Original Research ajog.

org

OBSTETRICS
Prediction of preeclampsia throughout gestation with
maternal characteristics and biophysical and
biochemical markers: a longitudinal study
Adi L. Tarca, PhD; Andreea Taran, MPH; Roberto Romero, MD, DMedSci; Eunjung Jung, MD; Carmen Paredes, MD;
Gaurav Bhatti, MSc; Corina Ghita; Tinnakorn Chaiworapongsa, MD; Nandor Gabor Than, MD, PhD;
Chaur-Dong Hsu, MD, MPH

BACKGROUND: The current approach to predict preeclampsia com-
bines maternal risk factors and evidence from biophysical markers (mean
arterial pressure, Doppler velocimetry of the uterine arteries) and maternal
blood proteins (placental growth factor, soluble vascular endothelial
growth factor receptor-1, pregnancy-associated plasma protein A). Such
models require the transformation of biomarker data into multiples of the
mean values by using population- and site-specific models. Previous
studies have focused on a narrow window in gestation and have not
included the maternal blood concentration of soluble endoglin, an
important antiangiogenic factor up-regulated in preeclampsia.
OBJECTIVE: This study aimed (1) to develop models for the calculation of
multiples of the mean values for mean arterial pressure and biochemical
markers; (2) to build and assess the predictive models for preeclampsia
based on maternal risk factors, the biophysical (mean arterial pressure) and
biochemical (placental growth factor, soluble vascular endothelial growth
factor receptor-1, and soluble endoglin) markers collected throughout
pregnancy; and (3) to evaluate how prediction accuracy is affected by the
presence of chronic hypertension and gestational age.
STUDY DESIGN: This longitudinal case-cohort study included 1150
pregnant women: women without preeclampsia with (n¼49) and without
chronic hypertension (n¼871) and those who developed preeclampsia
(n¼166) or superimposed preeclampsia (n¼64). Mean arterial pressure and
immunoassay-based maternal plasma placental growth factor, soluble
vascular endothelial growth factor receptor-1, and soluble endoglin con-
centrations were available throughout pregnancy (median of 5 observations
per patient). A prior-risk model for preeclampsia was established by using
Poisson regression based on maternal characteristics and obstetrical history.
Next, multiple regression was used to fit biophysical and biochemical marker
data as a function of maternal characteristics by using data collected at 8 to
15þ6, 16 to 19þ6, 20 to 23þ6, 24 to 27þ6, 28 to 31þ6, and 32 to 36þ6
week intervals, and observed values were converted into multiples of the
mean values. Then, multivariable prediction models for preeclampsia were fit
based on the biomarker multiples of the mean data and prior-risk estimates.
Separate models were derived for overall, preterm, and term preeclampsia,
which were evaluated by receiver operating characteristic curves and
sensitivity at fixed false-positive rates.
RESULTS: (1) The inclusion of soluble endoglin in prediction models for
all preeclampsia, together with the prior-risk estimates, mean arterial
pressure, placental growth factor, and soluble vascular endothelial growth
factor receptor-1, increased the sensitivity (at a fixed false-positive rate of
10%) for early prediction of superimposed preeclampsia, with the largest
increase (from 44% to 54%) noted at 20 to 23þ6 weeks (McNemar test,
P<.05); (2) combined evidence from prior-risk estimates and biomarkers
predicted preterm preeclampsia with a sensitivity (false-positive rate,
10%) of 55%, 48%, 62%, 72%, and 84% at 8 to 15þ6, 16 to 19þ6, 20 to
23þ6, 24 to 27þ6, and 28 to 31þ6 week intervals, respectively; (3) the
sensitivity for term preeclampsia (false-positive rate, 10%) was 36%,
36%, 41%, 43%, 39%, and 51% at 8 to 15þ6, 16 to 19þ6, 20 to 23þ6, 24
to 27þ6, 28 to 31þ6, and 32 to 36þ6 week intervals, respectively; (4) the
detection rate for superimposed preeclampsia among women with chronic
hypertension was similar to that in women without chronic hypertension,
especially earlier in pregnancy, reaching at most 54% at 20 to 23þ6 weeks
(false-positive rate, 10%); and (5) prediction models performed compa-
rably to the Fetal Medicine Foundation calculators when the same
maternal risk factors and biomarkers (mean arterial pressure, placental
growth factor, and soluble vascular endothelial growth factor receptor-1
multiples of the mean values) were used as input.
CONCLUSION: We introduced prediction models for preeclampsia
throughout pregnancy. These models can be useful to identify women at
risk during the first trimester who could benefit from aspirin treatment or
later in pregnancy to inform patient management. Relative to prediction
performance at 8 to 15þ6 weeks, there was a substantial improvement in
the detection rate for preterm and term preeclampsia by using data
collected after 20 and 32 weeks’ gestation, respectively. The inclusion of
plasma soluble endoglin improves the early prediction of superimposed
preeclampsia, which may be valuable when Doppler velocimetry of the
uterine arteries is not available.
Key words: aspirin, biomarker, chronic hypertension, placental growth
factor, Poisson regression, prediction, prevention, soluble endoglin, sol-
uble Flt, soluble vascular endothelial growth factor receptor-1, super-
imposed preeclampsia, toxemia of pregnancy

Cite this article as: Tarca AL, Taran A, Romero R, et al.
Prediction of preeclampsia throughout gestation with
maternal characteristics and biophysical and biochemical
markers: a longitudinal study. Am J Obstet Gynecol
2021;XX:x.exex.ex.
0002-9378/$36.00
ª 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2021.01.020
Introduction
Preeclampsia is a complex obstetrical
syndrome responsible for maternal and
infant morbidity and mortality world-
wide.1,2 A growing body of evidence in-
dicates several clinical subtypes (eg, early
or late, mild or severe, with or without
hemolysis, elevated liver enzymes, and
low platelet count syndrome) distin-
guishable at a molecular level involve
different pathways, which lead to the
clinical and laboratory manifestations
that define the syndrome.3e5 Among
these, an imbalance in angiogenic
(placental growth factor [PlGF]) and
antiangiogenic (soluble vascular

MONTH 2021 American Journal of Obstetrics & Gynecology 1.e1

Original Research OBSTETRICS ajog.org

American population attending the

AJOG at a Glance Detroit Medical Center that could
Why was this study conducted? determine MoM values to be used in
This study aimed to generate models and calculators for the prediction of pre- existing or novel prediction models for
eclampsia based on maternal risk factors and multiples of the mean of biophysical preeclampsia. A second goal was to
and biochemical markers collected longitudinally. assess the predictive performance of risk
models based on maternal characteris-
Key findings tics and obstetrical history and bio-
Relative to the results based on data collected at 8 to 15þ6 weeks, the sensitivity for physical and biochemical marker MoM
preterm and term preeclampsia improved after 20 and 32 weeks, respectively. The values throughout pregnancy. Finally, we
inclusion of plasma soluble endoglin (sEng) improved early prediction of disease. evaluated how the prediction perfor-
Models performed similarly to the Fetal Medicine Foundation calculators when mance of the novel models was affected
the same biomarker data were used as input, suggesting a modest impact of by the presence of chronic hypertension,
differences in the analytical approaches. the timing of delivery, and the method
used to combine prior-risk and
What does this add to what is known? biomarker-based evidence. This latter
Models and calculators to predict preeclampsia throughout gestation were aspect is important because state-of-the-
developed, and prediction performance increased with advancing gestational age. art approaches for the prediction of
The inclusion of sEng increased accuracy early in gestation for preterm and preeclampsia give equal weight to both
superimposed preeclampsia, which may be valuable when Doppler velocimetry of sources of evidence.
the uterine arteries is unavailable.
Materials and Methods
endothelial growth factor receptor-1 measurements but also standards to Study design
[sVEGFR-1] and soluble endoglin define their expected values, given This was a retrospective analysis of data
[sEng]) factors is considered central to the maternal characteristics, gestational age from 1150 pregnancies, previously
pathophysiology of the terminal pathway at measurement, and the type of assay described as part of a case-cohort of 1499
of preeclampsia, especially in cases neces- used to measure biochemical markers. pregnancies on which we reported the
sitating indicated preterm delivery.5e25 Such customized biomarker standards prediction of early delivery of placentas
Therefore, these biomarkers have been (referred to herein as MoM models) are presenting lesions of maternal vascular
proposed for the first-, second-, and third- then used to determine how abnormal underperfusion.54
trimester predictions of preeclampsia.14,21, the observed biomarker values are by The original multiple disease case-
23,25e29
The prognostic value of such calculating the MoM values. Additional cohort (n¼1499), from which this pre-
models14,18,21,23,25,28,30e36 for identifying customization of risk cutoff values may eclampsia case-cohort study (n¼1150)
patients at risk of preterm preeclampsia be required depending on ethnicity and was drawn, was designed in 2 stages to
was proven superior to historic-based clinical site. For example, a pooled include 1000 randomly selected women
methods31,32,37,38 and useful in clinical analysis of 3 prospective noninterven- and all remaining major obstetrical
practice to guide decision-making tion screening studies (61,174 women complications (ie, preeclampsia, pre-
regarding the administration of low-dose with a singleton pregnancy; 1770 cases of term labor, preterm prelabor rupture of
aspirin in the first trimester,39e42 steroids preeclampsia) found that first-trimester the membranes, and small-for-
for fetal lung maturity, magnesium for screening in white women detected gestational-age gestation [<5th percen-
seizure prophylaxis,43e46 and timing of 70% of preterm preeclampsia (<37 tile]) from a cohort of 4006 women with
delivery.18,21,47,48 weeks’ gestation) and 40% of term pre- a singleton pregnancy, enrolled at 6 to 22
State-of-the-art prediction models for eclampsia (37 weeks’ gestation) at a weeks’ gestation, in a longitudinal
preeclampsia were proposed in a series of 10% false-positive rate (FPR).38 The biomarker study.54 The preeclampsia
papers published by the Fetal Medicine same risk cutoff values applied in women case-cohort retained for this study
Foundation (FMF). These models of Afro-Caribbean racial origin led to included all women from the random
involve a combination of maternal risk detection rates of 92% for preterm pre- sample of 1000 pregnancies and all
factors and multiples of the mean eclampsia and 75% for term pre- additional preeclampsia cases from the
(MoM) values of mean arterial pressure eclampsia, yet the FPR was 3-fold higher cohort of 4006. Therefore, the resulting
(MAP), uterine artery pulsatility index than that of white women.53 preeclampsia case-cohort included
(UtA-PI), and blood concentrations of Therefore, based on a previously women without preeclampsia or chronic
PlGF, sVEGFR-1 (also known as sFLT-1), described retrospective longitudinal hypertension (normotensive controls,
and pregnancy-associated plasma pro- study design, we aimed first to develop n¼871), women with chronic hyper-
tein A (PAPP-A).49e52 The use of such MoM models for biophysical (MAP) and tension without preeclampsia (hyper-
prediction models in practice requires biochemical (PlGF, sVEGFR-1, and tensive controls, n¼49), women who
not only the availability of biomarker sEng) markers in our majority African developed preeclampsia (n¼166), or

1.e2 American Journal of Obstetrics & Gynecology MONTH 2021

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women with preeclampsia super-
imposed on chronic hypertension
(n¼64). Of the 230 cases of preeclamp-
sia, 83 were preterm preeclampsia (de-
livery at <37 weeks’ gestation).
Blood samples in the original case-
cohort were collected in 3 to 5 of 6 pre-
defined intervals of gestation (8e15þ6,
16e19þ6, 20e23þ6, 24e27þ6, 28e31þ6,
and 32e36þ6 weeks). Maternal plasma
PlGF, sEng, and sVEGFR-1 were deter-
mined by enzyme-linked immunosor-
bent assays. In total, 6035 samples across
multiple gestational intervals were
included in the current analysis (median
number of samples, 5; interquartile
range [IQR], 4e6).
The use of clinical data and biologic
specimens was approved by the Institu-
tional Review Boards of Wayne State
University and the Eunice Kennedy
Shriver National Institute of Child
Health and Human Development, Na-
tional Institutes of Health, United States
Department of Health and Human Ser-
vices. All patients provided written
informed consent before the collection
of samples.
Sample collection and
immunoassays
Samples were collected by venipuncture
into tubes containing ethyl-
enediaminetetraacetic acid, centrifuged,
and stored at 70 C. The most centrally
located venipuncture sample within each
of the 6 intervals of gestational age for
each patient was used for analysis. The
inter- and intra-assay coefficients of
variation of the assays were 1.4% and
3.9% for sVEGFR-1, 2.3% and 4.6% for
sEng, and 6.02% and 4.8% for PlGF,
respectively. The sensitivity of each assay
was 16.97 pg/mL for sVEGFR-1, 0.08 ng/
mL for sEng, and 9.52 pg/mL for PlGF.
Sample collection methods, biospecimen
processing, and validation of the assays
used were previously reported in greater
detail.55
Clinical definitions and outcomes
The primary outcome was the develop-
ment of preeclampsia. Secondary out-
comes were preterm (<37 weeks’
gestation) preeclampsia, term pre-
eclampsia, and superimposed
OBSTETRICS
preeclampsia. We defined uncompli-
cated pregnancy as a pregnancy with no
major obstetrical, medical, or surgical
complications, where women delivered a
term neonate. Preeclampsia was defined
as new-onset proteinuria and hyperten-
sion—blood pressure of 140/90 mm
Hg on 2 occasions at least 4 hours apart
or 160/110 mm Hg within a shorter
interval (minutes)—at 20 weeks’
gestation.3 Proteinuria was defined as a
urine protein of 300 mg in a 24-hour
urine collection, or 2 random urine
specimens, obtained 4 hours to 1 week
apart, showing 1þby dipstick.56 Hy-
pertension was defined as a systolic
blood pressure of 140 and/or a dia-
stolic blood pressure of 90 mm Hg,
measured at least on 2 occasions, 4 hours
to 1 week apart.56 Chronic hypertension
was defined in women with hyperten-
sion at <20 weeks’ gestation or in those
who reported a history of hypertension.
For women with chronic hypertension,
superimposed preeclampsia was diag-
nosed by a new onset of proteinuria
(either 300 mg/24 hours or 2þby
dipstick) or thrombocytopenia (platelet
count of <100103/mm3), elevated liver
enzymes (aspartate aminotransferase or
alanine aminotransferase of >70 IU/L),
or pulmonary edema.
Statistical analysis
Demographic data analysis
Demographic and clinical characteristics
were compared between the groups by
using Fisher exact tests for categorical
data and 2-tailed t tests for continuous
variables, respectively. P<.05 was
considered a statistically significant result.
Calculation of the multiples of the
mean for biomarkers
The plasma concentrations of PlGF,
sEng, and sVEGFR-1 and MAP were first
logarithmically transformed to improve
the normality of distribution and to
stabilize variance.57 The expected values
of these variables among controls (with
and without chronic hypertension) were
estimated as a function of maternal
characteristics and gestational age in
each interval of gestation by using linear
regression. The following maternal
characteristics were considered for
MONTH 2021 American Journal of Obstetrics & Gynecology
Original Research
inclusion in the regression models and
retained if they contributed to decreasing
the Akaike information criterion by us-
ing stepwise backward elimination:
gestational age at sample collection,
maternal age, nulliparity, history of
preeclampsia, weight, smoking status,
and interaction terms between these
covariates and chronic hypertension.
MoM values of biomarkers were then
calculated as the ratio between the
observed biomarker value and expected
values for gestational age and maternal
characteristics for all samples. MoM
values were further log10 transformed.
Box-and-whisker plots (median, IQR,
and range) of the biomarker log10 MoM
values for each outcome group were
created. Two-tailed t tests were used to
determine the significance of differences
in the MoM values between groups.
Prior-risk model for
preeclampsia by using maternal
risk factors and obstetrical
history
Poisson regression with sandwich
estimation of variance was used to es-
timate the prior (anterior) risk of pre-
eclampsia based on maternal
characteristics and obstetrical history.
Model selection was based on the
findings from a logistic regression
model with backward stepwise elimi-
nation of variables, starting with
maternal age, weight, height, nulli-
parity, smoking status, history of pre-
eclampsia, and interaction terms
between these covariates and chronic
hypertension. Once variables were
selected, the Poisson regression model
was fit, setting the weight of cases to
1.0, whereas the weights of the non-
cases were set so that the ratio of the
total weight of cases to controls was the
same as in the parent cohort of 4006
pregnancies.
Developing prediction models for
preeclampsia by using prior risk
and multiples of the mean data of
biophysical and biochemical
markers
Multivariable Poisson regression models
were fit by using data collected in each
interval of gestation (8e15þ6, 16e19þ6,
1.e3
Original Research OBSTETRICS ajog.org

TABLE 1
Demographic characteristics of the study population
Controls without Controls with Superimposed
chronic hypertension chronic hypertension Preeclampsia preeclampsia
Clinical features n¼871a n¼49a n¼166 (56a) n¼64 (24a)
Age in y, median (IQR) 23 (20e27) 26 (22e31)b 21 (19e26) 27 (22e32.2)b
Racial origin
African American, n (%) 850 (92.4) 47 (95.9) 159 (95.8)c 60 (93.8)b
White, n (%) 23 (2.5) 0 (0) 3 (1.8)b 1 (1.6)b
d c b
Other , n (%) 47 (5.1) 2 (4.1) 4 (2.4) 3 (4.7)b
Nulliparity, n (%) 354 (38.5) 15 (30.6)b 87 (52.4) 19 (29.7)b
History of preeclampsia, n (%) 29 (3.2) 4 (8.2) 11 (6.6) 10 (15.6)
b
Smoking, n (%) 188 (20.4) 12 (24.5) 28 (16.9) 22 (34.4)b
Weight (kg), median (IQR) 70 (59e86) 99 (73e115)b 73 (61e87.8) 91 (78e109)b
Height (cm), median (IQR) 162.6 (157.5e167.6) 165.1 (157.5e170.2) 162.6 (157.5e167.6) 165.1 (159.4e170.2)
c b
Birthweight (g), median (IQR) 3185 (2820e3485) 3060 (2637e3265) 2820 (2171.2e3268.8) 2725 (2087.5e3270)b
Gestational age at delivery in wk, 39.3 (38.1e40.3) 38.4 (37.6e39.3) 37.7 (36.1e39.1)b 37.2 (35.6e38.2)b
median (IQR)
Data are expressed as median (IQR) or number (percentage).
IQR, interquartile range.
a
Indicates the number of cases part of the random samples of 1000 pregnancies; b P<.001; c P<.05; d Includes women who identified as Hispanic, Asian, or “Other.” Maternal height and weight
were recorded in inches and pounds and then converted into cm and kg, respectively, before analysis. Statistically significant differences are reported vs normotensive controls (Fisher exact for
categorical variables and 2-sided t tests for continuous variables).
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

20e23þ6, 24e27þ6, 28e31þ6, and
32e36þ6 weeks). The models included
as predictors the log10 MoM of MAP,
PlGF, sVEGFR-1, sEng, and all pairwise
interaction terms among these variables.
The predicted risk (log thereof) based on
the prior-risk model was included as an
input in the biomarker-based model;
hence, the 2 types of evidence were
automatically weighted to maximize
model fit. As in the prior-risk model, the
weight of cases was set to 1.0 whereas the
weights of controls were set so that the
ratio of the total weight of cases to con-
trols was the same as in the parent cohort
of 4006 pregnancies. Cutoff values on
the predicted combined-risk scores were
identified so that the FPRs were either
10% or 20%. Performance indices (area
under the receiver operating character-
istic [ROC] curve [AUC], sensitivity,
specificity, and positive [þ] and nega-
tive [] predictive likelihood ratios)
were calculated for each interval of
gestation. A risk assessment calculator
is available from the authors’ website
(https://bioinformaticsprb.med.
wayne.edu/software/). Analysis was
performed using caret, ROCR, and
pROC packages for the R statistical
language and environment (www.r-
project.org).
Results
Maternal characteristics,
obstetrical history, and the prior
risk of preeclampsia
Demographic and clinical characteris-
tics of the study population according
to pregnancy outcome are presented in
Table 1. The Poisson regression model
used to calculate the prior risk of pre-
eclampsia based on maternal charac-
teristics and obstetrical history is
presented in Supplemental Table 1. Risk
factors included in the model were
chronic hypertension, maternal weight,
nulliparity, and history of preeclampsia,
and all were associated with an
increased risk of disease. Based on these
variables, the prior-risk model pre-
dicted overall preeclampsia, preterm
preeclampsia, and term preeclampsia
with an AUC of 0.7 (0.66e0.74), 0.67
(0.6e0.74), and 0.71 (0.67e0.76),
respectively (Figure 1).
Factors affecting the biophysical
and biochemical marker data in
women without preeclampsia
Concentrations of PlGF, sVEGFR-1, and
sEng were measured in 6035 maternal
plasma samples (median number of
samples, 5; IQR, 4e6) collected
throughout gestation from the 1150
women in the study case-cohort. The
MAP data were also available at the date
of blood sample collection. To create
standards for MoM calculation, the
biomarker data among women without
preeclampsia were fit as a function of
maternal characteristics and obstetrical
history by using linear regression. The
MoM models (Supplemental Table 2)
show that biochemical and biophysical
markers in women without preeclampsia
change with maternal weight, height,
parity, smoking status, and history of
preeclampsia and that the effect of these
covariates is modified by the presence of
chronic hypertension.

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FIGURE 1
Prediction performance of the preeclampsia prior-risk model and the combined-risk models
ROC curve for prediction of (A) overall preeclampsia (B) preterm preeclampsia, and (C) term preeclampsia based on the prior-risk model and the
combined evidence (prior risk and biomarkers).
ROC, receiver operating characteristic.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.
Distribution of biomarker multiples
of the mean data by the presence or
absence of preeclampsia, chronic
hypertension status, and
gestational age at blood sample
collection
The biomarker MoM values (log10
thereof) were displayed and compared
among groups based on disease status
(ie, preeclampsia) and the presence of
chronic hypertension (Supplemental
Figure 1). The angiogenic profiles
differed by preeclampsia and chronic
hypertension status throughout gesta-
tion (Supplemental Figure 1). The PlGF
MoM values were significantly lower and
sEng MoM values were higher in the
preeclampsia and/or superimposed pre-
eclampsia groups than in the normo-
tensive control group from the 20 to
23þ6 week interval onward (all P<.05).
The sVEGFR-1 MoM values were higher
in the preeclampsia and/or super-
imposed preeclampsia group than in the
normotensive control group from the 24
to 27þ6 week interval onward (all
P<.05). Of note, after 20 weeks onward,
the PlGF MoM values were more
abnormal in the preeclampsia group
than in the superimposed preeclampsia
group, relative to normotensive controls
(Supplemental Figure 1). The MAP
MoM values were significantly
OBSTETRICS
increased, starting with the 8 to 15þ6
week interval in the preeclampsia and/or
superimposed preeclampsia group
compared to the control group, and the
magnitude of the difference increased
with advancing gestational age.
At 8 to 15þ6 weeks, the log10 PlGF
MoM values showed a significant cor-
relation with gestational age at delivery
with preeclampsia, yet this was not the
case for MAP (Supplemental Figure 2).
This finding suggests that although
abnormally high MAP MoM values at
this gestational age are predictive of
preeclampsia, they do not predict gesta-
tional age at delivery with preeclampsia,
which was the case in other reports that
used a standardized approach to blood
pressure measurement.51
Prediction performance for
preeclampsia based on combined
prior risk and evidence from
biomarkers
Prediction models for preeclampsia,
which are based on combined prior risk
and evidence from biophysical and
biochemical marker values throughout
gestation, are presented in Supplemental
Table 3. Of note, the combined-risk
models displayed different weights for
the prior-risk component (coefficient
for prior-risk variable in Supplemental
MONTH 2021 American Journal of Obstetrics & Gynecology
Original Research
Table 3) depending on the gestational
age at measurements. The weight of the
prior-risk component diminished with
advancing gestational age at measure-
ment as the biomarker data became
more informative. Assigning a fixed
weight to the prior-risk component
would have resulted in significantly
lower sensitivity (FPR, 10%) than
allowing it to vary as shown in
Supplemental Table 3 (McNemar test,
P<.05 at 20e23þ6, 24e27þ6, and
28e31þ6 weeks when combining prior
risk with PlGF-derived evidence for
predicting all preeclampsia).
The ROC curves for the prediction of
preeclampsia by the prior-risk model
and the combination of prior risk with
biomarker-based evidence collected
throughout gestation are presented in
Figure 1. The AUC for the prediction of
all preeclampsia slightly improved from
0.75 (0.69e0.8), when only prior-risk
evidence was considered, to 0.76
(0.71e0.81) when the prior risk was
combined with evidence from the
biomarker-based model by using data
from patients with available biomarker
data collected at 8 to 15þ6 weeks
(Table 2). As gestational age increased,
hence approaching diagnosis, the AUC
increased to 0.86 (0.83e0.89) at 32 to
36þ6 weeks. The detection rates (FPR,
1.e5
 Original Research
1.e6 American Journal of Obstetrics & Gynecology MONTH 2021

TABLE 2
Screening performance for preeclampsia using the prior-risk model and the combined-risk model (prior risk and biomarkers)

Combined-risk Combined-risk FPR of 10% Combined-risk FPR of 20%

Gestational
age (wk) Prior-risk AUC AUC Cutoff Sensitivity LRþ LR Cutoff Sensitivity LRþ LR
All preeclampsia
8e15þ6 0.75 (0.69e0.8) 0.76 (0.71e0.81) 0.084 0.44 (0.35e0.54) 4.43 (3.14e6.24) 0.62 (0.52e0.73) 0.055 0.55 (0.45e0.64) 2.72 (2.12e3.49) 0.57 (0.46e0.7)
þ6
16e19 0.68 (0.63e0.73) 0.71 (0.66e0.76) 0.084 0.36 (0.28e0.45) 3.62 (2.61e5.01) 0.71 (0.63e0.81) 0.058 0.53 (0.44-0.61) 2.62 (2.09e3.28) 0.59 (0.5e0.71)
þ6
20e23 0.67 (0.62e0.72) 0.77 (0.72e0.81) 0.087 0.45 (0.37e0.53) 4.51 (3.4e5.98) 0.61 (0.53e0.7) 0.061 0.6 (0.52e0.67) 3.00 (2.46e3.65) 0.50 (0.41e0.61)
24e27þ6

OBSTETRICS
0.70 (0.65e0.74) 0.80 (0.76e0.83) 0.081 0.52 (0.44e0.59) 5.13 (3.97e6.63) 0.54 (0.46e0.63) 0.055 0.65 (0.57e0.72) 3.23 (2.7e3.86) 0.44 (0.36e0.54)
þ6
28e31 0.69 (0.64e0.73) 0.80 (0.76e0.84) 0.075 0.55 (0.48e0.63) 5.58 (4.35e7.15) 0.49 (0.42e0.58) 0.051 0.66 (0.59e0.73) 3.32 (2.79e3.95) 0.42 (0.34e0.52)
þ6
32e36 0.69 (0.65e0.74) 0.86 (0.83e0.89) 0.084 0.61 (0.54e0.69) 6.15 (4.86e7.79) 0.43 (0.36e0.52) 0.05 0.74 (0.67e0.8) 3.69 (3.14e4.34) 0.33 (0.25e0.42)
Preterm preeclampsia
8e15þ6 0.70 (0.6e0.8) 0.78 (0.7e0.86) 0.045 0.55 (0.39e0.7) 5.45 (3.71e8.02) 0.50 (0.36e0.7) 0.024 0.62 (0.46e0.76) 3.08 (2.29e4.15) 0.48 (0.32e0.7)
16e19þ6 0.65 (0.56e0.74) 0.80 (0.74e0.86) 0.04 0.48 (0.34e0.62) 4.84 (3.35e6.98) 0.58 (0.44e0.75) 0.026 0.63 (0.49e0.76) 3.14 (2.42e4.07) 0.46 (0.33e0.66)
20e23þ6 0.63 (0.54e0.72) 0.88 (0.83e0.92) 0.034 0.62 (0.48e0.75) 6.15 (4.53e8.36) 0.42 (0.3e0.59) 0.018 0.76 (0.63e0.87) 3.83 (3.1e4.73) 0.30 (0.18e0.48)
þ6
24e27 0.65 (0.56e0.73) 0.91 (0.88e0.95) 0.027 0.72 (0.6e0.83) 7.18 (5.53e9.32) 0.31 (0.21e0.46) 0.016 0.82 (0.7e0.9) 4.08 (3.39e4.9) 0.23 (0.14e0.39)
þ6
28e31 0.64 (0.55e0.73) 0.94 (0.91e0.98) 0.016 0.84 (0.71e0.92) 8.41 (6.61e10.68) 0.18 (0.1e0.33) 0.009 0.87 (0.76e0.95) 4.36 (3.67e5.17) 0.16 (0.08e0.32)
þ6
32e36 0.65 (0.56e0.73) 0.97 (0.95e0.99) 0.016 0.92 (0.81e0.98) 9.26 (7.44e11.53) 0.09 (0.03e0.22) 0.006 0.96 (0.87e1) 4.8 (4.14e5.55) 0.05 (0.01e0.19)
Term preeclampsia
8e15þ6 0.78 (0.72e0.84) 0.78 (0.72e0.84) 0.056 0.36 (0.25e0.49) 3.62 (2.38e5.5) 0.71 (0.59e0.85) 0.034 0.64 (0.51e0.75) 3.17 (2.45e4.1) 0.46 (0.33e0.63)
þ6
16e19 0.70 (0.64e0.76) 0.71 (0.65e0.77) 0.047 0.36 (0.26e0.48) 3.67 (2.53e5.3) 0.71 (0.6e0.83) 0.036 0.49 (0.38e0.6) 2.46 (1.88e3.22) 0.63 (0.51e0.78)
þ6
20e23 0.69 (0.64e0.75) 0.73 (0.68e0.79) 0.06 0.41 (0.32e0.51) 4.12 (2.99e5.68) 0.65 (0.55e0.77) 0.041 0.54 (0.44e0.64) 2.70 (2.14e3.41) 0.58 (0.47e0.71)
þ6
24e27 0.73 (0.68e0.78) 0.77 (0.72e0.82) 0.053 0.43 (0.34e0.53) 4.31 (3.19e5.81) 0.63 (0.53e0.74) 0.038 0.58 (0.48e0.67) 2.88 (2.32e3.56) 0.53 (0.43e0.66)
28e31þ6 0.71 (0.66e0.76) 0.75 (0.7e0.8) 0.054 0.39 (0.3e0.48) 3.92 (2.88e5.33) 0.68 (0.59e0.78) 0.036 0.59 (0.5e0.68) 2.96 (2.42e3.63) 0.51 (0.41e0.63)
þ6
32e36 0.71 (0.66e0.76) 0.82 (0.78e0.86) 0.061 0.51 (0.42e0.6) 5.14 (3.93e6.72) 0.54 (0.45e0.65) 0.04 0.68 (0.59e0.76) 3.38 (2.82e4.06) 0.40 (0.31e0.52)
The sensitivity at fixed 10% and 20% FPR for the gestational-age intervalespecific models predicting preeclampsia. Cutoffs were chosen so that FPR is 10% or 20%. AUC CIs were calculated using DeLong method. Note that slight variations in prediction performance
of the prior-risk model are caused by differences in the sets of cases and controls with an available sample in each interval.
AUC, area under the receiver operating characteristic curve; CI, confidence interval; FPR, false-positive rate; LR, likelihood ratio.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

ajog.org
ajog.org
10%) for preeclampsia (all cases) were
44%, 36%, 45%, 52%, 55%, and 61% at
8 to 15þ6, 16 to 19þ6, 20 to 23þ6, 24 to
27þ6, 28 to 31þ6, and 32 to 36þ6 week
intervals, respectively.
The AUC for prediction of term pre-
eclampsia by prior-risk and biomarkers
was 0.78 (0.72e0.84) at 8 to 15þ6 weeks
and did not improve with advancing
gestational age at measurements until
the 32 to 36þ6 week interval when it
reached 0.82 (0.78e0.86). The detection
rates (FPR, 10%) for term preeclampsia
were 36%, 36%, 41%, 43%, 39%, and
51% at 8 to 15þ6, 16 to 19þ6, 20 to 23þ6,
24 to 27þ6, 28 to 31þ6, and 32 to 36þ6
week intervals, respectively.
In agreement with previous reports,
the prediction of preterm preeclampsia
was more accurate than that of term
preeclampsia. The AUC for preterm
preeclampsia improved from 0.7
(0.6e0.8), when only prior-risk evidence
was considered, to 0.78 (0.7e0.86) when
the prior-risk evidence was combined
with evidence derived from biomarkers at
8 to 15þ6 weeks, and it reached 0.94
(0.91e0.98) at the 28 to 31þ6 week in-
terval. The detection rates (FPR, 10%) for
preterm preeclampsia were 55%, 48%,
62%, 72%, and 84% at 8 to 15þ6, 16 to
19þ6, 20 to 23þ6, 24 to 27þ6, and 28 to
31þ6 week intervals, respectively.
When the prediction models for all
preeclampsia were evaluated in the subset
of women with chronic hypertension
(comparison of superimposed pre-
eclampsia with chronic hypertension
without superimposed preeclampsia), the
detection rates (FPR, 10%) were 40%,
38% 54%, 48%, 38%, and 43% at 8 to
15þ6, 16 to 19þ6, 20 to 23þ6, 24 to 27þ6,
28 to 31þ6, and 32 to 36þ6 week intervals,
respectively (Figure 2, Table 3). Of note,
the risk cutoff values required to reach the
same FPR when screening patients with
chronic hypertension (Table 3) were
higher than the cutoff values used when
screening the entire study population
(Table 2). This finding can be explained
by the higher prior risk of disease among
women with chronic hypertension than
in the overall population.
To assess the added value of sEng, we
compared the prediction performance
for preterm preeclampsia and separately
OBSTETRICS
for superimposed preeclampsia based on
models with and without sEng and
found that the inclusion of sEng
increased the prediction performance in
the first 3 intervals of gestational age
(Table 4). The addition of sEng data in
the prediction models that included the
prior-risk estimate, MAP, PlGF, and
sVEGFR-1 increased the sensitivity
(FPR, 10%) for the prediction of super-
imposed preeclampsia from 31% to
40%, from 32% to 38%, and from 44%
to 54% at 8 to 15þ6, 16 to 19þ6, and 20 to
23þ6 week intervals, respectively
(McNemar test for paired sensitivity,
P<.05 for changes at 20e23þ6 weeks).
Point estimates of AUC for the predic-
tion of preterm preeclampsia were also
increased up to 0.03 units when sEng was
included in the 3 models based on data
collected at 24 weeks (Table 4).
Finally, to put into perspective the
results herein with those previously
published and to assess the potential for
the overfitting of our models to the
current cohort, we applied the FMF’s
preeclampsia risk models and compared
prediction performance on our study
population. In this analysis, the same
maternal risk factors used in our prior-
risk model (Supplemental Table 1) and
the MoM data for MAP, PlGF, and
sVEGFR-1 were used to fit combined-
risk models as described earlier, and
models were evaluated based on samples
collected in the gestational-age windows
defined by the FMF’s risk calculators.
The AUC of the prior and combined-risk
models developed herein performed
similarly with the existing preeclampsia
risk models when applied to patients
with available data collected at 11 to 14þ1
and 35 to 37þ6 week intervals (Figure 3,
Supplemental Table 4). However, the
combined-risk models developed herein
had modestly higher AUC (up to 0.07
difference) when applied to patients with
available data collected at 19 to 24þ6 and
30 to 34þ6 week intervals (Figure 3,
Supplemental Table 4). The sensitivity
for overall preeclampsia (FPR, 10%) was
48% vs 36%, 43% vs 36%, 53% vs 46%,
and 66% vs 53% for the models herein vs
those of the FMF at 11 to 14þ1, 19 to
24þ6, 30 to 34þ6, and 35 to 37þ6 weeks,
respectively. This finding suggests (1)
MONTH 2021 American Journal of Obstetrics & Gynecology
Original Research
minimal overfitting to the current
cohort of the models developed in this
work and (2) differences in prediction
performance reported herein and those
reported by the FMF are most likely
caused by the way biomarkers are
measured and to the patient pop-
ulations, as opposed to differences in
analytical approaches.
Comment
Principal findings
The longitudinal study herein focused
on the development of MoM models for
MAP- and blood-based biomarkers and
risk prediction models for preeclampsia
that can be used in similar populations.
Our findings are as follows: (1) inclusion
of sEng in the prediction models,
together with the currently used MAP,
PlGF, and sVEGFR-1 biomarkers and
prior-risk evidence (from maternal
characteristics and obstetrical history),
increased the sensitivity for the predic-
tion of superimposed preeclampsia early
in gestation; (2) the prediction of overall
preeclampsia was achieved with a sensi-
tivity ranging from 44% to 61% (FPR,
10%) as gestational age at measurement
increased from 8 to 15þ6 to 32 to 36þ6
week intervals, respectively; (3) the pre-
diction of preterm preeclampsia was
achieved with a sensitivity ranging from
55% to 84% (FPR, 10%) as gestational
age at measurement increased from 8 to
15þ6 to 28 to 31þ6 week intervals,
respectively; (4) the sensitivity for term
preeclampsia (FPR, 10%) ranged from
36% to 51% (FPR, 10%) as gestational
age at measurement increased from 8 to
15þ6 to 32 to 36þ6 week intervals,
respectively; and (5) the accuracy of
prediction models for superimposed
preeclampsia among women with
chronic hypertension was similar to that
among women without chronic hyper-
tension, especially earlier in pregnancy,
reaching at most 54% at 20 to 23þ6
weeks (FPR, 10%).
Results in the context of what is
known
There is substantial evidence that an
imbalance of maternal plasma concen-
trations of angiogenic PlGF and anti-
angiogenic factors (sVEGFR-1 and sEng)
1.e7
Original Research OBSTETRICS ajog.org

FIGURE 2
Prediction performance of the preeclampsia combined-risk models for patients with and without chronic hypertension

ROC curve for prediction of preeclampsia are based on the all preeclampsia risk models in Supplemental Table 3. Separate ROC curves are drawn for
patients with and without chronic hypertension.
ROC, receiver operating characteristic.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

is predictive of preeclampsia throughout membranes, small-for-gestational-age showed that an abnormal PlGF-to-

gestation.5e25 However, this imbalance
is not specific to preeclampsia but is also
present in other obstetrical syndromes,
including spontaneous preterm labor,
preterm premature rupture of the
gestation, and fetal death, which
involve placental disease.58e63 Indeed, in
a case-cohort derived from a parent
cohort of 4006 women involving these
obstetrical syndromes, our group
sVEGFR-1 ratio at 20 to 24 weeks’
gestation predicts early delivery in pa-
tients whose placentas had lesions of
maternal vascular underperfusion
regardless of clinical presentation54 and

1.e8 American Journal of Obstetrics & Gynecology MONTH 2021

ajog.org OBSTETRICS Original Research

those who subsequently would have a

fetal death.64 The angiogenic and anti-

The sensitivity at fixed 10% and 20% FPR for the GA intervalespecific models predicting preeclampsia. Cutoffs were chosen so that FPR is 10% or 20%. AUC CIs were calculated using DeLong method. Note that slight variations in prediction performance of the prior-
0.74 (0.54e1.03)
0.70 (0.51e0.97)
0.49 (0.34e0.72)
0.60 (0.44e0.83)
0.56 (0.39e0.79)
0.51 (0.35e0.74)
angiogenic imbalance in these syn-
dromes reflects severe placental
maldevelopment and uteroplacental
LR

insufficiency, which is most pronounced

in preterm preeclampsia.7,65e67
2.07 (0.91e4.72)

3.09 (1.65e5.79)
2.60 (1.32e5.09)
2.84 (1.45e5.56)
3.07 (1.62e5.79)
Traditionally, preeclampsia is consid-
2.29 (1.07e4.9)

ered a multistage disease involving

impaired trophoblastic invasion, which
leads to shallow placentation, defective
LRþ

spiral artery remodeling, placental le-

sions consistent with maternal vascular
Combined-risk FPR of 20%

0.40 (0.24e0.58)
0.43 (0.27e0.61)
0.60 (0.45e0.74)
0.52 (0.38e0.66)

0.59 (0.43e0.73)

underperfusion, and consequent syncy-

0.55 (0.4e0.7)

tiotrophoblast stress.63,68e71 In preterm

Sensitivity

preeclampsia, the ischemic-stressed

placenta is thought to release large
amounts of syncytiotrophoblast debris,
proinflammatory cytokines, and anti-
Cutoff

0.307
0.236
0.214
0.224
0.202
0.219

angiogenic molecules (sVEGFR-1 and

sEng) into the maternal
0.70 (0.53e0.92)
0.51 (0.37e0.71)
0.58 (0.44e0.76)
0.68 (0.53e0.88)
0.63 (0.48e0.83)

circulation,11,67,72e78 leading to an
0.66 (0.5e0.89)

exaggerated inflammatory response and

subsequently generalized endothelial
AUC, area under the receiver operating characteristic curve; CI, confidence interval; FPR, false-positive rate; GA, gestational age; LR, likelihood ratio.

dysfunction.61,70,71,77,79e86 Therefore,
LR

the imbalance of angiogenic and anti-

angiogenic factors may be considered
4.13 (1.31e13.05)

4.98 (2.09e11.86)

3.93 (1.45e10.66)
3.50 (1.27e9.64)

4.81 (1.82e12.7)

4.09 (1.68e9.97)

more broadly as biomarkers of syncy-

tiotrophoblast stress.67,72e77 By contrast,
in term preeclampsia, other pathologic
pathways, that is, those involving
LRþ

maternal proinflammatory and meta-

bolic conditions, may trigger placental
Combined-risk FPR of 10%
Prediction of preeclampsia in women with chronic hypertension

0.40 (0.24e0.58)
0.38 (0.22e0.55)
0.54 (0.39e0.69)
0.48 (0.34e0.62)
0.38 (0.25e0.54)
0.43 (0.29e0.59)

stress pathways later in

risk model are caused by differences in the sets of cases and controls with a sample in each interval.

pregnancy.5,72,87e89 Therefore, in term

Sensitivity

Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

preeclampsia, the angiogenic imbalance

starts later in pregnancy and its diag-
nostic and predictive power is
lower,6,7,65e67,90 which was also reflected
Cutoff

0.325
0.263
0.284
0.243
0.312
0.288

in the present study.

While developing prediction models
0.64 (0.51e0.77)

0.65 (0.53e0.76)
0.70 (0.59e0.81)
0.75 (0.65e0.85)

for preeclampsia, we used several ele-

0.67 (0.54e0.8)

0.69 (0.59e0.8)
Combined-risk

ments from the approach pioneered by

the FMF,51 such as creating a prior-risk
model based on maternal risk factors
AUC

and obstetrical history and, subse-

quently, combining the prior risk with
0.49 (0.34e0.63)
0.52 (0.39e0.66)
0.56 (0.44e0.68)
0.51 (0.39e0.63)
0.55 (0.43e0.67)
0.48 (0.36e0.6)

evidence from biomarkers. Such an

Prior-risk AUC

approach has the advantage that prior-

risk models can be based on larger da-
tabases in which biomarker data may not
All preeclampsia

be available for all patients. Moreover, we

TABLE 3

also transformed the biomarker data

þ6

þ6

24e27þ6
þ6

þ6
8e15þ6
GA (wk)

16e19
20e23

28e31
32e36

into MoM values that reflect the degree

of abnormality of the biomarkers’ mea-
surements after accounting for

MONTH 2021 American Journal of Obstetrics & Gynecology 1.e9

Original Research OBSTETRICS ajog.org

TABLE 4
Screening performance for preeclampsia based on combined-risk models with and without sEng
Prior riskþMAPþPlGFþsVEGFR-1 Prior riskþMAPþPlGFþsVEGFR-1þsEng
Gestational age (wk) AUC Sensitivity (FPR¼10%) AUC Sensitivity (FPR¼10%)
Prediction of preeclampsia in women with chronic hypertension based on all preeclampsia risk models
8e15þ6 0.67 (0.54e0.80) 0.31 (0.17e0.49) 0.67 (0.54e0.8) 0.40 (0.24e0.58)
þ6
16e19 0.63 (0.51e0.76) 0.32 (0.18e0.50) 0.64 (0.51e0.77) 0.38 (0.22e0.55)
þ6
20e23 0.67 (0.55e0.78) 0.44 (0.29e0.59) 0.69 (0.59e0.80) 0.54 (0.39e0.69)a
þ6
24e27 0.62 (0.50e0.73) 0.42 (0.29e0.57) 0.65 (0.53e0.76) 0.48 (0.34e0.62)
þ6
28e31 0.70 (0.59e0.81) 0.38 (0.25e0.54) 0.70 (0.59e0.81) 0.38 (0.25e0.54)
þ6
32e36 0.75 (0.64e0.85) 0.43 (0.29e0.59) 0.75 (0.65e0.85) 0.43 (0.29e0.59)
Prediction of preterm preeclampsia based on preterm preeclampsia risk models
8e15þ6 0.77 (0.69e0.85) 0.50 (0.34e0.66) 0.78 (0.70e0.86) 0.55 (0.39e0.70)
16e19þ6 0.77 (0.70e0.84) 0.48 (0.34e0.62) 0.80 (0.74e0.86) 0.48 (0.34e0.62)
þ6
20e23 0.86 (0.80e0.91) 0.60 (0.46e0.73) 0.88 (0.83e0.92) 0.62 (0.48e0.75)
þ6
24e27 0.91 (0.86e0.95) 0.75 (0.63e0.85) 0.91 (0.88e0.95) 0.72 (0.60e0.83)
þ6
28e31 0.94 (0.91e0.97) 0.82 (0.69e0.91) 0.94 (0.91e0.98) 0.84 (0.71e0.92)
þ6
32e36 0.97 (0.95e0.99) 0.92 (0.81e0.98) 0.97 (0.95e0.99) 0.92 (0.81e0.98)
AUC, area under the ROC curve; FPR, false-positive rate; MAP, mean arterial pressure; P1GF, placental growth factor; ROC, receiver operating characteristic; sEng, soluble endoglin; sVEGFR-1,
soluble vascular endothelial growth factor receptor-1.
a
P<.05 McNemar test for paired sensitivities indicating that the inclusion of sEng improves sensitivity at 10% FPR
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

gestational age and maternal risk factors
affecting biomarker levels in control
pregnancies. Such MoM models are akin
to customized standards of estimated
fetal weight91,92 and cervical length.93
After removing the effect of gestational
age and maternal characteristics on
biomarker levels, any remaining abnor-
mality in MoM values in cases relative to
controls is considered independent evi-
dence that can be used to improve ac-
curacy of predictions.
However, our approach differs from
the FMF in several aspects. Although the
FMF treats the outcome as a continuous
variable (gestational age at delivery with
preeclampsia), we modeled preeclamp-
sia as a binary outcome. A key assump-
tion of the FMF approach is that the
more abnormal the biomarker in any
given measurement interval (eg, 11e14
weeks’ gestation), the earlier the delivery
with preeclampsia. Our data support this
concept for PlGF because more
abnormal values (lower log10 MoM
values at 8e16 weeks’ gestation) are
observed in patients who deliver earlier
with preeclampsia (Supplemental
Figure 2); this is consistent with the
higher frequency of lesions of maternal
vascular underperfusion and the higher
magnitude of angiogenic imbalance in
preterm preeclampsia. For MAP, higher
MoM values were noted herein at 8 to 16
weeks’ gestation for women who devel-
oped preeclampsia compared to the
controls, yet there was no correlation
between the gestational age at delivery
with preeclampsia and log MAP MoM
values—likely owing to differences in the
protocol used for blood pressure mea-
surement among studies. Despite these
methodological differences, the predic-
tion performance on the data generated
in this study resulted only in an up to 7%
higher AUC for the combined-risk
models developed herein than the FMF
calculators given the same input data,
depending on the gestational-age inter-
val as assessment. Therefore, we
conclude that the analytical aspects alone
have modest effects on the prediction
performance (Figure 3 and
Supplemental Table 4).
The sensitivity of the FMF approach
based on prior risk, MAP, PlGF, UtA-PI,
and PAPP-A at 11 to 14 weeks’ gestation
in a mixed white and Afro-Caribbean
patient population was reported to be
75% and 41% for preterm and term
preeclampsia, respectively (FPR, 10%).
Our results, using prior risk, MAP, PlGF,
sVEGFR-1, and sEng at 8 to 16 weeks’
gestation, were 55% and 36% for pre-
term and term preeclampsia, respec-
tively (FPR, 10%) (Table 3). First-
trimester prediction of term pre-
eclampsia was suboptimal for both
studies based on the report herein and
that of Tan et al38; a similar gap in pre-
dictive performance for late-onset vs
early-onset disease was
noted.7,9,16,23,30,33,90,94e97
To improve the prediction of pre-
eclampsia beyond what is possible by
using MAP, Doppler velocimetry of the
uterine arteries, and the maternal blood
proteins PlGF and PAPP-A during the

1.e10 American Journal of Obstetrics & Gynecology MONTH 2021

ajog.org OBSTETRICS Original Research

FIGURE 3
Prediction performance for preeclampsia by models developed herein and the FMF models

ROC curve for prediction of all preeclampsia based on data collected in gestational-age intervals specified in FMF calculators. Separate curves are drawn
for prior-risk models and combined-risk models. For this analysis, the models in Supplemental Table 3 were modified to exclude the contribution of sEng,
which is not used in FMF models. The FMF models utilized a combination of maternal factors and clinical history (Supplemental Table 1), MAP, and PlGF.
For analyses based on data collected after 25 weeks’ gestation, sVEGFR-1 was also included.
FMF, Fetal Medicine Foundation; MAP, mean arterial pressure; PlGF, placental growth factor; ROC, receiver operating characteristic; sEng, soluble endoglin; sVEGFR-1, soluble vascular endothelial growth
factor receptor-1.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

first trimester, researchers have explored
the value of additional
biomarkers5,23e25,86 and whether their
measurement at subsequent gestational-
age intervals closer to delivery, or both,
would be helpful.23,25,86 Screening for
preeclampsia after the first trimester, at
19 to 24þ6 weeks,50 30 to 34 weeks,33 and
35 to 37 weeks,49 has shown that the
prediction of both term and preterm
preeclampsia increased with advancing
gestation, which is in agreement with the
data presented herein (Table 3). The
current study was especially well suited
to assess the effect of gestational age at
measurement on prediction perfor-
mance, given that longitudinal data were
available. Screening at 19 to 24þ6 weeks
based on MAP, PlGF, sVEGFR-1, and
UtA-PI by the FMF approach indicated a
sensitivity (FPR, 10%) of 85% and 46%
for the prediction of preterm and term
preeclampsia, respectively.50 Our
approach using sEng instead of UtA-PI
at 20 to 23þ6 weeks achieved a sensi-
tivity of 62% and 41% for preterm and
term preeclampsia, respectively
(Table 3). Moreover, screening at 30 to
34 weeks based on MAP, PlGF, sVEGFR-
1, and UtA-PI by the FMF approach was
reported to increase the detection rate
(FPR, 10%) of preterm and term pre-
eclampsia to 98% and 65%, respec-
tively.33 Our approach using sEng
instead of UtA-PI at 28 to 31þ6 achieved
a sensitivity of 84% for preterm pre-
eclampsia and 39% for term pre-
eclampsia (Table 3).
Clinical implications
Given that the models developed herein
produce similar results compared to
FMF models when the same data are
used as input, this study suggests that the
superior prediction reported in FMF
studies especially for preterm pre-
eclampsia is caused by additional
maternal risk factors considered in the
FMF prior-risk model (eg, diabetes
mellitus, autoimmune disease), which
did not reach significance to be included

MONTH 2021 American Journal of Obstetrics & Gynecology 1.e11

Original Research OBSTETRICS
here and, more importantly, to the more
accurate determination of MAP and the
inclusion of UtA-PI data in the FMF
reports. For clinical setups where stan-
dardized MAP determinations and UtA-
PI data are not available, the inclusion of
maternal plasma sEng in the prediction
models could be used to increase pre-
diction performance of superimposed
preeclampsia and, to some extent, pre-
term preeclampsia early in pregnancy
(Table 4). However, future prospective
studies would be needed to determine
whether the additional preterm pre-
eclampsia cases identified as being at risk
can also benefit from aspirin treatment.
In agreement with previous reports,
the prediction performance for pre-
eclampsia increased with advancing
gestational age at data collection, sug-
gesting utility for patient management.
Furthermore, the prediction of pre-
eclampsia in women with chronic hy-
pertension was achieved by the model
derived for overall preeclampsia with
detection rates (FPR, 10%) comparable
to those in women without chronic hy-
pertension. Of all risk factors deter-
mining the prior risk of preeclampsia
listed in Supplemental Table 1, the
presence of chronic hypertension is the
most powerful predictor; hence, when
prediction of preeclampsia is assessed
only in the subset of women with
chronic hypertension, the prediction by
prior risk alone is very low (AUC at most
0.56); hence, adding evidence from bio-
markers is important (Table 4 and
Supplemental Figure 1). However, to
maintain the same FPR when screening
among women with chronic hyperten-
sion, the combined-risk cutoff values
need to be higher given that this subset of
women have higher prior risk. For
example, to ensure an FPR of 10% when
screening at 8 to 16 weeks for overall
preeclampsia, a cutoff value of 1/12 on
the combined risk is required. However,
for women with chronic hypertension, a
cutoff value of 1/3 is necessary to
maintain the same FPR. Women with
chronic hypertension may not benefit
from low-dose aspirin to prevent pre-
term preeclampsia40,98; however, accu-
rately assessing the risk of preeclampsia
in chronic hypertensive women is
1.e12 American Journal of Obstetrics & Gynecology MONTH 2021
important for patient management.
Because baseline levels of biochemical
markers and their time-varying profiles
depend on chronic hypertension status,
we accommodated for such chronic hy-
pertension-specific effects when devel-
oping the MoM models (Supplemental
Table 2).
Research implications
Another observation in this study is that
the prior-risk evidence should not be
treated as equal to the biomarker-based
evidence. Indeed, when, for example,
equal weight is assigned to the prior-risk
evidence and evidence from 1 biomarker
(PlGF) in a combined-risk model, the
prediction performance was lower than
when the prior risk was allowed to be
automatically up- or downweighted
depending on the gestational-age inter-
val at screening. Early in gestation, when
biomarker data are less informative of
the future onset of preeclampsia, the
prior-risk contribution in the models
was higher (eg, coefficient of 1.25 for
early preeclampsia at 8e15þ6 weeks), yet
later in gestation when biomarker data
become more predictive of disease, the
weight of the prior-risk component was
lower than 1.0 (Supplemental Table 3).
This finding indicates the possibility that
the competing risk approach,51 in which
the prior-risk and biomarker-risk data
are treated as equal and simply multi-
plied according to Bayes’ theorem, can
also benefit by considering different
weights depending on the gestational age
at screening; however, additional
research is needed to test this hypothesis.
Strengths and limitations
This study focuses on the development
of prediction models for preeclampsia
based on a longitudinal case-cohort
design that comprises a combination of
plasma angiogenic and antiangiogenic
factors (PlGF, sVEGFR-1, and sEng),
maternal characteristics, and MAP.
Although previous longitudinal
biomarker studies included women with
superimposed preeclampsia, a few
included both chronic hypertensive and
normotensive control groups.99e103 An
additional strength of this work is the
implementation of the MoM-based
ajog.org
models and preeclampsia risk models
as online calculators that can be evalu-
ated by other researchers.
Although an independent test set
was not used to assess prediction per-
formance, we have provided evidence
for minimal overfitting to the current
cohort because the prediction perfor-
mance we report is similar to the one of
FMF calculators when the same input
data were used for 2 of the 4
gestational-age intervals considered.
Other limitations are the fact that
Doppler measurements were not
available to integrate with the other
biomarkers and that cases of pre-
eclampsia were not subclassified by
preterm or term acquiescence or
feature severity. Although not within
the scope of the current manuscript,
future work may assess the value of
multiple within-subject measurements
for improving prediction performance
relative to a single evaluation.
Conclusions
We introduced models and calculators
to determine MoM values of biophys-
ical and biochemical biomarkers and
risk of preeclampsia based on data
collected throughout pregnancy. These
models can be used to identify women
who may benefit from low-dose aspirin
treatment or, later in pregnancy, to
inform patient management. This
study suggests that the inclusion of
sEng in combination with MAP, PlGF,
and sVEGFR-1 improves the predic-
tion of women at risk of preterm and
superimposed preeclampsia, which is
important especially when Doppler
velocimetry of the uterine arteries is
not available. n
Acknowledgment
The authors acknowledge Maureen McGerty
(Wayne State University) for proofreading and
copyediting this manuscript.
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J Obstet Gynecol 2020 [Epub ahead of print]. women with chronic hypertension who sub-
94. Stepan H, Hund M, Andraczek T. Combining sequently develop superimposed pre-
biomarkers to predict pregnancy complications eclampsia. J Matern Fetal Neonatal Med
and redefine preeclampsia: the angiogenic- 2003;14:318–23.
placental syndrome. Hypertension 2020;75:
918–26. Author and article information
95. Crispi F, Domínguez C, Llurba E, Martín-
From the Perinatology Research Branch, Division of Ob-
Gallán P, Cabero L, Gratacós E. Placental
stetrics and Maternal-Fetal Medicine, Division of Intra-
angiogenic growth factors and uterine artery
mural Research, Eunice Kennedy Shriver National
Doppler findings for characterization of different
Institute of Child Health and Human Development, Na-
subsets in preeclampsia and in isolated intra-
tional Institutes of Health, United States Department of
uterine growth restriction. Am J Obstet Gynecol
Health and Human Services, Bethesda, MD, and Detroit,
2006;195:201–7.
MI (Dr Tarca; Ms Taran; Drs Romero, Jung, and Paredes;
96. Vatten LJ, Eskild A, Nilsen TI, Jeansson S,
Mr Bhatti; Ms Ghita; and Dr Hsu); Departments of Ob-
Jenum PA, Staff AC. Changes in circulating level
stetrics and Gynecology (Dr Tarca; Ms Taran; and Drs
of angiogenic factors from the first to second
Jung, Paredes, Chaiworapongsa, and Hsu) and Physi-
trimester as predictors of preeclampsia. Am J
ology (Dr Hsu), Wayne State University School of Medi-
Obstet Gynecol 2007;196:239.e1–6.
cine, Detroit, MI; Department of Computer Science,
97. Akolekar R, Zaragoza E, Poon LC,
Wayne State University College of Engineering, Detroit, MI
Pepes S, Nicolaides KH. Maternal serum
(Dr Tarca); Department of Obstetrics and Gynecology,
placental growth factor at 11 þ0 to 13 þ6
University of Michigan, Ann Arbor, MI (Dr Romero);
weeks of gestation in the prediction of pre-
Department of Epidemiology and Biostatistics, Michigan
eclampsia. Ultrasound Obstet Gynecol
State University, East Lansing, MI (Dr Romero); Center for
2008;32:732–9.
Molecular Medicine and Genetics, Wayne State Univer-
98. Wertaschnigg D, Reddy M, Mol BWJ, da
sity, Detroit, MI (Dr Romero); Detroit Medical Center,
Silva Costa F, Rolnik DL. Evidence-based pre-
Detroit, MI (Dr Romero); Department of Obstetrics and
vention of preeclampsia: commonly asked
Gynecology, Florida International University, Miami, FL (Dr
questions in clinical practice. J Pregnancy
Romero); Systems Biology of Reproduction Lendulet
2019;2019:2675101.
Research Group, Institute of Enzymology, Research
99. Becker DA, Machemehl HC, Biggio JR,
Centre for Natural Sciences, Budapest, Hungary (Dr
Siegel AM, Tita AT, Harper LM. Pregnancy out-
Than); and Maternity Clinic, Budapest, Hungary (Dr Than).
comes of exacerbated chronic hypertension
Received Dec. 9, 2020; revised Jan. 22, 2021;
compared with superimposed preeclampsia.
accepted Jan. 22, 2021.
Am J Perinatol 2019;36:872–8.
This research was supported, in part, by the Perina-
100. Caruso A, Caforio L, Testa AC,
tology Research Branch, Division of Obstetrics and
Ferrazzani S, Mastromarino C, Mancuso S.
Maternal-Fetal Medicine, and Division of Intramural
Chronic hypertension in pregnancy: color
Research, Eunice Kennedy Shriver National Institute of
Doppler investigation of uterine arteries as a
Child Health and Human Development, National Institutes
predictive test for superimposed preeclampsia
of Health, United States Department of Health and Human
and adverse perinatal outcome. J Perinat Med
Services (NICHD/NIH/DHHS), and, in part, with federal
1996;24:141–53.
funds from NICHD/NIH/DHHS under contract number
101. Perni U, Sison C, Sharma V, et al. Angio-
HHSN275201300006C. R.R. has contributed to this work
genic factors in superimposed preeclampsia: a
as part of his official duties as an employee of the United
longitudinal study of women with chronic hy-
States Federal Government.
pertension during pregnancy. Hypertension
R.R. and T.C. are listed as coinventors on a patent
2012;59:740–6.
related to the prediction and treatment of obstetrical
102. Roncaglia N, Crippa I, Locatelli A, et al.
complications (US2019/0285643 A1). The other authors
Prediction of superimposed preeclampsia using
report no conflict of interest.
uterine artery Doppler velocimetry in women with
Corresponding author: Adi L. Tarca, PhD. atarca@
chronic hypertension. Prenat Diagn 2008;28:
med.wayne.edu
710–4.
MONTH 2021 American Journal of Obstetrics & Gynecology 1.e15
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SUPPLEMENTAL FIGURE 1
Distribution of biophysical and biochemical marker MoM values among groups

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SUPPLEMENTAL FIGURE 1
(Continued )

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SUPPLEMENTAL FIGURE 2
Biomarker MoM values at 8e15D6 weeks’ gestation and gestational age at delivery with preeclampsia

0.6
slope=0.024

1.5
p=0.004

0.4
log10 sVEGFR1 MOM
log10 PlGF MOM

1.0

0.2
0.5

0.0
0.0
−0.5

−0.4
25 30 35 40 25 30 35 40

Gestational age at delivery with PE (weeks) Gestational age at delivery with PE (weeks)
0.4

0.00 0.05 0.10

log10 sEng MOM

log10 MAP MOM

0.2
0.0
−0.4 −0.2

−0.10

25 30 35 40 25 30 35 40

Gestational age at delivery with PE (weeks) Gestational age at delivery with PE (weeks)
The figure shows the log10 MoM values as a function of gestational age at delivery with preeclampsia at 8e15þ6 weeks’ gestation. The log10 PlGF MoM
values were positively correlated with gestational ages at delivery with preeclampsia.
MoM, multiple of the mean; PlGF, placental growth factor.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

=
Box-and-whisker plots (median, interquartile) of (A) PlGF, (B) sEng, (C) sVEGFR-1, and (D) MoM values in normotensive controls (gray) and controls with
CHTN (yellow), PE (blue), and sPE (red). MoMs were derived by using the models shown in Supplemental Table 3. Single asterisk denotes P<.001 in
comparison with normotensive controls, unless otherwise noted in brackets.
CHTN, women without preeclampsia with chronic hypertension; MoM, multiples of the mean; PE, preeclampsia; sPE, superimposed preeclampsia.
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SUPPLEMENTAL TABLE 1
Model coefficients for calculation of prior risk of preeclampsia
Variable Estimate Standard error P value
(Intercept) 3.3940 0.1102 <.001
Chronic hypertension 1.6034 0.1838 <.001
Maternal weight, 75 kg 0.0049 0.0031 .105
Nulliparity 0.5007 0.1499 .001
History of preeclampsia 0.8986 0.2715 .001
Nulliparity and history of preeclampsia are binary variables. As an example, to calculate risk for a multiparous woman who weighs 76 kg and has a history of preeclampsia and chronic hypertension in
the current pregnancy, we use the following formula: risk¼exp[3.394þ11.603þ(7675)0.0049 þ 00.5007þ10.898]¼0.41.
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SUPPLEMENTAL TABLE 2
MoM models coefficients for plasma PlGF, sEng, sVEGFR-1, and MAP
CHTN CHTN CHTN CHTN CHTN CHTN
Analyte Interval Intercept GA-start CHTN Age Weight Height Smoking Nulliparity weight height smoking sge HistPE nulliparity HistPE
MAP 8e15þ6 1.9349 0.0027 0.0444 0.0006 0.0005 0.0002 . 0.0091 . 0.0018 . . . . .
þ6
MAP 16e19 1.9180 . 0.0413 . 0.0004 . 0.0074 0.0073 . . . . . . .
MAP 20e23þ6 1.9157 . 0.0262 0.0003 0.0005 0.0004 0.0096 0.0099 . . . 0.0019 . . .
MAP 24e27þ6 1.9165 . 0.0328 . 0.0007 . . 0.0089 . . . . 0.0232 0.0248 0.0479
þ6
MAP 28e31 1.9126 0.0029 0.0199 0.0004 0.0005 . . 0.0094 . . . 0.0025 0.0176 . .

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þ6
MAP 32e36 1.9191 0.0025 0.0215 0.0009 0.0003 0.0004 . 0.0106 . . . . . . .
þ6
PlGF 8e15 1.1749 0.1140 0.0842 0.0011 0.0034 . 0.1166 0.0479 . . . 0.0172 . . .
PlGF 16e19þ6 2.1011 0.0724 0.0903 . 0.0036 . 0.0998 0.0353 0.0035 . . . 0.0055 . 0.4072
PlGF 20e23þ6 2.4210 0.0541 0.0053 0.0001 0.0043 0.0008 0.1306 . . 0.0083 . 0.0138 . . .
þ6
PlGF 24e27 2.6288 0.0389 0.0965 . 0.0048 0.0013 0.1282 0.0330 0.0033 0.0096 . . . . .
þ6
PlGF 28e31 2.8157 0.0182 0.0917 . 0.0047 0.0028 0.0811 . 0.0032 . . . 0.0966 . .
þ6
PlGF 32e36 2.8649 0.0351 0.1140 . 0.0041 . 0.0147 0.0363 0.0043 . 0.2036 . . 0.1789 .
sEng 8e15þ6 0.8387 0.0046 0.0435 . 0.0012 0.0001 0.0039 0.0411 0.0014 0.0044 0.1117 . . . .
sEng 16e19þ6 0.7887 0.0137 0.0205 . 0.0013 0.0008 . 0.0315 . 0.0042 . . . . .
þ6
sEng 20e23 0.7425 . 0.0147 . 0.0013 0.0009 . 0.0177 . 0.0035 . . 0.0409 . .
þ6
sEng 24e27 0.7394 0.0059 0.0331 0.0015 0.0011 0.0004 . 0.0155 0.0012 0.0046 . . 0.0218 . 0.0987
þ6
sEng 28e31 0.7673 0.0244 0.0221 0.0020 0.0009 0.0002 0.0046 0.0184 0.0014 0.0061 0.0837 . . 0.0888 .
sEng 32e36þ6 0.8818 0.0221 . 0.0023 0.0013 . . 0.0506 . . . . . . .
sVEGFR-1 8e15þ6 2.9574 . 0.0143 0.0036 0.0017 . 0.0233 0.0836 . . 0.1293 . . . .
þ6
sVEGFR-1 16e19 2.9475 0.0194 0.0569 0.0044 0.0023 . . 0.0790 . . . . . . .
þ6
sVEGFR-1 20e23 2.9166 . . 0.0048 0.0027 . . 0.0808 . . . . . . .
þ6
sVEGFR-1 24e27 2.9265 . . 0.0061 0.0031 . . 0.0584 . . . . . . .
sVEGFR-1 28e31þ6 2.9579 0.0154 0.0217 . 0.0027 0.0006 . 0.0692 . 0.0066 . . . . .
þ6
sVEGFR-1 32e36 3.0620 0.0485 0.0283 0.0026 0.0019 0.0032 . 0.1147 . 0.0100 . . . . .
þ6
The following variables were centered by subtracting the calculated means: age, 24 years; weight, 75 kg; and height, 163 cm. GA was offset by subtracting the value of the start of the GA interval (eg, start¼20 weeks for the 20e23 week interval). “.” indicates a
null coefficient for the corresponding variable (column). As an example, to calculate the expected log10sEngMoM value for a patient at 10 weeks’ gestation who is 25 years old, weighs 76 kg, is 170 cm tall, had 2 previous deliveries (nulliparity, 0), has CHTN, does
smoke, and has a history of PE, we use the equation above for sEng for the 8e15þ6 week interval as follows: expected log10sEng¼0.8387 0.0046(108)þ0.04351  0.0012(7675) e(170163)0.0001 e 10.0039  0.0014(76
75)þ0.00441(170163) 0.111711¼0.785. If the observed value of sEng at 10 weeks was 10 ng/mL, then the MoM can be calculated as observed/expected¼10/100.856¼1.64.
CHTN, chronic hypertension status; GA, gestational age; HistPE, history of preeclampsia; MAP, mean arterial pressure; MoM, multiple of the mean; P1GF, placental growth factor; sEng, soluble endoglin; sVEGFR-1, soluble vascular endothelial growth factor

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receptor-1.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.
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SUPPLEMENTAL TABLE 3
PE risk model coefficients based on prior risk and biomarkers
sVEGFR-1 sEng PlGF sVEGFR-1 sVEGFR-1 sEng
Outcome Interval Intercept Prior risk MAP PlGF sVEGFR-1 sEng sEng PlGF MAP PlGF MAP MAP
ALL PE 8e15þ6 0.1202 1.0686 7.8718 1.0559 1.0797 1.2826 8.2288 5.1406 19.5762 0.8956 13.3474 16.4718
þ6
ALL PE 1619 0.6108 0.8430 4.6875 0.8972 0.3611 2.6166 1.2331 2.6175 10.0090 1.6311 13.3081 41.6410
ALL PE 2023þ6 0.7049 0.8738 10.6076 1.8162 0.0063 2.5699 0.6289 3.4715 16.5989 2.0201 4.8094 5.9228
þ6
ALL PE 2427 0.6971 0.8920 11.2481 0.9722 0.8344 2.1170 0.3160 1.1305 1.2041 0.5118 3.3517 7.9670
þ6
ALL PE 2831 0.8269 0.8721 8.9072 1.3034 0.9985 1.2981 1.4653 0.5651 11.5049 0.8995 2.5952 3.9396
þ6
ALL PE 3236 1.1815 0.9020 20.4648 0.6288 1.2117 0.3282 0.7268 0.6653 11.6130 0.4909 7.6116 10.0733
þ6
Preterm PE 815 0.7714 1.2537 6.1118 2.8421 1.8331 4.5759 9.2669 7.9118 28.1042 3.6625 30.8271 69.5482
Preterm PE 1619þ6 1.6452 0.9275 6.0976 3.1082 0.6181 6.1603 2.7682 9.5572 25.9851 4.2670 21.3636 63.1223
þ6
Preterm PE 2023 2.3449 0.9031 16.2719 4.5352 0.5609 4.3894 0.0739 7.1916 28.0664 1.6351 2.6095 21.4030
þ6
Preterm PE 2427 3.1996 0.7020 21.1821 3.5461 1.3702 3.2879 0.3028 2.9491 17.5635 0.0151 2.9428 3.6563
þ6
Preterm PE 2831 3.9011 0.7363 23.3031 4.2432 2.4777 2.3102 0.9598 1.3322 25.6374 1.2197 0.9956 4.9074
þ6
Preterm PE 3236 3.8992 1.0317 39.1053 2.4014 1.0599 2.6969 0.5719 2.8244 13.6525 1.2452 20.7711 9.7698
Term PE 815þ6 0.4791 1.0883 9.4549 0.1044 1.0406 0.6782 3.6574 5.5440 11.4307 0.7475 6.0523 8.2593
Term PE 1619þ6 0.9524 0.8641 5.3363 0.3179 0.3441 0.9265 0.6988 0.7248 0.4748 1.6705 9.4922 28.9287
þ6
Term PE 2023 0.6793 0.9850 11.3022 0.2998 0.6077 0.7387 8.1010 5.1591 9.5779 0.2446 26.2442 41.9978
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Term PE 2427 0.3426 1.1008 9.9902 0.0136 0.5245 1.0688 0.3492 0.8826 9.9709 0.3422 1.8160 0.3052
þ6
Term PE 2831 0.4737 1.0454 6.4453 0.6336 0.5831 0.2541 2.6886 1.5020 7.4780 1.7555 13.9164 9.3967

OBSTETRICS
Term PE 3236þ6 1.0696 0.9676 17.4767 0.6302 0.6427 0.1030 1.6573 1.0419 26.5962 1.2727 8.5001 19.3735
Concentrations of chemical biomarkers and MAP are first converted into MoM values using models in Supplemental Table 2 and then log10 transformed before use as inputs in the models above. Using the same example as in legend of Supplemental Table 1 (prior
risk¼0.41) for which MAP and biochemical markers are determined at 28 weeks of gestation, with PlGF MoM¼0.6, whereas MoM values of MAP, sVEGFR-1 and sEng are all 1.0 (ie, log10 MoM¼0.0 for these 3 predictors), the combined-risk of any PE: risk¼exp
[0.8269þ0.872log(0.41)1.303log10(0.6)]¼0.268. Note this risk value is greater than the cutoff (0.075) shown in Table 2 for all PE at 28e31þ6 weeks, so the patient will be considered at risk.
MAP, mean arterial pressure; MoM, multiple of the mean; PE, preeclampsia; P1GF, placental growth factor; sEng, soluble endoglin; sVEGFR-1, soluble vascular endothelial growth factor receptor-1.
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SUPPLEMENTAL TABLE 4
Comparison of the FMF preeclampsia risk models to those derived in this study
FMF This study
P value for difference
for combined-risk
AUC Sensitivity AUC Sensitivity models
GA (wk) FPR FPR
Prior risk Combined risk FPR 10% FPR 20% Prior risk Combined risk FPR 10% FPR 20% AUC 10% 20%
11e14þ1 0.69 (0.59e0.79) 0.69 (0.6e0.79) 0.36 (0.22e0.52) 0.55 (0.39e0.7) 0.71 (0.61e0.8) 0.73 (0.64e0.81) 0.48 (0.32e0.63) 0.55 (0.39e0.7) 0.24 0.059 1

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19e25 0.67 (0.62e0.73) 0.72 (0.67e0.77) 0.36 (0.28e0.45) 0.48 (0.39e0.57) 0.68 (0.62e0.73) 0.76 (0.71e0.81) 0.43 (0.34e0.52) 0.56 (0.47e0.65) 0.002 0.045 0.025
30e35 0.66 (0.61e0.72) 0.74 (0.68e0.79) 0.46 (0.37e0.55) 0.52 (0.43e0.62) 0.66 (0.61e0.72) 0.81 (0.76e0.85) 0.53 (0.44e0.62) 0.65 (0.56e0.73) 0.0001 0.08 0.0027
35e38 0.70 (0.59e0.81) 0.83 (0.76e0.91) 0.53 (0.35e0.71) 0.62 (0.44e0.79) 0.74 (0.65e0.83) 0.87 (0.81e0.94) 0.66 (0.47e0.81) 0.75 (0.57e0.89) 0.101 0.045 0.0455
AUC and sensitivities at 10% and 20% FPR obtained with the bulk calculator from https://fetalmedicine.org/ and those obtained in this study. For this analysis, the models in Supplemental Table 3 were modified to exclude the contribution of sEng which is not used in
FMF models. FMF models utilized a combination of maternal factors and clinical history (same as in Supplemental Table 1), MAP, and PlGF. For analyses based on data collected after 25 weeks, sVEGFR-1 was also included. P values represent 2-tailed McNemar tests
for differences in paired sensitivities.
AUC, area under the receiver operating characteristic curve; FMF, Fetal Medicine Foundation; GA, gestational age; MAP, mean arterial pressure; PlGF, placental growth factor; sEng, soluble endoglin; sVEGFR-1, soluble vascular endothelial growth factor receptor-1.
Tarca et al. Prediction of preeclampsia throughout pregnancy. Am J Obstet Gynecol 2021.

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