Original Research
Placental Growth Factor and the Risk of
Adverse Neonatal and Maternal Outcomes
Jacqueline G. Parchem, MD, Clifton O. Brock, MD, Han-Yang Chen, PhD, Raghu Kalluri, MD, PhD,
John R. Barton, MD, and Baha M. Sibai, MD, for the Preeclampsia Triage by Rapid Assay Trial (PETRA)
Investigators*
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OBJECTIVE: To evaluate whether abnormal plasma pla-
cental growth factor (PlGF) level is associated with
adverse neonatal and maternal outcomes.
METHODS: This was a secondary analysis of the Pre-
eclampsia Triage by Rapid Assay Trial (PETRA), a prospective,
multicenter, observational study that enrolled women with
suspected preeclampsia. Our analysis included women
age 18–45 years with a singleton pregnancy between 20
*A list of the PETRA investigators is available in Appendix 1, available online
at http://links.lww.com/AOG/B721.
From the Department of Obstetrics, Gynecology and Reproductive Sciences,
McGovern Medical School at the University of Texas Health Science Center at
Houston (UTHealth), and the Department of Cancer Biology, Metastasis
Research Center, University of Texas MD Anderson Cancer Center, Houston,
Texas; and Baptist Health Lexington, Lexington, Kentucky.
The original PETRA study was an investigator-led study supported by funding
from Alere (San Diego, California). No funding was received for the present
study. Alere had no role in the study design, analysis or interpretation of the data,
or writing of the manuscript. No author has been paid by Alere to write or submit
this manuscript for publication.
Presented at the 39th Annual Meeting of the Society for Maternal-Fetal Medicine,
February 11–16, 2019, Las Vegas, Nevada.
The authors thank the women who participated in the trial and acknowledge the
efforts of the PETRA investigators and research teams who made this work
possible. Jacqueline G. Parchem is supported by a Foundation for the Society
for Maternal-Fetal Medicine/American Association of Obstetricians and Gyne-
cologists Foundation Scholarship.
Each author has confirmed compliance with the journal’s requirements for
authorship.
Corresponding author: Jacqueline G. Parchem, MD, Department of Obstetrics,
Gynecology and Reproductive Sciences, McGovern Medical School at the
University of Texas Health Science Center at Houston, Houston, TX; email:
jacqueline.g.parchem@uth.tmc.edu.
Financial Disclosure
Baha M. Sibai was previously a paid consultant for Alere. The other authors did
not report any potential conflicts of interest.
© 2020 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND),
where it is permissible to download and share the work provided it is properly
cited. The work cannot be changed in any way or used commercially without
permission from the journal.
ISSN: 0029-7844/20
VOL. 135, NO. 3, MARCH 2020
and 41 weeks of gestation. Plasma collected at enrollment
was used for PlGF measurement. Abnormal PlGF was
defined as low (100 pg/mL or less) or very low (less than
12 pg/mL). The primary outcomes were composite
adverse neonatal and maternal outcomes. We used mul-
tivariable Poisson regression models to examine the asso-
ciation between PlGF and outcomes.
RESULTS: Of 1,112 women who met the inclusion criteria,
plasma PlGF was low in 742 (67%) and very low in 353 (32%).
In the cohort, the overall rates of the composite adverse
neonatal and maternal outcomes were 6.4% and 4.8%, re-
spectively. Compared with normal PlGF (more than 100 pg/
mL), low PlGF was significantly associated with an increased
risk of the composite neonatal outcome (9.2% vs 0.8%;
adjusted relative risk [aRR] 17.2, 95% CI 5.2–56.3), and the
composite maternal outcome (6.2% vs 1.9%; aRR 3.6, 95% CI
1.7–8.0). Very low PlGF was also significantly associated with
both neonatal and maternal outcomes. The sensitivity and
specificity of low PlGF were 95.8% and 35.3%, respectively,
for the composite neonatal outcome, and 86.8% and 34.3%
for the composite maternal outcome. Although the positive
predictive values were low (9.2% and 6.2%, respectively),
the negative predictive value of low PlGF for neonatal and
maternal outcomes was 99.2% and 98.1%, respectively.
CONCLUSION: Among women being evaluated for
preeclampsia, those with abnormal PlGF are significantly
more likely to experience adverse neonatal and maternal
outcomes. These outcomes occur infrequently when the
PlGF is normal. These findings suggest that PlGF may be
useful for risk stratification of women with suspected
preeclampsia.
FUNDING SOURCE: No funding was received for this
study. The original PETRA study was supported by funding
from Alere.
(Obstet Gynecol 2020;135:665–73)
DOI: 10.1097/AOG.0000000000003694
P
reeclampsia is a common hypertensive disorder
of pregnancy and a leading cause of maternal
and neonatal morbidity and mortality.1 It remains
OBSTETRICS & GYNECOLOGY 665
a challenging diagnosis owing to variable clinical pre-
sentation, unpredictable progression, and limited
management options. Despite decades of research,
an incomplete understanding of disease pathophysiol-
ogy and attachment to established practice norms
has hindered progress.2–4 The inability to reliably
identify pregnancies at highest risk for adverse out-
comes has led to a conservative approach, which re-
sults in unnecessary interventions and health care
costs, including prolonged inpatient care and iatro-
genic preterm delivery.5 In addition, the emotional
and financial burden borne by women and their fam-
ilies can be substantial. Meaningful advances in the
management of preeclampsia and other hypertensive
disorders of pregnancy are needed, and will require
objective tools to aid in timely, accurate diagnosis and
risk stratification.
Angiogenic factors, including placental growth
factor (PlGF) and soluble fms-like tyrosine kinase-1
(sFlt-1), have been the dominant focus of placental
biomarkers studies in preeclampsia over the past 15
years (reviewed in references 6 and 7). PlGF, a proan-
giogenic member of the vascular endothelial growth
factor family, normally increases during pregnancy as
a function of gestational age, peaking at approxi-
mately 30 weeks of gestation.8–11 A dramatic reduc-
tion in PlGF is observed in preeclampsia, which
precedes the onset of disease and reflects underlying
placental dysfunction.11–15 Therefore, numerous stud-
ies have examined the utility of PlGF-based tests for
predicting preeclampsia.16–19
Prospective observational studies evaluating the
performance of point-of-care PlGF tests have shown
that a low PlGF (less than the 5th percentile or less
than 100 pg/mL) before 35 weeks of gestation has
a high sensitivity and negative predictive value for the
prediction of preeclampsia requiring delivery within
14 days.20,21 Although PlGF varies by gestational age,
absolute cutoffs have been adopted in many studies
instead of percentile-for-gestational-age cutoffs
because similar test performance has been reported.20
Few studies have evaluated the association between
abnormal PlGF and the broad range of outcomes
associated with preeclampsia and placental insuffi-
ciency. Therefore, we performed a secondary analysis
of the Preeclampsia Triage by Rapid Assay Trial
(PETRA) to evaluate whether PlGF is associated with
adverse neonatal and maternal outcomes.
ROLE OF THE FUNDING SOURCE
The original PETRA study was an investigator-led
study supported by funding from Alere.21 No funding
was received for the present study. Alere had no role
666 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes
in the study design, analysis or interpretation of the
data, or writing of the manuscript. No author has been
paid by Alere to write or submit this manuscript for
publication. Baha M. Sibai was previously a paid con-
sultant for Alere. The authors had access to relevant
aggregated study data and other information required
to understand and report research findings. The au-
thors take responsibility for the presentation and pub-
lication of the research findings, have been fully
involved at all stages of publication and presentation
development, and take public responsibility for all
aspects of the work. All individuals included as au-
thors and contributors who made substantial intellec-
tual contributions to the research, data analysis, and
publication or presentation development are listed
appropriately. The authors’ personal interests, finan-
cial or nonfinancial, relating to this research and its
publication have been disclosed.
METHODS
This was a secondary analysis of PETRA, a prospec-
tive, multicenter, observational study that recruited
women from 2010 to 2012 at 24 North American
centers (Appendix 1, available online at http://links.
lww.com/AOG/B721).21 The inclusion criteria and
protocol for the original trial, as well as details about
the Triage PlGF Assay have been described.21 Briefly,
women enrolled in PETRA were 18–45 years of age,
with a singleton or multiple pregnancy between 20
and 41 weeks of gestation, and presenting with signs
or symptoms of preeclampsia, including hyperten-
sion, proteinuria, abnormal laboratory results, exces-
sive weight gain, fetal growth restriction, or symptoms
(headache, epigastric or right upper quadrant pain, or
nausea and vomiting). The final diagnosis of pre-
eclampsia or other hypertensive disorder was adjudi-
cated by an independent panel of three experts using
definitions established in 2013 by the American Col-
lege of Obstetricians and Gynecologists (ACOG)
Hypertension in Pregnancy Task Force.22 Plasma ob-
tained and stored at enrollment was used for PlGF
measurements using the Triage PlGF Test. PlGF
measurements were performed retrospectively after
final pregnancy outcomes were recorded. Participat-
ing centers received institutional review board
approval before initiation of the study. A list of the
PETRA investigators and clinical sites is provided in
Appendix 1 (http://links.lww.com/AOG/B721).
For the present secondary analysis, women who
participated in PETRA were eligible for inclusion
if they had a singleton pregnancy and documented
PlGF. We excluded women with missing demo-
graphic or clinical data. Institutional review board
OBSTETRICS & GYNECOLOGY
approval for the study was obtained from the Uni-
versity of Texas Health Science Center at Houston
under a waiver of informed consent.
The main exposure variable was abnormal PlGF.
Two established cutoffs for abnormal PlGF were
used: low (100 pg/mL or less) and very low (less
than 12 pg/mL; detection limit of the assay).20,21 The
primary outcomes were composite adverse neonatal
and maternal outcomes. Composite adverse neonatal
outcome was defined as any of the following: fetal
death, neonatal death, Apgar score less than 4 at 5 mi-
nutes, seizure, grade III or IV intraventricular hemor-
rhage, retinopathy of prematurity, bronchopulmonary
dysplasia, or necrotizing enterocolitis. Composite
adverse maternal outcome included complications
attributable to preeclampsia, and was defined as any
of the following: death; eclampsia; hemolysis, ele-
vated liver enzymes, and low platelet count (HELLP)
syndrome; pulmonary edema; placental abruption;
receipt of a third antihypertensive agent; or occur-
rence of other rare maternal complication: acute renal
failure, myocardial infarction, hypertensive encepha-
lopathy, cortical blindness, retinal detachment, stroke,
disseminated intravascular coagulation, microangiop-
athy (such as thrombotic thrombocytopenia purpura),
acute fatty liver of pregnancy, or liver hematoma or
rupture. The secondary neonatal and maternal out-
comes included respiratory distress syndrome, small-
for-gestational-age (SGA) birth weight (less than the
10th percentile for gestational age), preterm delivery
before 37 and 34 weeks of gestation, postpartum hem-
orrhage, and cesarean delivery.
In PETRA, maternal hypertensive disorder
diagnoses were adjudicated using 2013 ACOG
criteria.22 For the present analysis, these diagnoses
were reclassified using 2019 ACOG recommenda-
tions and stratified according to PlGF.23 In accor-
dance with the most recent guidelines, women were
grouped into one of four categories: 1) preeclampsia
with severe features, 2) preeclampsia without severe
features or gestational hypertension, 3) chronic
hypertension (without evidence of preeclampsia),
or 4) no hypertensive disorder. Preeclampsia with
severe features included cases of gestational hyper-
tension with severe range blood pressure and super-
imposed preeclampsia. Women with isolated
gestational proteinuria were included in the no
hypertensive disorder group.
Differences in baseline characteristics, hyperten-
sive disorder categories, and neonatal and maternal
outcomes stratified by PlGF (low PlGF: 100 pg/mL
or less vs greater than 100 pg/mL; very low PlGF:
less than 12 pg/mL vs 12 pg/mL or greater) were
VOL. 135, NO. 3, MARCH 2020 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes
examined using t-test for continuous variables and x2
or Fisher exact tests for categorical variables, as
appropriate. We used multivariable Poisson regres-
sion models with robust error variance to examine
the association between PlGF (low or very low) and
the risks of neonatal and maternal outcomes while
adjusting for maternal age (younger than 20, 20–34,
35 years or older), nulliparity, history of preeclampsia
in a prior pregnancy, chronic hypertension, gesta-
tional diabetes, and gestational age at enrollment.
These potential confounders were identified based
on analysis of baseline maternal demographic or clin-
ical characteristics. In addition, we assessed the fre-
quency of the composite adverse neonatal outcome
stratified by hypertensive disorder and SGA, and per-
formed a subgroup analysis to assess the composite
adverse neonatal and maternal outcomes among
women without a hypertensive disorder. The results
were presented as adjusted relative risk (aRR) with
95% confidence interval (CI). We also reported the
sensitivity, specificity, positive predictive value, and
negative predictive value of the PlGF test. P,0.05
was considered significant. All statistical analyses were
conducted using SAS 9.4 and STATA 15.
RESULTS
Of 1,258 women enrolled in PETRA, 1,112 (88.4%)
met inclusion criteria for this analysis (Fig. 1). Plasma
PlGF was low in 742 (66.7%) women and very low in
353 (31.7%). The mean gestational age at enrollment
was 33 weeks. Women with low PlGF were more
likely to be younger than 20 or 35 years or older,
nulliparous, and to have gestational diabetes, and less
likely to have a personal history of preeclampsia or
chronic hypertension. Women with a very low PlGF
were more likely to be younger than 20 and nullipa-
rous. Women with low PlGF tended to be enrolled at
a slightly later gestational age than women with nor-
mal PlGF (greater than 100 pg/mL), whereas those
with very low PlGF were enrolled approximately 2
weeks earlier on average than those with PlGFs of
12 pg/mL or greater (Table 1).
Adverse neonatal outcomes were significantly
more likely to occur among women with abnormal
PlGFs (Table 2). The rate of the composite adverse
neonatal outcome was 6.4% overall. Women with low
or very low PlGF had higher rates of the composite
adverse neonatal outcome (9.2% vs 0.8% for low;
16.5% vs 1.7% for very low). After adjusting for poten-
tial confounders, neonates were significantly more
likely to experience the composite adverse outcome
if the PlGF was low (aRR 17.2, 95% CI 5.2–56.3) or
very low (aRR 6.7, 95% CI 3.7–12.2). Similarly,
667
 Fig. 1. Study cohort. *Not mutually
exclusive. PlGF, placental growth
factor.
Parchem. Placental Growth Factor and
Adverse Perinatal Outcomes. Obstet
Gynecol 2020.

respiratory distress syndrome, SGA, and preterm outcome was 27.963.6 weeks vs 36.063.4 weeks for
delivery were more likely to occur in the context of those without the composite outcome (P,.001). The
an abnormal PlGF value. The mean gestational age frequency of perinatal death was 2.2% (n525) overall.
of delivery for neonates with the composite adverse All perinatal deaths occurred in women with low PlGF.

Table 1. Demographic and Clinical Characteristics Associated With Two Placental Growth Factor
Thresholds: Low (100 pg/mL or Less) and Very Low (Less Than 12 pg/mL)
PlGF Category (pg/mL) PlGF Category (pg/mL)

100 or Less Greater Than 100 Less Than 12 12 or Greater

Characteristic (n5742) (n5370) P (n5353) (n5759) P

Maternal age (y) .035 .001

Younger than 20 196 (26.4) 82 (22.2) 114 (32.3) 164 (21.6)
20–34 372 (50.1) 216 (58.4) 165 (46.7) 423 (55.7)
35 or older 174 (23.5) 72 (19.5) 74 (21.0) 172 (22.7)
Race and ethnicity .381 .607
White 387 (52.2) 198 (53.5) 181 (51.3) 404 (53.2)
Black 174 (23.5) 97 (26.2) 94 (26.6) 177 (23.3)
Hispanic 124 (16.7) 47 (12.7) 55 (15.6) 116 (15.3)
Asian 49 (6.6) 22 (5.9) 18 (5.1) 53 (7.0)
Other 8 (1.1) 6 (1.6) 5 (1.4) 9 (1.2)
BMI (kg/m2) .640 .557
Less than 30 212 (28.6) 111 (30.0) 98 (27.9) 225 (29.6)
30 or higher 528 (71.4) 259 (70.0) 253 (72.1) 534 (70.4)
Mean6SD 35.368.7 35.468.9 .874 35.869.2 35.268.5 .280
Nulliparous 424 (57.1) 153 (41.4) ,.001 201 (56.9) 376 (49.5) .022
History of preeclampsia 120 (16.2) 85 (23.0) .006 56 (15.9) 149 (19.6) .132
Family history of preeclampsia* 73 (9.8) 27 (7.3) .163 34 (9.6) 66 (8.7) .612
Chronic hypertension 132 (17.8) 85 (23.0) .040 59 (16.7) 158 (20.8) .108
Pregestational diabetes mellitus 59 (8.0) 24 (6.5) .381 27 (7.6) 56 (7.4) .873
Gestational diabetes mellitus 100 (13.5) 32 (8.6) .019 34 (9.6) 98 (12.9) .116
Systemic lupus erythematosus 7 (0.9) 3 (0.8) .825 3 (0.8) 7 (0.9) .905
Smoking 48 (6.5) 32 (8.6) .185 24 (6.8) 56 (7.4) .728
Gestational age at enrollment (wk) .003 ,.001
Less than 34 359 (48.4) 211 (57.0) 251 (71.1) 319 (42.0)
34–36 211 (28.4) 104 (28.1) 65 (18.4) 250 (32.9)
37 or more 172 (23.2) 55 (14.9) 37 (10.5) 190 (25.0)
Mean6SD 33.464.3 32.264.5 ,.001 31.564.1 33.764.3 ,.001
Male neonate 358 (48.2) 184 (49.7) .641 168 (47.6) 374 (49.3) .601
PlGF, placental growth factor; BMI, body mass index.
Data are n (%) unless otherwise specified.
* First-degree relative (mother or sister) had preeclampsia.

668 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes OBSTETRICS & GYNECOLOGY
 Differences in the rates of adverse maternal
outcomes were also observed among women with
abnormal PlGF values (Table 3). Overall, 53 (4.8%)
women experienced the composite adverse maternal
outcome. Among those with a low PlGF, the rate of
the composite maternal outcome was 6.2% vs 1.9%
among those with normal PlGF (aRR 3.6, 95% CI
1.7–8.0); for very low PlGF, the rate was 9.6% vs
2.5% (aRR 3.1, 95% CI 1.8–5.3). Certain serious but
rare events included in the composite outcome did
not occur during the study (maternal death, acute
myocardial infarction, hypertensive encephalopathy,
cortical blindness, and liver hematoma or rupture).
There was a small but significant increase in the risk
of cesarean delivery among women with abnormal
PlGF. The risk of postpartum hemorrhage was not
associated with PlGF.
In this high-risk cohort, low PlGF had a sensitivity
of 95.8% and a specificity of 35.3% for the composite
neonatal outcome; sensitivity and specificity for the
composite maternal outcome were 86.8% and 34.3%,
respectively (Table 4). Using the very low cutoff
decreased the sensitivity and increased the specificity
of PlGF. The positive predictive value of low PlGF
was poor for neonatal and maternal outcomes (9.2%
and 6.2%, respectively). However, low PlGF had
a high negative predictive value for both neonatal
(99.2%) and maternal outcomes (98.1%).
Given the established and robust association
between abnormal PlGF and preeclampsia, we exam-
ined the rate of hypertensive disorders stratified by
PlGF (Appendix 2, available online at http://links.
lww.com/AOG/B721). Preeclampsia with severe fea-
tures was the most common diagnosis, occurring in
684 women (61.5%), reflective of the enrichment for
high-risk women in PETRA. As expected, a final diag-
nosis of preeclampsia was more common among
women with abnormal PlGF. Low PlGF was also asso-
ciated with SGA (Table 2), consistent with prior stud-
ies.14,15,24–27 Therefore, we questioned the extent
to which the relationship between abnormal PlGF
and adverse neonatal outcomes was affected by
SGA (Appendix 3, available online at http://links.
lww.com/AOG/B721). The overall rate of SGA was
29.8%; SGA occurred in 36.4% pregnancies compli-
cated by preeclampsia with severe features vs 20.2%,
23.5%, and 16.6% of women with preeclampsia with-
out severe features or gestational hypertension,
chronic hypertension, and no hypertensive disorder,
respectively. As expected, SGA neonates were more
likely to experience the composite adverse outcome
compared with non-SGA neonates. Interestingly, low
PlGF was associated with a 14.5% frequency of the
VOL. 135, NO. 3, MARCH 2020 Parchem et al
composite neonatal outcome among SGA neonates,
whereas the composite outcome did not occur in the
context of normal PlGF (greater than 100).
To investigate the significance of abnormal PlGFs
among normotensive women, we analyzed outcomes
for the subgroup of 190 women (17.1%) with no
hypertensive disease. The risk of the composite
adverse neonatal outcome was not significantly
increased among women with low PlGF in this small
sample (7.6% vs 0.9%; crude RR 8.2, 95% CI 1.0–
67.2). The risk of the composite adverse maternal out-
come was also not significantly increased (4.9% vs
2.8%; crude RR 1.8, 95% CI 0.4–7.8). Multivariable
adjusted regression analyses were not feasible owing
to small case numbers.
DISCUSSION
In this secondary analysis of a large and diverse
cohort of high-risk women, we examined the relation-
ship between abnormal PlGF and adverse neonatal
and maternal outcomes among women presenting
with signs or symptoms of preeclampsia. Using either
of two established cutoffs, we found that abnormal
plasma PlGF at the time of clinical presentation was
significantly associated with the composite adverse
neonatal and maternal outcomes, as well as respira-
tory distress syndrome, SGA, preterm delivery, and
cesarean delivery. Low PlGF had a high sensitivity
and negative predictive value for both neonatal and
maternal composite outcomes, but poor positive pre-
dictive value. Notably, among women with normal
PlGF, there were no perinatal deaths and no SGA
neonates with the composite adverse outcome. Col-
lectively, our results suggest that normal PlGF is
reassuring and may identify women and neonates at
lower risk for adverse outcomes, although only 1 in 3
women undergoing evaluation for preeclampsia had
a normal PlGF value in our study.
The primary PETRA analysis showed that PlGF
is significantly correlated with time to delivery; the
median time from enrollment to delivery was 45, 10,
and 2 days for normal, low, and very low PlGF,
respectively.21 Our analysis reveals the serious neo-
natal and maternal consequences of earlier delivery in
the abnormal PlGF groups. Among women enrolled
before 34 weeks of gestation (n5570), early preterm
delivery (before 34 weeks of gestation) occurred in
12.8% with normal PlGF at enrollment compared
with 81.3% with low and 90.8% with very low PlGF.
Our report differs from prior studies of PlGF in
that most have evaluated the utility of PlGF to predict
preeclampsia or SGA, whereas we report composite
adverse outcomes that encompass the range of
Placental Growth Factor and Adverse Perinatal Outcomes 669
Table 2. Neonatal Outcomes According to Placental Growth Factor Level: Low (100 pg/mL or Less) and
Very Low (Less than 12 pg/mL)
PlGF Category (pg/mL)

Outcome 100 or Less (n5742) Greater Than 100 (n5370) P uRR (95% CI)

Composite adverse neonatal outcome 68/737 (9.2) 3/368 (0.8) ,.001 11.3 (3.6–35.7)
Perinatal death 25 (3.4) 0 (0) ,.001 —
Fetal demise 10 (1.3) 0 (0) .036 —
Neonatal death 15 (2.0) 0 (0) .004 —
5-min Apgar score less than 4 24/731 (3.3) 2/368 (0.5) .003 6.0 (1.4–25.4)
Seizure 1 (0.1) 0 (0) 1.000 —
Intraventricular hemorrhage grade III/IV 4 (0.5) 0 (0) .308 —
Retinopathy of prematurity 25 (3.4) 1 (0.3) .001 12.5 (1.7–91.7)
Bronchopulmonary dysplasia 7 (0.9) 0 (0) .103 —
Necrotizing enterocolitis 8 (1.1) 0 (0) .058 —
Respiratory distress syndrome 166 (22.4) 20 (5.4) ,.001 4.1 (2.6–6.5)
Small for gestational age 286 (38.5) 46 (12.4) ,.001 3.1 (2.3–4.1)
Preterm delivery at less than 37 wk† 475/570 (83.3) 104/315 (33.0) ,.001 2.5 (2.1–3.0)
Preterm delivery at less than 34 wk‡ 292/359 (81.3) 27/211 (12.8) ,.001 6.4 (4.5–9.1)
PlGF, placental growth factor; aRR, adjusted relative risk; uRR, unadjusted relative risk; —, not calculable owing to zero or small case
numbers.
Data are n/N (%) or n (%) unless otherwise specified.
* Adjusted for maternal age, parity, history of preeclampsia, chronic hypertension, gestational diabetes, and gestational age at enrollment.
†
Among gestational age at enrollment less than 37 wk (n5885).
‡
Among gestational age at enrollment less than 34 wk (n5570).

complications associated with preeclampsia, placental
insufficiency, and medically indicated preterm deliv-
ery.14–16,20,24–31 One of the largest studies to report on
composite adverse perinatal outcomes was a second-
ary analysis of the PELICAN cohort from the United
Kingdom,20 which showed that low PlGF performed
better than ultrasound parameters and 46 other can-
didate biomarkers for the prediction of SGA less than
the 3rd percentile.24 Despite differences in the evalu-
ation and management of preeclampsia in the United
Kingdom compared with the United States, our results
agree with the primary finding that PlGF is a promising
biomarker for adverse perinatal outcomes.32
In both PETRA21 and PELICAN,20 health care
providers were blinded to PlGF results, leading to
the outstanding question of how PlGF might be in-
corporated into clinical practice and whether its
use will have any effect on outcomes. The largest
study that attempted to answer this question was the
recent PARROT trial, a multicenter, stepped-wedge,

Table 3. Maternal Outcomes According to Placental Growth Factor Level: Low (100 pg/mL or Less) and
Very Low (Less Than 12 pg/mL)
PlGF Category

Outcome 100 or Less (n5742) Greater Than 100 (n5370) P uRR (95% CI)

Composite adverse maternal outcome 46 (6.2) 7 (1.9) .002 3.3 (1.5–7.2)

Death 0 (0) 0 (0) — —
Eclampsia 3 (0.4) 0 (0) .555 —
HELLP syndrome 9 (1.2) 1 (0.3) .179 4.5 (0.6–35.3)
Pulmonary edema 9 (1.2) 2 (0.5) .721 1.6 (0.4–7.1)
Placental abruption 5 (0.7) 2 (0.5) 1.000 1.2 (0.2–6.4)
Need for 3rd antihypertensive agent 18 (2.4) 1 (0.3) .019 6.5 (0.9–46.9)
Other maternal complication† 5 (0.7) 1 (0.3) .670 2.5 (0.3–21.3)
Postpartum hemorrhage 11 (1.4) 9 (2.4) .337 0.6 (0.3–1.5)
Cesarean delivery 452 (60.9) 186 (50.3) ,.001 1.2 (1.1–1.4)
PlGF, placental growth factor; aRR, adjusted relative risk; uRR, unadjusted relative risk; —, not calculable owing to zero or small case
numbers; HELLP, hemolysis, elevated liver enzymes, and low platelet count.
Data are n (%) unless otherwise specified.
* Adjusted for: maternal age, parity, history of preeclampsia, chronic hypertension, gestational diabetes, and gestational age at enrollment.
†
Includes: acute renal failure, retinal detachment, stroke, disseminated intravascular coagulation, microangiopathy such as thrombotic
thrombocytopenia purpura, and acute fatty liver of pregnancy.

670 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes OBSTETRICS & GYNECOLOGY
 PlGF Category (pg/mL)

aRR* (95% CI) Less Than 12 (n5353) 12 or Greater (n5759) P uRR (95% CI) aRR* (95% CI)

17.2 (5.2–56.3) 58/351 (16.5) 13/754 (1.7) ,.001 9.6 (5.3–17.3) 6.7 (3.7–12.2)
— 22 (6.2) 3 (0.4) ,.001 15.8 (4.7–52.4) —
— 9 (2.5) 1 (0.1) ,.001 19.4 (2.5–152.3) —
— 13 (3.7) 2 (0.3) ,.001 14.0 (3.2–61.6) —
— 22/346 (6.4) 4/753 (0.5) ,.001 12.0 (4.2–34.5) —
— 1 (0.3) 0 (0) .317 — —
— 4 (1.1) 0 (0) .010 — —
— 22 (6.2) 4 (0.5) ,.001 11.8 (4.1–34.1) —
— 6 (1.7) 1 (0.1) .005 12.9 (1.6–106.9) —
— 6 (1.7) 2 (0.3) .015 6.5 (1.3–31.8) —
5.0 (3.1–8.0) 166 (22.4) 64 (8.4) ,.001 4.1 (3.1–5.4) 3.1 (2.4–4.1)
3.3 (2.5–4.5) 286 (38.5) 151 (19.9) ,.001 2.6 (2.2–3.1) 2.4 (2.0–2.8)
2.6 (2.2–3.0) 301/316 (95.3) 278/569 (48.9) ,.001 1.9 (1.8–2.1) 1.9 (1.8–2.1)
6.5 (4.6–9.3) 228/251 (90.8) 91/319 (28.5) ,.001 3.2 (2.7–3.8) 3.2 (2.6–3.8)

cluster-randomized controlled trial in the United
Kingdom that included more than 1,000 women and
compared time to preeclampsia diagnosis when PlGF
results were revealed compared with concealed from
health care providers.33 The primary finding was
a decrease in the median time to preeclampsia diag-
nosis in the revealed compared with the concealed
group (1.9 vs 4.1 days), which was associated with
a statistically significant reduction in maternal adverse
outcomes, but no difference in perinatal adverse out-
come or gestational age at delivery. Despite being
a randomized trial, the findings may not be applicable
to women in the United States owing to differences in
the manner by which preeclampsia is diagnosed and
managed in the United Kingdom. Additionally, the
study left some questions unanswered, including
how PlGF affected time to diagnosis when it is not
among the diagnostic criteria for preeclampsia, how
often knowledge of PlGF led to a deviation from usual
practice, and how the lack of universal ultrasound
screening for fetal growth restriction may have re-
sulted in selection bias.
The PETRA cohort differed from previously
studied cohorts in important ways. PETRA was larger,
included more women with preeclampsia, chronic
hypertension, and obesity, and enrolled fewer smok-
ers. Importantly, it was more racially and ethnically
diverse, reflective of enrollment at predominantly
U.S. sites. Despite demographic and management
differences, analyses of the PETRA, PELICAN, and
PARROT cohorts all concluded that PlGF may be
a promising adjunct test for predicting indicated

PlGF Category (pg/mL)

aRR* (95% CI) Less Than 12 (n5353) 12 or Greater (n5759) P uRR (95% CI) aRR* (95% CI)

3.6 (1.7–8.0) 34 (9.6) 19 (2.5) ,.001 3.8 (2.2–6.7) 3.1 (1.8–5.3)

— 0 (0) 0 (0) — — —
— 3 (0.8) 0 (0) .032 — —
— 8 (2.3) 2 (0.3) .002 8.6 (1.8–40.3) —
— 6 (1.7) 5 (0.7) .632 1.3 (0.4–4.0) —
— 3 (0.8) 4 (0.5) .686 1.6 (0.4–7.2) —
— 14 (4.0) 5 (0.7) .011 3.1 (1.2–7.8) —
— 3 (0.8) 3 (0.4) .389 2.2 (0.4–10.6) —
— 5 (1.4) 15 (2.0) .513 0.7 (0.3–2.0) —
1.3 (1.1–1.4) 239 (67.7) 399 (53.6) ,.001 1.3 (1.2–1.4) 1.2 (1.1–1.3)

VOL. 135, NO. 3, MARCH 2020 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes 671
Table 4. Placental Growth Factor Test Characteristics for Prediction of Composite Adverse Neonatal and
Maternal Outcomes
Outcome PlGF* Sensitivity (95% CI)
Composite neonatal Low 95.8 (88.1–99.1)
Very low 81.7 (70.7–89.9)
Composite maternal Low 86.8 (74.7–94.5)
Very low 64.2 (49.8–76.9)
PlGF, placental growth factor; PPV, positive predictive value; NPV, negative predictive value.
Data are % (95% CI).
* Low PlGF, 100 pg/mL or less; very low PlGF, less than 12 pg/mL.
delivery, severe SGA, and adverse perinatal out-
come.20,21,24,33 Indeed, in all of these large cohorts,
perinatal death was restricted to women with low
PlGF (less than 100 pg/mL), suggesting that risk strat-
ification by PlGF could aid in the identification of
pregnancies requiring higher surveillance, a higher
level of care, or prompt delivery.
Perhaps the most compelling result of this study is
the high negative predictive value of PlGF level. The
strong association between normal PlGF level and
a very low risk of serious adverse outcomes is
consistent with prior research. Although PlGF has
a low specificity and positive predictive value, it is
worth noting that we currently rely on inferior clinical
predictors of adverse outcome, such as blood pressure
and maternal symptoms.20,34 We speculate that PlGF
could be helpful in common cases of clinical uncer-
tainty, such as differentiating superimposed preeclamp-
sia from chronic hypertension exacerbation and
distinguishing pathologic fetal growth restriction from
constitutional smallness. Additionally, the availability
of a blood test that is highly sensitive for stillbirth could
potentially be used to inform fetal surveillance plans.
We acknowledge the limitations of the analysis. We
included women enrolled at a broad range of gestational
ages as these data were available and are relevant to
clinical practice. Because approximately 25% of women
with normal pregnancy outcomes will have low PlGF
after 35 weeks of gestation,8 a proportion of normal
term pregnancies were included in the abnormal PlGF
group, which could have affected our results. However,
this classification would tend to bias results toward the
null hypothesis and underestimate the association
between abnormal PlGF and adverse outcomes.
Although we adjusted for potential confounders, the
possibility of residual confounding exists, especially
because our understanding of the biology of PlGF in
pregnancy is incomplete.35 Given the overall low num-
ber of adverse outcomes in our study, the adjusted re-
sults should be interpreted with caution. Finally, because
the data are observational, the clinical consequences of
incorporating PlGF testing and the cost-benefit ratio of
672 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes
Specificity (95% CI) PPV (95% CI) NPV (95% CI)
35.5 (32.4–38.3) 9.2 (7.2–11.6) 99.2 (97.6–99.8)
71.7 (68.8–74.7) 16.5 (12.8–20.8) 98.3 (97.1–99.1)
34.3 (31.4–37.2) 6.2 (4.57–8.1) 98.1 (96.1–99.2)
69.9 (67.0–72.6) 9.6 (6.7–13.2) 97.5 (96.1–98.5)
screening remain uncertain, although a recent cost-
effectiveness analysis suggested overall cost savings.36
In summary, among women with suspected pre-
eclampsia, abnormal PlGF was associated with a signif-
icant increase in the risk of adverse neonatal and
maternal outcomes. The value of PlGF may be in
discriminating lower risk pregnancies from higher risk,
given its high sensitivity and negative predictive value.
Such a test could, in theory, reduce the use of
unnecessary maternal and fetal monitoring, hospitali-
zation, iatrogenic preterm delivery, and activity re-
strictions for those at low risk for decompensation. As
with all screening tests, the benefits would need to be
weighed carefully against the harms of false positive
and false negative results. While collectively the
evidence to date suggests that PlGF may be the best
single biomarker for poor outcomes related to pre-
eclampsia and placental insufficiency, randomized
trials including U.S. women will be required to
determine the value of PlGF testing as an adjunct to
current management, and would ideally include other
objective measures of placental function, such as
placental pathology, to further our understanding of
the biology and significance of PlGF.
REFERENCES
1. Ghulmiyyah L, Sibai B. Maternal mortality from preeclamp-
sia/eclampsia. Semin Perinatol 2012;36:56–9.
2. Clark SL, Belfort MA, Hankins GDV. The anachronistic termi-
nology of gestational hypertension: time for a change. Obstet
Gynecol 2015;126:294–6.
3. Sibai BM. Prevention of preeclampsia: a big disappointment.
Am J Obstet Gynecol 1998;179:1275–8.
4. Fisher SJ. Why is placentation abnormal in preeclampsia? Am J
Obstet Gynecol 2015;213(4 suppl):S115–22.
5. Hao J, Hassen D, Hao Q, Graham J, Paglia MJ, Brown J, et al.
Maternal and infant health care costs related to preeclampsia.
Obstet Gynecol 2019;134:1227–33.
6. Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-
eclampsia: pathogenesis, novel diagnostics and therapies. Nat
Rev Nephrol 2019;15:275–89.
7. Malshe AK, Sibai BM. Angiogenic and antiangiogenic markers
for prediction and risk classification of preeclampsia. Clin Ob-
stet Gynecol 2017;60:134–40.
OBSTETRICS & GYNECOLOGY
 8. Saffer C, Olson G, Boggess KA, Beyerlein R, Eubank C, Sibai
BM, et al. Determination of placental growth factor (PlGF) lev-
els in healthy pregnant women without signs or symptoms of
preeclampsia. Pregnancy Hypertens 2013;3:124–32.
9. Knudsen UB, Kronborg CS, von Dadelszen P, Kupfer K, Lee S-
W, Vittinghus E, et al. A single rapid point-of-care placental
growth factor determination as an aid in the diagnosis of pre-
eclampsia. Pregnancy Hypertens 2012;2:8–15.
10. Romero R, Erez O, Maymon E, Chaemsaithong P, Xu Z, Pa-
cora P, et al. The maternal plasma proteome changes as a func-
tion of gestational age in normal pregnancy: a longitudinal
study. Am J Obstet Gynecol 2017;217:67.e1–21.
11. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF,
et al. Circulating angiogenic factors and the risk of preeclamp-
sia. N Engl J Med 2004;350:672–83.
12. Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre-
eclampsia part 1: current understanding of its pathophysiology.
Nat Rev Nephrol 2014;10:466–80.
13. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S,
et al. Excess placental soluble fms-like tyrosine kinase 1
(sFlt1) may contribute to endothelial dysfunction, hyperten-
sion, and proteinuria in preeclampsia. J Clin Invest 2003;
111:649–58.
14. Benton SJ, McCowan LM, Heazell AEP, Grynspan D, Hutch-
eon JA, Senger C, et al. Placental growth factor as a marker of
fetal growth restriction caused by placental dysfunction. Pla-
centa 2016;42:1–8.
15. Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ,
North RA. Longitudinal serum concentrations of placental
growth factor: evidence for abnormal placental angiogenesis in
pathologic pregnancies. Am J Obstet Gynecol 2003;188:177–82.
16. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Senn-
ström M, et al. Predictive value of the sFlt-1:PlGF ratio in
women with suspected preeclampsia. N Engl J Med 2016;
374:13–22.
17. Barton JR, Sibai BM. Biomarkers for prediction, risk stratifica-
tion, and ruling out preeclampsia: what are the appropriate
goals and objectives? Am J Perinatol 2017;34:415–8.
18. Wright D, Tan MY, O’Gorman N, Poon LC, Syngelaki A,
Wright A, et al. Predictive performance of the competing risk
model in screening for preeclampsia. Am J Obstet Gynecol
2019;220:199.e1–13.
19. Dragan I, Wright D, Fiolna M, Leipold G, Nicolaides KH.
Development of pre-eclampsia within 4 weeks of sFlt-1/PlGF
ratio . 38: comparison of performance at 31-34 vs 35-37 weeks’
gestation. Ultrasound Obstet Gynecol 2017;49:209–12.
20. Chappell LC, Duckworth S, Seed PT, Griffin M, Myers J,
Mackillop L, et al. Diagnostic accuracy of placental growth
factor in women with suspected preeclampsia: a prospective
multicenter study. Circulation 2013;128:2121–31.
21. Barton JR, Woelkers DA, Newman RB, Combs CA, How HY,
Boggess KA, et al. Placental growth factor predicts time to
delivery in women with signs or symptoms of early preterm
preeclampsia: a prospective multicenter study. Am J Obstet
Gynecol 2019 Sep 10 [Epub ahead of print].
22. American College of Obstetricians and Gynecologists, Task Force
on Hypertension in Pregnancy. Hypertension in pregnancy. Report
of the American College of Obstetricians and Gynecologists’ Task
Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:
1122–31.
VOL. 135, NO. 3, MARCH 2020 Parchem et al Placental Growth Factor and Adverse Perinatal Outcomes
23. Gestational hypertension and preeclampsia. ACOG Practice
Bulletin No. 202. American College of Obstetricians and Gy-
necologists. Obstet Gynecol 2019;133:e1–25.
24. Griffin M, Seed PT, Duckworth S, North R, Myers J, Mackillop
L, et al. Predicting delivery of a small-for-gestational-age infant
and adverse perinatal outcome in women with suspected pre-
eclampsia. Ultrasound Obstet Gynecol 2018;51:387–95.
25. Sibiude J, Guibourdenche J, Dionne MD, Le Ray C, Anselem
O, Serreau R, et al. Placental growth factor for the prediction of
adverse outcomes in patients with suspected preeclampsia or
intrauterine growth restriction. PLoS One 2012;7:e50208.
26. Benton SJ, Hu Y, Xie F, Kupfer K, Lee S-W, Magee LA, et al.
Can placental growth factor in maternal circulation identify
fetuses with placental intrauterine growth restriction? Am J Ob-
stet Gynecol 2012;206:163.e1–7.
27. Molvarec A, Gullai N, Stenczer B, Fügedi G, Nagy B, Rigó J.
Comparison of placental growth factor and fetal flow Doppler
ultrasonography to identify fetal adverse outcomes in women
with hypertensive disorders of pregnancy: an observational
study. BMC Pregnancy Childbirth 2013;13:161.
28. Cetin I, Mazzocco MI, Giardini V, Cardellicchio M, Calabrese
S, Algeri P, et al. PlGF in a clinical setting of pregnancies at risk
of preeclampsia and/or intrauterine growth restriction. J Matern
Fetal Neonatal Med 2017;30:144–9.
29. Signore C, Mills JL, Qian C, Yu K, Lam C, Epstein FH, et al.
Circulating angiogenic factors and placental abruption. Obstet
Gynecol 2006;108:338–44.
30. Poon LCY, Zaragoza E, Akolekar R, Anagnostopoulos E, Nic-
olaides KH. Maternal serum placental growth factor (PlGF) in
small for gestational age pregnancy at 11(+0) to 13(+6) weeks of
gestation. Prenat Diagn 2008;28:1110–15.
31. Aupont JE, Akolekar R, Illian A, Neonakis S, Nicolaides KH.
Prediction of stillbirth from placental growth factor at 19-24
weeks. Ultrasound Obstet Gynecol 2016;48:631–5.
32. Kingdom JC. Re: predicting delivery of a small-for-gestational-age
infant and adverse perinatal outcome in women with suspected
pre-eclampsia. Ultrasound Obstet Gynecol 2018;51:304–5.
33. Duhig KE, Myers J, Seed PT, Sparkes J, Lowe J, Hunter RM,
et al. Placental growth factor testing to assess women with sus-
pected pre-eclampsia: a multicentre, pragmatic, stepped-wedge
cluster-randomised controlled trial. Lancet 2019;393:1807–18.
34. Yen T-W, Payne B, Qu Z, Hutcheon JA, Lee T, Magee LA,
et al. Using clinical symptoms to predict adverse maternal and
perinatal outcomes in women with preeclampsia: data from the
PIERS (Pre-eclampsia integrated estimate of RiSk) study.
J Obstet Gynaecol Can 2011;33:803–9.
35. Parchem JG, Kanasaki K, Kanasaki M, Sugimoto H, Xie L,
Hamano Y, et al. Loss of placental growth factor ameliorates
maternal hypertension and preeclampsia in mice. J Clin Invest
2018;128:5008–17.
36. Duhig KE, Seed PT, Myers JE, Bahl R, Bambridge G, Barnfield
S, et al. Placental growth factor testing for suspected pre-
eclampsia: a cost-effectiveness analysis. BJOG 2019;126:1390–8.
PEER REVIEW HISTORY
Received September 28, 2019. Received in revised form November
18, 2019. Accepted December 5, 2019. Peer reviews and author
correspondence are available at http://links.lww.com/AOG/B722.
673