Original Research ajog.

org

OBSTETRICS
A new model for screening for early-onset preeclampsia
Bernat Serra, MD1; Manel Mendoza, MD, PhD1; Elena Scazzocchio, MD, PhD; Eva Meler, MD, PhD; Martí Nolla;
Enric Sabrià, MD; Ignacio Rodríguez, MD; Elena Carreras, MD, PhD

BACKGROUND: Early identification of women with an increased risk
for preeclampsia is of utmost importance to minimize adverse perinatal
events. Models developed until now (mainly multiparametric algorithms)
are thought to be overfitted to the derivation population, which may affect
their reliability when applied to other populations. Options allowing
adaptation to a variety of populations are needed.
OBJECTIVE: The objective of the study was to assess the performance
of a first-trimester multivariate Gaussian distribution model including
maternal characteristics and biophysical/biochemical parameters for
screening of early-onset preeclampsia (delivery <34 weeks of gestation)
in a routine care low-risk setting.
STUDY DESIGN: Early-onset preeclampsia screening was under-
taken in a prospective cohort of singleton pregnancies undergoing
routine first-trimester screening (8 weeks 0/7 days to 13 weeks 6/7
days of gestation), mainly using a 2-step scheme, at 2 hospitals
from March 2014 to September 2017. A multivariate Gaussian
distribution model including maternal characteristics (a priori risk),
serum pregnancy-associated plasma protein-A and placental growth
factor assessed at 8 weeks 0/7 days to 13 weeks 6/7 days and
mean arterial pressure and uterine artery pulsatility index measured
at 11.0e13.6 weeks was used.
RESULTS: A total of 7908 pregnancies underwent examination, of
which 6893 were included in the analysis. Incidence of global pre-
eclampsia was 2.3% (n ¼ 161), while of early-onset preeclampsia was
0.2% (n ¼ 17). The combination of maternal characteristics, biophysical
parameters, and placental growth factor showed the best detection rate,
which was 59% for a 5% false-positive rate and 94% for a 10% false-
positive rate (area under the curve, 0.96, 95% confidence interval,
0.94e0.98). The addition of placental growth factor to biophysical
markers significantly improved the detection rate from 59% to 94%.
CONCLUSION: The multivariate Gaussian distribution model including
maternal factors, early placental growth factor determination (at 8 weeks
0/7 days to 13 weeks 6/7 days), and biophysical variables (mean arterial
pressure and uterine artery pulsatility index) at 11 weeks 0/7 days to 13
weeks 6/7 days is a feasible tool for early-onset preeclampsia screening in
the routine care setting. Performance of this model should be compared
with predicting models based on regression analysis.
Key words: aspirin, biomarkers, early-onset preeclampsia, first-trimester
screening, Gaussian model, mean arterial pressure, placental growth factor,
preeclampsia, pregnancy, pregnancy associated plasmatic protein-A, pre-
vention, prospective cohort study, uterine artery pulsatility index

P reeclampsia (PE), a disorder that

complicates 2e8% of pregnancies,
is a leading cause of maternal and
neonatal morbidity and mortality.1e3
Early-onset PE (ie, PE requiring de-
livery before 34 weeks of gestation) is
associated with an increased risk of both
short- and long-term maternal compli-
cations and perinatal mortality and
morbidity.4e8 Early identification of
women at increased risk for PE is of
utmost importance to minimize adverse
perinatal events by both closer moni-
toring and pharmacological intervention
Cite this article as: Serra B, Mendoza M, Scazzocchio E,
et al. A new model for screening for early-onset pre-
eclampsia. Am J Obstet Gynecol 2020;222:608.e1-18.
0002-9378
ª 2020 The Author(s). Published by Elsevier Inc. This is an
open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.ajog.2020.01.020
Click Supplemental Materials and
Video under article title in Contents at
early in pregnancy (ie, low-dose aspirin
16 weeks of gestation).9e17
Several screening models have been
developed to identify pregnancies at high
risk for PE at 11e13 weeks of
gestation.18e22 These are mainly multi-
parametric algorithms derived from lo-
gistic regression analysis combining
maternal characteristics and medical and
obstetric history (the so-called a priori
risk) with a series of biophysical and
biochemical markers (expressed as mul-
tiples of gestational ageespecific multi-
ples of the median [MoMs] and log-10
transformed to make their distribution
Gaussian) using their likelihood ratios
(LR) or regression coefficients to obtain a
patient-specific a posteriori risk for PE.23
Although these multiparametric algo-
rithms have shown high sensitivity for the
prediction of PE, they have shown a
poorer performance when applied to
populations other than the population
from which they were derived.24
A systematic review of 96 models for
prediction of PE conducted in 2015 has
shown that only 5 had been validated
externally, in general with lower predic-
tion performances than those reported
in the derivation populations.18
Different external validation studies
have also supported this finding.20,25e27
Multivariate Gaussian distribution
models are widely used in first-trimester
aneuploidy screening. These risk models
have been refined over 3 decades and,
moreover, share some of the markers
included in PE screening.24 In our area,
first-trimester aneuploidy screening is
commonly performed using a 2-step
scheme. On the contrary, first-trimester
preeclampsia screening models are
mainly derived from logistic regression
analysis and are available only in a 1-step
scheme.
One characteristic of multivariate
Gaussian distribution models is the use
of specific population medians to
calculate the MoMs of each marker.
MoMs are generally calculated from
locally derived normal medians, based
on regression curves, rather than

608.e1 American Journal of Obstetrics & Gynecology JUNE 2020

ajog.org OBSTETRICS Original Research

length at 8 weeks 0/7 days to 13 weeks

AJOG at a Glance 6/7 days.32 All procedures (measure-
Why was this study conducted? ments, data recording) were made ac-
Models developed until now (mainly multiparametric algorithms) have shown a cording to the routine clinical practice.
poorer performance when applied to populations other than the population from For this reason, women receiving low-
which they were derived. Options allowing adaptation to a variety of populations dose aspirin according to current clin-
are needed. ical guidelines during the study period
were not excluded.
Key findings A total of 164 women (2.4%) took
The multivariate Gaussian distribution model including maternal factors, bio- low-dose aspirin (100 mg/d). In-
physical variables (mean arterial pressure and uterine artery pulsatility index) at dications were impaired uterine Doppler
11 weeks 0/7days to 13 weeks 6/7 days and early placental growth factor deter- (mean uterine artery pulsatility index
mination (at 8 weeks 0/7 days to 13 weeks 6/7 days) is a feasible tool for early- [UtA-PI] >95th percentile), previous
onset preeclampsia screening in the routine care setting in general population, PE, chronic hypertension, thrombo-
with a detection rate of 94.1% for a 10% false-positive rate. philia, painful uterine fibroids, or a his-
tory of recurrent first-trimester
What does this add to what is known? pregnancy losses. Of these, 111 (1.6% of
A new approach for the screening of early-onset preeclampsia in a general the total population) started low-dose
population, potentially allowing adaptation to a variety of populations, is pre- aspirin before the 16th week of gesta-
sented. Early determination of placental growth factor, assessed as soon as 8 tion. Three women of the 17 developing
weeks of gestation, increased test performance. early-onset PE took low-dose aspirin, in
all cases starting after 16 weeks of
gestation.
published medians. Sample handling, plus biophysical and biochemical bio-
gestational dating, and population fac- markers assessed during the first Predictive variables
tors can contribute to normal medians, trimester of pregnancy in singleton Maternal characteristics and medical
and the local values are therefore most pregnancies being referred for aneuploidy and obstetric history were recorded at
appropriate.24 screening at 2 centers in Barcelona, Spain. the early first-trimester ultrasound via a
Multivariate Gaussian distribution patient questionnaire. The following
models combine the use of these local Materials and Methods maternal characteristics were recorded:
characteristics with the knowledge Study population age; height (centimeters); weight (kilo-
accumulated from different sources, This was a prospective cohort study of grams); ethnicity (white European,
chosen depending on the best quality general population singleton pregnan- South American, black, Asian, and
available information. For instance, in cies in women 18 years of age per- others); smoking during pregnancy (yes/
this model prior risk estimation has been formed concurrently with their routine no); and method of conception (sponta-
developed using information from a first-trimester aneuploidy screening (8 neous/assisted reproductive technology).
meta-analysis28 and wide prospective weeks 0/7 days to 13 weeks 6/7 days Medical history variables included the
study,29 while posterior risk estimates weeks of gestation) at the Dexeus Uni- presence of chronic hypertension, dia-
and correlations are based on other wide versity Hospital (Barcelona, Spain) from betes mellitus, renal disease, autoimmune
prospective studies.23,30 March 2014 to May 2016 and at the Vall disease, and acquired or congenital
Some studies have demonstrated that d’Hebron University Hospital (Barce- thrombophilic conditions. Obstetric his-
both approaches have similar perfor- lona, Spain) from October 2015 to tory variables included parity (nullipa-
mances predicting preeclampsia.31 Pro- September 2017. rous, defined as no previous deliveries
spective studies are needed to evaluate Pregnancies with aneuploidies, major before 24 weeks vs multiparous) and a
the performance of multivariate fetal abnormalities, or ending in termi- history of PE or intrauterine growth
Gaussian models to predict PE. Our nation, miscarriage or fetal death before restriction.
reason for using the multivariate 24 weeks of gestation were excluded. The Blood pressure (BP) was measured at
Gaussian distribution models is to apply Ethics Committee for Clinical Research 11 weeks 0/7 days to 13 weeks 6/7 days by
the knowledge obtained from Down of the Quirón Hospital Group (Barce- a nurse with a calibrated OMRON M6
syndrome screening in first-trimester to lona) and Vall d’Hebron Hospital (OMRON Health Care Europe, BV,
preeclampsia screening. approved the study protocol, and each Hoofddorp, The Netherlands) device in
The objective of this study was to patient provided written informed the Dexeus cohort and by a Microlife
evaluate the performance for the consent. watch BPR home device in the Vall
screening of early-onset PE of a multi- Following the hospital protocol, the d’Hebron cohort, randomly in the right
variate Gaussian distribution model that gestational age of all pregnancies was or left arm after a 5 min rest in the seated
includes maternal variables and history calculated based on the crown-rump position.

JUNE 2020 American Journal of Obstetrics & Gynecology 608.e2

Original Research OBSTETRICS
TABLE 1
Epidemiological and clinical characteristics and the biophysical and biochemical predicting variables of the study
population according to the centers of origin
Variable
Age, y, median (IQR)a
BMI, kg/m2, median (IQR)a
a
CRL, mm, median (IQR)
Biophysical variables, median (IQR)
MAP, mm Hga
a
Mean UtA-PI
Biochemical variables, MoM, median (IQR)
PAPP-A, mU/La
PlGF, pg/mLa
BMI, body mass index; CRL, crown-rump length; IQR, interquartile range; MAP, mean arterial pressure; MoM, multiples of the median; PAPP-A, pregnancy-associated plasma protein-A;
PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index.
a
Indicates significative difference (P < .001).
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.
Mean arterial pressure (MAP) was
calculated as diastolic BPþ (systolic
BPediastolic BP)/3. Uterine artery
(UtA) Doppler evaluation was per-
formed transvaginally in the Dexeus
cohort and transabdominally in the
Vall d’Hebron cohort at 11 weeks 0/7
days to 13 weeks 6/7 days of gestation,
as described by Gomez et al33
and Martin et al.34 Bilateral uterine
pulsatility indices (PIs) were measured
and mean UtA-PI was calculated
as (right uterine PI plus left uterine
PI)/2.
Blood samples for biochemical
markers were drawn between 8 weeks 0/
7 days to 13 weeks 6/7 days of gestation.
Maternal serum pregnancy-associated
plasma protein-A (PAPP-A) was
measured using a Cobas analyzer
(Roche Diagnostics, Penzberg, Ger-
many). Placental growth factor (PlGF)
was measured with the Elecsys PlGF
immunoassay on a Modular Analytics
E170 for the Dexeus cohort and on a
Cobas 8000 modular analyzer for the
Vall d’Hebron cohort (both from Roche
Diagnostics), which have a measuring
range of 3e10,000 pg/mL. Table 1
shows the medians of the different
markers in both centers, whereas the
formulas describing the population-
608.e3 American Journal of Obstetrics & Gynecology JUNE 2020
Dexeus series (n ¼ 4253)
34.6 (32.0e37.0)
22.5 (21.0e25.0)
65.0 (60.0e70.0)
78.3 (74.0e83.0)
1.5 (1.0e2.0)
1.0
625.2 (382.0e1030)
1.0
26.1 (20.0e34.0)
specific median of each marker,
depending on the gestational age, are
summarized in Table 2.
Risk calculation methodology
The construction of a multivariate
Gaussian distribution model for pre-
eclampsia screening consists of 3 steps:
prior risk definition, MoM calculation,
and posterior risk definition.
1. Prior risk definition.
As with Down syndrome screening,
multivariate Gaussian distribution
models estimate a priori risk using the
incidence of early-onset PE and
maternal characteristics. Because we
did not have any information about the
distributions of preeclampsia risk fac-
tors in our population, these were
deducted from a wide meta-analysis.28
Consequently, the a priori risk, deter-
mined by the incidence in our popula-
tion and expressed as an odds (Risk ¼
Odds
1þOdds) is then adjusted to maternal age,
ethnicity, parity, chronic hypertension,
and a personal history of preeclampsia
(Table 3) summarizes the factors that
have been used and Figures 1e4 reflect
the origin of their respective positive
and negative LRs).
ajog.org
Vall Hebron series (n ¼ 2640)
32 (28.0e36.0)
23.8 (21.0e28.0)
62.3 (57.0e68.0)
84.3 (79.0e91.0)
1.7 (1.0e2.0)
1.1
1358.0 (820.0e2370.0)
0.96
32.1 (24.0e43.0)
2. MoM calculation
Values of markers used for first-
trimester preeclampsia screening, as it
happens with markers used for aneu-
ploidy screening, change with gesta-
tional age in unaffected pregnancies,35
Therefore, it is routine practice to
transform their value to MoMs.
Marker’s MoMs are calculated dividing
the observed marker value by the
population median at the gestational
age in which the marker was deter-
mined. We defined an equation for
each marker median specific for each
center (see Table 2). Because each
center had a specific approach for
assessing mean UtA-PI, we described a
mean UtA-PI median equation specific
for a transvaginal and transabdominal
approach. Marker’s MoM adjustment
for covariables, such as adiposity, race,
and smoking habit, was also performed
using published data.24
3. Posterior risk definition
After logarithmic transformation, the
distribution of markers’ MoMs follows
an approximately normal (or Gaussian)
distribution, defined by their mean (0 in
unaffected pregnancies) and standard
ajog.org OBSTETRICS Original Research

deviation. LRs describe the relation of

each marker distribution between
affected and unaffected pregnancies in

F(X) ¼ 53243.8599014282 e 2918.3001203537X þ 59.5551365018X2 e

the study population (Supplemental
Tables 1e3). LRs are also modified by

F(X) ¼ 1570.5725966003 e 84.6766837146X þ 1.0844319881X2

the correlation coefficients between
markers within affected and unaffected
pregnancies. Gaussian modeling to
2
derive LRs was performed according to

2
F(X) ¼ e e 0.2770167911 þ 0.071084585X e 0.0002556448X

F(X) ¼ ee1.1071984908 þ 0.0874913975X e 0.0003475053X

the formula published by Reynolds and
2

2
F(X) ¼ e5.4754050872 e 0.023816328X þ 0.0001304068X

F(X) ¼ e5.4754050872 e 0.023816328X þ 0.0001304068X

Penney in 1990.36 Gauss distributions
and correlation between these bio-
F(X) ¼ 4.1011982023 e 0.0288248094X

F(X) ¼ 3.7421260268 e 0.0232424965X markers in affected and nonaffected

populations were taken from Cuckle.24
0.541313332X3 þ 0.001909531X4 Posterior risk is then obtained modi-
fying the a priori odds by the LR of a
multimarker profile and transforming
MAP, mean arterial pressure; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index; X, gestational age in weeks.
the resulting odds to a risk. This consists
of the successive multiplication of each
maker’s log MoM with its LR.
As an example of the risk calcula-
Formula

tion methodology, we will consider a

real case of positive risk. This is a
second pregnancy (LR, 0.646) of a 41
year old (LR, 1.47) white (LR, 0.71)
80.48

80.48
1.47

1.62
58.8

53.3
2845.2

3882.7

women with previous preeclampsia

(LR, 6.256) and no hypertension his-
Medians of biophysical and biochemical markers and models used to derive them

13

tory (LR, 0.974). Estimating the prior

risk of early preeclampsia consists of
81.04

81.04
1.67

1.79
48.9

44.3
2109.5

2559.2

converting the incidence of early-onset

preeclampsia into odds and then
12

multiplying these odds by the positive

or negative LR of each risk factor,
1.88

1.95
82.6

39.7

82.6

35.5
1480.1

1635.6

depending on whether the risk factor

Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

is present or absent and finally

11

reconverting the resulting early-onset

preeclampsia prior odds to a risk.
2.08

2.11
85.4

31.3

85.4

27.5
956.9

960.4

With an incidence of early-onset

10

preeclampsia (0.5% ¼ 1:200), the early-

onset preeclampsia prior risk of this
24.2

20.6
540.1

492.3

patient resulted 1:49 from: odds ¼

—
—

—
—
9

probability to be ill/probability to be
healthy ¼ p/(1-p) ¼ 0.005/(1e0.005) ¼
Weeks

229.5

299.9
18.2

14.9

0.005025. Subsequently, the early-onset

—
—

—
—
8

PE prior odds is calculated multipliying

the odds *LR1*LR2.*LRn, where n
Mean UtA-PI (transabdominal)

corresponds to the number of early-

Mean UtA-PI (transvaginal)

onset preeclampsia risk factors. There-

fore: early-onset PE prior odds ¼
0.005025 * 0.646 * 1.47 * 0.71* 6.256
Vall Hebron series

¼
PAPP-A, mIU/L

PAPP-A, mIU/L

*0.974 0.02064429. because

PlGF, pg/mL

PlGF, pg/mL

probability ¼ odds/(1 þ odds), the early-

Dexeus series

onset PE prior risk ¼ 0.02064429/

TABLE 2

Variable

MAP

MAP

(1 þ 0.02064429) ¼ 0.020226723 ¼ 1:49.

On the other hand, gestational age at
screening date was 13 weeks plus 3 days

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Original Research
TABLE 3
Risk factors modifying a priori risk deducted from meta-analysis
Risk factor
Nulliparous
Maternal age >40 years
Previous preeclampsia
Chronic hypertension
Afro-Caribbeana
CI, confidence interval; NLR, negative likelihood ratio; PLR, positive likelihood ratio.
a
Afro-Caribbean risk factor was obtained from Wright et al.29
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.
and the value of PAPP-A was 2.621 mU/L
(0.565 MoM), PLGF, 6.07 pg/mL (0.106
MoM), MAP, 85 mm Hg (1.058 MoM),
and UtA-PI, 1.87 (1.122 MoM).
The early-onset PE posterior odds
¼ early-onset PE prior odds
 LRmultimarker :
Given a known marker, the likeli-
hood ratio is the ratio of heights of the
Gaussian distribution of this marker for
affected and unaffected pregnancies.
However, when using multiple contin-
uous markers, we obtain a multimarker
likelihood ratio with matrix algebra.
This likelihood ratio is derived from the
division of the probability density
function of affected with the one
of unaffected populations (see
Supplemental Tables 1e3). In this case,
the multimarker likelihood ratio corre-
sponded to 4.546. Consequently, odds,
probability, and risk for early-onset PE
were:
Early-onset PE posterior odds
¼ 0:02064429  4:546 ¼ 0:0938:
Early-onset PE posterior probability
¼ 0:0938=ð1 þ 0:0938Þ ¼ 0:0858:
Early-onset PE posterior risk
¼ 1=0:0858 ¼ 1:12:
This patient developed early-onset
preeclampsia and delivered at 27 weeks
4/7 days.
608.e5 American Journal of Obstetrics & Gynecology JUNE 2020
OBSTETRICS
Negative
Positive likelihood
likelihood ratio 95% CI, PLR ratio
1.43 1.36e1.50 0.646
1.47 1.17e1.85 0.917
6.26 5.02e7.80 0.642
5.55 4.26e7.24 0.974
2.52 2.22e2.85 0.710
Differences between multivariate
Gaussian distribution models and
regression models
Multivariate Gaussian distribution
models are constructed using different
sources (previous knowledge, specific
population marker medians, risk factor
meta-analysis, and published literature).
Contrarily, in models that use regression
analysis, all data derive exclusively from
the study population and thus lose reli-
ability when applied to other pop-
ulations (model overfit).
Outcome measures
PE was defined in accordance with the
American College of Obstetricians and
Gynecologists as systolic BP 140 mm
Hg and/or diastolic BP 90 mm Hg on
at least 2 occasions 4 hours apart,
developing from 20 weeks of gestation
onward in previously normotensive
women and proteinuria 300 mg in a 24
hour urine specimen. In the absence of
proteinuria, it was considered the new
onset of hypertension with new onset of
any of the following37:
 Trombocitopenia: platelet count
<100,000/mL.
 Renal insufficiency: serum creatinine
concentration greater than 1.1 g/dL or
doubling the serum creatinine con-
centration in the absence of other
renal disease.
 Impared liver function: elevated con-
centrations of liver transaminases to
twice normal concentration.
ajog.org
Number Number
95% CI, NLR of studies of patients
0.59e0.71 25 2,975,158
0.84e1.01 16 4,260,202
0.49e0.84 20 3,720,885
0.94e1.01 20 6,589,661
0.65e0.77 1 120,492
 Pulmonary edema.
 Cerebral or visual symptoms.
PE superimposed on chronic hyper-
tension was defined as significant pro-
teinuria after 20 weeks of gestation in
women with known chronic hyperten-
sion diagnosed before pregnancy or
before 20 weeks of gestation. In this study
we focused on the risk of developing
early-onset PE, defined as PE requiring
delivery <34 weeks,38 which is the severe
subtype of preeclampsia. Preterm pre-
eclampsia (<37 weeks of pregnancy) can
be prevented by administering low-dose
aspirin to women classified as high risk
by multiparametric algorithms. The ob-
stetric records of women with preexisting
or pregnancy-associated hypertension
were examined to determine whether
the condition was chronic hypertension,
PE, or gestational hypertension.
Statistical analysis
The Pearson c2 test and the Mann-
Whitney U test were used to compare
qualitative and quantitative variables,
respectively.
The risks for the multivariate
Gaussian distribution model were
computed using SsdwLab6 version 6.1
package (SBP Soft 2007 S.L.), a prenatal
screening program calculating the risk
for aneuploidy and PE. Receiver-
operating characteristic (ROC) curves
were constructed to analyze the model
performance, which was expressed as
detection rates (DR) for different cutoffs
of false-positive rates (FPRs). All
ajog.org OBSTETRICS Original Research

FIGURE 1
Meta-analysis forest plots for PLR and NLR for nulliparity

Meta-analysis forest plots for positive and negative likelihood ratio for nulliparity as risk factor for preeclampsia. Adapted from Bartsch et al.28
NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

JUNE 2020 American Journal of Obstetrics & Gynecology 608.e6

Original Research OBSTETRICS ajog.org

FIGURE 2
Meta-analysis forest plots for PLR and NLR for maternal age >40

Meta-analysis forest plots for positive and negative likelihood ratio for maternal age older than 40 years as risk factor for preeclampsia. Adapted from
Bartsch et al.28
NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

statistical analyses were performed using
the open source, freely available R sta-
tistical software (R version 3.1.1). Paired
area under the curve (AUC) comparison
and meta-analysis were performed using
the pROC R and meta R add-on pack-
ages, respectively.39e41 A value of P <.05
was considered statistically significant.
Results
Screened population
A total of 7908 pregnancies were
consecutively screened. Of these, 1015
(12.8%) were excluded for the
following reasons (nonexclusively):
missing outcome (n ¼ 932), major
fetal defects or chromosomopathies
(n ¼ 39), miscarriage or fetal death
before 24 weeks (n ¼ 42), and termi-
nation of pregnancy for any other
reason (n ¼ 2). Patients with missing
outcome were mainly those who after
having the screening procedure done
decided to have the follow-up of their
pregnancies and/or the delivery in

608.e7 American Journal of Obstetrics & Gynecology JUNE 2020

ajog.org OBSTETRICS Original Research

FIGURE 3
Meta-analysis forest plots for PLR and NLR for previous preeclampsia

Meta-analysis forest plots for positive and negative likelihood ratio for previous preeclampsia as risk factor for preeclampsia. Adapted from Bartsch
et al.28
NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

other hospitals. A total of 6893 preg- Biochemical assessments were per- women (83.2%) and 1155 (16.8%) at
nancies were finally included in the formed at 8 weeks 0/7 days to 10 11 weeks 0/7 days to 13 weeks 6/7 days
analysis. weeks 6/7 days of gestation in 5738 of gestation in the rest. This latter

JUNE 2020 American Journal of Obstetrics & Gynecology 608.e8

Original Research OBSTETRICS ajog.org

FIGURE 4
Meta-analysis forest plots for PLR and NLR for chronic hypertension

Meta-analysis forest plots for positive and negative likelihood ratio for chronic hypertension as risk factor for preeclampsia. Adapted from Bartsch et al.28
NLR, negative likelihood ratio; PLR, positive likelihood ratio.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

group corresponds to women who had markers assessed the same day as the accounted for 36.8% of the cases,
their first visit at these weeks of ultrasound was performed. In the Vall compared with 4% of the Dexeus
pregnancy and had biochemical d’Hebron cohort, these women cohort. Incidence of PE was 2.3%

608.e9 American Journal of Obstetrics & Gynecology JUNE 2020

ajog.org
(n ¼ 161), with 0.2% cases (n ¼ 17)
of early-onset PE.
Table 4 shows the epidemiological
and clinical characteristics and the
biophysical and biochemical predicting
variables of the study population ac-
cording to the study groups. MAP and
mean UtA-PI were significantly higher
in early-onset PE compared with un-
affected pregnancies, while PlGF MoM
was significantly lower (P < .001 for
both).
Test performance
Table 5 shows the DR for early-onset PE
of each individual predictor and their
combinations. Highest DR at 5% and
10% FPR for a priori risk adding a single
biomarker was found with UtA-PI
(47.1% and 58.8%, respectively). The
addition of PAPP-A to the combination
of a priori risk plus biophysical markers
(MAP plus mean UtA-PI) did not
improve test performance, while the
addition of PlGF did it significantly: it
increased the DR for a 10% FPR from
58.8% to 94.1% and the AUC from 0.934
to 0.963 (P ¼ .011) (Figure 5).
Furthermore, as shown in Figure 6,
the addition of PlGF to the combina-
tion of maternal characteristics plus
MAP plus mean UtA-PI plus PAPP-A
significantly increased the AUC from
0.936 to 0.958 (P ¼ .037), with detec-
tion rates of 58.8% (95% confidence
interval [CI], 32.9e81.6) and 94.1%
(95% CI, 71.3e99.85) for a 5% and
10% false-positive rate, respectively.
Table 6 shows the detection rate and
positive and negative predictive values
with their 95% CI of this last
combination.
Because studies with few cases may
produce overoptimistic performance
estimates, we applied shrinkage estima-
tion methodology.42 The corrected
detection rates were 52.9% and 82.4%
for a 5% and 10% false-positive rate,
respectively (AUC, 0.95, 95% CI
0.92e0.98).
Comment
Principal findings
The results of our prospective study
support the effectiveness of a multivar-
iate Gaussian distribution model
OBSTETRICS
combining maternal characteristics and
history with biophysical (mean arterial
pressure and mean uterine artery pul-
satility index) and biochemical markers
for the prediction of early-onset pre-
eclampsia in a Mediterranean popula-
tion, characterized by having a low a
priori risk43 in a routine clinical care.
With regard to the tested biochemical
markers, (PlGF and PAPP-A), only the
addition of PlGF improved the perfor-
mance of the model.
The detection rate of our model was
94.1% for a 10% false positive rate in
a population in which the incidence of
early-onset PE was as low as 0.2%.
Detection rates of 2 multiparametric
algorithms derived from populations
of our same city, which included
populations similar to the one
included in this study (ie, Mediterra-
nean populations, characterized by
having a low a priori risk), are slightly
lower.
The model developed by Scazzocchio
et al,44 which included maternal factors,
mean arterial pressure, mean uterine
artery-PI, and PAPP-A, achieved
detection rates of 69% and 81% for 5%
and 10% false-positive rates, respec-
tively, with a recently published internal
validation study having reported similar
figures.45 Detection rates reported by
the same group46 using maternal fac-
tors, mean arterial pressure, uterine
artery-PI, and PlGF in another multi-
parametric algorithm were 82% and
89% for 5% and 10% false-positive rate,
respectively.
The greater detection rate of the
multivariate Gaussian distribution
model used in our study should, how-
ever, be interpreted with caution, given
the main limitation of our study: the
low number of events (17 cases of early-
onset PE). This limitation, which is
common to most published models,
may be in our case mostly due to the low
incidence of PE in our population,
which was even lower than the inci-
dence reported in the previously
mentioned studies conducted in our
geographical area (0.5e0.7%).44e46
The lower incidence in our series
may be influenced by the fact that
treatment with low-dose aspirin was
JUNE 2020 American Journal of Obstetrics & Gynecology
Original Research
allowed on the basis of the hospital’s
current clinical guidelines during the
study. In fact, 111 women (1.61% of
the total population) received low-
dose aspirin starting before week 16,
which has shown to reduce the inci-
dence of PE.9e11
In a recently published study per-
formed on a population with a 4 times
higher incidence of early preeclampsia
(1.22%), the authors obtained a detec-
tion rate of 85% for both 5% and 10%
false-positive rates.22 But the results of
this study may be skewed by the small
sample size and the high prevalence of
chronic hypertension in the studied
population.
Before the study, we have used only
the study data for testing the adequate
adjustment of available marker local
medians equations or constructing
new ones when no local median
equation for specific marker was
available. The use of local specific
marker medians obtains better pre-
diction performance.24,47,48
Results of the study in context of
what is already known
We did not observe any benefit of the
addition of PAPP-A in the model,
although these results can be caused by
the low incidence of early-onset pre-
eclampsia in this study. This is inter-
esting because, according to logistic
regression analysis, PAPP-A assessed at
11e13 weeks of pregnancy has been
shown to contribute to the prediction
of early-onset preeclampsia,49 and as
such it has been introduced in first-
prediction models (multiparametric
algorithms).
The weak association of PAPP-A
with preeclampsia has also been re-
ported by Scazzocchio et al.44 It should
be noted, however, that in this latter
study and in ours, the biochemical
component of screening was performed
at 8 weeks 0/7 days to 10 weeks 6/7
days of gestation in a high percentage
of women (70% in the study by Scaz-
zocchio et al, 83.2% in our study),
when women have the hospital visit for
aneuploidy assessment in our environ-
ment, which may have contributed to
the weak association.
608.e10
Original Research OBSTETRICS ajog.org

TABLE 4
Epidemiological and clinical characteristics and the biophysical and biochemical predicting variables of the study
population according to study groups
Variable Early-onset PE (n ¼ 17) Late-onset PE (n ¼ 144) No PE (n ¼ 6732)
Age, y, median (IQR) 34.0 (32.5e37.0) 35.0 (32.0e38.0) 33.9 (30.4e37.0)
2
BMI, kg/m , median (IQR) 23.1 (222.5e27.5) 24.8 (22.7e30.5) 22.9 (20.9e25.8)
Ethnicity, n (%)
White European 15 (88.2) 127 (88.2) 6133 (91.1)
South American 2 (11.8) 11 (7.6) 331 (4.9)
Black 0 (0) 2 (1.4) 84 (1.2)
Asian 0 (0) 3 (2.1) 150 (2.2)
North African 0 (0) 0 (0) 7 (0.1)
Other 0 (0) 1 (0.7) 27 (0.4)
Smoking habit, yes, n (%) 1 (5.9) 18 (12.5) 628 (9.3)
Assisted reproductive technologies, n (%) 1 (5.9) 21 (14.6) 544 (8.1)
Medical history, n (%)
Chronic hypertension 3 (17.6) 8 (5.6) 42 (0.6)
Diabetes mellitus 0 (0) 4 (2.8) 47 (0.7)
Renal disease 0 (0) 1 (0.7) 7 (0.1)
Autoimmune disease 0 (0) 6 (4.2) 236 (3.5)
Coagulation disorders 0 (0) 2 (1.4) 89 (1.3)
Obstetric history, n (%)
Nulliparous 8 (47.1) 93 (64.6) 3630 (53.9)
Previous PE 2 (11.8) 13 (9.0) 56 (0.8)
CRL, mm, median (IQR) 62.4 (59.9e71.2) 61.5 (57.0e68.0) 64.0 (58.7e69.7)
Biophysical variables, median (IQR)
MAP, mm Hga 94.3 (85.0e99.7) 89.0 (81.7e95.3) 80.0 (75.0e86.0)
a
Mean UtA-PI 2.1 (1.9e2.5) 1.6 (1.3e2.1) 1.5 (1.3e1.9)
Biochemical variables, MoM, median (IQR)
PAPP-A, mU/La .71 .91 1.03
890.0 (602e1669) 890 (482e1464) 830 (472e1470)
PlGF, pg/mLa .62 .91 1.0
19.5 (15.5e24.1) 26.5 (20.6e34.5) 28.1 (21.5e37.3)
BMI, body mass index; CRL, crown-rump Length; IQR, interquartile range; IUGR, intrauterine growth restriction; MAP, mean arterial pressure; MoM, multiples of the median; PAPP-A, pregnancy-
associated plasma protein-A; PE, preeclampsia; PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index.
a
Indicates significative difference (P < .001).
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

The fact that the predictive value of
PAPP-A for early-onset preeclampsia
seems to improve later at the end of the
first trimester contrasts with the value of
this biomarker in predicting trisomy 21,
which it is best at 9e10 weeks.50 How-
ever, because this marker is usually
included in aneuploidy screening, it adds
no cost to the preeclampsia screening
model and there is no reason for
excluding it from the model. On its turn,
PlGF increased the detection rate from
64.7% to 94.1% for a 10% false-positive
rate when added to the 2 biophysical
markers and PAPP-A.
Several reports have highlighted the
value of the addition of PlGF, a potent
angiogenic factor having an impact on
early placental vascular development
and whose levels are decreased in preg-
nancies with preeclampsia,51 to models
including maternal characteristics and
history and biophysical variables (mean
UtA-PI and/or MAP).46,49,52e54
Similarly, Crovetto et al46 reported an
increase of the detection rate for early-
onset preeclampsia from 80.7% to

608.e11 American Journal of Obstetrics & Gynecology JUNE 2020

ajog.org OBSTETRICS Original Research

89.5% for a 10% false-positive rate when

Detection rates, positive and negative predictive values, and positive and negative likelihood ratios for early-onset preeclampsia of each individual predictor

adding PlGF to the mean uterine artery-

AUC, area under the curve; CI, confidence interval; DR, detection rate; MAP, mean arterial pressure; NLR, negative likelihood ratio; NPV, negative predictive value; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; PLR, positive
10%
0.72
0.59
0.65
0.46
0.46
0.46
0.33
0.33
0.46
0.39
0.07
0.07
NLR for an
FPR of the
pulsatility index and mean arterial
following
pressure in a multiparametric algorithm

0.62
0.62
0.56

0.56

0.43
0.43
0.43
0.43
derived from logistic regression analysis.
5%
0.8

0.5

0.5
0.5
In our study, the addition of PlGF
increased the detection rate for early-
10%
3.53
4.72
4.11
5.87
5.89
5.86
7.06
7.04
5.87
6.46
9.41
9.41
onset preeclampsia of this markers
PLR for an
FPR of the
following

combination from 58.8% to 94.1%

4.72
8.18
8.25
9.46

9.35
10.46

10.49
10.61
11.72
11.76
11.76
11.69
for a 10% false-positive rate. It is
5%

noteworthy that in both, the Crovetto

study and ours, PlGF had a significant
FPR of the following

99.82%
99.85%
99.84%
99.89%
99.89%
99.89%
99.92%
99.92%
99.89%

99.98%
99.98%
NPV (95% CI) for an

effect on preeclampsia detection, even

99.9%
10%

though it was mainly assessed in early

first-trimester (8 weeks 0/7 days to 10
weeks 6/7 days of gestation). This is
99.85%
99.85%
99.86%
99.88%
99.86%
99.88%
99.88%
99.89%
99.89%
99.89%
99.89%
99.8%

especially interesting because the

5%

discriminatory accuracy of PlGF has

been reported to increase from 10 to
0.86%
1.15%
1.01%
1.43%
1.43%
1.43%
1.72%
1.71%
1.43%
1.57%
2.27%
2.27%
14 weeks of gestation when using a
PPV (95% CI) for

10%

multiparametric algorithm for pre-

an FPR of the

eclampsia detection in a low-risk

following

population.26 In our study, all PlGF

1.15%
1.98%

2.29%
2.52%
2.26%
2.53%
2.56%
2.82%
2.82%
2.82%
2.81%
5%

2%

measurements were performed in 2

laboratories using the modular ana-
lyzers (E170 and Cobas 8000, Roche
35.3%
47.1%
41.2%
58.8%
58.8%
58.8%
70.6%
70.6%
58.8%
64.7%
94.1%
94.1%
10%
DR (95% CI) for

Diagnostics), which are sensitive to

an FPR of the

values of PlGF as low as 3 pg/mL and

following

thus allowed measurement of PlGF in

23.5%
41.2%
41.2%
47.1%
52.3%
47.1%
52.9%
52.9%
58.8%
58.8%
58.8%
58.8%

all cases.
5%

Clinical implications
0.822 (0.73-0.91)
0.826 (0.73-0.92)

0.858 (0.79-0.93)
0.873 (0.85-0.97)
0.906 (0.84-0.96)
0.923 (0.89-0.96)
0.934 (0.90-0.97)
0.936 (0.90-0.97)
0.963 (0.95-0.98)
0.958 (0.94-0.98)
0.735 (0.6-0.87)

0.868 (0.8-0.94)

These results support the validity of a

AUC (95% CI)

strategy for preeclampsia screening in 2

Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

steps comparable and superimposable

with that performed for Down syn-
drome screening, with a blood sample
being obtained for PlGF and PAPP-A
likelihood ratio; PPV, positive predictive value; UtA-PI, uterine artery pulsatility index.
Screening variables, a priori risk plus the following factors

measurement at a gestational age of 8.0

to 10.6 weeks and the biophysical
markers measured at 11 weeks 0/7 days
to 13 weeks 6/7 days. The risk for early-
onset PE can be then calculated
MAP plus mean UtA-PI plus PlGF plus PAPP-A

instantly in this latter point, thus allow-

ing immediate intervention in terms of
MAP plus mean UtA-PI plus PAPP-A

low-dose aspirin prescription without

MAP plus mean UtA-PI plus PlGF

delay and without needing to call the

and their combinations

patient again.
Mean UtA-PI plus PAPP-A

And as the reason for performing

MAP plus mean UtA-PI
Mean UtA-PI plus PlGF

this predictive test is to decide whether

MAP plus PAPP-A

to initiate a preventive treatment of

MAP plus PlGF

preeclampsia in asymptomatic preg-

Mean UtA-PI
TABLE 5

nancies (low dose aspirin), a threshold

PAPP-A

upon which the test will be considered

MAP
PlGF

positive has to be defined. On deter-

mining the most appropriate test

JUNE 2020 American Journal of Obstetrics & Gynecology 608.e12

Original Research OBSTETRICS ajog.org

cutoff value, the cost of a false-

FIGURE 5
negative versus a false-positive result
ROC curves for early-onset PE prediction of multivariate Gaussian model
has to be balanced.
Because of its severity, in early-
onset preeclampsia the consequences
of a false-negative case are much
higher for the mother and fetus than
the overtreatment of a false-positive.
As in recent studies,11 we consider
that the cutoff value that offers this
balance is the one that corresponds to
a false-positive rate of 10%. Depend-
ing on the prevalence of early-onset
preeclampsia, this cutoff value will
vary in each population. In this study,
the false-positive rate of 10% corre-
sponds to a four-marker model (a
priori risk plus mean arterial pressure
plus mean uterine arteryepulsatility
index plus PlGF plus PAPP-A) risk of
1:244, considering a disease’s preva- Receiver operative characteristic curves for early-onset PE prediction of a multivariate Gaussian
lence of 0.2% and a baseline aspirin distribution model including a priori risk and biophysical markers with and without PlGF. The addition
treatment of 2.6%. of PlGF to the model significantly increases test performance (P value of AUC comparison). Sen-
The inclusion of PlGF when sitivities for the cutoff point that corresponds to a 10% false-positive rate are displayed.
screening for trisomy 21 has also AUC, area under the curve; PE, preeclampsia; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; ROC,
receiver operative characteristic.
shown to improve first-trimester
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.
screening for aneuploidies,55 although
the impact on the overall screening
performance is low and does not
justify the measurement of PlGF solely FIGURE 6
for trisomy 21 screening. Therefore, ROC curves for early-onset PE prediction of multivariate Gaussian model
inclusion of PlGF in PE screening
models may also benefit screening for
trisomy 21.

Research implications
We assessed the model in a large unse-
lected population in a routine clinical
care, but more studies are needed to
confirm these promising findings in
different populations.
As described in the Statistical anal-
ysis section, the Gauss distributions of
these biomarkers in affected and
nonaffected populations were taken
from Cuckle,24 but it would be inter-
esting to verify that these distributions
behave in the same way in other
populations. Otherwise, it would be
interesting to find out whether its Receiver operative characteristic curves for early-onset PE prediction of a multivariate Gaussian
adaptation to the population under distribution model including a priori risk and biophysical markers and PAPP-A with and without PlGF.
study would improve the performance The addition of PlGF to the model significantly increases test performance (P value of AUC com-
of the model. parison). Sensitivities for the cutoff point that corresponds to a 10% false-positive rate are displayed.
AUC, area under the curve; PE, preeclampsia; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; ROC,
A comparison with multiparametric receiver operative characteristic.
algorithms derived from logistic regres- Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.
sion analysis may also clarify whether its

608.e13 American Journal of Obstetrics & Gynecology JUNE 2020

ajog.org
TABLE 6
Detection rate and positive and negative predictive values for early-onset preeclampsia prediction of the combination
of MAP plus mean UtA-PI plus PlGF plus PAPP-A with their 95% CIs
Variables
Detection rate
Positive predictive value
Negative predictive value
The 95% confidence interval for the detection rate, positive predictive value, and negative predictive value corresponds to a 10% false-positive rate cutoff.
CI, confidence interval; MAP, mean arterial pressure; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.
value would benefit from local adapta-
tions of marker medians.
Strengths and limitations
The study was carried out in the context
of the usual clinical practice of 2 different
centers, a fact that reinforces the use-
fulness of the Gaussian method for the
prediction of preeclampsia in normal
medical practice. Previous algorithms
have been developed considering a single
approach to assess UtA Doppler (trans-
abdominal or transvaginal). This is the
first algorithm derived from a cohort of
patients in whom UtA-PI was obtained
using both approaches indistinctly,
rendering it more versatile for routine
clinical practice.
Furthermore, as far as we know, this is
the first study that supports the addition
of the early determination of PlGF (as
soon as 8 weeks of gestation) to the
screening of early-onset preeclampsia
using multivariate Gaussian distribution
model. This may be important in set-
tings in which Down syndrome
screening is usually performed using a 2
step scheme because performing both
screening procedures simultaneously
would ease the implementation of pre-
eclampsia screening.
In turn, as mentioned in the
Comment, the main limitation of the
study lies in the low rate of early pre-
eclampsia. This fact, despite the high
number of women recruited, has
conditioned a low number of cases.
Conclusions
The multivariate Gaussian distribution
model including maternal factors and
Estimate
94.12%
2.27%
99.98%
history, biophysical variables (MAP and
UtA-PI), and PlGF is a feasible tool for
early-onset PE screening in the routine
care setting, even in low risk pop-
ulations. Performance of this model
should be validated in different
populations. n Gynecol 2017;216:523.e1–7.
Acknowledgments
We thank Beatriz Viejo, PhD, freelance medical
writer, for writing and editorial assistance and
Raquel Mula, MD, and Marta Ricart, MD, for
reviewing medical records and Joan Nicolau,
MD, and Carmina Comas, PhD, for their sup-
port. This study has been carried out under the
auspices of the Càtedra d’Investigació en
Obstetrícia i Ginecologia of the Autonomous
University of Barcelona, Spain. Reagents for
PlGF determination were provided by Roche
Diagnostics, who had no influence on the study
design, the collection and analysis of data or the
interpretation of results. The views expressed
are therefore based on the opinions of the
authors.
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Author and article information
From the Department of Obstetrics, Gynecology, and
Reproductive Medicine, Dexeus University Hospital (Drs
Serra, Scazzocchio, Meler, and Rodrı́guez), and the
Department of Obstetrics and Reproductive Medicine,
Maternal-Fetal Medicine Unit, Hospital Universitari Vall
d’Hebron (Drs Mendoza, and Carreras), Universitat
Autònoma de Barcelona, Barcelona, Spain, Atenció a la
ajog.org OBSTETRICS Original Research

Salut Sexual I Reproductiva (ASSIR) de Barcelona, Institut
Català de la Salut (Drs Mendoza, Scazzocchio, and Car-
reras), Barcelona; the Fetal i + D Fetal Medicine Research
Center, BCNataleBarcelona Center for Maternal-Fetal
and Neonatal Medicine (Hospital Clı́nic and Hospital Sant
Joan de Deu), Institut d’Investigacions Biomèdiques
August Pi i Sunyer, Universitat de Barcelona (Dr Meler),
Barcelona; Epidemiology and Quality Controls, SBP Soft,
Girona (Mr Nolla); and the Department of Obstetrics and
Gynecology, HospitaleResidència Sant Camil (Consorci
Sanitari del Garraf), Sant Pere de Ribes (Dr Sabrià),
Barcelona, Spain.
1
Bernat Serra and Manel Mendoza contributed equally
to this work.
Received May 30, 2019; revised Nov. 17, 2019;
accepted Jan. 13, 2020.
This study was supported by Roche Diagnostics,
which provided the reagents used in the study for
placental growth factor determination. Roche Diagnostics
had no influence on the study design, the collection and
analysis of data, or the interpretation of results.
The authors report no conflict of interest.
Corresponding author: Bernat Serra, MD. berser@
dexeus.com

JUNE 2020 American Journal of Obstetrics & Gynecology 608.e16

Original Research OBSTETRICS ajog.org

Supplemental Material
Mathematical calculations for estimating the likelihood ratio of early-onset PE of multivariate normal distribution models1

Probability that the result is from an affected pregnancy ðʄaÞ

Likelihood ratio ¼
Probability that the result is from an unaffected pregnancy ðʄunÞ

Estimating the probability of affected and unaffected pregnancy of early-onset PE

The 2 probabilities should be calculated entering the appropriate population parameters and the log 10 MoM of each used
Gaussian marker to the formula [ʄa: affected and ʄun: unaffected]
Probability of affected or unaffected pregnancy of early-onset PE:

 1=2
f ðx1 ; :::xn Þ ¼ ð2pÞn=2 V 1 



exp  1 2 ðx  mÞt V 1 ðx  mÞ

where:
n ¼ number of markers used
x ¼ matrix of transformed sample values (MoM)
m ¼ matrix of transformed population means for unaffected or affected pregnancies
V ¼ matrix of correlation coefficients and standard deviations for unaffected or affected pregnancies
V 1 ¼ inverse matrix of V
V 1¼ determinant inverse matrix of V
T ¼ row vector
Population variables were used to estimate the probabilities of affected and unaffected pregnancies. MoM, multiple of the
median; PE, preeclampsia.
Serra. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.
References
1. Palomaki GE, Haddow JE. Maternal serum a-fetoprotein, age, and Down syndrome risk. Am J Obstet Gynecol 1987;156:460–3.
2. Cuckle HS. Screening for pre-eclampsia—lessons from aneuploidy screening. Placenta 2011;32(Suppl):S42–8.
3. Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, bio-
physical and biochemical markers at 11-13 weeks. Prenat Diagn 2011;31:66–74.

608.e17 American Journal of Obstetrics & Gynecology JUNE 2020

ajog.org OBSTETRICS Original Research

SUPPLEMENTAL TABLE 1
Means and standard deviations2
Variables PAPP-A PlGF MAP UtA-PI
Log 10 MoM means Unaffected 0 0 0 0
Early PE affected e0.236 e0.215 0.057 0.204
Standard deviations Unaffected 0.285 0.178 0.0386 0.126
Early PE affected 0.306 0.18 0.0372 0.0968
MAP, mean arterial pressure; MoM, multiples of the median; PE, preeclampsia; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

SUPPLEMENTAL TABLE 2
Correlations3 of unaffected women
Variables PAPP-A PlGF MAP UtA-PI
PAPP-A 1
PlGF 0.35 1
MAP e0.016 0.002 1
UtA-PI e0.154 e0.149 e0.047 1
MAP, mean arterial pressure; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

SUPPLEMENTAL TABLE 3
Correlations3 of early PE affected women
Variables PAPP-A PlGF MAP UtA-PI
PAPP-A 1
PlGF 0.399 1
MAP 0.21 e0.067 1
UtA-PI e0.094 0.074 e0.153 1
MAP, mean arterial pressure; PAPP-A, pregnancy-associated plasma protein-A; PlGF, placental growth factor; UtA-PI, uterine artery pulsatility index.
Serra et al. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020.

JUNE 2020 American Journal of Obstetrics & Gynecology 608.e18