Fetal Diagn Ther 2005;20:48–53
Accepted: December 24, 2003
DOI: 10.1159/000081369
Prediction of Preeclampsia or Intrauterine
Growth Restriction by Second Trimester Serum
Screening and Uterine Doppler Velocimetry
François Audibert a Yehouda Benchimol a Clarisse Benattar b
Catherine Champagne a René Frydman a
a Service de Gynécologie-Obstétrique, Hôpital Antoine Béclère, Assistance Publique Hôpitaux de Paris et
Université Paris XI, et b Service de Biochimie, Hôpital Antoine Béclère, Assistance Publique Hôpitaux de Paris et
Université Paris XI, Clamart, France
Key Words
·-Fetoprotein W Human chorionic gonadotropin W
Intrauterine growth restriction W Preeclampsia W Serum
markers W Uterine Doppler ultrasound
Abstract
Objective: To assess the performance of screening for
preeclampsia and intrauterine growth restriction by
combining second trimester maternal serum screening
and uterine Doppler ultrasound. Methods: A cohort of
2,615 women underwent both maternal serum screening
(using human chorionic gonadotropin (hCG) and ·-feto-
protein (AFP)), and second trimester uterine artery
Doppler. The sensitivity, specificity and predictive value
of different combinations of both tests were compared.
Results: The mean values for hCG and AFP were signifi-
cantly higher in women with subsequent preeclampsia
(p ! 0.0003 and p ! 0.03, respectively). Taking into
account obstetrical history, hCG and AFP levels, notch-
ing on uterine artery Doppler and parity, the adjusted
odds ratios were significantly higher for a high level of
hCG for preeclampsia, intrauterine growth restriction
(IUGR) and pregnancy-induced hypertension. AFP level
11.5 MoM (multiples of the median) was significantly
correlated with subsequent IUGR. The presence of a
© 2005 S. Karger AG, Basel
ABC 1015–3837/05/0201–0048$22.00/0
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E-Mail karger@karger.ch Accessible online at:
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Received: September 5, 2003
uterine notch was associated with a significantly higher
risk of both preeclampsia and IUGR. The combination of
an elevated serum level and the presence of a uterine
notch had a positive predictive value (PPV) for pre-
eclampsia of 25 and 21% for hCG and AFP, respectively.
The combination of a bilateral notch with a low level of
hCG or a high level of AFP had a PPV for IUGR of 50 and
43%, respectively. The sensitivity of the different tests
ranged from 2 to 40%. Conclusion: The combination of
serum markers and abnormal uterine Doppler ultra-
sound improves the identification of women at risk for
subsequent pregnancy complications. These results
should encourage care providers to perform a uterine
Doppler ultrasound when serum markers are abnormal.
However, the sensitivity of these tests is too low to pro-
vide an efficient generalized screening.
Copyright © 2005 S. Karger AG, Basel
Introduction
Complications of pregnancy such as preeclampsia,
pregnancy-induced hypertension (PIH), intrauterine
growth restriction (IUGR), and abruptio placentae are
important causes of fetal, maternal and neonatal morbidi-
ty and mortality [1]. Early screening of women at risk is
Dr. François Audibert
Service de Gynécologie-Obstétrique, Hôpital Sainte-Justine
3175 Côte Sainte-Catherine
Montréal H3T1R2 (Canada)
E-Mail francois.audibert@umontreal.ca
currently based on obstetrical history [2] and uterine
Doppler ultrasound, generally conducted in the second
trimester [3]. Previous reports suggest a correlation be-
tween the levels of maternal serum human chorionic
gonadotropin (hCG) or ·-fetoprotein (AFP), and subse-
quent pregnancy complications [4–9]. Early preventive
treatment with aspirin or other drugs for high-risk women
would appear to reduce the onset of these complications,
confirming the benefits of earlier and more effective
screening [10–14].
Routine screening of chromosomal abnormalities is
currently performed with the double (AFP and hCG) or
the triple (AFP, hCG and uE3) test, with a high uptake in
many countries. We aimed to assess the performance of
early screening for preeclampsia and IUGR by combining
maternal serum screening with uterine Doppler ultra-
sound.
Material and Methods
The study was conducted in a cohort of 2,615 women in whom
both a double test between 14 and 18 weeks (by maternal serum AFP
and total serum hCG assay), and a uterine Doppler ultrasound
between 18 and 26 weeks were performed. This cohort was taken
from an initial database of 4,556 women enrolled for Down’s syn-
drome screening, as previously described [15]. From May 1994
through April 1998, Down’s syndrome screening was offered to all
women registered before 14 weeks in our institution. An ultrasound
was conducted between 10 and 14 weeks to date the pregnancy, and
to measure nuchal translucency. This was followed by a maternal
serum marker assay using the double test between 14 and 18 weeks.
We excluded the following women from the analysis: multiple preg-
nancies, women without an ultrasound between 10 and 14 weeks,
women referred for increased nuchal translucency. From this initial
cohort of 4,556 women, 1,941 were excluded for the following rea-
sons: no Doppler ultrasound between 18 and 26 weeks (n = 1,878);
delivery ! 24 weeks (n = 55) (including 21 terminations of pregnancy
for chromosomal abnormalities, 8 for major structural anomaly, and
26 spontaneous pregnancy losses). Eight women were lost to follow-
up. Thus, the study population consisted of 2,615 women who had
both a double test (between 14 and 18 weeks), a uterine Doppler
ultrasound (between 18 and 26 weeks), who delivered after 24 weeks
and for whom outcome of pregnancy was known.
Preeclampsia was defined as a systolic blood pressure 6140 mm
Hg or a diastolic pressure 690 mm Hg on two occasions, associated
with proteinuria 1 0.3 g/24 h or at least ‘two-plus’ protein on the
urine dipstick [16]. Severe preeclampsia was defined by the presence
of at least one of the following criteria: systolic blood pressure
6160 mm Hg or diastolic pressure 6110 mm Hg, after 4 h of bed
rest; proteinuria 65 g/24 h or at least 3+ protein on the urine
dipstick; oliguria ^400 ml/24 h; cerebral or visual disturbances,
epigastric pain, pulmonary edema or cyanosis; thrombocytopenia
! 100,000 mm3. HELLP syndrome was defined by the association of:
hemolysis (presence of schistocytes on the blood smear, or LDH level
1 600 IU/l, haptoglobin level ! 0.4 g/l, total bilirubin 1 20 Ìmol/l);
Screening for Preeclampsia and IUGR
Table 1. Frequency of pregnancy complications (n = 2,615)
Pregnancy complication n Prevalence, %
Preeclampsia 51 1.95
PIH 122 4.66
HELLP syndrome 3 0.11
Chronic hypertension 44 1.68
Birthweight ! 10th percentile 230 8.79
IUFD 11 0.42
Abruptio placenta 7 0.27
PIH = Pregnancy-induced hypertension; IUFD = intrauterine
fetal demise.
elevation of AST (aspartate aminotransferase) 1 70 IU/l or ALT (ala-
nine aminotransferase) 1 60 IU/l; thrombocytopenia ! 100,000 plate-
lets/mm3 [17, 18].
IUGR was defined by a weight below the 10th percentile of our
reference charts [19]. PIH was defined as a systolic blood pressure
6140 mm Hg, or a diastolic blood pressure 690 mm Hg, measured
at least on two occasions, and diagnosed after 20 weeks.
We used the Amerlite® kit (Ortho Clinical Diagnostics, Issy-les-
Moulineaux, France) for the hCG and AFP assay. Pathological uter-
ine Doppler ultrasound was defined by the presence a protodiastolic
notch or a pulsatility index above the 1 95th percentile. Placental lat-
eral location was not recorded in the database.
The statistical analysis used the non-parametric Wilcoxon test to
compare continuous variables, the ¯2 test to compare categorical
variables and multivariate logistic regression to calculate the ad-
justed odds ratios. The statistical software used was Stata 7.0 (Stata
Corp., College Station, Tex., USA). The significance level was p !
0.05.
Results
The mean age of our population was 30.9 B 4.5 years,
and there were 48.5% nulliparas. The mean (SD) gesta-
tional age delivery was 39.7 (1.8) weeks and the mean
(SD) birth weight was 3,288 (530) g. The mean values for
maternal serum hCG and AFP expressed in multiples of
the median (MoM) were 1.03 and 1.05 MoM, respec-
tively.
We identified 426 women (16.3%) with at least one of
the following complications: preeclampsia, IUGR, PIH,
chronic hypertension, stillbirth or abruptio placenta (ta-
ble 1). Among women who developed preeclampsia, 59%
were nulliparous. The prevalence of preeclampsia, IUGR
and PIH was higher in nulliparas compared to multiparas
(respectively 2.4 vs. 1.6%, p = 0.051; 9.9 vs. 7.7%, p =
0.13 and 6.2 vs. 3.4%, p ! 0.001). Among women with a
Fetal Diagn Ther 2005;20:48–53 49
 Table 2. Logistic regression: independent prediction of the various tests for pregnancy complications

Preeclampsia (n = 51) IUGR (n = 230) PIH (n = 122)

ORa 95% CI ORa 95% CI ORa 95% CI

History of PE, PIH or IUGR 3.37 1.45–7.85 3.19 2.03–5.03 4.91 2.72–8.87
Multiparity 0.81 0.54–1.21 0.81 0.68–0.98 0.59 0.44–0.78
HCG 1 2 MoM 1.82 1.33–2.48 1.10 0.88–1.37 1.35 1.04–1.75
AFP 1 1.5 MoM 1.24 0.74–2.07 1.41 1.07–1.87 0.73 0.43–1.27
Notch (at least one) 2.42 1.68–3.50 1.72 1.38–2.16 1.29 0.95–1.76

PE = Preeclampsia; PIH = pregnancy-induced hypertension; IUGR = intrauterine growth restriction; ORa =

adjusted odds ratio; CI = confidence interval.

Table 3. Performance of different screening tests for predicting preeclampsia

Test Positive Sensitivity Specificity PPV NPV

tests, % % % % %

History of PE, PIH or IUGR 6.45 21.56 93.86 6.71 98.31

Bilateral notch 4.39 21.56 95.94 9.56 98.4
At least 1 notch 12.19 39.21 88.33 6.27 98.65
hCG 1 2 MoM 5.54 15.68 94.65 5.51 98.26
hCG 1 2 MoM and at least 1 notch 0.6 7.84 99.53 25 98.19
History of preeclampsia or bilateral notch
or hCG 1 2.5 MoM 9.04 41.17 91.61 9.13 98.7
AFP 1 1.5 MoM 9.79 19.6 90.4 3.9 98.26
AFP 1 1.5 MoM and at least 1 notch 1.1 7.84 99.02 13.79 98.18
AFP 1 1.5 MoM and bilateral notch 0.53 5.88 99.57 21.43 98.15

PE = Preeclampsia; PIH = pregnancy-induced hypertension; IUGR = intrauterine growth restriction; PPV =

positive predictive value; NPV = negative predictive value; MoM = multiples of the median. Prevalence of pre-
eclampsia = 1.95%.

history of preeclampsia, HELLP syndrome or abruptio
placenta (n = 50), 10% had a recurrence of preeclampsia,
14% of PIH and 12% of IUGR. Among those with a histo-
ry of IUGR (n = 64), 36% had a recurrence of IUGR.
Total hCG and AFP levels were significantly higher in
women with preeclampsia than in those without (respec-
tively 1.42 vs. 1.03 MoM, p ! 0.0003 for hCG, and 1.15
vs. 1.05 MoM, p ! 0.03 for AFP). Among women with
severe IUGR (!5th percentile) but without preeclampsia,
the AFP level was significantly higher than the rest of the
population, with levels of 1.12 vs. 1.05 MoM (p ! 0.03).
The AFP level was also significantly higher in cases of
intrauterine fetal demise with a mean value of 1.29 vs.
1.05 MoM (p ! 0.03).
Multivariate logistic regression including obstetrical
history, hCG and AFP levels, presence of at least one uter-
ine notch and multiparity, is shown in table 2. Taking
account of these five adjustment variables, the risk of
preeclampsia appeared to be significantly and indepen-
dently increased in the presence of nulliparity, obstetrical
history, high level of hCG, or uterine artery notching.
Similarly, the risk of IUGR was significantly associated
with nulliparity, obstetrical history, a high level of AFP,
or notching. The risk of PIH was associated with nullipar-
ity, obstetrical history, and with a high level of hCG.
Table 3 shows the sensitivity, specificity, positive pre-
dictive value (PPV) and negative predictive value of the
uterine Doppler ultrasound, serum markers and different
screening combinations for prediction of preeclampsia.

50 Fetal Diagn Ther 2005;20:48–53 Audibert/Benchimol/Benattar/Champagne/

Frydman
 Table 4. Performance of different screening tests for predicting IUGR

Test Positive Sensitivity Specificity PPV NPV

tests, % % % % %

History of PE, PIH or IUGR 6.45 15.69 94.43 21.34 92.09

Bilateral notch 4.39 13.04 96.43 26.08 92
At least 1 notch 12.19 22.6 88.8 16.3 92.24
hCG 1 1.5 MoM 15.87 20 84.52 11.08 91.63
hCG 1 2 MoM 5.54 9.13 94.8 14.48 91.53
hCG ! 0.5 MoM and at least one notch 1.33 3.04 98.82 20 91.35
hCG 1 1.7 MoM and at least one notch 1.45 4.78 98.86 28.94 91.5
hCG ! 0.5 MoM and bilateral notching 0.38 2.17 99.79 50 91.36
AFP 1 1.5 MoM 9.78 13.91 90.6 12.5 91.6
AFP 1 1.5 MoM and at least one notch 1.11 3.91 99.16 31.03 91.45
AFP 1 1.5 MoM and bilateral notching 0.53 2.6 99.66 42.85 91.38

PE = Preeclampsia; PIH = pregnancy-induced hypertension; IUGR = intrauterine growth restriction; PPV =

positive predictive value; NPV = negative predictive value; MoM = multiples of the median. Prevalence of IUGR =
8.79%.

The best sensitivity is obtained with at least one of the
following risk factors: obstetrical history, bilateral notch-
ing or hCG 12.5 MoM. The best PPV is obtained by asso-
ciating hCG 12 MoM and at least one notch (25%). With
an AFP level 11.5 MoM in addition to bilateral notching,
1 woman in 5 will develop preeclampsia.
Table 4 shows the sensitivity, specificity, PPV and neg-
ative predictive value of the uterine Doppler ultrasound,
serum markers and some of their combinations for
IUGR. For the prediction of IUGR, Doppler offers a bet-
ter sensitivity than other tests (22.6% with ‘at least one
notch’). The PPV of a bilateral notch rises from 26 to 43%
or to 50% when an AFP level 11.5 MoM or an hCG level
!0.5 MoM are respectively associated.
Discussion
This study offers the largest series to date assessing the
test properties of both uterine Doppler ultrasound and
maternal serum markers for the prediction of pregnancy
complications in the same group of women. We found a
significant correlation between a pathological level of
hCG or AFP on the one hand, the presence of notching on
the uterine Doppler on the other, and the occurrence of
pregnancy complications. The combination of these tests
improved the predictive value of screening.
Uterine Doppler ultrasound is currently recommended
in case of an obstetrical history or when a pregnancy com-
plication occurs. The predictive value of uterine Doppler
varies according to the prevalence of the different compli-
cations of pregnancy. The sensitivities and PPVs attribut-
ed to the uterine Doppler ultrasound in a low-risk popula-
tion are variable in the literature, ranging from 14 to 77%
and from 7 to 50% respectively for preeclampsia, and
from 7 to 32% and 10 to 50% for IUGR [20–22].
Many studies have examined a possible correlation
between the hCG level and the occurrence of pregnancy
complications, since the introduction of serum screening
for Down’s syndrome [5, 6, 23–29]. Most of these articles
are case-control studies. The sensitivity and PPVs for
preeclampsia reported in these studies for an hCG level
12 MoM are highly variable, ranging from 20 to 69% and
3 to 15% respectively [23–27, 29]. In a large retrospective
study, Walton et al. [9] have examined the association
between hCG levels and pregnancy outcome in 28,743
women. Despite a higher incidence of stillbirth, placental
abnormalities and PIH among women with elevated hCG
levels, the authors did not find any clinically relevant
association between this test and the most frequent preg-
nancy complications. In this study, the results were not
reported as sensitivities, specificities or predictive values.
As early as 1,939, a correlation was suggested between a
high serum hCG concentrations and the onset of pre-
eclampsia [30]. The hypothesis explaining the increase of
hCG in preeclampsia or IUGR is an initial drop in pla-
cental perfusion, at the origin of necrosis of syncytiotro-
phoblast cells and of increased cytotrophoblast mitotic

Screening for Preeclampsia and IUGR Fetal Diagn Ther 2005;20:48–53 51

activity. Morssink et al. [29] found a higher number of
placental lesions of the infarctal type and placental isch-
emia in cases of IUGR associated with a high level of
hCG. Interestingly, we also found an association between
very low levels of hCG (!0.5 MoM) and IUGR. This
seemingly contradictory fact could be due to an early
abnormal placental function leading to a very low hCG
secretion in a subgroup of women. Two studies have
addressed this issue, yielding conflicting results [31, 32].
Further studies are needed to confirm this finding.
Few studies have examined the combination of uterine
Doppler ultrasound and serum screening to predict pre-
eclampsia or IUGR. Most of them suggest an increase in
the risk of complications, but do not distinguish between
the various complications of pregnancy. These studies are
conducted on small numbers of women and in selected
populations of pathological serum markers levels [33, 34].
Based on our results, the combination of the three tests
with the highest PPV for preeclampsia and IUGR screen-
ing (hCG 12 MoM and at least one notch, or AFP
11.5 MoM associated with bilateral notching, or hCG
!0.5 MoM and bilateral notching) would enable to identi-
fy a group of women with a 44% risk of these complica-
tions, in our population with a risk of 1.5%. However, the
sensitivity of such a screening would be very low (6.4%).
Maternal serum screening is currently performed in
60–80% of pregnant women in France by routine screen-
ing for chromosomal abnormalities. The use of these
serum markers, in association with the uterine Doppler
ultrasound, represents a screening test which, despite a
poor sensitivity, offers a very high PPV value in a low-risk
population, multiplying the risk by 2–3 compared to
Doppler alone.
Although our study included 2,615 women out of an
initial population of 4,556 subjects, we do not believe that
we selected a high-risk population by eliminating from
our study 1,878 women who did not undergo a uterine
Doppler ultrasound between 18 and 26 weeks, since the
observed prevalence of the various pregnancy complica-
tions (preeclampsia: 1.95%, IUGR: 8.8%) and the preva-
lence of bilateral notch (4.4%) or at least one notch
(12.2%) are similar to those expected in a low-risk popula-
tion [20–22].
Given the results presented above, we believe that in
the absence of chromosomal abnormality or neural tube
defect, a high or unusually low level of hCG or a high level
of AFP, should lead to propose a uterine Doppler ultra-
sound. Furthermore, within the scope of screening for
complications of pregnancy, maternal serum markers
should be read individually for serum levels, expressed in
MoM and not just as combined risk, as is currently the
case in Down’s syndrome screening. An abnormal level of
a serum marker, once a chromosomal abnormality has
been ruled out, can be the first sign of a complication of
pregnancy. This study, even though carried out in an
unselected population, noted a pregnancy complication
rate in 50% of cases who tested positive. However, due to
its poor sensitivity, the test combining second trimester
serum markers and uterine Doppler ultrasound cannot be
proposed as a generalized screening method for pregnan-
cy complications in a low-risk population. By identifying
during the second trimester of pregnancy a group of wom-
en at very high risk of preeclampsia or IUGR, it is now
possible to offer closer clinical and ultrasound monitor-
ing. The predictive value of this combined screening test
should now be evaluated during the first trimester. If this
early screening proves to be efficient, prospective con-
trolled studies of prophylactic treatment (such as aspirin
or antioxidants) could be conducted in this high-risk pop-
ulation.

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