Screening for pre-eclampsia at 11–13 weeks’ gestation:

use of PAPP-A, PlGF or both

A. Mazer Zumaeta,1 A. Wright,2 A. Syngelaki,1 V.-A. Maritsa,1 A.B. Da Silva,1

K.H. Nicolaides.1

1. Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London,
UK.
2. Institute of Health Research, University of Exeter, Exeter, UK.

Correspondence:
Professor KH Nicolaides,
Harris Birthright Research Centre for Fetal Medicine,
Fetal Medicine Research Institute,
King's College Hospital,
Denmark Hill, London SE5 8BB, UK.
email: kypros@fetalmedicine.com

Short title: Screening for pre-eclampsia

Keywords: Pregnancy associated plasma protein-A, Placental growth factor, First

trimester screening, Preeclampsia, Aspirin, ASPRE, SPREE, Pyramid of pregnancy care,
Competing risk model, Uterine artery Doppler, Mean arterial pressure.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1002/uog.22093

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Contribution

What are the novel findings of this work?

In first trimester screening for PE the risk cut-off and screen positive rates to achieve a
desired detection rate of PE varies according to the racial composition of the study
population and whether the biomarkers used for screening are MAP, UtA-PI and PLGF or
MAP, UtA-PI and PAPP-A.

What are the clinical implications of this work?

In first trimester screening for PE the preferred biochemical marker is PLGF rather than
PAPP-A. However, if PAPP-A was to be used rather than PLGF the same detection rate
can be achieved but at a higher screen positive rate.

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ABSTRACT

Objective: First-trimester screening for preeclampsia (PE) is useful because treatment of

the high-risk group with aspirin reduces the rate of early-PE with delivery at <34 weeks’
gestation by about 80% and preterm-PE with delivery at <37 weeks by 60%. In previous
studies we reported that the best way of identifying the high-risk group is by a
combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility
index (UtA-PI), and serum placental growth factor (PLGF). An alternative biochemical
marker is pregnancy associated plasma protein-A (PAPP-A), which is widely used as part
of early screening for trisomies. The objective of this study is to examine the additive
value of PLGF and PAPP-A in first-trimester screening for preterm-PE by maternal
factors, MAP and UtA-PI and define the risk cut-off and screen positive rates to achieve a
desired detection rate of PE if PAPP-A rather than PLGF was to be used for first-trimester
screening.

Methods: This is a non-intervention screening study. Patient-specific risks of delivery with

PE at <37 weeks’ gestation were calculated using the competing risks model to combine
the prior distribution of the gestational age at delivery with PE, obtained from maternal
characteristics and medical history, with multiple of the median (MoM) values of MAP,
UtA-PI, PLGF and PAPP-A. The performance of screening in the total population and in
subgroups of women of White and Black racial origin were estimated. McNemar’s test
was used to compare the detection rate, for a fixed screen positive rate, of screening with
and without PLGF and PAPP-A. Risk cut-offs and screen positive rates to achieve
desired detection rates of preterm-PE were determined in screening with and without
PLGF and PAPP-A.

Results: The study population was coposed of 60,875 singleton pregnancies, including
1,736 (2.9%) that developed PE. There are three main findings of this study. First, the
performance of first trimester screening for PE by a combination of maternal factors, MAP,
UtA-PI and PLGF is superior to that of screening by maternal factors, MAP, UtA-PI and

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PAPP-A; for example in screening by maternal factors, MAP, UtA-PI and PLGF, at a
screen positive rate of 10%, the detection rate of PE with delivery at <37 weeks’ gestation
was 74.1%, which was 7.1% (95% CI 3.8-10.6) higher than in screening by maternal
factors, MAP, UtA-PI and PAPP-A. Second, addition of serum PAPP-A does not improve
the prediction of PE provided by maternal factors, MAP, UtA-PI and PLGF. Third, the risk
cut-off and screen positive rates to achieve a given fixed detection rate of preterm PE
varies according to the racial composition of the study population and whether the
biomarkers used for screening are MAP, UtA-PI and PLGF or MAP, UtA-PI and PAPP-A.
For example, in screening by a combination of maternal factors, MAP, UtA-PI and PLGF
in White women if the desired detection rate of preterm-PE was 75% the risk cut-off
should be 1 in 136 and the screen positive rate would be 14.1%; in Black women to
achieve a detection rate of 75% the risk cut-off should be 1 in 29 and the screen positive
rate would be 12.5%. In screening by a combination of maternal factors, MAP, UtA-PI and
PAPP-A in White women if the desired detection rate of peterm-PE was 75% the risk
cut-off should be 1 in 140 and the screen positive rate would be 16.9%; in Black women
to achieve a detection rate of 75% the risk cut-off should be 1 in 44 and the screen
positive rate would be 19.3%.

Conclusion: In first trimester screening for PE the preferred biochemical marker is PLGF
rather than PAPP-A. However, if PAPP-A was to be used rather than PLGF the same
detection rate can be achieved but at a higher screen positive rate.

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INTRODUCTION

The ASPRE trial has shown that in pregnancies at high-risk for preeclampsia (PE)
administration of aspirin (150 mg/day from 11-14 weeks’ gestation to 36 weeks) reduces
the rate of early-PE with delivery at <34 weeks’ gestation by about 80% and preterm-PE
with delivery at <37 weeks by 60%, but there is little evidence of a reduction in incidence
of PE with delivery at ≥37 weeks.1 The method of identifying the high-risk group was the
competing risks model which combines maternal factors and mean arterial pressure
(MAP), uterine artery pulsatility index (UtA-PI), serum pregnancy associated plasma
protein-A (PAPP-A) and serum placental growth factor (PLGF).1-4

One of the barriers to implementation of universal first-trimester screening for PE relates

to the additional cost of measuring PLGF. Recording maternal characteristics and
medical history, measurement of blood pressure and serum PAPP-A and ultrasound
examination at 11-13 weeks’ gestation are an integral part of routine antenatal care and
early screening for trisomies in many countries and can easily be adapted to screening
for PE with no additional cost to healthcare provision. Measurement of UtA-PI can be
carried out by the same sonographers and ultrasound machines as part of the 11-13
weeks scan. Measurement of serum PLGF can be undertaken on the same sample and
by the same machines as for PAPP-A, but at increased cost.

The objective of this study is to examine the additive value of PLGF and PAPP-A in
first-trimester screening for preterm-PE by maternal factors, MAP and UtA-PI and the
potential impact on performance of screening if serum PAPP-A and / or PLGF are
included or excluded from the method of screening.

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METHODS

Study population

This is a non-intervention screening study. The data were derived from prospective
screening for adverse obstetric outcomes in women attending for their routine
first-trimester hospital visit in pregnancy at King’s College Hospital and Medway Maritime
Hospital, UK. These visits, which were held at 11+0 -13+6 weeks’ gestation, included first,
recording of maternal characteristics and medical history,2 second, measurement of the
left and right UtA-PI by color Doppler ultrasound and calculation of the mean PI by
transabdominal ultrasound,5 third, measurement of MAP by validated automated devices
and standardized protocol,6 and fourth, measurement of serum concentration of PLGF
and PAPP-A. PLGF was measured by DELFIA Xpress system, PerkinElmer Life and
Analytical Sciences, Waltham, USA between March 2006 and July 2012 and between
August 2013 and March 2017 at King’s College Hospital and between April 2010 and July
2012 and between August 2013 and March 2017 at Medway Maritime Hospital; it was
also measured by Cobas e411, Roche Diagnostics, Penzberg, Germany between August
2012 and July 2012 in both hospitals. PAPP-A was measured by DELFIA Xpress system,
PerkinElmer Life and Analytical Sciences, Waltham, USA during the whole study period in
both hospitals. Gestational age was determined from the fetal crown-rump length.7 The
women gave written informed consent to participate in the study, which was approved by
the NHS Research Ethics Committee.

The inclusion criteria for this study were singleton pregnancy undergoing first-trimester
combined screening for aneuploidy and subsequently delivering a phenotypically normal
live birth or stillbirth at >24 weeks’ gestation. We excluded pregnancies with aneuploidies
and major fetal abnormalities and those ending in termination, miscarriage or fetal death
before 24 weeks.

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Outcome measures were early-PE, preterm-PE and term-PE. Data on pregnancy
outcome were collected from the hospital maternity records or the general medical
practitioners of the women. The obstetric records of all women with pre-existing or
pregnancy associated hypertension were examined to determine if the condition was PE,
as defined by the American College of Obstetricians and Gynecologists (ACOG).8
According to this definition, diagnosis of PE requires the presence of new onset
hypertension (blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic) at ≥ 20weeks’
gestation and either proteinuria (≥300 mg/24h or protein to creatinine ratio >30 mg/mmol
or ≥2 + on dipstick testing) or evidence of renal dysfunction (serum creatinine >97
µmol/L), hepatic dysfunction (transaminases ≥65 IU/L) or hematological dysfunction
(platelet count <100,000/µL).8

Statistical analysis

Patient-specific risks of delivery with PE at <37 weeks’ gestation were calculated using
the competing risks model to combine the prior distribution of the gestational age at
delivery with PE, obtained from maternal characteristics and medical history, with multiple
of the median (MoM) values of MAP, UtA-PI, PLGF and PAPP-A.2-4 The performance of
screening in the total population and in subgroups of women of White and Black racial
origin were estimated. McNemar’s test was used to compare differences in detection
rates between screening with and without PLGF and PAPP-A, for fixed screen positive
rates of 10%. Risk cut-offs and screen positive rates to achieve desired detection rates of
preterm-PE were determined in screening with and without PLGF and PAPP-A.

The statistical software package R was used for data analyses.9 The package pROC10
was used for the receiver operating characteristic (ROC) curve analysis. The package
PropCIs11 was used for calculation of confidence intervals for proportions.

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RESULTS

Characteristics of the study population

During the study period serum PAPP-A and PLGF were measured in 60,875 pregnancies,
including 1,736 (2.9%) that developed PE; in 57,131 of the pregnancies, including 1,590
(2.8%) that developed PE, MAP and UtA-PI were also measured. The characteristics of
the study population are summarized in Table 1. In women that developed PE, compared
to those who did not, there was a higher body mass index and interpregnancy interval,
larger proportion of women of Black racial origin, higher incidence of chronic hypertension,
diabetes mellitus type 1, SLE or APS, family history of PE and assisted conception and
lower incidence of smoking.

Performance of screening for preeclampsia

The performance of screening for PE with delivery at <37 weeks’ gestation with and
without PAPP-A and / or PLGF is shown in Figure 1. The area under the ROC curve in
screening by maternal factors, MAP, UtA-PI and PLGF (0.913, 95% CI 0.901- 0.925) was
higher than in screening by maternal factors, MAP, UtA-PI and PAPP-A (0.892, 95% CI
0.878-0.906; p<0.001).

Table 2 reports the detection rate of PE with delivery at <37, <34 and >37 weeks’
gestation, at fixed screen positive rate of 10%, in screening with and without PAPP-A and
/ or PLGF. Addition of serum PAPP-A did not improve the prediction of PE provided by
maternal factors and PLGF or maternal factors, MAP and UtA-PI or maternal factors,
MAP, UtA-PI and PLGF. In contrast, addition of serum PLGF significantly improved the
prediction of PE provided by maternal factors alone and maternal factors, MAP and
UtA-PI. The performance of screening by maternal factors and PLGF was significantly
better than screening by maternal factors and PAPP-A; similarly, performance of
screening by maternal factors, MAP, UtA-PI and PLGF was better than screening by

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maternal factors, MAP, UtA-PI and PAPP-A. In screening by maternal factors, MAP,
UtA-PI and PLGF, at a screen positive rate of 10%, the detection rate of PE with delivery
at <37, <34 and >37 weeks’ gestation was 74.1%, 84.0% and 44.0%, respectively; the
values in screening by maternal factors, MAP, UtA-PI and PAPP-A were 67.0%, 78.0%
and 42.3%.

The risk cut-off, false positive and screen positive rates to achieve fixed detection rates of
70%, 75% and 80% of PE with delivery at <37 weeks’ gestation varied according to the
racial composition of the study population and whether the biomarkers used for screening
were MAP, UtA-PI and PLGF or MAP, UtA-PI and PAPP-A (Table 3). For example, in
screening by a combination of maternal factors, MAP, UtA-PI and PLGF in White women
if the desired detection rate of PE at <37 weeks was 75% the risk cut-off should be 1 in
136 and the screen positive rate would be 14.1%; in Black women to achieve a detection
rate of 75% the risk cut-off should be 1 in 29 and the screen positive rate would be 12.5%.
In screening by a combination of maternal factors, MAP, UtA-PI and PAPPA in White
women if the desired detection rate of PE at <37 weeks was 75% the risk cut-off should
be 1 in 140 and the screen positive rate would be 16.9%; in Black women to achieve a
detection rate of 75% the risk cut-off should be 1 in 44 and the screen positive rate would
be 19.3%.

Table 4 reports the detection rate, false positive rate and screen positive rate of PE with
delivery at <37, <34 and ≥37 weeks’ gestation in screening the whole population and
subgroups of White and Black women by maternal factors and biomarkers at risk cut-off
of ≥1 in 70 and ≥1 in 100 for PE at <37 weeks. The risk cut-off of 1 in 70 was selected
because this results in a screen positive rate of about 10% in our total study population
and the cut-off of 1 in 100 was selected because this results in a screen positive rate of
about 10% in the subgroup of women of White racial origin. There are two conclusions
from the data in Table 4. The first is that the performance of screening by MAP, UtA-PI
and PLGF is superior to that of MAP, UtA-PI and PAPP-A in both the whole population
and in the subgroups of White and Black women. The second conclusion is that the

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performance of screening varies according to the racial composition of the study
population. In our racially mixed population, in screening by maternal factors, MAP,
UtA-PI and PLGF at risk cut-off of ≥1 in 70 the screen positive rate was about 10% and
the detection rate of PE with delivery at <37, <34 and ≥37 weeks was about 75%, 85%
and 42%, respectively; in White women the screen positive rate was about 7% and the
detection rates were 62%, 77% and 30%, whereas in Black women the screen positive
rate was about 26% and the detection rates were 89%, 93% and 63%. In screening at
risk cut-off of ≥1 in 100 the screen positive rate in White women was about 10% and the
detection rate of PE with delivery at <37, <34 and ≥37 weeks was about 70%, 80% and
38%, and the respective values for Black women were about 33% for screen positive rate
and 91%, 94% and 71% for detection rates.

Table 5 reports the risk cut-off and detection rate of PE with delivery at <37 weeks’
gestation associated with screen positive rates of 10%, 15% and 20% in screening by
maternal factors and biomarkers in White women. The table also provides the
consequent screen positive and detection rates n Black women. For example, if the
desired screen positive rate was 15% and the method of screening was by maternal
factors, MAP, UtA-PI and PLGF the risk cut-off would be 1 in 145 and the detection rate in
White women would be 75.6%; at the same risk cut-off of 1 in 145 the respective screen
positive and detection rates in Black women would be 40.6% and 93.4%. If the method of
screening was by maternal factors, MAP, UtA-PI and PAPP-A for a screen positive rate of
15% in White women the risk cut-off would be 1 in 125 and the detection rate would be
72%; at the same risk cut-off of 1 in 125 the respective screen positive and detection
rates in Black women would be 44.2% and 91.8%.

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DISCUSSION

Main findings of the study

The main findings of this study are: first, the performance of first trimester screening for
PE by a combination of maternal factors, MAP, UtA-PI and PLGF is superior to that of
screening by maternal factors, MAP, UtA-PI and PAPP-A; second, addition of serum
PAPP-A does not improve the prediction of PE provided by maternal factors, MAP, UtA-PI
and PLGF; third, the risk cut-off and screen positive rates to achieve a desired detection
rate of PE varies according to the racial composition of the study population and whether
the biomarkers used for screening are MAP, UtA-PI and PLGF or MAP, UtA-PI and
PAPP-A; and fourth, replacing PLGF by PAPP-A can achieve the same high detection
rate but at a higher screen positive rate.

Interpretation of results and implication for clinical practice

The objective of screening at 11-13 weeks’ gestation is the identification of a group at

high-risk for early- and preterm-PE and the reduction of such risk, by about 80% and 60%,
respectively, through the prophylactic use of aspirin.1,12 We have previously established
and confirm in this study that first, the best first-trimester biomarkers of PE are UtA-PI,
MAP and PLGF and that combined screening by maternal factors and these three
biomarkers can predict about 85% and 75% of deliveries with PE <34 and <37 weeks’
gestation, respectively, at screen positive rate of 10%3,13-16 and second, that the
performance of screening depends on the racial origin of the women and that for a given
risk cut-off the screen positive rate in Black women is about three times higher than in
White women and that inevitably the detection rate is also higher.15

In this study we provide the necessary data to allow screening for PE whereby PAPP-A
replaces PLGF in the triple test, because PAPP-A is already widely used as part of first
trimester combined screening for fetal trisomies. In a predominantly White population it is

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reasonable to undertake first trimester screening by maternal factors, MAP, UtA-PI and
PAPP-A and use the risk cut-off of 1 in 140 to identify the high-risk group that would
benefit from the use of low-dose aspirin. At this cut-off about 17% of the White women
would be classified as being at high-risk and this group would contain 75% of the cases
that would develop preterm PE. In a predominantly Black population detection of 75% of
cases of preterm PE would be achieved if the risk cut-off was 1 in 44 and in such case the
screen positive rate would be about 19%.

Strengths and limitations

The strengths of the study include, first, a large study population, second, use of a
specific methodology and appropriately trained operators to measure UtA-PI and MAP
and use of automated machines to provide accurate measurement of maternal serum
concentration of PAPP-A and PLGF, and third, use of the competing risk model to
combine the information from maternal characteristics and medical history with the values
of biomarkers to estimate patient-specific risks and the performance of screening for PE
delivering at different stages of pregnancy. As demonstrated in this study the
performance of screening, including screen positive and detection rates, for a given risk
cut-off varies according to the characteristics of the study population; consequently, in the
application of screening in different regions and countries it is likely that adjustments
would be necessary to achieve a desired detection rate or fix a specific screen positive
rate.

Conclusions

In first trimester screening for PE the preferred biochemical marker is PLGF rather than
PAPP-A. However, if PAPP-A was to be used rather than PLGF the same detection rate
can be achieved but at a higher screen positive rate.

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Competing interests: The authors report no conflict of interest.

Sources of Funding: This study was supported by grants from the Fetal Medicine
Foundation (UK Charity No: 1037116). Reagents and equipment for the measurement of
serum placental growth factor were provided free of charge by Roche Diagnostics, and
PerkinElmer Life and Analytical Sciences. These bodies had no involvement in the study
design; in the collection, analysis and interpretation of data; in the writing of the report; and
in the decision to submit the article for publication.

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FIGURE LEGENDS

Figure 1. Receiver operating characteristic curves for prediction of PE with delivery at

<37 weeks’ gestation by maternal factors and PAPP-A and / or PLGF (left) and
combination of maternal factors, MAP, UtA-PI and PAPP-A and / or PLGF (right).

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 Table 1. Maternal and pregnancy characteristics of the study population.

Population with PAPP-A and PLGF Population with PAPP-A, PLGF, MAP and UtA-PI
Characteristic Normal Preeclampsia Normal Preeclampsia
(n=59,139) (n=1,736) p-value (n=55,541) (n=1,590) p-value
Maternal age (year) 31.0 (26.6, 34.8) 31.2 (26.7, 35.2) 0.112 31.1 (26.7, 34.8) 31.2 (26.8, 35.2) 0.086
Maternal weight (kg) 67.0 (59.2, 78.0) 74.0 (63.9, 87.2) <0.0001 67.0 (59.3, 78.0) 74.0 (64.0, 87.0) <0.0001
Maternal height (cm) 165 (160, 169) 164 (159, 168) <0.0001 165 (160, 169) 164 (160, 168) <0.0001
Body mass index 24.7 (22.0, 28.6) 27.6 (23.8, 32.8) <0.0001 24.7 (22.0, 28.6) 27.6 (23.8, 32.7) <0.0001

Gestational age (day) 89.0 (86.0, 92.0) 89.0 (86.0, 92.0) 0.019 89.0 (86.0, 92.0) 89.0 (86.0, 92.0) 0.062
Racial origin <0.0001 <0.0001
White 43,963 (74.3%) 993 (57.2%) 41,030 (73.9%) 923 (58.1%)
Black 9,790 (16.6%) 599 (34.5%) 9,415 (16.9%) 536 (33.7%)
South Asian 2,641 (4.5%) 83 (4.8%) 2,486 (4.5%) 75 (4.7%)
East Asian 1,230 (2.1%) 24 (1.4%) 1,159 (2.1%) 22 (1.4%)
Mixed 1,515 (2.6%) 37 (2.1%) 1,451 (2.6%) 34 (2.1%)
Medical history
Chronic hypertension 630 (1.1%) 215 (12.4%) <0.0001 598 (1.1%) 195 (12.3%) <0.0001
Diabetes mellitus type 1 228 (0.4%) 12 (0.7%) <0.0001 209 (0.4%) 12 (0.8%) <0.0001
Diabetes mellitus type 2 294 (0.5%) 26 (1.5%) 274 (0.5%) 23 (1.5%)
SLE/APS 113 (0.2%) 9 (0.5%) 0.006 105 (0.2%) 6 (0.4%) 0.164
Smoking 5,667 (9.6%) 101 (5.8%) <0.0001 5,116 (9.2%) 92 (5.8%) <0.0001
Family history of PE 2,257 (3.8%) 136 (7.8%) <0.0001 2,109 (3.8%) 126 (7.9%) <0.0001
Method of conception <0.0001 <0.0001
Spontaneous 57,258 (96.8%) 1,644 (94.7%) 53,760 (96.8%) 1,504 (94.6%)
In vitro fertilization 1,408 (2.4%) 72 (4.2%) 1,339 (2.4%) 67 (4.2%)
Ovulation drugs 473 (0.8%) 20 (1.2%) 442 (0.8%) 19 (1.2%)
Parity <0.0001 <0.0001
Nulliparous 27,303 (46.2%) 1,008 (58.1%) 25,784 (46.4%) 923 (58.05%)
Parous no previous PE 30,179 (51.0%) 494 (28.5%) 28,233 (50.8%) 455 (28.6%)
Parous previous PE 1,657 (2.8%) 234 (13.5%) 1,524 (2.7%) 212 (13.3%)
Pregnancy interval (year) 3.0 (2.0, 4.9) 3.85 (2.3, 6.7) <0.0001 3.0 (2.0, 4.8) 3.9 (2.4, 6.8) <0.0001

PE = preeclampsia; IQR = interquartile range; SLE = systemic erythematosus lupus; APS = antiphospholipid syndrome.

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 Table 2. Comparison of detection rate of preeclampsia with delivery at <34, <37 and >37
weeks’ gestation, at screen positive rate of 10%.

Comparison of detection Difference in detection

by the two between the two
Method of screening N p-value
methods of screening methods of screening
n (%) vs. n (%) n (%; 95% CI)
Preeclampsia <37 weeks
Data set with PlGF and PAPP-A
History alone vs History + PAPP-A 498 224 (45.0) vs. 242 (48.6) 18 (3.6; 0.4-6.9) 0.036
History alone vs History + PlGF 498 224 (45.0) vs. 300 (60.2) 76 (15.3; 11.3-19.4) <0.0001
History + PAPP-A vs History + PlGF 498 242 (48.6) vs. 300 (60.2) 58 (11.6; 7.8-15.7) <0.0001
History + PlGF vs History + PlGF + PAPP-A 498 299 (60.0) vs. 299 (60.0) 0 (0.0; -1.8-1.8) 1.000
Data set with MAP, UtA-PI, PlGF and PAPP-A
History + MAP + UtA-PI vs History + MAP + UtA-PI + PAPP-A 452 302 (66.8) vs. 303 (67.0) 1 (0.2; -2.7-3.2) 1.000
History + MAP + UtA-PI vs History + MAP + UtA-PI + PlGF 452 302 (66.8) vs. 335 (74.1) 33 (7.3; 4.0-10.9) 0.0001
History + MAP + UtA-PI + PAPP-A vs History + MAP + UtA-PI + PlGF 452 303 (67.0) vs. 335 (74.1) 32 (7.1; 3.8-10.6) 0.0001
History + MAP + UtA-PI + PlGF vs History + MAP + UtA-PI + PlGF + PAPP-A 452 335 (74.1) vs. 332 (73.5) -3 (-0.7; -2.3-0.8) 0.505

Preeclampsia <34 weeks

Data set with PlGF and PAPP-A
History alone vs History + PAPP-A 221 111 (50.2) vs. 121(54.8) 10 (4.5; 0.0-9.4) 0.078
History alone vs History + PlGF 221 111 (50.2) vs. 147(66.5) 36 (16.3; 10.1-22.8) <0.0001
History + PAPP-A vs History + PlGF 221 121 (54.8) vs. 147(66.5) 26 (11.8; 5.7-18.1) 0.0004
History + PlGF vs History + PlGF + PAPP-A 221 146 (66.1) vs. 142(64.3) -4 (-1.8; -5.2-1.2) 0.343
Data set with MAP, UtA-PI, PlGF and PAPP-A
History + MAP + UtA-PI vs History + MAP + UtA-PI + PAPP-A 200 156 (78.0) vs. 156 (78.0) 0 (0.0; -4.1-4.1) 1.000
History + MAP + UtA-PI vs History + MAP + UtA-PI + PlGF 200 156 (78.0) vs. 168 (84.0) 12 (6.0; 1.8-10.9) 0.014
History + MAP + UtA-PI + PAPP-A vs History + MAP + UtA-PI + PlGF 200 156 (78.0) vs. 168 (84.0) 12 (6.0; 1.8-10.9) 0.014
History + MAP + UtA-PI + PlGF vs History + MAP + UtA-PI + PlGF + PAPP-A 200 168 (84.0) vs. 168 (84.0) 0 (0.0; -2.3-2.3) 1.000

Preeclampsia ≥37 weeks

Data set with PlGF and PAPP-A
History alone vs History + PAPP-A 1238 436 (35.2) vs. 444 (35.9) 8 (0.6; -0.7-2.1) 0.416
History alone vs History + PlGF 1238 436 (35.2) vs. 480 (38.8) 44 (3.6; 1.6-5.6) 0.0007
History + PAPP-A vs History + PlGF 1238 444 (35.9) vs. 480 (38.8) 36 (2.9; 1.0-4.8) 0.004
History + PlGF vs History + PlGF + PAPP-A 1238 480 (38.8) vs. 479 (38.7) -1 (-0.1; -0.9-0.8) 1.000
Data set with MAP, UtA-PI, PlGF and PAPP-A
History + MAP + UtA-PI vs History + MAP + UtA-PI + PAPP-A 1138 480 (42.2) vs. 481 (42.3) 1 (0.1; -1.1-1.3) 1.000
History + MAP + UtA-PI vs History + MAP + UtA-PI + PlGF 1138 480 (42.2) vs. 501 (44.0) 21 (1.8; 0.0-3.7) 0.055
History + MAP + UtA-PI + PAPP-A vs History + MAP + UtA-PI + PlGF 1138 481 (42.3) vs. 501 (44.0) 20 (1.8; 0.0-3.6) 0.068
History + MAP + UtA-PI + PlGF vs History + MAP + UtA-PI + PlGF + PAPP-A 1138 501 (44.0) vs. 506 (44.5) 5 (0.4; -0.3-1.3) 0.359

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Table 3. Risk cut-off, false positive and screen positive rates, with 95% confidence
interval, to achieve fixed detection rates of 70%, 75% and 80% of preeclampsia with
delivery at <37 weeks’ gestation in screening by maternal factors and biomarkers in the
whole population and subgroups of White and Black women.

Risk Detection of PE
Method of screening FPR (95% CI) SPR (95% CI)
cut-off n/N (%)
Whole population
Fixed detection rate of 70%
History + MAP + UtA-PI + PAPP-A 1 in 68 316/452 (70) 10.7 (10.5-11.0) 11.2 (11-11.5)
History + MAP + UtA-PI + PLGF 1 in 52 316/452 (70) 7.4 (7.2-7.6) 7.9 (7.7-8.1)
Fixed detection rate of 75%
History + MAP + UtA-PI + PAPP-A 1 in 86 339/452 (75) 13.8 (13.5-14.0) 14.2 (14.0-14.5)
History + MAP + UtA-PI + PLGF 1 in 71 339/452 (75) 10.1 (9.9-10.4) 10.6 (10.4-10.9)
Fixed detection rate of 80%
History + MAP + UtA-PI + PAPP-A 1 in 102 361/452 (80) 16.5 (16.2-16.8) 17.0 (16.7-17.3)
History + MAP + UtA-PI + PLGF 1 in 102 361/452 (80) 14.2 (13.9-14.5) 14.7 (14.5-15.0)
White women
Fixed detection rate of 70%
History + MAP + UtA-PI + PAPP-A 1 in 100 157/225 (70) 11.5 (11.2-11.8) 11.8 (11.5-12.1)
History + MAP + UtA-PI + PLGF 1 in 104 157/225 (70) 10.5 (10.2-10.8) 10.8 (10.5-11.1)
Fixed detection rate of 75%
History + MAP + UtA-PI + PAPP-A
1 in 140 168/225 (75) 16.6 (16.3-17.0) 16.9 (16.6-17.3)
History + MAP + UtA-PI + PLGF 1 in 136 168/225 (75) 13.8 (13.5-14.2) 14.1 (13.8-14.5)
Fixed detection rate of 80%
History + MAP + UtA-PI + PAPP-A 1 in 199 180/225 (80) 23.2 (22.8-23.6) 23.5 (23.1-23.9)
History + MAP + UtA-PI + PLGF 1 in 181 180/225 (80) 18.0 (17.7-18.4) 18.4 (18.0-18.7)
Black women
Fixed detection rate of 70%
History + MAP + UtA-PI + PAPP-A 1 in 37 128/183 (70) 15.3 (14.5-16.0) 16.3 (15.5-17.0)
History + MAP + UtA-PI + PLGF 1 in 20 128/183 (70) 8.2 (7.6-8.7) 9.3 (8.7-9.9)
Fixed detection rate of 75%
History + MAP + UtA-PI + PAPP-A 1 in 44 137/183 (75) 18.2 (17.5-19.0) 19.3 (18.5-20.0)
History + MAP + UtA-PI + PLGF 1 in 29 137/183 (75) 11.4 (10.8-12.0) 12.5 (11.9-13.2)
Fixed detection rate of 80%

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History + MAP + UtA-PI + PAPP-A 1 in 56 146/183 (80) 23.0 (22.2-23.9) 24.1 (23.2-24.9)
History + MAP + UtA-PI + PLGF 1 in 35 146/183 (80) 13.8 (13.2-14.5) 15.1 (14.4-15.8)

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 Table 4. Detection false positive and screen positive rates of preeclampsia with delivery
at <37, <34 and ≥37 weeks’ gestation in screening the whole population and subgroups of
White and Black women by maternal factors and biomarkers at risk cut-off of ≥1 in 70 and
≥1 in 100 for PE at <37 weeks.

Risk cut off 1 in 100

Risk cut off 1 in 70
Method of screening Outcome
n/N DR (95% CI) FPR SPR n/N DR (95% CI) FPR SPR

Whole population

PE <37 w 358/452 79.2 (75.2-82.9) 15.4 16.6 317/452 70.1 (65.7-74.3) 10.4 11.6

History + MAP + UtA-PI + PAPP-A PE <34 w 174/200 87.0 (81.5-91.3) 15.4 16.6 161/200 80.5 (74.3-85.8) 10.4 11.6

PE ≥37 w 582/1138 51.1 (48.2-54.1) 15.4 16.6 493/1138 43.3 (40.4-46.3) 10.4 11.6

PE <37 w 360/452 79.6 (75.6-83.3) 13.3 14.5 338/452 74.8 (70.5-78.7) 9.3 10.5

History + MAP + UtA-PI + PlGF PE <34 w 175/200 87.5 (82.1-91.7) 13.3 14.5 169/200 84.5 (78.7-89.2) 9.3 10.5

PE ≥37 w 558/1138 49.0 (46.1-52.0) 13.3 14.5 473/1138 41.6 (38.7-44.5) 9.3 10.5

White women

PE <37 w 156/225 69.3 (62.9-75.3) 11.0 11.8 133/225 59.1 (52.4-65.6) 6.9 7.6

History + MAP + UtA-PI + PAPP-A PE <34 w 78/93 83.9 (74.8-90.7) 11.0 11.8 70/93 75.3 (65.2-83.6) 6.9 7.6

PE ≥37 w 273/698 39.1 (35.5-42.8) 11.0 11.8 215/698 30.8 (27.4-34.4) 6.9 7.6

PE <37 w 156/225 69.3 (62.9-75.3) 9.5 10.3 140/225 62.2 (55.5-68.6) 6.1 6.8

History + MAP + UtA-PI + PlGF PE <34 w 74/93 79.6 (69.9-87.2) 9.5 10.3 72/93 77.4 (67.6-85.4) 6.1 6.8

PE ≥37 w 266/698 38.1 (34.5-41.8) 9.5 10.3 207/698 29.7 (26.3-33.2) 6.1 6.8

Black women

PE <37 w 167/183 91.3 (86.2-94.9) 35.4 37.8 154/183 84.2 (78.0-89.1) 26.4 28.9

History + MAP + UtA-PI + PAPP-A PE <34 w 83/89 93.3 (85.9-97.5) 35.4 37.8 78/89 87.6 (79.0-93.7) 26.4 28.9

PE ≥37 w 264/353 74.8 (69.9-79.2) 35.4 37.8 241/353 68.3 (63.1-73.1) 26.4 28.9
163/183
PE <37 w 166/183 90.7 (85.5-94.5) 30.0 32.5 89.1 (83.6-93.2) 23.3 26.1

History + MAP + UtA-PI + PlGF PE <34 w 84/89 94.4 (87.4-98.2) 30.0 32.5 83/89 93.3 (85.9-97.5) 23.3 26.1

PE ≥37 w 249/353 70.5 (65.5-75.2) 30.0 32.5 234/353 66.3 (61.1-71.2) 23.3 26.1

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Table 5. Risk cut-off and detection rate of preeclampsia with delivery at <37 weeks’
gestation, with 95% confidence interval, for fixed screen positive rates of 10%, 15% and
20% in screening by maternal factors and biomarkers in White women.

White women Black women

Method of screening Risk
cut-off DR (95% CI) SPR (%) DR (95% CI)
Screen positive rate of 10%
History + MAP + UtA-PI + PAPP-A 1 in 87 66.2 (59.6, 72.4) 34.2 86.9 (81.1, 91.4)
History + MAP + UtA-PI + PLGF 1 in 97 68.4 (61.9, 74.5) 32.0 90.2 (84.9, 94.1)
Screen positive rate of 15%
History + MAP + UtA-PI + PAPP-A 1 in 125 72.0 (65.7, 77.7) 44.2 91.8 (86.8, 95.3)
History + MAP + UtA-PI + PLGF 1 in 145 75.6 (69.4, 81.0) 40.6 93.4 (88.8, 96.6)
Screen positive rate of 20%
History + MAP + UtA-PI + PAPP-A 1 in 198 78.2 (72.3, 83.4) 44.2 94.0 (89.5, 97.0)
History + MAP + UtA-PI + PLGF 1 in 166 82.7 (77.1, 87.4) 40.6 95.6 (91.6, 98.1)

DR = detection rate; SPR = screen positive rate

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Accepted Article
100 100

80
Fo 80

rP
ee

Detection rate (%)

Detection rate (%)

60 60

rR
ev
40 40

20
Maternal factors + PLGF + PAPP-A
Maternal factors + PLGF
Maternal factors + PAPP-A
20
iew
Maternal factors + MAP + UtA-PI + PLGF + PAPP-A
Maternal factors + MAP + UtA-PI + PLGF
Maternal factors + MAP + UtA-PI + PAPP-A
Maternal factors Maternal factors + MAP + UtA-PI
0 0

0 20 40 60 80 100 0 20 40 60 80 100
False positive rate (%) False positive rate (%)

Figure 1

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