Research

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OBSTETRICS

Prediction of preeclampsia utilizing the first

trimester screening examination
Ahmet A. Baschat, MD; Laurence S. Magder, PhD; Lauren E. Doyle, MGC, CGC;
Robert O. Atlas, MD; Chuka B. Jenkins, MD; Miriam G. Blitzer, PhD
OBJECTIVE: To derive a prediction rule for preeclampsia and early

onset preeclampsia requiring delivery <34 weeks using first trimester

maternal, ultrasound, and serum markers.
STUDY DESIGN: Prospective cohort study of women enrolled at first

trimester screening. Maternal history, demographics, anthropometry,

ultrasound parameters, and serum analytes were compared between
women with preeclampsia and normal outcome. The prediction rule
was derived by Lasso logistic regression analysis.
RESULTS: In 2441 women, 108 (4.4%) women developed pre-

eclampsia, and 18 (0.7%) early preeclampsia. Nulliparity, prior

hypertension, diabetes, prior preeclampsia, mean arterial pressure,

and the log pregnancy-associate pregnancy protein-A multiples of the
median were primary risk factors. Prediction rules for preeclampsia/
early preeclampsia had an area under the curve of 0.82/0.83
respectively. Preeclampsia was predicted with 49% sensitivity and
early preeclampsia with 55% sensitivity for a 10% false positive rate.
CONCLUSION: First trimester prediction rules using parameters
currently available at first trimester screening identify a significant
proportion of women with subsequent preeclampsia.

Key words: first trimester, preeclampsia, screening

Cite this article as: Baschat AA, Magder LS, Doyle LE, et al. Prediction of preeclampsia utilizing the first trimester screening examination. Am J Obstet Gynecol
2014;211:514.e1-7.

reeclampsia (PET) remains a signicant contributor to maternal

and fetal morbidity and mortality.
Improved and early prediction of women at risk for PET would make it
possible to institute preventative measures and offer appropriate surveillance.1,2 Several studies have adopted
the approach that has been established
in rst-trimester aneuploidy screening
From the Departments of Obstetrics,
Gynecology, and Reproductive Sciences
(Dr Baschat and Ms Doyle), Epidemiology and
Public Health (Dr Magder), and Pediatrics
(Dr Blitzer), University of Maryland School of
Medicine; Department of Obstetrics and
Gynecology, Mercy Medical Center (Dr Atlas);
and Department of Obstetrics and Gynecology,
MedStar Harbor Hospital (Dr Jenkins),
Baltimore, MD.
Received Feb. 4, 2014; revised March 27, 2014;
accepted April 12, 2014.
The authors report no conict of interest.
This research was supported by a grant from
Diagnostic Technologies Limited and Perkin
Elmer. There was no outside assistance with
manuscript preparation.

and developed multimarker algorithms

for prediction of PET.3-4 Although
these studies agree that a multifactorial
approach is the most promising one,
they diverge in the reported predictive
accuracies. This could be because of
variations in population risk proles,2
the serum analytes used as well as the
statistical approach5 or use of low-dose
aspirin prophylaxis.6
For clinical implementation, a predictive method that can be incorporated
into existing obstetric care would be the
most practical one. Pregnancy-associated
plasma protein-A (PAPP-A) and free beta
human chorionic gonadotropin (bhCG)
concentrations are routinely determined
by rst-trimester testing.7 Yet, most rst
trimester screening studies use serum
analytes that are either not yet commercially available, or that have not been
validated for clinical use. It was the aim of
this study to develop a risk algorithm
for PET in prospectively enrolled women
using parameters that are available in
the context of rst-trimester screening.

Reprints not available from the authors.

M ATERIALS

0002-9378/$36.00
2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2014.04.018

Pregnant women presenting for rst

trimester screening to any of 4 centers
in the Baltimore, MD, metropolitan area

AND

514.e1 American Journal of Obstetrics & Gynecology NOVEMBER 2014

M ETHODS

for rst-trimester screening from 20072010 were offered enrollment in this

prospective observational study. The ultrasound examination and all study procedures were carried out after informed
written consent. The study was approved
by the institutional review boards of the
University of Maryland School of Medicine, Mercy Medical Center, and the
MedStar Research Institute. The standardized ultrasound examination at these
centers conrms pregnancy dating, and
includes crown-rump length measurements and transabdominal uterine artery
Doppler; the specic ultrasound techniques have been previously described.9
Uterine artery notching was dened as
early diastolic blood ow acceleration
after the end-systolic nadir, producing
a notched appearance of the waveform.
Standardized written questionnaires on
medical history, current and prior pregnancy histories, and social and demographic information were then obtained.
Following completion of the questionnaire, maternal height, weight, and
blood pressure were measured. After 5
minutes of rest, qualied staff performed
a single blood pressure measurement
with the woman in a seated position
and the arm at the level of the heart. The

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Dinamap Pro 1000 V3 (GE Medical Systems, Milwaukee, WI) automated sphygmomanometer was used, with a cuff
size appropriate for maternal arm circumference. Sphygmomanometer calibration occurred every 6 months in
accordance with the Association for the
Advancement of Medical Instrumentation guidelines. Blood samples were
obtained by trained nursing staff and
submitted on standardized lter paper
forms to NTD Labs (Perkin Elmer,
Melville, NY) for analysis. NTD Labs
reported the results as multiples of the
median after absolute measurements of
pregnancy-associated plasma protein-A
(PAPP-A) and free bhCG were compared with reference ranges of a normal
population.10
Women were followed through pregnancy by the respective study enrollment center. Pregnancy outcomes,
including the development of PET in the
current pregnancy, were recorded at
delivery. Proteinuric PET was dened
as new-onset or worsening proteinuria
(comparing results with the rsttrimester urinalysis) and maternal systolic blood pressure
140 mm Hg or
diastolic blood pressure
90 mm Hg on
2 separate occasions, 6 or more hours
apart, after 20 weeks gestation.8
All information from the collaborating clinical sites was reported directly
to the primary investigator at the University of Maryland School of Medicine.
Study data were collected, validated by
source documentation, and entered
into a dedicated study database. It is our
local practice to offer women at risk for
PET low dose aspirin if bilateral uterine
artery notching is noted on the ultrasound examination.9 For logistic purposes these women were enrolled but
subsequently excluded from this analysis
if aspirin was recommended before 16
weeks.9
Normality of continuous data was
tested using the Kolmogorov-Smirnov
test. We rst performed univariate analysis to identify factors that were associated
with an increased risk of PET. The statistical signicance of observed associations was assessed using Fisher exact test
as implemented for multiple-row tables
in SAS 9.2 (SAS Institute, Cary, NC).

To derive a multivariable prediction

rule we used lasso logistic regression10
as implemented by the R package
GLMnet.11 This approach ts a logistic
regression model, however, relative to
the standard logistic regression tting
approach, the parameter estimates from
the lasso approach are shrunk towards 0.
This avoids extreme values that are
likely to perform poorly in data not used
to t the model and has generally been
shown to result in better prediction.12
The lasso approach also automatically
chooses a subset of variables to include
in the model (ie, those that are not
shrunk all the way to zero). A tuning
parameter to determine the degree of
shrinkage was chosen by cross validation
of the model prediction in 10 equal sized
subsets of the patient population. Based
on univariate analysis in our population
and previously screening studies candidate variables for the prediction model
included: age, race, history of diabetes,
hypertension, nephropathy, thrombophilia, autoimmune disease, or prior
PET, parity, body mass index (BMI),
systolic, diastolic, and mean arterial
pressure, left and right uterine artery
pulsatility index as well as the mean
pulsatility index in both uterine arteries
multiples of the median (MoM), left and
right uterine artery notching, number
of early diastolic notches counting
both uterine arteries, PAPP-A MoM, and
free bhCG MoM. We then used receiver
operator curve statistics to determine
sensitivity and specicity and the 95%
condence interval (CI) for the area
under the curve for the predictive
probabilities derived from each prediction rule.

R ESULTS
Of 3422 screened and enrolled women,
323 (9.4%) were lost to follow-up, 634
(18.5%) received the recommendation
for rst-trimester aspirin, and 24 (0.7%)
were excluded for other reasons leaving
2441 meeting inclusion criteria. OF these
108 (4.4%) developed PET; 18 (0.7%)
required delivery before 34 weeks.
African-American and whites constituted the majority of ethnicities among
enrolled women (n 1196, 49% and
1068, 43.8%, respectively). The median

Research

maternal age was 30 years (range,

18e55) and 1058 (43.3%) were nulliparous. A prior history of chronic hypertension (n 174, 7.1%), diabetes
mellitus (n 91, 3.7%) were the most
common preexisting medical conditions, and 91 women (3.7%) reported a
history of prior PET (Table 1). Delivery
was at a median gestational age of 39.1
weeks (22.4-43 weeks gestation) and the
median birthweight was 3264 g (1005360 g). Of those, 171 (7%) infants were
large and 217 (8.9%) were small for
gestational age with a birthweight below
the 10th percentile.
Table 1 shows the rates of preeclampsia by patient demographics and
clinical history. The rates of early or any
PET differed signicantly by maternal
ethnicity and were signicantly higher
among those with a history of diabetes
and a history of hypertension. Nulliparous women were signicantly more
likely to develop PET and parous women
with a history of PETwere almost 5 times
more likely to develop recurrence.
Table 2 shows the relationship between variables measured at the rsttrimester screening and rates of PET.
Those with higher blood pressure (as
measured by either systolic, diastolic, or
mean arterial pressure) had signicantly
higher rates of PET. High BMI and low
PAPP-A-MoM were also associated with
higher rates of PET.
Using the lasso logistic regression
approach we derived a multivariable
prediction model for PET (Table 3).
The resulting model was as follows: logodds of PET 8.72 0.157 (if
nulliparous) 0.341 (for history of
hypertension) 0.635 (for history of
prior PET) 0.064 (per unit mean
arterial pressure)  0.186 (per unit of log
PAPP-A MoM). This prediction model
had an area under the curve of 0.82 (95%
CI, 0.78e0.86) and had 68% sensitivity
for a false-positive rate of 20% and 49%
sensitivity for a false-positive rate of
10%. For PET requiring delivery before
34 weeks the model was: Log-odds of
early-onset PET : 5.803 0.302 (for
history of diabetes) 0.767 (for history
of hypertension) 0.00948 (per unit
mean arterial pressure). This prediction
model had an area under the curve of

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TABLE 1

Rates of early or any preeclampsia by demographics and patient history

Patient characteristic

Number (%)
with early PET

P value

Age

Number (%)
with any PET

.99

.31

18-24 (n 605)

4 (0.7%)

35 (5.8%)

25-29 (n 561)

4 (0.7%)

26 (4.6%)

30-34 (n 578)

5 (0.9%)

19 (3.3%)

35-39 (n 570)

4 (0.7%)

24 (4.2%)

40 (n 127)

1 (0.8%)

4 (3.2%)

Race
Caucasian (n 1068)

.0030
35 (3.3%)

12 (1.0%)

65 (5.4%)

Asian (n 133)

2 (1.5%)

4 (3.0%)

Hispanic (n 34)

2 (5.9%)

4 (11.8%)

Other (n 10)

0 (0.0%)

0 (0.0%)

Prior deliveries
None (n 1058)

.63

.0027

11 (1.0%)

65 (6.1%)

1 (n 766)

4 (0.5%)

20 (2.6%)

2 (n 395)

2 (0.5%)

14 (3.5%)

3 (n 222)

1 (0.5%)

9 (4.0%)

History of diabetes
No (n 2350)
Yes (n 91)

.0004

.0001

13 (0.6%)

95 (4.0%)

5 (5.5%)

13 (14.3%)
< .0001

History of hypertension

< .0001

No (n 2267)

10 (0.4%)

82 (3.6%)

Yes (n 174)

8 (4.6%)

26 (14.9%)
> .99

History of nephropathy
No (n 2437)
Yes (n 4)

18 (0.7%)

Yes (n 16)

0 (0.0%)

1 (25.0%)
.11

Yes (n 21)

107 (4.4%)

1 (6.3%)

1 (6.3%)
> .99

Yes (n 91)

.61

18 (0.7%)

107 (4.4%)

0 (0.0%)

1 (4.8%)

History of PET
No (n 2350)

.52

17 (0.7%)

History of thrombophilia
No (n 2420)

.17
107 (4.4%)

History of autoimmune disease

No (n 2425)

C OMMENT
.025

2 (0.2%)

African-American (n 1196)

P value

< .0001

.14
16 (0.7%)

91 (3.9%)

2 (2.2%)

17 (18.7%)

Data are presented as numbers and percentages of the group; P values were calculated using c2 or Fisher exact tests
depending on cell size.
PET, preeclampsia.
Baschat. Early screening for preeclampsia. Am J Obstet Gynecol 2014.

514.e3 American Journal of Obstetrics & Gynecology NOVEMBER 2014

0.83 (95% CI, 0.74e0.91) and had 66%

sensitivity for a false-positive rate of 20%
and 55% sensitivity for a false-positive
rate of 10% (Figures 1 and 2). The estimated change in odds for each of the
model parameters is displayed in Table 3.
The clinical characteristics of women
delivered with a diagnosis of PET are
summarized in Table 4.
We present a multivariable rsttrimester prediction model for PET
that was derived using a prospectively
enrolled, urban population. Maternal
blood pressure, history of prior PET,
diabetes, nullparity, and low PAPP-A
were predictive of higher rates of PET.
Using a conservative analytic approach
the prediction rules identied a signicant proportion of women destined to
develop PET with higher prediction
rates for earlier-onset disease.
Several other investigators have developed predictive algorithms in cohorts
of women enrolled at rst-trimester
screening. These studies also identied
maternal hypertension, prior diabetes,
recurrent miscarriage, prior thrombophilia, and prior PET as the most significant historic risk factors. Maternal
blood pressure and body mass index are
the primary predictive physical characteristics whereas uterine artery Doppler
and PAPP-A or placental growth factor
levels are among the most consistently
reported markers of early placental success identifying women at risk for
PET.3,5,7,8,13,14 The prediction of early
onset PET appears consistently better
with sensitivities ranging from 42%15 to
as high as 96%8 for early-onset disease
and 19%16 to 77%17 for PET requiring
delivery after 34 weeks gestation. Although our study population shares
the same risk factors for PET our prediction models falls short of the high
accuracy reported in some studies.3,5,7,8
This could be because of several factors
including the characteristics of our study
population, the study design, the statistical approach, the biomarkers used, or
biologic variability in the disease evolution in a different population.
Our cohort had slightly higher overall prevalence of PET, but a rate of

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TABLE 2

Rates of early or any preeclampsia stratified by clinical variables

Characteristic

Distribution

BMI

<20 (n 145)

SBP

DBP

MAP

hCG MoM

LUA PI z-score

RUA PI z-score

MUA PI z-score

0 (0.0%)

P value
.23

Number (%) with

any PET
6 (4.1%)

20-25 (n 798)

6 (0.8%)

29 (3.6%)

25-30 (n 685)

2 (0.3%)

19 (2.8%)

30-35 (n 383)

5 (1.3%)

21 (5.5%)

35 (n 430)

5 (1.2%)

<120 (n 1635)

6 (0.4%)

33 (2.0%)

3 (0.6%)

32 (6.2%)

130-139 (n 202)

4 (2.0%)

27 (13.4%)

140 (n 90)

5 (5.6%)

16 (17.8%)

<70 (n 1584)

4 (0.3%)

< .0001

31 (2.0%)

70-79 (n 659)

5 (0.8%)

50 (7.6%)

80-89 (n 169)

7 (4.1%)

18 (10.7%)

90 (n 29)

2 (6.9%)

9 (31.0%)

<70 (n 78)

0 (0.0%)

< .0001

2 (2.6%)

70-80 (n 757)

0 (0.0%)

6 (0.8%)

80-90 (n 1103)

6 (0.5%)

35 (0.3%)

12 (2.4%)

65 (12.9%)

1st quartile (n 613)

7 (1.1%)

2nd quartile (n 595)

5 (0.8%)

21 (3.5%)

3rd quartile (n 611)

3 (0.5%)

17 (2.8%)

4th quartile (n 622)

3 (0.6%)

20 (3.2%)

1st quartile (n 625)

7 (1.1%)

2nd quartile (n 601)

2 (0.3%)

30 (5.0%)

3rd quartile (n 614)

5 (0.8%)

27 (4.4%)

4th quartile (n 601)

4 (0.7%)

24 (4.0%)

1st quartile (n 682)

1 (0.2%)

2nd quartile (n 635)

5 (0.8%)

19 (3.0%)

3rd quartile (n 605)

5 (0.8%)

36 (6.0%)

4th quartile (n 519)

7 (1.4%)

29 (5.6%)

1st quartile (n 685)

5 (0.7%)

2nd quartile (n 649)

2 (0.3%)

25 (3.9%)

3rd quartile (n 592)

5 (0.8%)

30 (5.1%)

.50

.45

.079

.37

50 (8.2%)

27 (4.3%)

24 (3.5%)

35 (5.1%)

4th quartile (n 515)

6 (1.1%)

1st quartile (n 687)

3 (0.4%)

2nd quartile (n 640)

4 (0.6%)

24 (3.8%)

3rd quartile (n 623)

3 (0.5%)

29 (4.7%)

4th quartile (n 491)

8 (1.6%)

25 (5.1%)

Baschat. Early screening for preeclampsia. Am J Obstet Gynecol 2014.

P value
.0024

33 (7.7%)
< .0001

120-129 (n 514)

90 (n 503)
PAPP-A MoM

Number (%) with

early PET

< .0001

< .0001

< .0001

< .0001

.87

.024

0.41

18 (3.5%)
.13

30 (4.4%)

0.72

(continued)

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TABLE 2

Rates of early or any preeclampsia stratified by clinical variables (continued)

Number (%) with
early PET

P value

Number (%) with

any PET

Characteristic

Distribution

Uterine artery notching

None (n 1504)

8 (0.5%)

1 (n 488)

4 (0.8%)

23 (4.7%)

6 (1.3%)

25 (5.6%)

2 (n 449)

.17

60 (4.0%)

P value
.32

Data are presented as numbers and percentages. P values were calculated using c or Fisher exact tests depending on cell size.
2

bhCG, beta human chorionic gonadotropin; BMI, body mass index; DBP, diastolic blood pressure in mm Hg; LUA, left uterine artery; MAP, mean arterial blood pressure in mm Hg; MoM, multiples of
the median; MUA, mean uterine artery; PAPP-A, pregnancy-associated plasma protein-A; PI, pulsatility index; RUA, right uterine artery; SBP, systlolic blood pressure in mm Hg.
Baschat. Early screening for preeclampsia. Am J Obstet Gynecol 2014.

early-onset PET that is comparable with

previous reports suggesting that our
cohort did not differ signicantly in
disease prevalence.3,8,18,19 Because it is
our local practice to place patients at
highest risk for PET on low-dose aspirin
we excluded a subpopulation that had
the highest prevalence of high resistance
uterine artery waveforms.9 Because
the prevalence of PET in these women
is high their exclusion may have attenuated the statistical impact of uterine
artery Doppler so that it was no longer
demonstrable as an independent predictive contributor.7,15,17,19
Of the presented statistical approaches
those that are modeled to predict the
disease latency appear to have higher
predictive accuracy8 although our more

conservative approach may explain the

lower sensitivity. However, these models
may overemphasize the risks factors that
cause early onset PET, and the performance of a prediction algorithm in
the sample that it was derived from
tends to be inated because of the fact
that the parameters are chosen to be
optimal for that sample (resulting in
overtting).20 The external validity of
most rst-trimester algorithms has
not been tested rigorously and there is
evidence that algorithms do not perform as well when applied to other
populations.21 We chose an approach
to reduce overtting by using crossvalidation and smaller coefcient estimates. This approach may have reduced
the performance of the algorithm on

TABLE 3

Estimated change in odds of preeclampsia with the selected predictors

Variable

Comparison

our own sample, but should result in

better performance in a new set of
patients.
In a recent study, Scholten and coworkers2 examined a large cohort of
women with a history of PET and found 4 major risk proles. Of these a
circulatory risk prole characterized
by hypertension, latent hypertension,
low plasma volume, or increased peripheral resistance was the most prevalent
prole in over 60% of women. In
contrast hyperhomcystinemia (18.7%),

FIGURE 1

Receiver operating
characteristic curve for the log
odds derived from the prediction
rule for PET irrespective of
gestational age at delivery
(any PET)

Odds ratio

Predictor for PET

Null parity

Yes vs No

1.17

History of hypertension

Yes vs No

1.03

History of PET

Yes vs No

1.89

Mean arterial pressure

Per 10 mm Hg increase

1.90

PAPP-A MoM

Per 1 unit decrease in

log PAPP-A MoM

1.20

Yes vs No

1.35

Predictor for early onset PET

History of diabetes
History of hypertension

Yes vs No

2.15

Mean arterial pressure

Per 10 mm Hg increase

1.10

MoM, multiples of the median; PAPP-A, pregnancy-associated plasma protein-A; PET, preeclampsia.
Baschat. Early screening for preeclampsia. Am J Obstet Gynecol 2014.

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PET, preeclampsia.
Baschat. Early screening for preeclampsia. Am J Obtet
Gynecol 2014.

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FIGURE 2

Receiver operating
characteristic curve for the log
odds derived from the prediction
rule for PET requiring delivery
prior to 34 wks gestation

PET, preeclampsia.
Baschat. Early screening for preeclampsia. Am J Obstet
Gynecol 2014.

metabolic syndrome (15.4%), and thrombophilia (10.8%) were less frequent. The cardiovascular risk prole
was found to have the widest overlap
with the other risk proles although
metabolic syndrome, thrombophilic,
and hyperhomcystinemic risk proles
were more distinct.
These ndings have important implications for the screening approach to
PET potentially explaining variability
in screening algorithms across populations. Among these risk factors the
cardiovascular risk prole can be identied by eliciting a history of hypertension or the measurement of blood
pressure; a history of diabetes and the
body mass index serve as surrogate
markers for the metabolic prole. Our
previous observation on women with
prior PET suggest that uterine artery
Doppler may be a marker that is sensitive
to the effects of thrombophilia on the
placental circulation.9 Accordingly, the
use of these markers in a given population is likely to be determined by the
relative prevalence and manifestation

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of these risk proles. This probably explains why chronic hypertension, mean
arterial blood pressure, and a history of
established diabetes are universal risk
factors, but BMI, thrombophilia, recurrent miscarriages, and ethnicity are only
important in certain populations.3,58,10,13-18
Given these potential variations
in risk factors and their expression the
role of additional biomarkers warrants
further study.
The strengths of our study include
its prospective design and the verication of PET at the time of delivery with
precise source documentation. Accordingly it is unlikely that we misdiagnosed
the primary study end-point. The sample size for early onset PET is small
and may have affected the selection
of signicant model parameters. We
demonstrate that rst-trimester prediction rules that use clinical variables
and serum analytes that are part of
clinically offered rst-trimester aneuploidy screening identify a signicant
proportion of women that subsequently
develop PET.
-

TABLE 4

Characteristics of women with preeclampsia at delivery

Characteristic
Cesarean delivery
Birthweight percentile

PET delivered before

34 wks (n [ 18)
14 (77.8%)
10.4 (0.2e97.5)

PET delivered after

34 wks (n[90)
42 (46.7%)
30.7 (0.04e97.9)

P value
.008
< .0001

Highest SBP in labor

170 (130e229)

163 (130e227)

.218

Highest DBP in labor

94 (68e121)

97 (74e129)

.361

Median level of proteinuria

< .001

Hgb, g/dL

11.8 (9.9e14.5)

11.4 (8.8e14.5)

.590

HCT, %

34.5 (24.4e43.2)

33.8 (27.3e44.1)

.933

Platelet count/mL

193 (46e430)

216 (55e453)

.140

AST, iU/mL

35 (17e622)

25 (11e144)

.001

ALT, iU/mL

38 (10e151)

18 (8e260)

.001

LDH, iU/mL

371 (164e557)

226 (109e749)

.005

HELLP syndrome

2 (11.1)

2 (2.2)

n.s.

Creatinine, mg/dL

0.89 (0.54e1.33)

0.7 (0.41e2.4)

.002

Uric acid, mg/dL

6.8 (4e10.3)

5.6 (3.5e9.2)

.004

Data are presented as numbers and percentages or median and range.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; HCT, hematocrit; HELLP, syndrome of hemolysis, elevated liver enzymes, and low platelets;
LDH, lactate dehydrogenase; n.s., not significant; PET, preeclampsia; SBP, systolic blood pressure.
Baschat. Early screening for preeclampsia. Am J Obstet Gynecol 2014.

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