The Journal of Maternal–Fetal and Neonatal Medicine 2002;12:78–88

Second-trimester uterine artery Doppler screening in

unselected populations: a review
A. T. Papageorghiou, C. K. H. Yu, S. Cicero, S. Bower and K. H. Nicolaides
Harris Birthright Research Centre for Fetal Medicin e, King’s College Hospital, L ondon, UK

Objective: Doppler ultrasound provides a non-invasive method for the study of the uteroplacental
circulation. In normal pregnancy, impedance to flow in the uterine arteries decreases with gestation,
which may be the consequence of trophoblastic invasion of the spiral arteries and their conversion
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15

into low-resistance vessels. Pre-eclampsia and fetal growth restriction are associated with failure of
trophoblastic invasion of spiral arteries, and Doppler studies, in these conditions, have shown that
impedance to flow in the uterine arteries is increased. A series of screening studies involving assess-
ment of impedance to flow in the uterine arteries have examined the potential value of Doppler in
identifying pregnancies at risk of the complications of impaired placentation. This review examines
the findings of Doppler studies in unselected populations.
Methods: Searches of a computerized medical database were performed to identify relevant studies.
Only those studies that provided sufficient data to allow calculation of the performance of the test
were included in the analysis. Likelihood ratios were calculated for each study and are reported
for pre-eclampsia, fetal growth restriction and perinatal death as well as for more severe forms of
pre-eclampsia and fetal growth restriction.
Results: The literature search identified 19 relevant studies, four of which were excluded from the
For personal use only.

further analysis. The main characteristics and results of the 15 remaining studies provided discrep-
ant results, which may be the consequence of differences in Doppler technique for sampling, the
definition of abnormal flow velocity waveform, differences in the populations examined, the gesta-
tional age at which women were studied and different criteria for the diagnosis of pre-eclampsia and
fetal growth restriction. Nevertheless, the studies provided evidence that increased impedance to
flow in the uterine arteries is associated with increased risk for subsequent development of
pre-eclampsia, fetal growth restriction and perinatal death. In addition, women with normal imped-
ance to flow in the uterine arteries constituted a group that have a low risk of developing obstetric
complications related to uteroplacental insufficiency.
Conclusions: The review suggests that increased impedance to flow in the uterine arteries in
pregnancies attending for routine antenatal care identifies about 40% of those who subsequently
develop pre-eclampsia and about 20% of those who develop fetal growth restriction. Following
a positive test, the likelihood of these complications is increased by about 6 and 3.5 times,
respectively.

Key words: DOPPLER ULTRASOUND ; UTERINE ARTERY; PREGNANCY SCREENING ; PRE-

ECLAMPSIA ; FETAL GROWTH RESTRICTION; PERINATAL DEATH

INTRODUCTION
In normal pregnancy, the spiral arteries, destined to
become the uteroplacental arteries in the placental bed,
undergo a complex series of morphological changes. The
vessels are invaded by trophoblast, which becomes incorpo-
rated into the vessel wall and replaces the endothelium,
muscular layer and neural tissue1–4. The result of these
physiological changes is the conversion of the small spiral
arteries into vessels of greater diameter with low resistance
and high compliance, that are unresponsive to maternal
vasomotor activity1,5. This vascular transformation in the
uterus is necessary to ensure a dramatic increase in blood
supply to the intervillous space.
In pre-eclampsia and fetal growth restriction, there is
failure of the perivascular and endovascular trophoblastic

Correspondence: Pr ofessor K. H. Nicolaides, Har ris Birthright Research Centre for Fetal Medicine, King’s College Hospital Medical
School, Denm ark Hill, L ondon SE5 9RS, UK
R EVIEW 78 Received 22–05–02 Accepted 01–06–02
 Second-trimester uterine artery Doppler screening
invasion of spiral arteries. Although, in 50–70% of the
spiral arteries, there is trophoblastic invasion, this is
confined to the decidual part of the vessels and does not
extend into the myometrial segments2,3,6,7. In addition,
many vessels are occluded by fibrinoid material and exhibit
adjacent foam cell accumulation and a perivascular mono-
nuclear cell infiltrate, which is referred to as atherosis8–10.
Doppler ultrasound provides a non-invasive method
for the study of the uteroplacental circulation. In normal
pregnancy, impedance to flow in the uterine arteries
decreases with gestation and this presumably reflects the
trophoblastic invasion of the spiral arteries and their con-
version into low-resistance vessels11. Cross-sectional
studies in pregnancies with pre-eclampsia or fetal growth
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restriction have shown that impedance to flow in the
uterine arteries is increased (Figures 1 and 2). This is com-
patible with the findings from histopathological studies
that, in such pregnancies, there is failure of the normal
development of maternal placental arteries into low-
resistance vessels.
A series of screening studies involving assessment of
impedance to flow in the uterine arteries have examined
the potential value of Doppler in identifying pregnancies at
risk of the complications of impaired placentation. This
For personal use only.
Figure 1 Normal flow velocity waveform from the uterine artery
at 24 weeks of gestation
Figure 2 Flow velocity waveform from the uterine artery at 24
weeks of gestation in a pregnancy with impaired placentation. In
early diastole, there is a notch and, in late diastole, there is
decreased flow
Papageorghiou et al.
review examines the findings of all available Doppler
studies of the uterine arteries during the second trimester
in unselected populations.
METHODS
Searches of a computerized medical database (PubMed)
were conducted independently by two of the researchers
(A.P., C.Y.). In addition to this, references from these
articles that were not identified by the original search were
included in the list of articles for review. The criteria for
reviewing the full articles were: pregnant subjects from
unselected populations, uterine artery Doppler assessment,
and outcome measures of pre-eclampsia, fetal growth
restriction or perinatal death. Only those studies that pro-
vided sufficient data to allow calculation of the perfor-
mance of the test were included in the analysis.
Likelihood ratios were calculated for each study after
construction of 2 ´ 2 tables of the screening test results and
outcomes of interest. In a number of papers, data for these
tables were calculated from the reported prevalence, sensi-
tivity and specificity. In the presence of zero in the 2 ´ 2
table, 0.5 was added to each cell in order to calculate the
likelihood ratios. Confidence intervals for the likelihood
ratios were calculated using the method suggested by Gart
and Nam12.
RESULTS
The literature search identified 19 relevant studies. From
these, four studies were excluded from the further analysis:
the studies of Campbell and colleagues13 and Hanretty and
associates14 because these examined arcuate rather than
uterine arteries; the study by Schulman and co-workers15
because the gestational age at examination was ill-defined;
and the study by Liberati and associates16 because, although
initial inclusion criteria were on an unselected basis, the
aim of the study was to evaluate the screening indices only
in those women with lateral placentas, and subsequent
analysis included only such women.
The main characteristics and results of the 15 remaining
studies are summarized in Tables 1–617–31. Two studies20,21
reported on the same study population using different
methodology and Doppler measurements (one-stage versus
two-stage screening). Only one of these 20 has been
included in the calculation of pooled likelihood ratios
for the three outcomes of interest, which are shown in
Tables 7–9.
The main features of the screening studies, including
number of patients, gestational age, Doppler technique
and definition of an abnormal result, are summarized in
Table 1. The early studies were limited by the use of con-
tinuous wave Doppler, which is a blind investigation.
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 Second-trimester uterine artery Doppler screening Papageorghiou et al.

Table 1 Characteristics of uterine artery Doppler screening studies used in this review
Gestation Screen Outcome
Reference n Doppler Abnormal result (weeks) positive (%) measure

Newnham et al., 501 CW S/D ratio > 2.18 18 4.8 FGR

199017
Bewley et al., 917 (913)‡ CW mean RI > 95th 16–24 5.6 (5.7)‡ PET, FGR
199118 centile
Steel et al., 199019 1014 CW/CW RI > 0.58 18 and 24 11.6 PET, FGR, PD
Bower et al., 2058 CW RI > 95th centile 18–22 16.0 PET, FGR, PD
199320* or notches
Bower et al., 2026 CW and color-PW bilateral notches 20 and 24 5.1 PET
199321*
Valensise et al., 272 color-PW mean RI > 0.58 22 9.6 PET, FGR
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199322
North et al., 199423 446 (457)‡ color-PW RI > 0.57 19–24 11.9 (12.3)‡ PET, FGR

Todros et al., 199524 916 CW or PW S/D ratio > 2.7 19–24 6.4 FGR
Harrington et al., 1204 CW and color-PW RI > 95th centile 20 and 24 9.1 PET, FGR, PD
199625 or notches
Frusca et al., 199726 419 CW and color-PW mean RI > 0.58 20 and 24 8.6 PET, FGR
Irion et al., 199827 1159 color-PW mean RI > 0.57 26 12.8 PET, FGR

Kurdi et al., 199828 946 color-PW mean RI > 0.55 and 19–21 12.4† PET, FGR
bilateral notches†
Albaiges et al., 1757 color-PW mean PI > 95th 22–24 7.3 PET, FGR, PD
For personal use only.

200029 centile or
bilateral notches
Aquilina et al., 640 color-PW mean RI ³ 0.65 and 19–20 9.8 PET, FGR, PD
200130 notches
Papageorghiou 7851 TV, color-PW mean PI > 95th 22–24 5.1 PET, FGR
et al., 200131 centile

n, number of cases used in the analysis after all exclusions; CW, continuous-wave Doppler without visualizing the vessel;
PW, pulsed-wave Doppler after identification of the vessel using B-mode ultrasound; color-PW, color flow imaging to identify the vessel
followed by pulsed-wave Doppler; TV, transvaginal; RI, resistance index; S/D systolic to diastolic ratio; PI, pulsatility index;
PET, pre-eclampsia; FGR, fetal growth restriction; PD, perinatal death
*These two studies report on the same population using one-stage and two-stage Doppler screening
†
In Kurdi et al., 199828, this definition of an abnormal result was used for the prediction of pre-eclampsia and fetal growth restriction
below the 5th centile. In the prediction of fetal growth restriction below the 10th centile, an abnormal result was defined as the presence
of bilateral notches and mean RI > 0.55, or unilateral notch and mean RI > 0.65, or mean RI > 0.7 (screen positive rate 22.8%)
‡
Pre-eclampsia (fetal growth restriction)

Subsequently, real-time ultrasound was used to identify the
vessels and pulsed wave Doppler was applied to obtain
the necessary waveforms. More recently, identification of
the vessels has been made easier with the use of color flow
mapping. This can be achieved either transabdominally
(at the apparent cross-over with the external iliac artery,
Figure 3) or transvaginally (lateral to the uterine cervix at
the level of the internal cervical os, Figure 4).
Discrepant results between the studies may be the conse-
quence of differences in Doppler technique for sampling
(for example, continuous wave, pulsed wave or color
Doppler to insonate the uterine arteries) and the definition
of abnormal flow velocity waveform (resistance or
pulsatility index above a certain cut-off or a centile or the
presence of an early diastolic notch). In addition, there
were differences in the populations examined (for example,
the prevalence of pre-eclampsia varied from 1.4% to 5.5%),
the gestational age at which women were studied (16–24
weeks) and in the criteria for the diagnosis of pre-eclampsia
and fetal growth restriction. Four of the studies reported on
two-stage screening; initial screening was carried out by
continuous wave Doppler at 18–20 weeks of gestation and,
in those with increased impedance to flow, the Doppler
studies were repeated at 24 weeks19,21,25,26.

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 Second-trimester uterine artery Doppler screening Papageorghiou et al.

Table 2 Results of uterine artery Doppler screening studies for the prediction of pre-eclampsia, providing data on the definition of
pre-eclampsia used, screen-positive rate, prevalence, sensitivity, specificity, positive predictive value (PPV) and negative predictive
value (NPV)
Screen-positive Prevalence Sensitivity Specificity PPV NPV
Reference rate (%) (%) (%) (%) (%) (%)

Bewley et al., 199118 5.6 4.6* 24 95 20 96

Steel et al., 199019 11.6 1.9† 63 89 10 99
Bower et al., 199320 16.0 2.5† 75 86 12 99
Bower et al., 199321 6.1 1.8† 78 96 28 99
Valensise et al., 199322 9.6 3.3† 89 93 31 99
North et al., 199423 11.9 3.4† 27 89 8 97
Harrington et al., 199625 9.1 3.7‡ 77 93 31 99
Frusca et al., 199726 8.6 1.9† 50 92 11 99
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Irion et al., 199827 12.8 3.3† 26 88 7 97

Kurdi et al., 199828 12.4 2.2* 62 89 11 99
Albaiges et al., 200029 7.3 3.7† 45 94 23 98
Aquilina et al., 200130 9.8 5.5† 60 93 33 98
Papageorghiou et al., 200131 5.1 1.4† 41 95 12 99

*Blood pressure ³ 140/90 and proteinuria > 150 mg/24 h

†
Blood pressure ³ 140/90 and proteinuria > 300 mg/24 h
‡
Blood pressure rise (systolic > 30 mmHg and diastolic > 25 mmHg) with proteinuria > 500 mg/24 h

Table 3 Likelihood ratios (LR) of uteroplacental Doppler screening in the prediction of pre-eclampsia
For personal use only.

Positive test Negative test

Reference n LR 95% CI n LR 95% CI

Bewley et al., 199118 10/51 5.08 2.69–9.03 32/866 0.80 0.64–0.91

Steel et al., 199019 12/118 5.93 3.73–8.17 7/896 0.41 0.21–0.66
Bower et al., 199320 39/329 5.19 4.17–6.14 13/1729 0.29 0.18–0.45
Valensise et al., 199322 8/26 12.99 7.16–20.99 1/246 0.12 0.02–0.47
North et al., 199423 4/53 2.35 0.93–4.88 11/393 0.83 0.54–1.01
Harrington et al., 199625 34/110 11.79 8.84–15.28 10/1094 0.24 0.14–0.40
Frusca et al., 199726 4/36 6.42 2.62–11.71 4/383 0.54 0.23–0.85
Irion et al., 199827 10/148 2.14 1.19–3.51 28/1011 0.84 0.66–0.97
Kurdi et al., 199828 13/117 5.51 3.52–7.59 8/829 0.43 0.23–0.67
Albaiges et al., 200029 29/128 7.63 5.38–10.42 36/1629 0.59 0.46–0.71
Aquilina et al., 200130 21/63 8.64 5.66–12.60 14/577 0.43 0.27–0.61
31
Papageorghiou et al., 2001 46/401 8.87 6.86–11.16 67/7450 0.62 0.52–0.71

Pooled LR 230/1580 5.90 5.30–6.52 231/17 103 0.55 0.50–0.60

CI, confidence interval

Summary of the screening studies Bewley and co-workers18 calculated the average resis-
tance index from the left and right uterine and arcuate
Newnham and associates17 measured the systolic/diastolic
arteries in 925 pregnancies at 16–24 weeks’ gestation. The
ratio in 501 women using continuous wave Doppler at 18
analysis for pre-eclampsia was based on 917 pregnancies
weeks of gestation. A screen-positive result (defined as a
and that for fetal growth restriction on 913. When the
systolic/diastolic ratio above the 95th centile) was found in
resistance index was greater than the 95th centile, there
4.8% of women and the sensitivity for fetal growth restric-
was a 10-fold increase in risk for a severe adverse outcome,
tion less than the 10th centile for gestation was 6.1% for a
defined by fetal death, placental abruption, fetal growth
specificity of 95%.
restriction or pre-eclampsia (prevalence 7%, sensitivity

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 Second-trimester uterine artery Doppler screening Papageorghiou et al.

Table 4 Results of uterine artery Doppler screening studies for the prediction of more severe forms of pre-eclampsia (PET), providing
data on the definition of screen-positive rate, severity of disease and likelihood ratios (LR) of a positive and negative test with 95% confi-
dence intervals (CI)
Screen- Incidence Positive test Negative test
positive rate Sensitivity
Reference (%) Disease n % (%) LR 95% CI LR 95% CI

PET/gestational hypertension
Frusca et al., 199726 8.6 PET 8 1.9 50 6.42 2.62–11.71 0.54 0.23–0.85
GH 24 5.7 25 3.29 1.48–6.59 0.81 0.60–0.96
Bewley et al., 199118 5.6 PET 42 4.6 24 5.08 2.69–9.03 0.80 0.64–0.91
GH 50 5.5 10 1.88 0.79–4.25 0.95 0.83–1.01
Steel et al., 199019 11.6 PET 19 1.9 63 5.93 3.73–8.17 0.41 0.21–0.66
GH 74 7.3 39 4.14 2.89–5.75 0.67 0.55–0.79
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Valensise et al., 9.6 PET 9 3.3 89 12.99 7.16–20.99 0.12 0.02–0.47

199322 GH 12 4.4 50 6.5 2.97–12.07 0.54 0.27–0.81

PET/PET preterm
Harrington et al., 3.9 PET 44 3.7 55 26.36 16.15–41.97 0.46 0.32–0.61
199625* PET del. < 35 weeks 16 1.3 81 27.58 17.39–40.14 0.19 0.07–0.44
Kurdi et al., 199828 12.4 PET 13 1.4 62 5.51 3.52–7.59 0.43 0.23–0.67
PET del. < 37 weeks 7 0.8 88 7.46 4.41–9.41 0.14 0.03–0.53
Albaiges et al., 7.3 PET 65 3.7 45 7.63 5.38–10.41 0.59 0.46–0.71
200029 PET del. < 34 weeks 10 0.6 90 13.21 8.53–16.37 0.11 0.02–0.43
Papageorghiou et al., 5.1 PET 113 1.4 41 8.87 6.86–11.17 0.62 0.52–0.71
200131 PET del. < 38 weeks 72 0.9 54 11.64 9.01–14.41 0.48 0.37–0.60
For personal use only.

PET del. < 36 weeks 47 0.6 70 14.88 11.66–17.89 0.31 0.20–0.46

PET del. < 34 weeks 36 0.5 81 16.92 13.41–19.83 0.20 0.10–0.37
PET del. < 32 weeks 20 0.3 90 18.4 14.11–21.08 0.11 0.03–0.32

PET/PET with FGR

Frusca et al., 199726 8.6 PET 8 1.9 50 6.42 2.62–11.71 0.54 0.23–0.85
PET with FGR 3 0.7 100 10.89 4.69–16.01 0.14 0.01–0.66
Papageorghiou et al., 5.1 PET 113 1.4 41 8.87 6.86–11.17 0.62 0.52–0.71
200131 PET with FGR 42 0.53 69 14.5 11.1–17.6 0.33 0.20–0.48

*In Harrington et al., 199625, the definition of an abnormal result for pre-eclampsia requiring preterm delivery was that of bilateral
uterine artery notches rather than the definition given in Table 1. GH, gestational hypertension; FGR, fetal growth restriction;
del., delivery

21%, specificity 95%, positive predictive value 25%). How-
ever, the sensitivities of the test for pre-eclampsia or
fetal growth restriction (below the 5th centile) were only
24% and 19%, respectively, with a specificity of about 95%
for both.
Steel and colleagues19 examined the uterine arteries in
1014 nulliparous women by continuous wave Doppler at 18
weeks of gestation, and, in those with increased impedance
(resistance index greater than 0.58), the Doppler studies
were repeated at 24 weeks. A screen-positive result
(increased impedance at 24 weeks) was found in 12% of
cases and the sensitivity of the test for pre-eclampsia was
63%, and, for fetal growth restriction, it was 43%. There
were 15 perinatal deaths (prevalence 1.5%), and abnormal
Doppler results identified 33% of these with a specificity
of 89%.
Bower and co-workers20 examined the uterine arteries in
2058 pregnancies at 18–22 weeks. An abnormal result,
defined by a resistance index above the 95th centile or the
presence of an early diastolic notch in either of the two
uterine arteries, was found in 16% of the pregnancies. The
sensitivity of the test was 75% for pre-eclampsia with speci-
ficity of 86%. This study highlighted that abnormal
Doppler results provide good prediction of the more severe
types of pregnancy complications. Thus, the sensitivity for
mild pre-eclampsia was only 29%, but, for moderate/severe
disease, the sensitivity was 82%. Similarly, the sensitivity
for birth weight below the 10th centile was 37% and, for
birth weight below the 5th centile, it was 46%. There were
27 fetal deaths (prevalence of 1.3%) and an abnormal
Doppler result predicted 18.5% of the cases with a specifi-
city of 84%.

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Table 5 Results of uterine artery Doppler screening studies for the prediction of fetal growth restriction providing data on the defini-
tion of fetal growth restriction (FGR) used, screen-positive rate, prevalence, sensitivity, specificity, positive predictive value (PPV) and
negative predictive value (NPV)
Screen-positive Prevalence Sensitivity Specificity PPV NPV
Reference FGR definition rate (%) (%) (%) (%) (%) (%)

Newnham et al., 199017 < 10th centile 4.8 9.8 6 95 13 90

Bewley et al., 199118 < 3rd centile 5.7 3.3 20 95 12 97
< 5th centile 5.7 19 95 19 95
< 10th centile 12.9 15 96 35 88
Steel et al., 199019 < 5th centile 11.6 4.8 43 90 18 97
< 10th centile 9.6 33 91 27 93
Bower et al., 199320 < 3rd centile 16.0 3.5 47 85 10 98
< 5th centile 5.2 46 86 15 97
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< 10th centile 10.9 37 87 26 92

Valensise et al., 199322 < 10th centile 9.6 7.7 67 95 54 97
North et al., 199423 < 10th centile 12.3 6.6 50 90 27 96
Todros et al., 199524 < 10th centile 6.4 4.6 12 94 8 96
Harrington et al., 199625 < 10th centile 9.1 10.9 32 94 38 92
Frusca et al., 199726 < 3rd centile 8.6 2.6 55 93 17 99
< 10th centile 7.2 43 94 36 96
Irion et al., 199827 < 10th centile 12.8 11 29 89 25 91
Kurdi et al., 199828 < 5th centile 12.4 6.0 37 89 18 95
< 10th centile 22.8* 16.5 45 82 32 88
Albaiges et al., 200029 < 3rd centile 7.3 3.0 30 93 13 98
< 10th centile 8.1 22 94 25 93
For personal use only.

Papageorghiou et al., 200131 < 10th centile 5.1 9.4 16 96 30 92

*In Kurdi et al.28, different definitions of an abnormal result were used for the prediction of fetal growth restriction below the 5th and
below the 10th centile, respectively (see Table 1)

Table 6 Results of uterine artery Doppler screening studies for the prediction of fetal or perinatal death providing data on screen
positive rate, prevalence, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)
Outcome Screen-positive Prevalence Sensitivity Specificity PPV NPV
Reference measure rate (%) (%) (%) (%) (%) (%)

Steel et al., 199019 perinatal death 11.6 15 (1.5) 33 89 4 99

Bower et al., 199320 fetal death 5.6 27 (1.3) 19 84 2 99
Harrington et al., 199625 perinatal death 9.1 12 (1.0) 8 91 1 99
Albaiges et al., 200029 fetal death 7.3 6 (0.3) 83 93 4 100

In another study by Bower and associates21, in a
subgroup of the 2058 unselected women who were
initially examined by continuous wave Doppler at 20 weeks
of gestation (see above) and found to have increased
impedance to flow (resistance index greater than the
95th centile or early diastolic notch in either of the two
uterine arteries), the Doppler studies were repeated by
color Doppler at 24 weeks. As 32 women did not have
the second stage of screening, the analysis is based on the
remaining 2026 women (see Table 1). Persistently
increased impedance was observed in 5.1% of the
patients (compared to 16% at 20 weeks). It was reported
that increased impedance provides good prediction of
pre-eclampsia (but not non-proteinuric pregnancy-induced
hypertension).
Valensise and colleagues22 examined the uterine arteries
in 272 primigravidas at 22 weeks of gestation. An abnormal
result, defined by increased impedance (mean resistance
index of more than 0.58) was found in 9.6% of patients.
The sensitivity of the test in predicting pre-eclampsia
was 89% and, for fetal growth restriction, it was 67%;
the specificities were 93% and 95%, respectively. The

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 Second-trimester uterine artery Doppler screening Papageorghiou et al.

Table 7 Likelihood ratios (LR) of uteroplacental Doppler screening in the prediction of fetal growth restriction (FGR)
Positive test Negative test

Reference n LR 95% CI n LR 95% CI

FGR < 10th centile

Newnham et al., 199017 3/24 1.32 0.42–3.87 46/477 0.98 0.87–1.03
Bewley et al., 199118 18/52 3.57 2.08–6.01 100/861 0.89 0.81–0.94
Steel et al., 199019 32/118 3.52 2.46–4.91 65/896 0.74 0.63–0.84
Bower et al., 199320 84/329 2.79 2.26–3.41 141/1729 0.72 0.65–0.79
Valensise et al., 199322 14/26 13.94 7.33–25.69 7/246 0.35 0.18–0.57
North et al., 199423 15/56 5.21 3.18–7.98 15/401 0.55 0.37–0.74
Todros et al., 199524 5/59 1.93 0.81–4.24 37/857 0.94 0.80–1.01
Harrington et al., 199625 42/110 5.06 3.58–7.04 89/1094 0.73 0.64–0.81
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Frusca et al., 199726 13/36 7.33 4.05–12.56 17/383 0.60 0.42–0.77

Irion et al., 199827 37/148 2.68 1.93–3.67 91/1011 0.80 0.70–0.88
Kurdi et al., 199828 70/216 2.43 1.92–3.03 86/730 0.68 0.58–0.77
Albaiges et al., 200029 32/128 3.76 2.60–5.34 111/1629 0.83 0.75–0.89
Papageorghiou et al., 200131 121/401 4.15 3.40–5.06 619/7450 0.87 0.84–0.90
486/1703 3.67 3.34–4.03 1424/17764 0.80 0.78–0.82

FGR < 5th centile

Bewley et al., 199118 10/52 3.84 1.74–7.67 42/861 0.84 0.66–0.96
Steel et al., 199019 21/118 4.26 2.86–6.02 28/896 0.64 0.48–0.78
Bower et al., 199320 49/329 3.22 2.52–4.01 57/1729 0.63 0.52–0.74
Kurdi et al., 199828 21/117 3.41 2.26–4.90 36/829 0.71 0.56–0.84
For personal use only.

101/616 3.38 2.82–4.00 163/4315 0.71 0.65–0.77

FGR < 3rd centile

Bewley et al., 199118 6/52 3.84 1.74–7.67 24/861 0.84 0.66–0.96
Bower et al., 199320 34/329 3.13 2.35–4.00 39/1729 0.63 0.49–0.76
Frusca et al., 199726 6/36 7.42 3.54–12.71 5/383 0.49 0.23–0.78
Albaiges et al., 200029 16/128 4.68 2.93–7.06 36/1629 0.74 0.60–0.86
62/545 3.85 3.08–4.72 104/4602 0.69 0.61–0.77

CI, confidence interval

Table 8 Likelihood ratios (LR) of uteroplacental Doppler screening in the prediction of perinatal death
Positive test Negative test

Reference n LR 95% CI n LR 95% CI

Steel et al., 199019 5/118 2.95 1.32–5.34 10/896 0.75 0.47–0.96

Bower et al., 199320 5/329 1.16 0.51–2.32 22/1729 0.97 0.75–1.09
Harrington et al., 199625 1/110 0.91 0.16–3.93 11/1094 1.01 0.71–1.09
29
Albaiges et al., 2000 5/128 11.86 6.11–15.32 1/1629 0.18 0.03–0.61

Pooled LR 16/685 2.37 1.54–3.44 44/5348 0.82 0.68–0.93

CI, confidence interval

sensitivity for predicting non-proteinuric pregnancy- they found increased impedance (resistance index
induced hypertension was 50%. greater than 0.57 on the placental side) in 12% of cases.
North and co-workers23 examined the uterine arteries at The sensitivity of the test for pre-eclampsia was 27% and,
19–24 weeks of gestation in 457 nulliparous women and for fetal growth restriction, it was 50%; the respective

84
J ournal of Maternal–Fetal and Neonatal Medicin e
 Second-trimester uterine artery Doppler screening
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Nyu Medical Center on 05/29/15
Figure 3 Transabdominal insonation of the uterine artery at the
cross-over with the iliac artery
For personal use only.
Figure 4 Transvaginal insonation of the uterine artery lateral to
the uterine cervix, at the level of the internal cervical os
specificities were 89% and 90%. The test detected women
with severe disease requiring delivery before 37 weeks with
a sensitivity of 83% and specificity of 88%.
Todros and associates24 examined the uterine arteries in
916 low-risk women (those with poor previous obstetric
history were excluded) at 19–24 weeks of gestation. The
prevalence of fetal growth restriction (defined as birth
weight below the 10th centile) was 4.6%, and 12% of these
were predicted by increased impedance to flow (systolic/
diastolic ratio greater than 2.7) with a specificity of 94%.
Harrington and his group25 examined the uterine
arteries in 1233 unselected women by continuous wave
Doppler at 20 weeks of gestation. In those with increased
impedance (resistance index greater than the 95th centile
or early diastolic notch in either of the uterine arteries), the
Doppler studies were repeated by color Doppler at 24
Papageorghiou et al.
weeks. Persistently increased impedance was observed in
9.1% of the patients. The sensitivity of the test for
pre-eclampsia was 77% and, for fetal growth restriction, it
was 32%. Bilateral notching at 24 weeks was observed in
3.9% of patients; the sensitivity for pre-eclampsia was 55%
and, for fetal growth restriction, it was 22%. The respective
sensitivities for those complications leading to delivery
before 35 weeks were 81% and 58%. There were 12
perinatal deaths (prevalence 1%) and abnormal Doppler
results identified 8% of these with a specificity of 91%.
Irion and colleagues27 examined the uterine arteries in
1159 nulliparous women at 26 weeks. Pre-eclampsia, fetal
growth restriction and preterm delivery occurred in 3%,
11% and 7% of the pregnancies, respectively. At 26 weeks,
increased impedance to flow (resistance index greater than
0.57) was present in 13% of cases, and the sensitivity of the
test was 26% for pre-eclampsia, 29% for growth restriction
and 15% for preterm delivery.
Frusca and colleagues26 examined the uterine arteries in
419 nulliparous women by continuous wave Doppler at 20
weeks of gestation. In those with increased mean resistance
index (greater than 0.58), the uterine arteries were exam-
ined by color Doppler at 24 weeks. Persistently high resis-
tance was observed in 8.6% of the patients. The sensitivity
of the test for pre-eclampsia was 50% and, for fetal growth
restriction, it was 43%. In the group with increased imped-
ance at 20 weeks, but normal results at 24 weeks, the preva-
lence of pregnancy complications was not increased
compared to those with normal impedance at 20 weeks.
Kurdi and co-workers28 examined the uterine arteries by
color Doppler in 946 unselected women at 19–21 weeks of
gestation. Pre-eclampsia and fetal growth restriction
(below the 5th centile) occurred in 2.2% and 6% of the
cases, respectively. For a specificity of 89%, the sensitivities
of increased impedance (bilateral notches and a mean
resistance index greater than 0.55) for pre-eclampsia and
fetal growth restriction (below the 5th centile) were 62%
and 37%, respectively, and, for these complications requir-
ing delivery before 37 weeks, the sensitivities were 88%
for both.
Albaiges and associates29 used color Doppler to examine
the uterine arteries in 1757 singleton pregnancies attend-
ing for routine ultrasound examination at 23 weeks.
Increased impedance was observed in 7.3% of patients,
including 5.1% with mean pulsatility index of more than
1.45 and 4.4% with bilateral notches. Increased pulsatility
index identified 35% of women who later developed
pre-eclampsia and 80% with pre-eclampsia requiring
delivery before 34 weeks; the respective values for bilateral
notches were 32% and 80%. The sensitivity of increased
pulsatility index for delivery of an infant with birth weight
below the 10th centile was 21%, and it was 70% for birth
weight below the 10th centile delivering before 34 weeks;
the respective values for bilateral notches were 13% and
8
J ournal of Maternal–Fetal and Neonatal Medicin e
 Second-trimester uterine artery Doppler screening
50%. Six fetal deaths (prevalence 0.34%) occurred and
abnormal Doppler results identified 83.3% of these, with a
specificity of 92.8%. The screening results were similar
if the high-risk group was defined as either those with
increased pulsatility index or bilateral notches.
Aquilina and colleagues30 examined 640 women at
19–21 weeks of gestation using color Doppler. Pre-
eclampsia occurred in 5.5% of pregnancies. Abnormal
uterine artery blood flow, as defined by mean resistance
index greater than or equal to 0.65 with unilateral or
bilateral notches, was present in 9.8% of cases, and the
sensitivity of predicting pre-eclampsia was 60% with a
specificity of 93%.
Papageorghiou and associates31 examined 7851 single-
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ton pregnancies attending for routine antenatal ultrasound
at 23 weeks using a transvaginal color Doppler approach.
The mean uterine artery pulsatility index of the two
arteries was calculated and the presence or absence of
notches was documented. A mean pulsatility index above
the 95th centile (1.63) was found in 5.1% of women and
this cut-off identified 41% of women who subsequently
developed pre-eclampsia and 16% of those delivering an
infant with a birth weight below the 10th centile with
specificities of 95% and 96%, respectively. The sensitivity
for pre-eclampsia and fetal growth restriction increased
For personal use only.
with the severity of the disease. Thus, the sensitivity for
pre-eclampsia requiring delivery before 38 weeks was 54%
and the sensitivity increased to 70%, 81% and 90% for
pre-eclampsia requiring delivery before 36, 34 and 32
weeks, respectively; the respective sensitivities for fetal
growth restriction below the 10th centile were 35%, 53%,
64% and 74%. The test was better at predicting pre-
eclampsia accompanied by fetal growth restriction (69%)
than pre-eclampsia in the absence of fetal growth restric-
tion (24%). Furthermore, the sensitivity for fetal growth
restriction defined by the 5th, rather than the 10th, centile
was higher (19% versus 16%). Bilateral notches were found
in 9.3% of women and, using this screening index, showed
similar sensitivities to using high pulsatility index, but with
a higher screen-positive rate. It was concluded that a
one-stage Doppler screening program at 23 weeks identifies
most women who subsequently develop severe pre-
eclampsia and/or fetal growth restriction.
Prediction of pre-eclampsia
The studies differed in the definition of hypertensive
disease, prevalence of this complication (1.4–5.5%), sensi-
tivity (24–89%) and specificity (86–96%) of the test
(Table 2). In the pooled data from all studies, the likeli-
hood ratios for the subsequent development of pre-
eclampsia in women with increased impedance to flow was
about 6 and, for those with normal Doppler results, the
ratio was about 0.5 (Table 3).
86
J ournal of Maternal–Fetal and Neonatal Medicin e
Papageorghiou et al.
The studies that examined different severities of this
complication reported that Doppler was better in predict-
ing more severe disease (Table 4). Thus, Bower and
associates20 reported that increased impedance provides
good prediction of pre-eclampsia but not pregnancy-
induced hypertension without proteinuria. The enhanced
predictive ability of uterine artery screening in more severe
disease is also shown in the study by Papageorghiou and
co-workers31 where sensitivities for more severe disease, as
defined by the presence of pre-eclampsia with fetal growth
restriction, were reported. In this study, pre-eclampsia with
fetal growth restriction occurred in 0.5% of cases, pre-
eclampsia without fetal growth restriction in 0.9% and fetal
growth restriction without pre-eclampsia in 8.9% of cases,
and the respective sensitivities were 69%, 24% and 13%.
Another measure of the severity of the disease is the
gestation at which delivery is undertaken. Harrington and
colleagues25 found that bilateral notching at 24 weeks
identified 55% of women who later developed pre-
eclampsia and 81% with pre-eclampsia requiring delivery
before 35 weeks. Similarly, Kurdi and associates28 found
that bilateral notches and a mean resistance index greater
than 0.55 identified 62% of women who later developed
pre-eclampsia and 88% with pre-eclampsia requiring
delivery before 37 weeks. Albaiges and co-workers29
showed that the sensitivity of increased pulsatility index or
bilateral notches in predicting pre-eclampsia was 45%,
while, for pre-eclampsia requiring delivery before 34 weeks,
the sensitivity was 90%. Papageorghiou and colleagues
reported that increased pulsatility index identified 41% of
women who later developed pre-eclampsia and that the
sensitivities increased to 54%, 70%, 81% and 90% for
pre-eclampsia requiring delivery before 38, 36, 34 and 32
weeks, respectively.
Prediction of fetal growth restriction
All studies defined this complication as the delivery of
an infant with birth weight below the 10th centile for
gestation. Some studies also provided data on birth weight
below the 5th and 3rd centiles. The range in the preva-
lence of fetal growth restriction, defined as birth weight
below the 10th centile, was 4.6–16.5%, the sensitivity was
6–67% and the specificity was 82–96% (Table 5). In the
pooled data from all studies, the likelihood ratio for
the subsequent delivery of a growth-restricted infant in
women with increased impedance to flow was about 3.7
and, for those with normal Doppler results, the ratio was
about 0.8 (Table 7).
There was agreement between the studies that the sensi-
tivity of increased impedance was higher in the prediction
of more severe degrees of growth restriction (Table 5). For
example, in the study of Bower and associates20, the sensi-
tivity for the prediction of birth weight below the 10th
 Second-trimester uterine artery Doppler screening
centile was 37%, and this increased to 47% for birth weight
below the 3rd centile. The respective sensitivities in the
study of Bewley18 were 15% and 20%; in the study of
Albaiges and co-workers29, they were 22% and 30%. In the
study of Steel and colleagues19, they were 33% and 43%
and in the study of Frusca26 they were 43% and 55%.
The same point of improved sensitivity in the prediction
of severe disease is made by Papageorghiou and co-
workers31, who reported that mean pulsatility index above
the 95th centile of the normal range at 23 weeks identified
16% of pregnancies delivering an infant with birth weight
below the 10th centile and that this increased to 35%,
53%, 64% and 74% for birth weight below the 10th centile
delivering before 38, 36, 34 and 32 weeks, respectively. In
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the study by Albaiges and associates29, sensitivities for
mean pulsatility index above the 95th centile or bilateral
notches were 22% for birth weight below the 10th centile
and 70% for birth weight below the 10th centile delivering
before 34 weeks. Harrington and colleagues25 found that
bilateral notching at 24 weeks identified 22% of women
who later delivered infants with a birth weight below the
10th centile, and the sensitivity improved to 58% for
growth restriction requiring delivery before 35 weeks.
Similarly, Kurdi and associates28 found that bilateral
notches and a mean resistance index greater than 0.55 at
For personal use only.
19–21 weeks identified 37% of women who later delivered
infants with a birth weight below the 5th centile, and the
sensitivity improved to 88% for growth restriction requir-
ing delivery before 37 weeks.
Prediction of perinatal death
There are only four studies providing sufficient data to
examine the performance of Doppler screening in the pre-
diction of fetal or perinatal death (Table 6). There were
large differences in the sensitivity (8–83%) of the test,
which may well reflect the small number of cases in each
study. In the largest study, involving 27 fetal deaths, the
sensitivity and specificity of increased impedance were 19%
and 84%, respectively19. In the pooled data from the four
studies, the likelihood ratio for subsequent fetal or perinatal
death in women with increased impedance to flow was 2.4
and, for those with normal Doppler results, the ratio was
0.8 (Table 8).
CONCLUSIONS
There is extensive evidence that increased impedance to
flow in the uterine arteries is associated with increased risk
for subsequent development of pre-eclampsia, fetal growth
restriction and perinatal death. In addition, women with
normal impedance to flow in the uterine arteries constitute
a group that has a low risk of developing obstetric compli-
cations related to uteroplacental insufficiency.
Papageorghiou et al.
During the last decade, uterine artery screening has
evolved from a blind method (using continuous wave
Doppler) to identification of the vessel using color flow
mapping. The use of continuous wave Doppler, without
visualization of the uterine artery prior to insonation, may
make it more difficult to distinguish uterine artery blood
flow from adjacent high resistance internal iliac vessels,
and the lower resistance arcuate arteries14.
There has been a move away from two-stage to
one-stage screening. Historically, two-stage screening
was performed because, in the mid-1990s, there was a
sparsity of color Doppler equipment, and because the
routine anomaly scan was performed at 20 weeks (lending
itself to the performance of the first stage). However,
two-stage screening relies on those patients with an abnor-
mal first-stage test result returning for the second stage. In
three of the four two-stage screening studies, the drop-out
from subsequent follow-up was between 10% and
27%21,25,26.
The gestational age at screening has moved to 23–24
weeks, as earlier screening has been associated with a
higher false-positive rate. The prevalence of bilateral
notches at 18–22 weeks is more than 10%, and, at 23–24
weeks, it is less than 5%. Two large recent studies have
shown that, at 23–24 weeks, the sensitivities are similar if
high impedance is defined by the presence of bilateral
notches or a mean pulsatility index above the 95th centile
of the normal range for gestation29,31. Using the pulsatility
index removes the element of subjectivity associated with
the interpretation of notches. Although, in both these
studies, inclusion of the presence of bilateral notches in
the definition of an abnormal resulted in a small increase in
sensitivity, this was achieved at the expense of a substantial
increase in the screen-positive rate.
The results obtained from one-stage screening tests at
23–24 weeks suggest that increased impedance to flow in
the uterine arteries in pregnancies attending for routine
antenatal care identifies about 40% of those who subse-
quently develop pre-eclampsia and about 20% of those who
develop fetal growth restriction. Following a positive test,
the likelihood of these complications is increased by about
6 and 3.5 times, respectively. Abnormal Doppler is better
in predicting severe rather than mild disease. The sensiti-
vity for severe disease requiring early delivery is about 80%
for pre-eclampsia and 60% for fetal growth restriction. The
sensitivity of screening for perinatal death is necessarily
based on small numbers, but the likelihood of this compli-
cation in those with an abnormal Doppler result is about
2.4 times higher than the background risk.
ACKNOWLEDGEMENT
This study was supported by a grant from the Fetal
Medicine Foundation (Charity No. 1037116).
8
J ournal of Maternal–Fetal and Neonatal Medicin e
 Second-trimester uterine artery Doppler screening
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