Original Article

Gynecol Obstet Invest 2015;80:99105

DOI: 10.1159/000370332

Received: July 21, 2014

Accepted after revision: December 3, 2014
Published online: April 22, 2015

Use of Placental Growth Factor and Uterine

Artery Doppler Pulsatility Index in Pregnancies
Involving Intrauterine Fetal Growth Restriction or
Preeclampsia to Predict Perinatal Outcomes
M. Dolores Gomez-Roig a, b Edurne Mazarico a, b Joan Sabria a, b Johanna Parra a
Laia Oton a Antonio Vela a, b
a

Department of Obstetrics and Gynecology, Sant Joan de Du University Hospital, Barcelona, and b SAMID Network
(Spanish Collaborative Maternal and Child Health Research Network), Institute Carlos III, Madrid, Spain

Abstract
Aim: The potential of uterine artery (UA) Doppler pulsatility
index (PI) and maternal serum placental growth factor (PlGF)
level to predict perinatal outcome was explored in pregnancies complicated by intrauterine fetal growth restriction (IUGR)
or preeclampsia (PE). Methods: This longitudinal, prospective,
and case-controlled study was conducted over a period of 24
months. At-risk pregnancies involving small-for-gestationalage (SGA) fetuses, IUGR, gestational hypertension (GH), or PE
were investigated, analyzing UA Doppler PI findings and maternal PlGF levels determined at the time of diagnosis (third
trimester). Results: UA Doppler PI and maternal serum PlGF
values differed significantly in pregnancies complicated by
IUGR and/or PE (vs. SGA or GH, p < 0.01). In the context of IUGR
or PE, both parameters also differed significantly by perinatal
outcome (adverse vs. normal, p < 0.01), although no predictive
advantage over UA Doppler PI alone was conferred by adding
a PlGF assay. Conclusion: UA Doppler PI and maternal serum
PlGF determinations in the third trimester help identify preg-

2015 S. Karger AG, Basel

03787346/15/08020099$39.50/0
E-Mail karger@karger.com
www.karger.com/goi

nancies at the highest risk of adverse perinatal outcomes due

to IUGR and/or PE. Although joint testing confers no predictive
benefit over UA Doppler PI alone, the two diagnostics are interchangeable for this purpose.
2015 S. Karger AG, Basel

Introduction

Pregnancies involving small-for-gestational-age

(SGA) fetuses, intrauterine growth restriction (IUGR),
gestational hypertension (GH), or preeclampsia (PE) are
primarily diagnosed during the third trimester of pregnancy, and all such complications are linked with adverse
birthing outcomes. However, perinatal outcomes are
generally worse in conditions of IUGR and PE than in
nonproteinuric GH and SGA states.
Abnormalities of developing placental vasculature
arising early in the pregnancy may eventuate in relative

This study is based on the following research project: FIS PI041637: Use
of VEGF and PlGF levels in maternal serum and UA Doppler pulsatility index to predict intrauterine growth restriction and preeclampsia.

M. Dolores Gomez-Roig
Department of Obstetrics and Gynecology
Sant Joan de Du University Hospital, Pg. Sant Joan de Du, 2
ES08950 Esplugues de Llobregat, Barcelona (Spain)
E-Mail lgomezroig@hsjdbcn.org

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Key Words
Placental growth factor Uterine artery Doppler pulsatility
index Intrauterine fetal growth restriction Preeclampsia

Materials and Methods

This longitudinal, prospective, and case-controlled study was
conducted at the Hospital Sant Joan de Du, Barcelona, Spain,
over a period of 24 months. Pregnancies associated with SGA,
IUGR, GH, or PE were included, where mean UA Doppler PI and
maternal serum PlGF determinations were obtained at the time of
diagnosis (third trimester). Eligible pregnancies (n = 156) were
those diagnosed, delivered, and followed up at our hospital (46
SGA, 20 IUGR, 25 GH, 42 PE, and 23 PE plus IUGR). Other uncomplicated pregnancies (n = 344) were monitored as controls (all
fetal and birth weights between the 10th and 90th percentiles of
the regional reference curves adjusted for gestational age and gender). Control subjects were normotensive and negative for proteinuria.
The following definitions were applied to the study group: (1)
IUGR: fetuses with an estimated fetal weight <10th percentile,
according to reference tables for the Spanish population, and an
umbilical artery PI >95th percentile [2123]; (2) SGA: fetuses
with an estimated fetal weight <10th percentile, according to reference tables for the Spanish population, and normal Doppler
velocimetry (umbilical artery PI, middle cerebral artery PI, cerebroplacental ratio and UAs) [2123]; (3) PE: systolic blood pressure (BP) 140 mm Hg and/or diastolic BP 90 mm Hg measured twice in 6 h after 10 min of rest with the mother sitting,
and the measure taken in the arm at heart level with a quantitative determination of proteinuria >300 mg in 24 h, and (4) GH:

100

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DOI: 10.1159/000370332

systolic BP 140 mm Hg and/or diastolic BP 90 mm Hg measured twice in 6 h after 10 min of rest with the mother sitting,
and the measure taken in the arm at heart level with negative
proteinuria [2427]. All percentiles of fetal weights were confirmed at birth.
In each instance, the estimated fetal weight was derived from
Hadlocks reference curves, using sonographic measurements of
biparietal diameter, femoral length, and circumferences of the abdomen and head. The gestational age in the first trimester was estimated by fetal crown-rump length (Robinson curves), adjusted
for the date of the last menstrual period, as needed [28].
For an estimated fetal weight <10th percentile, Doppler examinations were used to distinguish SGA from IUGR, based on
the measurements of the umbilical arteries, middle cerebral arteries, and UAs. At least 3 determinations were made at each site,
using the best figure for the final analysis. Pathologic PIs of umbilical (PI >95th percentile) and middle cerebral arteries (PI <5th
percentile) according to the reference curves by Arduini and Rizzo [29] constituted Doppler abnormalities. UA Doppler studies
were considered abnormal at a mean PI >95th percentile bilaterally.
PlGF was measured by enzyme-linked immunosorbent assay
(ELISA) kits (R&D Systems Europe, Ltd., Abingdon, UK). These
assays detect free but not bound growth factors. Venous blood serum was taken within 72 h after diagnosis of SGA, IUGR, GH, or
PE, separated by centrifugation at 1,400 g for 10 min, and stored at
80 C. All samples were collected, handled, and stored under the
same conditions and tested in duplicate. Plate-to-plate variability
was controlled with an independent standard curve on each plate.
Serum from cases and their matched control subjects were simultaneously and blindly run on the same plates. In all kits, the intraassay precision was always <5% and the interassay precision 10%.
The linear regression coefficients of the standard curves were never below 0.99.
Z-scores were calculated from reference tables for the Spanish
population [30]. The clinicians were blinded to PlGF determination and to UA Doppler information during the study. The clinicians had advanced experience in fetal ultrasound.
Exclusion criteria were as follows: (1) medications that possibly
affect fetal growth; (2) genetic variants impacting growth potential
(i.e. chromosomal abnormalities and genetic syndromes); (3) pregestational or gestational diabetes; (4) multiple pregnancies; (5)
infections; (6) medically unattended pregnancies or births; (7)
pregnancies or births at other hospitals (outside of protocol); (8)
no ultrasound before 20 weeks of estimated gestational age; (9)
IUGR/SGA, PE, or GH diagnosed after 37 weeks of gestation, and
(10) hypertension diagnosed in advance of pregnancy or before 20
weeks of gestation.
The following were considered adverse perinatal outcomes: (1)
non-reassuring fetal heart rate before labor; (2) prematurity (<34
weeks) due to PE or IUGR; (3) requiring neonatal unit care, and
(4) maternal complications due to PE or hypertension.
Standard statistical software (SPSS v19; SPSS Inc., Chicago, Ill.,
USA) was used for analysis. For group comparisons, 2 (qualitative
variables) and Students t test (quantitative variables) were applied.
Statistical significance was set to p 0.05.
Our study protocol was approved by the Institutional Review
Board of Barcelona University Hospital. Written informed consent was obtained from each patient before undergoing any studyrelated procedures.

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placental underperfusion, hypoxia, and ischemia. Accordingly, IUGR and PE are signs of placental decompensation [1]. Uterine artery (UA) Doppler studies reliably
detect inadequate placental perfusion in complicated
pregnancies (SGA, IUGR, GH, and/or PE conditions),
correlating well with maternal/fetal prognosis by the
third trimester [210].
Placental growth factor (PlGF) is a protein belonging
to a family of platelet-derived growth factors implicated
in angiogenesis. The placenta (specifically trophoblast)
is its chief source, so circulating PlGF is a ready index
of placental perfusion. Several studies have found diminished plasma levels of PlGF during the first and second trimesters in pregnancies where GH, PE, SGA, or
IUGR was later manifested [1116]. Studies done during the third trimester are less numerous, and some
have presented contradictory findings in this regard [7,
1720].
For the above reasons, a maternal serum PlGF assay
was added to the UA Doppler pulsatility index (PI) in the
third trimester of at-risk pregnancies (with SGA, IUGR,
GH, and/or PE as complications). Our intent was to assess its impact on differentiating these specific conditions
(IUGR vs. SGA and PE vs. GH) and to predict related
perinatal outcomes.

Table 1. Neonatal data

SGA
(n = 46)

IUGR
(n = 20)

GH
(n = 25)

PE
(n = 42)

59.18
14.29
26.53
39.59 1.92
3,274.91 466.54
52.3 19.3
7.24 0.05
7.28 0.06

67.5
15
17.5
38.57 1.55
2,590 382.71
7.1 2
7.25 0.07
7.29 0.07

28.48
8.66
62.86
36.06 2.50
2,250.62 481.52
3.4 6.8
7.24 0.07
7.29 0.06

61.2
10.5
28.3
37.01 2.40
2,813 367.43
36.21 8.9
7.26 0.04
7.28 0.05

48.98
51.02

47.5
52.5

62.73
37.27

49.1
50.9

p
value

<0.001
19.31
12.39
68.3
35.34 1.32
<0.001
2,250.45 211.5 <0.001
11.12 4.5
<0.001
7.24 0.07
0.639
7.28 0.06
0.072
0.071
45.6
54.4

Table 2. Maternal serum PlGF concentration in pregnancies in-

Table 3. Mean UA Doppler PI in pregnancies involving SGA,

volving SGA, IUGR, GH, PE, and PE plus IUGR relative to controls

IUGR, GH, PE, and PE plus IUGR relative to controls

Z-scores

Controls
PE
IUGR
PE plus IUGR
GH
SGA

344
42
20
23
25
46

0.1027
0.6524
0.7695
1.1431
0.3120
0.0444

Total

500

0.1836

p value
<0.01

Mean

Controls
PE
IUGR
PE plus IUGR
GH
SGA

344
42
20
23
25
46

0.8132
1.3251
1.4744
1.6817
0.7462
0.9446

Total

500

1.0077

p value
<0.01

Homogenous samples were collected for all groups.

None of the groups (SGA, IUGR, GH, PE, and controls)
differed significantly in terms of maternal age (30 6, 28
6, 29 3, 28 6, and 32 5 years, respectively), gender
of the fetus, obstetrical precedents, and gestational age at
diagnosis (34.98 2.17, 33.88 2.61, 34.33 1.9, 33.21
2.5, and 33.2 2.41 weeks, respectively). Perinatal data
are presented in table1.
Mean UA Doppler PI and maternal serum PlGF concentration differed significantly in pregnancies involving
SGA, IUGR, GH, PE, and IUGR plus PE, relative to controls (p < 0.01; tables 2, 3). When comparing pregnancies
complicated by PE and/or IUGR with all others (SGA/
GH and controls), significant differences in mean UA
Doppler PI (1.26 vs. 0.83) and maternal serum PlGF concentration (z-scores: 0.8163 vs. 0.0570) were evident
(p < 0.01). Also, when comparing pregnancies compli-

cated by PE and/or IUGR with pregnancies involving

SGA or GH, significant differences in mean UA Doppler
PI (1.46 vs. 0.89) and maternal serum PlGF concentration
(z-scores: 0.8163 vs. 0.0466) were evident (p < 0.01). Maternal serum PlGF concentration also differed significantly (p < 0.01) in PE and/or IUGR pregnancies relative
to controls, unlike SGA or GH.
Mean UA Doppler PI and maternal serum PlGF concentration differed significantly by perinatal outcome in
general (normal: PI 0.88, PlGF z-score: 0.0080 vs. adverse: PI 1.67, PlGF z-score: 1.0837; p < 0.01); in pregnancies involving PE, GH, SGA, and IUGR as complications (normal: PI 0.98, PlGF z-score: 0.0061 vs. adverse:
PI 1.67, PlGF z-score: 1.0837; p < 0.01), and in pregnancies complicated by PE and/or IUGR (normal: PI 1.14,
PlGF z-score: 0.0044 vs. adverse: PI 1.69, PlGF z-score
1.0233; p < 0.01).
Based on ROC curves generated for the stated parameters, the areas under the curve and sensitivity for a 10%

PlGF and UA Doppler PI in IUGR and

Preeclampsia

Gynecol Obstet Invest 2015;80:99105

DOI: 10.1159/000370332

Results

101

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Mode of delivery, %
Spontaneous delivery
Forceps delivery
Cesarean section
Gestational age at delivery, weeks
Birth weight, g
Birth weight percentile
Arterial pH
Venous pH
Gender of the neonate, %
Male
Female

Controls
(n = 344)

0.6

Origin of the curve

PI
PlGF (inverted)
Baseline

0.2

0.2

0.4
0.6
1 specificity

0.8

1.0

Color version available online

1.0

Susceptibility

0.8
0.6

Origin of the curve

PI
PlGF (inverted)
Baseline

0.2

0.2

Origin of the curve

PI
PlGF (inverted)
Baseline
0

0.2

0.4
0.6
1 specificity

0.8

1.0

Fig. 3. Prediction of adverse perinatal outcome.

ROC curve

0.4
0.2

Fig. 1. Prediction of PE and/or IUGR.

0.4

0.6

0.4
0.6
1 specificity

0.8

1.0

ROC curve
1.0
0.8
0.6
0.4

Origin of the curve

PI
PlGF (inverted)
Baseline

0.2
0

0.2

0.4
0.6
1 specificity

0.8

1.0

Fig. 2. Prediction of PE and/or IUGR in pregnancies complicated

with GH or SGA.

Fig. 4. Prediction of adverse perinatal outcome in complicated

false positive rate (FPR) for mean UA Doppler PI and

maternal serum PlGF, respectively, were as follows: (1)
PE and/or IUGR 0.877 and 0.855, with a sensitivity of
69 and 65% (fig.1); (2) PE and/or IUGR relative to all
complications (GH, PE, SGA, or IUGR) 0.847 and
0.828, with a sensitivity of 69 and 63% (fig.2); (3) adverse
perinatal outcome 0.926 and 0.931, with a sensitivity of
83.3 and 87.5% (fig.3); (4) adverse perinatal outcome in
complicated (PE, GH, SGA, or IUGR) pregnancies
0.887 and 0.911, with a sensitivity of 72.9 and 79.2%
(fig.4), and (5) adverse perinatal outcome with PE and/

or IUGR only 0.831 and 0.897, with a sensitivity of 63.8

and 80.9% (fig.5).
The positive likelihood ratios for a 10% FPR for mean
UA Doppler PI and maternal serum PlGF, respectively,
were as follows (table4): (1) PE and/or IUGR 6.91 and
6.54; (2) PE and/or IUGR relative to all complications
(GH, PE, SGA, or IUGR) 6.91 and 6.3; (3) adverse perinatal outcome 8.33 and 8.75; (4) adverse perinatal outcome in complicated (PE, GH, SGA, or IUGR) pregnancies 7.29 and 7.92, and (5) adverse perinatal outcome with
PE and/or IUGR only 6.38 and 8.09.

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pregnancies (GH, PE, SGA, or IUGR).

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0.8

Color version available online

0.4

1.0

Susceptibility

Susceptibility

0.8

Color version available online

1.0

ROC curve

Susceptibility

Color version available online

ROC curve

Table 4. Positive/negative likelihood ratios (LHR) for a 10% FPR for mean UA Doppler PI and maternal serum

PlGF
Positive LHR

Color version available online

PE and/or IUGR
PE and/or IUGR relative to all complications
Adverse perinatal outcome
Adverse perinatal outcome in complicated pregnancies
Adverse perinatal outcome with PE and/or IUGR

ROC curve

1.0

0.6

PlGF

mean UA
Doppler PI

PlGF

6.91
6.91
8.33
7.29
6.38

6.54
6.3
8.75
7.92
8.04

0.34
0.34
0.18
0.3
0.4

0.38
0.41
0.13
0.23
0.21

perinatal outcome in complicated (PE, GH, SGA, or

IUGR) pregnancies, it was 89.58% for PlGF and 86.73%
for mean UA Doppler PI, and in predicting adverse perinatal outcome with PE and/or IUGR only, it was 88.88%
for PlGF and 54.83% for mean UA Doppler PI. PlGF levels significantly correlated with UA Doppler PI (R 0.439;
p < 0.001).

Origin of the curve

0.4

PI
PlGF (inverted)
Baseline

0.2
0

mean UA
Doppler PI

Discussion

The negative likelihood ratios for a 10% FPR for mean

UA Doppler PI and maternal serum PlGF, respectively,
were as follows (table4): (1) PE and/or IUGR 0.34 and
0.38; (2) PE and/or IUGR relative to all complications
(GH, PE, SGA, or IUGR) 0.34 and 0.41; (3) adverse perinatal outcome 0.18 and 0.13; (4) adverse perinatal outcome in complicated (PE, GH, SGA, or IUGR) pregnancies 0.3 and 0.23, and (5) adverse perinatal outcome with
PE and/or IUGR only 0.4 and 0.21.
The positive predictive value in predicting PE and/or
IUGR was 78.43% for PlGF and 83.93% for mean UA
Doppler PI; in predicting PE and/or IUGR among all
complications (GH, PE, SGA, or IUGR), it was 65.11% for
PlGF and 69.13% for mean UA Doppler PI; in predicting
adverse perinatal outcome, it was 90.70% for PlGF and
92.66% for mean UA Doppler IP; in predicting adverse

The clinical challenge is finding markers to reliably

pinpoint more serious conditions, namely IUGR, PE, or
both. The most interesting point of our study and its
main contribution is the validation of the use of mean
UA Doppler PI in the third trimester to predict adverse
perinatal outcomes in at-risk pregnancies (with GH, PE,
SGA, or IUGR) and to identify subsets of GH or SGA
pregnancies destined for PE or IUGR. Llurba et al. [31]
already showed that UA Doppler in the third trimester
performs significantly better in detecting patients at risk
for late-onset placenta-related diseases than in the first
trimester. Maroni et al. [8] found a greater risk of IUGR
with elevated uterine PI at 34 weeks, although the risk of
late PE was not heightened. In accordance with our observations, Ghi et al. [9] reported that persistently elevated UA resistance in the third trimester corresponded with
a greater risk of both IUGR and PE and worse perinatal
outcomes, accounting for more admissions to neonatal
intensive care.
To date, several studies have shown that declines in
maternal serum PlGF concentration during the second
trimester correlate with SGA, IUGR, GH, or PE that develop later [1416, 18]. Our third-trimester data in turn
indicate that maternal serum PlGF level helps predict adverse birthing outcomes in these complicated pregnan-

PlGF and UA Doppler PI in IUGR and

Preeclampsia

Gynecol Obstet Invest 2015;80:99105

DOI: 10.1159/000370332

0.2

0.4
0.6
1 specificity

0.8

1.0

Fig. 5. Prediction of adverse perinatal outcome with PE and/or

IUGR only.

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Susceptibility

0.8

Negative LHR

cies. Sibiude et al. [17] have demonstrated that PlGF levels in instances of suspected PE or IUGR aid in identifying
cases with worse perinatal outcomes due to eclampsia,
HELLP syndrome, extreme IUGR (<3rd percentile), or
elective delivery at <34 weeks of gestation.
Moreover, another important contribution of our
study is that these markers in the third trimester are also
able to distinguish those pregnancies with GH or SGA at
a higher risk of complications, and not only in pregnancies complicated with IUGR and/or PE.
Interestingly, we found a moderate correlation between UA Doppler PI and PlGF levels. PlGF contributes
to uterine vascular remodeling during pregnancy [32],
which in turn accounts for placental vascular impedance.
Given these results, we corroborated that UA Doppler
and PlGF contributed independently to the prediction of
adverse outcome.

Comparing the results of the ROC curves, the sensitivities, the likelihood ratios and the positive predictive
value of PlGF and mean UA Doppler PI, our results
showed that adding PlGF determination to mean UA
Doppler PI conferred no benefit in terms of predicting
adverse perinatal outcome. However, a recent publication [7] assessing other biomarkers of PE and IUGR includes PlGF as a ratio of sFlt-1:PlGF. More research is
clearly needed to confirm the utility of PlGF alone or
combined with other prognosticators in this setting.

Acknowledgments
We would like to thank the Gynecology and Obstetrics Service
at Sant Joan de Du University Hospital, Barcelona, Spain, the
Fund for Health Research of the Spanish Social Security Service for
financing part of this project (Exp. PI041637), and the Spanish
Collaborative Maternal and Child Health Research Network.

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PlGF and UA Doppler PI in IUGR and

Preeclampsia

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