Ultrasound Obstet Gynecol 2016; 47: 680689

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.15873

Do knowledge of uterine artery resistance in the second

trimester and targeted surveillance improve maternal and
perinatal outcome? UTOPIA study: a randomized controlled
trial
B. GARCIA*#, E. LLURBA*#, L. VALLE, M. D. GOMEZ-ROIG, M. JUAN,
C. PEREZ-MATOS, M. FERNANDEZ, J. A. GARCIA-HERNANDEZ, J. ALIJOTAS-REIG*,
M. T. HIGUERAS*, I. CALERO*, M. GOYA*, S. PEREZ-HOYOS**, E. CARRERAS* and
L. CABERO*
*Department of Obstetrics, Maternal-Foetal Medicine Unit, Vall dHebron University Hospital, Universitat Autonoma de Barcelona,
Barcelona, Spain; Spanish Maternal and Child Health Network Retic (SAMID), Instituto de Salud Carlos III, Madrid, Spain; Department
of Obstetrics, Hospital Universitario MaternoInfantil de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; Department
of Obstetrics, BCNnatal, Hospital Sant Joan de Deu, Barcelona, Spain; Department of Obstetrics, Hospital Son Llatzer, Palma de
Mallorca, Spain; **Department of Statistics and Preventive Medicine, Vall dHebron University Hospital, Universitat Autonoma de
Barcelona, Barcelona, Spain

K E Y W O R D S: intrauterine growth restriction; perinatal outcome; pre-eclampsia; second trimester; uterine artery Doppler

ABSTRACT induction of labor) in patients developing placenta-related

Objectives To ascertain whether screening for
pre-eclampsia (PE) and intrauterine growth restric-
tion (IUGR) by uterine artery (UtA) Doppler in the
second trimester of pregnancy and targeted surveil-
lance improve maternal and perinatal outcomes in an
unselected population.
Methods This was a multicenter randomized open-label
controlled trial. At the routine second-trimester anomaly
scan, women were assigned randomly to UtA Doppler
or non-Doppler groups. Women with abnormal UtA
Doppler were offered intensive surveillance at high-risk
clinics of the participating centers with visits every
4 weeks that included measurement of maternal blood
pressure, dipstick proteinuria, fetal growth and Doppler
examination. The primary outcome was a composite
score for perinatal complications, defined as the pres-
ence of any of the following: PE, IUGR, spontaneous
labor < 37 weeks gestation, placental abruption, still-
birth, gestational hypertension, admission to neonatal
intensive care unit and neonatal complications. Sec-
ondary outcomes were a composite score for maternal
complications (disseminated intravascular coagulation,
maternal mortality, postpartum hemorrhage, pulmonary
edema, pulmonary embolism, sepsis), and medical inter-
ventions (for example, corticosteroid administration and
complications.
Results In total, 11 667 women were included in the
study. Overall, PE occurred in 348 (3.0%) cases,
early-onset PE in 48 (0.4%), IUGR in 722 (6.2%),
early-onset IUGR in 93 (0.8%) and early-onset PE
with IUGR in 32 (0.3%). UtA mean pulsatility
index > 90th percentile was able to detect 59% of
early-onset PE and 60% of early-onset IUGR with
a false-positive rate of 11.1%. When perinatal and
maternal data according to assigned group (UtA Doppler
vs non-Doppler) were compared, no differences were
found in perinatal or maternal complications. However,
screened patients had more medical interventions, such
as corticosteroid administration (relative risk (RR), 1.79
(95% CI, 1.42.3)) and induction of labor for IUGR
(RR, 1.36 (95% CI, 1.071.72)). In women developing
PE or IUGR, there was a trend towards fewer maternal
complications (RR, 0.46 (95% CI, 0.191.11)).
Conclusions Routine second-trimester UtA Doppler
ultrasound in an unselected population identifies approxi-
mately 60% of women at risk for placental complications;
however, application of this screening test failed to
improve short-term maternal and neonatal morbidity and
mortality. Copyright 2016 ISUOG. Published by John
Wiley & Sons Ltd.

Correspondence to: Dr E. Llurba, Maternal-Foetal Medicine Unit, Department of Obstetrics, Vall dHebron University Hospital, Universitat
Autonoma de Barcelona, Psg. Vall dHebron 129-139, 08035-Barcelona, Spain (e-mail: elisa.llurba@vhir.org)
#B.G. and E.L. contributed equally to this work.
Accepted: 22 January 2016

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. RANDOMIZED CONTROLLED TRIAL
Outcome of pregnancy according to second-trimester UtA Doppler and targeted surveillance
INTRODUCTION
Pre-eclampsia (PE) and intrauterine growth restriction
(IUGR) are estimated to affect 410% of all pregnancies,
accounting for a large proportion of premature iatrogenic
deliveries and maternal morbidity in developed countries1 .
Therefore, prediction and prevention of PE and IUGR
remain major goals in fetalmaternal medicine.
Both PE and IUGR are associated with pathogenic
evidence of placental underperfusion and ischemia2 . In
these cases, failure of the perivascular and endovascular
trophoblastic invasion into the spiral arteries has
been described3 , and maternal spiral arteries fail to
become low-resistance vessels. Uteroplacental blood flow
can be studied non-invasively by Doppler ultrasound.
Flow resistance in the uterine arteries (UtAs) decreases
progressively during the first and second trimesters in
normal pregnancy4 . However, in pregnancies with PE or
IUGR, flow resistance in the UtAs fails to decrease before
clinical signs of the disease become apparent5 . These
findings are supported by histological studies that show
that the Doppler resistance index is inversely related to
the percentage of vessels that demonstrate trophoblastic
invasion6,7 .
Over the last 25 years, a number of Doppler
ultrasound studies have confirmed that increased blood
flow resistance in the UtAs is associated with a
greater risk of the subsequent development of PE
and/or IUGR5 , especially severe early-onset types, with
sensitivities of 8090%8 . While there is no effective
therapeutic intervention for the prevention of PE and/or
IUGR, the UK National Institute for Health and Care
Excellence (NICE) guideline points out that a womans
degree of risk for PE should be evaluated so that an
appropriate plan for subsequent scheduling of antenatal
appointments and ultrasound growth scans can be
formulated9 . Early estimation of patient-specific risks for
these pregnancy complications could potentially improve
outcome by referring such patients to specialist clinics
for close monitoring and targeted intervention such as
administration of magnesium sulfate or corticosteroids
for fetal lung maturation10 . However, existing data do
not provide conclusive evidence that the use of routine
second-trimester UtA Doppler in low-risk or unselected
populations benefits either the mother or the baby11,12 .
The aim of this study was to ascertain whether
screening for the risk of PE and IUGR by UtA Doppler
in the second trimester of pregnancy and targeted
surveillance improve maternal and perinatal outcomes in
an unselected population.
SUBJECTS AND METHODS
Study population
The UTOPIA (Uterine Test tO detect Pre-eclampsIA)
study was a randomized controlled trial conducted at four
centers in Spain: Vall dHebron University Hospital, Sant
Joan de Deu University Hospital, Las Palmas de Gran
Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd.
681
Canaria University Hospital and Son Llatzer Hospital; the
ethics committee of each participating hospital approved
the study. At these centers, all pregnant women were
offered a transabdominal ultrasound examination at
1922 weeks gestation for measurement of fetal growth
and screening for fetal abnormalities. All women with a
singleton pregnancy and no major fetal abnormality were
offered the option of participating in the study. Written
informed consent was obtained in all cases.
Pregnant women were assigned randomly, according
to a computer-generated allocation sequence at a 1:1
ratio, to a group undergoing UtA Doppler examination
(UtA Doppler group) or a group without UtA Doppler
(non-Doppler group). Owing to the nature of the test, this
study was not masked. Examination results in the UtA
Doppler group were available to the clinicians. Women
with abnormal UtA Doppler, defined as a mean pulsatility
index (PI) > 90th percentile for gestational age13 , were
offered intensive surveillance at high-risk clinics of
the participating centers with visits every 4 weeks that
included measurement of maternal blood pressure, dip-
stick proteinuria, fetal growth and Doppler examination.
Additionally, the women were advised to have their
blood pressure and dipstick proteinuria measured once a
week and request an appointment if their blood pressure
was over 140/90 mmHg, protein in urine > 1+ or if they
had clinical signs of PE. Women in the non-Doppler
group were followed according to their baseline charac-
teristics and obstetric history and were offered a routine
third-trimester scan according to Spanish guidelines14 .
The primary outcome was a composite score for peri-
natal complications, defined as the presence of any of the
following: PE, IUGR, spontaneous labor < 37 weeks ges-
tation, placental abruption, stillbirth, gestational hyper-
tension, admission to the neonatal intensive care unit or
severe neonatal morbidity. Severe neonatal morbidity was
defined as the presence of one or more of the following:
severe respiratory distress, intraventricular hemorrhage
grade IIIIV, treated persistent ductus arteriosus, renal
dysfunction, necrotizing enterocolitis, intestinal perfo-
ration, vertical sepsis, nosocomial sepsis, retinopathy
of prematurity treated with laser, bronchopulmonary
dysplasia, periventricular leukomalacia, postnatal admin-
istration of corticosteroids or inotropic drugs and/or
death. Secondary outcomes were: (1) a composite score
for maternal complications (disseminated intravascular
coagulation, maternal mortality, postpartum hemorrhage,
pulmonary edema, pulmonary embolism, sepsis); and (2)
medical interventions (such as administration of corticos-
teroid or induction of labor) in patients developing any
complication derived from placental insufficiency (PE,
IUGR, small-for-gestational age (SGA), placental abrup-
tion, stillbirth).
Accepting an alpha risk of 0.05 and a beta risk of
0.2 in a two-sided test, 5989 subjects were necessary in
each group to detect a statistically significant proportion
difference, expected to be 0.17 in the non-Doppler group
and 0.15 in the UtA Doppler group. A drop-out rate of
12% was anticipated.
Ultrasound Obstet Gynecol 2016; 47: 680689.
682 Garca et al.

Women attending second-trimester

anomaly scan at participating
centers between
June 2006 and May 2010
(n = 13 599)

Excluded (n = 1932):
Multiple pregnancy, fetal
abnormality or lack of consent

Study population
(n = 11 667)

Women assigned to Women assigned to

UtA Doppler group non-Doppler group
(n = 5776) (n = 5891)

UtA-PI 90th UtA-PI > 90th

percentile percentile
(n = 5109) (n = 667) Routine
antenatal care

Routine BP and protein

antenatal care checked weekly,
fetal growth checked
every 4 weeks

Maternal and perinatal outcome

Figure 1 Flowchart of study population of pregnant women assigned randomly to undergo uterine artery (UtA) Doppler assessment or no
Doppler assessment in the second trimester. BP, blood pressure; PI, pulsatility index.

A first-trimester ultrasound examination had been Table 1 Demographic and clinical characteristics of study
performed in all patients, and crownrump length population of women with singleton pregnancy assigned randomly
to undergo uterine artery (UtA) Doppler assessment or no Doppler
measurement was used to date the pregnancy. No specific assessment in the second trimester, to screen for risk of
biochemical or biophysical assessment for PE risk was pre-eclampsia (PE) and intrauterine growth restriction (IUGR)
made in the first trimester of pregnancy. All ultrasound
scans were performed by obstetricians specialized in fetal Non-Doppler UtA Doppler
ultrasound. Quality control of screening, data handling Characteristic (n = 5891) (n = 5776) P
and verification of adherence to the protocol at the dif- Maternal age (years) 30 1 30 1 0.6
ferent centers were undertaken by the trial coordinators. Ethnicity 0.36
UtA Doppler velocimetry was evaluated at White 5213 (88.5) 5257 (91.0)
1922 weeks gestation by transabdominal ultra- South American 448 (7.6) 352 (6.1)
Black 84 (1.4) 43 (0.7)
sound using 3.55-MHz probes: Siemens Antares
Other 146 (2.5) 124 (2.1)
(Siemens Medical Solutions, Mountain View, CA, USA) Smoker (> 5 cigarettes/day) 396 (6.7) 371 (6.4) 0.07
or Voluson E8 (GE Medical Systems, Zipf, Austria). Body mass index (kg/m2 ) 25.2 5.3 25.4 5.4 0.08
Flow-velocity waveforms of the right and left UtAs were Nulliparous 3417 (58.0) 3310 (57.3) 0.44
visualized with the patient semi-recumbent and the UtA Chronic hypertension 104 (1.8) 135 (2.3) 0.1
was identified on a longitudinal scan, lateral to the uterus. Type I or II diabetes 39 (0.7) 61 (1.1) 0.58
Previous PE 26 (0.4) 25 (0.4) 0.7
In that position, the scan showed the bifurcation of the
Previous IUGR 7 (0.1) 9 (0.2) 0.17
common iliac artery. Recordings were made at the point
at which the UtA and the external iliac artery appeared Data are given as mean SD or n (%).
to have crossed each other, as detected by color-flow
Doppler. Pulsed-wave Doppler was then used to obtain
three consecutive waveforms. The PI was then measured Risk factors from maternal history were obtained
and the presence or absence of an early diastolic notch prospectively via a patient-completed questionnaire on
was noted. The process was repeated for the contralateral maternal age, race, height, weight, smoking status,
UtA and the mean PI of the two vessels was calculated. obstetric history (previous PE, IUGR, placental abruption

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2016; 47: 680689.
Outcome of pregnancy according to second-trimester UtA Doppler and targeted surveillance 683

or stillbirth) and medical history including chronic
hypertension or diabetes. Demographic characteristics
and Doppler findings were recorded in a computer
database at the time of Doppler examination at each
participating center. The study centers had a standardized
protocol for corticosteroids and magnesium sulfate
administration. The indications for elective delivery were
those of the common protocol published by Vall dHebron
University Hospital15 . Data on pregnancy outcomes were
obtained from examination of each patients clinical
history and labor-ward records.
For the purpose of this study, both IUGR and PE
were classified as early onset (requiring delivery < 34
weeks gestation) or late onset ( 34 weeks). The criteria
for the definition of PE were those of the International
Society for the Study of Hypertension in Pregnancy10 .
PE was diagnosed if a previously normotensive woman
had systolic or diastolic blood pressure > 140/90 mmHg
measured twice (4 h apart) and proteinuria > 300 mg in a
24-h urine specimen or 2+ protein on dipsticks in urine
(4 h apart) after 20 weeks gestation. IUGR was diagnosed
if the estimated fetal weight was < 10th percentile for
gestational age in our population, together with Doppler
umbilical artery PI > 95th percentile, or if the estimated
fetal weight was < 3rd percentile, irrespective of the
umbilical artery Doppler findings16 . SGA was defined
as an estimated fetal weight between the 3rd and the 10th
percentiles with normal umbilical Doppler16 .
Statistical analysis
Mean UtA-PI was not normally distributed and was there-
fore expressed as median interquartile range. Fishers
exact test was used to analyze variables from mater-
nal history and an independent t-test (MannWhitney
U-test) was used for analysis of continuous variables
where appropriate.
Sensitivity, specificity, positive predictive value, neg-
ative predictive value and likelihood ratio of a UtA-PI
cut-off of 1.40 (90th centile) in the prediction of PE
and/or IUGR were calculated; P < 0.05 was considered
to be statistically significant.
Logistic regression was used to obtain the odds
ratio and 95% CIs for PE in relation to variables
from maternal history. Multivariate analysis to calculate
receiveroperating characteristics (ROC) curves was
performed using variables from maternal history found to
be independent on univariate analysis.

Table 2 Performance of uterine artery pulsatility index > 1.40 at 1922 weeks gestation in screening for various pregnancy outcomes

Outcome Sensitivity (95% CI) (%) Specificity (95% CI) (%) LR+ (95% CI) LR (95% CI)

PE < 34 weeks 58.6 (38.976.5) 88.7 (87.889.5) 5.18 (3.77.1) 0.47 (0.30.7)
PE 34 weeks 38.4 (30.446.7) 89.1 (88.389.9) 2.33 (1.73.2) 0.84 (0.70.9)
Gestational hypertension 31.0 (19.544.5) 88.6 (87.889.4) 2.73 (1.84.0) 0.78 (0.60.9)
IUGR < 34 weeks 59.6 (44.273.6) 88.8 (88.089.6) 5.34 (4.26.8) 0.45 (0.030.6)
IUGR 34 weeks 24.0 (19.428.9) 89.2 (88.390.0) 2.22 (1.82.7) 0.85 (0.80.9)
PE and IUGR < 34 weeks 36.2 (28.045.7) 89.0 (88.289.8) 5.68 (3.98.1) 0.40 (0.20.8)
PE and IUGR 34 weeks 28.3 (24.332.6) 89.9 (89.190.7) 2.91 (1.65.3) 0.75 (0.61.0)
Small-for-gestational age 17.7 (14.022.0) 94.1 (93.494.7) 1.57 (1.22.0) 0.93 (0.91.0)

IUGR, intrauterine growth restriction; LR+, positive likelihood ratio; LR, negative likelihood ratio; PE, pre-eclampsia.

(a) 1.0 (b)

1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
Sensitivity

Sensitivity

0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
1 Specificity 1 Specificity

Figure 2 Receiveroperating characteristics curves showing sensitivities, for a given screen-positive rate, of mean uterine artery pulsatility
index (UtA-PI) ( ) and the combination of UtA-PI and maternal history characteristics ( ) in the detection of early-onset
pre-eclampsia (PE) and intrauterine growth restriction (IUGR) (a) and late-onset PE and IUGR (b) in a cohort of 11 667 pregnant women.

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2016; 47: 680689.
684 Garca et al.

Table 3 Perinatal outcome, according to second-trimester uterine artery pulsatility index (UtA-PI), in 5776 singleton pregnancies screened
for risk of pre-eclampsia (PE) and intrauterine growth restriction (IUGR)

UtA-PI 90th p UtA-PI > 90th p RR (95% CI)

Outcome (n = 5109) (n = 667) or P
GA at screening (weeks) 20 (19.122.3) 20.3 (19.222.6) P = 0.15
Pregnancy complication
PE < 34 weeks 12 (0.2) 17 (2.5) 10.8 (5.222.6)
PE 34 weeks 90 (1.8) 56 (8.3) 4.8 (3.456.59)
IUGR < 34 weeks 19 (0.4) 28 (4.2) 11.3 (6.320.1)
IUGR 34 weeks 254 (5.0) 80 (12.0) 2.4 (1.93)
Early-onset PE and IUGR 6 (0.1) 9 (1.3) 11.5 (4.132.2)
Small-for-gestational age 306 (6.0) 66 (9.7) 1.65 (1.282.1)
Placental abruption 16 (0.3) 12 (1.8) 2.7 (2.712)
Stillbirth 26 (0.5) 11 (1.6) 11.5 (4.132.1)
Gestational hypertension 40 (0.8) 18 (2.7) 3.4 (26)
Medical intervention
Magnesium sulfate 54 (1.1) 46 (6.8) 6.5 (4.49.6)
Corticosteroids for fetal lung maturation 78 (1.5) 96 (14.3) 9.4 (712.6)
Perinatal outcome
GA at delivery (weeks) 39.5 1.9 38.6 2.9 P < 0.0001
Spontaneous labor 4262 (83.4) 459 (68.8) 0.83 (0.780.87)
Spontaneous labor < 37 weeks 221 (4.3) 32 (4.8) 1.11 (0.771.59)
Indication for delivery
PE 129 (2.5) 47 (7) 2.79 (2.023.9)
IUGR 108 (2.1) 52 (7.7) 3.7 (2.68)
Placental abruption 10 (0.2) 5 (0.8) 1.5 (0.36.7)
Mode of delivery
Vaginal 4382 (85.8) 535 (80.2) 0.94 (0.90.97)
Cesarean section 727 (14.2) 132 (19.8) 1.39 (1.181.64)
Cesarean section due to abnormal cardiotocography 253 (5.0) 53 (7.9) 1.6 (1.212.13)
Birth weight (g) 3290 330 3100 290 P = 0.001
Birth weight < 10th p 641 (12.5) 165 (25.3) 1.97 (1.72.29)
5-min Apgar score 7 50 (1.0) 10 (1.5) 1.53 (0.783)
Umbilical artery pH < 7.1 60 (1.2) 13 (2.0) 1.66 (0.93)
Neonatal complication
Composite score for severe neonatal morbidity* 404 (7.9) 90 (13.4) 1.71 (1.382.1)
Days in NICU 10 0.7 22 23 P < 0.001
Neonatal mortality 25 (0.5) 8 (1.2) 2.45 (1.115.41)
Maternal complication
Composite score for maternal complications 97 (1.9) 7 (1.0) 0.55 (0.261.18)
Composite score for perinatal complications 1157 (22.6) 260 (39.0) 1.72 (1.541.91)

Data are given as median (interquartile range), mean SD or n (%). *Composite score for severe neonatal morbidity defined as presence of
any of the following: severe respiratory distress, intraventricular hemorrhage Grades IIIIV, treated ductus arteriosus persistence, renal
dysfunction, necrotizing enterocolitis, intestinal perforation, vertical sepsis, nosocomial sepsis, retinopathy of prematurity treated with laser,
bronchopulmonary dysplasia, periventricular leukomalacia, postnatal administration of corticosteroids or inotropic drugs and/or death.
Composite score for maternal complications defined as disseminated intravascular coagulation, maternal death, postpartum hemorrhage,
pulmonary edema, pulmonary embolism or sepsis. Composite score for perinatal complications defined as presence of any of the following:
PE, IUGR, spontaneous labor < 37 weeks, placental abruption, stillbirth, gestational hypertension, admission to neonatal intensive care unit
(NICU) and neonatal complications. GA, gestational age; p, percentile; RR, relative risk comparing Doppler group with non-Doppler group.

The sensitivity and specificity for different cut-offs of
marker levels were calculated and ROC curves were
constructed to compare the performance of UtA Doppler
and maternal risk factor tests for detecting early- or
late-onset PE. Relative risks (RR), with 95% CIs, for
maternal and fetal morbidity and mortality and medical
interventions were calculated, comparing the two study
groups. Data were analyzed using SPSS 13.0 (SPSS,
Chicago, IL, USA) and STATA/SE 8.2 (StataCorp, College
Station, TX, USA) statistical packages.
RESULTS
From June 2006 to May 2010, 13 599 women attended
the second-trimester anomaly scan at the participating
centers; 14.2% were not eligible owing to multiple
pregnancy, fetal abnormality or lack of consent to
participate in the study; therefore 11 667 (85.8%) cases
formed the study population. UtA-PI showed an asym-
metric distribution, skewed to the right with an average
value of 0.95, with the 90th percentile at 1.42 and the 95th
percentile at 1.64. The UtA Doppler group consisted of
5776 women, 667 (11.5%) of whom had a UtA-PI > 90th
percentile, and the non-Doppler group consisted of 5891
women (Figure 1).
No differences were found between the demographic
and screening characteristics of the two groups. Maternal
risk factors for the development of PE are shown in
Table 1. No differences were observed in age, ethnicity,
nulliparity, body mass index, smoking status, history of
hypertension or Type I diabetes, previous PE or IUGR
between the groups.

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2016; 47: 680689.
Outcome of pregnancy according to second-trimester UtA Doppler and targeted surveillance 685

Table 4 Perinatal outcome of study group of women with singleton pregnancy assigned randomly to undergo second-trimester uterine artery
(UtA) Doppler assessment or no Doppler assessment in screening for pre-eclampsia (PE) and intrauterine growth restriction (IUGR)

Non-Doppler UtA Doppler RR (95% CI)

Outcome (n = 5891) (n = 5776) or P

GA at screening (weeks) 20.2 (1922.5) 20.1 (19.122.6) P = 0.12

Pregnancy complications
PE < 34 weeks 19 (0.3) 29 (0.5) 1.56 (0.872.7)
PE 34 weeks 154 (2.6) 146 (2.5) 0.97 (0.71.2)
IUGR < 34 weeks 46 (0.8) 47 (0.8) 1.04 (0.71.5)
IUGR 34 weeks 295 (5.0) 334 (5.8) 1.15 (0.91.3)
Early-onset PE and IUGR 17 (0.3) 15 (0.3) 0.9 (0.41.8)
Small-for-gestational age 362 (6.1) 372 (6.4) 1 (0.91.2)
Placental abruption 18 (0.3) 28 (0.5) 1.59 (0.82.8)
Stillbirth 38 (0.6) 37 (0.6) 0.99 (0.61.5)
Gestational hypertension 52 (0.9) 58 (1.0) 1.14 (0.81.6)
Medical intervention
Magnesium sulfate 82 (1.4) 100 (1.7) 1.24 (0.931.6)
Corticosteroids for fetal lung maturation 99 (1.7) 174 (3.0) 1.79 (1.42.3)
Perinatal outcome
GA at delivery (weeks) 39.4 2.1 39.4 2.1 P = 0.87
Spontaneous labor 4831 (82.0) 4721 (81.7) 1 (0.91.01)
Spontaneous labor < 37 weeks 301 (5.1) 253 (4.4) 0.86 (0.71.01)
Indication for induction
PE 188 (3.2) 176 (3.0) 0.95 (0.71.17)
IUGR 120 (2.0) 160 (2.8) 1.36 (1.071.72)
Placental abruption 13 (0.2) 15 (0.3) 1.2 (0.52.5)
Mode of delivery
Vaginal 4944 (83.9) 4917 (85.1) 1.01 (11.03)
Cesarean section 947 (16.1) 859 (14.9) 0.93 (0.81.01)
Cesarean section due to abnormal cardiotocography 298 (5.1) 306 (5.3) 1.05 (0.91.2)
Birth weight (g) 3234 150 3236 14 P = 0.86
Birth weight < 10th percentile 812 (13.8) 806 (14.0) 1.01 (0.91.1)
5-min Apgar score 7 60 (1.0) 60 (1.0) 1.02 (0.71.5)
Umbilical artery pH < 7.1 65 (1.1) 73 (1.3) 1.15 (0.81.6)
Neonatal complication
Composite score for severe neonatal morbidity* 485 (8.2) 494 (8.6) 1.04 (0.91.1)
Days in NICU 11.7 0.8 12.4 0.8 P = 0.52
Neonatal mortality 30 (0.5) 33 (0.6) 1.12 (0.71.8)
Maternal complication
Composite score for maternal complications 111 (1.9) 104 (1.8) 0.96 (0.71.2)
Composite score for perinatal complications 1419 (24.1) 1417 (24.5) 1.02 (0.91.09)

Data are given as median (interquartile range), mean SD or n (%). *Composite score for severe neonatal morbidity defined as presence of
any of the following: severe respiratory distress, intraventricular hemorrhage Grades IIIIV, treated ductus arteriosus persistence, renal
dysfunction, necrotizing enterocolitis, intestinal perforation, vertical sepsis, nosocomial sepsis, retinopathy of prematurity treated with laser,
bronchopulmonary dysplasia, periventricular leukomalacia, postnatal administration of corticosteroids or inotropic drugs and/or death.
Composite score for maternal complications defined as disseminated intravascular coagulation, maternal death, postpartum hemorrhage,
pulmonary edema, pulmonary embolism or sepsis. Composite score for perinatal complications defined as presence of any of the following:
PE, IUGR, spontaneous labor < 37 weeks, placental abruption, stillbirth, gestational hypertension, admission to neonatal intensive care unit
(NICU) and neonatal complications. GA, gestational age; RR, relative risk comparing UtA Doppler group with non-Doppler group.

Overall, PE occurred in 348 (3.0%) cases, early-onset
PE in 48 (0.4%), SGA in 734 (6.3%), IUGR in 722
(6.2%), early-onset IUGR in 93 (0.8%) and early-onset
PE with IUGR in 32 (0.3%). The screening performance
of UtA-PI > 90th percentile for detecting placenta-related
complications is shown in Table 2. UtA-PI > 90th
percentile was able to detect 59% of early-onset PE
and 60% of early-onset IUGR with a false-positive rate
(FPR) of 11.1%. By comparing the areas under the ROC
curves (AUC), we observed that UtA-PI alone (AUC,
0.75 (95% CI, 0.690.82)) yielded similar results to
those achieved when combined with maternal history for
detecting early-onset PE and IUGR (AUC, 0.76 (95% CI,
0.690.83); P = 0.64; Figure 2a). In contrast, Doppler
combined with maternal history (AUC, 0.66 (95% CI,
0.600.73)) seemed to perform better than UtA-PI
alone (AUC, 0.60 (95% CI, 0.540.66); P = 0.001) in
predicting late-onset PE (Figure 2b). When combining
these two methods, the sensitivity for predicting both
early- and late-onset PE statistically increased (AUC,
0.71 (95% CI, 0.670.75) vs 0.68 (95% CI, 0.640.72);
P = 0.002).
As expected, women with abnormal UtA Doppler
had a higher risk of adverse perinatal outcome than

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2016; 47: 680689.
686
Table 5 Causes of stillbirth in study population of pregnant women assigned randomly to undergo second-trimester uterine artery (UtA)
Doppler assessment or no Doppler assessment in screening for pre-eclampsia and intrauterine growth restriction
UtA-PI 90th p
Cause Non-Doppler (n = 38/5891)
Placental insufficiency 10 (26.3)
Other* 28 (73.7)
Data are given as n (%). *Chorioamnionitis, premature rupture of membranes and unknown cause. p, percentile; PI, pulsatility index;
RR, relative risk comparing UtA Doppler group with non-Doppler group.
did those with UtA-PI 90th percentile (RR, 1.72
(95% CI, 1.541.91); Table 3). When perinatal and
maternal data according to the assigned group were
compared (Table 4), Doppler-screened patients had a
slight increase in the number of medical interven-
tions, such as corticosteroid administration (RR, 1.79
(95% CI, 1.42.3)) and induction of labor for IUGR
(RR, 1.36 (95% CI, 1.071.72)). However, no differ-
ences were found in the composite scores for peri-
natal complications (RR, 1.02 (95% CI, 0.91.09))
and severe neonatal morbidity (RR, 1.04 (95% CI,
0.91.11)) or neonatal mortality (RR, 1.12 (95% CI,
0.71.8)) or composite score for maternal complications
(RR, 0.96 (95% CI, 0.71.2)).
Two maternal deaths, one in each study group, and
75 intrauterine fetal deaths occurred during the study
period. No difference was found in the number of fetal
deaths according to the study group (non-Doppler, n = 38
vs Doppler, n = 37; RR, 0.91 (95% CI, 0.581.44))
(Table 5).
A secondary analysis was performed in patients
who developed placental insufficiency-related complica-
tions: PE, IUGR, SGA, placental abruption and still-
birth (Table 6). In these cases, women who underwent
UtA Doppler examination in the second trimester had
higher rates of administration of corticosteroids for
fetal lung maturation (RR, 1.65 (95% CI, 1.092.51))
(Figure 3) although no difference was found for neonatal
complications (RR, 1.13 (95% CI, 0.921.4)). How-
ever, among women developing PE or IUGR, those in
the Doppler-screening group had fewer maternal com-
plications (RR, 0.46 (95% CI, 0.191.11)), although
this difference did not reach statistical significance
(Figure 4).
A sub-analysis was performed comparing the perinatal
outcome and interventions in cases with prenatal
prediction of PE or IUGR due to abnormal UtA Doppler
and in cases with a lack of prediction due to normal
UtA Doppler or in which no Doppler was performed
(Table S1). Women with abnormal UtA Doppler had
an increased risk of complications whereas those who
developed placental insufficiency but had normal UtA
Doppler in the second trimester had a milder form of the
disease, which accounts for the better perinatal outcomes
in this group.
Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd.
Garca et al.
UtA Doppler (n = 37/5776)
UtA-PI > 90th p
(n = 26) (n = 11) RR (95% CI)
9 (34.6) 5 (45.5) 0.85 (0.32.0)
17 (65.4) 6 (54.5) 0.57 (0.31.04)
DISCUSSION
This study provides evidence that the use of routine
UtA-Doppler screening to assess the risk of PE and
IUGR in the second trimester of pregnancy and targeted
surveillance do not improve maternal and perinatal
outcomes. Screened women who subsequently developed
placental insufficiency-related complications underwent
more medical interventions, such as administration of
corticosteroids for fetal lung maturation and induction of
labor for abnormal fetal growth or Doppler findings.
However, anticipation of the complications in some
of these cases failed to improve short-term neonatal
morbidity and mortality in the screened group, although
a trend towards decreased maternal complications was
observed in this group.
Targeted surveillance in the screened group did not
prevent the development of disease or prematurity,
or improve maternal or neonatal outcomes owing
to the severity of these conditions and the lack of
effective treatment other than delivery. Evidence from
a meta-analysis has shown that prevention of PE with
low-dose aspirin may be possible if treatment is started
before 16 weeks gestation17 . The present study supports
efforts being made to shift PE prediction from the second
to the first trimester. Recently, a combination of maternal
history, UtA Doppler, blood pressure measurement and
serum measurements of pregnancy-associated plasma
protein-A and placental growth factor has been shown to
detect the development of early-onset PE with a sensitivity
of up to 93% at a FPR of up to 5%18 22 .
One of the main limitations of second-trimester UtA
Doppler screening is the relatively low detection rate,
especially for late-onset cases. In the present study, such
screening was able to identify only one in three women
who went on to develop late-onset PE. Although late-onset
PE results in lower perinatal morbidity and mortality, it
is up to eight times more common than early-onset PE
and is the leading cause of late iatrogenic prematurity;
furthermore, it is a major risk factor for maternal
complications (around 50%), some as serious as eclampsia
or maternal death23 . Late-onset PE is a heterogeneous
condition with minimal or no placental involvement; thus,
tests based on identifying signs of abnormal placentation
can be limited in predicting this entity24 . A further
problem in attempting to identify cases of late placental
insufficiency complications is that an insult may occur at
Ultrasound Obstet Gynecol 2016; 47: 680689.
Outcome of pregnancy according to second-trimester UtA Doppler and targeted surveillance 687

Table 6 Perinatal outcome in pregnant women who developed placental insufficiency complications, according to whether they underwent
second-trimester uterine artery (UtA) Doppler assessment

Non-Doppler UtA Doppler RR (95% CI)

Outcome (n = 869) (n = 923) or P

Medical intervention
Magnesium sulfate 41 (4.7) 50 (5.4) 1.15 (0.771.72)
Corticosteroids for fetal lung maturation 33 (3.8) 58 (6.3) 1.65 (1.092.51)
Perinatal outcome
GA at delivery (weeks) 38.7 0.1 38.6 0.2 P = 0.52
Spontaneous labor 526 (60.5) 530 (57.4) 1.07 (0.991.16)
Mode of delivery
Vaginal 732 (84.2) 770 (83.4) 1.12 (1.071.1)
Cesarean section 137 (15.8) 153 (16.6) 1.05 (0.851.30)
Cesarean section due to abnormal cardiotocography 95 (10.9) 110 (11.9) 1.23 (0.951.6)
Birth weight (g) 2746 37 3100 290 P = 0.49
Birth weight < 10th percentile 352 (40.5) 371 (40.2) 1.12 (11.2)
Birth-weight centile 19.4 0.9 18.5 0.9 P = 0.49
5-min Apgar score 7 25 (2.9) 27 (2.9) 1.15 (0.61.9)
Umbilical artery pH < 7.1 31 (3.6) 30 (3.3) 1.03 (0.61.7)
Neonatal complication
Composite score for severe neonatal morbidity* 149 (17.1) 159 (17.2) 1.13 (0.921.4)
Days in NICU 19.3 1.8 20 1.7 P = 0.79
Neonatal mortality 30 (3.5) 33 (3.6) 1.17 (0.71.9)
Maternal complication
Composite score for maternal complications 16 (1.8) 7 (0.8) 0.46 (0.191.11)

Data are given as mean SD or n (%). *Composite score for severe neonatal morbidity defined as presence of any of the following: severe
respiratory distress, intraventricular hemorrhage grades IIIIV, treated ductus arteriosus persistence, renal dysfunction, necrotizing
enterocolitis, intestinal perforation, vertical sepsis, nosocomial sepsis, retinopathy of prematurity treated with laser, bronchopulmonary
dysplasia, periventricular leukomalacia, postnatal administration of corticosteroids or inotropic drugs and/or death. Composite score for
maternal complications defined as disseminated intravascular coagulation, maternal death, postpartum hemorrhage, pulmonary edema,
pulmonary embolism or sepsis. GA, gestational age; NICU, neonatal intensive care unit; RR, relative risk comparing UtA Doppler group
with non-Doppler group.

Events Events
UtA Doppler Non-Doppler
Intervention (n = 923) (n = 869) RR (95% CI)
Cesarean section 153 137 1.05 (0.851.30)
Induction of labor 393 343 1.08 (0.971.21)
Induction of labor for IUGR 86 53 1.53 (1.102.12)
Corticosteroid treatment 58 33 1.65 (1.092.51)
MgSO4 treatment 50 41 1.15 (0.771.72)
Composite score 740 607 1.15 (1.091.21)

0.5 0.7 1.5 2.0

Figure 3 Forest plot showing relative risk (RR) of medical interventions in pregnant women with placenta-related complications, including
pre-eclampsia, intrauterine growth restriction (IUGR), placental abruption or stillbirth, according to whether they underwent second-
trimester uterine artery (UtA) Doppler assessment. MgSO4 , magnesium sulfate.

the end of the second or in the third trimester, resulting in
failure of placental resistance to diminish, and therefore
it would not be observable on first- and second-trimester
evaluations. Thus, in a previous study, 80% of cases with
increased uteroplacental resistance in the third trimester
had shown no such change in the first25 .
Regarding the diagnosis of late-onset IUGR, we were
unable to show any improvement in the detection
of SGA or IUGR in the screened group compared
with the non-Doppler group. It should be emphasized
that routine third-trimester growth examination by
ultrasound is offered to all low- and high-risk pregnant
women according to Spanish guidelines14 and, therefore,
identification of women at risk and targeted surveillance
in the UtA Doppler group may have had a slight impact on
the detection of IUGR or SGA. Fortunately, appropriate
antenatal care, even in unexpected conditions, resulted
in good maternal and fetal outcomes26 . The results of
this study may have differed had it been carried out in a
different population with limited access to perinatal care.
UtA Doppler was able to predict the majority of
women who developed early-onset PE or IUGR; however,

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2016; 47: 680689.
688
Events Events
UtA Doppler Non-Doppler
Outcome (n = 923) (n = 869)
DIC 3 2
Hypertensive disorder 0 1
Maternal mortality 1 1
Postpartum hemorrhage 2 8
Pulmonary edema 1 2
Pulmonary embolism 0 1
Sepsis 0 1
Composite score 7 16
Figure 4 Forest plot showing relative risk (RR) of maternal morbidity and mortality in pregnant women with placenta-related
complications, including pre-eclampsia, intrauterine growth restriction, placental abruption or stillbirth, according to whether they
underwent second-trimester uterine artery (UtA) Doppler assessment. DIC, disseminated intravascular coagulation.
it was not useful in predicting adverse maternal or
fetal outcomes. Two maternal deaths occurred in our
population, one in each group. The first, in the
non-Doppler group, was a high-risk pregnancy with
chronic hypertension, obesity and previous PE in which
IUGR was diagnosed at 28 weeks gestation. However,
the patient failed to attend her antenatal appointments
and, at 32 weeks, was admitted to the emergency room
with respiratory distress syndrome and severe PE; she
suffered cardiorespiratory arrest while a Cesarean section
was being performed. The second case, in the UtA Doppler
group, was that of a pregnant woman with normal
second-trimester UtA Doppler who developed HELLP
syndrome at 38 weeks, complicated by intravascular
disseminated coagulation and hemorrhagic shock. In
addition, 37 and 38 intrauterine fetal deaths occurred in
the UtA Doppler and non-Doppler groups, respectively.
In the UtA Doppler group, 37.8% of fetal deaths were
attributed to placental causes vs 26% in the non-Doppler
group, which would suggest that the improvement in
diagnosis did not prevent this adverse outcome.
Limitations of the study
Although common criteria have been previously estab-
lished for the diagnosis and management of pregnancy
complications, the fact that this was a multicenter study
could account for slight intercenter differences in man-
agement. We also acknowledge that the gestation-specific
90th percentile for mean UtA-PI would have been more
accurate in selecting the population at risk, however,
a single cut-off value was chosen to facilitate clinical
recruitment. A further limitation of the study is that the
accuracy of current screening methods for the detection
and correct diagnosis of PE and IUGR is limited. Although
we did show that pre-selection of a high-risk population
by UtA Doppler improved the prenatal diagnosis of IUGR,
the study was not sufficiently powered to demonstrate
an impact on perinatal death. Moreover, the study was
also not sufficiently powered for the secondary outcome,
which was a composite score for maternal complications
Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd.
Garca et al.
RR (95% CI)
1.41 (0.248.43)
0.94 (0.0615.03)
0.24 (0.051.11)
0.47 (0.045.18)
0.46 (0.191.11)
0.01 0.1 10 100
(disseminated intravascular coagulation, maternal
mortality, postpartum hemorrhage, pulmonary edema,
pulmonary embolism, sepsis). In addition, owing to
the nature of the proposed intervention (comprehensive
control), blinding of physicians and patients was not
possible, and there might have been bias resulting in
overestimation of the prevalence of PE and IUGR.
Furthermore, the economic burden and psychological
impact of the implementation of this screening test were
not addressed.
Conclusions
Routine second-trimester UtA Doppler ultrasound in
unselected populations identifies approximately 60% of
women at risk of placental complications, however, appli-
cation of this screening test failed to improve short-term
maternal and neonatal morbidity and mortality. In light
of these conclusions, we recommend that second-trimester
UtA Doppler examination should be reserved for high-risk
pregnancies. Accordingly, current standards of practice
should be re-evaluated.
ACKNOWLEDGMENTS
This study was supported by research grants (06/1213,
07/1095) from the Fondo de Investigacion Sanitaria and
Maternal and Child Network SAMID (RD 08/0072 and
RD12/0026), financed by the Carlos III Institute of Health
in Spain and the European Regional Development Fund
(ERDF). The authors are grateful to Christine OHara for
her help with the English version of the paper.
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Table S1 Perinatal outcome in pregnant women who developed placental insufficiency complications,
according to prenatal prediction of pre-eclampsia (PE) and intrauterine growth restriction (IUGR) by
second-trimester uterine artery (UtA) Doppler assessment
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