) 3.0 (1.0) 6.0 (2.0) 11.0 (3.5) 8.5 (3.5) 7.0 (3.0)
1500-2000 g 32-36 wk 6.0 (2.0) 3.0 (1.0) 2.5 (1.0) 3.0 (1.0) 6.0 (2.0) 5.0 (1.5) 4.5 (1.5)
2000-2500 g 36-40 wk 4.0 (1.0) 3.0 (1.0) 2.5 (1.0) 2.0 (1.0) 3.0 (1.0) 3.0 (1.0) 3.0 (1.0)
>2500 g Term 4.0 (1.5) 3.0 (1.0) 2.0 (1.0) 2.0 (1.0) 2.0 (0.5) 2.0 (0.5) 2.0 (0.5)
*Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) in cubic micrometers and
picograms, respectively, depend on red cell counts that are not generally reliable.
Mean Hematocrit by Age in

Table C-11.
Hours and Gestational Age
Gestational Age (wk)
Age (hr) 35-42 29-34 22-28

0 51 50 45
1 52 50 44
2 54 50 42
3 53 50 41
4 53 48 39
Data for three groups of neonates are shown (N = 23,534),
categorized by gestational age.
Modified from Jopling J, Henry E, Wiedmeier SE, et al:
Reference ranges for hematocrit and blood hemoglobin
concentration during the neonatal period: data from a
multihospital health care system, Pediatrics 123(2):e333,
2009.
Table C-12. White Cell and Differential Counts in Premature Infants

Birth Weight <1500 g Birth Weight 1500-2500 g
Age in Weeks Age in Weeks
1 2 4 1 2 4
Total count (× 103/mm3)
Mean 16.8 15.4 12.1 13.0 10.0 8.4
Range 6.1-32.8 10.4-21.3 8.7-17.2 6.7-14.7 7.0-14.1 5.8-12.4
Percentage of total polymorphs
Segmented 54 45 40 55 43 41
Unsegmented 7 6 5 8 8 6
Eosinophils 2 3 3 2 3 3
Basophils 1 1 1 1 1 1
Monocytes 6 10 10 5 9 11
Lymphocytes 30 35 41 9 36 38
30
5th percentile
95th percentile
25 Average
20
Neutrophils 103/µL
15
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Hours of age
Figure C-1. Neutrophils per microliter of blood during the first 72 hours after birth in term and near-term (>36 weeks’
gestation) neonates. A total of 12,149 values were obtained for the analysis. The 5th percentile, the mean, and the 95th
percentile values are shown. (From Schmutz N, Henry E, Jopling J, et al: Expected ranges for blood neutrophil
concentrations of neonates: the Manroe and Mouzinho charts revisited, J Perinatol 28:275, 2008.)
30
5th percentile
95th percentile
25 Average
20
Neutrophils 103/µL
15
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Hours of age
Figure C-2. Neutrophils per microliter of blood during the first 72 hours after birth in 28- to 36-week gestation preterm
neonates. A total of 8896 values were obtained for the analysis. The 5th percentile, the mean, and the 95th percentile
values are shown. (From Schmutz N, Henry E, Jopling J, et al: Expected ranges for blood neutrophil concentrations
of neonates: the Manroe and Mouzinho charts revisited, J Perinatol 28:275, 2008.)
45
5th percentile
40 95th percentile
Average
35
30
Neutrophils 103/µL
25
20
15
10
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Hours of age
Figure C-3. Neutrophils per microliter of blood during the first 72 hours after birth in preterm neonates of less than 28
weeks’ gestation. A total of 852 values were obtained for the analysis. The 5th percentile, the mean, and the 95th percentile
values are shown. (From Schmutz N, Henry E, Jopling J, et al: Expected ranges for blood neutrophil concentrations
of neonates: the Manroe and Mouzinho charts revisited, J Perinatol 28:275, 2008.)
20,000
18,000 Average
+2 standard
Immature neutrophils (per mm3)

16,000 deviations
14,000
12,000
10,000
8000
6000
4000
2000
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Time (hrs)
Figure C-4. Immature neutrophils (band neutrophils plus metamyelocytes) per microliter of blood during the first 72 hours
after birth in term and near-term (>36 weeks’ gestation) neonates. A total of 12,857 values were obtained for the analysis.
Values for the average and 2 standard deviations above the mean are shown. (From Schmutz N, Henry E, Jopling J,
et al: Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited,
J Perinatol 28:275, 2008.)
CEREBROSPINAL FLUID VALUES

Table C-13. Cerebrospinal Fluid Values in Infants with Birth Weight of 1000 Grams or Less
Postnatal Age (Days)
0-7 8-28 29-84
Mean ± SD Range Mean ± SD Range Mean ± SD Range

Birthweight (g) 822 ± 116 630-980 752 ± 112 550-970 750 ± 120 550-907
Gestational age at birth (wk) 26 ± 1.2 24-27 26 ± 1.5 24-28 26 ± 1.0 24-27
Leukocytes/μL 3±3 1-8 4±4 0-14 4±3 0-11
Erythrocytes/μL 335 ± 709 0-1780 1465 ± 4062 0-19050 808 ± 1843 0-6850
Polymorphonuclear cells (%) 11 ± 20 0-50 8 ± 17 0-66 2±9 0-36
Glucose (mg/dL) 70 ± 17 41-89 68 ± 48 33-217 49 ± 22 29-90
Protein (mg/dL) 162 ± 37 115-222 159 ± 77 95-370 137 ± 61 76-260
Modified from Rodriguez AF, Kaplan SL, Mason EO Jr: Cerebrospinal fluid values in the very low birth
weight infant, J Pediatr 116:971, 1990.
Table C-14. Cerebrospinal Fluid Values in Infants with Birth Weight of 1000 to 1500 Grams
Postnatal Age (Days)
0-7 8-28 29-84
Mean ± SD Range Mean ± SD Range Mean ± SD Range

Birth weight (g) 1428 ± 107 1180-1500 1245 ± 162 1020-1480 1211 ± 86 1080-1300
Gestational age at birth 31 ± 1.5 28-33 29 ± 1.2 27-31 29 ± 0.7 27-29
(wk)
Leukocytes/μL 4±4 1-10 7 ± 11 0-44 8±8 0-23
Erythrocytes/μL 407 ± 853 0-2450 1101 ± 2643 0-9750 661 ± 1198 0-3800
Polymorphonuclear cells 4 ± 10 0-28 10 ± 19 0-60 11 ± 19 0-48
(%)
Glucose (mg/dL) 74 ± 19 50-96 59 ± 23 39-109 47 ± 13 31-76
Protein (mg/dL) 136 ± 35 85-176 137 ± 46 54-227 122 ± 47 45-187
Modified from Rodriguez AF, Kaplan SL, Mason EO Jr: Cerebrospinal fluid values in the very low birth
weight infant, J Pediatr 116:971, 1990.
100
80
Cumulative percentage
60
40
117 neonates without meningitis

21 neonates with group B
20
β-hemolytic streptococcus
meningitis
98 neonates with gram-negative
meningitis
0
1 10 100 1000 10,000 100,000
Cerebrospinal fluid (WBC count/mm3)
Figure C-5. Comparison of cerebrospinal fluid white blood cell (WBC) counts in neonates with and without meningitis.
578
Table C-15. Cerebrospinal Fluid Values in Term Neonates*
White Blood Cells (per μL) Protein (mg/dL) Glucose (mg/dL)
No. of
Week Age (days) Neonates Mean ± SD 95% CI Median Range 90th Percentile Mean ± SD Mean ± SD
1 0-7 17 15.3 ± 30.3 12.5-18.1 6 1-130 18 80.8 ± 30.8 45.9 ± 7.5
2 8-14 33 5.4 ± 4.4 4.6-6.1 6 0-18 10 69 ± 22.6 54.3 ± 17
3 15-21 25 7.7 ± 12.1 6.3-9.1 4 0-62 12.5 59.8 ± 23.4 46.8 ± 8.8
4 22-30 33 4.8 ± 3.4 4.1-5.4 4 0-18 8 54.1 ± 16.2 54.1 ± 16.2
All 108 7.3 ± 13.9 6.6-8 4 0-130 11 64.2 ± 24.2 51.2 ± 12.9
Modified from Rodriguez AF, Kaplan SL, Mason EO Jr: Cerebrospinal fluid values in the very low birth weight infant, J Pediatr 116:971, 1990.
*All neonates tested were suspected of having an infection, but no central nervous system infection was found.
CI, Confidence interval; SD, standard deviation.

PHYSIOLOGIC PARAMETERS
GROWTH CHARTS
97th
55
90th
4500 97th 75th
Length Length 50th
90th 50 25th
4000 10th
75th
3rd
3500 50th 45
25th
3000 40
Centimeters
10th
Weight (g)
3rd 97th
90th
2500 75th
35 50th
25th
10th
2000 3rd
30
1500
Head circumference 25 Head circumference
1000
20
500
23 25 27 29 31 33 35 37 39 41 23 25 27 29 31 33 35 37 39 41
A Gestational age (wk) B Gestational age (wk)
97th
90th
55
97th 75th
Length 50th
4500 Length 90th 25th
50 10th
75th
4000 3rd
50th
45
3500 25th
10th
40
Centimeters
3000
Weight (g)
3rd 97th
90th
75th
2500 35 50th
25th
10th
3rd
2000
30
1500
Head circumference 25 Head circumference
1000
20
500
23 25 27 29 31 33 35 37 39 41 23 25 27 29 31 33 35 37 39 41
C Gestational age (wk) D Gestational age (wk)
Figure C-6. New gender-specific intrauterine growth curves for girls’ weight for age (A), girls’ length and head
circumference for age (B), boys’ weight for age (C), and boys’ length and head circumference for age (D). The 3rd and 97th
percentile values on all curves for 23 weeks should be interpreted cautiously because of the small sample size; for boys’
head circumference at 24 weeks, all percentile curves should be interpreted cautiously, because the distribution of data is
skewed left. (Adapted from Groveman SA: New preterm infant growth curves: influence of gender and race on birth size,
master’s thesis, Philadelphia, 2008, Drexel University.)
4000
Lubchenco
3500 Brenner
Williams
Ott
3000 Alexander
2500
Birth weight (g)
2000
1500
1000
500
0
20 22 24 26 28 30 32 34 36 38 40 42 44
Gestational age (complete wk)
Figure C-7. Fetal growth data from selected sources. (Data from Lubchenko LO, Hansman C, Dressler M, et al:
Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation, Pediatrics 32:793,
1963; Brenner WE, Edelman DA, Hendricks CH: A standard of fetal growth for the United States of America,
Am J Obstet Gynecol 126:555, 1976; Williams RL: Intrauterine growth curves: Intra- and international comparisons
with different ethnic groups in california, Prevent Med 4:163, 1975; Ott W: Intrauterine growth retardation and
preterm delivery, Am J Obstet Gynecol 168:1710, 1993; Alexander GR, Himes JH, Kaufman RB, et al: A United
States reference for fetal growth, Obstet Gynecol 87:163, 1996.)
65 65
60 60
97%
90%
55 55
50%
h
ngt
Centimeters
Le 10%
50 3% 50
45 45
40 97% 40
ce 90%
ren
u mfe 50%
circ 10%
35 ad 6.0
Centimeters
He 3%
30 5.5
97%
25 90% 5.0
20 4.5
50%
4.0 4.0
t
gh
ei
3.5 10% 3.5

W
Weight (kg)
3%
3.0 3.0
Weight (kg)
2.5 2.5
2.0 2.0
1.5 1.5
1.0 1.0
0.5 0.5
0 0
22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Date:
Gestational age (wk)

Figure C-8. Fetal-infant growth chart developed through a meta-analysis of published reference materials. (From Fenton
TR: A new growth chart for preterm babies: Babson and Benda’s chart updated with recent data and a new
format, BMC Pediatr 3:13, 2003.)
60 97 23.6
59 90 23.2
58 75 22.8
57 50 22.4
56 25 22.1
55 10 21.7
54 3 21.3
53 20.9
52 20.5
51 20.1
Head circumference (cm)
Head circumference (in)

50 19.7
49 19.3
48 18.9
47 18.5
46 18.1
45 17.7
44 17.3
43 16.9
42 16.5
41 16.1
40 15.8
39 15.4
38 15.0
37 14.6
36 14.2
35 13.8
34 13.4
33 13.0
32 12.6
31 12.2
0 2 4 6 8 10 12 14 16 18 20 22 2 3 4 5 6 7 8 9 10 11 12 13 1415 16 17 1819 20 21
A Age (mo) Age (yr)
58 22.8
57 97 22.4
56 90 22.1
75
55 21.7
50
54 25 21.3
53 10 20.9
52 3 20.5
51 20.1
50 19.7
49 19.3
Head circumference (in)

48 18.9
47 18.5
46 18.1
45 17.7
44 17.3
43 16.9
42 16.5
41 16.1
40 15.8
39 15.4
38 15.0
37 14.6
36 14.2
35 13.8
34 13.4
33 13.0
32 12.6
31 12.2
0 2 4 6 8 10 12 14 16 18 20 22 2 3 4 5 6 7 8 9 10 11 12 13 1415 16 17 1819 20 21
B Age (mo) Age (yr)

Figure C-9. Proposed occipitofrontal circumference growth curves for males (A) and females (B). (From Rollins JD, Collins
JS, Holden KR: United States head circumference growth reference charts: birth to 21 years, J Pediatr 156[6]:907,
2010.)
1401 1301 1201 1101 1001 901 801 701 601

2000
501
1750
1500
Weight (g)
1250
1000
750
500
1 14 28 42 56 70 84 98
Postnatal age (days)
Figure C-10. Average daily body weight as a function of postnatal age in days for infants stratified by 100-g birth-weight
intervals. (From Ehrenkranz RA, Younes N, Lemons JA, et al: Longitudinal growth of hospitalized very low birth
weight infants, Pediatrics 104:280, 1999.)
35
1001 901 801 701 601 501

1201 1101
1301
1401
30
25
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Postnatal age (wk)
Figure C-11. Average weekly head circumference as a function of postnatal age in weeks for infants stratified by 100-g
birth-weight intervals. (From Ehrenkranz RA, Younes N, Lemons JA, et al: Longitudinal growth of hospitalized very low
birth weight infants, Pediatrics 104:280, 1999.)
1301 1101
to 1500 to 1300 901 to 1100 501 to 700
2000 701 to 900
1750
1500
Weight (g)
1250
1000
750
No major morbidity
Major morbidity
500
1 14 28 42 56 70 84 98
Postnatal age (days)
Figure C-12. Growth curves of infants with major morbidities (dashed lines) and reference infants without major morbidities
(solid line) as a function of postnatal age in days. The infants are stratified by 200-g birth-weight intervals. Reference group
infants without major morbidities were appropriate size for gestational age and survived to discharge without development
of chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late-onset sepsis. (From Ehrenkranz
RA, Younes N, Lemons JA, et al: Longitudinal growth of hospitalized very low birth weight infants, Pediatrics
104:280, 1999.)
TIME OF FIRST VOID AND STOOL
Table C-16. Time of First Void and Stool

Time of Passage of First Stool by 920
Time of First Void by 920 Full-Term Infants Full-Term Infants
Time No. % Cumulative % Time No. % Cumulative %

Delivery room 139 15.1 15.1 Delivery room 210 22.8 22.8
Hours Hours
1-24 743 80.8 95.9 1-24 674 73.3 96.1
24-48 35 3.8 99.7 24-48 35 3.8 99.9
>48 3 0.3 100.0 >48 1 0.1 100.0
Time of Passage of First Stool by 280
Time of First Void by 280 Premature Infants Premature Infants
Time No. % Cumulative % Time No. % Cumulative %

Delivery room 62 22.1 22.1 Delivery room 30 10.7 10.7
Hours Hours
1-24 201 71.8 93.9 1-24 191 68.2 78.9
24-48 17 6.1 100.0 24-48 46 16.4 95.3
>48 >48 13 4.7 100.0
Adapted from Sherry S, Kramer I: The time of passage of the first stool and first urine by the newborn
infant, J Pediatr 46:158, 1955; Kramer I, Sherry S: The time of passage of the first stool and urine by the
premature infant, J Pediatr 51:353, 1957; and Clark D: Times of first void and stool in 500 newborns,
Pediatrics 60:457, 1977.
BLOOD PRESSURE
Mean Arterial Blood Pressure
Table C-17.
(MAP) by Birth Weight
Mean MAP ± SD
Birth Weight (g) Day 3 Day 17 Day 31

501-750 38 ± 8 44 ± 8 46 ± 11
751-1000 43 ± 9 45 ± 7 47 ± 9
1001-1250 43 ± 8 46 ± 9 48 ± 8
1251-1500 45 ± 8 47 ± 8 47 ± 9
From Fanaroff AA, Wright E for the NICHD Neonatal
Research Network Bethesda, MD: Profiles of mean arterial
blood pressure (MAP) for infants weighing 501-1500 grams,
Pediatr Res 27:205A, 1990.
80 80
Systolic BP Systolic BP
70 70
Systolic BP (mm Hg)
Systolic BP (mm Hg)

60 60
50
50
40
40
30
30
20
500 1000 1500 2000 2500 3000 3500 4000 4500 5000 22 24 26 28 30 32 34 36 38 40 42 44
A1 Birth body weight (g) A2 Gestational age (wk)
55 Diastolic BP 55
Diastolic BP
50 50

45 45
40 40
35 35
30
30
25
25
20
20
15
15
10
10
500 1000 1500 2000 2500 3000 3500 4000 4500 5000 24 26 28 30 32 34 36 38 40 42 44
B1 Birth body weight (g) B2 Gestational age (weeks)
60 60
55 MBP 55 MBP
50 50
MBP (mm Hg)
MBP (mm Hg)
45 45
40 40
35
35
30
30
25
25
20
20
15
500 1000 1500 2000 2500 3000 3500 4000 4500 5000 24 26 28 30 32 34 36 38 40 42 44
C1 Birth body weight (g) C2 Gestational age (wk)
Figure C-13. Linear regression of systolic blood pressure (top row), diastolic blood pressure (middle row), and mean
blood pressure (bottom row) on birth weight (left column) and gestational age (right column) on day 1 of life, with 95%
confidence limits (upper and lower solid lines). The 95% confidence limits approximate ±2 standard deviations (SDs) from
the mean. BP, Blood pressure; MBP, mean blood pressure. (From Pejovic B, Peco-Antic A, Marinkoviv-Eri J: Blood
pressure in non-critically ill preterm and full-term neonates, Pediatr Nephrol 22:249, 2007.)
80 ≥37
wk
75 55
Diastolic blood pressure (mm Hg)

Systolic blood pressure (mm Hg)
33-36
wk ≥37
70 50 wk
29-32
65 wk 45 33-36
wk
≤28 29-32
60 40 wk
wk
≤28
55 35 wk
50 30
45 25
40 20
1 2 3 4 5 1 2 3 4 5
Day of life Day of life
Figure C-14. Systolic blood pressure and diastolic blood pressure in the first 5 days of life, with each day subdivided
into 8-hour periods. Infants are stratified by gestational age into four groups: 28 weeks or less (n = 33), 29 to 32 weeks
(n = 73), 33 to 36 weeks (n = 100), and 37 weeks or more (n = 110). (From Zubrow AB, Hulman S, Kushner H, et al:
Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study.
Philadelphia Neonatal Blood Pressure Study Group, J Perinatol 15:470, 1995.)
MORBIDITY AND MORTALITY
100
90
80
70
60
Percentage
50
40
30
20
10
0
22 23 24 25 26 27 28 Overall
Gestational age (wk)
Figure C-15. Mean survival to discharge as a function of gestational age for 9575 low-birth-weight infants born in National
Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 2003 and
December 31, 2007. The thin lines indicate ranges across centers. (From Stoll BJ, Hansen NI, Bell EF, et al for the
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network:
Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network, Pediatrics 126:443,
2010.)
Birth weight (g)

501–750 751–1000 1001–1250 1251–1500
100
80
60
Percent
40
20
0
1
0
–9
–9
–0
–9
–9
–0
–9
–9
–0
–9
–9
–0
90
95
97
90
95
97
90
95
97
90
95
97
Year of birth
Mortality Survived with morbidity Survived without morbidity

Figure C-16. Comparison of mortality, morbidity, and morbidity-free survival for very low-birth-weight infants cared for in
12 National Institute of Child Health and Human Development Neonatal Research Network centers in 1990 to 1991, 1995
to 1996, and 1997 to 2000. Data are for singleton infants born in the centers and stratified by 250-g birth weight intervals.
(From Fanaroff AA, Stoll BJ, Wright LL, et al for the NICHD Neonatal Research Network: Trends in neonatal
morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196:147.e1-e8, 2007.)
MALES (N = 6563) FEMALES (N = 6493)
1600 1600
1400 1400
1200 1200
Birthweight (g)
Birthweight (g)
1000 1000
0.05
800 0.1 800 0.05
0.2 0.1
0.3
600 0.4 600 0.2
0.5 0.3
0.6 0.4
0.5
0.9 0.8 0.7 0.6
400 400 0.7
0.9 0.8
22 24 26 28 30 32 22 24 26 28 30 32
Gestational age (wk) Gestational age (wk)
Figure C-17. Mortality rates by birth weight, gestational age, and gender from the National Institute of Child Health and
Human Development from 1997 to 2002. The upper and lower limits of the shaded areas are the 95th and 5th percentiles,
respectively, for birth weight for each gestational age. The curved lines indicate combinations of birth weight and gestational
age with the same estimated probability of mortality (10% to 90%). The gradation in shading denotes the change in
estimated probability of death: dark shading indicates combinations of lower gestational ages and birth weights associated
with greater likelihood of death; light shading indicates combinations of higher gestational ages and birth weights associated
with lower likelihood of death. The methods used underestimate mortality at 22 and 23 weeks for infants with a birth weight
of up to 600 g. (From Fanaroff AA, Stoll BJ, Wright LL, et al for the NICHD Neonatal Research Network: Trends in
neonatal morbidity and mortality for very low birthweight infants, Am J Obstet Gynecol 196:147.e1-e8, 2007.)
10
IMR
Per 1000 live births
FMR
NMR
5
LFMR EFMR
PNMR
0
1990 1995 2000 2004
Year
Figure C-18. Fetal, neonatal, and infant mortality rates in the United States from 1990 to 2004 (final data). EFMR, Early fetal
mortality rate—early fetal deaths (20-27 weeks’ gestation) per 1000 live births plus fetal deaths; FMR, fetal mortality rate—
fetal deaths per 1000 live births plus fetal deaths; IMR, infant mortality rate—infant deaths per 1000 live births; LFMR, late
fetal mortality rate—late fetal deaths (≥28 weeks’ gestation) per 1000 live births plus fetal deaths; NMR, neonatal mortality
rate—neonatal deaths per 1000 live births; PNMR, postneonatal mortality rate—postneonatal deaths per 1000 live births.
(From Hamilton BE, Miniño AM, Martin JA, et al: Annual summary of vital statistics: 2005, Pediatrics 119:345, 2007.)
For comparison, in 2008: IMR = 6.59 deaths per 1000 live births; NMR = 4.27 per 1000 live births. (From Annual
Summary of Vital Statistics 2008.)
D
Umbilical Vessel
Catheterization
Ricardo J. Rodriguez
Use of central catheters requires careful con- high and low placement.2 Resolution of the
sideration of the risks involved (Box D-1). thrombus or development of collateral circu-
The relatively easy access to the umbili- lation generally occurs, even when extensive
cal vessels makes these vessels a very good thrombosis (e.g., aorta distal to renal arter-
option for central access in emergency situ- ies, common iliac) has been documented.1,3
ations. A central catheter inserted into the Occasionally a neonatal death is consid-
aorta via an umbilical artery may be required ered a direct consequence of complications
in the management of the sick neonate for related to umbilical vessel catheterization.4
monitoring of blood pressure, intermittent Hypertension in the neonate following use
blood sampling to check acid-base status, of high umbilical artery catheters has been
and, while in place, infusion of parenteral described. However, in a prospective study,
fluids and medications. the incidence of hypertension was similar
Umbilical artery catheters must be pre- with low and high catheters.5
cisely located. A major objective is to avoid Hemorrhage, either resulting from loose
the origin of the renal arteries, because a cath- connections or careless use of the stop-
eter may occlude a renal artery and catheters cocks or occurring at the time of removal,
in the area may produce thrombosis.1 Both is a major complication of arterial catheters.
situations can result in renal infarction. Some Another major complication is thrombus
prefer to position the catheter in the midtho- formation with release of microemboli into
racic aorta (high); others prefer to locate the the systemic circulation. It is speculated that
catheter tip between L3 and L4 (low). Throm- the catheter tip can traumatize the vessel
botic complications are reported with both wall, which may release tissue thromboplas-
tin and activate intravascular coagulation.
Alternatively, the presence of the catheter
Box D-1. Catheter Complications itself may produce clot formation. More
rare complications include intimal flap
Hemorrhage formation and aneurysmatic dilatation of
Perforation into the abdominal artery. Ultrasonographic
• Peritoneal cavity examination of the abdominal aorta and
• Urachus its branches is indicated when any of these
• Pericardium complications is suspected.
Hepatic laceration Arterial blood samples may be obtained
Thrombi and emboli by multiple arterial punctures (of the radial
• Splenic vein thrombus or embolus artery) or an indwelling radial artery can-
• Displacement of thrombus in ductus nula as the method of choice or in cases in
venosus which umbilical artery catheterization is
• Pulmonary infarction (pulmonary vein unsuccessful.6,7
thrombus) In general, umbilical vein catheterization
Retained broken-off catheter fragment is technically easier. However, it should be
Calcification of portal vein or umbilical vein avoided except when immediate access to
a vein is needed because of an unexpected
Adapted from Oestreich AE: Umbilical vein
emergency (e.g., the need for delivery
catheterization—appropriate and inappropriate
placement, Pediatr Radiol 40:1941, 2010.
room resuscitation), because complications
may be serious and difficult to avoid. An
590
APPENDIX D Umbilical Vessel Catheterization 591
umbilical vein catheter tip may locate in a puts on sterile gloves. A 3.5F or 4F (for infants
branch of the portal vein and lead to areas weighing <1500 g) or a 5F catheter with
of liver necrosis without perforation of the rounded tip, which has a radiopaque line
vein wall following infusions of hypertonic and end hole (Argyle umbilical artery cath-
solutions, such as sodium bicarbonate and eter, coridien, mausfield, MASS) is attached
hypertonic glucose. Portal vein thrombo- to a syringe by a three-way stopcock. The sys-
sis and aseptic abscess formation have also tem is filled with heparinized saline solution
occurred with and without infection. In (1 U heparin per milliliter of normal or half-
addition, spontaneous perforation of the normal saline). (Box D-2 lists the equipment
colon after exchange transfusion via an found on the catheterization tray.) Before the
umbilical vein catheter has been reported. procedure is begun, the length of the catheter
Radiographic verification of catheter tip to be inserted should be marked according
location was not performed in any of these to the location desired (Figs. D-1 and D-2).
cases; most likely, the catheter tip was in the After the umbilical stump and surrounding
portal vein, and the cause of perforation was abdominal wall are carefully prepared with an
local necrosis of the bowel wall following antiseptic solution, sterile towels are placed
hemorrhagic infarction as a result of retro- around the stump and a circumcision drape
grade microemboli or obstructive hemody- is placed with the hole over the stump. The
namic changes. A more rare complication, base of the cord is loosely tied with umbilical
air embolism in the portal system, has also tape, with care taken to avoid the skin. The
been observed. cord stump is then grasped and cut perpen-
In the first hour or so of life in a normal dicular to its axis to within approximately
term infant, or for many hours and occa- 1.5 cm of the abdominal wall with a surgical
sionally for many days in a sick or preterm blade. The exposed vessels are identified—
infant, an umbilical vein catheter may be thin-walled oval vein and two smaller thick-
passed through the ductus venosus into the walled round arteries with tightly constricted
inferior vena cava. lumens. Occasionally, only one artery is pres-
Depending on the circumstances and ent. The cord is stabilized by grasping the
preference of the physician, exchange trans- Wharton jelly with one or two Kelly clamps.
fusions can be done using either vessel or The lumen of the vessel to be used is gen-
both, but not by infusing into the artery. tly dilated with curved Iris dressing forceps
The umbilical vessel catheter should be or a small obturator (Fig. D-3, A and B).
removed as soon as possible and a periph- The catheter is then inserted and gently
eral intravenous line substituted, if neces- advanced. Obstruction at the level of the
sary. In an undistressed newborn infant abdominal wall may be relieved by applying
requiring parenteral fluids, under no cir- gentle traction on the umbilical cord stump
cumstances should an umbilical vessel accompanied by steady but gentle pres-
catheter be used when a peripheral intrave- sure for about 30 seconds. During umbilical
nous line could be started via a scalp vein artery catheterization, obstruction may also
or an extremity vein. In the extremely low- occur at the level of the bladder. It may be
birth-weight group, in whom parenteral
nutrition is essential until enteral feeds are
established, common practice is to rou- Equipment Found on the Umbilical
tinely place percutaneous indwelling cen- Catheterization Tray at University
tral catheters and remove umbilical lines as Box D-2.
Hospitals Case Medical Center,
soon as possible. Cleveland, Ohio
2 Iris dressing forceps, 4-inch curved
TECHNIQUE OF CATHETERIZATION
1 Iris dressing forceps, 4-inch straight
In the small premature infant, the entire 2 Halsted mosquito forceps, 4-inch curved
catheterization should be done as an oper- 2 Halsted mosquito forceps, 4-inch straight
ating room procedure with the infant in an 1 Derf needle holder, 4.75 inches
incubator or under a radiant warmer to pre- 1 Iris scissors, 4.5 inches
vent hypothermia. In the delivery room, a 1 Operating scissors, 5.5 inches
radiant heater should be used. 1 Medicine cup
When not precluded by an emergency 4 Gauze preparation sponges, 3 × 3 inch
(e.g., acute asphyxia), the following protocol 1 Huck towel, folded
should be followed. The operator carefully 1 Steam chemical integrator
scrubs hands and arms to the elbows and
592 APPENDIX D Umbilical Vessel Catheterization
12
Length of catheter in umbilical vessel (cm)
10
Umbilical vein—to junction of inferior

vena cava and right atrium
Umbilical artery—to bifurcation of aorta
4
8 10 12 14 16 18
Shoulder-umbilicus distance (cm)
Figure D-1. Determination of the length of catheter to be inserted for appropriate arterial or venous placement.
The length of the catheter read from the diagram is to the umbilical ring; the length of the umbilical cord stump
present must be added. The shoulder-umbilicus distance is the perpendicular distance between parallel lines
at the level of the umbilicus and through the distal ends of the clavicles. (Adapted from data in Dunn P:
Localization of the umbilical catheter by post-mortem measurement, Arch Dis Child 41:69, 1966.)
20 High
(T8)
16
catheter length (cm)
12
Umbilical artery
Low
(L4)
0 32 3640 44 48 52 56
Total body length (cm)
Figure D-2. Catheter position determined from total body length. (Modified from Rosenfield W, Biagtan
J, Schaeffer H, et al: A new graph for insertion of umbilical artery catheters, J Pediatr 96:735, 1980.)
APPENDIX D Umbilical Vessel Catheterization 593
A B
C
Figure D-3. A, Cross section of the umbilical cord showing tie in place and dilatation of artery with Iris forceps. B, Insertion
of catheter into umbilical artery. C, Bridge technique used to secure catheter after suturing. A purse string suture is used
that incorporates all three vessels. A square knot is tied at the base of the catheter, and a second knot is tied 1 cm above
the base. The tape bridge further ensures against the line’s becoming dislodged.
overcome by application of gentle, steady through the ductus venosus into the inferior
pressure for 30 seconds. Alternatively, vena cava. Gentle application of caudal trac-
marked resistance may be found where the tion to the umbilical cord stump sometimes
umbilical artery meets the internal iliac facilitates the introduction of an umbilical
artery (usually at 5 cm). The operator should venous line. Occasionally it is not possible to
avoid applying undue pressure to overcome get the catheter into the inferior vena cava
this point of resistance because of the possi- for anatomic reasons, and vigorous attempts
bility of perforation of the vessel and severe to advance the catheter are to be avoided.
hemorrhage. If continued resistance is met, An umbilical vessel catheter should
the other artery should be used. If at any be tied in place with a silk suture around
point during or after the line placement per- the vessel and catheter and sutured to the
sistent blanching or cyanosis of the ipsilat- umbilical stump or taped to the abdominal
eral or contralateral extremity is observed, wall. Disastrous hemorrhage can occur if the
the catheter should be promptly removed. catheter is inadvertently pulled out or the
Cyanosis involving the toes or part of the stopcocks are disconnected by the activity
foot on the side of the catheter may be of the infant. The position of the catheter
relieved by warming the contralateral foot; must be identified by radiography immedi-
if this is not successful, the catheter should ately after insertion. It is important that the
be removed. Both lower extremities and umbilical vein catheter tip be at least well
buttocks should be carefully watched for into the ductus venosus (Fig. D-4) to protect
alterations in blood supply when an umbili- the portal system from receiving hypertonic
cal artery catheter is in place. solutions.
If an umbilical vein catheterization is per- If the radiograph obtained after umbili-
formed, the next site of obstruction after the cal vessel catheterization indicates that the
abdominal wall is the portal system. (The catheter has been inserted too far, it may be
catheter meets resistance several centimeters gently withdrawn an estimated amount for
before the distance marked on the catheter appropriate placement. If the catheter is not
is reached.) The catheter should be within far enough, it must be completely with-
drawn several centimeters, gently rotated, drawn and a new sterile one inserted after
and reinserted in an attempt to get the tip the area is appropriately prepared again.
594 APPENDIX D Umbilical Vessel Catheterization
REFERENCES
The reference list for this appendix can be found
Figure D-4. Anteroposterior radiographic

image showing the preferred location of
the umbilical vein catheter tip at the most
superior portion of the inferior vena cava,
where it receives the hepatic veins and
the ductus venosus and is about to empty
into the right atrium. (From Oestreich AE:
Umbilical vein catheterization—appropriate
and inappropriate placement, Pediatr
Radiol 40:1941, 2010.)
Conversion Charts
Table E-1. Conversion of Pounds and Ounces to Grams
Ounces
Pounds 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0 — 28 57 85 113 142 170 198 227 255 283 312 340 369 397 425
1 454 482 510 539 567 595 624 652 680 709 737 765 794 822 850 879
2 907 936 964 992 1021 1049 1077 1106 1134 1162 1191 1219 1247 1276 1304 1332
3 1361 1389 1417 1446 1474 1503 1531 1559 1588 1616 1644 1673 1701 1729 1758 1786
4 1814 1843 1871 1899 1928 1956 1984 2013 2041 2070 2098 2126 2155 2183 2211 2240
5 2268 2296 2325 2353 2381 2410 2438 2466 2495 2523 2551 2580 2608 2637 2665 2693
6 2722 2750 2778 2807 2835 2863 2892 2920 2948 2977 3005 3033 3062 3090 3118 3147
7 3175 3203 3232 3260 3289 3317 3345 3374 3402 3430 3459 3487 3515 3544 3572 3600
8 3629 3657 3685 3714 3742 3770 3799 3827 3856 3884 3912 3941 3969 3997 4026 4054
9 4082 4111 4139 4167 4196 4224 4252 4281 4309 4337 4366 4394 4423 4451 4479 4508
10 4536 4564 4593 4621 4649 4678 4706 4734 4763 4791 4819 4848 4876 4904 4933 4961
11 4990 5018 5046 5075 5103 5131 5160 5188 5216 5245 5273 5301 5330 5358 5386 5415
12 5443 5471 5500 5528 5557 5585 5613 5642 5670 5698 5727 5755 5783 5812 5840 5868
13 5897 5925 5953 5982 6010 6038 6067 6095 6123 6152 6180 6209 6237 6265 6294 6322
14 6350 6379 6407 6435 6464 6492 6520 6549 6577 6605 6634 6662 6690 6719 6747 6776
15 6804 6832 6860 6889 6917 6945 6973 7002 7030 7059 7087 7115 7144 7172 7201 7228
16 7257 7286 7313 7342 7371 7399 7427 7456 7484 7512 7541 7569 7597 7626 7654 7682
17 7711 7739 7768 7796 7824 7853 7881 7909 7938 7966 7994 8023 8051 8079 8108 8136
18 8165 8192 8221 8249 8278 8306 8335 8363 8391 8420 8448 8476 8504 8533 8561 8590
19 8618 8646 8675 8703 8731 8760 8788 8816 8845 8873 8902 8930 8958 8987 9015 9043
20 9072 9100 9128 9157 9185 9213 9242 9270 9298 9327 9355 9383 9412 9440 9469 9497
21 9525 9554 9582 9610 9639 9667 9695 9724 9752 9780 9809 9837 9865 9894 9922 9950
22 9979 10,007 10,036 10,064 10,092 10,120 10,149 10,177 10,206 10,234 10,262 10,291 10,319 10,347 10,376 10,404
E
595
596 APPENDIX E Conversion Charts
Table E-2. Conversion to International System (SI) Units
Component Conventional Unit × Conversion Factor = SI Unit

CLINICAL HEMATOLOGY
Erythrocytes per mm3 1 106/L
Hematocrit % 0.01 (1) volume of
RBCs/volume of
whole blood
Hemoglobin g/dL 10 g/L
Leukocytes per mm3 1 106/L
Mean corpuscular hemoglobin g/dL 10 g/L
concentration (MCHC)
Mean corpuscular volume (MCV) μm3 1 fL
Platelet count 103/mm3 1 109/L
Reticulocyte count % 10 10-3
CLINICAL CHEMISTRY
Acetone mg/dL 0.1722 mmol/L
Albumin g/dL 10 g/L
Aldosterone ng/dL 27.74 pmol/L
Ammonia (as nitrogen) μg/dL 0.7139 μmol/L
Bicarbonate mEq/L 1 mmol/L
Bilirubin mg/dL 17.1 μmol/L
Calcium mg/dL 0.2495 mmol/L
Calcium ion mEq/L 0.50 mmol/L
Carotenes μg/dL 0.01836 μmol/L
Ceruloplasmin mg/dL 10.0 mg/L
Chloride mEq/L 1 mmol/L
Cholesterol mg/dL 0.02586 mmol/L
Complement, C3 or C4 mg/dL 0.01 g/L
Copper μg/dL 0.1574 μmol/L
Cortisol μg/dL 27.59 nmol/L
Creatine mg/dL 76.25 μmol/L
Creatinine mg/dL 88.40 μmol/L
Digoxin ng/mL 1.281 nmol/L
Epinephrine pg/mL 5.458 pmol/L
Fatty acids mg/dL 10.0 mg/L
Ferritin ng/mL 1 μg/L
α-Fetoprotein ng/mL 1 μg/L
Fibrinogen mg/dL 0.01 g/L
Folate ng/mL 2.266 nmol/L
Fructose mg/dL 0.05551 mmol/L
Galactose mg/dL 0.05551 mmol/L
Gases
Po2 mm Hg (= torr) 0.1333 kPa
Pco2 mm Hg (= torr) 0.1333 kPa
Glucagon pg/mL 1 ng/L
Glucose mg/dL 0.05551 mmol/L
Glycerol mg/dL 0.1086 mmol/L
Growth hormone ng/mL 1 μg/L
Haptoglobin mg/dL 0.01 g/L
Hemoglobin g/dL 10 g/L
Insulin μg/L 172.2 pmol/L
mU/L 7.175 pmol/L
Iron μg/dL 0.1791 μmol/L
Iron-binding capacity μg/dL 0.1791 μmol/L
Lactate mEq/L 1 mmol/L
Lead μg/dL 0.04826 μmol/L
Lipoproteins mg/dL 0.02586 mmol/L
Magnesium mg/dL 0.4114 mmol/L
mEq/L 0.50 mmol/L
Osmolality mOsm/kg H2O 1 mmol/kg H2O
Phenobarbital mg/dL 43.06 μmol/L
APPENDIX E Conversion Charts 597
Table E-2. Conversion to International System (SI) Units—cont’d
Component Conventional Unit × Conversion Factor = SI Unit

Phenytoin mg/L 3.964 μmol/L
Phosphate mg/dL 0.3229 mmol/L
Potassium mEq/L 1 mmol/L
mg/dL 0.2558 mmol/L
Protein g/dL 10.0 g/L
Pyruvate mg/dL 113.6 μmol/L
Sodium ion mEq/L 1 mmol/L
Steroids
17-hydroxycorticosteroids mg/24 hr 2.759 μmol/day
17-ketosteroids mg/24 hr 3.467 μmol/day
Testosterone ng/mL 3.467 nmol/L
Theophylline mg/L 5.550 μmol/L
THYROID TESTS
Thyroid-stimulating hormone μU/mL 1 mU/L
Thyroxine (T4) μg/dL 12.87 nmol/L
Thyroxine free ng/dL 12.87 pmol/L
Triiodothyronine (T3) ng/dL 0.01536 nmol/L
Transferrin mg/dL 0.01 g/L
Triglycerides mg/dL 0.01129 mmol/L
Urea nitrogen mg/dL 0.3570 mmol/L
Uric acid (urate) mg/dL 59.48 μmol/L
Vitamin A (retinol) μg/dL 0.03491 μmol/L
Vitamin B12 pg/mL 0.7378 pmol/L
Vitamin C (ascorbic acid) mg/dL 56.78 μmol/L
Vitamin D
Cholecalciferol μg/mL 2.599 nmol/L
25 OH-cholecalciferol ng/mL 2.496 nmol/L
Vitamin (Eα-tocopherol) mg/dL 23.22 μmol/L
d-Xylose mg/dL 0.06661 mmol/L
Zinc μg/dL 0.1530 μmol/L
ENERGY kcal (kilocalorie) 4.1868 kJ (kilojoule)
BLOOD PRESSURE mm Hg (= torr) 1.333 mbar
Modified from Young DS: Implementation of SI units for clinical laboratory data. Style specifications and
conversion tables, Ann Intern Med 106:114, 1987.
RBC, Red blood cell.
598 APPENDIX E Conversion Charts
Pco2 Po2 Blood Plasma Plasma Serum

Pressure
glucose urea creatinine bilirubin
400 500
20.0 150 25 450 11.0 13.0
50 50 300 220
19.0 400
140 20 40 250
350 350 900 12.0
18.0 10.0 200
45 130 300 200
17.0 30
15 11.0
16.0 120 250 25 150 800 9.0 180
40 300
15.0 200 20 10.0
110
14.0 10 100 700 8.0 160
35 100 9 15 90 9.0
250 13.0 8 150 80
70 7.0 140
12.0 90 7 600 8.0
mg/100 mL
10 60
mg/100 mL
mg/100 mL
mg/100 mL
30
mm Hg
11.0 6 9
kPa
mmol/L
6.0
µmol /L
80 100 8 50 120 7.0
mmol/L
200
µmol/L
mm Hg
10.0 5 90 7 500
25 70 40
80
kPa
9.0 6 5.0 6.0

4 70 100
8.0 60 5 30 400
20 150 60
4.0 5.0
7.0 3 4 80
50 50
6.0 20 300
15 3 4.0
100 40 40 3.0 60
5.0
2 3.0
10 4.0 30 200
30 2 2.0
3.0 40
50 20 10 2.0
5 2.0 100 1.0
10 20 1.0
1.0 20
0 0 1 1 0 0
0.133 0.0555 0.166 0 88.4 0
0.133
17.1
Figure E-1. Conversion chart for pressure, gases, and selected blood chemistry values. Shading indicates the normal
range where appropriate. To convert from an old (conventional) unit (right side of each scale) to a new (SI) unit (left side of
each scale), multiply by the conversion factor at the foot of each column. (Modified from Halliday HL, McClure G, Reid
M: Handbook of neonatal intensive care, ed 2, Philadelphia, 1985, Saunders.)
F
Selected Radiology
of the Newborn
Sheila C. Berlin
Figure F-1. Newborn chest radiograph showing normal findings.
A B
Figure F-2. The thymus. A, Absent thymus. B, Thymus (arrows).
All figures courtesy of Sheila Berlin, MD.
599
600 APPENDIX F Selected Radiology of the Newborn
Figure F-3. Pulmonary hypoplasia accompanied by a bell-shaped thorax.
A B
Figure F-4. Transient tachypnea of the newborn. Initial chest radiography demonstrates increased interstitial and
alveolar opacity that clears by 48 hours of age. A, Radiograph at 4 hours of age. B, Radiograph at 48 hours of age.
APPENDIX F Selected Radiology of the Newborn 601
A B
Figure F-5. Respiratory distress syndrome. Chest radiography demonstrates diffuse reticulogranular opacity that improves
following surfactant therapy. A, Air bronchograms and bilateral symmetric lung consolidation (“white out”) before treatment
with surfactant. B, Improved aeration following surfactant administration.
Figure F-6. Pulmonary interstitial emphysema. Note the Figure F-7. Chronic lung disease/bronchopulmonary
characteristic tortuous tubular and cystic lucencies. dysplasia. Coarse reticular disease and hyperinflation are
present.
A B
Figure F-8. Congestive heart failure before and after treatment with furosemide (Lasix). Bilateral alveolar infiltrates improve
with treatment. A, Before furosemide. B, After furosemide.
Figure F-9. Neonatal pneumonia. Bilateral interstitial Figure F-10. Meconium aspiration syndrome with
and alveolar infiltrates as well as fluid in the minor fissure pneumothorax. Bilateral asymmetric alveolar infiltrates as
are present. well as right pneumothorax (arrow) are noted.
Figure F-12. Pneumomediastinum with air tracking into

neck (arrows). Characteristic elevation of both lobes of the
thymus (t) is noted.
Figure F-11. Congenital diaphragmatic hernia. Note
bowel in left chest with mediastinum shifted to right.
A B
Figure F-13. Pneumothorax. A, Hyperlucency of the right lower hemithorax. B, Cross-table lateral view demonstrating a
pneumothorax with absence of lung markings between the anterior margin of the lung (arrows) and chest wall.
A B
Figure F-14. Tension pneumothorax. A, Note mediastinal shift and compressive atelectasis of the left lung. B, The
mediastinum returns to midline with effective decompression.
Figure F-15. Pneumoretroperitoneum. Note outline of the right kidney (K) and adrenal gland (a) by retroperitoneal air.
A B
Figure F-16. Necrotizing enterocolitis. A, Note pneumatosis intestinalis and portal venous gas. B, Note pneumatosis
intestinalis and free air under the liver.
Figure F-17. Necrotizing enterocolitis with perforation. Figure F-18. Malrotation of bowel. Spot film from an
Cross-table lateral view shows free air over the anterior upper gastrointestinal series shows a high grade of
margin of the liver. obstruction and a duodenal-jejunal junction to the right of
midline and far below the pylorus.
A B
Figure F-19. Distal bowel obstruction. A, The bowel loops are elongated and appeared “stacked.” B, Contrast enema confirms
a small left colon.
Figure F-20. Esophageal atresia with fistula. Note Figure F-21. Esophageal atresia without fistula. Note tip
nasogastric tube coiled at obstruction (arrow) and air in the of nasogastric tube at the level of the esophageal pouch
stomach and bowel from a tracheoesophageal fistula. (asterisk) and gasless abdomen.
Figure F-22. Imperforate anus. Dilated bowel loops Figure F-24. Total anomalous pulmonary venous return
suggest a distal obstruction. No gas overlies the rectum. (infracardiac). There is interstitial edema with pleural
effusions. Note characteristic normal-sized heart.
Figure F-23. Tetralogy of Fallot. Boot-shaped heart

reflects hypoplasia of the main pulmonary artery segment
(arrow) and right ventricular hypertrophy (asterisk). Vascular
markings are decreased.

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Avroy A.

Fanaroff, MD, FRCP, FRCPCH

Jonathan M. Fanaroff, MD, JD

KLAUS & FANAROFF’S CARE OF THE HIGH-RISK NEONATE ISBN: 978-1-4160-4001-9

Library of Congress Cataloging-in-Publication Data

Senior Content Strategist: Stefanie Jewell-Thomas

Printed in the United States

Last digit is the print number: 9 8 7 6 5 4 3 2 1

David H. Adamkin, MD Waldemar A. Carlo, MD

Jonathan M. Fanaroff, MD, JD David N. Kenagy, MD

Tina A. Leone, MD M. Jeffrey Maisels, MB, BCh, DSc

Paula G. Radmacher, MSPH, PhD Philip T. Thrush, MD

Roya L. Rezaee, MD, FACOG Michael R. Uhing

Phil Steer, Bsc, MD, FRCOG Deanne Wilson-Costello, MD

Michael Caplan, MD Jonathan Hellmann, MBBCh,

THE EVOLUTION OF EVIDENCE- A PRESCRIPTION FOR EVIDENCE-

 Steps in the Practice of Evidence- superior to ampicillin in the treatment of

Table 1-1. The GRADE System

Study Design Quality of Evidence Lower/Higher Level of Quality if:

CHAPTER 1 EVIDENCE-BASED MEDICINE AND THE ROLE OF NETWORKS

CHAPTER 1 EVIDENCE-BASED MEDICINE AND THE ROLE OF NETWORKS

Table prepared by N. Newman BA, RN, from data at neonatal.rti.org/studies.cfm.

Maternal lifestyles study

Observational trial Ongoing

Pierre Budin, The Nursling

Preparations can be made for certain medi-

Table 2-1. Scoring System* for Risk of Preterm Delivery

Socioeconomic Status Past History Daily Habits

Table 2-3. Common Teratogens

Type of Teratogen Agent Defect

Table 2-4. Viral-Induced Teratogenesis and Selected Fetal Infections

Agent Observed Effects Exposure Risk

of non–African-American women. Finally, seen with prenatal surgery. A composite

twin-to-twin transfusion syndrome (TTTS), acardiac twins. Acardia is lethal in the

in the nonpresenting twin. It seems that optimal management is unclear. As with

When fetal growth is restricted, however,

Reactivity Terms Criteria

AST, Acoustic stimulation test; NST, nonstress test.

jeopardy. The CST evaluates uteroplacental

Table 2-6. Technique of Biophysical Profile Scoring

Biophysical Variable Normal (score = 2) Abnormal (score = 0)

during the standard NST. Because reactivity is Fetal Biophysical Profile

Doppler Velocimetry the heritable disorders of the fetus, diagno-

is that FHR patterns reflect states of hypox- presence of decelerations.42 Complications

Table 2-7. 2008 Electronic Fetal Monitoring Definitions

Three-Tiered Fetal Heart Rate FHR 180

Category III (beats/min) 100

Adapted from Macones GA, Hankins GD, Spong CY,

Planning Care of the High-Risk findings of an intrapartum origin that are

Box 2-6. An Overview of Fetal Therapy Criteria for the Diagnosis

minimal to no benefit or conflicting results hemorrhage, neonatal infection, and neo-

Normal Weight and Obesity macrosomia, defined as weight greater than

in women with pregestational diabetes is However, universal consensus on the diag-

Table 2-9. Clinical Status of Diabetes: Timing of Assessments

restriction or multiple gestation).

EDITORIAL COMMENT: Many studies confirm the

Preterm birth <37 weeks (%)

Medically indicated Spontaneous preterm birth

maternal reproductive history, and charac- unpredictable, and no threshold of contrac-

KLAUS & FANAROFF’S CARE OF THE HIGH-RISK NEONATE ISBN: 978-1-4160-4001-9

Steps in the Practice of Evidence- superior to ampicillin in the treatment of

Three-Tiered Fetal Heart Rate FHR 180

Planning Care of the High-Risk findings of an intrapartum origin that are

Box 2-6. An Overview of Fetal Therapy Criteria for the Diagnosis

Normal Weight and Obesity macrosomia, defined as weight greater than

Box 3-1. Risk Factors Related to Resuscitation at Birth

Box 4-1. Review of Obstetric and Perinatal History

the stabilization, transport, and ongo- actation counseling needs to be available

to deliver a growth-restricted baby, even if Effect of Chronic Hypertension

Incidence of Respiratory fetal growth restriction in infants >32 weeks’