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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


complications.
Objectives To ascertain whether screening for
pre-eclampsia (PE) and intrauterine growth restric- Results In total, 11 667 women were included in the
tion (IUGR) by uterine artery (UtA) Doppler in the study. Overall, PE occurred in 348 (3.0%) cases,
second trimester of pregnancy and targeted surveil- early-onset PE in 48 (0.4%), IUGR in 722 (6.2%),
lance improve maternal and perinatal outcomes in an early-onset IUGR in 93 (0.8%) and early-onset PE
unselected population. with IUGR in 32 (0.3%). UtA mean pulsatility
index > 90th percentile was able to detect 59% of
Methods This was a multicenter randomized open-label
early-onset PE and 60% of early-onset IUGR with
controlled trial. At the routine second-trimester anomaly
a false-positive rate of 11.1%. When perinatal and
scan, women were assigned randomly to UtA Doppler
maternal data according to assigned group (UtA Doppler
or non-Doppler groups. Women with abnormal UtA
vs non-Doppler) were compared, no differences were
Doppler were offered intensive surveillance at high-risk
found in perinatal or maternal complications. However,
clinics of the participating centers with visits every
screened patients had more medical interventions, such
4 weeks that included measurement of maternal blood
as corticosteroid administration (relative risk (RR), 1.79
pressure, dipstick proteinuria, fetal growth and Doppler
(95% CI, 1.42.3)) and induction of labor for IUGR
examination. The primary outcome was a composite
(RR, 1.36 (95% CI, 1.071.72)). In women developing
score for perinatal complications, defined as the pres-
PE or IUGR, there was a trend towards fewer maternal
ence of any of the following: PE, IUGR, spontaneous
complications (RR, 0.46 (95% CI, 0.191.11)).
labor < 37 weeks gestation, placental abruption, still-
birth, gestational hypertension, admission to neonatal Conclusions Routine second-trimester UtA Doppler
intensive care unit and neonatal complications. Sec- ultrasound in an unselected population identifies approxi-
ondary outcomes were a composite score for maternal mately 60% of women at risk for placental complications;
complications (disseminated intravascular coagulation, however, application of this screening test failed to
maternal mortality, postpartum hemorrhage, pulmonary improve short-term maternal and neonatal morbidity and
edema, pulmonary embolism, sepsis), and medical inter- mortality. Copyright 2016 ISUOG. Published by John
ventions (for example, corticosteroid administration and 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 681

INTRODUCTION Canaria University Hospital and Son Llatzer Hospital; the


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

Copyright 2016 ISUOG. Published by John Wiley & Sons Ltd. 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 fetal weight was < 3rd percentile, irrespective of the
hypertension or diabetes. Demographic characteristics umbilical artery Doppler findings16 . SGA was defined
and Doppler findings were recorded in a computer as an estimated fetal weight between the 3rd and the 10th
database at the time of Doppler examination at each percentiles with normal umbilical Doppler16 .
participating center. The study centers had a standardized
protocol for corticosteroids and magnesium sulfate Statistical analysis
administration. The indications for elective delivery were
those of the common protocol published by Vall dHebron Mean UtA-PI was not normally distributed and was there-
University Hospital15 . Data on pregnancy outcomes were fore expressed as median interquartile range. Fishers
obtained from examination of each patients clinical exact test was used to analyze variables from mater-
history and labor-ward records. nal history and an independent t-test (MannWhitney
For the purpose of this study, both IUGR and PE U-test) was used for analysis of continuous variables
were classified as early onset (requiring delivery < 34 where appropriate.
weeks gestation) or late onset ( 34 weeks). The criteria Sensitivity, specificity, positive predictive value, neg-
for the definition of PE were those of the International ative predictive value and likelihood ratio of a UtA-PI
Society for the Study of Hypertension in Pregnancy10 . cut-off of 1.40 (90th centile) in the prediction of PE
PE was diagnosed if a previously normotensive woman and/or IUGR were calculated; P < 0.05 was considered
had systolic or diastolic blood pressure > 140/90 mmHg to be statistically significant.
measured twice (4 h apart) and proteinuria > 300 mg in a Logistic regression was used to obtain the odds
24-h urine specimen or 2+ protein on dipsticks in urine ratio and 95% CIs for PE in relation to variables
(4 h apart) after 20 weeks gestation. IUGR was diagnosed from maternal history. Multivariate analysis to calculate
if the estimated fetal weight was < 10th percentile for receiveroperating characteristics (ROC) curves was
gestational age in our population, together with Doppler performed using variables from maternal history found to
umbilical artery PI > 95th percentile, or if the estimated 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 pregnancy, fetal abnormality or lack of consent to
marker levels were calculated and ROC curves were participate in the study; therefore 11 667 (85.8%) cases
constructed to compare the performance of UtA Doppler formed the study population. UtA-PI showed an asym-
and maternal risk factor tests for detecting early- or metric distribution, skewed to the right with an average
late-onset PE. Relative risks (RR), with 95% CIs, for value of 0.95, with the 90th percentile at 1.42 and the 95th
maternal and fetal morbidity and mortality and medical percentile at 1.64. The UtA Doppler group consisted of
interventions were calculated, comparing the two study 5776 women, 667 (11.5%) of whom had a UtA-PI > 90th
groups. Data were analyzed using SPSS 13.0 (SPSS, percentile, and the non-Doppler group consisted of 5891
Chicago, IL, USA) and STATA/SE 8.2 (StataCorp, College women (Figure 1).
Station, TX, USA) statistical packages. No differences were found between the demographic
and screening characteristics of the two groups. Maternal
RESULTS risk factors for the development of PE are shown in
Table 1. No differences were observed in age, ethnicity,
From June 2006 to May 2010, 13 599 women attended nulliparity, body mass index, smoking status, history of
the second-trimester anomaly scan at the participating hypertension or Type I diabetes, previous PE or IUGR
centers; 14.2% were not eligible owing to multiple 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 detecting early-onset PE and IUGR (AUC, 0.76 (95% CI,
PE in 48 (0.4%), SGA in 734 (6.3%), IUGR in 722 0.690.83); P = 0.64; Figure 2a). In contrast, Doppler
(6.2%), early-onset IUGR in 93 (0.8%) and early-onset combined with maternal history (AUC, 0.66 (95% CI,
PE with IUGR in 32 (0.3%). The screening performance 0.600.73)) seemed to perform better than UtA-PI
of UtA-PI > 90th percentile for detecting placenta-related alone (AUC, 0.60 (95% CI, 0.540.66); P = 0.001) in
complications is shown in Table 2. UtA-PI > 90th predicting late-onset PE (Figure 2b). When combining
percentile was able to detect 59% of early-onset PE these two methods, the sensitivity for predicting both
and 60% of early-onset IUGR with a false-positive rate early- and late-onset PE statistically increased (AUC,
(FPR) of 11.1%. By comparing the areas under the ROC 0.71 (95% CI, 0.670.75) vs 0.68 (95% CI, 0.640.72);
curves (AUC), we observed that UtA-PI alone (AUC, P = 0.002).
0.75 (95% CI, 0.690.82)) yielded similar results to As expected, women with abnormal UtA Doppler
those achieved when combined with maternal history for 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 Garca et al.

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 Doppler (n = 37/5776)


UtA-PI 90th p UtA-PI > 90th p
Cause Non-Doppler (n = 38/5891) (n = 26) (n = 11) RR (95% CI)

Placental insufficiency 10 (26.3) 9 (34.6) 5 (45.5) 0.85 (0.32.0)


Other* 28 (73.7) 17 (65.4) 6 (54.5) 0.57 (0.31.04)

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 DISCUSSION


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

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

Events Events
UtA Doppler Non-Doppler
Outcome (n = 923) (n = 869) RR (95% CI)

DIC 3 2 1.41 (0.248.43)


Hypertensive disorder 0 1
Maternal mortality 1 1 0.94 (0.0615.03)
Postpartum hemorrhage 2 8 0.24 (0.051.11)
Pulmonary edema 1 2 0.47 (0.045.18)
Pulmonary embolism 0 1
Sepsis 0 1
Composite score 7 16 0.46 (0.191.11)

0.01 0.1 10 100

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 (disseminated intravascular coagulation, maternal
fetal outcomes. Two maternal deaths occurred in our mortality, postpartum hemorrhage, pulmonary edema,
population, one in each group. The first, in the pulmonary embolism, sepsis). In addition, owing to
non-Doppler group, was a high-risk pregnancy with the nature of the proposed intervention (comprehensive
chronic hypertension, obesity and previous PE in which control), blinding of physicians and patients was not
IUGR was diagnosed at 28 weeks gestation. However, possible, and there might have been bias resulting in
the patient failed to attend her antenatal appointments overestimation of the prevalence of PE and IUGR.
and, at 32 weeks, was admitted to the emergency room Furthermore, the economic burden and psychological
with respiratory distress syndrome and severe PE; she impact of the implementation of this screening test were
suffered cardiorespiratory arrest while a Cesarean section not addressed.
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 Conclusions
syndrome at 38 weeks, complicated by intravascular Routine second-trimester UtA Doppler ultrasound in
disseminated coagulation and hemorrhagic shock. In unselected populations identifies approximately 60% of
addition, 37 and 38 intrauterine fetal deaths occurred in women at risk of placental complications, however, appli-
the UtA Doppler and non-Doppler groups, respectively. cation of this screening test failed to improve short-term
In the UtA Doppler group, 37.8% of fetal deaths were maternal and neonatal morbidity and mortality. In light
attributed to placental causes vs 26% in the non-Doppler of these conclusions, we recommend that second-trimester
group, which would suggest that the improvement in UtA Doppler examination should be reserved for high-risk
diagnosis did not prevent this adverse outcome. pregnancies. Accordingly, current standards of practice
should be re-evaluated.
Limitations of the study

Although common criteria have been previously estab- ACKNOWLEDGMENTS


lished for the diagnosis and management of pregnancy
This study was supported by research grants (06/1213,
complications, the fact that this was a multicenter study
07/1095) from the Fondo de Investigacion Sanitaria and
could account for slight intercenter differences in man-
Maternal and Child Network SAMID (RD 08/0072 and
agement. We also acknowledge that the gestation-specific
RD12/0026), financed by the Carlos III Institute of Health
90th percentile for mean UtA-PI would have been more
in Spain and the European Regional Development Fund
accurate in selecting the population at risk, however,
(ERDF). The authors are grateful to Christine OHara for
a single cut-off value was chosen to facilitate clinical
her help with the English version of the paper.
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
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SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:
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

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