Altered Fetal Growth, Placental Abnormalities, and Stillbirth

RESEARCH ARTICLE
Altered fetal growth, placental abnormalities,

and stillbirth
Radek Bukowski1*, Nellie I. Hansen2, Halit Pinar3, Marian Willinger4, Uma M. Reddy4,
Corette B. Parker2, Robert M. Silver5, Donald J. Dudley6, Barbara J. Stoll7, George
R. Saade8, Matthew A. Koch2, Carol Hogue9, Michael W. Varner5, Deborah L. Conway10,
Donald Coustan3, Robert L. Goldenberg11, for the Eunice Kennedy Shriver National
Institute of Child Health and Human Development (NICHD) Stillbirth Collaborative
Research Network (SCRN)¶
1 The University of Texas at Austin Dell Medical School, Austin, Texas, United States of America, 2 RTI
a1111111111 International, Research Triangle Park, North Carolina, United States of America, 3 Brown University School
a1111111111 of Medicine, Providence, Rhode Island, United States of America, 4 The Pregnancy and Perinatology
a1111111111 Branch, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National
a1111111111 Institutes of Health, Bethesda, Maryland, United States of America, 5 University of Utah School of Medicine
a1111111111 and Intermountain Health Care, Salt Lake City, Utah, United States of America, 6 University of Virginia
School of Medicine, Charlottesville, Virginia, United States of America, 7 University of Texas Health Science
Center Houston, Houston, Texas, United States of America, 8 University of Texas Medical Branch at
Galveston, Galveston, Texas, United States of America, 9 Rollins School of Public Health, Emory University,
Atlanta, Georgia, United States of America, 10 University of Texas Health Science Center at San Antonio,
San Antonio, Texas, United States of America, 11 Columbia University Medical Center, New York, New York,
OPEN ACCESS United States of America
Citation: Bukowski R, Hansen NI, Pinar H,
¶ Membership of the Stillbirth Collaborative Research Network is provided in the Acknowledgments.
Willinger M, Reddy UM, Parker CB, et al. (2017) * [email protected]
Altered fetal growth, placental abnormalities, and
stillbirth. PLoS ONE 12(8): e0182874. https://doi.
org/10.1371/journal.pone.0182874
Editor: Stefan Gebhardt, Stellenbosch University,

Abstract
SOUTH AFRICA
Background
Received: March 20, 2017
Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental
Accepted: July 26, 2017
abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim
Published: August 18, 2017 of this study was to identify patterns of association between placental abnormalities, fetal
Copyright: This is an open access article, free of all growth, and stillbirth.
copyright, and may be freely reproduced,
distributed, transmitted, modified, built upon, or
otherwise used by anyone for any lawful purpose.
Methods and findings
The work is made available under the Creative Population-based case-control study of all stillbirths and a representative sample of live
Commons CC0 public domain dedication.
births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were cate-
Data Availability Statement: All relevant data are gorized as small (<10th percentile) and large (>90th percentile) for gestational age at death
within the paper. (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by peri-
Funding: This work including the design and natal pathologists was performed using a standardized protocol. Data were weighted to
conduct of the study; collection, management, account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live
analysis, and interpretation of the data; and
preparation, review and approval of the manuscript
births at 24 weeks at death or delivery respectively, 25 placental findings were investi-
was supported by grant funding from the Eunice gated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also
Kennedy Shriver National Institute of Child Health associated with fetal growth abnormalities (single umbilical artery; velamentous insertion;
and Human Development: U10-HD045953 Brown
terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparench-
University, Rhode Island; U10-HD045925 Emory
University, Georgia; U10-HD045952 University of ymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placen-
Texas Medical Branch at Galveston, Texas; U10- tal weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth
PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 1 / 27

Stillbirth, growth and placenta
HDO45955 University of Texas Health Sciences abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of
Center at San Antonio, Texas; U10-HD045944 chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin,
University of Utah Health Sciences Center, Utah;
and U01-HD045954 RTI International, RTP.
fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were ob-
Program officers from the funding agency (Reddy served: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2)
and Willinger) were members of the Steering fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only;
Committee of the study, and contributed to the
(4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different
study design, management, interpretation of the
data, as well as preparation, review and approval of pattern of fetal growth abnormalities in stillbirths and live births.
the manuscript. Otherwise the funders did not have
any involvement in the design of the study; the Conclusions
collection, analysis, and interpretation of the data;
the writing of the article; or the decision to submit The patterns of association between placental abnormalities, fetal growth, and stillbirth pro-
the article for publication. vide insights into the mechanism of impaired placental function and stillbirth. They also sug-
Competing interests: The authors have declared gest implications for clinical care, especially for placental findings amenable to prenatal
that no competing interests exist. diagnosis using ultrasound that may be associated with term stillbirths.
Introduction
Worldwide over 2.6 million pregnancies result in third trimester stillbirths annually [1]. In the
US, about 1 in 160 pregnancies results in stillbirth [2]. The number of stillbirths occurring
globally would place it as the fifth leading cause of death following ischemic heart disease,
stroke, chronic obstructive pulmonary disease, and lower respiratory infections (WHO www.
who.int/mediacentre/factsheets/fs310/en/). While the last decades have seen a steady improve-
ment in neonatal and infant mortality, the rate of stillbirth has declined five times more slowly
and exceeded the infant mortality rate in the U.S. in 2013 [2, 3]. Limited understanding of the
mechanism and ability to predict and prevent stillbirth contribute to the lack of significant
improvement in the stillbirth rate. Currently in 25–40% of stillbirths, the underlying cause
cannot be determined and only approximately 20% of stillbirths are potentially predictable in
early pregnancy [4–6].
Altered fetal growth and placental abnormalities are the strongest and most prevalent
known risk factors for stillbirth [6–8]. However, most pregnancies with placental abnormali-
ties or fetal growth aberrations do not result in stillbirth [7, 8]. An understanding of these
interrelationships may contribute to a better understanding of stillbirth mechanisms.
We hypothesized that a combination of certain placental abnormalities and fetal growth
aberrations may result in an increased risk of stillbirth. Insight into which placental findings
are associated only with stillbirth, only with growth abnormalities, and with both may further
our understanding of stillbirth. Fetal growth aberrations and some placental abnormalities are
amenable to prenatal detection by ultrasound. Prenatal identification of placental findings and
fetal growth abnormalities would likely also improve stillbirth prediction and thus prevention.
Delivery effectively prevents stillbirth in pregnancies at high risk of fetal death. In term preg-
nancies at high risk of stillbirth, delivery is an especially effective intervention for stillbirth pre-
vention, given the minimal risk of neonatal mortality.
Materials and methods

Ethics statement
The study was approved by the Institutional Review Boards at each of the clinical recruiting
sites and the data coordinating center (Brown University; Emory University; University of

Texas Medical Branch at Galveston; University of Texas Health Sciences Center at San Anto-
nio; University of Utah Health Sciences Center; RTI International). All mothers participating
in the study gave written informed consent.
Study design
Women with singleton stillbirths and live births enrolled in the Stillbirth Collaborative
Research Network (SCRN) who consented to placental examination were analyzed. The SCRN
was a population-based case-control study conducted in five geographic areas in the United
States defined by state and county lines: the state of Rhode Island and specific counties in Mas-
sachusetts, Georgia, Texas, and Utah. Women were recruited between March 2006 and Sep-
tember 2008 at the time of delivery in 59 community and academic, urban and rural hospitals
in the 5 areas with a cumulative average of 80,000 deliveries per year. The hospitals were
selected to ensure access to at least 90% of all pregnancies ending in either stillbirth or live
birth within each geographic area based on estimates from vital statistics data. All women
whose pregnancies resulted in stillbirth and a representative sample of women with live births,
oversampled for women delivering live-born infants at <32 weeks’ gestation and those of Afri-
can-American descent delivering live-born infants at 32 weeks’ gestation, were approached
for enrollment. Oversampling of live births <32 weeks’ gestation was necessary due to the dif-
ference in gestational age distribution between stillbirths and live births, while oversampling of
African-American women delivering live births 32 weeks’ gestation was undertaken to
achieve a ratio of approximately twice the number of live births to stillbirths, similar to the
ratio seen among white non-Hispanic women and Hispanic women, out of concern for the
increased burden of stillbirth in this population and the potential interaction of race with
some hypothesized stillbirth risk factors. Terminations of pregnancy were excluded. Details of
the study design have been reported previously [9].
Stillbirth
Fetal death was defined by Apgar scores of 0 at 1 and 5 minutes, and no signs of life by direct
observation, at 20 weeks 0 days of pregnancy or later. This analysis was limited to stillbirths
and live births at 24 weeks 0 days gestation. Births < 24 weeks gestation were excluded to
avoid confounding due to variable clinical management of live births at periviable gestational
ages. Guidelines for determining grades of maceration were defined in the postmortem exami-
nation protocol for intact fetuses as: Grade 0—No maceration, Grade I—Desquamation
involving 1% of total body surface and brown-red discoloration of umbilical cord stump,
Grade II—Desquamation of face, abdomen, or back involving >1% and 5% total body sur-
face, Grade III—Desquamation involving >5% of body surface, Grade IV—Total brown skin
discoloration, Grade V—Mummification; and for fragmented fetuses as: Grade 0—No macer-
ation, Grade I-II—Tissue appears red/pink and fresh, Grade III—Tissue appears red/pink and
mixed with brown, Grade IV—Tissue appears brown/gray, Grade IV—Tissue appears gray.
Placental abnormalities
The study included a standardized placental examination protocol [10]. This protocol included
digital imaging, macroscopic examination, collection of frozen and ambient temperature sam-
ples of the cord, membranes and the placental disc, and microscopic examination of sections
collected according to a specific sampling protocol. A minimum of five full-thickness placental
tissue samples were obtained, one at the umbilical cord insertion and four others determined
by random numbers that specified the axes and spacing of sampling. This strategy was used
to avoid systematic differences in sampling locations and to ensure dispersion of the tissue

sampling sites. All perinatal pathologists participated in training sessions to assure uniform
execution of the protocol. The details of placental examination, sample and data collection
were described previously [10]. General descriptions of the placental abnormalities investi-
gated are given in Table 1.
Fetal growth abnormalities

Gestational age (GA) at death (for stillbirths) or delivery (for live births) was estimated using
an algorithm developed by the SCRN investigators [11]. Preterm birth was defined as GA at
delivery or death < 37 weeks 0 days. Birth weight percentiles were determined using birth
weight, the SCRN estimate of GA at death (stillbirths) or delivery (live births), and an expected
weight for GA based on ultrasound norms [12]. Ultrasound norms were used for both live
births and stillbirths because they were derived using ultrasound measurements from ongoing
uncomplicated pregnancies and have been shown to identify more babies as abnormally
grown compared to population norms which are derived from birth weights of all live births,
including preterm and/or with growth abnormalities, and underestimate the proportion of
babies with abnormal growth [8, 13].
Small for gestational age (SGA) was defined as birth weight less than the 10th percentile,
average for gestational age (AGA) as birth weight between the 10th and 90th percentiles, and
large for gestational age (LGA) as birth weight above the 90th percentile.
Statistical analysis
Analysis was restricted to singletons with an adequate placental examination. Fragmented pla-
centas and placentas from mummified stillbirths were excluded. Mummified stillbirths were
defined as fragmented babies who had Grade IV-V maceration and intact babies who had
Grade V maceration. In addition, stillbirths and live births with missing birth weight or with
GA < 24 weeks by SCRN algorithm were excluded.
Data were weighted to take into account the study design and other aspects of the sampling
plus differential availability of an adequate placental examination. Weighted analyses were
conducted using SUDAAN version 11.0.1 software. Proportions of stillbirths and live births
with selected maternal and infant characteristics and with each placental finding were com-
pared with statistical significance determined by the Wald chi-square test. Comparisons of the
continuous measures placental weight and ratio birth weight to placental weight were based
on weighted ranks and conducted using regression models that included the stillbirth indica-
tor (stillbirth/live birth) only. Next, tests of association between each placental finding and
birth weight percentile were conducted for stillbirths and live births separately with statistical
significance determined by the adjusted Wald F test. Regression models used for comparisons
of continuous measures based on weighted ranks included the percentile group indicator only.
Subsequently, tests for whether the association between each placental finding and birth
weight percentile differed for stillbirths and live births were conducted using a logistic or linear
regression model with a placental finding as the dependent variable and the percentile group
indicator, stillbirth indicator, and effects for the interaction as independent variables, with the
p-value associated with the interaction between percentile group and stillbirth indicator
reported. Where a placental finding was not noted for any stillbirths or live births in a birth
weight percentile category (or conversely when noted for all in a category), the observation in
that percentile group with the smallest analysis weight was recoded as having the finding (or
not having the finding) for the purpose of providing an upper bound on the p-value for the
interaction in the presence of these zero cells. An asterisk next to the p-value indicates it was
derived in this manner. All proportions reported, as well as all other p-values, were based on

Table 1. Descriptions of the placental findings.

General Terms Definitions
Focal Present in one area on a single slide.
Multifocal Present in more than one area and/or in multiple slides.
Patchy Patches or clusters form when multifocal lesions coalesce to
form larger aggregates. In this pattern, the distribution is
uneven and all sections do not show the same degree of
involvement.
Diffuse The term diffuse is used when the distribution of lesions
involves the full thickness and all the sections to the same
degree.
Placental findings Descriptions
Single umbilical artery This is a condition in which a single artery is present in the
umbilical cord instead of the usual two arteries.
Velamentous umbilical cord insertion Normally, the umbilical cord inserts directly into the placenta
so that the fetal blood vessels are protected. In velamentous
cord insertion, the umbilical cord inserts into the fetal
membranes so that the fetal blood vessels travel within the
membranes before entering the placental disc. The blood
vessels lose the protection provided by Wharton’s substance
and are susceptible to injury.
Furcate umbilical cord insertion In furcate insertion, the umbilical blood vessels lose their
protective Wharton’s substance before entering the placental
disc. The vessels enter the chorionic plate separately. There
are combinations of various types of insertion. It is not
infrequent to see a furcate insertion to the placental
membranes. This qualifies as both as a furcate and a
velamentous insertion.
Circummarginate insertion of the placental This condition is similar to circumvallate insertion but the
membranes marginal white/yellow ring of membrane attachment is flat and
does not have a ridge
Circumvallate insertion of the placental In circumvallate insertion, the membranes are folded over at
membranes the margin and decrease the surface area of the placenta.
The marginal white/yellow rim of membranes is folded or
rolled back to form a distinct raised ridge. This results in
doubling of the membranes at the margin and accumulation of
fibrin and blood clots.
Terminal (distal) villous immaturity Terminal villous immaturity is a placental phenotype
characterized by enlarged distal (terminal) villi with excessive
stroma, hypercellular villous trophoblast, paucity of
vasculosyncytial membranes, and a decreased fetoplacental
weight ratio.
Terminal (distal) villous hypoplasia Terminal villous hypoplasia is a decrease in the number and
modal diameter of distal villi at the center of the lobule after
adjustment for plane of section and gestational age. The
decrease in the number of centrilobular distal villi is estimated
relative to the number of adjacent stem villi. The extent of
terminal villous hypoplasia is estimated as the percentage of
villous parenchyma occupied by lobules with centrilobular
distal villi that are too few and too small for gestational age in
the lower 75% of a full-thickness section.
Acute chorioamnionitis of the placental Chorioamnionitis is an inflammation of the fetal membranes
membranes and chorionic plate due to infection. The presence of inflammatory cells is
sufficient to make the diagnosis of chorioamnionitis. No
grades or stages were assigned. Presence of
polymorphonuclear leukocytes without mononuclear cells
indicates acute infection.
(Continued)

Table 1. (Continued)
Acute funisitis When the acute inflammatory process involves the Wharton’s
substance, a diagnosis of funisitis is made. This is the
morphological expression of involvement of the fetal
compartment.
Acute umbilical cord arteritis This is acute infection/inflammation of one or both arteries in
the umbilical cord.
Acute umbilical cord phlebitis This is acute infection/inflammation of the vein in the umbilical
cord.
Chorionic plate acute vasculitis of the fetal This is acute infection/inflammation of the fetal blood vessels
blood vessels in the chorionic plate.
Chorionic plate vascular degenerative These changes may be caused by the prolonged presence of
changes meconium within the amniotic cavity. The degeneration
consists largely of a homogenization of the muscular wall,
which displays eosinophilia, while the nuclei do not stain.
Acute villitis This is involvement of the chorionic villi with acute
inflammatory cells. It ranges from collection of occasional
cells to microabscess formation. Pathogenic agents are
frequently bacteria such as Listeria monocytogenes.
Chronic villitis This is involvement of the chorionic villi with chronic
inflammatory cells. It can involve plasma cells. It can be
specific (i.e. CMV, herpes) or nonspecific (villitis of unknown
etiology [VUE]).
Retroplacental hematoma This is a hematoma behind the placenta. Abruptio placenta is
defined as detachment of the placenta from the inner wall of
the uterus. Pathologically this results in a retroplacental
hematoma. Eventually the villous tissue underlying the
hematoma infarct. If they are fresh (less than two hours) it
may be difficult to distinguish them from normal postpartum
blood clots. After several hours however, the retroplacental
clot will become adherent to the maternal surface and
identifiable on macroscopic examination. Compression of the
underlying villous tissue then follows in a few hours.
Parenchymal infarction Placental infarcts are the most common lesions seen in the
placenta. They represent dead villous tissue due to
compromised intervillous (maternal) circulation. When
parenchymal infarcts are identified away from the placental
margins and particularly when they are randomly distributed,
placental compromised perfusion is confirmed. Parenchymal
infarcts in any location in the first and second trimester
placentas are always abnormal.
Intraparenchymal (intervillous) thrombus Intraparenchymal thrombi are common parenchymal lesions.
They are localized clots in the intervillous space. They
frequently develop in the maternal circulation due to increased
thrombosis in the setting of maternal thrombophilias and
preeclampsia. Some intraparenchymal thrombi may occur
secondary to leakage from the fetal capillaries resulting in
fetal maternal hemorrhage.
Perivillous, intervillous fibrin, fibrinoid This is perivillous fibrin encasing of chorionic villi. It often
deposition patterns accompanies a significant increase of fibrin deposition in the
basal plate and can present with or without extravillous
trophoblastic proliferation of the villi. Maternal floor infarction/
Gitterinfarkt is a specific pattern of massive perivillous fibrin
deposition with extensive involvement of terminal villi in the
basal portion of the placenta by a surrounding matrix of
varying proportions of pink fibrinoid material containing
extravillous trophoblast and true fibrin often arranged in
swirling whorls and fascicles.
(Continued)

Fetal vascular thrombi in the chorionic These are thrombi identified in the chorionic plate fetal blood
plate vessels. Whatever the etiology, the presence of even one
thrombus is considered significant. If this lesion is associated
with downstream avascular villi, it is usually not related to
infection and called fetal thrombotic vasculopathy. (After fetal
death, fetal circulation stops and fetal vascular thrombi are not
formed).
Avascular villi Loss of villous capillaries and bland hyalinization of the villous
stroma in a distribution consistent with a single upstream
occlusive event. This is different than the villous changes
seen with fetal death.
Placental edema The villous tissue is diffusely boggy, and friable. There are
pools of extracellular fluid expanding the stromal area and
often accompanied by increased Hofbauer cells,
cytotrophoblast hyperplasia, and artifactual dehiscence of
trophoblast from stroma. When seen with hydrops fetalis, it is
considered a lethal lesion.
https://doi.org/10.1371/journal.pone.0182874.t001
the data without recoding zero cells. In each case where the interaction p-value was approxi-
mated by recoding zero cells, the revised proportions were checked to verify that the recoding
did not introduce more extreme results than were present in the original data. Examples are
provided in S1 Table.
In the primary analyses, comparisons of placental weight and the ratio birth weight/placen-
tal weight were additionally conducted with adjustment for GA. Linear regression models that
included GA as a continuous variable and models that included GA as a categorical variable
(groups as noted in table footnotes) were compared with similar inference. P-values from
models that included categorical GA are reported in brackets beside unadjusted p-values in
the tables.
Results
Consent for placental exam was obtained for 613 of the 620 singleton stillbirth pregnancies
and for 1,747 of the 1,871 singleton live birth pregnancies. Ninety-five stillbirth placentas and
547 live birth placentas were excluded from analysis because of inadequate examination, frag-
mentation, or mummification, leaving 518 stillbirth placentas and 1,200 live birth placentas.
From these, 199 stillbirths (16 missing birth weight, 183 with GA <24 weeks) and 81 live births
(17 missing birth weight, 64 with GA <24 weeks) were excluded. Thus, 319 singleton stillbirths
and 1119 singleton live births with a GA of 24 weeks at death or delivery were studied.
A greater proportion of women who delivered stillbirths had hypertension before preg-
nancy (11% versus 5%, p<0.001), gestational hypertension/pre-eclampsia (20% versus 11%,
p<0.001), and pregestational diabetes (7% versus 2%, p<0.001) (Table 2). Stillborn infants had
lower GA compared to live born infants (median 33 versus 39 weeks, p<0.001) and lower
birth weight (median 1,949 versus 3,321 grams, p<0.001) and a larger proportion had a con-
genital anomaly (13% versus 3%, p<0.001) (Table 2). Less than a third of the 319 stillborn
infants were born at term (unweighted n = 88; weighted n = 87, 28%) while the majority of the
1119 live births were born at term (unweighted n = 942; weighted n = 854, 90%). A median of
2 days elapsed between estimated death and delivery of stillborn infants (interquartile range 1
to 4 days). No maceration was reported for 36 (13%) of the 282 stillbirths with information,
Grade I maceration for 41 (15%), Grade II for 65 (23%), Grade III for 120 (43%), and Grade
IV for 20 (7%). No consent for postmortem exam was given for 36 stillborn infants and infor-
mation about maceration information was missing for one.

Table 2. Characteristics of singleton stillbirths and live births 24 weeks GA with adequate placental examination.
Characteristic, column % or as shown 1/ Stillbirth Live birth P-value 2/
Unweighted number 319 1119
Weighted number 314 948
MOTHER
Age at delivery, years
Median 26 27 0.59
Interquartile range 22 to 32 22 to 31
Race/ethnicity 0.02
Non-Hispanic white 36 45
Non-Hispanic black 17 11
Hispanic 41 36
Other 6 7
Chronic hypertension 11 5 0.007
Gestational hypertension/pre-eclampsia 20 11 <0.001
Pre-gestational diabetes 7 2 <0.001
Gestational diabetes 7 8 0.63
INFANT
GA, weeks <0.001
Median 33 39
Interquartile range 28 to 37 38 to 40
GA category <0.001
24–31 wk 41 1
32–26 wk 31 8
37+ wk 28 90
Birth weight, grams <0.001
Median 1,949 3,321
Interquartile range 984 to 2,873 3,005 to 3,638
Male sex 55 50 0.13
Congenital anomaly 13 3 <0.001
1/
Weighted percentages and other statistics are shown. Information was missing as follows (unweighted n): pre-pregnancy hypertension, 4; pre-pregnancy
diabetes, 4; male sex, 2.
2/
P-value for a difference between stillbirths and live births by the Wald chi-square test (categorical variables) or the median test (continuous variables).
The placental examination investigated 25 findings, of which 15 were significantly associ-

ated with stillbirth (Table 3). The 13 significant findings reported as percentages were more
common among stillbirths than live births. Median placental weight and median birth weight
to placental weight ratio were each significantly lower in stillbirths than in live births. Ten of
the 15 placental findings associated with stillbirth were also associated with fetal growth abnor-
malities (Fig 1; single umbilical artery, velamentous insertion, terminal villous immaturity, ret-
roplacental hematoma, parenchymal infarction, intraparenchymal thrombus, avascular villi,
placental edema, placental weight, and ratio birth weight/placental weight) while 5 of the 15
findings more common in stillbirths were not associated with fetal growth abnormalities
(acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate;
chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposi-
tion; fetal vascular thrombi in the chorionic plate). Terminal villous hypoplasia was the only
placental finding associated with fetal growth that was not significantly more common among
stillbirths than among live births (Fig 1; Table 3).

Table 3. Placental findings in singleton stillbirths and live births 24 weeks GA.
Characteristic, column % or as shown 1/ Stillbirth Live birth P-value 2/
Unweighted number 319 1119
Weighted number 314 948
DEVELOPMENTAL DISORDERS
Umbilical cord
Single umbilical artery 8.4 1.7 <0.001
Velamentous insertion 3.9 1.2 0.02
Furcate insertion 1.9 3.5 0.12
Placental membranes
Circummarginate insertion 13.4 10.8 0.23
Circumvallate insertion 2.2 1.4 0.40
Fetal villous capillaries
Terminal villous immaturity (diffuse) 10.1 2.3 <0.001
Terminal villous hypoplasia (diffuse) 3.4 1.8 0.21
INFLAMMATORY DISORDERS
Maternal inflammatory response
Acute chorioamnionitis—placental membranes 24.5 11.9 <0.001
Acute chorioamnionitis—chorionic plate 17.3 11.8 0.02
Fetal inflammatory response
Acute funisitis 3.0 3.2 0.86
Acute umbilical cord arteritis (one or more arteries) 0.6 1.7 0.05
Acute umbilical cord phlebitis 2.5 2.9 0.65
Chorionic plate acute vasculitis 3.0 5.0 0.10
Chorionic plate vascular degenerative changes 5.7 0.5 <0.001
Villitis
Acute diffuse villitis 0.8 0.1 0.16
Chronic diffuse villitis 2.1 0.5 0.07
CIRCULATORY DISORDERS
Maternal circulatory disorders
Retroplacental hematoma 17.1 4.2 <0.001
Parenchymal infarction 33.3 15.8 <0.001
Intraparenchymal thrombus 22.7 13.5 <0.001
Perivillous, intervillous fibrin, fibrinoid deposition (diffuse) 9.2 1.5 <0.001
Fetal circulatory disorders
Fetal vascular thrombi in the chorionic plate 28.6 7.1 <0.001
Avascular villi 19.4 6.9 <0.001
Placental edema 4.0 1.0 0.01
Placental weight, median (IQR) 300 (185–414) 435 (376–508) <0.001
Ratio birth weight/placental weight, median (IQR) 6.3 (4.9–8.0) 7.5 (6.7–8.5) <0.001
1/
Weighted percentages and other statistics are shown. Information was missing as follows (unweighted n): single umbilical artery, 8; velamentous
insertion, 27; furcate insertion, 33; circummarginate insertion, 46; circumvallate insertion, 46; terminal villous immaturity, 9; terminal villous hypoplasia, 13;
any developmental disorder, 74; acute chorioamnionitis—placental membraines, 18; acute chorioamnionitis—chorionic plate, 15; acute funisitis, 11; acute
umbilical cord arteritis, 31; acute umbilical cord phlebitis, 16; chorionic plate acute vasculitis, 16; chorionic plate vascular degenerative changes, 17; acute
diffuse villitis, 7; chronic diffuse villitis, 8; any inflammatory disorder, 46; retroplacental hematoma, 8; parenchymal infarction, 7; intraparenchymal thrombus,
12; perivillous, intervillous fibrin, fibrinoid deposition, 64; any maternal circulatory disorder, 44; fetal vascular thrombi in the chorionic plate, 10; avascular
villi, 7; edema, 10; any fetal circulatory disorder, 13; placental weight, 14; ration birth weight/placental weight, 14.
2/
P-value for an association between the placental finding and stillbirth by the Wald chi-square test based on observed minus expected frequencies for
categorical variables. For each continuous measurement, the test is for mean difference in weighted ranks.

Fig 1. The relationship between 25 placental abnormalities studied, fetal growth, and stillbirth. A total
of 15 placental findings were associated with an increased risk of stillbirth of which 10 were also associated
with fetal growth abnormalities. Terminal villous hypoplasia (TVH) was associated with fetal growth but not
stillbirth.
https://doi.org/10.1371/journal.pone.0182874.g001
The associations between placental findings, fetal growth abnormalities, and stillbirth showed
five distinct patterns: placental findings associated with (1) stillbirth but not fetal growth abnor-
malities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live
births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a
different pattern of fetal growth abnormalities in stillbirths and live births (Table 4).
(1) Placental findings associated with stillbirth but not fetal growth abnormalities.
Acute chorioamnionitis of the placental membranes and chorionic plate; chorionic plate
vascular degenerative changes; perivillous or intervillous fibrin, fibrinoid depositions; and fetal
vascular thrombi in the chorionic plate were more common among stillbirths than among live
births (Table 3). Although associated with stillbirth, no significant associations were found
between these placental findings and fetal growth abnormalities in either preterm stillbirths
and live births (Table 5) or term stillbirths and live births (Table 6).
(2) Placental findings associated with fetal growth abnormalities in stillbirths only.
Velamentous umbilical cord insertion, terminal villous hypoplasia, and parenchymal
infarction were significantly associated with fetal growth abnormalities in preterm stillbirths
but a significant association was not found in preterm live births (Table 5). The proportion
with each of these findings was larger in SGA preterm stillbirths than in AGA and LGA pre-
term stillbirths. In term stillbirths the proportion with each of these findings was also highest
in those who were SGA. However, significant associations with fetal growth were not observed
in term stillbirths (Table 6).

Table 4. Patterns of association between placental findings, fetal growth and stillbirth.
PLACENTAL FINDINGS
(1) associated with stillbirth but not fetal growth
Acute chorioamnionitis of placental membranes
Acute chorioamnionitis of chorionic plate
Chorionic plate vascular degenerative changes
Perivillous, intervillous fibrin, fibrinoid deposition
Fetal vascular thrombi in the chorionic plate
(2) associated with fetal growth abnormalities in stillbirths only
Velamentous umbilical cord insertion in preterm pregnancies
Terminal villous hypoplasia in preterm pregnancies
Parenchymal infarction in preterm pregnancies
(3) associated with fetal growth abnormalities in live births only
Single umbilical artery in term pregnancies
Terminal villous hypoplasia in term pregnancies*
Parenchymal infarction in term pregnancies
(4) associated with fetal growth abnormalities in stillbirths and live births in a similar manner
Placental weight in preterm pregnancies
Intraparenchymal thrombus in term pregnancies
(5) with a different pattern of fetal growth abnormalities in stillbirths and live births
Terminal villous immaturity (diffuse) in preterm pregnancies
Retroplacental hematoma in preterm and term pregnancies
Avascular villi in preterm pregnancies
Placental edema in preterm pregnancies
Placental weight in term pregnancies
Ratio birth weight/placental weight in term pregnancies
* Terminal villous hypoplasia is almost twice as common in stillbirths (3.4%) as in live births (1.8%), but this
difference did not reach statistical significance.
(3) Placental findings associated with fetal growth abnormalities in live births only.
Single umbilical artery, terminal villous hypoplasia and parenchymal infarction were signif-
icantly associated with fetal growth abnormalities in term live births but not in term stillbirths
(Table 6). Each of these findings was either not observed or less common in LGA than in AGA
and SGA term live births. Although each of these findings was similarly not observed or less
common in preterm LGA compared to AGA and SGA live births, statistically significant dif-
ferences were not observed in preterm live births (Table 5).
(4) Placental findings associated with fetal growth abnormalities in stillbirths and live births
in a similar manner.
Placental weight in preterm pregnancies and intraparenchymal thrombus in term pregnan-
cies were significantly associated with fetal growth abnormalities in both stillbirths and live
births in a similar manner (Tables 5 and 6). These two placental findings were respectively
higher or more common in LGA than in AGA and SGA stillbirths and live births.
(5) Placental findings with a different pattern of fetal growth abnormalities in stillbirths and
live births.
Among preterm pregnancies, patterns of association between fetal growth abnormalities
and each of terminal villous immaturity, avascular villi, placental edema and retroplacental
hematoma differed for stillbirths and live births (Table 5, significant p value for interaction).
Terminal villous immaturity, avascular villi, and placental edema were not observed among

Table 5. Placental findings in preterm (24–36 weeks) stillbirths and live births small, average, and large for gestational age.1/
Characteristic, column % or as shown 2/ SGA AGA LGA P-value for association, SBs & P-value for
LBs interaction 4/
separately3/
Unweighted number of stillbirths 122 87 22
Weighted number of stillbirths 121 84 22
Unweighted number of live births 46 113 18
Weighted number of live births 23 58 13
Umbilical cord
Single umbilical artery 0.24*
Stillbirths 8.4 10.7 10.8 0.85
Live births 3.0 1.1 0.0 0.41
Velamentous insertion 0.47*
Stillbirths 5.2 4.7 0.0 0.03
Live births 2.9 2.4 0.0 0.21
Furcate insertion 0.07*
Stillbirths 1.7 1.5 0.0 0.26
Live births 0.0 2.2 8.7 0.27
Placental membranes
Circummarginate insertion 0.99
Stillbirths 10.6 14.9 22.0 0.38
Live births 4.8 7.3 12.1 0.73
Circumvallate insertion 0.21*
Stillbirths 2.3 3.0 3.8 0.91
Live births 0.0 1.6 0.0 0.32
Terminal villous immaturity (diffuse) 0.009*
Stillbirths 7.3 8.1 19.6 0.44
Live births 7.2 1.7 0.0 0.22
Terminal villous hypoplasia (diffuse) 0.17*
Stillbirths 7.1 0.0 0.0 0.03
Live births 10.8 1.7 0.0 0.21
Acute chorioamnionitis—placental 0.87
membranes
Stillbirths 28.7 19.4 16.7 0.22
Live births 26.5 12.5 14.3 0.71
Acute chorioamnionitis—chorionic plate 0.95
Stillbirths 16.3 13.1 20.1 0.68
Live births 21.8 15.0 28.1 0.63
Acute funisitis 0.55*
Stillbirths 2.7 4.1 0.0 0.06
Live births 2.6 4.0 0.6 0.13
Acute umbilical cord arteritis 0.69*
Stillbirths 0.0 0.0 4.6 0.60
Live births 1.5 3.0 3.9 0.60
Acute umbilical cord phlebitis 0.83
(Continued)

LBs interaction 4/
separately3/
Stillbirths 0.7 2.8 4.6 0.42
Live births 2.1 3.9 10.5 0.43
Chorionic plate acute vasculitis 0.22
Stillbirths 1.6 2.8 3.4 0.80
Live births 1.9 8.4 0.6 0.10
Chorionic plate vascular degenerative 0.99*
changes
Stillbirths 3.4 7.5 11.1 0.26
Live births 0.0 0.2 0.0 0.61
Villitis
Acute diffuse villitis 0.88*
Stillbirths 1.5 0.9 0.0 0.27
Live births 0.0 0.1 0.0 0.61
Chronic diffuse villitis 0.44*
Stillbirths 3.4 0.0 0.0 0.14
Live births 2.5 0.3 0.0 0.23
Retroplacental hematoma 0.03*
Stillbirths 26.7 16.9 0.0 <0.001
Live births 5.7 2.7 15.3 0.39
Parenchymal infarction 0.40
Stillbirths 48.1 25.9 14.6 <0.001
Live births 17.6 16.1 7.2 0.52
Intraparenchymal thrombus 0.34
Stillbirths 17.9 23.2 25.4 0.58
Live births 14.4 11.1 34.6 0.32
Perivillous, intervillous fibrin, fibrinoid 0.43
deposition
Stillbirths 14.8 8.1 5.8 0.25
Live births 6.4 1.7 0.3 0.34
Fetal vascular thrombi in the chorionic plate 0.91
Stillbirths 21.8 26.9 33.3 0.51
Live births 8.8 9.4 8.8 1.00
Avascular villi 0.04*
Stillbirths 19.3 21.3 16.8 0.87
Live births 4.6 8.4 0.0 0.09
Placental edema 0.01*
Stillbirths 3.2 2.3 11.1 0.51
Live births 0.5 3.8 0.0 0.15
Placental weight 0.66 [0.90]
Stillbirths <0.001 [<0.001]
Median (IQR) 180 (134– 281 (208– 421 (306–
247) 390) 513)
Live births <0.001 [<0.001]
(Continued)

LBs interaction 4/
separately3/
Median (IQR) 318 (234– 361 (301– 483 (396–
330) 425) 573)
Ratio birth weight/placental weight 0.32 [0.40]
Stillbirths 0.62 [0.45]
Median (IQR) 5.5 (4.1–7.7) 6.1 (4.6–7.0) 6.0 (4.7–7.6)
Live births 0.17 [0.44]
Median (IQR) 6.1 (5.9–6.9) 6.8 (5.7–7.8) 6.5 (5.9–7.4)
1/
Birth weight percentiles for GA were determined using Hadlock ultrasound norms and GA at death (stillbirths) or delivery (live births) by the SCRN
algorithm.
2/
Weighted percentages and other statistics are shown. For stillbirths, information was missing as follows (unweighted n): single umbilical artery, 1;
velamentous insertion, 2; furcate insertion, 3; circummarginate insertion, 8; circumvallate insertion, 8; terminal villous immaturity, 3; terminal villous
hypoplasia, 3; any developmental disorder, 12; acute chorioamnionitis—chorionic plate, 2; acute funisitis, 1; acute umbilical cord arteritis, 5; acute umbilical
cord phlebitis, 3; chorionic plate acute vasculitis, 7; chorionic plate vascular degenerative changes, 7; acute diffuse villitis, 1; chronic diffuse villitis, 2; any
inflammatory disorder, 10; retroplacental hematoma, 4; parenchymal infarction, 3; intraparenchymal thrombus, 2; perivillous, intervillous fibrin, fibrinoid
deposition, 12; any maternal circulatory disorder, 8; fetal vascular thrombi in the chorionic place, 5; avascular villi, 2; edema, 6; any fetal circulatory disorder,
6; placental weight, 3; ratio birth weight/placental weight, 3. For live births, information was missing as follows (unweighted n): velamentous insertion, 4;
furcate insertion, 5; circummarginate insertion, 8; circumvallate insertion, 8; terminal villous immaturity, 1; terminal villous hypoplasia, 3; any developmental
disorder, 13; acute chorioamnionitis—placental membranes, 2; acute chorioamnionitis—chorionic plate, 2; acute umbilical cord arteritis, 4; chorionic plate
acute vasculitis, 1; chorionic plate vascular degenerative changes, 1; acute diffuse villitis, 2; chronic diffuse villitis, 2; any inflammatory disorder, 1;
retroplacental hematoma, 1; parenchymal infarction, 1; intraparenchymal thrombus, 1; perivillous, intervillous fibrin, fibrinoid deposition, 14; any maternal
circulatory disorder, 10; fetal vascular thrombi in the chorionic plate, 1; avascular villi, 1; any fetal circulatory disorder, 1.
3/
P-value by the adjusted Wald F test for an association between a placental finding and birth weight percentile among stillbirths and live births separately.
For each continuous measurement, the test is for mean difference in weighted ranks; p-values after adjustment for GA (24–31, 32–36) are shown in
brackets.
4/
P-value by the adjusted Wald F test for whether the association between a placental finding and birth weight percentile differs for stillbirths and live births.
For each continuous measure, the test was based on weighted ranks; p-values after adjustment for GA (24–31, 32–36) are shown in brackets.
* None of the births in one or more group had the placental finding. The p-value reported was estimated as described in Statistical Analysis.
preterm LGA live births but were common among preterm LGA stillbirths. Retroplacental
hematoma was significantly associated with fetal growth among preterm stillbirths with a
quarter of SGA and none of the LGA preterm stillbirths demonstrating retroplacental hema-
toma. Among preterm live births, the proportion with retroplacental hematoma was highest
among those with LGA pregnancies (Table 5).
In term pregnancies, different fetal growth patterns were observed in stillbirths and live
births for retroplacental hematoma, placental weight, and the ratio of birth weight to placental
weight (Table 6, significant p value for interaction). Retroplacental hematoma was found most
frequently in term SGA stillbirths and was not observed among term LGA stillbirths but was
observed among term LGA live births. In term stillbirths, the median placental weight was 20g
larger in SGA, 40g smaller in AGA and 90g smaller in LGA than in term live births (Table 6).
Median birth weight to placental weight ratio was almost identical for all fetal growth catego-
ries among term live births. The ratio was markedly smaller among term SGA stillbirths
(median (IQR): 6.8 (6.1–7.8) vs. 7.7 (6.8–8.8), respectively) and substantially larger in term
LGA stillbirths compared to term live births (median (IQR): 9.3 (6.0–10.5) vs. 7.4 (6.8–8.5),
respectively) (Table 6; Fig 2). Among preterm pregnancies, there was no significant association
between birth weight to placental weight ratio and the birth weight categories among stillbirths

Table 6. Placental findings in term (37+ weeks) stillbirths and live births small, average, and large for gestational age.1/
Characteristic, column % or as shown 2/ SGA AGA LGA P-value for association, SBs & LBs P-value for
separately 3/ interaction4/
Unweighted number of stillbirths 28 50 10
Weighted number of stillbirths 28 50 9
Unweighted number of live births 156 729 57
Weighted number of live births 138 666 50
Umbilical cord
Single umbilical artery 0.69*
Stillbirths 3.7 7.4 0.0 0.16
Live births 1.9 1.9 0.0 0.002
Velamentous insertion 0.93*
Stillbirths 3.8 1.9 0.0 0.42
Live births 1.0 0.9 2.8 0.65
Furcate insertion 0.46*
Stillbirths 8.9 0.0 0.0 0.36
Live births 5.4 3.3 2.6 0.57
Placental membranes
Circummarginate insertion 0.90
Stillbirths 13.3 12.7 18.6 0.90
Live births 8.9 11.5 13.8 0.61
Circumvallate insertion 0.61*
Stillbirths 0.0 1.4 0.0 0.61
Live births 1.6 1.4 1.2 0.97
Terminal villous immaturity (diffuse) 0.70*
Stillbirths 14.8 14.9 0.0 0.05
Live births 1.1 2.5 1.2 0.30
Terminal villous hypoplasia (diffuse) 0.45*
Stillbirths 3.5 1.9 0.0 0.42
Live births 3.4 1.4 0.0 0.006
Acute chorioamnionitis—placental 0.63
membranes
Stillbirths 19.4 27.1 36.9 0.54
Live births 12.0 10.5 21.7 0.26
Acute chorioamnionitis—chorionic plate 0.09
Stillbirths 11.9 28.6 16.4 0.17
Live births 12.6 10.2 18.1 0.36
Acute funisitis 0.87*
Stillbirths 2.7 4.1 0.0 0.30
Live births 2.8 2.8 9.7 0.43
Acute umbilical cord arteritis (one or more 0.69*
arteries)
Stillbirths 2.7 0.0 0.0 0.60
Live births 1.1 1.6 2.0 0.83
Acute umbilical cord phlebitis 0.45*
(Continued)

Stillbirths 2.7 5.7 0.0 0.22
Live births 3.5 2.1 9.5 0.17
Chorionic plate acute vasculitis 0.99*
Stillbirths 6.1 5.4 0.0 0.16
Live births 5.5 4.6 7.3 0.71
Chorionic plate vascular degenerative 0.95*
changes
Stillbirths 6.5 6.2 0.0 0.17
Live births 0.8 0.5 0.0 0.17
Villitis
Acute diffuse villitis 1.00*
Stillbirths 0.0 0.0 0.0
Live births 0.0 0.2 0.0 0.61
Chronic diffuse villitis 0.78*
Stillbirths 3.8 2.5 0.0 0.41
Live births 0.0 0.6 0.0 0.14
Retroplacental hematoma 0.02*
Stillbirths 23.0 1.9 0.0 0.05
Live births 2.0 4.7 2.0 0.13
Parenchymal infarction 0.26
Stillbirths 35.2 18.7 20.0 0.31
Live births 17.5 16.3 5.4 0.005
Intraparenchymal thrombus 0.72
Stillbirths 10.3 34.4 49.7 0.01
Live births 5.1 14.9 16.7 <0.001
Perivillous, intervillous fibrin, fibrinoid 0.62*
deposition
Stillbirths 9.4 0.0 0.0 0.37
Live births 2.6 1.1 1.1 0.57
Fetal vascular thrombi in the chorionic 0.66
plate
Stillbirths 45.8 30.5 56.3 0.23
Live births 9.5 6.2 7.6 0.49
Avascular villi 0.18
Stillbirths 32.8 10.2 18.8 0.09
Live births 8.1 6.7 6.5 0.84
Placental edema 0.81*
Stillbirths 0.0 7.0 9.9 0.14
Live births 0.7 0.9 1.2 0.94
Placental weight 0.03 [0.03]
Stillbirths, median (IQR) 385 (329– 434 (353– 466 (381– 0.01 [0.003]
439) 484) 648)
Live births, median (IQR) 364 (313– 451 (400– 554 (502– <0.001 [<0.001]
406) 516) 610)
Ratio birth weight/placental weight 0.02 [0.02]
(Continued)

Stillbirths, median (IQR) 6.8 (6.1– 7.7 (7.0– 9.3 (6.0– 0.04 [0.05]
7.8) 8.7) 10.5)
Live births, median (IQR) 7.7 (6.8– 7.6 (6.8– 7.4 (6.8– 0.53 [0.52]
8.8) 8.5) 8.5)
1/
Birth weight percentiles for GA were determined using Hadlock ultrasound norms and GA at death (stillbirths) or delivery (live births) by the SCRN
algorithm.
2/
Weighted percentages and other statistics are shown. For stillbirths, information was missing as follows (unweighted n): velamentous insertion, 1; furcate
insertion, 2; circummarginate insertion, 3; circumvallate insertion, 3; terminal villous immaturity, 1; terminal villous hypoplasia, 2; any developmental
disorder, 4; acute chorioamnionitis—placental membranes, 1; acute umbilical cord arteritis, 1; chorionic plate acute vasculitis, 2; chorionic plate vascular
degenerative changes, 2; any inflammatory disorder, 3; intraparenchymal thrombus, 1; perivillous, intervillous fibrin, fibrinoid deposition, 9; any maternal
circulatory disorder, 1; edema, 1; any fetal circulatory disorder, 1. For live births, information was missing as follows (unweighted n): single umbilical artery,
7; velamentous insertion, 20; furcate insertion, 23; circummarginate insertion, 27; circumvallate insertion, 27; terminal villous immaturity, 4; terminal villous
hypoplasia, 5; any developmental disorder, 45; acute chorioamnionitis—placental membranes, 15; acute chorioamnionitis—chorionic plate, 11; acute
funisitis, 10; acute umbilical cord arteritis, 21; acute umbilical cord phlebitis, 13; chorionic plate acute vasculitis, 6; chorionic plate vascular degenerative
changes, 7; acute diffuse villitis, 4; chronic diffuse villitis, 4; any inflammatory disorder, 32; retroplacental hematoma, 3; parenchymal infarction, 3;
intraparenchymal thrombus, 8; perivillous, intervillous fibrin, fibrinoid deposition, 29; any maternal circulatory disorder, 25; fetal vascular thrombi in the
chorionic plate, 4; avascular villi, 4; edema, 3; any fetal circulatory disorder, 5; placental weight, 11; ratio birth weight/placental weight, 11.
3/
P-value by the adjusted Wald F test for an association between a placental finding and birth weight percentile among stillbirths and live births separately.
For each continuous measurement, the test is for mean difference in weighted ranks; p-values after adjustment for GA (37–38, 39+) are shown in brackets.
4/
P-value by the adjusted Wald F test for whether the association between a placental finding and birth weight percentile differs for stillbirths and live births.
For each continuous measure, the test was based on weighted ranks; p-values after adjustment for GA (37–38, 39+) are shown in brackets.
* None of the births in one or more group had the placental finding. The p-value reported was estimated as described in Statistical Analysis.
or live births nor was there a difference in this association between stillbirths and live births.
(Table 5; Fig 2).
Associations between placental findings and fetal growth among preterm births were essentially
similar in the subsets of preterm births at 24–31 and 32–26 weeks gestation (S2 and S3 Tables).
Discussion
This study provides evidence that placental abnormalities may be associated with fetal growth
abnormalities culminating in stillbirth or they may be associated with stillbirth without growth
abnormalities. This conclusion is supported by the observation that 10 of the 11 placental
findings associated with fetal growth abnormalities were also associated with higher risk of
stillbirth. Another 5 placental findings were associated with stillbirth but not fetal growth
abnormalities. Five patterns of association between placental findings, fetal growth abnormali-
ties, and stillbirth were identified. Placental findings were associated with: (1) stillbirth but not
fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth
abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a
similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live
births. These distinct patterns of association may indicate different mechanisms of placental
function impairment and suggest different clinical management strategies.
Mechanistic insights
Placental findings associated with stillbirth but not fetal growth abnormalities (group 1) may
affect placental function acutely and severely. Such a sudden and severe impairment of

Fig 2. Birth weight to placental weight ratio in preterm and term pregnancies. P-value for a test of whether
the association between the ratio and birth weight percentile group differed for stillbirths and live births after
adjustment for gestational age is shown.
https://doi.org/10.1371/journal.pone.0182874.g002

placental function could lead to stillbirth without sufficient time necessary to affect fetal
growth or through mechanisms unrelated to fetal growth. Acute chorioamnionitis of the pla-
cental membranes and chorionic plate, fetal chorionic plate vascular degenerative changes,
perivillous or intervillous fibrin or fibrinoid depositions, and fetal vascular thrombi in the cho-
rionic plate were findings of this type. It is unlikely that the five placental findings associated
with stillbirth but not fetal growth could in some cases represent post-mortem changes. The
changes the placental tissue undergoes in fetal death are well established and are unlikely to be
confused with the underlying pathology. The only lesion that can continue for a limited time
and to a very limited degree is acute chorioamnionitis of the placental membranes. There can
be a mild polymorphonuclear response in the membranes after fetal death, especially in a case
of severe amniotic fluid infection syndrome but that can be differentiated by other findings.
The second group of placental findings, consisting of velamentous umbilical cord insertion,
terminal villous hypoplasia, and parenchymal infarction, was associated with fetal growth
abnormalities among preterm stillbirths only (group 2). This suggests that when these findings
impair placental function chronically and severely leading to fetal growth abnormalities still-
birth may result. Milder forms might not substantially affect fetal growth and may result in live
birth rather than stillbirth.
A single umbilical artery was associated with fetal growth abnormalities in term live births
only (group 3). This pattern of association suggests that single umbilical artery may impair pla-
cental function chronically and mildly leading to fetal growth impairment that becomes obvi-
ous late in pregnancy and without causing stillbirth.
Terminal villous hypoplasia and parenchymal infarction appear to have different effects in
preterm and term pregnancies. In preterm pregnancies significant associations with fetal
growth abnormalities were found in stillbirths only (group 2), while in term pregnancies sig-
nificant associations with fetal growth abnormalities were found among live births only (group
3). This may suggest that a more severe form of terminal villous hypoplasia and parenchymal
infarction can lead to fetal growth abnormalities culminating in stillbirth of the fetus before
reaching term, while a less severe form of these placental findings leads to fetal growth abnor-
malities, but does not lead to stillbirth and results in fetal growth abnormalities reaching term.
However, it should be noted that the relatively small (weighted) numbers of preterm live births
and of term stillbirths in the fetal growth categories likely limited our ability to detect signifi-
cant associations in these groups.
Similar relationships with fetal growth in stillbirths and live births (group 4) were observed
for placental weight in both preterm stillbirths and live births and for intraparenchymal
thrombus in term stillbirths and live births. The similar patterns of association suggest chronic
impairment of placental function leading to fetal growth abnormalities in both stillbirths and
live births. In pregnancies ending in stillbirth, this pattern suggests a second hit phenomenon
in consequence of which the stillbirth occurs. The first hit may result in fetal growth abnormal-
ities without resulting in stillbirth such that some placental findings are associated with fetal
growth abnormalities in both live births and stillbirths. In some of the pregnancies with such
induced growth abnormalities, a second insult may result in a stillbirth.
The last group includes placental findings with a different patterm of fetal growth in still-
births and live births (group 5). This suggests that these placental findings impair placental
function chronically affecting fetal growth. In pregnancies ending in stillbirth the placental
findings may be more severe resulting in growth abnormalities incompatible with live birth. In
live births the placental findings may be milder resulting in growth abnormalities but without
stillbirth. In preterm pregnancies, the placental findings of this type were terminal villous
immaturity, avascular villi, placental edema and retroplacental hematoma and in term preg-
nancies retroplacental hematoma, placental weight, and birth weight to placental weight ratio.

In term pregnancies, placental weight was similar between SGA and AGA stillbirths and live
births, but was substantially higher in LGA live births than in LGA stillbirths. The birth weight
to placental weight ratio in term pregnancies was similar in all fetal growth groups among live
births, but was substantially smaller in SGA stillbirths and larger in LGA stillbirths. Term SGA
stillbirths had mean birth weight to placental weight ratio of 6.8, substantially lower than AGA
and LGA term stillbirths (7.7 and 9.3, respectively). Thus birth weight was approximately 6, 7,
and 9 times larger than placenta weight in the term stillbirth groups. Such an observation sug-
gests absolute placental insufficiency in SGA stillbirths with placental size and function insuffi-
cient to support fetal growth and then life. In LGA stillbirths, the high birth weight to placental
weight ratio indicates a relative placental insufficiency with placental size and function large
but insufficient to support an even larger fetus [14].
Stillbirths and live births with congenital anomalies were included in the analysis as well as
births resulting from pregnancies with complications. Although the proportion of babies with
congenital anomalies was higher in stillbirths than in live births, as were the proportions born
to mothers with pregnancy complications including chronic hypertension, gestational hyper-
tension/pre-eclampsia, and pre-gestational diabetes, we have previously shown that the pattern
of association observed between fetal growth and stillbirth in the complete cohort was similar
to that in the subset excluding births with congenital anomalies and the subset without mater-
nal diabetes or hypertension/pre-eclampsia [8]. Further, since pregnancy complications are
very likely mediating factors in the relationship between fetal growth abnormalities and pla-
cental findings, it would not be appropriate to adjust for them in the multivariable analysis.
Macerated stillbirths were also included. Although maceration may have made evaluation of
birth weight more difficult, we previously found that the association between fetal growth and
risk of stillbirth observed in the entire study population was also observed in the subset with
optimal estimates of fetal age that included non-macerated stillbirths with a short interval of
less than 7 days between the time they were last reported alive and first identified as demised
[8]. Subset analyses of the association between fetal growth and placental findings were not
undertaken here due to small sample sizes in some birth weight percentile categories and the
corresponding risk of false negative findings. Although preterm pregnancies and their pla-
centas, including AGA pregnancies, are not normal by definition, their inclusion allowed us to
account for the effects of preterm gestational age while examining associations between pla-
cental findings and fetal growth abnormalities.
Clinical implications
These distinct patterns of association between placental abnormalities, fetal growth, and still-
birth suggest not only different mechanisms of placental function impairment, but also differ-
ent clinical management strategies. Some of the placental abnormalities, such as velamentous
cord insertion, single umbilical artery, and placental volume can be detected during pregnancy
using ultrasound [15, 16]. Placental volume correlates well with placental weight and is a good
proxy for placental weight [17]. Other placental abnormalities, which are associated with still-
birth are at this time not detectable prenatally, but provide an important target of investigation
within initiatives such as The Human Placenta Project [18]. The Human Placenta Project is a
collaborative effort undertaken by the Eunice Kennedy Shriver National Institute of Child
Health and Development “to understand the role of the placenta in health and disease”. It
“aims to develop new tools to study the organ in real time to learn how it develops and func-
tions throughout pregnancy. That knowledge may one day prevent and treat a range of com-
mon pregnancy complications, while providing insights into other areas of science and
medicine as well.” https://www.nichd.nih.gov/research/HPP/Pages/default.aspx

The group of placental findings associated with stillbirth but not fetal growth abnormalities
(group 1) appears to impair placental function in stillbirths severely and acutely and thus their diag-
nosis is at this time unlikely to affect clinical management in preterm pregnancies. This is because
preterm delivery, which would prevent stillbirth, is associated with significant risk of neonatal mor-
tality and morbidity that strongly depends on gestational age at delivery [19, 20]. In preterm preg-
nancies with these placental abnormalities, it would be difficult to decide when to intervene with
delivery. However, presence of these placental abnormalities in term pregnancies could be a rea-
sonable indication for delivery, if validated in future studies, since at term the risks of neonatal
mortality and morbidity are very low and are likely outweighed by the risk of stillbirth [20–22].
In pregnancies with placental findings associated with fetal growth abnormalities in still-
births only (group 2), and with placental findings associated with fetal growth abnormalities in
both stillbirths and live births (group 4 and 5), the placental function appears to be affected
chronically and severely in pregnancies ending in stillbirth. When growth abnormalities occur
with these placental abnormalities, the risk of stillbirth may be substantially increased. Further
studies are needed to quantify the risk of stillbirth in pregnancies with these placental findings
and growth abnormalities to determine the gestational age at which delivery is associated with
a net benefit of preventing stillbirth while minimizing the risk of neonatal mortality and mor-
bidity. The net benefit in preterm pregnancies depends strongly on gestational age and the
associated neonatal mortality and morbidity risk. However, at term, the risk of stillbirth associ-
ated with concurrent presence of these placental abnormalities and fetal growth abnormalities
would likely outweigh the very low risk of neonatal mortality and morbidity [20–22]. Simila-
rily, intervention in pregnancies with placental findings associated with fetal growth abnor-
malities in live births only (group 3) would require knowledge of the risk of adverse pregnancy
outcomes, especially neonatal mortality and morbidity, associated with those findings. Also
needed are studies of novel methods of non-invasive evaluation of placental structure and
function, such as the ones conducted within The Human Placental Project, which would allow
prenatal identification of these placental findings [18].
The clinical applicability at this stage is limited and likely restricted to birth weight to pla-
cental weight ratio and a few other placental findings identifiable by ultrasound examination.
Recent developments in the estimation of placental weight hold the promise of clinical applica-
tion but will have to be evaluated for clinical effectiveness.
Strengths
There are several strengths of this study. The SCRN was a population-based study, which
attempted to capture all stillbirths and a representative sample of live births with geographic,
racial and ethnic diversity. The population-based design strengthens the external validity of
the study findings and thus their generalizability. This is also one of the largest studies of still-
births with over 500 fetal deaths and well characterized phenotype. Another strength of the
study is the use of an algorithm developed to estimate gestational age of stillbirths at the time
of death [11]. This allowed a more accurate estimation of gestational age of stillbirth than one
based on age at delivery, which is critical in precise estimation of fetal growth and its abnor-
malities [8]. Another strength of the study is a standardized placental examination with central
training for pathologists [10]. Standardization of the placental examination increases its objec-
tivity and decreases the variability of the placental findings.
Limitations
Despite the large number of stillbirths in the study, the numbers in individual fetal growth cat-
egories stratified into preterm and term pregnancies were relatively small, particularly those

for term stillbirths. This may have resulted in insufficient power to detect more subtle differ-
ences in the patterns of association between placental abnormalities and fetal growth and still-
birth. Thus, interpretation of placental findings in the groups with smaller numbers of subjects
requires caution. While estimation of GA in stillbirth based on time of death rather than time
of birth significantly improves the accuracy of assessment of fetal growth [8], the exact time of
death is not known and thus estimation of GA is not absolutely precise and is subject to some
misclassification. Nevertheless, our prior study demonstrated that the algorithm used to esti-
mate time of death in stillbirths performs well in estimation of GA and fetal growth in still-
births [8, 11]. Pathologists could not be blinded to the origin of the placenta from stillbirths or
live births due to the need to perform both clinical and research placental examinations.
Chronic chorioamnionitis was not included in this analysis, because it is clinically significant
only if it is associated with diffuse chronic villitis (of unknown etiology). There were very few
cases of chronic chorioamnionitis with diffuse chronic villitis among the stillbirths in the
cohort preventing analysis of the association with fetal growth. For these reasons, we did not
examine chronic chorioamnionitis.
The clinical management implications are limited by the fact that many of the placental
findings cannot be detected prenatally at this time. However, there is a large initiative under-
way within The Human Placenta Project to develop novel methods of prenatal evaluation of
placental structure and function [18]. It is thus likely that more placental abnormalities associ-
ated with the risk of stillbirth and fetal growth will become amenable to diagnosis prenatally.
Summary
Placental function supports fetal growth and development and its impairment may result in
fetal growth abnormalities and stillbirth. We identified placental abnormalities which impair
placental function as demonstrated by fetal growth abnormalities and / or stillbirth. All placen-
tal abnormalities associated with fetal growth aberrations, except for terminal villous hypopla-
sia, were also associated with stillbirth. This observation indicates that these placental
abnormalities are important for placental function.
Implications
The patterns of association between placental abnormalities, fetal growth, and stillbirth pro-
vide insights into the mechanism of placental function impairment and stillbirth. They also
suggest implications for clinical care, especially for the placental findings amenable to prenatal
diagnosis using ultrasound and associated with stillbirth in pregnancies at term. Clinical impli-
cations are especially clear for birth weight to placental weight ratio. The birth weight to pla-
cental weight ratio could be estimated prenatally using estimated fetal weight to placental
volume ratio. Pregnancies with the abnormal ratio, at increased risk of stillbirth at term, may
benefit from early term delivery, because of very low risk of neonatal mortality and morbidity
at term.
Supporting information
S1 Table. Examples of recoding 0 cells.
As noted in Statistical Analysis, the observation with the smallest analysis weight was recoded
as having the placental finding in cases where no infants in a birth weight percentile group had
the finding for the purpose of estimating the interaction p-value. Also as noted, the revised
proportions and resulting p-values for association for stillbirths and live births separately are
not reported. However, below are two examples to illustrate the effect of this recoding on the
proportions and the subsequent interaction test. Note that the effect is generally more

pronounced among stillbirths, which have analysis weights near 1, than among live births,
many of whom have very small weights.
24+ weeks GA at death (stillibirths) or delivery (live births).
A. Single umbilical artery.
B. Velamentous insertion.
(DOCX)
S2 Table. Placental findings in stillbirths and live births small, average, and large for gesta-
tional age 24–31 weeks1/.
1/
Birth weight percentiles for GA were determined using Hadlock ultrasound norms and GA
at death (stillbirths) or delivery (live births) by the SCRN algorithm.
2/
Weighted percentages and other statistics are shown. For stillbirths, information was miss-
ing as follows (unweighted n): velamentous insertion, 1; furcate insertion, 1; circummarginate
insertion, 7; circumvallate insertion, 7; terminal villous immaturity, 2; terminal villous hypo-
plasia, 3; any developmental disorder, 8; acute chorioamnionitis—chorionic plate, 2; acute
umbilical cord arteritis, 2; acute umbilical cord phlebitis, 1; chorionic plate acute vasculitis,
7; chorionic plate vascular degenerative changes, 7; acute diffuse villitis, 1; chronic diffuse villi-
tis, 2; any inflammatory disorder, 9; retroplacental hematoma, 4; parenchymal infarction, 3;
intraparenchymal thrombus, 2; perivillous, intervillous fibrin, fibrinoid deposition, 9; any
maternal circulatory disorder, 7; fetal vascular thrombi in the chorionic plate, 5; avascular villi,
2; edema, 4; any fetal circulatory disorder, 5; placental weight, 2; ratio birth weight/placental
weight, 2.
For live births, information was missing as follows (unweighted n): velamentous insertion, 2;
furcate insertion, 2; circummarginate insertion, 6; circumvallate insertion, 6; terminal villous
hypoplasia, 2; any developmental disorder, 8; acute chorioamnionitis—placental membranes,
2; acute chorioamnionitis—chorionic plate, 1; acute umbilical cord arteritis, 4; acute diffuse
villitis, 1; chronic diffuse villitis, 1; retroplacental hematoma, 1; perivillous, intervillous fibrin,
fibrinoid deposition, 7; any maternal circulatory disorder, 4.
3/
P-value by the adjusted Wald F test for an association between a placental finding and birth
weight percentile among stillbirths and live births separately. For each continuous measure-
ment, the test is for mean difference in weighted ranks.
4/
P-value by the adjusted Wald F test for whether the association between a placental finding
and birth weight percentile differs for stillbirths and live births. For each continuous measure,
the test was based on weighted ranks.
(DOCX)
S3 Table. Placental findings in stillbirths and live births small, average, and large for gesta-
tional age 32–36 weeks1/.
1/
Birth weight percentiles for GA were determined using Hadlock ultrasound norms and GA
at death (stillbirths) or delivery (live births) by the SCRN algorithm.
2/
Weighted percentages and other statistics are shown. For stillbirths, information was miss-
ing as follows (unweighted n): single umbilical artery, 1; velamentous insertion, 1; furcate
insertion, 2; circummarginate insertion, 1; circumvallate insertion, 1; terminal villous immatu-
rity, 1; any developmental disorder, 4; acute funisitis, 1; acute umbilical cord arteritis, 3; acute
umbilical cord phlebitis, 2; any inflammatory disorder, 1; perivillous, intervillous fibrin, fibri-
noid deposition, 3; any maternal circulatory disorder, 1; edema, 2; any fetal circulatory disor-
der, 1; placental weight, 1; ratio birth weight/placental weight, 1.
For live births, information was missing as follows (unweighted n): velamentous insertion,
2; furcate insertion, 3; circummarginate insertion, 2; circumvallate insertion, 2; terminal vil-
lous immaturity, 1; terminal villous hypoplasia, 1; any developmental disorder, 5; acute

chorioamnionitis—chorionic plate, 1; chorionic plate acute vasculitis, 1; chorionic plate vascu-

lar degenerative changes, 1; acute diffuse villitis, 1; chronic diffuse villitis, 1; any inflammatory
disorder, 1 parenchymal infarction, 1; intraparenchymal thrombus, 1; perivillous, intervillous
fibrin, fibrinoid deposition, 7; any maternal circulatory disorder, 6; fetal vascular thrombi in
the chorionic plate, 1; avascular villi, 1; any fetal circulatory disorder, 1.
3/
P-value by the adjusted Wald F test for an association between a placental finding and birth
weight percentile among stillbirths and live births separately. For each continuous measure-
ment, the test is for mean difference in weighted ranks.
4/
P-value by the adjusted Wald F test for whether the association between a placental finding
and birth weight percentile differs for stillbirths and live births. For each continuous measure,
the test was based on weighted ranks.
(DOCX)
S4 Table. STROBE checklist. STROBE 2007 (v4) Statement—Checklist of items that
should be included in reports of case-control studies

Give information separately for cases and controls in case-control studies and, if applicable,
for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives method-
ological background and published examples of transparent reporting. The STROBE checklist
is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine
at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and
Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available
at www.strobe-statement.org.
(DOCX)
Acknowledgments
Financial disclosures
This work including the design and conduct of the study; collection, management, analysis,
and interpretation of the data; and preparation, review and approval of the manuscript was
supported by grant funding from the Eunice Kennedy Shriver National Institute of Child
Health and Human Development: U10-HD045953 Brown University, Rhode Island; U10-
HD045925 Emory University, Georgia; U10-HD045952 University of Texas Medical Branch
at Galveston, Texas; U10-HDO45955 University of Texas Health Sciences Center at San Anto-
nio, Texas; U10-HD045944 University of Utah Health Sciences Center, Utah; and U01-
HD045954 RTI International, RTP. Program officers from the funding agency (Reddy and
Willinger) were members of the Steering Committee of the study, and contributed to the study
design, management, interpretation of the data, as well as preparation, review and approval of
the manuscript. Otherwise the funders did not have any involvement in the design of the
study; the collection, analysis, and interpretation of the data; the writing of the article; or the
decision to submit the article for publication.
The Stillbirth Collaborative Research Network is solely responsible for the design and con-
duct of the study; collection, management, analysis, and interpretation of the data; and prepa-
ration, review, or approval of the manuscript. The following institutions and researchers
comprise the Stillbirth Collaborative Research Network: University of Texas Health Science
Center at San Antonio–Donald J. Dudley, Deborah Conway, Karen Aufdemorte, Angela
Rodriguez, Monica Pina; University of Utah School of Medicine–Robert M. Silver, Michael W.
Varner, Kristi Nelson; Emory University School of Medicine and the Rollins School of Public

Health–Carol J. Rowland Hogue, Barbara Stoll, Janice Daniels Tinsley, Bahig Shehata, Carlos
Abramowsky; Brown University–Donald Coustan, Halit Pinar, Marshall Carpenter, Susan
Kubaska; University of Texas Medical Branch at Galveston–George R. Saade, Radek Bukowski,
Jennifer Lee Rollins, Hal Hawkins, Elena Sbrana; RTI International–Corette B. Parker, Mat-
thew A. Koch, Vanessa R. Thorsten, Holly Franklin, Pinliang Chen; Pregnancy and Perinatal-
ogy Branch, Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health–Marian Willinger, Uma M. Reddy; Columbia
University School of Medicine–Robert Goldenberg.
Additional contributions
We would like to acknowledge the members of the NICHD Scientific Advisory and Safety
Monitoring Board for their review of the study protocol, materials, and progress, as well as all
of the other physicians, study coordinators, research nurses, and patients who participated in
the Stillbirth Collaborative Research Network.
Author Contributions
Conceptualization: Radek Bukowski, Nellie I. Hansen, Halit Pinar, Marian Willinger, Uma
M. Reddy, Corette B. Parker, Robert M. Silver, Donald J. Dudley, Barbara J. Stoll, George R.
Saade, Matthew A. Koch, Carol Hogue, Michael W. Varner, Deborah L. Conway, Donald
Coustan, Robert L. Goldenberg.
Data curation: Nellie I. Hansen, Corette B. Parker, Matthew A. Koch.
Formal analysis: Nellie I. Hansen, Corette B. Parker, Matthew A. Koch.
Funding acquisition: Radek Bukowski, Halit Pinar, Corette B. Parker, Robert M. Silver, Don-
ald J. Dudley, Barbara J. Stoll, George R. Saade, Matthew A. Koch, Carol Hogue, Michael
W. Varner, Deborah L. Conway.
Investigation: Radek Bukowski, Halit Pinar, Marian Willinger, Uma M. Reddy, Corette B.
Parker, Robert M. Silver, Donald J. Dudley, Barbara J. Stoll, George R. Saade, Matthew A.
Koch, Carol Hogue, Michael W. Varner, Deborah L. Conway, Donald Coustan, Robert L.
Goldenberg.
Methodology: Radek Bukowski, Nellie I. Hansen, Halit Pinar, Marian Willinger, Uma M.
Reddy, Corette B. Parker, Robert M. Silver, Donald J. Dudley, Barbara J. Stoll, George R.
Saade, Matthew A. Koch, Carol Hogue, Michael W. Varner, Deborah L. Conway, Donald
Coustan, Robert L. Goldenberg.
Project administration: Radek Bukowski, Nellie I. Hansen, Halit Pinar, Marian Willinger,
Uma M. Reddy, Corette B. Parker, Robert M. Silver, Donald J. Dudley, Barbara J. Stoll,
George R. Saade, Matthew A. Koch, Carol Hogue, Michael W. Varner, Deborah L. Conway,
Donald Coustan, Robert L. Goldenberg.
Resources: Radek Bukowski, Nellie I. Hansen, Marian Willinger, Uma M. Reddy.
Writing – original draft: Radek Bukowski, Nellie I. Hansen, Corette B. Parker, Robert L.
Goldenberg.
Writing – review & editing: Radek Bukowski, Nellie I. Hansen, Halit Pinar, Marian Willinger,
Uma M. Reddy, Corette B. Parker, Robert M. Silver, Donald J. Dudley, Barbara J. Stoll,
George R. Saade, Matthew A. Koch, Carol Hogue, Michael W. Varner, Deborah L. Conway,
Donald Coustan, Robert L. Goldenberg.

References
1. Lawn JE, Blencowe H, Waiswa P, Amouzou A, Mathers C, Hogan D, et al. Stillbirths: rates, risk factors,
and acceleration towards 2030. Lancet. 2016; 387(10018):587–603. https://doi.org/10.1016/S0140-
6736(15)00837-5 PMID: 26794078.
2. MacDorman MF, Gregory EC. Fetal and Perinatal Mortality: United States, 2013. National vital statistics
reports: from the Centers for Disease Control and Prevention, National Center for Health Statistics,
National Vital Statistics System. 2015; 64(8):1–24. PMID: 26222771.
3. Qureshi ZU, Millum J, Blencowe H, Kelley M, Fottrell E, Lawn JE, et al. Stillbirth should be given greater
priority on the global health agenda. BMJ. 2015; 351:h4620. https://doi.org/10.1136/bmj.h4620 PMID:
26400645; PubMed Central PMCID: PMC4707511.
4. Bukowski R, Carpenter M, Conway D, Coustan D, Dudley DJ, Goldenberg RL, et al. Causes of Death
Among Stillbirths. JAMA. 2011; 306(22):2459–68. https://doi.org/10.1001/jama.2011.1823 PMID:
22166605
5. Stillbirth Collaborative Research Network Writing Group. Association between stillbirth and risk factors
known at pregnancy confirmation. JAMA. 2011; 306(22):2469–79. https://doi.org/10.1001/jama.2011.
1798 PMID: 22166606; PubMed Central PMCID: PMC3807602.
6. Smith GC, Fretts RC. Stillbirth. Lancet. 2007; 370(9600):1715–25. https://doi.org/10.1016/S0140-6736
(07)61723-1 PMID: 18022035.
7. Flenady V, Koopmans L, Middleton P, Froen JF, Smith GC, Gibbons K, et al. Major risk factors for still-
birth in high-income countries: a systematic review and meta-analysis. Lancet. 2011; 377(9774):1331–
40. https://doi.org/10.1016/S0140-6736(10)62233-7 PMID: 21496916.
8. Bukowski R, Hansen NI, Willinger M, Reddy UM, Parker CB, Pinar H, et al. Fetal growth and risk of still-
birth: a population-based case-control study. PLoS medicine. 2014; 11(4):e1001633. https://doi.org/10.
1371/journal.pmed.1001633 PMID: 24755550; PubMed Central PMCID: PMC3995658.
9. Parker CB, Hogue CJ, Koch MA, Willinger M, Reddy UM, Thorsten VR, et al. Stillbirth Collaborative
Research Network: design, methods and recruitment experience. Paediatric and perinatal epidemiol-
ogy. 2011; 25(5):425–35. https://doi.org/10.1111/j.1365-3016.2011.01218.x PMID: 21819424; PubMed
Central PMCID: PMC3665402.
10. Pinar H, Koch MA, Hawkins H, Heim-Hall J, Shehata B, Thorsten VR, et al. The Stillbirth Collaborative
Research Network (SCRN) placental and umbilical cord examination protocol. American journal of peri-
natology. 2011; 28(10):781–92. https://doi.org/10.1055/s-0031-1281509 PMID: 21717387; PubMed
Central PMCID: PMC4316371.
11. Conway DL, Hansen NI, Dudley DJ, Parker CB, Reddy UM, Silver RM, et al. An algorithm for the esti-
mation of gestational age at the time of fetal death. Paediatric and perinatal epidemiology. 2013; 27
(2):145–57. https://doi.org/10.1111/ppe.12037 PMID: 23374059; PubMed Central PMCID:
PMC3564237.
12. Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight stan-
dard. Radiology. 1991; 181(1):129–33. https://doi.org/10.1148/radiology.181.1.1887021 PMID:
1887021
13. Bukowski R, Uchida T, Smith GC, Malone FD, Ball RH, Nyberg DA, et al. Individualized norms of opti-
mal fetal growth: fetal growth potential. Obstetrics and gynecology. 2008; 111(5):1065–76. https://doi.
org/10.1097/AOG.0b013e3181704e48 PMID: 18448737.
14. Burmeister B, Zaleski C, Cold C, McPherson E. Wisconsin Stillbirth Service Program: analysis of large
for gestational age cases. American journal of medical genetics Part A. 2012; 158A(10):2493–8. https://
doi.org/10.1002/ajmg.a.35578 PMID: 22965821.
15. Arleo EK, Troiano RN, da Silva R, Greenbaum D, Kliman HJ. Utilizing two-dimensional ultrasound to
develop normative curves for estimated placental volume. American journal of perinatology. 2014; 31
(8):683–8. https://doi.org/10.1055/s-0033-1357265 PMID: 24108663.
16. Sherer DM, Anyaegbunam A. Prenatal ultrasonographic morphologic assessment of the umbilical cord:
a review. Part I. Obstetrical & gynecological survey. 1997; 52(8):506–14. PMID: 9267868.
17. Sivarao S, Vidyadaran MK, Jammal AB, Zainab S, Goh YM, Ramesh KN. Weight, volume and surface
area of placenta of normal pregnant women and their relation to maternal and neonatal parameters in
Malay, Chinese and Indian ethnic groups. Placenta. 2002; 23(8–9):691–6. PMID: 12361688.
18. Guttmacher AE, Spong CY. The human placenta project: it’s time for real time. American journal of
obstetrics and gynecology. 2015; 213(4 Suppl):S3–5. https://doi.org/10.1016/j.ajog.2015.08.037 PMID:
26428502.
19. MacDorman MF, Kirmeyer SE, Wilson EC. Fetal and perinatal mortality, United States, 2006. National
vital statistics reports: from the Centers for Disease Control and Prevention, National Center for Health
Statistics, National Vital Statistics System. 2012; 60(8):1–22. PMID: 24979970.

20. Mandujano A, Waters TP, Myers SA. The risk of fetal death: current concepts of best gestational age
for delivery. American journal of obstetrics and gynecology. 2013; 208(3):207 e1-8. https://doi.org/10.
1016/j.ajog.2012.12.005 PMID: 23220510.
21. Smith GC. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnan-
cies. American journal of obstetrics and gynecology. 2001; 184(3):489–96. https://doi.org/10.1067/
mob.2001.109735 PMID: 11228508.
22. Rand L, Robinson JN, Economy KE, Norwitz ER. Post-term induction of labor revisited. Obstetrics and
gynecology. 2000; 96(5 Pt 1):779–83. PMID: 11042317.

Altered Fetal Growth, Placental Abnormalities, and Stillbirth

Uploaded by

Copyright:

Available Formats

Altered Fetal Growth, Placental Abnormalities, and Stillbirth

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Altered Fetal Growth, Placental Abnormalities, and Stillbirth

Uploaded by

Copyright:

Available Formats

RESEARCH ARTICLE

Altered fetal growth, placental abnormalities,

Editor: Stefan Gebhardt, Stellenbosch University,

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 1 / 27

Materials and methods

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 2 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 3 / 27

Fetal growth abnormalities

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 4 / 27

Table 1. Descriptions of the placental findings.

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 5 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 6 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 7 / 27

The placental examination investigated 25 findings, of which 15 were significantly associ-

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 8 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 9 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 10 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 11 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 12 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 13 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 14 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 15 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 16 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 17 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 18 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 19 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 20 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 21 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 22 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 23 / 27

chorioamnionitis—chorionic plate, 1; chorionic plate acute vasculitis, 1; chorionic plate vascu-

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 24 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 25 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 26 / 27

PLOS ONE | https://doi.org/10.1371/journal.pone.0182874 August 18, 2017 27 / 27

You might also like