Acog

HYPERTENSION
IN PREGNANCY
Hypertension in Pregnancy was developed by the Task Force on
Hypertension in Pregnancy. The information in Hypertension in
Pregnancy should not be viewed as a body of rigid rules. The guidelines
are general and intended to be adapted to many different situations,
taking into account the needs and resources particular to the locality,
the institution, or the type of practice. Variations and innovations that
improve the quality of patient care are to be encouraged rather than
restricted. The purpose of these guidelines will be well served if they
provide a firm basis on which local norms may be built.
Library of Congress Cataloging-in-Publication Data
American College of Obstetricians and Gynecologists. Task Force on Hypertension in
Pregnancy, author.
Hypertension in pregnancy / developed by the Task Force on Hypertension in Pregnancy.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-934984-28-4
I. American College of Obstetricians and Gynecologists, issuing body. II. Title.
[DNLM: 1. Hypertension, Pregnancy-InducedPractice Guideline. WQ 244]
RG575.5
618.3'6132dc23
2013022521
Copyright 2013 by the American College of Obstetricians and Gynecologists,

409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920. All rights
reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted, in any form or by an means, electronic, mechanical,
photocopying, recording, or otherwise, without prior written permission from
the publisher.
12345/76543
Contents
Task Force on Hypertension in Pregnancy v
Endorsements vii
Foreword ix
Executive Summary 1
Chapter 1: Classification of Hypertensive Disorders 13
PreeclampsiaEclampsia 13
Chronic Hypertension 14
Chronic Hypertension With Superimposed Preeclampsia 14
Gestational Hypertension 14
Postpartum Hypertension 15
Chapter 2: Establishing the Diagnosis of Preeclampsia and Eclampsia 17
Preeclampsia 17
Eclampsia 19
Chapter 3: Prediction of Preeclampsia 21
Definition of an Ideal Predictive Test 21
Epidemiology of and Risk Factors for Preeclampsia 21
Prediction of Preeclampsia Using Uterine Artery Doppler Velocimetry 22
Prediction of Preeclampsia Using Biomarkers 22
Prediction of Adverse Outcomes in Patients With Gestational Hypertension and
Preeclampsia 23
Clinical Considerations 23
Chapter 4: Prevention of Preeclampsia 27
Antiplatelet Agents 27
Antioxidant Supplementation With Vitamin C and Vitamin E 28
Other Nutritional Interventions 28
iii
iv
CONTENTS
Dietary Salt Intake 29
Lifestyle Modifications 29
Chapter 5: Management of Preeclampsia and HELLP Syndrome 31
Antepartum Management 31
Intrapartum Management 34
Severe Preeclampsia 36
Route of Delivery in Preeclampsia 40
Eclampsia 40
HELLP Syndrome 41
Anesthetic Considerations 42
Postpartum Hypertension and Preeclampsia 43
Chapter 6: Management of Women With Prior Preeclampsia 47
Preconception Management 47
Antepartum Management 49
Chapter 7: Chronic Hypertension in Pregnancy and Superimposed Preeclampsia 51
Chronic Hypertension in Pregnancy 51
Superimposed Preeclampsia 61
Management of Women With Chronic Hypertension in the Postpartum Period 65
Chapter 8: Later-Life Cardiovascular Disease in Women With Prior Preeclampsia
71
Chapter 9: Patient Education 73
Importance of Patient Education 73
Patient Education Strategies 74
Patient Education Barriers 75
Chapter 10: State of the Science and Research Recommendations 79
Fundamental Advances in the Understanding of Preeclampsia 79
Summary of Fundamental Research Recommendations by the Task Force 83
Task Force on Hypertension in Pregnancy
James M. Roberts, MD, Chair
Maurice Druzin, MD
Investigator Magee-Womens Research Institute
Professor of Obstetrics and Gynecology and
Professor, Department of Obstetrics, Gynecology and
Maternal-Fetal Medicine
Reproductive Sciences, Epidemiology and Clinical
Stanford University
Translational Research
Stanford, CA
University of Pittsburgh
Robert R. Gaiser, MD
Pittsburgh, PA
Professor of Anesthesiology and Critical Care
Phyllis A. August, MD, MPH
University of Pennsylvania
Professor of Medicine in Obstetrics and Gynecology
Philadelphia, PA
New York Presbyterian
Joey P. Granger, PhD
Weill Cornell Physicians
Billy S. Guyton Distinguished Professor
New York, NY
Professor of Physiology and Medicine
George Bakris, MD
Director, Center for Excellence in Cardiovascular-
Professor of Medicine
Renal Research
Director, Comprehensive Hypertension Center
Dean, School of Graduate Studies in Health Sciences
University of Chicago
University of Mississippi Medical Center
Chicago, IL
Jackson, MS
John R. Barton, MD
Arun Jeyabalan, MD, MS
Director, Maternal-Fetal Medicine
Associate Professor, Department of Obstetrics,
Baptist Health Lexington
Gynecology and Reproductive Sciences
Lexington, KY
University of Pittsburgh
Pittsburgh, PA
Ira M. Bernstein, MD
John VanSicklen Maeck Professor and Chair
Donna D. Johnson, MD
Department of Obstetrics, Gynecology and
Lawrence L. Hester Professor and Chair
Reproductive Sciences
Department of Obstetrics and Gynecology
Senior Associate Dean for Research
Medical University of South Carolina
University of Vermont
Charleston, SC
Burlington, VT
v
vi
TASK FORCE ON HYPERTENSION IN PREGNANCY
S. Ananth Karumanchi, MD
Catherine Y. Spong, MD
Associate Professor of Medicine
Director, Extramural Research
Beth Israel Deaconess Medical Center
Eunice Kennedy Shriver National Institute of Child
Harvard Medical School
Health and Human Development, National
Boston, MA
Institutes of Health
Bethesda, MD
Marshall D. Lindheimer, MD
Professor Emeritus, Departments of Obstetrics &
Eleni Tsigas
Gynecology, Medicine, and Committee on Clinical
Executive Director
Pharmacology and Pharmacogenomics
Preeclampsia Foundation
University of Chicago
Melbourne, FL
Chicago, IL
James N. Martin Jr, MD
Michelle Y. Owens, MD, MS
Ex Officio Task Force Member
Associate Professor
Past President, American College of Obstetricians
Vice-Chair of Obstetrics and Gynecology
and Gynecologists and American Congress of
Obstetricians and Gynecologists (20112012)
Jackson, MS
Vice Chair, Research and Academic Development
Director, Division of Maternal-Fetal Medicine
George R. Saade, MD
Professor, Department of Obstetrics and Gynecology
Jackson, MS
Director, Division of Maternal-Fetal Medicine
University of Texas Medical Branch
American College of Obstetricians and Gynecologists
Galveston, TX
Staff
Gerald F. Joseph Jr, MD, Vice President of Practice
Baha M. Sibai, MD
Activities
Professor, Department of Obstetrics, Gynecology and
Nancy OReilly, MHS
Reproductive Sciences
Alyssa Politzer
University of Texas Health Science Center
Sarah Son, MPH
Houston, TX
Karina Ngaiza
Conflict of Interest Disclosures
The following task force members reported no financial relationships or potential
conflicts of interest to disclose: James M. Roberts, MD; Ira M. Bernstein, MD; Maurice Druzin,
MD; Robert R. Gaiser, MD; Joey P. Granger, PhD;
Arun Jeyabalan, MD; Donna D. Johnson, MD; Marshall Lindheimer, MD; Michelle Y.
Owens, MD, MS;
George R. Saade, MD; Catherine Y. Spong, MD; and Eleni Tsigas.

George Bakris, MD, has Investigator Initiated grants from Takeda and CVRx paid
directly to the University
of Chicago. He received a salary for being National Clinical Trial Principal Investigator
for Medtronic (15%), Relypsa (15%) (the percentage is salary support.) He is a consultant for
Takeda, Abbott, CVRx, Johnson&
Johnson, Eli Lilly, Daichi-Sankyo, Boerhinger-Ingelheim, and the U.S. Food and Drug
Administration. He is an
editor for the American Journal of Nephrology and the Hypertension section of
UpToDate, and an associate editor for Diabetes Care and Nephrology Dialysis and
Transplantation. John R. Barton, MD, provides research support
to Alere and Beckman Coulter. S. Ananth Karumanchi, MD, has served as consultant to
Beckman Coulter, Roche
and Siemens; has a financial interest in Aggamin Therapeutics LLC, Co; and is an
inventor on patents related to preeclampsia biomarkers held by Beth Israel Deaconess Medical
Center. Baha M. Sibai, MD, is a consultant
for Alere Womens Health who is investigating a biomarker for preeclampsia.
Endorsements
The following professional organizations have reviewed, endorsed, and support this
report:
American Academy of Physician Assistants
American Academy of Neurology*
American College of Occupational and Environmental Medicine
American Optometric Association
American Osteopathic Association
American Society of Hypertension
Preeclampsia Foundation
Society for Maternal-Fetal Medicine
* The American Academy of Neurology has affirmed the value of this report. Please see
the American Academy of Neurology Guideline Endorsement Policy for further information.
vii
Foreword
Hypertensive disorders of pregnancy, including pre Preeclampsia is a risk factor for future cardiovascueclampsia, complicate up to 10% of pregnancies
lar disease and metabolic disease in women.
worldwide, constituting one of the greatest causes of
Despite considerable research, the etiology of prematernal and perinatal morbidity and mortality
eclampsia remains unclear.
worldwide. In early 2011, as the 62nd President Elect
of the American College of Obstetricians and Gyne Within the past 10 years, substantial advances in
cologists (the College) and the American Congress of
the understanding of preeclampsia pathophysiology
Obstetricians and Gynecologists, I decided to make

as well as increased efforts to obtain evidence to
this issue a Presidential Initiative for the following
guide therapy have emerged. However, this inforreasons:
mation has not translated into improved clinical
practice.
The incidence of preeclampsia has increased by
25% in the United States during the past two New best practice recommendations are
greatly
decades (1).
needed to guide clinicians in the care of women
with all forms of preeclampsia and hypertension
Preeclampsia is a leading cause of maternal and
that occur during pregnancy, particularly women
perinatal morbidity and mortality, with an estimated
with acute severe hypertension and superimposed
50,00060,000 preeclampsia-related deaths per
preeclampsia. Also needed is a system for continuyear worldwide (2, 3).
ally updating these guidelines and integrating them
For every preeclampsia-related death that occurs
into daily obstetric practice.
in the United States, there are probably 50100
Identification of patients with severe forms of preother women who experience near miss signifieclampsia continues to challenge clinicians.
cant maternal morbidity that stops short of death
but still results in significant health risk and health
Improved patient education and counseling stratecare cost (4, 5).
gies are needed to convey more effectively the
dangers of preeclampsia and hypertension and the
What can be considered less-than-optimal" care of
importance of early detection to women with varypatients with preeclampsia and other hypertensive
ing degrees of health literacy.
disorders of pregnancy reportedly occurs with some
frequency worldwide, contributing to maternal and
Research on preeclampsia and other hypertensive
perinatal injury that might have been avoidable (6).
disorders of pregnancy in both the laboratory and
clinical arenas requires continued emphasis and
Hypertensive disorders of pregnancy are major
funding.
contributors to prematurity.
ix
x
FOREWORD
To address these important issues, the Task Force
In addition, I would like to give special thanks to
on Hypertension in Pregnancy, composed of 17 experts
Dr. James M. Roberts of the University of Pittsburghs
in the fields of obstetrics, maternalfetal medicine,
Magee-Womens Research Institute for his superb
hypertension, internal medicine, nephrology, anestheleadership of the task force and to Nancy OReilly,
siology, physiology, and patient advocacy, was created
Senior Director of Practice Bulletins, and Dr. Gerald F.
and charged with three tasks: 1) summarize the curJoseph Jr, Vice President of Practice Activities, at the
rent state of knowledge about preeclampsia and other
College for their support throughout the process.
hypertensive disorders in pregnancy by reviewing and
Efforts are now underway to achieve global consengrading the quality of the extant world literature;
sus on best practice guidelines for the diagnosis and
2) translate this information into practice guidelines management of preeclampsia and
other hypertensive
for health care providers who treat obstetric patients
disorders of pregnancy. It is my fervent hope that the
affected by these disorders; and 3) identify and prioriwork of the Task Force on Hypertension in Pregnancy
tize the most compelling areas of laboratory and cliniserves as a springboard to these efforts and ultimately
cal research to bridge gaps in our current knowledge.
translates into improved obstetric care for patients
Members of the task force met three times over 9 with preeclampsia and other
hypertensive disorders of
months during 2011 and 2012 at the College headpregnancy in this country and throughout the world.
quarters in Washington, DC. They spent countless
additional hours writing and deliberating to achieve James N. Martin Jr, MD
consensus on the practice recommendations that folImmediate Past President
low in the Executive Summary.
The American College of Obstetricians and Gynecologists
I am deeply grateful to each member of the Task
20122013
Force on Hypertension in Pregnancy for their hard The American Congress of
Obstetricians and Gynecologists
work and dedication to this important endeavor. 20122013

References
1. Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in
4. Callaghan WM, Mackay AP, Berg CJ. Identification of
the rates of preeclampsia, eclampsia, and gestational hypersevere maternal morbidity during delivery hospitalizatension, United States, 19872004. Am J Hypertens
tions, United States, 19912003. Am J Obstet Gynecol
2008;21:5216. [PubMed] ^
2008;199:133.e18. [PubMed] [Full Text] ^
2. World Health Organization. The world health report:
5. Kuklina EV, Ayala C, Callaghan WM. Hypertensive disor2005: make every mother and child count. Geneva: WHO;
ders and severe obstetric morbidity in the United States.
2005. Available at: http://www.who.int/whr/2005/whr
Obstet Gynecol 2009;113:1299306. [PubMed] [Obstet2005_en.pdf. Retrieved March 20, 2013.
rics & Gynecology] ^
3. Duley L. Maternal mortality associated with hypertensive
6. van Dillen J, Mesman JA, Zwart JJ, Bloemenkamp KW,
disorders of pregnancy in Africa, Asia, Latin America and
van Roosmalen J. Introducing maternal morbidity audit
the Caribbean. Br J Obstet Gynaecol 1992;99:54753.
in the Netherlands. BJOG2010;117:41621. [PubMed]
[PubMed] ^
[Full Text] ^
Executive Summary
The American College of Obstetricians and ill. Optimal management requires close
observation
Gynecologists (the College) convened a task
for signs and premonitory findings and, after establishforce of experts in the management of hypering the diagnosis, delivery at the optimal time for both
tension in pregnancy to review available data
maternal and fetal well-being. More recent clinical eviand publish evidence-based recommendations for clindence to guide this timing is now available. Chronic
ical practice. The Task Force on Hypertension in Preghypertension is associated with fetal morbidity in the
nancy comprised 17 clinicianscientists from the fields
form of growth restriction and maternal morbidity
of obstetrics, maternalfetal medicine, hypertension,
manifested as severely increased blood pressure (BP).
internal medicine, nephrology, anesthesiology, physiHowever, maternal and fetal morbidity increase draology, and patient advocacy. This executive summary
matically with the superimposition of preeclampsia.

includes a synopsis of the content and task force recOne of the major challenges in the care of women with
ommendations of each chapter in the report and is inchronic hypertension is deciphering whether chronic
tended to complement, not substitute, the report.
hypertension has worsened or whether preeclampsia
Hypertensive disorders of pregnancy remain a has developed. In this report, the task force
provides
major health issue for women and their infants in the
suggestions for the recognition and management of
United States. Preeclampsia, either alone or superimthis challenging condition.
posed on preexisting (chronic) hypertension, presents
In the past 10 years, there have been substantial
the major risk. Although appropriate prenatal care,
advances in the understanding of preeclampsia as well
with observation of women for signs of preeclampsia
as increased efforts to obtain evidence to guide therapy.
and then delivery to terminate the disorder, has
Nonetheless, there remain areas on which evidence is
reduced the number and extent of poor outcomes,
scant. The evidence is now clear that preeclampsia is
serious maternalfetal morbidity and mortality still associated with later-life
cardiovascular (CV) disease; occur. Some of these adverse outcomes are avoidable,
however, further research is needed to determine how
whereas others can be ameliorated. Also, although
best to use this information to help patients. The task
some of the problems that face neonates are related
force also has identified issues in the management of
directly to preeclampsia, a large proportion are secpreeclampsia that warrant special attention. First, is
ondary to prematurity that results from the approprithe failure by health care providers to appreciate the
ate induced delivery of the fetuses of women who are
multisystemic nature of preeclampsia. This is in part
1
2
EXECUTIVE SUMMARY
due to attempts at rigid diagnosis, which is addressed
based on the values and judgment and underlying
in the report. Second, preeclampsia is a dynamic prohealth condition of a particular patient in a particular
cess, and a diagnosis such as mild preeclampsia
situation.
(which is discouraged) applies only at the moment the

diagnosis is established because preeclampsia by Classification of Hypertensive
Disorders
nature is progressive, although at different rates.
Appropriate management mandates frequent reevaluof Pregnancy
ation for severe features that indicate the actions outThe task force chose to continue using the classification
lined in the recommendations (which are listed after
schema first introduced in 1972 by the College and
the chapter summaries). It has been known for many
modified in the 1990 and 2000 reports of the Working
years that preeclampsia can worsen or present for the
Group of the National High Blood Pressure Education
first time after delivery, which can be a major scenario
Program. Similar classifications can be found in the
for adverse maternal events. In this report, the task
American Society of Hypertension guidelines, as well
force provides guidelines to attempt to reduce materas College Practice Bulletins. Although the task force
nal morbidity and mortality in the postpartum period.
has modified some of the components of the classification, this basic, precise, and practical classification was
The Approach
used, which considers hypertension during pregnancy
in only four categories: 1) preeclampsiaeclampsia,
The task force used the evidence assessment and rec2) chronic hypertension (of any cause), 3) chronic
ommendation strategy developed by the Grading of hypertension with superimposed
preeclampsia, and
Recommendations Assessment, Development and
4) gestational hypertension. Importantly, the followEvaluation (GRADE) Working Group (available at www.
ing components were modified. In recognition of the
gradeworkinggroup.org/index.htm). Because of its
syndromic nature of preeclampsia, the task force has
utility, this strategy has been adapted worldwide by a
eliminated the dependence of the diagnosis on prolarge number of organizations. With the GRADE Workteinuria. In the absence of proteinuria, preeclampsia is
ing Group approach, the function of expert task forces
diagnosed as hypertension in association with thromand working groups is to evaluate the available evibocytopenia (platelet count less than 100,000/microlidence regarding a clinical decision that, because of limter), impaired liver function (elevated blood levels of
ited time and resources, would be difficult for the

liver transaminases to twice the normal concentraaverage health care provider to accomplish. The expert
tion), the new development of renal insufficiency (elegroup then makes recommendations based on the evivated serum creatinine greater than 1.1 mg/dL or a
dence that are consistent with typical patient values doubling of serum creatinine in the
absence of other
and preferences. The task force evaluated the evidence
renal disease), pulmonary edema, or new-onset cerefor each recommendation, the implications, and the
bral or visual disturbances (see Box E-1). Gestational
confidence in estimates of effect. With this combination,
hypertension is BP elevation after 20 weeks of gestathe available information was evaluated and recomtion in the absence of proteinuria or the aforemenmendations were made. In this report, the confidence
tioned systemic findings, chronic hypertension is
in estimates of effect (quality) of the available evidence
hypertension that predates pregnancy, and superimis judged as very low, low, moderate, or high.
posed preeclampsia is chronic hypertension in associaRecommendations are practices agreed to by the tion with preeclampsia.
task force as the most appropriate course of action;
they are graded as strong or qualified. A strong recomEstablishing the Diagnosis of
mendation is one that is so well supported that it
would be the approach appropriate for virtually all Preeclampsia or Eclampsia
patients. It could be the basis for health care policy. A
The BP criteria are maintained from prior recommendaqualified recommendation is also one that would be
tions. Proteinuria is defined as the excretion of 300 mg
judged as appropriate for most patients, but it might
or more of protein in a 24-hour urine collection. Alternot be the optimal recommendation for some patients
natively, a timed excretion that is extrapolated to this
(whose values and preferences differ, or who have dif24-hour urine value or a protein/creatinine ratio of at
ferent attitudes toward uncertainty in estimates of least 0.3 (each measured as mg/dL) is
used. Because of
effect). When the task force has made a qualified recthe variability of qualitative determinations (dipstick
ommendation, the health care provider and patient
test), this method is discouraged for diagnostic use
are encouraged to work together to arrive at a decision
unless other approaches are not readily available. If
EXECUTIVE SUMMARY
3
BOX E-1. Severe Features of Preeclampsia (Any of these findings) ^
Systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm
Hg or higher
on two occasions at least 4 hours apart while the patient is on bed rest (unless
antihypertensive
therapy is initiated before this time)
Thrombocytopenia (platelet count less than 100,000/microliter)
Impaired liver function as indicated by abnormally elevated blood concentrations of
liver enzymes
(to twice normal concentration), severe persistent right upper quadrant or epigastric pain
unresponsive to medication and not accounted for by alternative diagnoses, or both
Progressive renal insufficiency (serum creatinine concentration greater than 1.1 mg/dL
or a doubling
of the serum creatinine concentration in the absence of other renal disease)
Pulmonary edema
New-onset cerebral or visual disturbances
this approach must be used, a determination of 1+ is
or adverse outcomes from preeclampsia in unselected
considered as the cutoff for the diagnosis of proteinwomen at high risk or low risk of preeclampsia. Calciuria. In view of recent studies that indicate a minimal
um may be useful to reduce the severity of preeclamprelationship between the quantity of urinary protein sia in populations with low calcium
intake, but this and pregnancy outcome in preeclampsia, massive pro-finding is not relevant to a
population with adequate
teinuria (greater than 5 g) has been eliminated from
calcium intake, such as in the United States. The
the consideration of preeclampsia as severe. Also,
administration of low-dose aspirin (6080 mg) to prebecause fetal growth restriction is managed similarly
vent preeclampsia has been examined in meta-analyin pregnant women with and without preeclampsia, it
ses of more than 30,000 women, and it appears that
has been removed as a finding indicative of severe prethere is a slight effect to reduce preeclampsia and
eclampsia (Table E-1).
adverse perinatal outcomes. These findings are not
clinically relevant to low-risk women but may be relevant to populations at very high risk in whom the numPrediction of Preeclampsia
ber to treat to achieve the desired outcome will be
A great deal of effort has been directed at the identifi-
substantially less. There is no evidence that bed rest or

cation of demographic factors, biochemical analytes,
salt restriction reduces preeclampsia risk.
or biophysical findings, alone or in combination, to
predict early in pregnancy the later development of TASK FORCE
RECOMMENDATIONS
preeclampsia. Although there are some encouraging For women with a medical history
of early-onset prefindings, these tests are not yet ready for clinical use.
eclampsia and preterm delivery at less than 34 0/7
weeks of gestation or preeclampsia in more than
TASK FORCE RECOMMENDATION
one prior pregnancy, initiating the administration of
daily low-dose (6080 mg) aspirin beginning in the
Screening to predict preeclampsia beyond obtainlate first trimester is suggested.*
ing an appropriate medical history to evaluate for
Quality of evidence: Moderate
risk factors is not recommended.
Strength of recommendation: Qualified
*Meta-analysis of more than 30,000 women in randomized
Strength of recommendation: Strong
trials of aspirin to prevent preeclampsia indicates a small
reduction in the incidence and morbidity of preeclampsia
Prevention of Preeclampsia
and reveals no evidence of acute risk, although long-term
fetal effects cannot be excluded. The number of women to
treat to have a therapeutic effect is determined by prevaIt is clear that the antioxidants vitamin C and vitamin E
lence. In view of maternal safety, a discussion of the use of
are not effective interventions to prevent preeclampsia
aspirin in light of individual risk is justified.
4
EXECUTIVE SUMMARY
TABLE E-1. Diagnostic Criteria for Preeclampsia ^
Blood pressure
Greater than or equal to 140 mm Hg systolic or greater than or equal to 90 mm Hg
diastolic on two occasions at least 4 hours apart after 20 weeks of gestation in a
woman with a previously normal blood pressure
diastolic, hypertension can be confirmed within a short interval (minutes) to facilitate
timely antihypertensive therapy
and
Proteinuria
Greater than or equal to 300 mg per 24-hour urine collection (or this amount
extrapolated from a timed collection)
or
Protein/creatinine ratio greater than or equal to 0.3*
Dipstick reading of 1+ (used only if other quantitative methods not available)
Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the
following:
Thrombocytopenia
Platelet count less than 100,000/microliter
Renal insufficiency
Serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum
creatinine concentration in the absence of other renal disease
Impaired liver function Elevated blood concentrations of liver transaminases to twice
normal concentration Pulmonary edema
Cerebral or visual
symptoms
* Each measured as mg/dL.
The administration of vitamin C or vitamin E to deaths could be avoided if health care
providers remain
prevent preeclampsia is not recommended.
alert to the likelihood that preeclampsia will progress.
Quality of evidence: High
The same reviews indicate that intervention in acutely
ill women with multiple organ dysfunction is sometimes
delayed because of the absence of proteinuria. Further It is suggested that dietary salt not be restricted durmore, accumulating information indicates that the
ing pregnancy for the prevention of preeclampsia.
amount of proteinuria does not predict maternal or fetal
Quality of evidence: Low
outcome. It is for these reasons that the task force has
recommended that alternative systemic findings with
new-onset hypertension can fulfill the diagnosis of pre It is suggested that bed rest or the restriction of other
eclampsia even in the absence of proteinuria.
physical activity not be used for the primary prevenPerhaps the biggest changes in preeclampsia mantion of preeclampsia and its complications.
agement relate to the timing of delivery in women
with preeclampsia without severe features, which

based on evidence is suggested at 37 0/7 weeks of gestation, and an increasing awareness of the importance
Management of Preeclampsia
of preeclampsia in the postpartum period. Health care
providers are reminded of the contribution of nonsteand HELLP Syndrome
roidal antiinflammatory agents to increased BP. It is
Clinical trials have provided an evidence base to guide
suggested that these commonly used postpartum pain
management of several aspects of preeclampsia. Nonerelief agents be replaced by other analgesics in women
theless, several important questions remain unanwith hypertension that persists for more than 1 day
swered. Reviews of maternal mortality data reveal that
postpartum.
EXECUTIVE SUMMARY
5
If evidence of fetal growth restriction is found in
TASK FORCE RECOMMENDATIONS
women with preeclampsia, fetoplacental assess The close monitoring of women with gestational
ment that includes umbilical artery Doppler velocihypertension or preeclampsia without severe feametry as an adjunct antenatal test is recommended.
tures, with serial assessment of maternal symptoms
and fetal movement (daily by the woman), serial
measurements of BP (twice weekly), and assessment of platelet counts and liver enzymes (weekly)
For women with mild gestational hypertension or
is suggested.
preeclampsia without severe features and no indication for delivery at less than 37 0/7 weeks of gesQuality of evidence: Moderate
tation, expectant management with maternal and
fetal monitoring is suggested.
For women with gestational hypertension, monitorQuality of evidence: Low
ing BP at least once weekly with proteinuria assessStrength of recommendation: Qualified
ment in the office and with an additional weekly
measurement of BP at home or in the office is sug-

gested.
preeclampsia without severe features at or beyond
37 0/7 weeks of gestation, delivery rather than conQuality of evidence: Moderate
tinued observation is suggested.
preeclampsia with a persistent BP of less than
160 mm Hg systolic or 110 mm Hg diastolic, it is
For women with preeclampsia with systolic BP of
suggested that antihypertensive medications not be
less than 160 mm Hg and a diastolic BP less than
administered.
110 mm Hg and no maternal symptoms, it is suggested that magnesium sulfate not be administered
universally for the prevention of eclampsia.
For women with gestational hypertension or preStrength of recommendation: Qualified
eclampsia without severe features, it is suggested
that strict bed rest not be prescribed.*
For women with severe preeclampsia at or beyond
34 0/7 weeks of gestation, and in those with unQuality of evidence: Low
stable maternal or fetal conditions irrespective of
gestational age, delivery soon after maternal stabili* The task force acknowledged that there may be situations
zation is recommended.
in which different levels of rest, either at home or in the
hospital, may be indicated for individual women. The
previous recommendations do not cover advice regardStrength of recommendation: Strong
ing overall physical activity and manual or office work.
For women with severe preeclampsia at less than
Women may need to be hospitalized for reasons other
than bed rest, such as for maternal and fetal surveillance.
34 0/7 weeks of gestation with stable maternal and
The task force agreed that hospitalization for maternal
fetal conditions, it is recommended that continued
and fetal surveillance is resource intensive and should be

pregnancy be undertaken only at facilities with
considered as a priority for research and future recomadequate maternal and neonatal intensive care
mendations.
resources.
For women with preeclampsia without severe feaQuality of evidence: Moderate
tures, use of ultrasonography to assess fetal growth
and antenatal testing to assess fetal status is suggested.
For women with severe preeclampsia receiving
expectant management at 34 0/7 weeks or less of
gestation, the administration of corticosteroids for
fetal lung maturity benefit is recommended.
6
EXECUTIVE SUMMARY
For women with preeclampsia with severe hyper It is recommended that corticosteroids be given if
tension during pregnancy (sustained systolic BP
the fetus is viable and at 33 6/7 weeks or less of
of at least 160 mm Hg or diastolic BP of at least
gestation, but that delivery not be delayed after ini110 mm Hg), the use of antihypertensive therapy
tial maternal stabilization regardless of gestational
is recommended.
age for women with severe preeclampsia that is
complicated further with any of the following:
uncontrollable severe hypertension
eclampsia
For women with preeclampsia, it is suggested that a
pulmonary edema
delivery decision should not be based on the
abruptio placentae
amount of proteinuria or change in the amount of
disseminated intravascular coagulation
proteinuria.
evidence of nonreassuring fetal status

intrapartum fetal demise
For women with severe preeclampsia and before
fetal viability, delivery after maternal stabilization is
recommended. Expectant management is not rec For women with preeclampsia, it is suggested that
ommended.
the mode of delivery need not be cesarean delivery.
The mode of delivery should be determined by fetal
gestational age, fetal presentation, cervical status,
and maternal and fetal conditions.
It is suggested that corticosteroids be administered
and delivery deferred for 48 hours if maternal and
fetal conditions remain stable for women with
severe preeclampsia and a viable fetus at 33 6/7 For women with eclampsia, the
administration of
weeks or less of gestation with any of the following:
parenteral magnesium sulfate is recommended.
preterm premature rupture of membranes
labor
low platelet count (less than 100,000/microliter)
For women with severe preeclampsia, the adminis persistently abnormal hepatic enzyme concentratration of intrapartumpostpartum magnesium sultions (twice or more the upper normal values)
fate to prevent eclampsia is recommended.
fetal growth restriction (less than the fifth percentile)
severe oligohydramnios (amniotic fluid index
less than 5 cm)
For women with preeclampsia undergoing cesarean
reversed end-diastolic flow on umbilical artery
delivery, the continued intraoperative administraDoppler studies
tion of parenteral magnesium sulfate to prevent

new-onset renal dysfunction or increasing renal
eclampsia is recommended.
dysfunction
For women with HELLP syndrome and before the
gestational age of fetal viability, it is recommended
that delivery be undertaken shortly after initial
maternal stabilization.
EXECUTIVE SUMMARY
7
For women with HELLP syndrome at 34 0/7 weeks
For all women in the postpartum period (not just
or more of gestation, it is recommended that delivwomen with preeclampsia), it is suggested that disery be undertaken soon after initial maternal stabicharge instructions include information about the
lization.
signs and symptoms of preeclampsia as well as the
importance of prompt reporting of this information
to their health care providers.
For women with HELLP syndrome from the gestaStrength of recommendation: Qualified
tional age of fetal viability to 33 6/7 weeks of gestation, it is suggested that delivery be delayed for
For women in the postpartum period who present
24 48 hours if maternal and fetal condition rewith new-onset hypertension associated with headmains stable to complete a course of corticosteroids
aches or blurred vision or preeclampsia with severe
for fetal benefit.*
hypertension, the parenteral administration of magQuality of evidence: Low
nesium sulfate is suggested.
*Corticosteroids have been used in randomized controlled

trials to attempt to improve maternal and fetal condition.
For women with persistent postpartum hypertenIn these studies, there was no evidence of benefit to
improve overall maternal and fetal outcome (although
sion, BP of 150 mm Hg systolic or 100 mm Hg diathis has been suggested in observational studies). There is
stolic or higher, on at least two occasions that are at
evidence in the randomized trials of improvement of
least 46 hours apart, antihypertensive therapy is
platelet counts with corticosteroid treatment. In clinical
suggested. Persistent BP of 160 mm Hg systolic or
settings in which an improvement in platelet count is con110 mm Hg diastolic or higher should be treated
sidered useful, corticosteroids may be justified.
within 1 hour.
For women with preeclampsia who require analgeQuality of evidence: Low
sia for labor or anesthesia for cesarean delivery and
with a clinical situation that permits sufficient time
for establishment of anesthesia, the administration
of neuraxial anesthesia (either spinal or epidural
Management of Women With
anesthesia) is recommended.
Prior Preeclampsia
Women who have had preeclampsia in a prior pregStrength of recommendation: Strong
nancy should receive counseling and assessments
before their next pregnancy. This can be initiated at the
For women with severe preeclampsia, it is suggested
postpartum visit but is ideally accomplished at a prethat invasive hemodynamic monitoring not be used
conception visit before the next planned pregnancy.
routinely.
During the preconception visit, the previous pregnancy
history should be reviewed and the prognosis for the
upcoming pregnancy should be discussed. Potentially
For women in whom gestational hypertension, premodifiable lifestyle activities, such as weight loss and
eclampsia, or superimposed preeclampsia is diagincreased physical activity, should be encouraged. The
nosed, it is suggested that BP be monitored in the
current status of medical problems should be assessed,

hospital or that equivalent outpatient surveillance including laboratory evaluation if
appropriate. Medical
be performed for at least 72 hours postpartum and
problems such as hypertension and diabetes should be
again 710 days after delivery or earlier in women
brought into the best control possible. The effect of
with symptoms.
medical problems on the pregnancy should be discussed. Medications should be reviewed and their
administration modified for upcoming pregnancy. Folic
acid supplementation should be recommended. If a
woman has given birth to a preterm infant during a
preeclamptic pregnancy or has had preeclampsia in
more than one pregnancy, the use of low-dose aspirin
in the upcoming pregnancy should be suggested.
8
EXECUTIVE SUMMARY
Women with a medical history of preeclampsia should
be instructed to return for care early in pregnancy. TASK FORCE
RECOMMENDATIONS
During the next pregnancy, early ultrasonography
For women with features suggestive of secondary
should be performed to determine gestational age, and
hypertension, referral to a physician with expertise
assessment and visits should be tailored to the prior
in treating hypertension to direct the workup is sugpregnancy outcome, with frequent visits beginning
gested.
earlier in women with prior preterm preeclampsia. The
woman should be educated about the signs and sympStrength of recommendation: Qualified
toms of preeclampsia and instructed when and how to
contact her health care provider.
For pregnant women with chronic hypertension
and poorly controlled BP, the use of home BP monitoring is suggested.
For women with preeclampsia in a prior pregnancy,
preconception counseling and assessment is suggested.
For women with suspected white coat hypertension,

the use of ambulatory BP monitoring to confirm the
diagnosis before the initiation of antihypertensive
therapy is suggested.
Chronic Hypertension and
Superimposed Preeclampsia
It is suggested that weight loss and extremely lowChronic hypertension (hypertension predating pregsodium diets (less than 100 mEq/d) not be used for
nancy), presents special challenges to health care promanaging chronic hypertension in pregnancy.
viders. Health care providers must first confirm that
the BP elevation is not preeclampsia. Once this is estabQuality of evidence: Low
lished, if the BP elevation has not been previously evalStrength of recommendation: Qualified
uated, a workup should be performed to document
For women with chronic hypertension who are
that BP is truly elevated (ie, not white coat hypertenaccustomed to exercising, and in whom BP is well
sion) and to check for secondary hypertension and
controlled, it is recommended that moderate exerend-organ damage. The choice of which women to
cise be continued during pregnancy.
treat and how to treat them requires special considerQuality of evidence: Low
ations during pregnancy, especially in light of emergStrength of recommendation: Qualified
ing data that suggest lowering BP excessively might
have adverse fetal effects.
For pregnant women with persistent chronic hyperPerhaps the greatest challenge is the recognition of
tension with systolic BP of 160 mm Hg or higher or
preeclampsia superimposed on chronic hypertension, a
diastolic BP of 105 mm Hg or higher, antihypertencondition that is commonly associated with adverse
sive therapy is recommended.
maternal and fetal outcomes. Recommendations are
provided to guide health care providers in distinguishStrength of recommendation: Strong
ing women who may have superimposed preeclampsia
without severe features (only hypertension and protein For pregnant women with chronic hypertension
uria) and require only observation from women who
and BP less than 160 mm Hg systolic or 105 mm Hg
may have superimposed preeclampsia with severe feadiastolic and no evidence of end-organ damage, it is
tures (evidence of systemic involvement beyond hypersuggested that they not be treated with pharmacotension and proteinuria) and require intervention.
logic antihypertensive therapy.
EXECUTIVE SUMMARY
9
For pregnant women with chronic hypertension For women with chronic hypertension,
the use of
treated with antihypertensive medication, it is
ultrasonography to screen for fetal growth restricsuggested that BP levels be maintained between
tion is suggested.
120 mm Hg systolic and 80 mm Hg diastolic and
160 mm Hg systolic and 105 mm Hg diastolic.
women with chronic hypertension, fetoplacental as For the initial treatment of pregnant women with
sessment to include umbilical artery Doppler velocichronic hypertension who require pharmacologic
metry as an adjunct antenatal test is recommended.
therapy, labetalol, nifedipine, or methyldopa are
recommended above all other antihypertensive
drugs.
For women with chronic hypertension complicated
by issues such as the need for medication, other
underlying medical conditions that affect fetal
For women with uncomplicated chronic hypertenoutcome, or any evidence of fetal growth restricsion in pregnancy, the use of angiotensin-converting
tion, and superimposed preeclampsia, antenatal

enzyme inhibitors, angiotensin receptor blockers,
fetal testing is suggested.
renin inhibitors, and mineralocorticoid receptor
antagonists is not recommended.
For women with chronic hypertension and no addiStrength of recommendation: Strong
tional maternal or fetal complications, delivery be For women of reproductive age with chronic hyperfore 38 0/7 weeks of gestation is not recommended.
tension, the use of angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers, renin
inhibitors, and mineralocorticoid receptor antagonists is not recommended unless there is a compel For women with superimposed preeclampsia who
ling reason, such as the presence of proteinuric
receive expectant management at less than 34 0/7
renal disease.
weeks of gestation, the administration of corticosteroids for fetal lung maturity benefit is recomQuality of evidence: Low
mended.
For women with chronic hypertension who are at
a greatly increased risk of adverse pregnancy outcomes (history of early-onset preeclampsia and For women with chronic hypertension
and superimpreterm delivery at less than 34 0/7 weeks of
posed preeclampsia with severe features, the admingestation or preeclampsia in more than one prior
istration of intrapartumpostpartum parenteral
pregnancy), initiating the administration of daily
magnesium sulfate to prevent eclampsia is recomlow-dose aspirin (6080 mg) beginning in the late
mended.
first trimester is suggested.*

For women with superimposed preeclampsia with* Meta-analysis of more than 30,000 women in randomized
out severe features and stable maternal and fetal
conditions, expectant management until 37 0/7
weeks of gestation is suggested.
treat to have a therapeutic effect is determined by prevaStrength of recommendation: Qualified
lence. In view of maternal safety, a discussion of the use
of aspirin in light of individual risk is justified.
10
EXECUTIVE SUMMARY
Delivery soon after maternal stabilization is recomyears provide all of the information that would be
mended irrespective of gestational age or full cortigained by knowing a woman had a past preeclamptic
costeroid benefit for women with superimposed
pregnancy? Would it be valuable to perform this
preeclampsia that is complicated further by any of
assessment at a younger age in women who had a
the following:
past preeclamptic pregnancy? If the risk was identi uncontrollable severe hypertension
fied earlier, what intervention (other than lifestyle
eclampsia
modification) would potentially be useful and would
pulmonary edema
it make a difference? Are there risk factors that could
abruptio placentae
be unmasked by pregnancy other than conventional
risk factors? Further research is needed to determine
nonreassuring fetal status
how to take advantage of this information relating
preeclampsia to later-life CV disease. At this time, the
task force cautiously recommends lifestyle modificaStrength of the recommendation: Strong
tion (maintenance of a healthy weight, increased
For women with superimposed preeclampsia with physical activity, and not smoking)
and suggests early
severe features at less than 34 0/7 weeks of gestaevaluation for the most high-risk women.
tion with stable maternal and fetal conditions, it is
recommended that continued pregnancy should be
undertaken only at facilities with adequate materTASK FORCE RECOMMENDATION
nal and neonatal intensive care resources.
For women with a medical history of preeclampsia
who gave birth preterm (less than 37 0/7 weeks of
Strength of evidence: Strong
gestation) or who have a medical history of recurrent preeclampsia, yearly assessment of BP, lipids,
For women with superimposed preeclampsia with
fasting blood glucose, and body mass index is sugsevere features, expectant management beyond
gested.*
34 0/7 weeks of gestation is not recommended.
Strength of the recommendation: Strong
*Although there is clear evidence of an association between preeclampsia and later-life CV disease, the value
Later-Life Cardiovascular Disease in
and appropriate timing of assessment is not yet estabWomen With Prior Preeclampsia
lished. Health care providers and patients should make
this decision based on their judgment of the relative value
Over the past 10 years, information has accumulated
of extra information versus expense and inconvenience.
indicating that a woman who has had a preeclamptic
pregnancy is at an increased risk of later-life CV disease.
Patient Education
This increase ranges from a doubling of risk in all cases to an eightfold to ninefold increase in women with
Patient and health care provider education is key to
preeclampsia who gave birth before 34 0/7 weeks of
the successful recognition and management of pregestation. This has been recognized by the American
eclampsia. Health care providers need to inform
Heart Association, which now recommends that a
women during the prenatal and postpartum periods
pregnancy history be part of the evaluation of CV risk
of the signs and symptoms of preeclampsia and stress
in women. It is the general belief that preeclampsia
the importance of contacting health care providers if

does not cause CV disease, but rather preeclampsia
these are evident. The recognition of the importance
and CV disease share common risk factors. Awareness
of patient education must be complemented by the
that a woman has had a preeclamptic pregnancy recognition and use of strategies that
facilitate the
might allow for the identification of women not previsuccessful transfer of this information to women with
ously recognized as at-risk for earlier assessment and
varying degrees of health literacy. Recommended
potential intervention. However, it is unknown if this
strategies to facilitate this process include using plain
will be a valuable adjunct to previous information. If
nonmedical language, taking time to speak slowly,
this is the case, would the current recommendation of
reinforcing key issues in print using pictorially based
assessing risk factors for women by medical history,
information, and requesting feedback to indicate that
lifestyle evaluation, testing for metabolic abnormalithe patient understands, and, where applicable, her
ties, and possibly inflammatory activation at age 40
partner.
EXECUTIVE SUMMARY
11
and inflammation, and secondary mediators that
include modifiers of endothelial function and angio It is suggested that health care providers convey genesis. This understanding of
preeclampsia pathoinformation about preeclampsia in the context of
physiology has not translated into predictors or
prenatal care and postpartum care using proven preventers of preeclampsia or to
improved clinical
health communication practices.
care. This has led to a reassessment of this conceptual
framework, with attention to the possibility that preStrength of recommendation: Qualified
eclampsia is not one disease but that the syndrome
may include subsets of pathophysiology.
The State of the Science and
Clinical research advances have shown approaches
to therapy that work (eg, delivery for women with gesResearch Recommendations
tational hypertension and preeclampsia without

In the past 10 years, striking increases in the undersevere features at 37 0/7 weeks of gestation) or do not
standing of the pathophysiology of preeclampsia have
work (vitamin C and vitamin E to prevent preeclampoccurred. Clinical research advances also have emsia). However, there are few clinical recommendations
erged that have provided evidence to guide therapy. It
that can be classified as strong because there are
is now understood that preeclampsia is a multisystemhuge gaps in the evidence base that guides therapy.
ic disease that affects all organ systems and is far more
These knowledge gaps form the basis for research recthan high BP and renal dysfunction. The placenta is ommendations to guide future
therapy.
evident as the root cause of preeclampsia. It is with the
delivery of the placenta that preeclampsia begins to Conclusion
resolve. The insult to the placenta is proposed as an
immunologically initiated alteration in trophoblast The task force provides evidencebased recommendafunction, and the reduction in trophoblast invasion
tions for the management of patients with hypertenleads to failed vascular remodeling of the maternal sion during and after pregnancy.
Recommendations
spiral arteries that perfuse the placenta. The resulting
are graded as strong or qualified based on evidence of
reduced perfusion and increased velocity of blood effectiveness weighed against evidence
of potential
perfusing the intervillous space alter placental funcharm. In all instances, the final decision is made by the
tion. The altered placental function leads to materhealth care provider and patient after consideration of
nal disease through putative primary mediators,
the strength of the recommendations in relation to the
including oxidative and endoplasmic reticulum stress
values and judgments of the individual patient.
1
CHAPTER
Classification of Hypertensive Disorders
The major goals of a hypertension classifica- 1) preeclampsiaeclampsia, 2) chronic
hypertension
tion schema, which describes hypertension
(of any cause), 3) chronic hypertension with superimthat complicates pregnancy, are to differ-
posed preeclampsia; and 4) gestational hypertension.

entiate diseases preceding conception from
It has been suggested that an older category,
those specific to pregnancy, identify the most omiunclassified, be reintroduced or replaced by susnous causes, and create categories ideal for record
pected or presumptive preeclampsia. This may be
keeping and eventual epidemiologic research. Neveruseful in management because one should always be
theless, health care professionals continue to be conprepared for the disorder with the greatest risk. Howfused by the differences in terminology that abound
ever, although these latter terms may help guide cliniin the literature, especially the differences in publicacal practice, they may hinder record keeping for
tions from national and international societies. These
precise epidemiological research.
latter reports continue to introduce schema that differ in various documents and may contrast with those
PreeclampsiaEclampsia
recommended here. This confusion has obviously
affected both management and outcome research
Preeclampsia is a pregnancy-specific hypertensive disand recommendations.
ease with multisystem involvement. It usually occurs
The American College of Obstetricians and Gyneafter 20 weeks of gestation, most often near term, and
cologists (the College) Task Force on Hypertension in
can be superimposed on another hypertensive disorPregnancy chose to continue using the classification
der. Preeclampsia, the most common form of high
schema first introduced in 1972 by the College and
blood pressure (BP) that complicates pregnancy, is primodified in the 1990 and 2000 reports of the National
marily defined by the occurrence of new-onset hyperHigh Blood Pressure Education Program Working
tension plus new-onset proteinuria. However, although
Group (1). Similar classifications can be found in the
these two criteria are considered the classic definition
American Society of Hypertension guidelines, as well
of preeclampsia, some women present with hypertenas College Practice Bulletins (2, 3). Although the sion and multisystemic signs usually
indicative of dis-task force has modified some of the components of
ease severity in the absence of proteinuria. In the
the classification, it continues with this basic, precise,
absence of proteinuria, preeclampsia is diagnosed as
and practical classification, which considers hyperhypertension in association with thrombocytopenia

tension during pregnancy in only four categories: (platelet count less than
100,000/microliter), impaired
13
14
CLASSIFICATION OF HYPERTENSIVE DISORDERS
liver function (elevated blood levels of liver transamihalf of pregnancy and normalizes postpartum, the
nases to twice the normal concentration), the new
diagnosis should be changed to transient hypertendevelopment of renal insufficiency (elevated serum
sion of pregnancy. However, because discharge
creatinine greater than 1.1 mg/dL or a doubling of records are rarely modified, the task
force recomserum creatinine in the absence of other renal dismends against instituting this latter terminology.
ease), pulmonary edema, or new-onset cerebral or
visual disturbances.
Chronic Hypertension With
Hypertension is defined as either a systolic BP of
140 mm Hg or greater, a diastolic BP of 90 mm Hg
or greater, or both. Hypertension is considered
Preeclampsia may complicate all other hypertensive
mild until diastolic or systolic levels reach or exceed
disorders, and in fact the incidence is four to five times
110 mm Hg and 160 mm Hg, respectively. It is recomthat in nonhypertensive pregnant women (4). In such
mended that a diagnosis of hypertension require at
cases, prognosis for the woman and her fetus is worse
least two determinations at least 4 hours apart,
than either condition alone. Although evidence from
although on occasion, especially when faced with
renal biopsy studies suggests that the diagnosis of
severe hypertension, the diagnosis can be confirmed
superimposed preeclampsia may be often erroneous
within a shorter interval (even minutes) to facilitate
(5), the diagnosis is more likely in the following seven
timely antihypertensive therapy.
scenarios: women with hypertension only in early gesProteinuria is diagnosed when 24-hour excretion
tation who develop proteinuria after 20 weeks of gesequals or exceeds 300 mg in 24 hours or the ratio of
tation and women with proteinuria before 20 weeks of

measured protein to creatinine in a single voided urine
gestation who 1) experience a sudden exacerbation of
measures or exceeds 3.0 (each measured as mg/dL),
hypertension, or a need to escalate the antihypertensive
termed the protein/creatinine ratio. As discussed in drug dose especially when previously
well controlled
Chapter 2 Establishing the Diagnosis of Preeclampsia
with these medications; 2) suddenly manifest other
and Eclampsia, qualitative dipstick readings of 1+
signs and symptoms, such as an increase in liver enzymes
suggest proteinuria but have many false-positive and
to abnormal levels; 3) present with a decrement in
false-negative results and should be reserved for use
their platelet levels to below 100,000/microliter;
when quantitative methods are not available or rapid
4) manifest symptoms such as right upper quadrant
decisions are required.
pain and severe headaches; 5) develop pulmonary
Eclampsia is the convulsive phase of the disorder congestion or edema; 6) develop renal
insufficiency
and is among the more severe manifestations of the (creatinine level doubling or
increasing to or above 1.1
disease. It is often preceded by premonitory events,
mg/dL in women without other renal disease); and 7)
such as severe headaches and hyperreflexia, but it can
have sudden, substantial, and sustained increases in
occur in the absence of warning signs or symptoms.
protein excretion.
Specific biochemical markers have been linked to
If the only manifestation is elevation in BP to levels
increased morbidity in hypertensive complications of
less than 160 mm Hg systolic and 110 mm Hg diastolic
pregnancy (eg, hyperuricemia), but these should not
and proteinuria, this is considered to be superimbe used for diagnosis. Although some label preeclampposed preeclampsia without severe features. The
sia as less severe or more severe, or mild and
presence of organ dysfunction is considered to be
severe, these are not specific classifications, and the
superimposed preeclampsia with severe features. For
consideration of preeclampsia as mild should be
classification purposes, both variants are termed
avoided. The task force recommends that the term superimposed preeclampsia, but
management is
mild preeclampsia be replaced by preeclampsia
guided by the subcategory (analogous to preeclampwithout severe features. These points are more extensia with severe features and preeclampsia without
sively discussed in Chapter 2 Establishing the Diagnosevere features).
sis of Preeclampsia and Eclampsia.
Gestational Hypertension
Chronic Hypertension
Gestational hypertension is characterized most often by
During pregnancy, chronic hypertension is defined as
new-onset elevations of BP after 20 weeks of gestation,
high BP known to predate conception or detected often near term, in the absence of
accompanying probefore 20 weeks of gestation. Previously, some sugteinuria. The failure of BP to normalize postpartum
gested that when high BP is first diagnosed in the first
requires changing the diagnosis to chronic hypertension.
CLASSIFICATION OF HYPERTENSIVE DISORDERS
15
Outcomes in women with gestational hypertension
hypertension (usually mild) in a period that ranges
usually are quite successful, although some of these
from 2 weeks to 6 months postpartum. Blood pressure
women experience BP elevations to the severe level
remains labile for months postpartum, usually normalwith outcomes similar to women with preeclampsia izing by the end of the first year.
Little is known of this
(6). The cause of this entity is unclear, but many of
entity, and, like gestational hypertension, it may be a
these women have preeclampsia before proteinuria predictor of future chronic
hypertension.
and other organ manifestations have occurred. Thus,
gestational hypertension, even when BP elevations are
References
mild, requires enhanced surveillance.
Gestational hypertension, although transient in
1. Report of the National High Blood Pressure Education
nature, may also be a sign of future chronic hypertenProgram Working Group on High Blood Pressure in Pregsion. Thus, even when benign, it is an important
nancy. Am J Obstet Gynecol 2000;183:S1S22.
marker regarding follow-up and preventive medicine
[PubMed] [Full Text] ^
decisions (7).
2. Lindheimer MD, Taler SJ, Cunningham FG. Hyperten-
sion in pregnancy. J Am Soc Hypertens 2010;4:6878.

[PubMed] ^
Postpartum Hypertension
3. Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin No. 33. American College of
It is important to remember that preeclampsia
Obstetricians and Gynecologists. Obstet Gynecol 2002;
including preeclampsia with severe systemic organ
99:15967. [PubMed] [ Obstetrics & Gynecology] ^
involvement and seizurescan first develop in the
4. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M,
postpartum period. Because early hospital discharge is
Thom E, et al. Low-dose aspirin to prevent preeclampsia
the current practice in the United States, this manin women at high risk. National Institute of Child Health
and Human Development Network of Maternal-Fetaldates instruction of women at discharge from the hosMedicine Units. N Engl J Med 1998;338:7015.
pital to be aware of symptoms (eg, severe headache,
visual disturbances, or epigastric pain) that should be
5. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hyperreported to a health care provider.
tension in pregnancy: clinical-pathological correlations
Although not recommended in this classification
and remote prognosis. Medicine (Baltimore) 1981;60:
schema, the task force calls attention to a phenome26776.
non once labeled late postpartum hypertension, a
6. Buchbinder A, Sibai BM, Caritis S, Macpherson C, Hauth J,
disorder that was more frequently diagnosed when
Lindheimer MD, et al. Adverse perinatal outcomes are
significantly higher in severe gestational hypertension
women in the postpartum period routinely remained
than in mild preeclampsia. National Institute of Child
hospitalized for as long as 2 weeks. It was defined as
Health and Human Development Network of Maternalwomen with normotensive gestations who develop
Fetal Medicine Units. Am J Obstet Gynecol 2002;186:
6671. [PubMed] [Full Text] ^
7. Williams D. Long-term complications of preeclampsia.
Semin Nephrol 2011;31:11122. [PubMed] ^
2
CHAPTER
Establishing the Diagnosis of
Preeclampsia and Eclampsia

^
Specific criteria must be met to establish the the middle of the cuff on the upper arm is at
the level
diagnosis of preeclampsia, preeclampsia with
of the right atrium (the midpoint of the sternum). The
severe features, and eclampsia. More recent
patient should be instructed to relax and not talk
criteria for the definition of preeclampsia have
during the measurement procedure; ideally, 5 minutes
been established based on their association with adshould elapse before the first reading is taken. If eleverse clinical outcomes. Several preexisting criteria for
vated on initial assessment, the BP measurement
preeclampsia with severe features have been eliminatshould be repeated after several minutes to attempt to
ed based largely on whether evidence suggests that eliminate spuriously elevated BP
determinations (3).
their presence should outline clinical management in
It is worth noting that measurement of BP taken in the
the preterm setting.
upper arm with the woman in the left lateral position
will falsely lower BP readings because the blood presPreeclampsia
sure cuff will be above the heart when these readings
are made. This approach is discouraged.
Definition
Hypertension does not mean that a patient has prePreeclampsia is a syndrome that chiefly includes the
eclampsia; other criteria are required. In most cases,
development of new-onset hypertension in the second
this will be new-onset proteinuria, but in the absence of
half of pregnancy. Although often accompanied by proteinuria that meets or exceeds the
diagnostic threshnew-onset proteinuria, preeclampsia can be associated
old, any of the following can establish the diagnosis:
with many other signs and symptoms, including visual
new-onset thrombocytopenia, impaired liver function,
disturbances, headaches, epigastric pain, and the rapid
renal insufficiency, pulmonary edema, or visual or ceredevelopment of edema.
bral disturbances. Proteinuria is defined by the excreDiagnostic criteria include the development of tion of 300 mg or more of protein in a 24hour urine
hypertension, defined as a persistent systolic blood
collection (or this amount extrapolated from a timed

pressure (BP) of 140 mm Hg or higher, or a diastolic
collection) (4). Alternatively, a protein/creatinine ratio
BP of 90 mm Hg or higher after 20 weeks of gestation
of at least 0.3 (each measured as mg/dL) is an equivain a women with previously normal blood pressure (1,
lent acceptable threshold for the diagnosis to be estab2) (Table 2-1). The optimal measurement of BP is lished because this ratio has been
demonstrated to made with the patient comfortably seated, legs
match or exceed a 24-hour urine protein collection of
uncrossed, and the back and arm supported, so that
300 mg (5). A dipstick reading of 1+ also suggests
17
18
ESTABLISHING THE DIAGNOSIS OF PREECLAMPSIA AND ECLAMPSIA
TABLE 2-1. Diagnostic Criteria for Preeclampsia ^
Blood pressure
diastolic on two occasions at least 4 hours apart after 20 weeks of gestation in a
woman with a previously normal blood pressure
diastolic, hypertension can be confirmed within a short interval (minutes) to facilitate
timely antihypertensive therapy
and
Proteinuria
Greater than or equal to 300 mg per 24 hour urine collection (or this amount
extrapolated from a timed collection)
or
Protein/creatinine ratio greater than or equal to 0.3*
Dipstick reading of 1+ (used only if other quantitative methods not available)
Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the
following:
Thrombocytopenia
Platelet count less than 100,000/microliter
Renal insufficiency
Serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum
creatinine concentration in the absence of other renal disease
Impaired liver function Elevated blood concentrations of liver transaminases to twice
normal concentration Pulmonary edema
Cerebral or visual
symptoms
* Each measured as mg/dL.
proteinuria, but because this qualitative method has
constellation of laboratory findings is often considered
many false-positive and false-negative results, it should
a preeclamptic subtype. The segregation of HELLP
be used for diagnosis only when quantitative methods
syndrome from thrombotic thrombocytopenic purpura
are not available. Alternatively, the diagnosis may be
may be helped by the measurement of serum lactate
established by the presence of hypertension as defined
dehydrogenase when additional criteria for prepreviously in association with thrombocytopenia (plateeclampsia are absent (7).
let count less than 100,000/microliter), impaired liver
function (elevated blood concentrations of liver transPrediagnostic Findings Warranting
aminases to twice the normal concentration), the new
Increased Surveillance
development of renal insufficiency (serum creatinine
Some maternal symptoms, even in the absence of a
concentration greater than 1.1 mg/dL or a doubling of
confirmed diagnosis of preeclampsia, should prompt
the serum creatinine concentration in the absence of the obstetric care provider to closely
evaluate materother renal disease), pulmonary edema, or new-onset
nal status for specific signs of preeclampsia. These
cerebral or visual disturbances. Proteinuria is not absoinclude the new onset of headache or visual disturlutely required for the diagnosis of preeclampsia (6).
bances, as well as abdominal pain, particularly in the
Preeclampsia with the absence of severe manifestaright upper quadrant, or epigastric pain.
tions often has been characterized as mild. It should
Additional findings that warrant close observation
be noted that this characterization can be misleading;
for the subsequent development of preeclampsia
even in the absence of severe disease (defined in this
include fetal growth restriction or new-onset proteinchapter), morbidity and mortality are significantly
uria in the second half of pregnancy (8, 9). Elevations increased. Therefore, the task force
recommends that
in BP during pregnancy (comparing late pregnancy
the term preeclampsia without severe features be
with early pregnancy) that exceed 15 mm Hg diastolic
used instead. Some pregnant women present with a or 30 mm Hg systolic are common in
uncomplicated
specific constellation of laboratory findingshemolypregnancies (10). Nevertheless, women who demonsis, elevated liver enzymes, and low platelet count
strate this degree of elevation in BP warrant close
that has been labeled HELLP syndrome. This
observation, as suggested by the National High Blood
19
Pressure Education Program Working Group (2).
Additionally, biochemical markers can be associated
with poorer outcomes in women in whom preeclampBOX 2-1. Severe Features of Preeclampsia
sia has been diagnosed. These markers may have value
(Any of these findings) ^
in the management of specific patients, but they do not
contribute to establishing the diagnosis. Among these
Systolic blood pressure of 160 mm Hg or higher, or diastolic
markers is uric acid concentration (11). It is important
blood pressure of 110 mm Hg or higher on two occasions at
to note that these findings warn that preeclampsia may
least 4 hours apart while the patient is on bed rest (unless
be impending, which may influence patterns of clinical
antihypertensive therapy is initiated before this time)
observation, but the findings do not support the initia Thrombocytopenia (platelet count less than 100,000/microliter)
tion of specific interventions in and of themselves.
Although clinically evident edema or rapid weight
Impaired liver function as indicated by abnormally elevated
gain, or both, may raise the clinical suspicion for preblood concentrations of liver enzymes (to twice normal
eclampsia, it is not a diagnostic criterion. Nondepenconcentration), severe persistent right upper quadrant or
dent edema occurs in 1015% of women who remain
epigastric pain unresponsive to medication and not accounted
normotensive throughout pregnancy, and it is neither
for by alternative diagnoses, or both
a sensitive nor specific sign of preeclampsia (12).
Progressive renal insufficiency (serum creatinine concentration
greater than 1.1 mg/dL or a doubling of the serum creatinine
Assessing the Severity of Preeclampsia
concentration in the absence of other renal disease)
Some clinical findings increase the risk of morbidity
and mortality in the setting of preeclampsia and, when
Pulmonary edema
present, segregate preeclampsia into a more severe

Cerebral or visual disturbances
category (13). The more severe forms of preeclampsia
are characterized by the certain findings in women
meeting the basic criteria for diagnosing the disorder
(Box 2-1). Additionally, women who have met the basic
criteria for preeclampsia with systolic BP levels of 140
160 mm Hg or diastolic BP levels of 90110 mm Hg,
References
along with new evidence of thrombocytopenia,
impaired liver dysfunction, renal insufficiency, pulmo1. Stone P, Cook D, Hutton J, Purdie G, Murray H, Harcourt L.
nary edema, or visual loss or cerebral disturbance, also
Measurements of blood pressure, oedema and proteinuria in a pregnant population of New Zealand. Aust N Z
should be considered as having severe disease.
J Obstet Gynaecol 1995;35:327. [PubMed] ^
In view of recent studies that indicate a minimal rela2. Report of the National High Blood Pressure Education
tionship between the quantity of urinary protein and
Program Working Group on High Blood Pressure in Pregpregnancy outcome in preeclampsia, massive proteinnancy. Am J Obstet Gynecol 2000;183:S1S22.
uria (greater than 5 g) has been eliminated from the
consideration of preeclampsia as severe. Also, because
3. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J,
fetal growth restriction is managed similarly in pregnant
Hill MN, et al. Recommendations for blood pressure
measurement in humans and experimental animals: Part
women with and without preeclampsia, it has been
1: blood pressure measurement in humans: a statement
removed as a finding indicating severe preeclampsia.
for professionals from the Subcommittee of Professional
and Public Education of the American Heart Association
Council on High Blood Pressure Research. Subcommittee
Eclampsia
of Professional and Public Education of the American
Heart Association Council on High Blood Pressure
Eclampsia is defined as the presence of new-onset
Research. Hypertension 2005;45:14261. [PubMed]
grand mal seizures in a woman with preeclampsia.
[Full Text] ^
Eclampsia can occur before, during, or after labor.
4. Kuo VS, Koumantakis G, Gallery ED. Proteinuria and its
Other causes of seizures in addition to eclampsia
assessment in normal and hypertensive pregnancy. Am J

include a bleeding arteriovenous malformation, rupObstet Gynecol 1992;167:7238. [PubMed] ^
tured aneurysm, or idiopathic seizure disorder. These
5. Wheeler TL 2nd, Blackhurst DW, Dellinger EH, Ramsey PS.
alternative diagnoses may be more likely in cases in
Usage of spot urine protein to creatinine ratios in the
evaluation of preeclampsia. Am J Obstet Gynecol 2007;
which new-onset seizures occur after 4872 hours
196:465.e14. [PubMed] [Full Text] ^
postpartum or when seizures occur during use of 6. Homer CS, Brown MA, Mangos G,
Davis GK. Nonantiepileptic therapy with magnesium sulfate.
proteinuric pre-eclampsia: a novel risk indicator in
20
women with gestational hypertension. J Hypertens 2008;
10. MacGillivray I, Rose GA, Rowe B. Blood pressure survey
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in pregnancy. Clin Sci 1969;37:395407. [PubMed] ^
7. Keiser SD, Boyd KW, Rehberg JF, Elkins S, Owens MY,
11. Hawkins TL, Roberts JM, Mangos GJ, Davis GK,
Sunesara I, et al. A high LDH to AST ratio helps to differRoberts LM, Brown MA. Plasma uric acid remains a
entiate pregnancy-associated thrombotic thrombocytomarker of poor outcome in hypertensive pregnancy: a
penic purpura (TTP) from HELLP syndrome. J Matern
retrospective cohort study. BJOG 2012;119:48492.
Fetal Neonatal Med 2012;25:105963. [PubMed] [Full
Text] ^
12. Thomson AM, Hytten FE, Billewicz WZ. The epidemiology
8. Fox NS, Huang M, Chasen ST. Second-trimester fetal
of oedema during pregnancy. J Obstet Gynaecol Br Comgrowth and the risk of poor obstetric and neonatal outmonw 1967;74:110. [PubMed] ^
comes. Ultrasound Obstet Gynecol 2008;32:615. 13. von Dadelszen P, Payne B, Li J,
Ansermino JM, Broughton
Pipkin F, Cote AM, et al. Prediction of adverse maternal
9. Morikawa M, Yamada T, Yamada T, Cho K, Yamada H,
outcomes in pre-eclampsia: development and validation
Sakuragi N, et al. Pregnancy outcome of women who deof the fullPIERS model. PIERS Study Group. Lancet
veloped proteinuria in the absence of hypertension after
2011;377:21927. [PubMed] [Full Text] ^
mid-gestation. J Perinat Med 2008;36:41924. [PubMed]

^
3
CHAPTER
Prediction of Preeclampsia
Agreat deal of effort has been directed at the preventive approaches and therapeutic
interventions
identification of demographic factors, bioare available or if close follow-up after prediction
chemical analytes, or biophysical findings,
demonstrates improved maternal or fetal outcomes.
alone or in combination, to predict early
in pregnancy the later development of preeclampsia.
Epidemiology of and Risk Factors
Evidence relating to the reliability of prediction tests
for preeclampsia is reviewed as follows.
for Preeclampsia
A number of clinical circumstances, summarized in
Definition of an Ideal Predictive Test
Box 3-1, increase the risk of preeclampsia (3). The risk of preeclampsia is increased
twofold to fourfold if a
The utility of a predictive test will depend on the overpatient has a first-degree relative with a medical hisall prevalence of the disease (1). Although sensitivity
tory of the disorder and is increased sevenfold if preand specificity have been used to assess how well a test
eclampsia complicated a previous pregnancy (3, 4).
is able to identify patients with a disease, they do not
Multiple gestation is an additional risk factor; triplet
focus on the meaning of a single test result. In this gestation is a greater risk than twin
gestation. Classic respect, the best way to assess the value of a specific
cardiovascular risk factors also are associated with
test result is by use of likelihood ratios (2). The likeliincreased probability of preeclampsia, as are maternal
hood ratio (LR) of a particular test result is the proporage older than 40 years, diabetes, obesity, and preextion of participants with the target condition who have
isting hypertension. The increased prevalence of
a positive test result relative to the proportion without
chronic hypertension and other comorbid medical illthe target condition who have the same test result. nesses in women older than 35 years
may explain the
Because the incidence of preeclampsia is relatively increased frequency of preeclampsia
among older
low, screening tests with positive test results require

women. Racial differences in the incidence and severhigh LRs to adequately predict the diseases probability of preeclampsia have been difficult to assess
ity, and tests with negative results require low LRs to
because of confounding by socioeconomic and cultural
confidently exclude the disorder. Thus, useful predicfactors. Nonetheless, it is important to remember that
tion for preeclampsia would require a high LR (greater
most cases of preeclampsia occur in healthy nullipathan 10) for a positive test as well as a low LR for a
rous women with no other obvious risks.
negative result (less than 0.2). Even the most reliable
Attempts to predict preeclampsia during early pregprediction test will only have clinical utility if effective
nancy using clinical risk factors have revealed modest
21
22
PREDICTION OF PREECLAMPSIA
Prediction of Preeclampsia Using
Biomarkers
BOX 3-1. Risk Factors for Preeclampsia ^
Biomarkers for the prediction of preeclampsia are inte Primiparity
gral to disease stratification and targeted therapy (1).
Previous preeclamptic pregnancy
Results from mechanistic studies not only have pro Chronic hypertension or chronic renal disease or both
vided insights into the pathogenesis of the disease, but
History of thrombophilia
also have created opportunities to study circulating
Multifetal pregnancy
and urinary biomarkers to predict the disease (8).
In vitro fertilization
Family history of preeclampsia
Angiogenesis-Related Biomarkers
Type I diabetes mellitus or type II diabetes mellitus
Alterations in a number of circulating antiangiogenic
Obesity
proteins (soluble fms-like tyrosine kinase 1 [sFlt-1]
Systemic lupus erythematosus
and soluble endoglin) and proangiogenic proteins
Advanced maternal age (older than 40 years)
(placenta growth factor [PlGF] and vascular endothe-
lial growth factor [VEGF]) have been evaluated as

potential biomarkers for use in preeclampsia (8).
Because alterations in concentrations of sFlt-1, PlGF,
and soluble endoglin in the maternal circulation prepredictive values, with detection of 37% of those who
cede the clinical onset of preeclampsia by several
developed early-onset preeclampsia and 29% who weeks to months, their predictive
potential has been
developed late-onset preeclampsia, with false-positive
evaluated. Many of the studies focused on sFlt-1, an
rates of 5% (5). A study, which used an algorithm that
antiangiogenic protein, as a potential predictor of
included known risk factors for preeclampsia in nullipearly-onset preeclampsia (9). Examining odds ratios,
arous women, detected 37% of women who develsensitivity, and specificity for various sFlt-1 cutoff valoped preeclampsia with a false-positive rate of 10% ues in different trimesters led to the
conclusion that
(positive LR = 3.6) (6).
the higher the sFlt-1 concentration, the more predictive it is of early-onset preeclampsia (1). However,
Prediction of Preeclampsia Using
because sFlt-1 is altered only 45 weeks before the
Uterine Artery Doppler Velocimetry
onset of clinical symptoms, it is not useful when used
alone as a screening test earlier in gestation. In contrast,
The utility of uterine artery Doppler studies to predict
PlGF concentrations begin to decrease 911 weeks
preeclampsia has been extensively studied (7).
before the appearance of hypertension and proteinIncreased resistance to flow within the uterine arteruria, which accelerates during the 5 weeks before the
ies results in an abnormal waveform pattern, repreonset of disease (10). There are several studies evalusented by either an increased resistance or pulsatility
ating first-trimester use of PlGF that reveal, at most,
indices or by the persistence of a unilateral or bilateral
modest predictive values for early-onset preeclampsia.
diastolic notch (1). In general, uterine artery Doppler
However, combining PlGF concentrations with other
studies are better at predicting early preeclampsia than
biochemical markers, uterine artery Doppler studies,
term preeclampsia (7). Several studies have assessed or both, substantially improves the
predictive value.
the predictive value for early-onset preeclampsia and
One study evaluated 7,797 women with singleton
have noted positive LRs that ranged from 5.0 to 20 and

pregnancies during 1113 weeks of gestation (11).
negative LRs that ranged from 0.1 to 0.8 (7). It appears
An algorithm developed by logistic regression that
that irrespective of the index or combinations of indices
combined the logs of uterine pulsatility index, mean
used, uterine artery Doppler studies alone have a low
arterial pressure, pregnancy-associated plasma propredictive value for the development of early-onset tein A (PAPP-A), serum-free PlGF,
body mass index,
preeclampsia. Major pitfalls with this technique are the
and presence of nulliparity or previous preeclampsia
wide variability (likely related to operator expertise)
revealed the following: at a 5% false-positive rate,
and poor predictive accuracy. A review of the literature
the detection rate for early preeclampsia was 93.1%;
found no randomized clinical trials that demonstrated
more impressively, the positive LR was 16.5 and the
improved maternal outcomes or fetal outcomes or both
negative LR was 0.06 (11). Although the results of
in patients who have undergone uterine artery Doppler
these studies are promising, the task force does not
screening.
recommend using this for clinical practice because
23
evidence that maternalfetal outcomes are improved
lating angiogenic factors also have been evaluated in
by early screening is still lacking.
the triage setting in women with suspicion of preBecause PlGF is a small protein, it is easily filtered
eclampsia and have been found to be of potential use
by the normally functioning kidney; therefore, meain identifying subsequent adverse maternalfetal outsuring urinary PlGF combined with confirmation by
comes (2325). Among participants who presented
measuring the circulating sFlt-1/PlGF ratio has been preterm (less than 34 weeks of
gestation), an sFlt-1/
proposed as another strategy for the prediction of PlGF ratio of 85 or greater had a
positive predictive
preterm preeclampsia (12). In one study, researchers
value of 86.0% and a positive LR of 12.2 for predicting
measured sFlt-1, PlGF, and soluble endoglin in 1,622
adverse maternalfetal outcomes occurring within
consecutive pregnant women with singleton gesta2 weeks of presentation (24).

tions during early pregnancy and in midtrimester and
The greatest utility of these tests would be to rule
found superior performances for the PlGF/soluble out progression of gestational
hypertension to preendoglin ratio during midtrimester with sensitivity of
eclampsia or adverse outcomes. Angiogenic factors
100% and specificity of 98% for early-onset prealso have been evaluated for this purpose. In one
eclampsia (positive LR, 57.6; 95% confidence interval,
study, among participants who were evaluated in the
37.657.6, and negative LR, 0.0; 95% confidence
triage unit before 34 weeks of gestation (n=176), a
interval, 0.00.3) (13). Other studies that used angioplasma sFlt-1/PlGF ratio of less than 85 had a negative
genic markers in high-risk populations have found predictive value of 87.3% and a
negative LR of 0.29
more modest results (14, 15). None of these findings
(24). A total of 16 women had false-negative test
have been validated in an independent cohort. Future
results; 10 of them had adverse outcomes that could
studies to evaluate the clinical utility of early predicnot be attributed to preeclampsia. Another study
tion using biomarkers as it relates to preeclampsiafound that a PlGF/sFlt-1 ratio of 0.033 multiples of the
related adverse maternalfetal outcomes are needed.
median had a 93% sensitivity with a negative LR of
0.09 for the identification of patients who presented at
Placental Protein-13 and Other Markers
less than 34 weeks of gestation and who gave birth
A few studies have suggested first-trimester circulating
within 14 days because of preeclampsia (25). The
levels of placental protein-13 are significantly lower in
availability of biomarkers to quickly and accurately
women who go on to develop early-onset preeclampassess at initial presentation the risk of progression to
sia and preterm birth (16, 17). Combining firstpreeclampsia or to adverse outcomes could greatly aid
trimester placental protein-13 with other predictive in the management of patients with
gestational hypermarkers may further improve predictive performance.
tension. Similarly, being able to differentiate preOne study suggested that 14 different plasma metaboeclampsia that would or would not be associated with
lites have robust discriminatory power in identifying
adverse outcomes would be useful to guide managepreeclampsia at 15 weeks of gestation (18). Larger ment. However, both of these demand
high certainty prospective studies are needed to determine whether
(negative predictive value and low negative LRs) that
these novel biomarkers will be valuable for the predicthe patient will not progress to adverse outcomes.
tion of early preeclampsia.
Large prospective trials evaluating the clinical utility of
biomarkers in this context are needed before recomPrediction of Adverse Outcomes in
mendations can be made.
Patients With Gestational Hypertension
and Preeclampsia
Clinical Considerations
Biomarkers also may be useful to evaluate adverse As of 2012, no single test reliably
predicts preeclampoutcomes in patients who present with gestational sia. Extensive work clearly identifies
angiogenic fac-hypertension or preeclampsia. Uric acid has been torsespecially sFlt-1, PlGF,
and soluble endoglin
extensively studied in this setting, and elevated conearly in the second trimesteras likely tools for the
centrations have been suggested as useful in identifyprediction of early-onset preeclampsia; however, this
ing women with gestational hypertension who may requires further investigation (1).
Current evidence
progress to preeclampsia, develop adverse maternal
suggests that a combination of these biomarkers along
fetal outcomes, or both (1921). A recent prospective
with uterine artery Doppler studies may provide the
study suggested that uric acid might be an accurate best predictive accuracy for the
identification of early-predictor in this population, with a positive predictive
onset preeclampsia (26). It also is important for pracvalue of 91.4% for a cutoff of 5.2 mg/dL (22). Circuticing obstetricians to realize that these biomarkers are
24
not approved by the U.S. Food and Drug Administragenic factors and implications for later cardiovascular distion and, therefore, are not available for clinical use.
ease. Circulation 2011;123:285669. [PubMed] [Full
Standardization of these assays across the various
Text] ^
automated platforms and prospective studies that 9. Lam C, Lim KH, Karumanchi SA.
Circulating angiogenic
factors in the pathogenesis and prediction of preeclampdemonstrate clinical utility are needed. No evidence
sia. Hypertension 2005;46:107785. [PubMed] [Full

was located to support the hypothesis that accurate
Text] ^
prediction of early-onset preeclampsia can be followed
10. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu
by interventions or close follow-up that improve
KF, et al. Circulating angiogenic factors and the risk ofmaternal outcome or fetal outcome or both. The use of
preeclampsia. N Engl J Med 2004;350:67283. [PubMed]
predictors to differentiate women with gestational
[Full Text] ^
hypertension who are at risk of progression to pre11. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides
eclampsia or adverse outcomes would be useful. Tests
KH. First-trimester prediction of hypertensive disorders
in pregnancy. Hypertension 2009;53:8128. [PubMed]
for this purpose demand high certainty that outcomes
[Full Text] ^
will not be bad and demand rigorous testing for clini12. Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF,
cal utility, which has not yet taken place.
et al. Urinary placental growth factor and risk of preeclampsia. JAMA 2005;293:7785. [PubMed] [Full Text]
^
13. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O,
Screening to predict preeclampsia beyond obtainMittal P, Vaisbuch E, et al. A prospective cohort study of
ing an appropriate medical history to evaluate for
the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and
risk factors is not recommended.
midtrimester in the identification of patients destined to
develop preeclampsia. J Matern Fetal Neonatal Med
2009;22:102138. [PubMed] [Full Text] ^
14. Powers RW, Jeyabalan A, Clifton RG, Van Dorsten P,
Hauth JC, Klebanoff MA, et al. Soluble fms-like tyrosine
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nice Kennedy Shriver National Institute of Child Health
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4
CHAPTER
Prevention of Preeclampsia
Strategies to prevent preeclampsia have been A follow-up Cochrane meta-analysis of 59
trials
studied extensively over the past 20 years. No
with more than 37,000 women found a 17% reduction
intervention to date has been proved unequivin risk of preeclampsia associated with use of antiocally effective.
platelet agents, with a significant increase in absolute
risk reduction in women who are at high risk of the
Antiplatelet Agents
disease (7). Concern remains that this finding may
reflect publication bias (ie, a small, early, positive trial
It has been hypothesized that alterations in systemic
is more likely to be published than a small, negative
prostacyclinthromboxane balance contribute to pretrial) or chance findings because the largest trials in
eclampsia. Furthermore, inflammation is increased in
the analysis did not show a significant protective
preeclampsia (1). Low-dose aspirin (81 mg or less), an
effect. Nevertheless, low-dose aspirin appears to be
antiinflammatory agent that blocks the production of
safe with no major adverse effects or evidence of
thromboxanes, has been studied in dozens of trials for
increased bleeding or abruptio placentae. The number
the prevention of preeclampsia, both in high-risk
of patients needed to treat is determined by the disgroups and in healthy nulliparous women. For women
ease prevalence and the effect size of the treatment.
at high risk of preeclampsia, several small, early trials
For low-risk women with a prevalence of 2%, it would
suggested daily aspirin had a significant protective
be necessary to treat 500 women to prevent one case
effect (2, 3). These initially promising findings were
of preeclampsia. In contrast, among high-risk women
not confirmed in three large randomized controlled
with a prevalence of 20%, it would be necessary to
trials (46). All three studies found a nonsignificant
treat 50 women to prevent one case of preeclampsia
trend toward a lower incidence of preeclampsia in the

(see Table 4-1 for numbers needed to treat based on
aspirin-treated groups with no major adverse effects. A
prevalence.) Several high-risk conditions (chronic
subsequent comprehensive meta-analysis of antiplatehypertension, previous preterm preeclampsia, and dialet agents to prevent preeclampsia that included more
betes) exhibit this degree of risk. Given the modest but
than 30,000 women from 31 trials at varying risk stasignificant protective effect, low-dose aspirin prophytuses suggested that antiplatelet agents have a modest
laxis may be considered as primary prevention for prebenefit, with a relative risk (RR) of preeclampsia of
eclampsia in women at high baseline risk and, if used,
0.90 (95% confidence interval [CI], 0.840.97) for
should be initiated in the late first trimester (8).
aspirin-treated participants (7).
27
28
PREVENTION OF PREECLAMPSIA
TABLE 4-1. PARIS number needed-to-treat with sample baseline event rates ^
Sample baseline PARIS relative risk
Number needed-to-treat
event rate
(95%CI)
(95% CI)
Pre-eclampsia
18%
090 (084097)
56 (35185)
6%
167 (104556)
2%
500 (3131667)
Preterm <34 weeks
20%
090 (083098)
50 (29250)
10%
100 (59500)
2%
500 (2942500)
Perinatal death
7%
091 (081103)
159 (75476)
4%
278 (132833)
1%
1111 (5263333)
Small for gestational age baby
15%
090 (081101)
67 (35667)
10%
100 (531000)
1%
1000 (52610 000)
Pregnancy with serious adverse outcome
25%
090 (085096)
40 (27100)
15%
67 (44167)
7%
143 (95357)
Reprinted from The Lancet, Vol. 369, Askie LM, Duley L, Henderson-Smart DJ, Stewart
LA, Antiplatelet agents for prevention of preeclampsia: a meta-analysis of individual patient
data, PARIS Collaborative Group. 179198, Copyright 2007, with Permission from Elsevier.
various populations (912). A recent Cochrane sysTASK FORCE RECOMMENDATION
tematic review of 15 randomized controlled trials
For women with a medical history of early-onset pre(20,748 women) that used vitamin C and vitamin E
eclampsia and preterm delivery at less than 34 0/7
for the prevention of preeclampsia found no benefit
weeks of gestation or preeclampsia in more than (RR, 0.94; 95% CI, 0.821.07) (13).
one prior pregnancy, initiating the administration
of daily low-dose (6080 mg) aspirin beginning in
the late first trimester is suggested.*
The administration of vitamin C or vitamin E to
prevent preeclampsia is not recommended.
Other Nutritional Interventions
treat to have a therapeutic effect is determined by prevalence. In view of maternal safety, a discussion of the use of
Several studies have examined the effectiveness of calaspirin in light of individual risk is justified.
cium supplementation to prevent preeclampsia. In a
large U.S. cohort of healthy primiparous women, calciAntioxidant Supplementation With
um supplementation did not reduce incidence of preeclampsia (14). However, calcium supplementation
Vitamin C and Vitamin E
might be expected to be of greater benefit in women
Because oxidative stress appears to contribute to the
who have a nutritional deficiency of calcium. A
pathogenesis of preeclampsia, it has been suggested
meta-analysis of 13 trials that involved 15,730 women
that antioxidants may prevent preeclampsia. Despite
reported a significant reduction in preeclampsia risk
initial enthusiasm for using a combination of the antiwith calcium supplementation (RR, 0.45; 95% CI,
oxidants vitamin C and vitamin E for this purpose,
0.310.65), with the greatest effect among women
large randomized, placebo-controlled trials conducted

with low baseline calcium intake (RR, 0.36; 95% CI,
during pregnancy found that supplementation with 0.200.65) (15). Thus, calcium
supplementation (1.5
vitamin C and vitamin E did not reduce the risk of pre2 g) may be considered in pregnant women from popeclampsia or improve maternal and fetal outcomes in
ulations with low baseline calcium intake (less than
29
600 mg/d). This is not the case in the United States or
randomized controlled clinical trials are needed that
other developed countries.
can evaluate whether moderate exercise can reverse
Vitamin D deficiency has been suggested as a factor
markers of endothelial dysfunction and prevent
contributing to preeclampsia (16); however, whether
adverse pregnancy outcomes.
supplementation with vitamin D is helpful is unknown.
Evidence is insufficient for reliable conclusions with
regard to other nutritional interventions, such as fish
oil or garlic, which have been used to prevent pre It is suggested that bed rest or the restriction of
eclampsia. Protein and calorie restriction for obese
other physical activity not be used for the primary
pregnant women shows no reduction in the risk of preprevention of preeclampsia and its complications.
eclampsia or gestational hypertension and may
increase the risk of intrauterine growth restriction and
should be avoided.
References
Dietary Salt Intake
1. Redman CW, Sargent IL. Latest advances in understandOne systematic review of all the trials that studied
ing preeclampsia. Science 2005;308:15924. [PubMed]
sodium restriction (603 women) found no significant
^
benefits (RR, 1.11) (17). However, the trials may not
2. Schiff E, Peleg E, Goldenberg M, Rosenthal T, Ruppin E,
have had adequate power to detect a benefit. SimilTamarkin M, et al. The use of aspirin to prevent pregarly, meta-analysis of approximately 7,000 random-
nancy-induced hypertension and lower the ratio of

ized patients from clinical trials suggested that diuretthromboxane A2 to prostacyclin in relatively high risk
pregnancies. N Engl J Med 1989;321:3516. [PubMed]
ics did not reduce the incidence of preeclampsia (18).
^
3. Wallenburg HC, Dekker GA, Makovitz JW, Rotmans P.
Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primi It is suggested that dietary salt not be restricted
gravidae. Lancet 1986;1:13. [PubMed] ^
during pregnancy for the prevention of pre4. Low-dose aspirin in prevention and treatment of intrautereclampsia.
ine growth retardation and pregnancy-induced hypertension. Italian study of aspirin in pregnancy. Lancet
1993;341:396400. [PubMed] ^
5. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364
pregnant women. CLASP (Collaborative Low-dose Aspirin
Lifestyle Modifications
Study in Pregnancy) Collaborative Group. Lancet 1994;
343:61929. [PubMed] ^
Although bed rest has been suggested as a preventive
strategy, the evidence for this is scarce (19). The only
two studies located that evaluated bed rest as a prein women at high risk. National Institute of Child Health
ventive strategy were both small (32 participants and
and Human Development Network of Maternal-Fetal72 participants) and did not evaluate perinatal and
Medicine Units. N Engl J Med 1998;338:7015.
maternal morbidity and mortality and adverse effects
of bed rest. However, regular exercise has been hypoth7. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiesized to prevent preeclampsia by improving vascular
platelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews
function (20, 21). In women who are not pregnant,
2007, Issue 2. Art. No.: CD004659. DOI: 10.1002/
moderate exercise has been shown to reduce hyper-
14651858.CD004659.pub2. [PubMed] [Full Text] ^

tension and cardiovascular disease. Thirty minutes of
8. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F,
moderate exercise on most days is currently recomMarcoux S, et al. Prevention of preeclampsia and intramended during normal pregnancy (22). Moderate
uterine growth restriction with aspirin started in early
exercise also has been hypothesized to stimulate plapregnancy: a meta-analysis. Obstet Gynecol 2010;116:
cental angiogenesis and improve maternal endothelial
40214. [PubMed] ^
dysfunction. Several small clinical trials have eval9. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women at risk for
uated the utility of modest exercise for the prevention
pre-eclampsia(VIP trial): randomised placebo-controlled
of preeclampsia, but the CIs were too wide to make
trial. Vitamins in Pre-eclampsia (VIP) Trial Consortium.
any reliable conclusions about the efficacy (23). Large
Lancet 2006;367:114554. [PubMed] [Full Text] ^
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10. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC,
RW, Roberts JM. Maternal vitamin D deficiency increases
Leveno KJ, et al. Vitamins C and E to prevent complications
the risk of preeclampsia. J Clin Endocrinol Metab 2007;
of pregnancy-associated hypertension. Eunice Kennedy
92:351722. [PubMed] [Full Text] ^
Shriver National Institute of Child Health and Human
17. Duley L, Henderson-Smart DJ, Meher S. Altered dietary
Development Maternal-Fetal Medicine Units Network.
salt for preventing pre-eclampsia, and its complications.
N Engl J Med 2010;362:128291. [PubMed] [Full Text]
Cochrane Database of Systematic Reviews 2005, Issue 4.
^
Art. No.: CD005548. DOI: 10.1002/14651858.CD005548.
11. Rumbold AR, Crowther CA, Haslam RR, Dekker GA,
Robinson JS. Vitamins C and E and the risks of pre18. Collins R, Yusuf S, Peto R. Overview of randomised trials
eclampsia and perinatal complications. ACTS Studyof diuretics in pregnancy. Br Med J (Clin Res Ed)
Group. N Engl J Med 2006;354:1796806. [PubMed]
1985;290:1723. [PubMed] [Full Text] ^
[Full Text] ^
19. Meher S, Duley L. Rest during pregnancy for preventing
12. Spinnato JA 2nd, Freire S, Pinto E Silva JL, Cunha Rudge

pre-eclampsia and its complications in women with norMV, Martins-Costa S, Koch MA, et al. Antioxidant therapy
mal blood pressure. Cochrane Database of Systematic
to prevent preeclampsia: a randomized controlled trial.
Reviews 2006, Issue 2. Art. No.: CD005939. DOI:
Obstet Gynecol 2007;110:13118. [PubMed] [ Obstetrics
10.1002/14651858.CD005939. [PubMed] [Full Text] ^
& Gynecology] ^
20. Weissgerber TL, Wolfe LA, Davies GA. The role of regular
13. Rumbold A, Duley L, Crowther CA, Haslam RR. Antioxiphysical activity in preeclampsia prevention. Med Sci
dants for preventing pre-eclampsia. Cochrane Database
Sports Exerc 2004;36:202431. [PubMed] ^
of Systematic Reviews 2008, Issue 1. Art. No.: CD004227.
21. Yeo S, Davidge ST. Possible beneficial effect of exercise,
DOI: 10.1002/14651858.CD004227.pub3. [PubMed]
by reducing oxidative stress, on the incidence of pre[Full Text] ^
eclampsia. J Womens Health Gend Based Med 2001;
14. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM,
Morris CD, et al. Trial of calcium to prevent preeclamp22. Zavorsky GS, Longo LD. Adding strength training, exersia. N Engl J Med 1997;337:6976. [PubMed] [Full Text]
cise intensity, and caloric expenditure to exercise guide^
lines in pregnancy. Obstet Gynecol 2011;117:1399402.
15. Hofmeyr GJ, Lawrie TA, Atallah N, Duley L. Calcium
[PubMed] [ Obstetrics & Gynecology] ^
supplementation during pregnancy for preventing hyper23. Meher S, Duley L. Exercise or other physical activity for
tensive disorders and related problems. Cochrane Datapreventing pre-eclampsia and its complications. Cochrane
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CD005942. DOI: 10.1002/14651858.CD005942. [Pub
Med] [Full Text] ^
16. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers
5
CHAPTER
Management of Preeclampsia and
HELLP Syndrome
^49 ^83
The first consideration in the management of 34 0/7 weeks or more of gestation, plus
any of the
women with mild gestational hypertension
following:
or preeclampsia without severe features is
Progressive labor or rupture of membranes
always safety of the woman and her fetus.
Ultrasonographic estimate of fetal weight less
The second is delivery of a mature newborn that will
than fifth percentile
not require intensive or prolonged neonatal care (1).
Oligohydramnios (persistent amniotic fluid index
Once the diagnosis of mild gestational hypertension
less than 5 cm)
or preeclampsia without severe features is established,
Persistent BPP 6/10 or less (normal 8/10
subsequent management will depend on the results of
10/10)
maternal and fetal evaluation, gestational age, presence of labor or rupture of membranes, vaginal bleedFor women who have not given birth, management
ing, and wishes of the woman (Fig. 5-1).
can occur in the hospital or at home with restricted
activity and serial maternal and fetal evaluation.
Antepartum Management
Continued Evaluation
Initial Evaluation
Continued evaluation of women who have not given
At time of diagnosis, all women should have a combirth who have mild gestational hypertension or preplete blood count (CBC) with platelet count and assesseclampsia without severe features consists of the folment of serum creatinine and liver enzyme levels, be
lowing:
evaluated for urine protein (24-hour collection or
Fetal evaluation includes daily kick count, ultrasoprotein/creatinine ratio), and be asked about symptoms
nography to determine fetal growth every 3 weeks,
of severe preeclampsia. Fetal evaluation should include
and amniotic fluid volume assessment at least
ultrasonographic evaluation for estimated fetal weight
once weekly. In addition, an NST once weekly for
and amniotic fluid index (calculated in centimeters),
patients with gestational hypertension and an NST

nonstress test (NST), and biophysical profile (BPP) if
twice weekly for patients with preeclampsia withNST is nonreactive. Best practice indicates hospitalizaout severe features is suggested. The presence of
tion and delivery for one or more of the following:
a nonreactive NST requires BPP testing. The fre 37 0/7 weeks or more of gestation
quency of these tests may be modified based on
Suspected abruptio placentae
subsequent clinical findings.
31
32
MANAGEMENT OF PREECLAMPSIA AND HELLP SYNDROME
Maternal and Fetal Findings
37 0/7 weeks or more of gestation
or
34 0/7 weeks or more of gestation with:
Labor or rupture of membranes
Yes
Abnormal maternalfetal test results
Delivery
Ultrasonographic estimate of fetal
Prostaglandins if needed for induction
weight less than fifth percentile
No
Less than 37 0/7 weeks of gestation
Inpatient or outpatient management
Maternal evaluation: twice weekly
Fetal evaluation
With preeclampsia: twice weekly
nonstress test
With gestational hypertension:
weekly nonstress test
37 0/7 weeks or more of gestation
Yes
Worsening maternal or fetal condition*
Labor or premature rupture of membranes
FIGURE 5-1. Management of mild gestational hypertension or preeclampsia
without severe features. ^
At the time of office or clinic visit for antenatal test-
Patients are instructed to have a regular diet with

ing, blood pressure (BP) is to be assessed. In patients
no salt restriction.
with gestational hypertension, an additional BP de At the time of diagnosis and at each subsequent
termination should be performed in addition to
visit, women are instructed to report symptoms of
that obtained at the weekly NST. This additional BP
severe preeclampsia (severe headaches, visual
determination may be performed in the office or
changes, epigastric pain, and shortness of breath).
at home. Further, women with gestational hyperThey also are advised to immediately come to the
tension are to be evaluated for proteinuria at each
hospital or office if they develop persistent sympantenatal visit, but following the diagnosis of pretoms, abdominal pain, contractions, vaginal spoteclampsia, additional evaluation of proteinuria is
ting, rupture of membranes, or decreased fetal
no longer necessary.
movements.
Maternal laboratory evaluation includes a CBC and
During management outside of the hospital, the
liver enzyme and serum creatinine level assessonset of decreased fetal movement or abnormal
ment at least once a week. The frequency of these
fundal height growth (less than 3 cm of what is
tests may be modified based on subsequent cliniexpected for gestational age) requires prompt
cal findings.
fetal testing with NST and estimation of amniotic
33
fluid volume. The development of new signs or
[CI], 0.410.61) but no effect on the development of
symptoms of severe preeclampsia or severe or progression to preeclampsia (RR, 0.97;
95% CI,
hypertension (systolic BP of 160 mm Hg or higher
0.831.13), eclampsia, pulmonary edema, fetal or
or diastolic BP of 110 mm Hg or higher on repeat
neonatal death (RR, 0.73; 95% CI, 0.5010.8),
measurements) or evidence of fetal growth preterm birth (RR, 1.02; 95% CI, 0.891.16),
or
restriction require immediate hospitalization. In
small-for-gestational-age infants (RR, 1.04; 95% CI,
addition, an increased concentration of liver

0.841.27) (7). Of 29 trials that evaluated oral
enzymes or thrombocytopenia requires hospital-blockers, these agents were found to be associated
ization.
with a decrease in risk of severe hypertension (RR,
In women with mild gestational hypertension, the
0.37; 95% CI, 0.260.53) but with an increase in the
progression to severe gestational hypertension or prerate of small-for-gestational-age infants (RR, 1.36;
eclampsia often develops within 13 weeks after diag95% CI, 1.021.82) (7). These reviews concluded
nosis, whereas in women with preeclampsia without
that there was insufficient evidence that treatment of
severe features, the progression to severe preeclampnonsevere hypertension improves maternal and neosia could happen within days (2).
natal outcomes (4, 7). The National Institute for
Health and Clinical Excellence guidelines recommended treatment at BP levels at 150 mm Hg systolic
or 100 mm Hg diastolic, or both (8). Given the rarity
The close monitoring of women with gestational of cerebral hemorrhage and congestive
heart failure
hypertension or preeclampsia without severe feaand their lack of association with gestational hypertures with serial assessment of maternal symptoms
tension, antihypertensive therapy for this outcome is
and fetal movement (daily by the woman) and not beneficial in patients with mild to
moderate gesserial measurements of BP (twice weekly), and
tational hypertension, and treatment exposes the
assessment of platelet counts and liver enzymes woman and her fetus to potentially
harmful medica(weekly) is suggested.
tions without clear evidence of benefit (9, 10).
In addition, concern exists that reducing maternal
BP may compromise blood flow to the fetoplacental
unit (11).
For women with gestational hypertension, monitoring at least once weekly with proteinuria assessTASK FORCE RECOMMENDATION
ment in the office and with an additional weekly
measurement of BP at home or in the office is sug-

gested.
preeclampsia with a persistent BP of less than 160
mm Hg systolic or 110 mm Hg diastolic, it is sugStrength of recommendation: Qualified
gested that antihypertensive medications not be
administered.
Antihypertensive Therapy
Antihypertensive therapy is used to prevent severe
gestational hypertension and maternal hemorrhagic
strokes. Overall, there is no consensus regarding the
Bed Rest
management of nonsevere hypertension; prior trials Complete or partial bed rest has been
recommended
have not been designed to define the maternal and
to improve pregnancy outcome in women with gestaperinatal benefits and risks. Therapy may decrease
tional hypertension or preeclampsia without severe
progression to severe hypertension but also may be features. However, a Cochrane
review of four randomassociated with impairment of fetal growth (36). A
ized trials that compared bed rest with no rest in pregrecent systematic review of 46 trials (4,282 women)
nant women with mild hypertension found insufficient
evaluated BP control in women with mild to moderevidence to provide guidance for clinical practice,
ate hypertension (4, 6). The authors concluded that it
suggesting that bed rest should not routinely be
is unclear whether antihypertensive therapy is worthrecommended for management of hypertension in
while. In trials that compared therapy with placebo,
pregnancy (12). In addition, prolonged bed rest for
the risk of developing severe hypertension was cut in
the duration of pregnancy increases the risk of thromhalf (risk ratio [RR], 0.50; 95% confidence interval
boembolism.
34
risks associated with expectant management include
the development of severe hypertension (1015%),
For women with gestational hypertension or preeclampsia (0.20.5%), HELLP (hemolysis, elevated
eclampsia without severe features, it is suggested

liver enzymes, and low platelet count) syndrome
that strict bed rest not be prescribed.*
(12%), abruptio placentae (0.52%), fetal growth
restriction (1012%), and fetal death (0.20.5%)
(15). However, immediate delivery is associated with
increased rates of admission to the neonatal intensive
*The task force acknowledged that there may be situations
care unit, neonatal respiratory complications, and a
in which different levels of rest, either at home or in the
hospital, may be indicated for individual women. The
slight increase in neonatal death compared with
previous recommendations do not cover advice regarding
infants born at or beyond 37 0/7 weeks of gestation.
overall physical activity and manual or office work.
Therefore, considering the riskbenefit ratio between
Women may need to be hospitalized for reasons other than
the two management plans, available retrospective
bed rest, such as for maternal and fetal surveillance. The
data suggest that the balance should be in favor of
task force agreed that hospitalization for maternal and fetal
continued monitoring and delivery to 37 0/7 weeks of
surveillance is resource intensive and should be considered
as a priority for research and future recommendations.
gestation in the absence of abnormal fetal testing or
other severe conditions (eg, premature rupture of
Fetal Testing
membranes, preterm labor, or vaginal bleeding) (15).
Maternal hypertension or preeclampsia is a known risk
factor for perinatal death and is a common indication
for antenatal testing. Limited to no data exist regarding when to start fetal testing, the frequency of testing,
and which test to use in the absence of fetal growth
preeclampsia without severe features and no indirestriction (13). In the absence of randomized trials
cation for delivery at less than 37 0/7 weeks of
comparing testing versus no testing, it remains unclear
gestation, expectant management with maternal
whether antenatal fetal testing improves outcome in
and fetal monitoring is suggested.
these pregnancies (14).

In women with mild gestational hypertension or
For women with preeclampsia without severe feapreeclampsia without severe features, a large multitures, use of ultrasonography to assess fetal growth
center trial from the Netherlands was conducted,
and antenatal testing to assess fetal status is sugwhich included 756 women with singleton gestations
gested.
at 3641 6/7 weeks of gestation who were allocated
to induction of labor or expectant monitoring (16).
The primary outcome was a composite of adverse
maternal outcome (new-onset severe preeclampsia,
If evidence of fetal growth restriction is found in HELLP syndrome, eclampsia,
pulmonary edema, or
women with preeclampsia, fetoplacental assessabruptio placentae). Secondary outcomes were neoment that includes umbilical artery Doppler velocinatal morbidities and rate of cesarean delivery. Inducmetry as an adjunct antenatal test is recommended.
tion of labor was associated with a significant
reduction in composite adverse maternal outcome
(RR, 0.71; 95% CI, 0.590.86) but no differences in
rates of neonatal complications or cesarean delivery.
Intrapartum Management
Timing of Delivery
In women with mild gestational hypertension or pre For women with mild gestational hypertension or
eclampsia without severe features between 34 0/7
preeclampsia without severe features at or beyond
weeks of gestation and 37 0/7 weeks of gestation,
37 0/7 weeks of gestation, delivery rather than
there are no randomized controlled trials that indicate
continued observation is suggested.
that expectant management will either improve periQuality of evidence: Moderate
natal outcomes or increase maternal or fetal risks. The
35
Magnesium Sulfate Prophylaxis
Antihypertensive Drugs to Treat Severe
There are only two double-blind, placebo controlled
Hypertension in Pregnancy
trials that have evaluated the use of magnesium sulThe objectives of treating severe hypertension are to
fate in women with preeclampsia without severe feaprevent potential cardiovascular (congestive heart failtures (17, 18). No instances of eclampsia occurred ure and myocardial ischemia), renal
(renal injury or among 181 women assigned to placebo, and no dif-failure), or cerebrovascular
(ischemic or hemorrhagic
ferences occurred in the percentage of women who stroke) complications related to
uncontrolled severe
progressed to severe preeclampsia (12.5% in magnehypertension. No randomized trials in pregnancy
sium group versus 13.8% in the placebo group; RR,
could be identified to determine the level of hyperten0.90; 95% CI, 0.521.54). However, the number of
sion to treat to prevent these complications. Data from
women enrolled in these trials is too limited to draw
case seriesas well as from developing countries
any valid conclusions (17, 18). Based on a rate of
where antihypertensive medications were not used in
eclampsia of 0.5%, and assuming a 50% reduction
women with severe gestational hypertension or severe
by magnesium sulfate (0.25% rate) (a = .05 and preeclampsiareveal increased rates of
heart failure,
= 0.2) approximately 10,000 women would need to
pulmonary edema, and death. These life-threatening
be enrolled in each group to find a significant reducmaternal complications justify recommending the use
tion in eclampsia in women with preeclampsia withof medications to lower BP to a safe range even though
out severe features treated with magnesium sulfate the magnitude of this risk is unknown.
(17). The number of women necessary to be studied
Several randomized trials compared different antito address serious maternal morbidity other than hypertensive drugs in pregnancy. In
these trials, pareneclampsia is even higher (18).
teral hydralazine was compared with labetalol or oral
Although the universal use of magnesium sulfate
nifedipine. An updated Cochrane systematic review of
therapy in preeclampsia without severe features is 35 trials that involved 3,573 women
found no signifinot recommended, certain signs and symptoms
cant differences regarding either efficacy or safety

(headache, altered mental state, blurred vision, scobetween hydralazine and labetalol, or between hydraltomata, clonus, and right upper quadrant abdominal
azine and any calcium channel blocker (19). The
pain) have traditionally been considered as premoniresults of these trials suggest that hydralazine, labetatory to seizures and should be considered in the lol, or oral nifedipine can be used to treat
acute severe
choice for initiation of magnesium sulfate therapy. hypertension in pregnancy as long as
the medical proBecause the clinical course of women with previder is familiar with the drug to be used, including
eclampsia without severe features can suddenly dosage, expected time of onset of action,
and potential
change during labor, all women with preeclampsia
adverse effects and contraindications (19).
without severe features who are in labor must be
Theoretical concern exists that the combined use of
monitored closely for early detection of progression
nifedipine and magnesium sulfate can result in excesto severe disease. This should include monitoring of
sive hypotension and neuromuscular blockade. A
BP and maternal symptoms during labor and delivery
review on the subject concluded that the combined use
as well as immediately postpartum. Magnesium sulof these drugs does not increase such risks; however,
fate therapy should then be initiated if there is prothis recommendation was based on limited data (20).
gression to severe disease.
In women requiring antihypertensive medications
for severe hypertension, the choice and route of
administration of drugs should be based primarily on
the physicians familiarity and experience, adverse
For women with preeclampsia with systolic BP of
effects and contraindications to the prescribed drug,
less than 160 mm Hg and a diastolic BP of less than
local availability, and cost.
110 mm Hg and no maternal symptoms, it is suggested that magnesium sulfate not be administered
universally for the prevention of eclampsia.
For women with preeclampsia with severe hypertenStrength of recommendation: Qualified
sion during pregnancy (sustained systolic BP of at

least 160 mm Hg or diastolic BP of at least 110 mm
Hg), the use of antihypertensive therapy is recommended.
36
Severe Preeclampsia
ery (7.1 days versus 1.3 days; P<.05) and gestational
age at delivery (223 days versus 221 days; P<.05)
Severe preeclampsia can result in both acute and longwere both greater with expectant management,
term complications for both the woman and her newwhereas total neonatal complications were reduced
born (1, 4, 2123). Maternal complications of severe
(33% versus 75%; P<.05) compared with planned
preeclampsia include pulmonary edema, myocardial
delivery. Another group of researchers studied 95
infarction, stroke, acute respiratory distress syndrome,
women with severe preeclampsia and no concurrent
coagulopathy, severe renal failure, and retinal injury.
medical (renal disease, type 1 diabetes mellitus, or
These complications are more likely to occur in the connective tissue disease) or obstetric
(vaginal bleedpresence of preexistent medical disorders and with
ing, premature rupture of membranes, multifetal gesacute maternal organ dysfunction related to pretation, or preterm labor) complications at 2832
eclampsia (1, 2123). Fetal and newborn complicaweeks of gestation (25). Those randomized to receive
tions of severe preeclampsia result from exposure to
expectant management gave birth at a more advanced
uteroplacental insufficiency or from preterm birth, or
gestational age (32.9 weeks of gestation versus 30.8
both (1, 2123).
weeks of gestation; P=.01) and had newborns who
The clinical course of severe preeclampsia is often
required less frequent neonatal intensive care unit
characterized by progressive deterioration of maternal
admission (76% versus 100%; P<.01), had less freand fetal conditions if delivery is not pursued (2123).
quent respiratory distress syndrome (22.4% versus
Therefore, in the interest of the woman and her fetus,
50%; P=.002), and had less frequent necrotizing
delivery is recommended when gestational age is at or
enterocolitis (0% versus 10.9%; P=.02), but more frebeyond 34 0/7 weeks. In addition, prompt delivery is
quent small-for-gestational-age birth weight (30.1
the safest option for the woman and her fetus when
versus 10.9; P=.04). No cases of maternal eclampsia
there is evidence of pulmonary edema, renal failure,
or pulmonary edema were reported in either trial.
abruptio placentae, severe thrombocytopenia, dissemCases of abruptio placentae were similar in frequency
inated intravascular coagulation, persistent cerebral
between the randomized groups in both studies;
symptoms, nonreassuring fetal testing, or fetal demise
HELLP syndrome complicated only two expectantly
irrespective of gestational age in women with severe
managed cases and one aggressively managed case in
preeclampsia at less than 34 0/7 weeks of gestation the latter study (4.1% versus 2.1%).
(2123) (Fig. 5-2).
Observational Studies
Observational studies of expectant management of
severe preeclampsia have varied in their inclusion
For women with severe preeclampsia at or beyond
criteria and indications for delivery (2123, 26).
34 0/7 weeks of gestation, and in those with unstaSome included only women who remained stable
ble maternalfetal conditions irrespective of gestaafter 24 48 hours of observation, whereas others
tional age, delivery soon after maternal stabilization
included women expectantly managed from the time
is recommended.
of diagnosis. In one review, maternal outcomes for
Quality of data: Moderate
expectant management of severe preeclampsia at less
than 34 weeks of gestation (presented as median percentile; interquartile range) included intensive care
Expectant Management
unit admission, 27.6 (1.5, 52.6); HELLP syndrome,
Randomized Trials
11.0 (5.3, 17.6); recurrent severe hypertension, 8.5
The task force found only two published randomized
(3.3, 27.5); abruptio placentae, 5.1 (2.2, 8.5); pultrials of delivery versus expectant management of
monary edema, 2.9 (1.4, 4.3); eclampsia, 1.1 (0,
preterm severe preeclampsia (24, 25). One group of
2.0); subcapsular liver hematoma, 0.5 (0.2, 0.7); and
researchers studied 38 women with severe preeclampstroke, 0.4 (0, 3.1) (26). Perinatal outcomes in this
sia between 28 weeks of gestation and 34 weeks of
study included stillbirth, 2.5 (0, 11.3); neonatal
gestation (24). Eighteen women received antenatal death, 7.3 (5.0, 10.7); perinatal
asphyxia, 7.4 (5.0,
corticosteroids for fetal maturation and were then 10.0); and any neonatal complication,
65.9 (39.7,
treated expectantly, with delivery only for specific
75.7) (26). Small-for-gestational-age infants were
maternal or fetal indications. Another 20 patients common (3050%) after expectant
management.
were assigned to receive antenatal corticosteroids Indications for delivery with expectant
management
with planned delivery after 48 hours. Latency to delivof severe preeclampsia at less than 34 weeks of gestaMANAGEMENT OF PREECLAMPSIA AND HELLP SYNDROME
37
Observe in labor and delivery for first 2448 hours
Corticosteroids, magnesium sulfate prophylaxis, and
antihypertensive medications
Ultrasonography, monitoring of fetal heart rate, symptoms,
and laboratory tests
Contraindications to continued expectant management
Eclampsia
Nonviable fetus
Delivery once maternal
Yes
Pulmonary edema
Abnormal fetal test results
condition is stable
Disseminated intravascular Abruptio placentae
coagulation
Intrapartum fetal demise
Uncontrollable severe
hypertension
Are there additional expectant complications?
Greater than or equal to 33 5/7 weeks of gestation
Persistent symptoms
Corticosteroids for fetal
HELLP or partial HELLP syndrome
Yes
maturation
Fetal growth restriction (less than fifth percentile)
Delivery after 48 hours

Severe oligohydramnios
Reversed end-diastolic flow (umbilical artery Doppler studies)
Significant renal dysfunction
Expectant management
Facilities with adequate maternal and neonatal intensive
care resources
Fetal viability33 6/7 weeks of gestation
Inpatient only and stop magnesium sulfate
Daily maternalfetal tests
Vital signs, symptoms, and blood tests
Oral antihypertensive drugs
Achievement of 34 0/7 weeks of gestation
Yes
New-onset contraindications to expectant management
Delivery
Abnormal maternalfetal test results
FIGURE 5-2. Management of severe preeclampsia at less than 34 weeks of gestation.
^
Abbreviation: HELLP, hemolysis, elevated liver enzymes, and low platelet count.
38
tion were fetal (36%), maternal (40%), or maternal
proteinuria (defined as 5 g/24 h or greater), signifiand fetal (8.8%) (26). The frequency of these complicant pregnancy prolongation occurred, maternal comcations, however, is unknown in the absence of
plications were not increased, and resolution of renal
expectant management.
dysfunction occurred in all women by 3 months after
delivery (29). A second study categorized women with
severe preeclampsia according to the severity of proTASK FORCE RECOMMENDATION
teinuria as mild (less than 5 g/24 h), severe (59.9 g/
For women with severe preeclampsia at less than
24 h), or massive (more than 10 g/24 h) (30). No dif34 0/7 weeks of gestation with stable maternal and
ferences in the rates of eclampsia, abruptio placentae,
fetal conditions, it is recommended that continued
pulmonary edema, HELLP syndrome, neonatal death,
pregnancy be undertaken only at facilities with or neonatal morbidity were identified
between these
adequate maternal and neonatal intensive care groups. Although the amount of
proteinuria increases
resources.
over time with expectant management, this change is
not predictive of pregnancy prolongation or perinatal
outcomes (29). On the basis of these data, severe proteinuria alone and the degree of change in proteinuria
Corticosteroids for Fetal Lung Maturity
should not be considered criteria to avoid or terminate
Although data specific to expectantly managed severe
preeclampsia are limited, randomized controlled trials
that involved pregnancies complicated by hypertenTASK FORCE RECOMMENDATION
sion syndromes have found antenatal corticosteroid
treatment to result in less frequent respiratory distress
For women with preeclampsia, it is suggested that
syndrome (RR, 0.50; 95% CI, 0.350.72), neonatal
a delivery decision should not be based on the
death (RR, 0.50; 95% CI, 0.290.87), and intravenamount of proteinuria or change in the amount of
tricular hemorrhage (RR, 0.38; 95% CI, 0.170.87)
proteinuria.
(27). In a single placebo-controlled study of weekly
betamethasone for women with severe preeclampsia
between 26 weeks of gestation and 34 weeks of gestation, treatment (mean exposure 1.7 doses) reduced
Management Before the Limit of Fetal Viability
the frequency of respiratory distress syndrome (RR,
Severe preeclampsia that develops near the limit of fetal
0.53; 95% CI, 0.350.82) and intraventricular hemorviability is associated with a high likelihood of perirhage (RR, 0.35; 95% CI, 0.150.86), among other
natal morbidities and mortality, regardless of expectcomplications (28). If not previously given, and if it is
ant management (2123, 26, 31, 32). However, data
anticipated that there will be time for fetal benefit
regarding outcomes with expectant management catfrom this intervention, antenatal corticosteroid adminegorized by gestational week at diagnosis are limited.
istration should be considered regardless of a plan for
Survival rates of 0/34 (0%), 4/22 (18.2%), and
15/26 (57.7%) have been reported after expectant
management of severe preeclampsia initiated before

23 0/7 weeks of gestation, at 23 0/7 weeks of gestation, and at 24 0/7 weeks of gestation, respectively
For women with severe preeclampsia receiving (21, 23, 31). Other reports also have
suggested rare
expectant management at 34 0/7 weeks or less of
survival with expectant management of severe pregestation, the administration of corticosteroids for
eclampsia at less than 2324 weeks of gestation (32).
fetal lung maturity benefit is recommended.
Explicit counseling regarding the likelihood of poor
perinatal outcomesincluding severe respiratory
distress syndrome, chronic lung disease, and severe
intraventricular hemorrhagewith expectant manSevere Proteinuria
agement should be provided. This is especially
The presence of severe proteinuria in women with important in the presence of severe
fetal growth
severe preeclampsia undergoing expectant managerestriction at less than 23 0/7 weeks of gestation,
ment is not associated with worse outcomes. In one when the perinatal mortality rate
approaches 100%
study of 42 expectantly managed women with severe
(31, 32). Further, maternal complications such as
39
HELLP syndrome, pulmonary edema, and renal failnausea, or vomiting; and those who develop preterm
ure must be balanced with poor perinatal outcome.
labor or premature rupture of membranes (21, 23).
Maternal indications for delivery
Recurrent severe hypertension
Recurrent symptoms of severe preeclampsia
For women with severe preeclampsia and before Progressive renal insufficiency
(serum creatinine
fetal viability, delivery after maternal stabilization
concentration greater than 1.1 mg/dL or a douis recommended. Expectant management is not
bling of the serum creatinine concentration in the
recommended.
absence of other renal disease)

Persistent thrombocytopenia or HELLP syndrome
Pulmonary edema
Eclampsia
Maternal and Fetal Monitoring
During expectant management, maternal and fetal
Progressive labor or rupture of membranes
conditions should be frequently monitored as follows:
Fetal indications for delivery
Maternal assessment
Gestational age of 34 0/7 weeks
Vital signs, fluid intake, and urine output should be
Severe fetal growth restriction (ultrasonographic
monitored at least every 8 hours
estimate of fetal weight less than the fifth percentile)
Symptoms of severe preeclampsia (headaches,
Persistent oligohydramnios (maximum vertical
visual changes, retrosternal pain or pressure, shortpocket less than 2 cm)
ness of breath, nausea and vomiting, and epigastric
BPP of 4/10 or less on at least two occasions
pain) should be monitored at least every 8 hours
6 hours apart
Presence of contractions, rupture of membranes,
Reversed end-diastolic flow on umbilical artery
abdominal pain, or bleeding should be monitored
Doppler studies
at least every 8 hours
Recurrent variable or late decelerations during NST
Laboratory testing (CBC and assessment of platelet
Fetal death
count, liver enzyme, and serum creatinine levels)
should be performed daily. (These tests can then be
spaced to every other day if they remain stable and
the patient remains asymptomatic.)
It is suggested that corticosteroids be administered
and delivery deferred for 48 hours if maternal and
Fetal assessment
fetal conditions remain stable for women with se Kick count and NST with uterine contraction monivere preeclampsia and a viable fetus at 33 6/7
tored daily
weeks or less of gestation with any of the following:
Biophysical profile twice weekly

Serial fetal growth should be performed every 2
preterm premature rupture of membranes
weeks and umbilical artery Doppler studies should
labor
be performed every 2 weeks if fetal growth restric low platelet count (less than 100,000/microtion is suspected
liter)
persistently abnormal hepatic enzyme concenIndications for Delivery During Expectant
trations (twice or more the upper normal valManagement
ues)
In the published studies of preterm severe preeclampsia
fetal growth restriction (less than the fifth permanaged expectantly, delivery has typically been purcentile)
sued at approximately 34 weeks of gestation. However,
severe oligohydramnios (amniotic fluid index
deterioration of maternal or fetal conditions before this
less than 5 cm)
gestational age is the most common reason for delivery
reversed end-diastolic flow on umbilical artery
(21, 23, 27). Maternal indications for delivery are delinDoppler studies
eated in Figure 5-2. Delivery should also be considered
new-onset renal dysfunction or increasing renal
for women whose health is declining or who are nonaddysfunction
herent with ongoing inpatient observation; those develQuality of evidence: Moderate
oping persistent epigastric or right upper quadrant pain,
40
It is recommended that corticosteroids be given if
oping countries (36). For many years, these were
the fetus is viable and at 33 6/7 weeks or less of
treated with several different anticonvulsants, and
gestation, but delivery not be delayed after initial
attempts to prevent eclamptic seizures were exercised
maternal stabilization regardless of gestational age
sporadically (37).
for women with severe preeclampsia that is compliSystematic reviews of magnesium sulfate for the
cated further with any of the following:

treatment of eclampsia have demonstrated its superi uncontrollable severe hypertension
ority to phenytoin and diazepam (38). For women
eclampsia
with eclampsia, magnesium sulfate should be contin pulmonary edema
ued for at least 24 hours after the last convulsion. Fur abruptio placentae
thermore, a systematic review of six randomized trials
that included more than 11,000 women demonstrated
evidence of nonreassurring fetal status
that in women with preeclampsia, magnesium de intrapartum fetal demise
creases the rate of eclampsia by 50% (RR, 0.41; 95%
CI, 0.290.58) (39). In this review, the regimens of
magnesium sulfate used included an intravenous loadStrength of recommendation: Strong
ing dose of 46 g followed by a maintenance dose of
12 g/h for at least 24 hours. In addition, some studies
Route of Delivery in Preeclampsia
used an intramuscular maintenance regimen that is
not used in the United States. Women treated with
When delivery is indicated, vaginal delivery can often
magnesium sulfate to prevent or treat eclamptic seibe accomplished, but this is less likely with decreasing
zures should receive an intravenous loading dose of
gestational age. With labor induction, the likelihood of
46 g followed by a maintenance dose of 12 g/h concesarean delivery increases with decreasing gestational
tinued for at least 24 hours.
age (range, 9397% at less than 28 weeks of gestation,
Several observational and retrospective studies
5365% at 2832 weeks of gestation, and 3138% at
found that expectant management of eclampsia to
3234 weeks of gestation) (23, 33, 34).
prolong gestation for fetal benefit is associated with a
substantial increase of maternal and perinatal morTASK FORCE RECOMMENDATION
bidity and mortality (40). One retrospective study,
however, found that expectant management of
For women with preeclampsia, it is suggested that
eclampsia (antepartum onset before 34 weeks of gesthe mode of delivery does not need to be cesarean
tation) for 2448 hours to administer corticosteroids

delivery. The mode of delivery should be deterfor fetal benefit can be undertaken if meticulous
mined by fetal gestational age, fetal presentation,
maternal and fetal monitoring remains reassuring
cervical status, and maternalfetal condition.
while continuously infused magnesium sulfate and
antihypertensive agents to prevent severe hypertenStrength of recommendation: Qualified
sion are administered for maternal stabilization;
however, the safety of such an approach has not been
Eclampsia
proved (41). In all other circumstances, there is general agreement that women with eclampsia should
Eclampsia is defined as the presence of new-onset
undergo delivery following stabilization. Patients
grand mal seizures in a woman with preeclampsia. with severe preeclampsia undergoing
cesarean delivEclampsia is preceded by a wide range of signs and ery remain at risk of developing
eclampsia. The
symptoms, ranging from severe to absent or minimal
induction of anesthesia and the stress of delivery may
hypertension, massive to no proteinuria, and promireduce their seizure threshold and increase the likelinent to no edema (35). Several clinical symptoms are
hood of eclampsia. Discontinuing magnesium sulfate
potentially helpful in predicting impending eclampsia.
infusions in the operative suite will not abate the
These include persistent occipital or frontal headaches,
potential interactions of magnesium sulfate with
blurred vision, photophobia, epigastric or right upper
anesthetic agents and furthermore increases the likequadrant pain or both, and altered mental status (35,
lihood of a subtherapeutic serum magnesium level in
36). Eclamptic seizures contribute substantially to the recovery room or postpartum suite,
placing the maternal morbidity and mortality, especially in devel-patient at risk of postpartum
eclampsia.
41
with HELLP syndrome. Because a significant fetal
benefit of corticosteroid administration exists for
For women with eclampsia, the administration of
women with severe preeclampsia, similar fetal bene-
parenteral magnesium sulfate is recommended.

fit should exist for women with antepartum HELLP
syndrome.
Several observational and retrospective studies
have found that in combination with magnesium sul For women with severe preeclampsia, the adminisfate therapy and control of severe hypertension, differtration of intrapartumpostpartum magnesium sulent regimens of steroids have been associated with a
fate to prevent eclampsia is recommended.
major maternal morbidityrelated decrease in HELLP
syndrome (44, 45). However, data on maternal beneStrength of recommendation: Strong
fits of dexamethasone in women with HELLP syndrome are conflicting (46, 47). A 2010 Cochrane
For women with preeclampsia undergoing cesarean
meta-analysis of 11 randomized controlled trials evaldelivery, the continued intraoperative administrauated the effect of antenatal maternal corticosteroid
tion of parenteral magnesium sulfate to prevent treatment on perinatal outcomes during
expectant
eclampsia is recommended.
management of HELLP syndrome (48). Among these
trials, only four trials (362 women) reported maternal
death; three trials (278 women) reported maternal
death or severe maternal morbidity; two trials (91
HELLP Syndrome
women) reported maternal liver hematoma, rupture,
or failure; and three trials (297 women) reported
Hemolysis, abnormal liver function tests, and thrommaternal pulmonary edema. This systematic review
bocytopenia have been recognized as complications of
found significantly improved maternal platelet counts
preeclampsia and eclampsia for many years. The term
when corticosteroids are given, but no evidence of
HELLP syndrome is an acronym for the following
improvements in maternal mortality or severe materpresentation: hemolysis, elevated liver enzymes, and
nal morbidities was reported. More robust and prolow platelet count (42).
perly performed randomized trials are needed to
The development of HELLP syndrome may occur clarify what value this intervention
may bring to
antepartum or postpartum (43). The clinical course of
HELLP syndrome management.
women with HELLP syndrome is often characterized
by progressive and sometimes sudden deterioration in
maternal and fetal condition. Because the presence of
this syndrome has been associated with increased For women with HELLP syndrome
and before the
rates of maternal morbidity and mortality, many
gestational age of fetal viability, it is recommended
authors consider its presence to be an indication for
that delivery be undertaken shortly after initial
immediate delivery. A consensus of opinion is that
maternal stabilization.
prompt delivery is indicated if the syndrome develops
beyond 34 weeks of gestation or earlier if there is disStrength of recommendation: Strong
seminated intravascular coagulation, liver infarction
or hemorrhage, renal failure, pulmonary edema, sus For women with HELLP syndrome at 34 0/7 weeks
pected abruptio placentae, or nonreassuring fetal staor more of gestation, it is recommended that delivtus (43). Because the management of patients with
ery be undertaken soon after initial maternal stabiHELLP syndrome requires the availability of neonatal
lization.
and obstetric intensive care units and personnel with
special expertise, patients with HELLP syndrome who
are remote from term should receive care at a tertiary
care center (43).
For women with HELLP syndrome from the gestaThe task force found no randomized trials that
tional age of fetal viability to 33 6/7 weeks of gesevaluated the benefits versus risks of a short course of
tation, it is suggested that delivery be delayed for
corticosteroids for fetal lung maturation in women
2448 hours if maternal and fetal condition remain
42
stable to complete a course of corticosteroids for development of an epidural hematoma.
The enlarged
fetal benefit.*
epidural veins accompanying pregnancy increase the
risk of puncture of these vessels during needle or
catheter placement. Risk factors for hematoma
include difficult placement, coagulopathy, and cathe*Corticosteroids have been used in randomized controlled
trials to attempt to improve maternal and fetal condition.
ter removal (52). The task force found no studies that
In these studies, there was no evidence of benefit to imexamined the safe limit for platelet count and neuraxprove overall maternal and fetal outcome (although this
ial anesthesia. There are numerous case reports of
has been suggested in observational studies). There is eviepidural placement in patients with low platelet
dence in the randomized trials of improvement of platelet
counts (as low as 20,000/microliter). These case
counts with corticosteroid treatment. In clinical settings
in which an improvement in platelet count is considered
reports do not establish a safe limit. The American
useful, corticosteroids may be justified.
Society of Anesthesiologists has not recommended a
safe limit for the platelet count in parturient women
with preeclampsia, relying on the health care providAnesthetic Considerations
ers judgment following review of the laboratory valHypotension
ues (53). A review article of case series and case
Spinal anesthesia results in hypotension secondary to
reports on epidural and spinal anesthesia in patients
sympathetic blockade, which decreases uteroplacental
with thrombocytopenia concluded that 80,000/
blood flow. The incidence and severity of hypotension
microliter is a safe platelet count for the placement of
following spinal anesthesia was compared in parturiepidural or spinal anesthesia and for the removal of
ent women with severe preeclampsia (65 patients) an epidural catheter. This conclusion
by these authors
and women without the disease process (71 patients)
is dependent on a stable platelet count and the
(49). Hypotension, defined as a 30% decrease in mean
absence of coagulopathy (54).
arterial pressure, was less common in the parturient
women with severe preeclampsia (24.6% versus Magnesium Sulfate
40.8%), with no difference in the severity of the
Magnesium sulfate has significant anesthetic implicahypotension.

tions. It prolongs the duration of nondepolarizing
The task force found no meta-analyses that commuscle relaxants and has led to practitioners stopping
pared spinal anesthesia with general anesthesia for magnesium sulfate administration
during surgical procesarean delivery in women with severe preeclampsia.
cedures. However, because magnesium has a half-life
However, there is one randomized trial that compared
of 5 hours, discontinuing the intravenous infusion of
spinal anesthesia with epidural anesthesia for women
magnesium sulfate before cesarean delivery minimally
with severe preeclampsia who underwent cesarean reduces magnesium concentration at
the time of delivdelivery (50). The spinal group consisted of 53 patients,
ery and possibly increases the risk of seizure (55).
and 47 patients were in the epidural group. HypotenWomen with preeclampsia who require cesarean delivsion was defined as a systolic BP less than 100 mm Hg.
ery should continue magnesium sulfate infusion
The incidence of hypotension was higher in the spinal
during the delivery.
group (51% versus 23%) but was easily treated and of
short duration (less than 1 minute). There were no Invasive Hemodynamic Monitoring
adverse effects on the woman or the neonate.
Invasive monitoring allows for the direct measurement of BP as well as cardiac filling pressure. The use
Thrombocytopenia
of an arterial catheter for direct measurement of BP is
Thrombocytopenia is the most common hematologic
used in parturient women who may require frequent
abnormality in women with preeclampsia. Its inciarterial specimens for pH and blood gas analysis. It
dence depends on the severity of the disease and the
also may be indicated in patients who receive continupresence or absence of abruptio placentae. In one ous infusions of potent vasoactive
drugs. With proper
survey, a platelet count of less than 150,000/microliuse, the risk of arterial catheterization is low, primarily
ter was found in 50% of parturient women with preincluding infection (dependent on location of arterial
eclampsia and a platelet count of less than 100,000/
catheter, with femoral placement having a greater
microliter in 36% of the women (51). The major risk) and thrombosis (56). There are,
however, no spe-concern with neuraxial anesthesia and analgesia in
cific data concerning the risk of arterial catheterization

parturient women with thrombocytopenia is the in the parturient woman.
43
Placement of a catheter in a central vein for deterPostpartum Hypertension and
mination of a central venous pressure (CVP) or of a
Preeclampsia
pulmonary artery catheter allows for the administration of medication, improved venous access, and
The exact incidence of postpartum hypertension and
hemodynamic monitoring. These monitors may allow
preeclampsia is difficult to ascertain because most
for the measurement of filling pressure of the heart
women in the postpartum period will not have their
and assessment of vascular resistance, cardiac funcBP checked until the 6-week postpartum visit (61). In
tion, and oxygen uptake and delivery. The correlation
addition, most women with hypertension usually are
between CVP and pulmonary artery occlusion presasymptomatic, and those with symptoms frequently
sure in preeclampsia is moderate, which limits the
are seen and managed in emergency departments.
usefulness of CVP determinations (57). In 30 parturiSeveral studies have reported that many women will
ent women with severe preeclampsia, the correlation
be hospitalized postpartum because of severe hypercoefficient between CVP and pulmonary artery occlutension and preeclampsia, and a 2010 large populasion pressure was 0.64, if the patient did not receive
tion-based study reported that 0.3% of all postpartum
treatment. Treatment of the disease process reduced
visits to emergency departments were due to hyperthe correlation coefficient to 0.53. This lack of cortension and preeclampsia (62). Postpartum hypertenrelation is further confounded by the lack of data sion and preeclampsia are either
secondary to
from randomized controlled trials that demonstrate
persistent hypertension or exacerbation of hypertenthe usefulness of pulmonary artery catheters (58),
sion in women with previous gestational hypetension,
but pulmonary artery catheterization is not without
preeclampsia, chronic hypertension or because of a
risk (59). Four of the 100 patients who were reviewed
new-onset condition (61). In women with preeclamp-
retrospectively had either a venous thrombosis or celsia or superimposed preeclampsia, BP usually delulitis. A retrospective case series of patients who creases within 48 hours following
delivery, but the BP
received central venous catheters was performed. Of
increases again 36 days postpartum (61). Several
85 patients, 20 had preeclampsia. A high incidence of
studies have emphasized the potential value of educatinfection (14%) was reported in those parturient ing patients and health care providers to
report signs
women who received central venous catheters (60).
and symptoms of preeclampsia that commonly preOther complications included superficial and deep
cede eclampsia, hypertensive encephalopathy, pulmovein thrombosis, hematoma, ventricular tachycardia,
nary edema, or stroke (6366). However, it remains
and discomfort.
unclear whether such reporting will lead to the prevention of eclampsia and adverse maternal outcomes.
Several retrospective studies have found that most
women who presented with eclampsia and stroke in
For women with preeclampsia who require analgethe postpartum period had these symptoms for hours
sia for labor or anesthesia for cesarean delivery and
and days before presentation (6366). In addition,
with a clinical situation that permits sufficient time
many of these symptoms were not considered importfor establishment of anesthesia, the administration
ant by patients or medical providers. The group also
of neuraxial anesthesia (either spinal or epidural
believed that many medical providers (nurses, obsteanesthesia) is recommended.
tricians, nursemidwives, emergency department physicians, and internists) may not be aware that
preeclampsia and eclampsia can develop up to 4 weeks
postpartum. Health care providers are reminded of the
For women with severe preeclampsia, it is sugcontribution of nonsteroidal antiinflammatory agents
gested that invasive hemodynamic monitoring not
to increase BP. It is suggested that these commonly
be used routinely.
used postpartum pain relief agents be replaced by
other analgesics in women with hypertension that perStrength of recommendation: Qualified

sists for more than 1 day postpartum.
For women in whom gestational hypertension, preeclampsia, or superimposed preeclampsia is diagnosed, it is suggested that BP be monitored in the
hospital or that equivalent outpatient surveillance
44
be performed for at least 72 hours postpartum and
again 710 days after delivery or earlier in women
with symptoms.
For women with persistent postpartum hypertension,
BP of 150 mm Hg systolic or higher or 100 mm Hg
diastolic or higher, on at least two occasions that are
For all women in the postpartum period (not just
at least 46 hours apart, antihypertensive therapy is
women with preeclampsia), it is suggested that dissuggested. Persistent BP of 160 mm Hg systolic or
charge instructions include information about the
100 mm Hg diastolic or higher should be treated
signs and symptoms of preeclampsia as well as the
within 1 hour.
importance of prompt reporting of this information
to their health care providers.
References
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tension and preeclampsia. Obstet Gynecol 2003;102:
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NK, Jacques DL, Sibai BM.
found no placebo-controlled trials that evaluated the
Mild gestational hypertension remote from term: progrestreatment of postpartum hypertension or evaluated
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magnesium sulfate versus placebo in women with 3. Magee LA, Abalos E, von
Dadelszen P, Sibai B, Easterling T, late postpartum preeclampsia (61). A few trials that
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54. van Veen JJ, Nokes TJ, Makris M. The risk of spinal haema6
CHAPTER
Management of Women With
Prior Preeclampsia
The primary objectives in the management of including the presence of infertility and
preexisting
patients with a history of preeclampsia are comorbidities such as obesity, chronic
hypertension,
to reduce risk factors for recurrence by optirenal disease, diabetes mellitus, connective tissue dismizing maternal health before conception, to
orders, and acquired thrombophilias. A baseline labodetect obstetric complications, and to achieve optimal
ratory evaluation could include a complete blood
perinatal outcome during subsequent pregnancy. These
count, metabolic profile, and urinalysis. A detailed
objectives can be achieved by formulating a rational obstetric history should include
maternal as well as
approach that includes preconception evaluation and perinatal outcomes in the previous
pregnancy (2, 3).

counseling, early antenatal care, frequent antepartum
Therefore, information should be obtained from
visits to monitor both maternal and fetal well-being,
medical records concerning the gestational age at
and timely delivery (see Box 6-1) (1).
onset of preeclampsia, maternal complications
(HELLP [hemolysis, elevated liver enzymes, and low
Preconception Management
platelet count] syndrome, eclampsia, pulmonary edema, renal failure, and abruptio placentae), perinatal
Treatment of a patient with a previous pregnancy comcomplications (fetal growth restriction, perinatal morplicated by preeclampsia ideally should begin before
bidity, and perinatal death), and laboratory test valconception. If the patient is unlikely to have a preconues, including those for acquired thrombophilia and
ception visit, this assessment should be conducted at
connective tissue disorders as well as placental patholthe 6-week postpartum visit, including patient counogy, if available.
seling on risk of preeclampsia recurrence and riskThe status of maternal comorbidities ideally should
modification strategies. Results should be forwarded
be optimized before conception. High body mass index
to her primary health care provider.
is a risk factor for preeclampsia. Overweight or obese
For women who present before conception, manpatients should be counseled on the potential benefit
agement should include a thorough medical history of
of weight loss as a modifiable risk factor. They should
preexisting risk factors and medical conditions reportbe referred for nutritional counseling in an attempt to
edly associated with preeclampsia to allow appropriachieve a healthy body mass index. Weight loss and
ate counseling as to the magnitude of the risk of lifestyle modification also may reduce
the likelihood of
preeclampsia in subsequent pregnancy. Also, attention
chronic hypertension and type 2 diabetes mellitus.
should be given to the outcome of the previous pregBecause the risk of preeclampsia correlates with the
nancy as well as assessment of maternal risk factors,
severity of maternal hypertension and glycemic control,
47
48
MANAGEMENT OF WOMEN WITH PRIOR PREECLAMPSIA
BOX 6-1. Evaluation and Management of Women at Risk of Preeclampsia
Recurrence ^
Preconception
Identify risk factors (ie, type 2 diabetes mellitus, obesity, hypertension, and family
history).
Review outcome of previous pregnancy (abruptio placentae, fetal death, fetal growth
restriction,
and gestational age at delivery).
Perform baseline metabolic profile and urinalysis.
Optimize maternal health.
Supplement with folic acid.
First Trimester
Perform the following:
Ultrasonography for assessment of gestational age and fetal number
Baseline metabolic profile and complete blood count
Baseline urinalysis
Continue folic acid supplementation.
Offer first-trimester combined screening.
For women with prior preeclampsia that led to delivery before 34 weeks of gestation or
occurring in
more than one pregnancy, offer low-dose aspirin late in the first trimester and discuss the
risks and
benefits of low-dose aspirin with other women.
Second Trimester
Counsel patient about signs and symptoms of preeclampsia beginning at 20 weeks of
gestation;
reinforce this information with printed handouts.
Monitor for signs and symptoms of preeclampsia.
Monitor blood pressure at prenatal visits, with nursing contacts, or at home.
Perform ultrasonography at 1822 weeks of gestation for fetal anomaly evaluation and
to rule out
molar gestation.
Hospitalize for severe gestational hypertension, severe fetal growth, or recurrent
preeclampsia.
Third Trimester
Monitor for signs and symptoms of preeclampsia.
Monitor blood pressure at prenatal visits, with nursing contacts, or at home.
Perform the following as indicated by clinical situation:
Laboratory testing
Serial ultrasonography for fetal growth and amniotic fluid assessment
Umbilical artery Doppler with nonstress test, biophysical profile, or both
Hospitalize for severe gestational hypertension or recurrent preeclampsia.
Modified from Barton JR, Sibai BM. Prediction and prevention of recurrent
preeclampsia. Obstet Gynecol 2008;112:35972.
women with chronic hypertension, diabetes mellitus,

come as well as the effect of pregnancy on these conor both, should have their blood pressure, blood gluditions. In addition, if the patient is taking medications
cose, or both, optimized before conception. It is
for a chronic medical disorder, there should be a
unknown, however, whether amelioration of altered
review of these medications with special emphasis on
hemodynamics or optimization of glucose control will
those to be avoided, such as angiotensin receptor
definitively reduce the recurrence risk of preeclampblockers and some immunosuppressive agents. As for
sia. During the preconception visit, discussion should
any woman contemplating conception, folic acid supinclude the effects of these diseases on pregnancy outplementation should be prescribed.
MANAGEMENT OF WOMEN WITH PRIOR PREECLAMPSIA
49
Antepartum Management
Early and frequent prenatal visits are the key for a sucBOX 6-2. Symptoms of Preeclampsia^
cessful pregnancy outcome in women with preeclampsia in a previous pregnancy, particularly those with
Swelling of the face or hands
early-onset disease. First-trimester ultrasound exam Headache that will not go away
ination is essential to determine accurate gestational
Seeing spots or changes in eyesight
age and establish fetal number. For women with prior
preeclampsia leading to delivery before 34 weeks of
Pain in upper right quadrant or stomach
gestation or occurring in more than one pregnancy,
Nausea or vomiting (in second half of
low-dose aspirin should be offered late in the first tripregnancy)
mester, and the risks and benefits of low-dose aspirin
Sudden weight gain
should be discussed with other women with prior preeclampsia.
Difficulty breathing
During each antepartum visit, the woman should
be monitored closely for signs and symptoms of preeclampsia (Box 6-2). She also should be educated
about symptoms of organ dysfunction and instructed
to report any symptoms, such as severe headache,

visual change, right upper quadrant or epigastric pain,
nausea and vomiting, and changes in fetal movement.
For women with preeclampsia in a prior pregnancy,
The frequency of antepartum visits may be modified
preconception counseling and assessment is sugaccording to the gestational age at the onset of pregested.
eclampsia in the previous pregnancy as well as the
results of maternal and fetal surveillance. Health care
providers must be cautioned that these recommendations concerning antepartum management and assessReferences
ment are not evidence-based because there are no
randomized studies addressing this subject. Fetal 1. Barton JR, Sibai BM. Prediction and
prevention of recur-growth should be monitored serially, given the known
rent preeclampsia. Obstet Gynecol 2008;112:35972.
relationship between fetal growth restriction and pre[PubMed] [ Obstetrics & Gynecology] ^
eclampsia. During antepartum surveillance of women
2. Hjartardottir S, Leifsson BG, Geirsson RT, Steinthorsdottir V.
Recurrence of hypertensive disorder in second pregnanwith previous preeclampsia, the development of severe
cy. Am J Obstet Gynecol 2006;194:91620. [PubMed]
gestational hypertension, fetal growth restriction, or
[Full Text] ^
recurrent preeclampsia requires maternal hospitaliza3. Brown MA, Mackenzie C, Dunsmuir W, Roberts L, Ikin K,
tion for more frequent maternal and fetal evaluation
Matthews J, et al. Can we predict recurrence of pre(see Chapter 5 Management of Preeclampsia and
eclampsia or gestational hypertension? BJOG 2007;114:
HELLP Syndrome).
7
CHAPTER
Chronic Hypertension in Pregnancy
and Superimposed Preeclampsia
Chronic hypertension presents special chal- 110 mm Hg or higher), although a distinction
is not
lenges to health care providers. Health made between chronic, gestational, or
preeclamptic
care providers must first confirm that blood

hypertension. Most women with chronic hypertension
pressure (BP) elevation is not preeclampsia.
will have essential (also called primary) hypertension,
Perhaps the greatest challenge is the recognition of but as many as 10% may have
underlying renal or
preeclampsia superimposed on chronic hypertension,
endocrine disorders (ie, secondary hypertension).
a condition that is commonly associated with adverse
The diagnosis of chronic hypertension is easily
maternal and fetal outcomes.
established when prepregnancy hypertension is well
documented and in women already receiving antihyChronic Hypertension in Pregnancy
pertensive medications. Chronic hypertension also is
the most likely diagnosis when hypertension is present
Definition and Diagnosis
in the first trimester. Difficulties may arise when pregChronic hypertension in pregnancy is defined as hypernant women with prepregnancy, undiagnosed hypertension present before pregnancy or before 20 weeks of
tension initially present in the second trimester with
gestation (1). Chronic hypertension is present in up to
normal BP after having experienced the pregnancy5% of pregnant women; rates vary according to the associated physiologic decrease in
BP. These women
population studied and the criteria used to establish will have been presumed to be
normotensive, and if BP
the diagnosis (13). Chronic hypertension complicating
increases in the third trimester, they may be erronepregnancy is diagnosed when high BP is known to preously diagnosed with either gestational hypertension
date pregnancy. When prepregnancy BP is not known,
or, if proteinuria is present, with preeclampsia rather
elevated BP detected before 20 weeks of gestation is
than superimposed preeclampsia. Thus, chronic hyperoften due to chronic hypertension. However, if BP was
tension may not be diagnosed until well after delivery.
normal in the first trimester and then increases before
In other instances, women with well-documented
20 weeks of gestation, gestational hypertension or early
hypertension before pregnancy will demonstrate norpreeclampsia also should be considered (4). Hypertenmal BP throughout the entire pregnancy only to return
sion is defined as either a systolic BP of 140 mm Hg or
to prepregnancy hypertensive levels postpartum.
greater, or a diastolic BP of 90 mm Hg or greater, or both.

In pregnancy, BP is categorized as mild to moderate
Maternal and Fetal Outcomes
(systolic, 140159 mm Hg or diastolic, 90109 mm Hg)
Reports of outcomes of pregnancies complicated by
or severe (systolic, 160 mm Hg or higher, diastolic
chronic hypertension have not uniformly distinguished
51
52
CHRONIC HYPERTENSION IN PREGNANCY AND SUPERIMPOSED
PREECLAMPSIA
between women with superimposed preeclampsia and
ated with chronic hypertension in pregnancy is the
those with uncomplicated chronic hypertension. Preexposure to antihypertensive medications in utero that
existing hypertension is a recognized risk factor for
may cause growth restriction and fetal malformations;
preeclampsia. Superimposed preeclampsia develops in
this has been extensively evaluated. Although most
13 40% of women with chronic hypertension, dependantihypertensive agents considered safe in pregnancy
ing on diagnostic criteria, etiology (essential versus
have not been shown to be associated with fetal malsecondary), duration, and the severity of hypertension
formations, the question of whether they have an
(5, 6). A major reason for this wide range in incidence
effect on growth is still controversial. Clinical trials
is that the definition of superimposed preeclampsia is
that evaluated long-term outcomes of exposed offused liberally in some studies.
spring have been conducted with a limited number of
Women with chronic hypertension who develop
agents, primarily, methyldopa.
superimposed preeclampsia have higher rates of
adverse maternalfetal outcomes, but the indepenChronic Hypertension With Superimposed
dent risks associated with uncomplicated chronic Preeclampsia
hypertension are less clear. An analysis of 1,807
Preexisting hypertension is a recognized risk factor for
deliveries in women with chronic hypertension found
preeclampsia, and superimposed preeclampsia is assothat uncomplicated chronic hypertension was still ciated with considerable maternalfetal
morbidity and
associated with a greater risk of cesarean delivery mortality. Superimposed preeclampsia
develops in
(odds ratio [OR], 2.7; 95% confidence interval [CI],
1340% of women with chronic hypertension, depend2.43.0) and postpartum hemorrhage (OR, 2.2;
ing on diagnostic criteria, etiology (essential versus
95% CI, 1.43.7) compared with women without
secondary), duration, and the severity of hypertension
hypertension (2). Other adverse maternal outcomes
(5, 6). A major reason for this wide range in incidence
in women with chronic hypertension include acceleris that the definition of superimposed preeclampsia is
ated hypertension with resultant target organ damliberally used in some studies.
age (eg, to the heart, brain, and kidneys), although in
the absence of preeclampsia, this is extremely uncomPreconception Counseling
mon. Women with higher prepregnancy BP or those
Preconception counseling should include explanation
with secondary hypertension are at greater risk of of the risks associated with chronic
hypertension and
developing severe hypertension during pregnancy. education about the signs and
symptoms of preeclampChronic hypertension is associated with an increased
sia. Maternal characteristics that increase the risk of
risk of gestational diabetes (OR, 1.8; 95% CI, 1.4 2)
superimposed preeclampsia include the presence of
(2, 7, 8). This may reflect similar risk factors for both
diabetes, obesity, or renal disease; history of preconditions (eg, obesity) as well as similar pathogeeclampsia, particularly early preeclampsia; severity
netic mechanisms (eg, insulin resistance). The risk of
and duration of hypertension before pregnancy; and
abruptio placentae is increased threefold in women
presence of secondary hypertension, such as pheowith chronic hypertension, although most of the
chromocytoma and renovascular hypertension (5, 11).
increased risk is associated with superimposed preMedications with known fetal adverse effects often
eclampsia (5, 9, 10). Women with chronic hypertenprescribed to women with chronic hypertension
sion in pregnancy are more likely to be hospitalized
should be discontinued before conception. In particufor hypertension (8).
lar, angiotensin-converting enzyme (ACE) inhibitors,
Perinatal mortality is higher in pregnancies associangiotensin receptor blockers, and mineralocorticoid
ated with chronic hypertension, most of this increased

antagonists are contraindicated. Statins, which are
attributable risk is the result of superimposed prewidely used in individuals with hypertension who also
eclampsia (5, 10). The relative risk of perinatal death
have elevated cholesterol, should be avoided because
is reported to be approximately 3.6 in women with
there is conflicting evidence about the safety of their
superimposed preeclampsia compared with those with
use in pregnancy (12).
uncomplicated chronic hypertension (8). Perinatal
death also is higher in women with uncomplicated Antepartum Management
hypertension compared with normotensive controls
(relative risk, 2.3) (8).
Initial Evaluation of Women With Known or
Fetal growth restriction is more frequent with Suspected Chronic Hypertension
chronic hypertension and is usually associated with All women with preexisting
hypertension should be assuperimposed preeclampsia (6). Another risk associsessed either before pregnancy or early in pregnancy
PREECLAMPSIA
53
as outlined by the Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure and the National
BOX 7-1. Findings Suggestive of
Secondary Hypertension ^
High Blood Pressure Education Program guidelines
to rule out secondary (and potentially curable)
Any of the following findings are suggestive
hypertension if appropriate and to seek out evidence
of secondary hypertension:
of target organ damage, unless such evaluations were
previously performed. Baseline concentrations of
Resistant hypertension
serum creatinine, electrolytes, uric acid, liver
Hypokalemia (potassium level less than
enzymes, platelet count, and urine protein (either
3.0 mEq/L)
dipstick test or quantification of urine protein) should
Elevated serum creatinine level (greater
be documented to use as comparators if superimthan 1.1 mg/dL)
posed preeclampsia is suspected later in pregnancy.
Glucose tolerance testing should be performed early

Strong family history of kidney disease
in pregnancy for women at risk of gestational diabetes (obese, history of gestational diabetes, or strong
family history of type 2 diabetes mellitus). Good clinical practice suggests performing assessment of left
ventricular function with either echocardiography or
electrocardiography in women with severe hypertension of long duration (eg, more than 4 years).
For women with features suggestive of secondary
hypertension, referral to a physician with expertise
Screening for Secondary Hypertension
in treating hypertension to direct the workup is
The most common cause of secondary hypertension
suggested.
is chronic kidney disease, and screening is easily
accomplished with routine blood chemistries and uriStrength of recommendation: Qualified
nalysis. If proteinuria is detected on urinalysis (1+ or
greater), either a 24-hour urine should be collected
Monitoring Blood Pressure
or a protein/creatinine ratio measured in a spot urine
Blood pressure is checked monthly in all pregnant
to quantify the level of proteinuria. If evidence of women as part of standard obstetric
practice. Although
chronic kidney disease is detected (abnormal urinalyincreased frequency of BP monitoring has not been
sis or elevated serum creatinine), or if there is a
evaluated as a strategy for improving pregnancy outstrong family history of kidney disease, then renal
comes, good clinical practice dictates increased moniultrasonography should be performed to rule out toring for women with BP above desired
targets.
polycystic kidney disease, the most common genetic
Although most superimposed preeclampsia occurs
type of kidney disease. Other causes of secondary near term, it can occur before 24 weeks
of gestation,
hypertension that may be present in women of childand there are even anecdotal reports of its occurrence
bearing age include primary aldosteronism, renovasbefore 20 weeks of gestation. Therefore, increased
cular hypertension, pheochromocytoma, and Cushing
monitoring may be particularly useful in the second
disease. Suggestive clinical features of secondary half of pregnancy. Because of a
considerable body of
hypertension (resistant hypertension, hypokalemia,
literature of hypertension in patients who are not
palpitations, lack of family history of hypertension,
pregnant, which documents the use of home BP moniand age younger than 35 years) warrant considertoring as an aid to achieving BP targets and monitoration of further diagnostic workup. Case series and
ing responses to treatment, the task force suggests this
case reports suggest that particular diagnoses such as
approach for pregnant women.
pheochromocytoma and renovascular hypertension
are associated with adverse maternal and fetal outTASK FORCE RECOMMENDATION
comes, and that if the underlying disorder is treated,
outcomes are improved. There is variability in the For pregnant women with chronic
hypertension
recommended strategies for diagnosing secondary
and poorly controlled BP, the use of home BP monhypertension; therefore, the task force suggests referitoring is suggested.
ral to a hypertension specialist if secondary hypertenQuality of evidence: Moderate
sion is a consideration (Box 7-1).
54
PREECLAMPSIA
White coat hypertension, defined as elevated BP primarexercise, maintaining ideal body weight, moderation
ily in the presence of health care providers, may
of alcohol intake, adopting specific diets (such as the
account for up to 1015% of individuals with office
DASH [Dietary Approaches to Stop Hypertension]
hypertension. The prevalence in pregnancy is not diet, a diet with abundant fruits and
vegetables, lowknown. Ambulatory BP monitoring is the preferred test
fat dairy products, and high fiber), and reducing
to diagnose white coat hypertension in an individual sodium intake. Some of these
approaches are either
who is not pregnant. White coat hypertension should
not appropriate for pregnancy or have not been evalbe suspected if BP is higher in the doctors office comuated in the context of pregnancy. Weight loss and
pared with other settings. Failure to recognize white regular aerobic exercise have been
shown to be bene-
coat hypertension may result in overtreatment of BP ficial in hypertensive individuals

who are not preg-and unnecessary adverse effects of treatment.
nant because it lowers BP and favorably affects weight
and insulin sensitivity (13, 14). Exercise regimens
have been tested in pregnancy, primarily as a strategy
for preventing excessive weight gain (15), and mod For women with suspected white coat hypertenerate-level physical activity in pregnant women
sion, the use of ambulatory BP monitoring to confirm
without medical and obstetric complications is recomthe diagnosis before the initiation of antihypertenmended (16). This approach has not been assessed as
sive therapy is suggested.
a strategy for lowering BP in pregnant women with
chronic hypertension. Observational research and
small clinical trials suggest that exercise may be beneficial in preventing preeclampsia (16, 17); however,
Treatment
these studies have not specified the effect in women
Hypertension is a strong risk factor for stroke, coronary
with chronic hypertension. Whether any exercise or
heart disease, congestive heart failure, kidney disease,
vigorous aerobic exercise is harmful in women
and death; lowering BP has been conclusively shown
with chronic hypertension has not been adequately
to prevent these complications in hypertensive individstudied.
uals who are not pregnant. The course of vascular
damage and cardiovascular (CV) complications associTASK FORCE RECOMMENDATIONS
ated with hypertension is years; stage 1 hypertension
(BP, 140159 mm Hg, systolic/9099 mm Hg, diastolic)
It is suggested that weight loss and extremely
is associated with a 40% increased risk of stroke (comlow-sodium diets (less than 100 mEq/d) not be used
pared with age-matched individuals without hypertenfor managing chronic hypertension in pregnancy.
sion), which is usually apparent after 10 years of
untreated hypertension. In populations of individuals
who are not pregnant, demonstration of such benefits
requires years of treatment, whereas in pregnancy, the

For women with chronic hypertension who are
goals of treatment are more focused on preventing
accustomed to exercising, and in whom BP is well
acute complications of hypertension in the woman and
controlled, it is suggested that moderate exercise
maintaining a healthy pregnancy for as long as possibe continued during pregnancy.
ble. The goals of therapy also include minimizing risks
to the fetus that are attributable to hypertension,
vascular disease, and the possible effects of antihyperAntihypertensive pharmacologic treatment. Treatment
tensive medications that may alter maternal hemoof severe hypertensionThe task force found limited
dynamics and reduce uteroplacental perfusion, or that
evidence regarding the precise BP level at which antimay cross the placenta and be harmful to the fetus. hypertensive therapy is indicated
during pregnancy in
Preventing long-term maternal CV morbidity and morwomen with chronic hypertension. Severe elevations
tality is not the primary concern during pregnancy.
in BP are associated with acute maternal cerebrovasNonpharmacologic treatment. Treatment of hypertencular and coronary events, although the BP level at
sive individuals who are not pregnant is focused which risk of these adverse events
increases is not preon two basic strategies: 1) lowering BP and 2) minicisely known and is likely to vary and depend on
mizing additional CV risk factors. Nonpharmacologic
comorbidities and other factors such as baseline B P,
approaches that have successfully lowered BP in indiand rate of increase. In an adult who is not pregnant,
viduals who are not pregnant include regular aerobic
antihypertensive therapy is recommended when the
PREECLAMPSIA
55
systolic BP is 140 mm Hg or higher or the diastolic BP
is 90 mm Hg or higher, and this approach is supported
by large clinical trials that have clearly demonstrated
For pregnant women with persistent chronic hyperbenefits of treatment (18).
tension with systolic BP of 160 mm Hg or higher or

Few clinical trials have been performed that
diastolic BP of 105 mm Hg or higher, antihypertenspecifically address the optimum level of BP during
sive therapy is recommended.
pregnancy in women with preexisting (chronic)
hypertension. Most studies that address this have not
been limited to women with chronic hypertension
and also have included women with gestational Treatment of mild to moderate
hypertensionWhen
hypertension or preeclampsia. Antihypertensive therand how to use antihypertensive drugs in women with
apy has been compared with placebo or no therapy,
chronic hypertension in pregnancy who do not have
and outcomes assessed in these studies have been severely elevated levels of BP is less
clear. To justify the variable (eg, development of superimposed pre-use of antihypertensive
therapy during pregnancy in
eclampsia, progression of hypertension, and fetal
women with chronic hypertension with mild to moderweight and survival.) A Cochrane systematic review
ately elevated BP (systolic BP of 140 mm Hg or higher
of drug treatment for severe hypertension during and less than 160 mm Hg or diastolic
BP of 90 mm Hg
pregnancy, which included 35 trials involving 3,573
or higher and less than 110 mm Hg), the maternal
women, included few women with chronic hypertenbenefit and improvement in perinatal outcomes that
sion (19). Drug therapy was instituted when diastolic
are due to treatment must outweigh the potential risk
BP levels reached or exceeded 100110 mm Hg, and
of adverse effects on fetal and neonatal safety, includin the majority of the studies, not until the third triing the possibility that pharmacologic reductions in
mester. Women with chronic hypertension were genermaternal systemic BP result in compromised uteroplaally excluded, and if included, no subgroup analysis
cental blood flow.
was reported. Thus, there is a paucity of evidence
Results from seven placebo-controlled randomized
addressing thresholds for initiating antihypertensive trials that involved 650 women with
mild to moderate
drugs in pregnant women with chronic hypertension.
chronic hypertension did not demonstrate an improve-
Future placebo-controlled trials addressing the treatment in either maternal or perinatal outcomes with
ment of severe hypertension are unlikely to be initantihypertensive therapy (6, 2026). Published in
iated and are not recommended given ethical consid2007, a Cochrane systematic review of antihypertenerations. Therefore, recommendations for treating
sive drug therapy for mild to moderate hypertension in
women with chronic hypertension with severely elepregnancy (including all diagnoses) that included 46
vated BP are based on indirect evidence from treating
trials (4,282 women) concluded that treatment
pregnant women with new acute onset of severe gesreduced the risk of developing severe hypertension but
tational hypertension or preeclampsia (19). Given the
had no effect on the incidence of preeclampsia (27).
limitations of the data as well as the higher likelihood
There were no effects, either positive or negative, on
of outpatient therapy with less frequent BP monitorperinatal outcomes such as preterm birth, small-for-gesing among pregnant women with chronic hypertentational-age (SGA) infants, or fetal death. Of the studsion, treatment is suggested at a lower diastolic BP
ies included, only five trials focused exclusively on
threshold of 105 mm Hg. Most of these trials focused
women with chronic hypertension. Similar to the overon diastolic BP, and specific cutoff values for the treatall findings, there was a risk reduction in progression
ment of elevated systolic BP are not as well defined;
to severe hypertension with treatment in this subgroup
however, if indirect evidence from these trials and the
(RR, 0.57; 95% CI, 0.340.98) but no effect on perinaSeventh Report of the Joint National Committee on Pretal outcomes (27). No harm was associated with treatvention, Detection, Evaluation, and Treatment of High
ment. Thus, the currently available evidence suggests
Blood Pressure recommendations for adults who are
potential maternal benefit of antihypertensive treatnot pregnant are applied to pregnant women with ment by reducing the progression to
severe hypertenchronic hypertension, pharmacologic treatment
sion, but no direct fetal benefit or significant
should be used to maintain systolic BP below 160 improvement in perinatal outcomes
among women
mm Hg (18, 19). Overly aggressive BP lowering is
with chronic hypertension.
discouraged because of concerns that uteroplacental

Although the 2007 Cochrane review did not find
blood flow may be compromised at pharmacologievidence of fetal harm associated with lowering BP,
cally induced low BP.
two meta-regression analyses evaluated the effect of
56
PREECLAMPSIA
lowering BP specifically on fetal birth weight; there
pertensive therapy is initiated in pregnant women
were seven trials of women with chronic hypertension
with chronic hypertension. Two pilot randomized triand 38 trials of women with late-onset hypertension in
als that included women with either mild to moderate
pregnancy (2729). A decrease of 10 mm Hg (mean chronic or gestational hypertension
were included in a arterial pressure) was associated with an average Cochrane review (256
women) that compared tight
decrease in infant birth weight of 145 g; however, the
(systolic BP less than 130 mm Hg and diastolic BP less
relationship between a decrease in BP and SGA was less
than 80 mm Hg) BP with less tight (systolic BP less
convincing in women with chronic hypertension, possithan 140 mm Hg and diastolic BP less than 90 mm Hg)
bly because of the limited power of the overall study. A
BP control (3437). No significant adverse outcomes
2010 casecontrol analysis of the Quebec Pregnancy
were identified, and the evidence was insufficient to
Registry data reported that after adjusting for potential
determine optimal BP control needed to improve
confounders, antihypertensive medication use during
maternal and fetal or neonatal outcomes.
the second trimester or third trimester of the pregnancy
was significantly associated with an increased risk of
SGA (OR, 1.53; 95% CI, 1.171.99) (30). Another
important issue regarding treatment of maternal hyper For pregnant women with chronic hypertension
tension during pregnancy is the risk of teratogenicity
treated with antihypertensive medication, it is
attributable to drugs. There is conflicting evidence; two
suggested that BP levels be maintained between
population-based studies suggest that exposure to any
120 mm Hg systolic and 80 mm Hg diastolic, and
antihypertensive medication may be associated with
160 mm Hg systolic and 105 mm Hg diastolic.
an increased risk of fetal cardiac abnormalities (31,

32), but these findings were not corroborated by othStrength of recommendation: Qualified
ers (30, 33).
Many limitations exist to these population-based
Treatment of women receiving antihypertensive
studies, including the small numbers of malformations
therapy prior to pregnancyIn women who enter pregoverall; furthermore, it is not possible to discern
nancy with well-controlled or mild hypertension with
whether these are specific medication effects, effects of
medication, there are minimal data to guide decisions
elevated BP, or, alternatively, effects of low BP secondas to continuing or discontinuing therapy. A review of
ary to treatment. Although the increased number of 298 women in whom medication
dosage was reduced
malformations are modest, these data support the genor stopped reported no increase in preeclampsia, abruperal strategy of being cautious when prescribing any
tio placentae, and perinatal death compared with
drug during pregnancy, particularly during the first
untreated groups (8). A recent casecontrol study also
trimester, and emphasize the need for additional,
found no difference in preeclampsia or eclampsia with
well-conducted prospective trials to clarify risks and discontinuation of antihypertensive
drugs in the first tri-benefits. Therefore, in the absence of strong evidence
mester (37). Although decision making must be individsupporting use of antihypertensive therapy for mild to
ualized, discontinuing medications during the first
moderate chronic hypertension during pregnancy,
trimester and restarting them if BP approaches the
initiation of therapy is not suggested unless BP approachsevere range is reasonable practice. For women with
es 160 mm Hg systolic or higher or 105 mm Hg diaend-organ damage, such as chronic renal disease or carstolic or higher, or both).
diac disease, BP goals are lower (systolic BP less than
140 mm Hg and diastolic BP less than 90 mm Hg) to
avoid progression of disease during pregnancy and
associated complications. As noted previously, end-or For pregnant women with chronic hypertension gan damage of the kidney and heart
should be assessed
and BP less than 160 mm Hg systolic or 105 mm Hg
before pregnancy or during early pregnancy, or both. A

diastolic and no evidence of end-organ damage, it
detailed review of the medical history as well as baseis suggested that they not be treated with pharmaline assessment of renal function (serum creatinine, crecologic antihypertensive therapy.
atinine clearance, and urinary protein excretion) and
cardiac function (echocardiography or electrocardiogStrength of recommendation: Qualified
raphy) is useful, and women should be monitored closely if medications are withdrawn. This is clearly a case in
Blood pressure targets for antihypertensive treatment
which an informed discussion with the pregnant patient
Minimal data address the ideal target BP once antihyshould guide the choice of therapy or no therapy.
PREECLAMPSIA
57
Types of Antihypertensive Medication
ine and intravenous magnesium sulfate can result in
When choosing an antihypertensive medication to use
hypotension and neuromuscular blockade. One review
for the treatment of chronic hypertension in pregconcluded that the combined use of these drugs does
nancy, an important consideration is the goal of therapy,
not increase such risks (38); however, given the plausiwhich is either 1) acute lowering of severe hypertenbility of the mechanism (both are calcium antagonists),
sion in the hospital setting (Table 7-1) or 2) chronic
careful monitoring of women receiving both is advistreatment of BP to keep levels below the severe range,
able. In view of these data, in women requiring antihyoften in the outpatient setting (Table 7-2).
pertensive medications for severe hypertension, the
choice and route of administration of drugs should
Drugs for urgent lowering of blood pressure. Thirtybe based primarily on the physicians familiarity and
five randomized controlled trials that involved 3,573
experience, adverse effects and contraindications to
women were included in a Cochrane systematic review
the prescribed drug, local availability, and cost.
that compared antihypertensive medications with each
other for acute lowering of severely elevated BP in Drugs for continuous management.
Oral agents are pregnancy (19). Most of these trials included only used for outpatient treatment
of pregnant women
women with preeclampsia or gestational hypertension
with chronic hypertension (39). Randomized conin the third trimester and excluded women with known
trolled trials of drug therapy have focused on methylchronic hypertension or previous antihypertensive dopa (included in five trials) (2022,
24, 26) and therapy use. Hydralazine, labetalol, and calcium chan-labetalol (included in one trial)
(26). The largest trial
nel blockers are among the medications that were comthat included pregnant women with chronic hypertenpared with each other. Based on the findings of the
sion randomized 263 women to labetalol, methyldopa,
systematic review, evidence is inadequate to demonor no treatment; there were no differences in outstrate the superior safety or efficacy of any of these
comes or safety (29). Commonly used oral agents for
medications (19). Therefore, the authors conclude that
chronic hypertension management in pregnancy are
the choice of antihypertensive medication should summarized in Table 7-2.
depend on the potential adverse effects and contraindiMethyldopa, a centrally acting alpha-2 adrenergic
cations as well as the individual clinicians experience
agonist, remains a commonly used drug mainly
and familiarity with a particular drug (19). Given the
because of the long history of use in pregnancy and
unlikelihood of future trials focusing specifically on
childhood safety data. Blood pressure control is gradacute treatment of pregnant women with chronic ual, over 68 hours, as a result of the
indirect mechahypertension, it is reasonable to extrapolate managenism of action. Methyldopa has been prospectively
ment recommendations based on these data. Intravestudied specifically in chronic hypertension comnous labetalol, intravenous hydralazine, or oral
pared with placebo (2022, 24, 26), as well as in a
nifedipine are reasonable first-line agents for acute
mixed group of hypertensive women (4042). There
lowering of BP in the hospital setting (Table 7-1). There
are no apparent adverse effects on uteroplacental or
is theoretical concern that the combined use of nifedipfetal hemodynamics or on fetal well-being (26, 43).
TABLE 7-1. Antihypertensive Agents Used for Urgent Blood Pressure Control in
Pregnancy ^
Drug
Dose
Comments
Labetalol
1020 mg IV, then 2080 mg
Considered a first-line agent
every 2030 min to a maximum
Tachycardia is less common and fewer
dose of 300 mg
adverse effects
or
Contraindicated in patients with asthma,
Constant infusion 12 mg/min IV
heart disease, or congestive heart failure
Hydralazine
5 mg IV or IM, then 510 mg IV
Higher or frequent dosage associated with
every 2040 min
maternal hypotension, headaches, and fetal
or
distressmay be more common than other
Constant infusion 0.510 mg/h
agents
Nifedipine
1020 mg orally, repeat in
May observe reflex tachycardia and headaches
30 minutes if needed; then
1020 mg every 26 hours
Abbreviations: IM, intramuscularly; IV, intravenously.
58
PREECLAMPSIA
TABLE 7-2. Common Oral Antihypertensive Agents in Pregnancy ^
Drug
Dosage
Comments
Labetalol
2002,400 mg/d orally in two to
Well tolerated
three divided doses

Potential bronchoconstrictive effects
Avoid in patients with asthma and
congestive heart failure
Nifedipine
30120 mg/d orally of a slowDo not use sublingual form
release preparation
Methyldopa
0.53 g/d orally in two to three
Childhood safety data up to 7 years of age
divided doses
May not be as effective in control of severe
hypertension
Thiazide diuretics
Depends on agent
Second-line agent
Angiotensin-converting
Associated with fetal anomalies
enzyme inhibitors/
Contraindicated in pregnancy and
angiotensin receptor
preconception period
blockers
Birth weight, neonatal complications, and developpregnancy, in which nifedipine was the most comment at 1 year were similar in infants exposed to
monly prescribed calcium channel blocker, indicates
methyldopa in utero compared with no therapy (44,
no increase in adverse perinatal outcomes (26, 48).
45). A follow-up study of children at 7 years of age
Furthermore, nifedipine does not appear to adversely
did not show any difference in neurocognitive develaffect uterine or umbilical blood flow (49, 50).
opment or intelligence compared with controls (46).
Diuretics are generally considered second-line
Serious adverse effects include hepatic dysfunction
drugs for the treatment of hypertension in pregnancy

and necrosis as well as hemolytic anemia. Methyldo(51). Theoretical concern has been raised regarding
pa may be less effective in preventing severe hyperthe potential for diuretics to cause intravascular voltension based on the Cochrane analysis of a subset of
ume depletion and thereby lead to fetal growth restricstudies compared with -blocker and calcium chantion. However, this is not supported based on data
nel blocker classes combined (OR, 0.75; 95% CI,
from a meta-analysis of nine randomized trials as well
0.590.94) (27).
as a Cochrane systematic review of diuretics for the
Labetalol, a nonselective -blocker with vascular prevention of preeclampsia (52, 53).
Thus, diuretics alpha receptor-blocking ability, is commonly used in
may be used in pregnancy with dose adjustments to
pregnancy. In women with chronic hypertension,
minimize adverse effects and risks such as hypokalethere were no significant differences in perinatal outmia. They may be especially useful in women with
comes when compared with placebo or methyldopa
known salt-sensitive hypertension, particularly in the
(26, 42). Based on comparisons with placebo or
setting of reduced renal function.
other antihypertensive agents for mild to moderate
Angiotensin-converting enzyme inhibitors and
hypertension in pregnancy, labetalol is a reasonable
angiotensin receptor blockers used in the second and
choice in women with chronic hypertension (27). third trimesters of pregnancy are
associated with fetal
Adverse effects include lethargy, fatigue, sleep disturabnormalities (including renal failure, oligohydrambances, and bronchoconstriction. Labetalol should be
nios, pulmonary hypoplasia, calvarial abnormalities,
avoided in women with asthma, heart disease, or
and fetal growth restriction) as well as postdelivery
congestive heart failure. Beta-blockers alone have effects such as oliguria and anuria
(54). Serious con-been used extensively in pregnancy and are effective
cerns also have been raised regarding first-trimester
in lowering BP (27). However, -blockers may be exposure and congenital anomalies.
Based on a review
associated with an increase in SGA infants (RR, 1.34;
of 29,096 Tennessee Medicaid records, 209 infants
95% CI, 1.011.79) compared with placebo or no
were exposed to ACE inhibitors in the first trimester
treatment (47).
with an RR for congenital malformations of 2.71

Calcium channel blockers are a class of drugs that
(95% CI, 1.724.27) compared with women not takhas not been extensively studied in pregnant women
ing antihypertensive drugs (55). Cardiac and central
with chronic hypertension. Extrapolation from the
nervous system anomalies were most common. In the
comparison trials for mild to moderate hypertension in
Kaiser Northern California database, first-trimester
PREECLAMPSIA
59
ACE inhibitor use was associated with a higher rate of
The task force could locate few studies that have been
cardiac malformations compared with normal controls
performed exclusively in women with chronic hyperten(adjusted OR, 1.54; 95% CI, 0.92.62), but not signifision; however, hypertensive women have been included
cantly higher than women with chronic hypertension
as subgroups in trials of high-risk women.
with or without other medications (adjusted OR, 1.14;
Meta-analysis and systematic reviews have demon95% CI, 0.651.98).
strated that the use of antiplatelet agents (eg, lowBased on the currently available data, the task force
dose aspirin) is associated with a small but statistically
recommends discontinuation of ACE inhibitors and significant reduction (17%) in
preeclampsia (56).
angiotensin-receptor blockers, as well as associated
Women considered to be at high risk (including those
classes of medications such as the renin inhibitors and
with chronic hypertension) may experience a benefit
mineralocorticoid receptor antagonists, during pregas great as a 25% reduction (95% CI, 3415% reducnancy (33). Because 50% of pregnancies are untion) (57). Small effects (approximately a 10% reducplanned, these medications should be avoided in
tion) on fetal outcomes (fetal survival or preterm
women of reproductive age. If these medications are birth) also were observed. Another
meta-analysis sugunavoidable or strongly indicated (eg, proteinuric
gested that benefits were greater when low-dose aspirenal disease), then women should be counseled
rin was initiated earlier in pregnancy (58).
regarding risks and effective contraception recom-
Calcium supplementation also has been extensively

mended. In select and rare cases in which there is a studied for the prevention of
preeclampsia. A Cochrane
compelling reason to continue ACE inhibitors until conmeta-analysis of 13 studies (more than 15,000 women)
ception, extensive counseling of risk and benefits is
concluded that calcium supplementation of 1 g or
warranted.
greater was associated with an approximate 50%
reduction in BP and development of preeclampsia
(17). The effect was greatest for high-risk women (five
trials, 587 women; risk ratio [RR], 0.22; 95% CI, 0.12
For the initial treatment of pregnant women with
0.42) and those with low baseline calcium intake
chronic hypertension who require pharmacologic (eight trials, 10,678 women; RR, 0.36;
95% CI, 0.20
therapy, labetalol, nifedipine, or methyldopa are
0.65). Preterm birth was reduced modestly (RR, 0.76;
recommended above all other antihypertensive 95% CI, 0.600.97) and among women at
high risk of
drugs.
developing preeclampsia recruited to four small trials
(568 women; RR, 0.45; 95% CI, 0.240.83). AddiStrength of recommendation: Strong
tional preventive strategies that have been tested, primarily in low-risk women, have not been shown to
For women with uncomplicated chronic hyperreduce the rate of preeclampsia or improve maternal
tension in pregnancy, the use of ACE inhibitors,
and fetal outcomes.
angiotensin receptor blockers, renin inhibitors, and
mineralocorticoid receptor antagonists is not rec For women with chronic hypertension who are at a
ommended.
greatly increased risk of adverse pregnancy outcomes (history of early-onset preeclampsia and
preterm delivery at less than 34 0/7 weeks of
gestation or preeclampsia in more than one prior
For women of reproductive age with chronic hyperpregnancy), initiating the administration of daily
tension, the use of ACE inhibitors, angiotensin
low-dose aspirin (6080 mg) beginning in the late
receptor blockers, renin inhibitors, and mineralofirst trimester is suggested.*

corticoid receptor antagonists is not recommended
unless there is a compelling reason, such as the
presence of proteinuric renal disease.
Prevention of superimposed preeclampsia. Various nutriand reveals no evidence of acute risk, although long-term
tional modifications, addition of supplemental vitamins,
treat to have a therapeutic effect is determined by prevaand medications have been evaluated in large randomlence. In view of maternal safety, a discussion of the use of
ized controlled trials designed to prevent preeclampsia.
aspirin in light of individual risk is justified.
60
PREECLAMPSIA
Fetal Surveillance for Women With Chronic
antenatal testing to determine the optimal timing of
Hypertension
delivery in a fetus with growth restriction. Absent
The risk of fetal growth restriction is higher in pregend-diastolic flow and reversed end-diastolic flow are
nant women with chronic hypertension. In patients indicative of fetal compromise. If
umbilical artery Dopwith mild chronic hypertension, the incidence of SGA
pler velocimetry is abnormal, timing of the delivery is
infants is 815.5%, but in women with severe chronic
based on the gestational age and the severity of the
hypertension, the incidence may be as high as 40%
Doppler velocimetry abnormality.
(1, 8, 59). Fetuses with growth restriction are at an
In a systematic review of 10,156 high-risk pregnanincreased risk of perinatal morbidity (60).
cies from 18 randomized studies, the use of umbilical
Ideally, identification of fetal growth restriction
artery Doppler testing compared with either no Dopshould allow obstetric interventions to decrease peripler or nonstress test (NST) alone reduced perinatal
natal risks. Two methods primarily used to screen for

mortality by 29% (RR, 0.71; 95% CI, 0.520.98) withfetal growth restriction are 1) measurement of fundal
out increasing rates of induction of labor (RR, 0.89;
height and 2) ultrasonographic estimation of fetal 95% CI, 0.800.99) or cesarean
delivery (RR, 0.92; weight. Fundal height measurements are more suit-95% CI, 0.840.97).
Studies incorporated into this
able in women who are at low risk of fetal growth analysis were not of high quality and
were not limited
restriction. The sensitivity for fundal height measureto patients with hypertension with or without fetal
ment to detect fetal growth restriction is inadequate
growth restriction (65).
for high-risk women (61). In pregnancies at high risk
of fetal growth restriction based on maternal disease
such as hypertension, the preferred method for
screening is ultrasonography. Based on observational
data, the best predictor of fetal growth restriction is
women with chronic hypertension, fetoplacental
serial ultrasonographic assessments of either fetal
assessment to include umbilical artery Doppler
weight or abdominal circumference (62). The optivelocimetry as an adjunct antenatal test is recommal timing and frequency of examinations is not
mended.
known. The timing and frequency of ultrasonography
for fetal growth is based on the clinical scenario, such
as prior obstetric history, severity of hypertension,
and coexisting morbidities.
Fetal antenatal surveillance with either an NST, bioIt remains unclear whether the antenatal detection
physical profile (BPP), or a modified BPP may be beneof fetal growth restriction decreases perinatal morficial in reducing perinatal morbidity and mortality in
tality. In a systematic review of more than 27,000 lowhigh-risk pregnancies (66). In patients with chronic
risk women, screening compared with no screening
hypertension, data for the specific time to initiate antewith ultrasonography after 24 weeks of gestation did
natal testing, the testing interval, and the most effecnot improve perinatal outcomes (63). In high-risk tive antenatal test to use are lacking.
Based on pregnancies, no data exist to address this issue. Based
observational studies in populations at high risk of

on expert opinion, early detection and appropriate
intrauterine fetal demise, antepartum fetal surveillance
management of fetal growth restriction is expected to
with either is often recommended to decrease perinatal
decrease the stillbirth rate by 20% (64).
morbidity. Patients with chronic hypertension at highest risk of perinatal mortality have either fetal growth
restriction or superimposed preeclampsia.
A systematic review of NSTs compared with no or
For women with chronic hypertension, the use of
concealed NSTs in 2,105 high-risk women from six
ultrasonography to screen for fetal growth restricrandomized or quasi-randomized trials showed no diftion is suggested.
ference in perinatal mortality (RR, 2.05; 95% CI,
0.954.42) or potentially preventable deaths (RR,
2.46; 95% CI, 0.966.30) (65). When BPPs were compared with NSTs or modified BPPs in a systematic
Doppler velocimetry studies of the fetoplacental unit
review of five trials that involved 2,974 high-risk
can be used antenatally to detect increased placental
women, there was no significant difference in perinaresistance and fetal vascular response. Umbilical artery
tal deaths between the groups (RR, 1.33; 95% CI,
Doppler velocimetry is often used in conjunction with
0.602.98) (67).
PREECLAMPSIA
61
Definition and Diagnosis
For women with chronic hypertension complicated
by issues such as the need for medication, other
Superimposed preeclampsia refers to women with
underlying medical conditions that affect fetal outchronic hypertension who develop preeclampsia. Discome, any evidence of fetal growth restriction, and
tinguishing superimposed preeclampsia from benign
superimposed preeclampsia, antenatal fetal testing
gestational increases in BP and proteinuria that are
is suggested.
often observed in women with chronic hypertension
can be quite challenging. Given the higher risk of
adverse pregnancy outcomes with superimposed preStrength of recommendation: Qualified
eclampsia, overdiagnosis may be preferable, with the
goal of increasing vigilance and preventing catastroIntrapartum Management
phic maternal and fetal outcomes. Alternatively, a
The optimal delivery time to reduce maternal and fetal
more specific and stratified approach based on severity
morbidity and mortality in women with chronic hyperand predictors of adverse outcome may be useful in
tension, with or without maternal or fetal complicaguiding clinical management and avoiding unnecestions, has not been studied. Trials that have been
sary preterm births.
conducted included women with hypertensive disorBased on these considerations, the task force proders of pregnancy, such as gestational hypertension
poses that superimposed preeclampsia be stratified
and preeclampsia with or without preexisting hyperinto two groups to guide management: 1) superimtension. Hypertensive disorders of pregnancy affect a
posed preeclampsia and 2) superimposed preeclampheterogeneous population, but data are often extraposia with severe features.
lated to women with chronic hypertension.
Superimposed preeclampsia is likely when any of
In women with chronic hypertension and without
the following are present:
any obstetric complications, a small clinical trial suggests that the risk of adverse perinatal outcomes is A sudden increase in BP that was
previously well
similar to women without chronic hypertension (59).
controlled or escalation of antihypertensive mediFindings in a population-based cohort study suggest
cations to control BP
that the optimal timing for women with uncomplicated
New onset of proteinuria or a sudden increase in
hypertension is between 38 weeks of gestation and
proteinuria in a woman with known proteinuria
39 weeks of gestation (68). Delivery in this gestational
before or early in pregnancy
age group optimizes fetal outcomes while decreasing
neonatal morbidity. In a systematic review of 22 studThe diagnosis of superimposed preeclampsia with

ies that involved almost 30 million infants, late
severe features is established when any of the followpreterm birth is associated with increased neonatal ing are present:
complications and death within the first year of life
Severe-range BP despite escalation of antihyper(69). Without a known maternal or fetal benefit but
tensive therapy
with known risk of neonatal complications, delivery
before 3839 weeks of gestation is not warranted in
Thrombocytopenia (platelet count less than
patients with only isolated, uncomplicated chronic
100,000/microliter)
hypertension (70).
Elevated liver transaminases (two times the upper
limit of normal concentration for a particular laboTASK FORCE RECOMMENDATION
ratory)
For women with chronic hypertension and no ad New-onset and worsening renal insufficiency
ditional maternal or fetal complications, delivery
Pulmonary edema
before 38 0/7 weeks of gestation is not recommended.
Persistent cerebral or visual disturbances
Clinicians should recognize that there is often
ambiguity in the diagnosis of superimposed preeclampsia and that the clinical spectrum of disease is
broad. Furthermore, women with superimposed preeclampsia can progress and develop end-organ
62
PREECLAMPSIA
involvement and adverse outcomes. Therefore,
lished. Therefore, recommendations regarding antiincreased surveillance but not intervention (eg, delivhypertensive treatment in this group are extrapolated
ery) is warranted even if the diagnosis is suspected from the evidence based on chronic
hypertension in
and not definitive. Future investigation is needed to
pregnancy and preeclampsia. Pharmacologic antihyfurther refine the diagnosis, potentially including
pertensive therapy should be used for women with
markers that are predictive of adverse outcome.

hypertension (systolic BP 160 mm Hg or higher or
diastolic BP 105 mm Hg or higher) or at even lower
Initial Evaluation of Women With
levels if there is evidence of end-organ involvement to
prevent acute maternal cerebrovascular and coronary
Initial evaluation of women with superimposed preevents (19). Treatment of women with systolic BP
eclampsia should occur in a hospital setting to con140160 mm Hg or diastolic BP 90105 mm Hg has
firm the diagnosis, evaluate maternalfetal status,
not been shown to be beneficial in decreasing adverse
and monitor for progressive worsening of the disease.
perinatal outcomes but reduces progression to severe
The clinical workup should include questions about
hypertension (27). Initiation of antihypertensive
symptoms associated with preeclampsia (neurologic
medications or an increase in dosages because of
symptoms, epigastric or right upper quadrant pain,
worsening BP in the setting of superimposed prenausea and vomiting, vaginal bleeding, and fetal
eclampsia should occur in the hospital setting while
movement). Serial BP measurements should be monitoring for worsening maternalfetal
status.
obtained. Physical examination should be performed
Acute lowering of severe hypertension may be accomwith attention to signs of preeclampsia and associated
plished by intravenous or oral medications (intravecomplications. Proteinuria should be assessed by a nous labetalol, intravenous
hydralazine, or oral
protein/creatinine ratio or 24-hour urine collection.
nifedipine) (Table 7-1). Long-term treatment of BP
Laboratory evaluation should also include a complete
that maintains levels below the severe range generally
blood count with platelets, liver transaminases, lactic
involves the use of oral agents such as labetalol, nifeddehydrogenase, and creatinine assessment. Uric acid
ipine, or methyldopa as initial agents (Table 7-2).
assessment also may be helpful if uric acid concentrations are known from early pregnancy because hyperAntepartum Management of Superimposed
uricemia is associated with adverse outcomes in Preeclampsia
superimposed preeclampsia and also with early renal
General considerations in the antepartum managedysfunction, which may be present with chronic
ment of women with superimposed preeclampsia

hypertension (71, 72). Ideally, these laboratory
include the administration of antenatal corticosteroids
results are compared with baseline information and use of magnesium sulfate for seizure
prophylaxis.
obtained in early pregnancy. If abnormalities are of
Ongoing management and timing of delivery is based
new-onset, then the diagnosis of superimposed preon gestational age and the severity of disease.
eclampsia; end-organ involvement; or hemolysis, elevated liver enzymes, and low platelet count (HELLP)
Antenatal Corticosteroids
syndrome can be confirmed. If abnormalities are
Women with superimposed preeclampsia diagnosed
long-standing or of unknown duration, results should
before 37 weeks of gestation are at increased risk of
be cautiously interpreted before a definitive diagnopreterm delivery. Therefore, antenatal corticosteroids
sis is established. Although not included in the diagshould be administered at less than 34 weeks of gestanostic criteria for superimposed preeclampsia, fetal
tion for fetal lung maturity benefit to decrease neonagrowth and well-being should be assessed when tal morbidity and mortality (73).
superimposed preeclampsia is suspected. Additional
testing or interventions or both may be warranted if
there are concerns regarding fetal status.
For women with superimposed preeclampsia who
Antihypertensive Treatment for
receive expectant management at less than 34 0/7
weeks of gestation, the administration of corticoClinical trials that have evaluated antihypertensive
steroids for fetal lung maturity benefit is recomtherapy that included women with chronic hypertenmeded.
sion have not specifically addressed lowering BP once
the diagnosis of superimposed preeclampsia is estabStrength of the recommendation: Strong
PREECLAMPSIA
63
Magnesium Sulfate for Seizure Prophylaxis
Gestational age of 37 weeks or older. Delivery is sug-
Eclampsia is associated with maternal mortality in the

gested for superimposed preeclampsia diagnosed at
range of 0.31% and serious morbidity, including renal
term (37 weeks of gestation or more). Neonatal outfailure, pulmonary edema, aspiration pneumonia,
comes are favorable, and continuation of pregnancy
stroke, and cardiopulmonary arrest (74). There also is
incurs risk to the woman and her fetus (70).
evidence of long-term maternal sequelae, such as perGestational age of less than 37 weeks. In the absence of
sistence of white-matter lesions and impaired cognitive
severe features and with reassuring fetal status, expectfunction (75, 76). Magnesium sulfate has been shown
ant management with ongoing close maternal and fetal
to be superior to a number of other agents for the prevention of seizures in women with preeclampsia.
surveillance is reasonable. There is a paucity of data to
The frequency of eclampsia in women with chronic
support outpatient management of superimposed prehypertension and superimposed preeclampsia is not eclampsia. However, if an outpatient
approach is
well defined but ranges from 0% to 2.4% as reported
undertaken, maternal adherence to home BP monitorin observational and small retrospective studies (77,
ing, reporting of symptoms, physician visits one to two
78). Currently, no data appear to specifically address
times a week, weekly laboratory testing, and fetal surthe use of magnesium sulfate for seizure prophylaxis
veillance are important. Women with superimposed
for the subgroup of women with superimposed prepreeclampsia with worsening disease, severe features,
eclampsia. Therefore, evidence from the general
or concern for fetal well-being should be monitored as
preeclampsia literature must be used to guide manageinpatients (see the following section Management of
ment. For women with chronic hypertension and Superimposed Preeclampsia With
Severe Features).
superimposed preeclampsia with severe features, the
Optimal delivery timing between 34 weeks of gestask force recommends the administration of intrapartation and 37 weeks of gestation in superimposed pretumpostpartum parenteral magnesium sulfate to preeclampsia without any evidence of severe features or
vent eclampsia. In the absence of data that specifically
worsening disease is unclear. A retrospective cohort
address superimposed preeclampsia without any study that used a perinatal database
found no differsevere features, the collective opinion of the task force

ence in perinatal outcomes between superimposed
is against the use of magnesium sulfate for seizure propreeclampsia and preeclampsia; however, there was a
phylaxis during labor and delivery in this subgroup.
higher rate of delivery at less than 34 weeks of gestaHowever, signs and symptoms that have traditionally
tion (17.3% versus 8.7%; P<0.001), cesarean delivery
been considered premonitory to eclampsia (eg, neuro(46.2% versus 36.3%; P<0.001), and neonatal inlogic symptoms, clonus, and right upper quadrant
tensive care unit admission (16.3% versus 11.4%;
pain), as well as worsening clinical course to severe
P<0.002) (79). These data indicate a higher risk of
disease, should be considered in the decision to initiate
intervention-related events and morbidity among
magnesium during labor and delivery.
women with superimposed preeclampsia compared
with women with preeclampsia, thus raising the issue
of potentially unnecessary iatrogenic preterm births
with superimposed preeclampsia. If extrapolated from
For women with chronic hypertension and superthe general preeclampsia literature, delivery for severe
imposed preeclampsia with severe features, the
preeclampsia (expectantly managed) is suggested at
administration of intrapartumpostpartum paren34 weeks of gestation and at 37 weeks of gestation for
teral magnesium sulfate to prevent eclampsia is preeclampsia without severe features (70,
80, 81).
recommended.
The task force suggests that superimposed preeclampsia with severe features be managed in a manner
similar to severe preeclampsia and superimposed preStrength of recommendation: Strong
eclampsia without severe features be managed in a
Timing and Indications for Delivery
manner similar to preeclampsia without severe feaIndications for and timing of delivery in superimposed
tures. Future research and investigation is needed to
preeclampsia are based on gestational age, severity of
better delineate the riskbenefit balance of pregnancy
disease, progression of disease, and ongoing assesscontinuation between 34 weeks of gestation and 37
ment of maternal and fetal well-being. With any

weeks of gestation among women with superimposed
attempts to prolong pregnancy, the potential fetal
preeclampsia. If the disease has remained stable withneonatal benefits must be weighed against maternal
out evidence of progression or severe features, delivand fetal morbidity and mortality.
ery at 37 weeks of gestation is suggested.
64
PREECLAMPSIA
regarding expectant management beyond the 48 hours
to achieve steroid benefit are limited. Thus, manage For women with superimposed preeclampsia withment is based on extrapolation of indirect evidence
out severe features and stable maternal and fetal from management of severe
preeclampsia, as well as
conditions, expectant management until 37 0/7
direct evidence from retrospective studies of expectant
weeks of gestation is suggested.
management of superimposed preeclampsia. ExpectQuality of evidence: Low
ant management beyond the 48 hours of antenatal corStrength of the recommendation: Qualified
ticosteroid administration in two randomized trials of
severe preeclampsia at less than 34 weeks of gestation
Management of Superimposed Preeclampsia
was associated with significant prolongation of pregWith Severe Features
nancy, reduction in neonatal respiratory distress synBefore 34 weeks of gestation, management options
drome, fewer days in the neonatal intensive care units,
for superimposed preeclampsia with severe features
and higher birth weight with reasonable maternal safeare as follows: immediate delivery after maternal staty in the expectantly managed group (8082). Women
bilization, short-term prolongation to achieve steroid
with severe preeclampsia were candidates for expectbenefit for the fetus, or long-term prolongation
ant management if BP was controlled, there was no
(expectant management) to increase gestational age
evidence of severe end-organ involvement, and fetal
and improve neonatal outcomes. Given the paucity of
status was reassuring without growth restriction.
clinical trials and prospective studies in women with
The subgroup of women with superimposed presuperimposed preeclampsia, the indications and timeclampsia diagnosed before 34 weeks of gestation is
ing of delivery are based on indirect evidence from
typically excluded from studies focusing on the expectthe management of preeclampsia (11). Two randomant management of preeclampsia, and if included,
ized trials that included 133 women and a number of
their outcomes are generally not reported separately
observational studies provide the basis for manage(81, 82, 86, 87). Prospective studies of women with
ment of severe preeclampsia (8082). Because of the
chronic hypertension allude to expectant management
significant maternalfetal or maternalneonatal morof women with superimposed preeclampsia, but this
bidity, immediate delivery after maternal stabilizaissue is not clearly addressed. For example, in a protion is recommended if any of the following are spective cohort of 861 women with
chronic hypertenpresent: uncontrollable severe hypertension, eclampsion enrolled in the Vitamins in Preeclampsia Trial, the
sia, pulmonary edema, disseminated intravascular
incidence of superimposed preeclampsia was 22%,
coagulation, new or increasing renal dysfunction or
and 51% of these women gave birth before 37 weeks
both, abruptio placentae, or nonreassuring fetal staof gestation (77). The average antenatal inpatient stay
tus. Many of these studies do not clearly differentiate
was 7.3 days, suggesting that an expectant managebetween immediate delivery and an attempt to ment approach was taken in at least a
subset of
achieve some level of steroid benefit (80, 83). Given
patients with superimposed preeclampsia. A retrothe neonatal benefit of antenatal corticosteroids and
spective case series of expectant management of presome data supporting the expectant management of
eclampsia specifically reported on a subset of 29
HELLP syndrome and fetal growth restriction (80,
women with superimposed preeclampsia (88). Com8385), it is reasonable to delay delivery in a subset
pared with women with severe preeclampsia in this
of women with severe disease to achieve the benefits
series, women with superimposed preeclampsia had
of antenatal corticosteroid use (48 hours). Women
similar latency periods (8.4 days versus 8.5 days) and
with neurologic or epigastric pain symptoms, HELLP
no difference in the rates of abruptio placentae, oligusyndrome or partial HELLP syndrome, thrombocytoria, or HELLP syndrome.
penia, elevated liver transaminases, or fetal growth
Another retrospective review focused on women
restriction are potential candidates for short-term with superimposed preeclampsia at a
single institupregnancy prolongation with close inpatient monition in the United States who were expectantly mantoring and readily available tertiary obstetric, neonaaged beyond 48 hours to achieve steroid benefit and
tal, and anesthesia services. Delivery is recommended
gave birth before 37 weeks of gestation (78). In this
if there is worsening of maternal or fetal status. Parseries of 41 women, the median gestational age at
enteral magnesium sulfate is recommended for seidiagnosis was 31.6 weeks, and the mean time from
zure prophylaxis.
diagnosis to delivery was 9.7 days, with a wide range
For women with superimposed preeclampsia diagof 234 days. There were no perinatal deaths, and
nosed before 34 weeks of gestation, published data
adverse outcomes included two cases of abruptio
PREECLAMPSIA
65
placentae, one pulmonary edema, one case of pro For women with superimposed preeclampsia with
gression to HELLP syndrome, and an average neonasevere features, expectant management beyond
tal intensive care unit stay of 17.9 days. Although
34 0/7 weeks of gestation is not recommended.
these studies are small and fraught with limitations,
they suggest that the rate of adverse outcomes and
latency periods are comparable with those observed
with expectant management of preterm severe preeclampsia (80). Thus, expectant management in
Management of Women With Chronic
women with superimposed preeclampsia before 34 Hypertension in the Postpartum
Period
weeks of gestation in the hospital setting, as espoused
Women with chronic hypertension before and during
with preterm severe preeclampsia, appears reason-
pregnancy will usually require treatment with antihyable. Prospective studies are needed to quantify the
pertensive medications in the postpartum period, even
risks and benefits of this approach.
if they were not treated during pregnancy. Because the
For women with superimposed preeclampsia with
American College of Obstetricians and Gynecologists
severe features undergoing expectant management
encourages all women to breastfeed their infants, antibefore 34 weeks of gestation, inpatient management is
hypertensive medications that are safe for breastfeedrecommended with delivery at 34 weeks of gestation.
ing (ie, they tend not to be secreted into breast milk)
This is based on the morbidity associated with severe
should be prescribed.
preeclampsia and the approach taken in randomized
The task force is not aware of clinical trials that
clinical trials (80, 82, 83). As with the expectant manspecifically address management of postpartum hyperagement of severe preeclampsia, parenteral magnetension in women with any form of hypertension in
sium sulfate is recommended during the initial pregnancy. Blood pressure in the
postpartum period is
evaluation and stabilization period (generally 24 hours)
often higher compared with antepartum levels, particbefore expectant management.
ularly in the first 12 weeks (89, 90). Medication
As with severe preeclampsia, if superimposed preshould be adjusted to maintain BP in a safe range (less
eclampsia with severe features is newly diagnosed than 160 mm Hg systolic and 100 mm
Hg diastolic).
after 34 weeks of gestation, delivery should be accomUse of nonsteroidal antiinflammatory agents should
plished after stabilization of maternal status.
be avoided in the postpartum period in women with
chronic hypertension, particularly those with superimTASK FORCE RECOMMENDATIONS
posed preeclampsia. Extensive documentation exists
that nonsteroidal antiinflammatory agents increase BP
Delivery soon after maternal stabilization is recomand sodium retention in patients who are not pregmended irrespective of gestational age or full cortinant. Although use of these medications have not been
costeroid benefit for women with superimposed
investigated in the postpartum period, alternative
preeclampsia that is complicated further by any of
strategies are recommended.

the following:
Magnesium sulfate is indicated if there are signs
uncontrollable severe hypertension
and symptoms of persistent or new-onset superim eclampsia
posed preeclampsia, such as severe headache, visual
pulmonary edema
disturbances, shortness of breath, and signs of HELLP
abruptio placentae
syndrome. Older women, women with comorbidities
(obesity, diabetes, or kidney disease), and those with
nonreassuring fetal status
an onset of hypertension at an earlier gestational age
may be at greater risk of prolonged elevations in BP
postpartum (89). It also has been observed that
eclampsia and adverse cerebrovascular events associ For women with superimposed preeclampsia with
ated with pregnancy are more likely to occur in the
severe features at less than 34 0/7 weeks of gestapostpartum period (90). The role of BP control in
tion with stable maternal and fetal conditions, it is
preventing these outcomes has not been well studied;
recommended that continued pregnancy be underhowever, antihypertensive medications may be used
taken only at facilities with adequate maternal and
more liberally in the postpartum period, and if cereneonatal intensive care resources.
bral symptoms are present, BP should be lowered.
If hypertension in the postpartum period remains
Strength of evidence: Strong
severe despite adequate doses of two antihypertensive
66
PREECLAMPSIA
medications, the woman should be referred to a hyper6. Ferrer RL, Sibai BM, Mulrow CD, Chiquette E, Stevens
tension specialist to rule out secondary causes.
KR, Cornell J. Management of mild chronic hypertension
during pregnancy: a review. Obstet Gynecol 2000;96:
Breastfeeding
7. Zetterstrom K, Lindeberg SN, Haglund B, Hanson U.

Good clinical practice suggests that women with
Maternal complications in women with chronic hyperchronic hypertension should be encouraged to breasttension: a population-based cohort study. Acta Obstet
feed, although the task force is not aware of clinical
Gynecol Scand 2005;84:41924. [PubMed] [Full Text]
trials that have assessed either maternal or fetal out^
comes in this patient population. Many, if not most,
8. Rey E, Couturier A. The prognosis of pregnancy in womtypes of antihypertensive medications are detectable,
en with chronic hypertension. Am J Obstet Gynecol
1994;171:4106. [PubMed] ^
albeit at low concentrations, in breast milk.
9. Williams MA, Mittendorf R, Monson RR. Chronic hyperIn general, drugs that are bound to plasma proteins
tension, cigarette smoking, and abruptio placentae.
are not transferred to breast milk. Lipid-soluble drugs
Epidemiology 1991;2:4503. [PubMed] ^
may achieve higher concentrations compared with 10. Ananth CV, Savitz DA, Bowes WA
Jr, Luther ER. Influence water-soluble drugs. Methyldopa is considered safe,
of hypertensive disorders and cigarette smoking on plaand concentrations in breast milk are low. Several
cental abruption and uterine bleeding during pregnancy.
-blockers are concentrated in breast milk, with atenoBr J Obstet Gynaecol 1997;104:5728. [PubMed] ^
lol and metoprolol resulting in high concentrations,
11. Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV,
and propranolol and labetalol resulting in low concenMartins-Costa S, et al. The impact of prior preeclampsia
on the risk of superimposed preeclampsia and other adtrations. Both captopril and enalapril concentrations
verse pregnancy outcomes in patients with chronic hyin breast milk have been reported as low, and many
pertension. Am J Obstet Gynecol 2011;204:345.e16.
consider these drugs to be safe for breastfeeding; how[PubMed] [Full Text] ^
ever, in women who require high doses, other agents
12. Taguchi N, Rubin ET, Hosokawa A, Choi J, Ying AY,
are appropriate. There are only limited reports of calMoretti ME, et al. Prenatal exposure to HMG-CoA reduccium channel blockers and their transfer into breast
tase inhibitors: effects on fetal and neonatal outcomes.
Reprod Toxicol 2008;26:1757. [PubMed] [Full Text] ^
milk; no adverse effects have been reported. Although
13. Siebenhofer A, Jeitler K, Berghold A, Waltering A,

the concentration of diuretics in breast milk is usually
Hemkens LG, Semlitsch T, et al. Long-term effects of
low, these agents may reduce the quantity of milk proweight-reducing diets in hypertensive patients. Cochrane
duction and interfere with the ability to successfully
breastfeed. The task force is unaware of clinical trials
CD008274. DOI: 10.1002/14651858.CD008274.pub2.
that evaluate outcomes of children exposed to antihy[PubMed] [Full Text] ^
pertensive medications in breast milk.
14. Blumenthal JA, Babyak MA, Sherwood A, Craighead L,
Lin PH, Johnson J, et al. Effects of the dietary approaches
to stop hypertension diet alone and in combination with
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8
CHAPTER
Later-Life Cardiovascular Disease
in Women With Prior Preeclampsia
Several large epidemiologic studies demonstrate stroke, and congestive heart failure) (3)
and, therefore,
that all women with a history of preeclampsia
should be advised to 1) maintain ideal body weight;
have an increased risk of cardiovascular (CV)
2) engage in aerobic exercise regularly (five times per
diseases later in life. For many years, the older
week); 3) eat a diet high in fiber, vegetables, and fruits
literature was misinterpreted to suggest that women and low in fat (the Dietary
Approaches to Stop Hyperwith preeclampsia only in a first pregnancy were not
tension diet); and 4) avoid tobacco. Evaluation for risk
at increased risk. However, more recent studies with
of later-life CV disease requires health care provider
larger numbers of participants and longer follow-up and patient consideration (Box 8-1).
indicate an increased risk of later-life CV disease even
with preeclampsia in a first pregnancy (1). This risk is

much greater if the woman has recurrent preeclampsia
(2), gave birth preterm (less than 37 weeks of gesta For women with a medical history of preeclampsia
tion), or had a pregnancy with fetal growth restriction
who gave birth preterm (less than 37 0/7 weeks of
(1, 3, 4), with risk rates at least equaling the CV risk gestation) or who have a medical
history of recurwith obesity or smoking (5). In 2011, the American
rent preeclampsia, yearly assessment of blood presHeart Association added preeclampsia to its list of risk
sure, lipids, fasting blood glucose, and body mass
factors for CV disease (6). Prepregnancy risk factors
index is suggested.*
and preeclampsia may both contribute to the developQuality of evidence: Low
ment of long-term CV disease risk (7). Preeclampsia,
particularly when associated with preterm delivery,
should be considered as a strong risk factor for CV dis*Although there is clear evidence of an association
ease (data exist to support that it is quantitatively simbetween preeclampsia and later-life CV disease, the value
ilar in magnitude to the increase in the risk of having
and appropriate timing is not yet established. Health care
providers and patients should make this decision based
diabetes) (7). These individuals are at increased risk
on their judgment of the relative value of extra informaof hypertension and CV disease (myocardial infarction,
tion versus expense and inconvenience.
71
72
LATER-LIFE CARDIOVASCULAR DISEASE IN WOMEN WITH PRIOR
PREECLAMPSIA
BOX 8-1. Evaluation for Risk Factors ^
How many pregnancies have you had?
How many miscarriages have you had?
Were any of your babies born early (more than 3 weeks before your due date)?
How many?
Did this occur spontaneously or were the babies delivered early because you were ill?
Did you have preeclampsia in any of your pregnancies?
Which pregnancy?
How many times?

Was the baby delivered early because you had preeclampsia?
How many weeks before your due date was the baby delivered?
Did you have high blood pressure in any pregnancy?
Did you have protein in your urine in that pregnancy?
Do you have a family history of preeclampsia? Is there a history of preeclampsia in
your partners
family?
Did you have gestational diabetes?
Were you treated with insulin or blood glucose-lowering pills?
What were the birth weights of your babies, and how many weeks before your due date
were they
delivered?
Do you have a medical history of high blood pressure or chronic kidney disease?
Modified from Roberts JM, Catov JM. Pregnancy is a screening test for later life
cardiovascular disease: now what? Research recommendations. Womens Health Issues
2012;22:e1238.
References
4. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes
1. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term
(CHAMPS): population-based retrospective cohort study.
mortality of mothers and fathers after pre-eclampsia:
Lancet 2005;366:1797803. [PubMed] [Full Text] ^
population based cohort study. BMJ 2001;323:12137.
5. Roberts JM, Hubel CA. Pregnancy: a screening test for
later life cardiovascular disease. Womens Health Issues
2. Funai EF, Paltiel OB, Malaspina D, Friedlander Y, Deutsch
2010;20:3047. [PubMed] [Full Text] ^
L, Harlap S. Risk factors for pre-eclampsia in nulliparous
6. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ,
and parous women: the Jerusalem perinatal study.
Lloyd-Jones DM, et al. Effectiveness-based guidelines for
Paediatr Perinat Epidemiol 2005;19:5968. [PubMed] ^
the prevention of cardiovascular disease in women--2011
3. Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampupdate: a guideline from the American Heart Associasia and cardiovascular disease death: prospective evition. American Heart Association [published erratum
dence from the child health and development studies
appears in J Am Coll Cardiol 2012;59:1663]. J Am Coll
cohort. Hypertension 2010;56:16671. [PubMed] [Full
Cardiol 2011;57:140423. [PubMed] [Full Text] ^
Text] ^
7. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ.

Hypertension in pregnancy and later cardiovascular risk:
common antecedents? Circulation 2010;122:57984.
9
CHAPTER
Patient Education
Many millions of dollars have been spent literacy skills have been researched and
described in
on clinical and laboratory research in an
the literature. These can be applied to patient educaeffort to discover the pathogenesis of protion about preeclampsia with the goal of ensuring that
phylactic measures for and optimal treatthe best possible outcomes are achieved with the
ment of preeclampsia. Although these goals are of the
resources currently available.
utmost importance, a more effective use of currently
available information and resources may reduce the Importance of Patient Education
burden of morbidity and mortality that arises in association with preeclampsia. Health services intervenIn the developed world, the frequency of adverse
tions, including patient education, may not only help
maternal and perinatal events related to preeclampsia
to reduce this burden, particularly among populations
remains markedly lower than in developing countries,
at greatest risk (eg, those with low health literacy or
largely because of the greater number of available
at highest risk of developing preeclampsia), but also
resources and routine hypertension and proteinuria
may reach that goal at a relatively low cost. Patient screening (35). Interventions for
women with disease and health care provider education is key to the suc-include increased
monitoring, magnesium sulfate,
cessful recognition and management of preeclampsia.
antihypertensive medications, corticosteroids for fetal
Health care providers need to inform women during
lung maturation, and delivery. To maximally benefit
the prenatal and postpartum periods of the signs and
from these resources, however, women must first seek
symptoms of preeclampsia and stress the importance
medical care in a timely fashion.
of contacting health care providers if these are eviThe possibility that women do not seek timely care
dent. This can be accomplished without increasing may be increased if they have a poor
understanding of
patient anxiety (1).
the signs and symptoms of preeclampsia. Several recent
Little is understood about how to best educate studies emphasized the potential value of
educating
women about preeclampsia and provide them with the
patients to report and their health care providers to act
information needed to seek prompt and appropriate on signs and symptoms of severe
preeclampsia that
care. What is known is that the population, in general,
commonly precede eclampsia, hypertensive encephahas difficulty understanding even basic health inforlopathy, pulmonary edema, or stroke (611). This
mation, and preeclampsia, specifically, is a poorly
hypothesis is further supported by studies of women in
understood complication of pregnancy (2). Education
whom preeclampsia was diagnosed, received timely
techniques that are appropriate for patients with poor
and proper surveillance, and had fewer adverse events
73
74
PATIENT EDUCATION
than those with delayed diagnosis (12). Regardless of
viders can effect change in the practice environment as
literacy level and understanding of preeclampsia, this
it relates to patient education when considering a popknowledge deficit appears to be modifiable because
ulation with limited health literacy (16). A summary
women who acknowledge receiving information about
of recommendations is listed in Box 9-1.
the disease demonstrate greater preeclampsia-specific
Predicting who is affected by inadequate health litknowledge (2).
eracy skills is challenging because the problem is ubiqBeyond improving outcomes, it is the ethical
uitous, spanning all races and income and education
responsibility of the health care system and the health
levels. Certainly, an obstetric care provider can relay
care providers who work within that system to ensure
both the symptoms of preeclampsia in nonmedical lanthat patients have been educated about the implicaguage (Box 9-1) and the appropriate actions that
tions and complications of a specific health state,
should be taken should those symptoms arise; how-
including pregnancy. According to the American Medever, if that message is relayed in a manner that is
ical Association, Patients have the right to understand
poorly understood by the patient, it is of little to no
healthcare information that is necessary for them to value. Hence, any educational
intervention should be
safely care for themselves, and to choose among availcreated so that patients with even limited literacy skills
able alternatives. Health care providers have a duty to
can understand and act on the information.
provide information in simple, clear and plain lanIt is not only important that medical care providers
guage and to check that the patients have understood
offer easy-to-understand and straightforward verbal
the information before ending the conversation (13).
communication, but also that appropriate aids are
used for women to take with them that offer visual
Patient Education Strategies
reminders at home. These should be written at no
greater than a fifth-grade or sixth-grade reading level,
Although few would debate the importance of patient
be graphic-based, and be culturally sensitive (1621).
education, the question still remains as to how best to
For example, relaying to a patient that she should noprovide such education about preeclampsia. The solutify her health care provider if she experiences right
tion is complex because it is estimated that approxiupper quadrant pain, headache, or visual alterations
mately one half of the American population has a may be confusing to the patient and her
family. The
limited capacity to obtain, process, and understand
health care provider should instead explain that the
basic health information and services needed to make
patient should notify her health care provider if she
appropriate health decisions (14, 15). In addition, an
has pain in her stomach, has a headache, or sees spots.
overall paucity of published research addresses patient
The health care provider could then point to the areas
education in the context of pregnancy. Consequently,
of concern (abdomen, head, and eyes) and provide a
models for successful interventions that address graphic-based tool intended to relay the
same concept
health-related outcomes are found outside the context
(22, 23). A group of researchers found that after disof pregnancy. In 2007, the American Medical Associatributing a card depicting pictures of preeclampsia
tion Foundation published a monograph summarizing

signs and symptoms to women in certain Jamaican
research related to health literacy. The publication also
parishes, women from these parishes had lower rates
provided recommendations on how health care proof preeclampsia-related morbidity than women from
BOX 9-1. Key Components of Effective Health Communication and Patient
Education ^
Do not assume a patients literacy level or understanding based on her appearance.
In both oral and written communication, use plain, nonmedical language.
Speak slowly.
Organize information into two or three components.
Ask the patient to teach back information to confirm understanding.
Data from Nielsen-Bohlman L, Panzer AM, Kindig DA, editors. Health literacy: a
prescription to end confusion. Committee on Health Literacy, Board on Neuroscience and
Behavioral Health, Institute of Medicine. Washington, D.C.: The National Academies Press;
2004. p. 345.
PATIENT EDUCATION
75
parishes who had not received the card (22). The fifth-grade to sixth-grade reading level.
Group prenatal
health care provider should also ask the patient to care, often called centering
pregnancy, has been found
teach back the information to confirm the patients
to be effective in conveying information and improving
understanding. An example would include, We have
perinatal outcomes at no added cost (26).
gone over a lot of information. In your own words, can
you tell me what we discussed today? What would
Patient Education Barriers
make you call your health care provider or come to the
hospital? This should take the place of close-ended
There are several barriers that may preclude a health
questions such as, Did you understand the material
care providers ability to educate patients about prediscussed today? (16).
eclampsia (Box 9-3). The amount of time available for
Grouping information together and then checking each prenatal visit is limited, and a
great deal of inforfor understandingchunk and checkalso is a way
mation has to be relayed in a typical prenatal appointto provide information that is easier to understand and
ment. It is important to note that many of the
remember. When applying this concept to preeclampaforementioned techniques actually require little time.
sia, a health care provider could break down the conIf they are spread out over several visits starting as
versation by explaining the syndrome, its implications,
early as 15 weeks of gestation, but no later than 20
the associated symptoms, and the appropriate actions
weeks of gestation, and reviewed several times during
that should be used if a patient experiences symptoms.
the course of the pregnancy, it would only take a few
Each of these broad ideas could include two or three
minutes to discuss this information. In some settings,
details (Box 9-2). The health care provider should health care systems have successfully
used a centering check for understanding using the teach-back method
pregnancy model, whereby women are grouped
before moving on to the next idea (16).
together by due dates for prenatal education and supMobile applications are increasingly being used to port (2729). Some may believe that
providing a
reach diverse populations. More than 85% of Ameripatient with information about preeclampsia will procans own a cell phone, and 72% of cell phone users
duce unnecessary anxiety. There is evidence to the
send or receive text messages (24). Text4Baby, a
contrary because failure to educate patients about pretext-messaging program that sends out timed prenatal
eclampsia may cause women to experience greater
and postpartum information to registered mobile fear because of lack of information (1).
phones, recently reported positive results since its
Evidence suggests that health care providers who
launch in February 2010 (25). Time spent in the patient
fail to inform patients about preeclampsia may do so
reception area can be used to convey information by because the health care provider is
underinformed. A
way of TV monitors and print material written at the
2002 survey of obstetriciangynecologists revealed
BOX 9-2. Chunk-and-Check ^
What is it?
Definition of preeclampsia in laymans terms: Preeclampsia is a serious disease related
to high blood
pressure. It can happen to any pregnant woman.
Why should you care?
Explanation of risks to the patient and her infant, emphasizing the seriousness of
responding in a
timely manner: There are risks to you: seizures, stroke, organ damage, or death; and to
your baby:
premature birth or death.
What should you pay attention to?
Explanation of potentially concerning signs and symptoms accompanied by graphics and

simply
written description: Symptoms include
What should you do?
Explanation of appropriate actions that should be taken if a patient experiences
symptoms:
"If you experience any concerning symptoms, call you health care provider right away.
Finding
preeclampsia early is important for you and your baby.
76
PATIENT EDUCATION
BOX 9-3. Most Commonly Reported Barriers to Providing Preeclampsia Education
^
Health care providers have too many important issues to address and not enough time.
Information overload is causing women to be too anxious about their pregnancies.
Materials that are written simply, available in other languages, and affordable, are not
available.
Health care providers are unsure about what information needs to be provided that will
affect outcomes.
great disparities in their knowledge and clinical manprescribed management. This all leads to improved
agement of hypertensive disorders of pregnancy (30).
pregnancy outcomes.
Health care providers need to understand that preeclampsia without severe features can progress quickly
and unexpectedly; that proteinuria is not always present, even in severe forms of preeclampsia; that women
It is suggested that health care providers convey inremain at risk of preeclampsia postpartum; and that a
formation about preeclampsia in the context of prewomans symptoms should not be dismissed without a
natal care and postpartum care using proven health
proper assessment. This is corroborated by thousands
communication practices.
of patient experiences reported to the Preeclampsia
Foundation (31). Many clinicians and patients are
unaware that preeclampsia can still occur after delivery. Postpartum hypertension or preeclampsia either is
This chapter was developed with the assistance of
a new-onset condition or is secondary to persistence or
Whitney You, MD.
exacerbation of hypertension in women with previous
gestational hypertension, preeclampsia, or chronic

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10
CHAPTER
State of the Science and
Research Recommendations
An important charge of the American Col- includes a cascade of secondary effector
mechanisms,
lege of Obstetricians and Gynecologists including altered proangiogenic and
antiangiogenic
Task Force on Hypertension in Pregnancy factor balance, increased maternal oxidative
stress, and
was to review the state of the science and
endothelial and immunological dysfunction (5, 6). Furto develop corresponding research recommendations
ther elucidation of these mechanisms will hopefully
relating to management of hypertension during preglead to a more complete understanding of the pathonancy. The last such formal review of scientific data
physiology of preeclampsia and to specific and successdates back to the National High Blood Pressure Edful therapeutic intervention.
ucation Programs presentation in 2000 (1). Summarized as follows is the progress of research from 2000
Abnormal Implantation and Vasculogenesis
through 2012, with suggested areas in which focused
Although the underlying molecular mechanisms that
investigations are needed or should continue.
lead to the preeclampsia syndrome are not clear, a
major mechanism is believed to be placental insuffiFundamental Advances in the
ciency due to inadequate remodeling of the maternal
vasculature perfusing the intervillous space. During
Understanding of Preeclampsia
normal pregnancy, fetally derived cytotrophoblasts
Preeclampsia, at least early-onset preeclampsia, is
invade the maternal uterine spiral arteries, replacing
believed to evolve in two stages (27). The first stage
their endothelium, and differentiating into an endo(less than 20 weeks of gestation) involves poor placenthelial-like phenotype (8). This complex process
tation, at which time there are neither signs nor sympresults in a conversion of the high-resistance,
toms of the disorder. The second stage involves the small-diameter vessels into highcapacitance, lowconsequences of poor placentation, probably evoked by
resistance vessels and ensures adequate delivery of
relative placental hypoxia and hypoxia reperfusion,
maternal blood to the developing uteroplacental
resulting in a damaged syncytium and limited fetal unit. In the woman destined to
develop preeclampgrowth, with these and other events leading to the clinsia, poorly understood errors in this carefully orchesical findings of preeclampsia. The link between the reltrated scheme lead to inadequate delivery of blood to
atively hypoxic placenta and the maternal syndrome

the developing uteroplacental unit and increase the
79
80
STATE OF THE SCIENCE AND RESEARCH RECOMMENDATIONS
degree of hypoxemia and oxidative and endoplasmic
Endothelial Activation and Dysfunction
reticulum stress.
The maternal vascular endothelium of women destined
The exact mechanisms responsible for the abnorto develop preeclampsia appears to be an important tarmal trophoblast invasion and vascular remodeling in
get of factors that are presumably generated through
preeclampsia are unclear, but a series of studies have
placental ischemia and hypoxia (5, 6, 11). The vascular
now appeared that are enhancing the understanding
endothelium has many important functions, including
of these important adaptations and of potential mechcontrol of smooth muscle tone through the release of
anisms that may lead to maladaptations (27). In vasoconstrictors and vasodilators and
the regulation of
one study, researches provided evidence that Notch
anticoagulation, antiplatelet, and fibrinolytic functions
signaling may be a crucial component of the process
by release of different soluble factors. Alterations in the
whereby fetal trophoblast cells invade and remodel circulating concentration of many
markers of endomaternal blood vessels (9). They reported that failure
thelial dysfunction have been reported in women that
of this physiologic transformation in the absence of develop preeclampsia (5, 6, 11). This
suggests that the Notch2 is associated with reduced vessel diameter and
disease is an endothelial cell disorder. The fact that this
placental perfusion. Their findings that perivascular
endothelial dysfunction can be demonstrated before
and endovascular cytotrophoblasts often fail to express
overt disease supports a causal role.
the Notch ligand, JAG1, in preeclampsia provides furMaternal status may influence the endothelial
ther evidence that defects in Notch signaling may be
response to factors triggered by placental ischemia and
an important part of the pathogenesis of this preghypoxia in preeclampsia. There is compelling evidence,
nancy complication.
for example, that obesity, a major epidemic in devel-
Other studies also have suggested that variability of

oped countries, including the United States, increases
immune system genes that code for major histocomthe risk of preeclampsia. A body mass index (calculated
patibility complex molecules and natural killer recepas weight in kilograms divided by height in meters
tors also may affect human placentation (10). They squared) characteristic of obesity
(greater than 39) reported that specific combinations of fetal major his-increases this risk
threefold (12). Despite this and
tocompatibility complex molecules and maternal natumany other studies linking obesity to preeclampsia, the
ral killer receptor genes in humans correlate with the
pathophysiologic mechanisms whereby obesity inrisk of preeclampsia, recurrent miscarriage, and fetal
creases the risk of developing preeclampsia are unclear.
growth restriction. Researchers have begun to explore
Thus, further research into how obesity and metabolic
the similarities and differences between human and
factors such as leptin, insulin, and free fatty acids,
mice natural killer cells and potential trophoblast affect the various stages of
preeclampsia is warranted.
ligands with the aim of developing mouse models that
will elucidate how natural killer celltrophoblast interFactors Linking Placental Ischemia and
actions contribute to placentation.
Hypoxia With the Maternal Syndrome
Studies like the aforementioned studies, have
Angiogenic Factors
established abnormalities in vasculogenic and angioIn response to placental hypoxia, the placenta is progenic signaling pathways as important candidates to posed to produce pathogenic factors
that enter the
explain mechanisms by which placentation goes awry
maternal blood stream and are responsible for the endoin preeclampsia, leading the task force to strongly recthelial dysfunction and other clinical manifestations of
ommend the need for more emphasis on the study of
the disorder. A variety of molecules are released but
placentation during pregnancy and preeclampsia. amongst them, antiangiogenic and
autoimmune or
Although genetic manipulation in mouse models can
inflammatory factors have recently received the greatest
be an important tool in providing insights into the proattention (13, 14). In these respects, perhaps the most
cess of placentation, the placentas of these animals
intensely studied pathway in the manifestation of pre-
differ significantly from those in women, underscoring

eclampsia is that related to vascular endothelial growth
a critical need to perform such research in primates,
factor (VEGF) signaling. Vascular endothelial growth
where placentation is similar to that in humans.
factor and placental growth factor (PlGF-1), besides
In addition, use of state-of-the-art technologies and
their role in angiogenesis, also are important in the
experimental approaches such as genomic, proteomic,
maintenance of proper endothelial cell function. This
metabolomic, and microRNA analyses should provide
signaling pathway came to prominence with the discovnew and important information regarding molecular ery of elevated circulating and
placental concentrations
pathways involved in the process of placentation.
of the soluble form of the VEGF receptor Flt-1 (sFlt-1).
81
The soluble form of the VEGF receptor Flt-1 is a circulatwhich includes both exosomes and microvesicles.
ing soluble receptor for both VEGF and PlGF, that when
They speculate that changes not only in the numbers,
increased in maternal plasma leads to less circulating but also in the size (beneficial
syncytiotrophoblast exo-free-VEGF and free-PlGF, thus preventing their availabilsomes and harmful microvesicles), might be important
ity to stimulate angiogenesis and maintain endothelial
in the maternal syndrome of preeclampsia.
integrity. In the kidney, this inactivation of free-VEGF is
Another area related to the immune component of
believed to cause glomerular endotheliosis with consepreeclampsia is research relating to the agonistic antiquent proteinuria (13, 14). Studies of the regulation of
body AT1-AA (18, 19). These autoantibodies, isolated
sFlt-1 in cell culture and placental tissue in vitro have
more than a decade ago in women who had preeclampdemonstrated that sFlt-1 is released from placental villi
sia, have been studied more intensively recently,
and trophoblast cells in response to reduced oxygen tenincluding their identification in the circulation of rats
sion similar to that seen in an ischemic placenta. A undergoing placental ischemia. These
antibodies
promising pilot study demonstrated that sFlt-1 could be
appear to be induced by the production of the cytoremoved from the maternal circulation by apheresis kine, tumor necrosis factor (TNF)-a
because infusion
safely, and that this therapy reduced both blood
of TNF-a into pregnant rats also results in production
pressure (BP) and proteinuria, with a trend toward
of the antibody at concentrations comparable to that
increased gestational duration (15).
seen in pregnant women with preeclampsia and the
Although compelling data derived from animal and
Reduced Uterine Perfusion Pressure (RUPP) rat (20).
human studies suggest an important role for angioIt also has been demonstrated that infusion of AT1-AA
genic imbalance in the pathophysiology of preeclampdirectly into pregnant rats results in moderate hypersia, there are many unanswered questions and many
tension. However, the pathogenic importance of these
opportunities for future research. For example, the
antibodies remains to be fully elucidated because their
molecular mechanisms involved in the regulation of presence has been noted postpartum
in a subset of
sFlt-1 production have yet to be fully elucidated. Morepatients who had preeclampsia with no discernible
over, although sFlt-1 appears to play an important role
phenotype. Further studies are needed, including
in the pathogenesis of preeclampsia, specific inhibitors
determining how these unique antibodies are produced
of sFt-1 production are not available at this time. Thus,
and how they interact with the other pathogenic agents
research into the discovery of inhibitors of sFlt-1, or
in preeclampsia to produce the clinical phenotype.
ways to stimulate greater production of VEGF and
PlGF, is of critical importance.
Endothelin
There is growing evidence to suggest an important
Immune Factors and Inflammation
role for endothelin-1 (ET-1) in the pathophysiology of
One of the earliest and most persistent theories about
preeclampsia. Given the myriad experimental models
the origins of preeclampsia was that it is a disorder of
of preeclampsia (placental ischemia, sFlt-1 infusion,
immunity and inflammation (16). Of interest is work
TNF-a infusion, and AT1-AA infusion) that have
that suggests the inflammatory response is triggered
proved susceptible to ETA antagonism, could the ET-1
by particles shed from the syncytial surface of the system be a potential therapeutic target
for the treathuman placenta ranging from large deported multinu-
ment of preeclampsia (21)? Because there is evidence

clear fragments to subcellular components. These cirthat interfering with the ETA receptor in early animal
culating particles are increased in preeclampsia. In this
pregnancy may abort the pregnancy or lead to develrespect, researchers have proposed that the fragments
opmental anomalies, research here should focus later
include proinflammatory proteins that may contribute
in gestation where ETA-receptor antagonists might
to the systemic inflammatory response in normal pregprove safe and efficacious, which is started when
nancy and the exaggerated inflammatory response in
symptoms appear. Alternatively, development of ETApreeclampsia (16). There is new evidence from the receptor antagonists, which do not
cross the placental
same researchers of a large hidden population of barrier, would be welcome. Researchers
recently
microvesicles and nanovesicles (including exosomes),
reported that a selective ETA-receptor antagonist had
not easily studied because of their small size (17).
limited access to the fetal compartment during chronic
Using nanoparticle tracking analysis to measure the maternal administration late in
pregnancy (22).
size and concentration of syncytiotrophoblast vesicles
prepared by placental perfusion, they found that vesiNitric Oxide
cles range in size from 50 nanometers to 1 micrometer
Studies have suggested important roles for nitric oxide
with the majority being less than 500 nanometers,
as a regulator of arterial pressure under various physi82
ologic and pathophysiologic conditions (6). Nitric oxide
eclampsia should help shed further light into the
production is elevated in normal pregnancy, and these
importance of oxidative stress in the pathophysiology
increments appear to play an important role in the vasoof preeclampsia and perhaps allow the identification
dilatation of pregnancy. Thus, it was postulated that
of useful antioxidant strategies. It remains to be seen
nitric oxide deficiency during preeclampsia might be
whether reactive oxygen species production is a priinvolved in the disease process. Studies from several mary or secondary cause of
preeclampsia pathophysilaboratories have found that chronic nitric oxide synology, and how effective manipulation of the system
thase inhibition in pregnant rats produces hypertension

will be in the search for effective therapies.
associated with peripheral and renal vasoconstriction,
There also appears to be an excess of endoplasmic
proteinuria, intrauterine growth restriction, and inreticulum stress in placentas from women with earlycreased fetal morbidity, a pattern resembling the findonset preeclampsia (26). Endoplasmic reticulum stress
ings of preeclampsia (6). However, whether there is a
activates a number of signaling pathways aimed at
reduction in nitric oxide production during preeclamprestoring homeostasis. Researchers have proposed that
sia is controversial. Much of the uncertainty originates
this homeostatic mechanism fails and apoptotic pathfrom the difficulty in directly assessing the activity of
ways are activated to alter placental function in
the nitric oxide system in a clinical setting. Assessment
women who develop preeclampsia (26). In addition
of whole-body nitric oxide production by measurement
chronic, low concentrations of endoplasmic reticulum
of 24-hour nitratenitrite excretion has yielded variable
stress during the second trimester and third trimester
results because of difficulties in controlling for factors
may result in a growth restricted phenotype. They also
such as nitrate intake, thus, the relative importance of
propose that higher concentrations of endoplasmic
nitric oxide deficiency in the pathogenesis of preeclampreticulum stress lead to activation of proinflammatory
sia has yet to be fully elucidated.
pathways that may contribute to maternal endothelial
cell activation. Although endoplasmic reticulum stress
Oxidative and Endoplasmic Reticulum Stress
is known to occur in preeclampsia, the importance of
Oxidative stress also has been implicated in prethis abnormality in the pathophysiology has yet to be
eclampsia because increased concentration of several
fully elucidated.
oxidative stress markers also have been reported systemically in women with preeclampsia, among these
Hemeoxygenase
peroxynitrites (23, 24). Peroxynitrite concentrations in
It also appears that the stress response gene, hemevascular endothelium were much higher in women oxygenase-1 (HO-1), and its catalytic
product, carbon
with preeclampsia compared with women with nor-
monoxide also may be involved in the pathogenesis of

mal pregnancies, concurrent with decreased concenpreeclampsia (27). Genetic or pharmacologic blocktrations of superoxide dismutase and nitric oxide
ade of HO-1 in pregnant animals lead to preeclampsiasynthase (25). There also is evidence of increased oxilike phenotypes (27). It also appears that induction of
dative stress during gestation in the RUPP rat hyperthe HO-1 gene may be involved and, thus, this too is
tensive model, suggesting a link between placental
an area in which to explore therapeutic approaches.
ischemia and hypoxia with the production of reactive
There are several lines of evidence that HO-1 and its
oxygen species (6). Treating this model with two difcatalytic products may protect against the progression
ferent antioxidants, 1) vitamin C and 2) vitamin E, had
of preeclampsia by interfering at sites in the pathway
no effect on the gestational hypertension. The superthat links placental hypoxia and hypertension (28
oxide dismutase mimetic drug, tempol, however, led
30). Of interest, in this respect, are studies suggesting
to significant attenuation of the hypertensive response.
that combustion products of tobacco, such as carbon
In a related study, administration of the reduced form
monoxide, reduce the risk of preeclampsia by more
of nicotinamide adenine dinucleotide phospate oxithan 35% (29). In addition, TNF-a mediated cellular
dase inhibitor, apocynin, also significantly attenuated
damage in placental villous explants can be prevented
RUPP-induced gestational hypertension, implicating
by up-regulating HO-1 enzyme activity (28). Heme
that enzyme as an important source of pathogenic oxygenase pathways have also been
shown to inhibit
reactive oxygen species in the RUPP animal (6). Failthe release of sFlt-1 in several in vitro models (30).
ure of the drug to fully normalize BP, however, leaves
Induction of the HO-1 enzyme or chronic administraopen the possibility that alternative reactive oxygen
tion of HO-1 metabolites have also been reported to
species production pathways are at work in the RUPP
ameliorate hypertension in several animal models of
model. Further studies into the mechanism of reactive
hypertension that involve BP regulatory factors similar
oxygen species production in animal models of preto that observed in women with preeclampsia. More

83
compelling evidence that supports the concept that the management of preeclampsia.
Cogent examples
HO-1 and its catalytic products may protect against are the clinical trials of magnesium
sulfate to prevent
the progression of preeclampsia are data that indicate
and treat eclampsia that resolved decades of controthat chronic administration of an HO-1 enzyme inducer
versy. Obstetricians in the United Sates used magne(cobalt protoporphyrin IX chloride) or carbon monoxsium sulfate for almost 70 years with little attention
ide releasing molecule-A1 significantly attenuates
from other parts of the world and with scorn from the
hypertension in response to placental ischemia (31).
neurological community. However, studies in the past
These findings, taken together, make heme oxygenase
two decades have now established that magnesium
a potential target for studies to improve the treatment
sulfate can be used safely, including administering it in
of preeclampsia. In this respect, the cardiovascular (CV)
developing countries. Magnesium sulfate therapy was
drugs, statins, have been shown to stimulate HO-1
shown to be superior to phenytoin or diazepam for
expression and inhibit sFlt-1 release in vivo and in vitro;
treating eclampsia and is more effective than phenytothus, they have the potential to ameliorate early-onset
in or placebo for preventing preeclampsia (3234).
preeclampsia. The pavaStatin to Ameliorate Early This has had a major effect on
modifying treatment
Onset Pre-eclampsia trial is underway to address this outside the United States. In the
United States magneand, if positive, its outcome could lead to therapeutic
sium sulfate is accepted as the drug of choice but the
intervention to prolong affected pregnancies.
answer to the question of whom to treat remains
unclear. In Chapter 5 Management of Preeclampsia
Summary of Fundamental Research
and HELLP Syndrome, the available data are reviewed
and recommendations are made to guide rational use
Recommendations by the Task Force
of the drug.
As noted, there has been enormous progress toward
At times empirically guided, but also guided by
understanding the pathophysiology of preeclampsia research results, a plethora of
potential predictive tests during the past two decades, but many unresolved and
have been examined. None of these have been shown

critical questions remain. The full elucidation of the to be clinically useful, although
current investigations molecular and cellular mechanisms involved in the using combinations of
tests has engendered cautious
various stages of the disease process will hopefully optimism that clinically useful ways
to predict prelead to a more complete understanding of the etiology
eclampsia may be on the horizon (35, 36). In this
of preeclampsia and eventually lead to successful therrespect, the use of combinations of analytes and bioapeutic intervention through the targeted disruption physical testing (eg, uterine artery
Doppler velocimeof new and novel pathways. As follows are basic scitry) has encouraging preliminary results (35).
ence research recommendations to attempt to resolve
Prevention is another critical focus of clinical studsome of these unsolved questions over the next several
ies. Several strategies have been tested, retested, or
years:
reanalyzed with, at best, minimal evidence of success.
More research on the study of placentation, inThe latest entry into prevention testing was the use of
cluding immunological abnormalities and abnorantioxidant vitamins. The presence of oxidative stress
malities of angiogenic signaling pathways during in preeclampsia has been evident for
many years in
pregnancy and preeclampsia, is needed.
multiple tissues (although there has been some controversy) (37, 38). By the late 1990s the evidence seemed
Continued research on the role of genetic and episufficient to warrant a trial of the antioxidants vitamin
genetic factors in preeclampsia is warranted.
C and vitamin E, to modify the pathophysiology of pre Research on the molecular mechanisms involved in
eclampsia. In a small pilot study, performed in England,
the regulation of proangiogenic and antiangiogenic
vitamin C and vitamin E were administered in pharfactors also is needed.
macologic doses (far exceeding those present in prenatal vitamins) with the intent of reducing evidence of
Research into the discovery of novel inhibitors of endothelial activation (39).
Antioxidant vitamin treat-sFlt-1 is of critical importance.
ment was associated not only with reduced endothe Further development of animal models is needed.
lial activation and reduced oxidative stress, but also
with a significant reduction in the frequency of pre-
Advances in Clinical Research

eclampsia. The findings stimulated large trials in
Clinical research stimulated by and performed followEngland, Canada, Australia, and the United States and
ing the last National High Blood Pressure Education in developing countries. Both lowrisk and high-risk
Program report also has led to important advances in
women were studied. However, none of the studies
84
demonstrated any evidence of a beneficial effect (40).
calcium success, it could be postulated that there
Whether the lack of success was due to timing, dosage,
might be a subset of women with preeclampsia in
or the particular antioxidant used is not known, but it
whom low-dose aspirin therapy would be effective.
is clear that the use of vitamin C and vitamin E in unseThis was studied using an approach termed individulected low-risk or high-risk women is not indicated for
al patient meta-analysis in which the data from studthe prevention of preeclampsia.
ies are brought together for reanalysis. In this study, it
The findings with vitamin C and vitamin E mirror
was not possible to identify any subset of patients in
the findings of studies that used low-dose aspirin and
whom therapy was uniquely effective (48). The study
calcium to prevent preeclampsia. In all studies, these
did confirm the significant effects of aspirin therapy
agents were successful in initial small studies, but that
reported in standard meta-analysis to prevent presuccess was not validated in larger trials (4145). The
eclampsia, and to reduce prematurity and perinatal
most likely explanation for this discrepancy is that the
mortality. However, the effects of aspirin were not clinsmall studies are underpowered and reflect publicaically useful in these analyses because the usual prevation bias. That is, small studies that are successful are
lence of preeclampsia in low-risk populations was
reported, whereas small studies that do not succeed
23%; therefore, 500 women would need to be treated
are not likely to be reported and published. There are
in order to prevent one case of preeclampsia. However,
other interesting possibilities. One treatment may not
it is important to remember that as the prevalence of a
be effective for all cases of preeclampsia. Thus, sucdisease increases, the number of patients necessary to
cesses in small studies in homogenous populations are

treat for a successful outcome reduces. Thus, in indinot substantiated in larger studies, which characterisviduals who have preexisting risk factors that increase
tically are not only larger but also more heterogeneous
preeclampsia prevalence to 20%, it would only require
because they are usually performed in several centers.
treating 50 patients to prevent one case of preeclampThis was a consideration in the studies of calcium to
sia. For this reason the task force suggests low-dose
prevent preeclampsia where the early small successful
aspirin prophylaxis in patients at high risk of pretrials largely took place in developing countries where
eclampsia. Specifically, low-dose aspirin is recommany women had low calcium intake, whereas the
mended beginning late in the first trimester for women
large unsuccessful trial was conducted in the United
with a medical history of preeclampsia in more than
States where the vast majority of women had adeone prior pregnancy or in whom preeclampsia in a
quate calcium intake (40, 41). The World Health Orgaprior pregnancy resulted in the birth of an infant at
nization tested this possibility in a study in which less than 34 weeks of gestation. These
women have a
calcium was supplemented in pregnant women from
prevalence of preeclampsia of at least 40%. Thus,
populations known to have a low calcium intake (46).
approximately 20 women would need to be treated to
There was no reduction in the incidence of preeclampprevent one case of preeclampsia. Additionally, the
sia with calcium treatment. However, the frequency of
treatment of 35,000 women with low-dose aspirin in
severe adverse outcomes, including eclampsia and
the numerous previous trials indicated no acute
severe hypertension was lower. Further, treatment
adverse outcomes for the woman or her infant. Howreduced a composite outcome of adverse maternal ever, there is no information on the
long-range safety
outcomes. Although the body of the calcium studies of the drug. Based on this
information, it would seem
supports the concept of prevention with a particular reasonable to discuss the possibility
of low-dose aspiagent being pertinent in some, but not all, popularin therapy with an individual woman at less extreme
tions, it also indicates calcium supplementation is not
risk, pointing out the potential benefit to her and the
useful in a population with adequate calcium intake as

established safety of the drug acutely, but also the
occurs in the United States.
unknown long-term safety. The decision for therapy
An attempt was made to evaluate the efficacy of
would then be based on the importance of these parlow-dose aspirin by meta-analysis of approximately
ticular factors to the particular woman.
35,000 women who had been included in trials of
Another possibility that arises from the failure of
aspirin to prevent preeclampsia. There was no evipredictors to predict preeclampsia and therapy based
dence of significant reduction in preeclampsia in any
on well-established pathophysiology to prevent preof the large individual trials. However, in the
eclampsia is that preeclampsia may actually be more
meta-analysis of this large number of participants,
than one disease. This possibility certainly is supported
there was a significant reduction in the frequency of
by clinical and epidemiologic data, which indicate propreeclampsia, premature births, and perinatal mortalfoundly different effects of the disorder in different
ity with low-dose aspirin therapy (47). Based on the
women and at different times in pregnancy and differSTATE OF THE SCIENCE AND RESEARCH RECOMMENDATIONS
85
ent long-term CV outcome with early-onset preeclampweeks of gestation have an 810-fold increased risk,
sia and late-onset preeclampsia (49). Thus, the task
and women with recurrent preeclampsia have an
force encourages attempts to identify subtypes of preincrease in death from CV disease earlier in life than
eclampsia as one of the targets for future research. The
women who only have preeclampsia in their first preganalogy of diabetes in which the disease is recognized
nancies (55). It seems most likely that the increase in
as insulin-resistant or is insulinopenic with each subset
CV disease in later life in women with preeclampsia is
that requires different therapy indicates the value of
due to common risk factors for both conditions
this approach.
although a component of residual injury from preIn a clinical trial performed in the Netherlands,
eclampsia cannot be completely excluded. The Ameriinvestigators examined whether in women with mild
can Heart Association recognized the relationship of

preeclampsia or mild gestational hypertension (hyperpreeclampsia and later-life CV disease in its recent
tension, but no proteinuria) it is safer for them to give
guidelines (56). These guidelines list a pregnancy hisbirth at 37 weeks of gestation or it is safer to observe
tory as a part of the assessment of CV risk for women.
them (50). The study showed a reduction in adverse
They also state that preeclampsia and gestational diamaternal outcomes with delivery at 37 weeks of gestabetes should be part of the risk score for CV disease.
tion compared with observation. There was no increase
The challenge is to determine how to use this informain neonatal morbidity. For this reason the task force tion (57). This raises the idea that a
history of pre-recommends delivery at 37 weeks of gestation in eclampsia might suggest that
these women be tested
women with mild preeclampsia and mild gestational
for CV disease earlier than age 40 years.
hypertension. Nonetheless, this study should be repliIn reviewing the recommendations that the task
cated in a U.S. population.
force has prepared, it becomes evident that there are
A problem inherent in this recommendation must
few clinical issues for which there is strong evidence.
be resolved by future research. There is abundant eviTherefore, the task force has prepared the following
dence that gestational hypertension is not simply a lists of research recommendations to
attempt to
mild form of preeclampsia. Twenty five percent of
resolve some of these problems in the near future.
women in whom gestational hypertension is diagnosed at 34 weeks of gestation will later develop proTask Force Recommendations for Clinical
teinuria and thus preeclampsia (51). It also is likely Research
that another portion of the women have preeclampsia
Prediction and Risk Stratification
without developing proteinuria by the time they give
birth. Another portion of women with gestational Prospective clinical trials should be
performed to
hypertension have chronic hypertension that was
demonstrate the clinical utility of biomarkers or their
masked by the decrease of BP in early pregnancy.
combinations with biophysical variables that can
However, it is also evident there is another group of
directly affect management decisions as follows:
women with mild gestational hypertension in whom
Ways to differentiate women destined to dethere is no risk other than hypertension. This is evident
velop preeclampsia from those who will not at a
from studies of women with mild gestational hyperperiod during gestation when available intertension in whom, as the components of the syndrome
ventions will improve outcome.
of preeclampsia decrease (eg, no evidence of hyperuri Clarification if such markers or BP thresholds
cemia or an increase in cellular fibronectin), the likelican identify an increased risk of perinatal morhood of adverse outcomes is reduced until it is difficult
bidity in subsets of women
to differentiate their outcome from that of normoten Clarification if uric acid level assessment will
sive women (52, 53). Thus, a target for research recserve as a biomarker given its ease and minimal
ommended by the task force is to develop tests that
cost of its measurement.
can be performed on women with gestational hypertension to predict the likelihood that they have or will
There is evidence that subsets of preeclampsia exist
proceed to preeclampsia or adverse outcome.
characterized by gestational age onset, gestational
For many years, it has been evident that women
age at delivery, the presence or absence of fetal
with preeclampsia have an increased risk of CV disease
growth restriction, or the long-term risk of maternal
later in life. Recent epidemiological studies indicate
CV disease. Additional research is needed to help
this to be an approximate twofold increase for all
verify and characterize the subsets of the disease in a
women with a history of preeclampsia (54). However,
manner that helps clarify morbidity and mortality
women with preeclampsia who give birth before 34
risks as well as specific management options.
86
Additional evaluation is needed to show whether Major perinatal morbidity with
HELLP syndrome
the magnitude of 24-hour protein excretion discrimoccurring before 2324 weeks of gestation has not
inates the ongoing risk of morbidity in preeclampsia,
been improved with any current management
and, if so what the ideal cutoff needs to be.
scheme used because delivery is usually mandated.
Work is needed to develop effective therapeutic in Future research on more novel technologies, such
terventions to safely prolong pregnancy to viability
as plasma or urine metabolite profiles and circulatof the fetus without endangering maternal welfare.
ing microRNAs, may prove to not only be useful for
understanding the pathogenesis of the disease, but
Therapy to effectively treat patients with prealso in the development of novel therapies.
eclampsia that fails to improve or resolve postpartum
using standard therapy requires more extensive
Identify biophysical variables or biomarkers (or
investigation and standardization.
combinations) that distinguish women with mild
gestational hypertension who will not have adverse
A Clinical Trials Network for the performance of
outcomes with a negative predictive value suffipreeclampsia-focused research should be considcient to allow follow-up and management as a lowered for implementation.
risk patient.
Management of Preeclampsia, Eclampsia, and HELLP
All of these recommended studies should focus not
Syndrome
only on clinical usefulness but how they directly
affect obstetricians management decisions, improve
More research should be performed to determine
health outcomes, and reduce costs to the health care
the most appropriate antihypertensive treatment
system.
for persistent postpartum hypertension.
Randomized trials to determine optimum delivery
Therapy and Prevention of Preeclampsia, Eclampsia,
timing in women with mild gestational hypertenand HELLP Syndrome
sion and preeclampsia should be repeated in U.S.
Research collaboration between investigators, the
populations.
pharmaceutical industry, and governmental agen Maternal mortality data should be assessed to betcies should be encouraged to develop novel therater identify causes of death in hypertensive pregpies for the treatment of preeclampsia.
nant women.
The role of potent corticosteroids to prevent pro Some cases of eclampsia appear to be manifesta-
gression and accelerate recovery from HELLP syntions of posterior reversible encephalopathy syndrome requires further study in a large randomized
drome. It should be determined whether or not
prospective clinical trial that is appropriately strucwomen with preeclampsia and milder cerebrovastured to include only patients who do not require
cular symptoms (headache or visual disturbances)
corticosteroids for fetal indications (greater than
also have posterior reversible encephalopathy syn34 weeks of gestation).
drome.
Research should be directed at determining the Identification of early posterior
reversible encephamost appropriate antihypertensive treatment for
lopathy syndrome and prevention of its progression
persistent postpartum hypertension.
might prevent eclampsia. Studies are needed to
The optimal use of diuretics in the postpartum
determine if posterior reversible encephalopathy synmanagement of patients with preeclampsia, ecdrome can be detected without a magnetic resonance
lampsia, and HELLP syndrome requires study and
imaging examination and whether any intervention
clarification to augment current management
such as magnesium sulfate, steroids, diuretics, or othschemes.
er agents can be targeted to patients at greatest risk.
The administration of potent corticosteroids appears
Management of eclampsia occurring before 34
to benefit patients with cerebral edema. The potenweeks of gestation requires further investigation to
tial role of any of these agents to benefit patients
determine if delay of delivery for 24 72 hours may
with eclampsia or patients developing cerebral
significantly improve perinatal outcome without
edema or posterior reversible encephalopathy synadversely affecting maternal outcome.
drome deserves investigation.
87
How often to evaluate patients in the postpartum Long Range Follow-Up of Women
Who Have Had Preperiod with severe forms of preeclampsia following eclampsia
hospital discharge remains unclear. Protocols to Studies are needed to determine the
best immedievaluate possible management schemes are desirate and remote postpartum follow-up procedures
able to undertake so that best practices can be
in relation to the increased remote CV disease in
determined and implemented.
women who have had preeclampsia. The following
Nifedipine use for BP control in the patient with
questions need to be answered:
preeclampsia receiving magnesium sulfate requires
When and how often they should be evaluated?
further study to determine the limits of safety for
What tests should be performed?
use of both drugs concurrently.
Can risk be stratified with considerations in
Persistent moderate hypertension several days into
addition to early-onset, severe, recurrent prethe puerperium in patients with a severe form of
eclampsia?
preeclampsia requires study as to which antihyper Are there women with normal pregnancy outtensive agents are best to administer and how best
comes with increased risk of CV disease who can
to monitor and assess their effectiveness.
be identified by assessments of metabolic and
A subset of patients with HELLP syndrome present
vascular changes during pregnancy?
with evidence of renal compromise early in the More research on fetal programming of
CV diseases
course of the disease. The factors leading to this
(in utero influences on the development of CV
and the optimal management of the adversely
issues later in life) is needed.
affected kidneys in these patients requires further
investigation.
Studies of the psychologic effect of preeclampsia
are needed.
The role of umbilical artery Doppler velocimetry
and its effect on perinatal morbidity and mortality Chronic Hypertension
in the complicated pregnancies without IUGR,
including pregnancies complicated by hyperten Current data regarding teratogenicity of drugs that
sion, diabetes, and other disorders associated with
decrease angiotensin production or their actions
placental abnormalities requires further investi-
have been questioned. This combined with the

gation.
problem of stopping therapy in some women with
hypertensive preeclampsia, dictates more research
Mechanistic Clinical Research
to determine the effects of renin angiotensin system inhibitors during early pregnancy on fetal out Research is needed to identify the mechanisms that
comes.
account for the increased risk of CV disease in women with a medical history of preeclampsia.
More clinical evidence is needed to guide the management of hypertension during pregnancy. Specif Research on the molecular mechanisms involved in
ically, it is not known whether lowering moderate
the regulation of proangiogenic and antiangiogenic
chronic hypertension (greater than 150 mm Hg sysfactors is needed.
tolic and 95 mm Hg diastolic; less than 160 mm Hg
Research on the mechanisms whereby obesity
systolic and 110 mm Hg diastolic) confers either
affects placentation is warranted.
maternal or fetal risk or benefit during pregnancy.
Clinical trials should evaluate specific BP targets,
Research on the mechanisms whereby chronic
using specific antihypertensive agents, and evaluathypertension increases the risk of developing preing meaningful clinical outcomes such as preterm
eclampsia is needed.
birth, IUGR, and severe maternal disease, including
Further studies of the renal abnormalities in preeclampsia and HELLP syndrome.
eclampsia are warranted to better explain the basis
for the decreased glomerular filtration rate and Education
strategies to reverse the renal pathology and Evaluation of the effect of prenatal
education for
decreasing glomerular filtration rate.
women with low literacy on pregnancy outcomes is
needed.
88
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HYPERTENSION

Copyright 2013 by the American College of Obstetricians and Gynecologists,

George R. Saade, MD; Catherine Y. Spong, MD; and Eleni Tsigas.

Obstetricians and Gynecologists, I decided to make

work and dedication to this important endeavor. 20122013

matically with the superimposition of preeclampsia.

(which is discouraged) applies only at the moment the

ited time and resources, would be difficult for the

substantially less. There is no evidence that bed rest or

Strength of recommendation: Qualified

For women with mild gestational hypertension or

and fetal surveillance is resource intensive and should be

Quality of evidence: Moderate

tion of parenteral magnesium sulfate to prevent

Strength of recommendation: Qualified

current status of medical problems should be assessed,

For women with suspected white coat hypertension,

tion, and superimposed preeclampsia, antenatal

Strength of recommendation: Qualified

the importance of contacting health care providers if

tational hypertension and preeclampsia without

posed preeclampsia; and 4) gestational hypertension.

and practical classification, which considers hyperhypertension in association with thrombocytopenia

tation and women with proteinuria before 20 weeks of

sion in pregnancy. J Am Soc Hypertens 2010;4:6878.

Preeclampsia and Eclampsia

collection (or this amount extrapolated from a timed

present, segregate preeclampsia into a more severe

assessment in normal and hypertensive pregnancy. Am J

mid-gestation. J Perinat Med 2008;36:41924. [PubMed]

low, screening tests with positive test results require

lial growth factor [VEGF]) have been evaluated as

have noted positive LRs that ranged from 5.0 to 20 and

consecutive pregnant women with singleton gesta2 weeks of presentation (24).

sia. Hypertension 2005;46:107785. [PubMed] [Full

ed. Amsterdam ; Boston: Academic Press/Elsevier; 2011.

sonography to predict pre-eclampsia and intrauterine 19. Wu Y, Xiong X, Fraser WD,

nostic potential in preeclamptic patients. Am J Obstet

trend toward a lower incidence of preeclampsia in the

large randomized, placebo-controlled trials conducted

nancy-induced hypertension and lower the ratio of

14651858.CD004659.pub2. [PubMed] [Full Text] ^

12. Spinnato JA 2nd, Freire S, Pinto E Silva JL, Cunha Rudge

patients with gestational hypertension and an NST

Patients are instructed to have a regular diet with

addition, an increased concentration of liver

For women with mild gestational hypertension or

eclampsia without severe features, it is suggested

Strength of recommendation: Qualified

cant differences regarding either efficacy or safety

sion during pregnancy (sustained systolic BP of at

Delivery after 48 hours

management of severe preeclampsia initiated before

Quality of evidence: Moderate

Biophysical profile twice weekly

cated further with any of the following:

tation) for 2448 hours to administer corticosteroids

parenteral magnesium sulfate is recommended.

Magnesium sulfate has significant anesthetic implicahypotension.