Utero-Placental Doppler Ultrasound For Improving Pregnancy Outcome (Review)

Utero-placental Doppler ultrasound for improving pregnancy
outcome (Review)
Stampalija T, Gyte GML, Alfirevic Z
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 9
http://www.thecochranelibrary.com
Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Uterine artery Doppler ultrasound versus no Doppler ultrasound, 2nd trimester, Outcome 1
Any perinatal death after randomisation. . . . . . . . . . . . . . . . . . . . . . . . .
Hypertensive disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stillbirth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Any potentially preventable perinatal death after randomisation. . . . . . . . . . . . . . . . .
Intrauterine growth restriction. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neonatal resuscitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Apgar score < 7 at 5 min. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neonatal admission to SCBU or NICU.
. . . . . . . . . . . . . . . . . . . . . . . .
Iatrogenic preterm birth (< 37 weeks). . . . . . . . . . . . . . . . . . . . . . . . . .
Caesarean section (both elective and emergency).
. . . . . . . . . . . . . . . . . . . . .
Elective caesarean section.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Emergency caesarean section. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gestational age at birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Infant birthweight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1
1
2
2
4
4
7
8
10
11
11
11
16
25
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
47
47
48
48
48
48
[Intervention Review]
Utero-placental Doppler ultrasound for improving pregnancy

outcome
Tamara Stampalija1 , Gillian ML Gyte2 , Zarko Alfirevic3
1 Department
of Obstetrics and Gynaecology, Childrens Hospital V. Buzzi, Milano, Italy. 2 Cochrane Pregnancy and Childbirth
Group, School of Reproductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine, The University of
Liverpool, Liverpool, UK. 3 School of Reproductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine,
The University of Liverpool, Liverpool, UK
Contact address: Tamara Stampalija, Department of Obstetrics and Gynaecology, Childrens Hospital V. Buzzi, Via Castelvetro 32,
Milano, 20154, Italy. stampta@libero.it.
Editorial group: Cochrane Pregnancy and Childbirth Group.
Publication status and date: New, published in Issue 9, 2010.
Review content assessed as up-to-date: 15 July 2010.
Citation: Stampalija T, Gyte GML, Alfirevic Z. Utero-placental Doppler ultrasound for improving pregnancy outcome. Cochrane
Database of Systematic Reviews 2010, Issue 9. Art. No.: CD008363. DOI: 10.1002/14651858.CD008363.pub2.
ABSTRACT
Background
Impaired placentation can cause some of the most important obstetrical complications such as pre-eclampsia and intrauterine growth
restriction and has been linked to increased fetal morbidity and mortality. The failure to undergo physiological trophoblastic vascular
changes is reflected by the high impedance to the blood flow at the level of the uterine arteries. Doppler ultrasound study of uteroplacental blood vessels, using waveform indices or notching, may help to identify the at-risk women in the first and second trimester
of pregnancy, such that interventions might be used to reduce maternal and fetal morbidity and/or mortality.
Objectives
To assess the effects on pregnancy outcome, and obstetric practice, of routine utero-placental Doppler ultrasound in first and second
trimester of pregnancy in pregnant women at high and low risk of hypertensive complications.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (June 2010) and the reference lists of identified studies.
Selection criteria
Randomised and quasi-randomised controlled trials of Doppler ultrasound for the investigation of utero-placental vessel waveforms in
first and second trimester compared with no Doppler ultrasound. We have excluded studies where uterine vessels have been assessed
together with fetal and umbilical vessels.
Data collection and analysis
Two authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We checked data
entry.
Main results
We found two studies involving 4993 participants. The methodological quality of the trials was good. Both studies included women
at low risk for hypertensive disorders, with Doppler ultrasound of the uterine arteries performed in the second trimester of pregnancy.
In both studies, pathological finding of uterine arteries was followed by low-dose aspirin administration.
We identified no difference in short-term maternal and fetal clinical outcomes.
We identified no randomised studies assessing the utero-placental vessels in the first trimester or in women at high risk for hypertensive
disorders.
Authors conclusions
Present evidence failed to show any benefit to either the baby or the mother when utero-placental Doppler ultrasound was used in
the second trimester of pregnancy in women at low risk for hypertensive disorders. Nevertheless, this evidence cannot be considered
conclusive with only two studies included. There were no randomised studies in the first trimester, or in women at high risk. More
research is needed to investigate whether the use of utero-placental Doppler ultrasound may improve pregnancy outcome.
PLAIN LANGUAGE SUMMARY

Doppler ultrasound of blood vessels in the placenta and uterus of pregnant women as a way of improving outcome for babies
and their mothers
One of the main aims of routine antenatal care is to identify mothers or babies at risk of adverse outcomes. Doppler ultrasound
uses sound waves to detect the movement of blood in blood vessels. It is used in pregnancy to study blood circulation in the baby,
the mothers uterus and the placenta. If abnormal blood circulation is identified, then it is possible that medical interventions might
improve outcomes. We set out to assess the value of using Doppler ultrasound of the mothers uterus or placenta (utero-placental
Doppler ultrasound) as a screening tool. Other reviews have looked at the use of Doppler ultrasound on the babies vessels (fetal and
umbilical Doppler ultrasound). We also choose to look at women with low-risk and high-risk pregnancies, and in their first or second
trimesters. This screening offers a potential for benefit, but also a possibility of unnecessary interventions and adverse effects. The
review of randomised controlled trials of routine Doppler ultrasound of the uterus or placenta identified two studies involving 4993
women. All the women were in the second trimester of pregnancy and at low risk for hypertensive disorders. The studies were of good
quality but small in size. We identified no improvements for the baby or the mother. However, more data would be needed to show
whether maternal Doppler is effective, or not, for improving outcomes. We did not find any studies in the first trimester of pregnancy
or in women at risk of high blood pressure disorders. More research is needed on this important aspect of care.
BACKGROUND
Description of the condition

The blood supply to the uterus is provided mainly by the uterine
arteries and also by the ovarian arteries. Once the arterial vessels
reach myometrium, they divide into arcuate arteries, then into
the radial arteries which ultimately branch into the spiral arteries.
During the first and second trimester of pregnancy, trophoblast
invades the spiral arteries - a process that is fundamental for normal
placentation. The most important change, but not the only one,
is replacement of the muscular and elastic arterial layer by collagen

(Espinoza 2006). As the trophoblastic invasion continues during
the first half of pregnancy, the resistance to the blood flow in the
uterine arteries progressively decreases.
The failure to undergo these physiologic vascular changes has
been associated not just with pre-eclampsia (Brosens 1972; Khong
1991; Sibai 2005; Von Dadelszen 2002) and intrauterine growth
restriction (IUGR) (Bernstein 2000; Fisk 2001; Khong 1991), but
also with other maternal diseases such as diabetes mellitus (Khong
1991), lupus erythematosus (Nayar 1996), antiphospholipid antibody syndrome (Levy 1998) and others (Barker 2004).

Description of the intervention

Doppler ultrasound velocimetry uses the Doppler principle to
analyse the properties of the blood flow in a vessel of interest. This
physical principle explains the observed change in wave frequency
relative to the speed of a moving object. In case of Doppler ultrasound, the emitted ultrasound frequency will change when ultrasound beam encounters moving blood. The principle can be
applied using different ultrasound modalities such as continuouswave Doppler, pulsed-wave Doppler, colour and power Doppler
wave (Burns 1993; Chen 1996; Owen 2001). While colour and
power Doppler provide visualisation of the blood flow and its direction, pulsed Doppler allows reproducible measurements of the
blood velocities. The measurements obtained will reflect, in any
vessel studied, the cardiac contraction force, density of the blood,
vessel wall elasticity, but more importantly peripheral and downstream resistance (Owen 2001).
Physiological process of the trophoblastic invasion of spiral arteries takes place between six and 24 weeks of gestation in normal
pregnancies. The blood flow from the uterine arteries to the placenta will progressively increase during that time. By studying the
uterine arteries with pulse Doppler ultrasound, it is possible to assess the progressive decrease in resistance to blood flow. The rationale of using the Doppler velocimetry of uterine arteries to assess
the failure of the placentation is related to fact that the lack of
physiological transformation of the spiral arteries will cause high
resistance to blood flow within uterus and subsequently in uterine
arteries.
At least 15 different uterine artery Doppler indices have been used
to quantify the uterine arteries perfusion and predict pre-eclampsia and IUGR (Cnossen 2008). The most commonly used indices
are the pulsatility and resistant index (PI and RI) which showed
the highest predictive value (Cnossen 2008). The qualitative description focuses on the presence or absence of early diastolic notch
that could be either unilateral or bilateral.
The abnormal findings in uterine arteries are usually defined as PI
or RI above the 95 percentile at a given gestational age (Albaiges
2000; Bower 1993) and the presence of notching (a qualitative assessment of flow velocity waveform - Harrington 1996). Numerous studies have linked the high impedance and bilateral notching
in uterine arteries to early onset pre-eclampsia, IUGR and higher
perinatal mortality (Aardema 2001; Albaiges 2000; Bower 1993;
Harrington 1996; Olofsson 1993).
Reported sensitivity and detection rate of the uterine artery
Doppler to predict pre-eclampsia in unselected population range
from 50% to 60%, meaning that only half of the women that
subsequently develop the disease will be correctly identified by the
increased resistance in uterine arteries. On the other hand the reported specificity is around 95%, which means that most women
with normal uterine artery Doppler will not develop pre-eclampsia. The performance of uterine artery Doppler as a screening test
is higher when pre-eclampsia is divided in severe or early onset and
mild or late onset pre-eclampsia. In that case, the sensitivity rises
from 80% to 85% for severe pre-eclampsia, requiring delivery before 34 weeks (Papageorghiou 2001; Yu 2005) and 90% for severe
pre-eclampsia indicating delivery before 32 weeks (Papageorghiou
2001).
More recently, the interest for uterine artery measurements has
moved from the second to the first trimester of pregnancy (13+6
to 11+0 weeks of gestation). The rationale of measuring the uterine artery Doppler in the first trimester is the possibility to intervene with some prophylactic therapy such as antithrombotic
drugs while the trophoblastic invasion is still ongoing. The uterine
artery Doppler has been found to be less predictive when compared
with the second trimester examination. Reported detection rate
for uterine artery Doppler alone in the first trimester ranged from
40% to 67% for early onset pre-eclampsia and 15% to 20% for late
onset pre-eclampsia (Martin 2001; Parra 2005). In the attempt to
improve the performance of the uterine artery as a screening test,
new algorithms that take into account the maternal characteristics,
history and/or biochemical markers have been proposed. In fact,
uterine artery Doppler in the first and second trimester, in combination with several biochemical markers, has been extensively
tested as a predictive test for pre-eclampsia and IUGR, and the first
results are encouraging (Nicolaides 2006; Parra 2005; Plasencia
2007; Spencer 2007; Zhong 2010). Nevertheless, at present the
literature comprises several large uncontrolled cohort studies and
as yet there are no randomised studies in this field, and the costeffectiveness remains to be proven.
How the intervention might work

It is hoped that early detection of abnormal placental vasculature, before maternal and fetal complications develop, would allow preventative interventions and more targeted maternal and
fetal surveillance. Low-dose aspirin is an example of a preventative
intervention that could be targeted to those with abnormal uteroplacental Doppler (Askie 2007).
Why it is important to do this review

Doppler ultrasound has become an integral part of obstetric care
(Alfirevic 2010a) and more clinicians are being trained to use it.
Using a non-invasive and relatively easy screening tool such as
Doppler ultrasound of the uterine arteries to predict pre-eclampsia and IUGR is undoubtedly appealing. Early recognition of preeclampsia and IUGR could improve maternal and perinatal outcome by administration antiplatelet therapy, appropriate antihypertensive therapy, medication for fetal lung maturation and early
delivery. Nevertheless, labelling woman as at risk could cause significant anxiety and increase the number of unnecessary examinations and interventions (blood tests, hospital admission and possibly early delivery).

Criteria for considering studies for this review
revealed versus Doppler of utero-placental vessels concealed) in

first trimester of pregnancy.
2. Doppler ultrasound of utero-placental vessels versus no
Doppler ultrasound of utero-placental vessels (including
comparisons of Doppler ultrasound of utero-placental vessels
revealed versus Doppler of utero-placental vessels concealed) in
second trimester of pregnancy.
3. Comparison of different forms of Doppler ultrasound of
utero-placental vessels versus other types of Doppler ultrasound
of utero-placental vessels in first trimester of pregnancy.
4. Comparison of different forms of Doppler ultrasound of
utero-placental vessels versus other types of Doppler ultrasound
of utero-placental vessels in second trimester of pregnancy.
5. Comparison of different methods of Doppler ultrasound
measurements of utero-placental vessels in first trimester of
pregnancy.
6. Comparison of different methods of Doppler ultrasound
measurements of utero-placental vessels in second trimester of
pregnancy.
Types of studies
Types of outcome measures
This review will complement two other Cochrane reviews that

focus on the fetal and umbilical Doppler ultrasound in highrisk populations (Alfirevic 2010a), and in low-risk populations
(Alfirevic 2010b).
OBJECTIVES
To assess whether the use of utero-placental Doppler ultrasound
(uterine arteries and placental vessels) improves the outcome of
low- and high-risk pregnancies.
METHODS
All randomised trials and quasi-randomised studies comparing

utero-placental Doppler ultrasound (uterine, arcuate, radial and
spiral arteries) in low- and high-risk pregnancies. We planned to
perform sensitivity analysis by trial quality. We included study
abstracts. We have considered cluster trials, though we found none,
but we did not think cross-over trials would be suitable for this
topic.
Types of participants
Pregnant women, considered to be either low- or high-risk, who
had utero-placental Doppler ultrasound performed at first or second trimester of pregnancy. We planned to include twin pregnancies and to perform subgroup analysis for that population but
there were insufficient data.
Types of interventions
Doppler ultrasound of the utero-placental circulation (uterine,
arcuate, radial and spiral arteries) in pregnancies at low and high
risk. We did not include studies that considered the combination
of utero-placental Doppler and fetal or umbilical Doppler in this
review, but did include them in fetal and umbilical Doppler reviews
(Alfirevic 2010a; Alfirevic 2010b).
Comparisons
1. Doppler ultrasound of utero-placental vessels versus no

Doppler ultrasound of utero-placental vessels (including
comparisons of Doppler ultrasound of utero-placental vessels
Primary outcomes
1. Any perinatal death after randomisation.

2. Hypertensive disorders (pre-eclampsia, eclampsia,
haemolysis elevated liver enzymes and low platelets, chronic
hypertension).
Secondary outcomes
1. Stillbirth (as defined by trialists).

2. Neonatal death (as defined by trialists).
3. Any potentially preventable perinatal death.*
4. Serious neonatal morbidity - composite outcome including
hypoxic Ischaemic encephalopathy, intraventricular
haemorrhage, bronchopulmonary dysplasia, necrotising
enterocolitis.
5. IUGR (as defined by the trialists).
6. Fetal distress (as defined by the study authors).
7. Neonatal resuscitation required (as defined by trialists).
8. Infant requiring intubation/ventilation.
9. Infant respiratory distress syndrome.
10. Apgar score less than seven at five minutes.
11. Neonatal admission to special care or intensive care unit, or
both.
12. Preterm birth (birth before 37 completed weeks of
pregnancy):
i) spontaneous preterm birth;
ii) iatrogenic preterm birth.
13. Caesarean section (elective and emergency).
14. Caesarean section - elective.

15. Caesarean section - emergency.

16. Serious maternal morbidity and mortality (composite
outcome with death of a woman while pregnant or within 42
days of termination of pregnancy).
17. Mothers admission to special care or intensive care unit, or
both.
18. Gestational age at birth.
19. Infant birthweight.
20. Length of infant hospital stay.
21. Length of maternal hospital stay.
* Perinatal death excluding chromosomal abnormalities, termination of pregnancies, birth before fetal viability (as defined by trialists) and fetal death before use of the intervention.
Data collection and analysis

The methodology for data collection and analysis was based on the
Cochrane Handbook of Systematic Reviews of Interventions (Higgins
2008).
Selection of studies
Two review authors (TS, GG) independently assessed for inclusion
all potential studies we identified as a result of the search strategy.
We resolved any disagreement through discussion or, if required,
we consulted the third author (ZA).
Data extraction and management
Search methods for identification of studies
Electronic searches
We contacted the Trials Search Co-ordinator to search the
Cochrane Pregnancy and Childbirth Groups Trials Register (June
2010).
The Cochrane Pregnancy and Childbirth Groups Trials Register
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
1. quarterly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL);
2. weekly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major
conferences;
4. weekly current awareness alerts for a further 44 journals
plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE,
the list of handsearched journals and conference proceedings, and
the list of journals reviewed via the current awareness service can
be found in the Specialized Register section within the editorial information about the Cochrane Pregnancy and Childbirth
Group.
Trials identified through the searching activities described above
are each assigned to a review topic (or topics). The Trials Search
Co-ordinator searches the register for each review using the topic
list rather than keywords.
Searching other resources

We searched the reference lists at the end of papers for further
studies.
We did not apply any language restrictions.
We designed a form to extract data. For eligible studies, two review authors (TS, GG) extracted the data using the agreed form,
with additional help at times (Stephania Livio). We resolved discrepancies through discussion or, if required, we consulted the
third author (ZA). We entered data into Review Manager software
(RevMan 2008) (TS) and checked for accuracy (GG).
When information regarding any of the above was unclear, we
attempted to contact authors of the original reports to provide
further details.
Assessment of risk of bias in included studies

Two review authors (TS, GG) independently assessed risk of bias
for each study using the criteria outlined in the Cochrane Handbook
for Systematic Reviews of Interventions (Higgins 2008). We resolved
any disagreement by discussion or by involving the third author
(ZA).
(1) Sequence generation (checking for possible selection

bias)
We describe for each included study the method used to generate

the allocation sequence in sufficient detail to allow an assessment
of whether it should produce comparable groups.
We assessed the method as:
adequate (any truly random process, e.g. random number
table; computer random-number generator);
inadequate (any non-random process, e.g. odd or even date
of birth; hospital or clinic record number);
unclear.
(2) Allocation concealment (checking for possible selection

bias)
We describe for each included study the method used to conceal

the allocation sequence in sufficient detail and determine whether
intervention allocation could have been foreseen in advance of, or
during recruitment, or changed after assignment.

We assessed the methods as:

adequate (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
inadequate (open random allocation; unsealed or nonopaque envelopes, alternation; date of birth);
unclear.
(3) Blinding (checking for possible performance bias)
We describe for each included study the methods used, if any, to

blind study participants and personnel from knowledge of which
intervention a participant received. We judged studies at low risk
of bias if they were blinded, or if we judged that the lack of blinding
could not have affected the results. We assessed blinding separately
for different outcomes or classes of outcomes.
adequate, inadequate or unclear for participants;
adequate, inadequate or unclear for personnel;
adequate, inadequate or unclear for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations)
We describe for each included study, and for each outcome or class
of outcomes, the completeness of data including attrition and exclusions from the analysis. We state whether attrition and exclusions were reported, the numbers included in the analysis at each
stage (compared with the total randomised participants), reasons
for attrition or exclusion where reported, and whether missing data
were balanced across groups or were related to outcomes. Where
sufficient information was reported, or was supplied by the trial
authors, we have re-included missing data in the analyses which
we undertook. We assessed methods as:
adequate;
inadequate:
unclear.
We were to discuss whether missing data greater than 20% might
impact on outcomes, acknowledging that with long-term follow
up, complete data are difficult to attain. However, none of the
included studies had greater than 20% missing data.
incompletely and so cannot be used; study fails to include results

of a key outcome that would have been expected to have been
reported);
unclear.
(6) Other sources of bias
We describe for each included study any important concerns we

have about other possible sources of bias.
We assessed whether each study was free of other problems that
could put it at risk of bias:
yes;
no;
unclear.
(7) Overall risk of bias
We made explicit judgements about whether studies were at high

risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). With
reference to (1) to (6) above, we assessed the likely magnitude and
direction of the bias and whether we considered it is likely to impact on the findings. We explored the impact of the level of bias
through undertaking sensitivity analyses - see Sensitivity analysis.
Measures of treatment effect
Dichotomous data
For dichotomous data, we present results as summary risk ratio

with 95% confidence intervals.
Continuous data
For continuous data, we used the mean difference if outcomes are

measured in the same way between trials. We used the standardised
mean difference to combine trials that measure the same outcome,
but used different methods.
Unit of analysis issues
(5) Selective reporting bias
We describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
adequate (where it was clear that all of the studys prespecified outcomes and all expected outcomes of interest to the
review have been reported);
inadequate (where not all the studys pre-specified outcomes
have been reported; one or more reported primary outcomes
were not pre-specified; outcomes of interest were reported
Cluster-randomised trials
We would have included cluster-randomised trials in the analyses

along with individually randomised trials, had we identified any.
We would have make adjustments using the methods described
in the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2008) using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), or from another
source. If ICCs from other sources had been used, we would have
reported this and conducted sensitivity analyses to investigate the

effect of variation in the ICC. If we had identified both clusterrandomised trials and individually-randomised trials, we would
have planned to synthesise the relevant information. We would
have considered it reasonable to combine the results from both if
there was little heterogeneity between the study designs and the
interaction between the effect of intervention and the choice of
randomisation unit were considered to be unlikely.
We would also have acknowledged any heterogeneity in the randomisation unit and perform a separate meta-analysis.
Cross-over trials
We considered cross-over designs inappropriate for this research

question.
Dealing with missing data

For included studies, we noted levels of attrition. We would have
explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we carried out analyses, as far as possible, on an
intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses. The denominator
for each outcome in each trial is the number randomised minus
any participants whose outcomes were known to be missing. We
would have excluded data on outcomes where there was greater
than 20% missing data on short term outcomes had we encountered such data.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta-analysis using
the T (tau-squared), I and Chi statistics. We regarded heterogeneity as substantial if T was greater than zero and either I was
greater than 30% or there was a low P-value (less than 0.10) in the
Chi test for heterogeneity. Where we found heterogeneity and
random-effects was used, we have reported the average risk ratio,
or average mean difference or average standard mean difference.
Assessment of reporting biases

If there had been 10 or more studies in a meta-analysis we would
have investigated reporting biases (such as publication bias) using
funnel plots. We would have assessed funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes, we would have used the test proposed by Egger
1997, and for dichotomous outcomes we would have used the
tests proposed by Harbord 2006. If asymmetry had been detected
by any of these tests or was suggested by a visual assessment, we
would have performed exploratory analyses to investigate it. We
would seek statistical help if necessary.
Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2008). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were
estimating the same underlying treatment effect: i.e. where trials
were examining the same intervention, and the trials populations
and methods were judged sufficiently similar. If there was clinical
heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity
was detected, we would have used random-effects analysis to produce an overall summary, if this was considered clinically meaningful. If an average treatment effect across trials was not clinically
meaningful, we would not have combined heterogeneous trials. If
we used random-effects analyses, the results have been presented
as the average treatment effect and its 95% confidence interval,
the 95% prediction interval for the underlying treatment effect,
and the estimates of T and I (Higgins 2009).
Subgroup analysis and investigation of heterogeneity
We had planned to carry out the following subgroup analyses on
all outcomes:
1. measurements in high-risk population, low-risk population
and unselected population;
2. in singleton and twin pregnancies.
However, there were insufficient data to perform any subgroup
analyses. We had also planned to pull together the three subgroups
for the overall estimation.
For fixed-effect meta-analyses, we had planned to conduct the
planned subgroup analyses classifying whole trials by interaction
tests as described by Deeks 2001. For random-effects meta-analyses, we would have assessed differences between subgroups by inspection of the subgroups confidence intervals; non-overlapping
confidence intervals indicate a statistically significant difference in
treatment effect between the subgroups.
Sensitivity analysis
We would have performed sensitivity analysis on the primary outcomes based on trial quality, separating high-quality trials from
trials of lower quality. High quality would, for the purposes of
this sensitivity analysis, have been defined as a trial having adequate sequence generation and allocation concealment.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of studies awaiting classification.

Results of the search

The search was designed to identify all randomised controlled trials
on assessing the effectiveness of Doppler ultrasound, whether using fetal-umbilical or utero-placental (maternal) vessels. We identified 58 publications from 34 studies, of which we have included
two in this review, involving data on 4993 women and 5009
neonates (Goffinet 2001; Subtil 2003).
We have excluded 30 studies, mainly because they assessed both fetal and umbilical vessels. For further details of trial characteristics,
please refer to the tables of Characteristics of included studies and
Characteristics of excluded studies. Two studies are awaiting classification as we are trying to locate the authors but they both appear
to remain unpublished (Ellwood 1997; Snaith 2006). The large
number of excluded studies reflects the fact that the search was
designed for all Doppler ultrasound studies, including both uteroplacental vessels and fetal-umbilical vessels. Most of the studies
identified focused on fetal-umbilical vessels and are included by
two other Doppler ultrasound reviews (Alfirevic 2010a; Alfirevic
2010b).
Included studies compared uterine artery Doppler assessments in

the experimental group with no uterine artery Doppler performed
in the control groups (Goffinet 2001; Subtil 2003). In both studies, low-dose aspirin was administrated in cases of abnormal uterine artery Doppler findings (Goffinet 2001; Subtil 2003).
Both studies were of assessments of women in the second trimester,
around time for fetal anomaly scan, and both included women at
low risk for hypertensive disorders (Goffinet 2001; Subtil 2003).
One of the studies involved a mixture of singleton and twin pregnancies (Subtil 2003), while the other did not state specifically if
it included multiple pregnancies, although reported numbers suggest only singleton pregnancies were included (Goffinet 2001).
Excluded studies
We excluded 30 studies, mostly because they assessed umbilical
artery Doppler ultrasound. See Characteristics of excluded studies.
Risk of bias in included studies

Included studies
The quality of the three included studies was reasonable, although

blinding was not possible (Figure 1).
Figure 1. Methodological quality summary: review authors judgements about each methodological quality
item for each included study.

Allocation
Both studies had adequate sequence generation and concealment
allocation (Goffinet 2001; Subtil 2003).
Blinding
Blinding women and/or staff in these trials was not generally feasible. Some outcomes like induction of labour and caesarean section may be influenced by the knowledge of Doppler results, but
it may be possible to avoid bias in neonatal assessment. Unfortunately, the information on the attempts to protect against biased
assessment was not available.
Incomplete outcome data
The two studies had adequate outcome data (Goffinet 2001; Subtil
2003). One of the studies awaiting classification (Ellwood 1997)
aimed to recruit 524 women, but undertook the analysis after 364
women had entered the trial, though data were available on only
164. As this was not a block randomisation, we cannot be sure
these are randomised groups being compared so we are awaiting
the full study to be reported before including any data.
We found no studies assessing uterine artery Doppler ultrasound

in the first trimester.
2. Uterine artery Doppler ultrasound versus no

Doppler ultrasound, 2nd trimester (two studies, 4993
women)
We identified two studies assessing uterine artery Doppler ultrasound in the second trimester in women at low risk for hypertensive disorders (Goffinet 2001; Subtil 2003). Both were full publications (Goffinet 2001; Subtil 2003). Overall the quality of the
included studies was good for the main criteria of randomisation, allocation concealment and low percentage of missing data
(Goffinet 2001; Subtil 2003), see Figure 1.
Primary outcomes
It is important to emphasise that this review remains underpowered to detect clinically important differences in serious maternal
and neonatal morbidity.
Selective reporting
We assessed both included studies as unclear because we did not
assess the trial protocols.
Other potential sources of bias
One study appeared free of other biases (Subtil 2003), whilst for
the other this was unclear (Goffinet 2001).
Sensitivity analyses
For sensitivity analyses by quality of studies, we have used both adequate labelled sequence generation and adequate allocation concealment as essential criteria for high quality. Two of three studies met these criteria (Goffinet 2001; Subtil 2003), see Figure 1.
However, we feel there are insufficient data to perform a sensitivity
analysis by quality.
Effects of interventions
1. Uterine artery Doppler ultrasound versus no

Doppler ultrasound, 1st trimester (no studies)
Any perinatal death after randomisation

The difference in perinatal mortality between two groups was not
statistically significant (average risk ratio (RR) 1.61, 95% confidence interval (CI) 0.48 to 5.39, two studies, 5009 babies, Analysis
2.1). The heterogeneity was high (T = 0.55, Chi P = 0.06, I
= 72%) and therefore, we used the random-effects model for the
analysis. We were unable to calculate the prediction interval as
there were only two studies.
Subtil 2003 reported significantly fewer deaths in the control
group (RR 3.14, 95% CI 1.10 to 8.98). This difference was contributed to by 17 abortions or medically indicated terminations of
pregnancy in the 1253 women in the Doppler group (1.4%) compared with three out of 617 in the control group (0.5%). In addition, 78 of the 1253 women randomised to Doppler group (6.2%)
did not receive their allocated treatment. The reason was termination of pregnancies for medical or social reasons in 15 women and
perinatal deaths in two babies, but the reasons for the remainder
of the women not receiving the Doppler ultrasound were not documented. The analysis for Any potentially preventable perinatal
death after randomisation which excluded all terminations and
perinatal deaths for chromosomal abnormalities is more clinically
relevant and showed no detectable difference (see below).

Hypertensive disorders
Sensitivity analysis
There was no difference identified in maternal hypertensive disorders between two groups (RR 1.08, 95% CI 0.87 to 1.33, two
studies, 4987 women, Analysis 2.2).
Since we assessed both studies as adequate for sequence generation

and allocation concealment (Goffinet 2001; Subtil 2003), we did
not undertake sensitivity analysis by quality.
Secondary outcomes
DISCUSSION
We found no significant difference in the pooled estimate of the intervention effect for the range of secondary outcomes with low heterogeneity where a fixed-effect meta-analysis was used. Most prespecified secondary outcomes had high heterogeneity and therefore an intervention effect estimate across studies was calculated
using random-effects.
There was no significant difference in stillbirths (average RR 1.44,
95% CI 0.38 to 5.49, two studies, 5003 babies, random-effects
T = 0.70, Chi P = 0.04, I = 75%, Analysis 2.3), or for neonatal
deaths (RR 2.39, 95% CI 0.39 to 14.83, two studies, 5009 babies,
Analysis 2.4). Similarly for Any potentially preventable perinatal
death after randomisation (average RR 1.29, 95% CI 0.21 to 7.94,
two studies, 5009 babies, random-effects T 1.09, Chi P = 0.11, I
= 60%, Analysis 2.5). These data should be interpreted cautiously
because the numbers are small and heterogeneity is high.
The data for neonatal admission to special care baby unit (SCBU)
or neonatal intensive care unit (NICU) (RR 1.12, 95% CI 0.92
to 1.37, two studies, 5001 babies, Analysis 2.13) and iatrogenic
preterm birth (average RR 0.92, 95% CI 0.51 to 1.65, two studies,
4982 women, random-effects T = 0.09, Chi P = 0.15, I = 51%,
Analysis 2.15) are consistent with the overall picture showing no
significant difference in two groups. The meta-analysis also failed
to identify any difference in IUGR (average RR 0.98, 95% CI
0.64 to 1.50, two studies, 5006 babies, random-effects T = 0.08,
Chi P = 0.02, I = 82%, Analysis 2.7), although there was high
heterogeneity, so it is also possible that there are different effects
in the different studies, for unknown reasons.
Only one study assessed neonatal resuscitation (RR 0.94, 95% CI
0.75 to 1.19, 3133 babies, Analysis 2.9), Apgar score less than
seven at five minutes (RR 1.08, 95% CI 0.48 to 2.45, 3133 babies)
(Analysis 2.12) and caesarean sections (emergency plus elective)
(RR 1.09, 95% CI 0.91 to 1.29, 3133 women) (Analysis 2.16).
We found no significant difference for any of these outcomes.
None of the studies assessed the following outcomes: Serious
neonatal morbidity, Fetal distress, Infant requiring intubation/
ventilation, Infant respiratory distress syndrome, Spontaneous
preterm birth, Serious maternal morbidity and Maternal admission to special care.
Increasing interest in maternal Doppler in first and second

trimester led us to undertake this review which completes a trio
of reviews on Doppler ultrasound in pregnancy. The other two
reviews focused on the use of fetal-umbilical Doppler ultrasound
in high risk (Alfirevic 2010a) and normal pregnancies (Alfirevic
2010a).
Non-prespecified outcomes
We did not include any non-prespecified outcomes.
Despite wide use of uterine artery Doppler ultrasound in clinical

practice, we identified just two randomised studies assessing this
intervention in the second trimester of pregnancy involving 4993
women at low risk of hypertensive disorders (Goffinet 2001; Subtil
2003) and found no difference in any perinatal or maternal outcomes. Considering that both included studies involved women at
low risk for hypertensive disorders, this could possibly explain the
lack of benefit identified for uterine artery Doppler application
as incidence of adverse outcomes was low (any potentially preventable perinatal death 0.4%, hypertensive disorders 7%, IUGR
11%).
In both studies (Goffinet 2001; Subtil 2003), the finding of pathological uterine artery Doppler was followed by low-dose aspirin
administration. When interpreting these data, it is important to
highlight the presence of heterogeneity and small number of participants that makes our review underpowered rare events such as
perinatal mortality and severe maternal outcomes.
Suprisingly, lower perinatal mortality was observed in the control group in one study (Subtil 2003: risk ratio 3.14, 95% confidence interval 1.10 to 8.98, Analysis 2.1). This could be possibly
explained by a higher percentage of women with termination of
pregnancy or perinatal death that occurred in the Doppler group
by chance before the Doppler ultrasound was carried out.
Summary of main results

We found no differences in any of the perinatal and maternal
outcomes when comparing uterine artery Doppler ultrasound in
the second trimester in women at low risk for hypertensive disorders versus controls. There were no studies of women in the first
trimester.
Overall completeness and applicability of

evidence

10
There were only two studies involving 4993 women, and clearly
the meta-analysis remains underpowered to show clinically important differences in primary outcomes. The identification of an
abnormal results also needs an effective intervention before the
screening test can be said to be helpful.
Quality of the evidence

The studies were of reasonable quality, but involved insufficient
numbers of women overall to assess the rare outcomes of perinatal
death and morbidity.
Potential biases in the review process

We attempted to minimise bias in a number of ways; two review
authors assessed eligibility for inclusion, carried out data extraction
and assessed risk of bias. Each worked independently. Nevertheless,
the process of assessing risk of bias, for example, is not an exact
science and includes many personal judgements.
Agreements and disagreements with other

studies or reviews
Findings from this meta-analysis are not in disagreement with
other non-randomised studies that examined the role of uterine
arteries in low-risk population in second trimester of pregnancy.
AUTHORS CONCLUSIONS
Implications for practice

Data in this meta-analysis failed to show that the use of uterine
artery Doppler in second trimester in low-risk population for hypertensive disorders provides benefit for the baby or mother.
Uterine artery Doppler ultrasound is widely used in high-risk pregnancy and progressively its use is spreading into the first trimester,
although there are no randomised studies to show clear benefit in
this population of women. Futher research is needed to prove the
appropriateness of this clinical practice application.
Implications for research

As previously highlighted, larger studies are needed with enough
power to show clearly the presence or absence of benefit when
using uterine artery Doppler ultrasound in second trimester in
low-risk women for hypertensive disorders. Moreover, randomised
controlled trials of uterine artery Doppler in the first and second
trimester, in combination with womans history and/or biochemical serum markers, are needed to evaluate the benefit of combined
models.
ACKNOWLEDGEMENTS
We would also like to thank Stefania Livio, who helped with some
of the data extractions, and Eugenie Ong, who translated the de
Rochambeau 1992 study.
As part of the pre-publication editorial process, this review has been
commented on by two peers (an editor and referee who is external
to the editorial team), a member of the Pregnancy and Childbirth
Groups international panel of consumers and the Groups Statistical Adviser.
REFERENCES
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Subtil 2003 {published data only}
Subtil D, Goeusse P, Houfflin-Debarge V, Puech F,

Lequien P, Breart G, et al.Randomised comparison of
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Hypertension in Pregnancy 2000;19(Suppl 1):9.
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Almstrom H, Axelsson O, Ekman G, Ingemarsson I,
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11
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Mason 1993 {published data only}
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McCowan 1996 {published data only}
McCowan LME, Harding J, Roberts AB, Barker S,
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McParland 1988 {published data only}
McParland P, Pearce JM. Doppler blood flow in pregnancy.
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Neales 1994 {published data only}
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Newnham 1991 {published data only}

Newnham JP, ODea MRA, Reid KP, Diepeveen DA.
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Bower S, Schuchter K, Campbell S. Doppler ultrasound
screening as part of routine antenatal screening: prediction
of pre-eclampsia and intrauterine growth retardation.
British Journal of Obstetrics and Gynaecology 1993;100(11):
98994.
Brosens 1972
Brosens IA, Robertson WB, Dixon HG. The role of the
spiral arteries in the pathogenesis of preeclampsia. Obstetrics
and Gynecology Annual 1972;1:17791.
Burns 1993
Burns PN. Principles of Doppler and colour flow. Radiology
in Medicine 1993;85:316.
Chen 1996
Chen JF, Fowlkes JB, Carson PL, Rubin JM, Adler RS.
Autocorrelation of integrated power Doppler signals and its
application. Ultrasound in Medicine and Biology 1996;22:
10537.
Cnossen 2008
Cnossen JS, Morris RK, ter Riet G, Mol BW, van der Post
JA, Coomarasamy A, et al.Use of uterine artery Doppler
ultrasonography to predict pre-eclampsia and intrauterine
growth restriction: a systematic review and bivariable metaanalysis. Canadian Medical Association Journal 2008;178
(6):70111.
Deeks 2001
Deeks JJ, Altman DG, Bradburn MJ. Statistical methods
for examining heterogeneity and combining results from

14
several studies in meta-analysis. In: Egger M, Davey Smith

G, Altman DG editor(s). Systematic reviews in health care:
meta-analysis in context. London: BMJ Books, 2001.
Egger 1997
Egger M, Smith GD, Schneider M, Minder C. Bias in
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Espinoza 2006
Espinoza J, Romero R, Kim YM, Kusanovic JP, Hassan
S, Erez O, et al.Normal and abnormal transformation of
the spiral arteries during pregnancy. Journal of Perinatal
Medicine 2006;34:44758.
Fisk 2001
Fisk NM, Smith RP. Fetal growth restriction; small for
gestational age. In: Chamberlain G, Steer P editor(s).
Turnbulls obstetrics. 3rd Edition. Edinburgh: Churchill
Livingstone, 2001:197209.
Harbord 2006
Harbord RM, Egger M, Sterne JA. A modified test for
small-study effects in meta-analyses of controlled trials
with binary endpoints. Statistics in Medicine 2006;25(20):
344357.
Harrington 1996
Harrington K, Cooper D, Lees C, Hecher K, Campbell S.
Doppler ultrasound of the uterine arteries: the importance
of bilateral notching in the prediction of pre-eclampsia,
placental abruption or delivery of small-for-gestational-age
baby. Ultrasound in Obstetrics and Gynecology 1996;7(3):
1828.
Higgins 2008
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Khong 1991
Khong TY. Acute atherosis in pregnancies complicated by
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mellitus. Archives of Pathology and Laboratory Medicine
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in antiphospholipid syndrome. Lupus 1998;7(Suppl 2):S81.
Martin 2001
Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH.
Screening for pre-eclampsia and fetal growth restriction
by uterine artery Doppler at 11-14 weeks of gestation.
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of the literature. Human Pathology 1996;27(2):2016.
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Nicolaides KH, Bindra R, Turan OM, Chefetz I, Sammar
M, Meiri H, et al.A novel approach to first trimester
screening for early pre-eclampsia combining serum PP13 and Doppler ultrasound. Ultrasound in Obstetrics and
Gynecology 2006;27(1):137.
Olofsson 1993
Olofsson P, Laurini RN, Marsal K. A high uterine artery
pulsatility index reflects a defective development of
placental bed spiral arteries in pregnancies complicated by
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of Obstetrics & Gynecology and Reproductive Biology 1993;49
(3):1618.
Owen 2001
Owen P. Fetal assessment in the third trimester: fetal growth
and biophysical methods. In: Chamberlain G, Steer P
editor(s). Turnbulls obstetrics. 3rd Edition. Edinburgh:
Churchill Livingstone, 2001.
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Papageorghiou AT, Yu CK, Bindra R, Pandis G, Nicolaides
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Parra M, Rodrigo R, Barja P, Bosco C, Fernndez V, Muoz
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Journal of Obstetrics and Gynecology 2005;193:148691.
Plasencia 2007
Plasencia W, Maiz N, Bonino S, Kaihura C, Nicolaides
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prediction of pre-eclampsia. Ultrasound in Obstetrics and
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Sibai 2005
Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet
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Spencer 2007
Spencer K, Cowans NJ, Chefetz I, Tal J, Meiri H. First
trimester maternal serum PP-13, PAPP-A and second
trimester uterine artery Doppler pulsatility index as marker
of pre-eclampsia. Ultrasound Obstetrics and Gynecology
2007;29:12834.
Von Dadelszen 2002
Von Dadelszen P, Magee LA. Could an infectious trigger
explain the differential maternal response to the shared
placental pathology of preeclampsia and normotensive

15
intrauterine growth restriction?. Acta Obstetricia et

Gynecologica Scandinavica 2002;81(7):6428.
Yu 2005
Yu CK, Smith GC, Papageorghiou AT, Cacho AM,
Nicolaides KH, Fetal Medicine Foundation Second
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293308.
Indicates the major publication for the study

16
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Goffinet 2001
Methods
Multicentre randomised trial. Stratified by centre and parity (nulliparous or multiparous)

. Blocks of 4. Randomisatioin numbers were established using tables of order 4 permutations
Individual woman.
Participants
Inclusion criteria:
All women attending for a routine antenatal visit before 24 weeks.
Nulliparaus and multiparus.
Low risk.
N = 3317, though analysis on 3133.
Exclusion criteria:
Women who had indications for UAD including chronic hypertension, diabetes,
previous fetal death, IUGR, hypertensive disorders of pregnancy.
Women known to be at high risk before 24 weeks did not enter the trial.
Women with contraindications to aspirin were also excluded.
Interventions
Experimental intervention: uterine artery Doppler US

Uterine artery Doppler performed between 20 and 24. 100 mg of aspirin daily
until the 35th week was prescribed to patients with abnormal results.
N = 1672 randomised though 100 lost to follow up = 1572.
Control/comparison intervention: no Doppler US
Women allocated to the control group did not have a uterine artery Doppler on
the day of the second-trimester abdominal US examination.
N = 1645 though 84 lost to follow up = 1561.
Outcomes
Principal outcome: IUGR (birthweight < 10% and < 3% according to gestational age)
Pre-eclampsia, gestational hypertension.
Uterine bleeding, oligohydramnios, abnormal CTG.
Number of antenatal consultations, days of antenatal hospitalisation, CTG
measurements, ultrasound and Doppler tests.
Peri and neonatal death, fetal distress defined by abnormal CTG resulting in
intervention (caesarean or instrumental delivery), Apgar score, neonatal resuscitation,
neonatal transfer.
Notes
Risk of bias
Item
Authors judgement
Description
Adequate sequence generation?
Yes
The randomisation was stratified

according to centre and parity (nulliparae
or multiparae).
The randomisation numbers were

17
Goffinet 2001
(Continued)
established using tables of order four

permutation.
Allocation concealment?
Yes
Randomisation procedure using

sealed envelopes.
The randomisation procedure was
verified by checking all unused envelopes
at the end of the trial and confirming that
envelopes had been used in ascending
order.
Blinding?
All outcomes
No
Not possible to blind.
Incomplete outcome data addressed?

All outcomes
Yes
Loss of participants to follow up at each

data collection point:
115 follow-up data missing.
Overall 100/1672 (6%) lost from
Doppler.
Overall 84/1765 (5%) lost from
control group.
Exclusion of participants after randomisation:
Shortly after randomisation, follow
up ceased for 69 women: 39 in Doppler
group and 30 in control group. Of those:
1. 48 (27 in Doppler and 21 in control)
follow up ended when verification of
admission criteria indicated that they
should not have been randomised.
2. 4 women refused further
participation after randomisation.
3. 6 had miscarriages before
ultrasound.
Free of selective reporting?
Unclear
We did not assess the trial protocol.
Free of other bias?
Unclear
2 centres stopped inclusions a few month

after the beginning of the study and did
not send the records of 11 women they had
included
Describe any baseline in balance: none
identified.

18
Subtil 2003
Methods
Multicentre randomised controlled trial (12 centres). Block randomisation - blocks of 8

or 16, stratified by centre
Unit of randomisation: individual woman, 2:1 ratio for randomisation of Doppler vs
placebo
Part of a larger study (Essai Regional Aspirine Mere Enfant, ERASME trial) which
evaluated the routine prescription of low-dose aspirin (100mg) in nulliparous women
Participants
Inclusion criteria:
Nulliparae (no previous delivery 22 weeks) between 14 and 20+6 weeks.
Singletons and twins.
N = 1870. 2491 women agreed to participate and were randomised. 621 were
excluded from the current evaluation as they were allocated to routine aspirin leaving
1870 in the current evaluation. Data available on 1860 women.
Exclusion criteria:
No history of hypertension.
No clear indications for or contraindications to the prescription of aspirin or
another anticoagulant during the pregnancy.
Interventions
Experimental intervention: uterine artery Doppler US

Half underwent utero-placental artery Doppler at the same time as the secondtrimester anatomical ultrasound (22-24 weeks), with low-dose aspirin (100 mg)
prescribed only if the findings were abnormal until 36 weeks.
N = 1253 women (22 twin pregnancies). Outcomes on 1244 women and 1249
neonates.
Control/comparison intervention: no Doppler US
The other half (1238) was further divided randomly into 2 groups:
i) daily treatment with low-dose aspirin 100 mg (N = 621) excluded from the
current evaluation;
ii) or placebo until the end of 34 weeks (N = 617).
The group of patients receiving aspirin or placebo began treatment the day after
randomisation (between 14+1 and 21+0 weeks) and stopped after 34 weeks.
N = 617 women (14 twin pregnancies). Outcomes on 616 women and 627
neonates.
Outcomes
Pre-eclampsia, pregnancy related hypertension, very low or low birthweight for gestational age (birthweight 3rd and 10th centile of the standard curves used in France),
HELLP syndrome, placental abruption or a caesarean section because of fetal indication
(uncompensated maternal hypertension, suspected IUGR, meconium stained amniotic
fluid or placental abruption)
Notes
Doppler group included 22 twin pregnancies and the control group included 14 twin
pregnancies
Risk of bias
Item
Authors judgement
Description
Adequate sequence generation?
Yes
...a randomisation list was computer generated by the manufacturer of the treatment

19
Subtil 2003
(Continued)
boxes before the study began. Treatment

randomisation was balanced in blocks of 8
and stratified by centre. Each block of eight
box numbers was then randomly mixed,
according to a random number table, with
eight boxes labelled Doppler. The randomisation was thus balanced by blocks of
16 in these centres, and the box numbers
were not consecutive.
Allocation concealment?
Yes
...each patient was randomly allocated to a

group immediately after inclusion by connection to an always available server.... After verifying the inclusion criteria and the
patients consent, the server provided either a treatment box number or the word
Doppler to the physician investigator. At
the end of prenatal consultation the physician gave the patient a numbered treatment
box (neither the physician nor the patient
knew whether this was aspirin or placebo)
or an appointment (between 22 and 24
weeks) for a utero-placental artery Doppler.
Blinding?
All outcomes
No
It was not possible to blind participants and

clinicians with regard to the use of Doppler
US or not (and the outcome assessor would
often be the clinician), although participants and clinicians were blind to the use
of aspirin or placebo in women with abnormal Doppler US results
Incomplete outcome data addressed?

All outcomes
Yes
Loss of participants to follow up at each

data collection point:
9 women lost to follow up in the
Doppler group and 1 in the no Dopper
group. (0.7% to 0.2 = %, NS).
Exclusion of participants after randomisation:
2491 women agreed to participate
and were randomised. 621 were excluded
from the current evaluation as they were
allocated to routine aspirin (not included
in current evaluation). As the allocation to
aspirin was done by randomisation of the
no Doppler group, the randomisation
assessed in this comparison still stands.
Doppler not performed on 78 (6%)

20
Subtil 2003
(Continued)
women in Doppler group.

26 lost to follow up in Doppler
group of which 17 were ToP. In the
placebo group it was 4 of which 3 were
ToP.
Intention-to-treat analysis.
Free of selective reporting?
Unclear
We did not assess the trial protocol.
Free of other bias?
Yes
The study was not stopped early.

No baseline in balance:
no imbalances on: maternal age; low
educational level; smoking; height;
weight; BMI; systolic BP; diastolic BP;
gestational age at inclusion; multiple
pregnancy.
AFI: amniotic fluid index

BMI: basal metabolic rate
BP: blood pressure
CTG: cardiotocography
HELLP: haemolysis, elevated liver enzymes, low platelets
IUGR: intrauterine growth restriction
NS: not significant
ToP: termination of pregnancy
UAD: uterine artery Doppler
US: ultrasound
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Almstrom 1992
Study assessing umbilical artery Doppler ultrasound.
Ben-Ami 1995
This study is not randomised.
Biljan 1992
Burke 1992
Davies 1992
Study assessing umbilical artery and uterine artery Doppler ultrasound, see Alfirevic 2010b.
de Rochambeau 1992

21
(Continued)
Doppler 1997
Giles 2003
Study assessing umbilical artery Doppler ultrasound with biometry
Gonsoulin 1991
Conference abstract - not clear whether high-risk/low-risk/unselected pregnancies, and no data suitable for
inclusion. Further details were sought from the authors by the authors of the previous Doppler for unselected
population review, without success.
Haley 1997
Hofmeyr 1991
Johnstone 1993
Mason 1993
McCowan 1996
Conference abstract only but outcomes were comparing women with normal and abnormal Doppler ultrasound readings, so not a randomised comparison
McParland 1988
This study has never been reported in full although it has been partly reported in a review article (McParland
1988) and a full manuscript has been given to the review authors by Dr Pearce, who has been accused of
publishing reports of trials whose veracity cannot be confirmed (BJOG 1995). Consequently, the Doppler
trial data are not now thought by the review authors to be sufficiently reliable to be retained within this
review.
Neales 1994
Newnham 1991
Study assessing umbilical artery and uterine artery Doppler ultrasound, see Alfirevic 2010a.
Newnham 1993
Study assessing umbilical artery and uterine artery Doppler ultrasound (see Alfirevic 2010b).
Nienhuis 1997
Nimrod 1992
Norman 1992
Omtzigt 1994
Pattinson 1994
Pearce 1992
Dr Pearce has been accused of publishing reports of trials whose veracity cannot be confirmed (BJOG 1995)
. Consequently, the Doppler trial data are not now thought by the review authors to be sufficiently reliable
to be retained within this review.
Schneider 1992
Conference abstract in English language identified - unexplained difference in numbers (250 vs 329) in
Doppler vs control groups suggesting allocation bias. The definitive publication after translation from Ger-

22
(Continued)
man did not explain this difference and failed to outline the trial methodology
Scholler 1993
This study was translated from German for us. It was a quasi-RCT of 211 women undergoing Doppler
ultrasound versus no Doppler ultrasound. It was excluded for a combination of the following reasons: the
only outcome relevant to our review was induction of labour; the study had high risk of bias being a quasiRCT; further information was needed from the authors before this data could be included. Data reported
for induction of labour: Doppler group 37/108 and no Doppler group 41/103
Trudinger 1987
Tyrrell 1990
Study assessing umbilical artery and uterine artery Doppler ultrasound, see Alfirevic 2010a.
Whittle 1994
Williams 2003
RCT: randomised controlled trial

vs: versus
Characteristics of studies awaiting assessment [ordered by study ID]

Ellwood 1997
Methods
Randomised controlled trial.

Individual woman.
Participants
Inclusion criteria
Pregnant women with no pre-existing medical condition.
First ongoing pregnancy (one first trimester pregnancy loss is allowed).
Exclusion criteria
Medical conditions, previous pregnancies.
Interventions
Experimental intervention: uterine artery Doppler

18-20 weeks: routine scan.
24-26 weeks: uterine artery Doppler waveform studies and transvaginal assessment of the cervix.
38 weeks: AFI assessment.
Control/comparison intervention: no uterine artery Doppler
Routine ultrasound at 18-20 weeks and other scans as clinically indicated.
Outcomes
Pre-specified outcomes: gestational age at delivery, rate of preterm birth, unplanned admissions for pre-eclampsia
and fetal growth restriction and bed days, neonates with Apgar scores < 7 at 5 min, neonatal admissions and special
care nursery bed days
Notes
The study was still ongoing when this report was written. The plan was to recruit 524 women, 262 in each group
(power calculation done on admission to neonatal nursery). At time of report 364 women had been randomised and
145 had given birth and been followed up

23
Ellwood 1997
(Continued)
We are trying to contact the authors for further information
Snaith 2006
Methods
Randomised controlled trial.
Participants
Low-risk primiparous women.
Interventions
Structured telephone support intervention provided by midwife +/- uterine artery Doppler screening
Outcomes
Primary outcome: number of antenatal contacts with health professionals

Secondary outcomes: number of antenatal admissions to hospital, anxiety, level of perceived social support, satisfaction
with care, economic evaluation, major clinical outcomes
Notes
Registered protocol: Current Controlled Trials (http://controlled-trials.com/mrct)

We are contacting the author for further information as this trial should have completed but we can find no publication
AFI: amniotic fluid index

24
DATA AND ANALYSES
Comparison 1. Uterine artery Doppler ultrasound versus no Doppler ultrasound, 1st trimester
Outcome or subgroup title

1 Any perinatal death after
randomisation
1.1 Women at increased risk
of complications
1.2 Women at low risk of
complications
1.3 Unselected population of
women
2 Hypertensive disorders
of complications
complications
women
3 Stillbirth
of complications
complications
women
4 Neonatal death
of complications
complications
women
5 Any potentially preventable
perinatal death after
randomisation
of complications
complications
women
6 Serious neonatal morbidity composite
of complications
No. of
studies
No. of
participants
Risk Ratio (M-H, Fixed, 95% CI)
Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Statistical method

Effect size
25

complications
women
7 Intrauterine growth restriction
of complications
complications
women
8 Fetal distress
of complications
complications
women
9 Neonatal resuscitation
of complications
complications
women
10 Infant requiring intubation/
ventilation
of complications
complications
women
11 Infant respiratory distress
syndrome
of complications
complications
women
12 Apgar score < 7 at 5 min
of complications
complications
women
13 Neonatal admission to SCBU
or NICU
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
Not estimable

26

of complications
complications
women
14 Spontaneous preterm birth (<
37 weeks)
of complications
complications
women
15 Iatrogenic preterm birth (< 37
weeks)
of complications
complications
women
16 Caesarean section (both elective
and emergency)
of complications
complications
women
17 Elective caesarean section
of complications
complications
women
18 Emergency caesarean section
of complications
complications
women
19 Serious maternal morbidity and
mortality
of complications
complications
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable

27

women
20 Mothers admission to special
care or intensive care unit
of complications
complications
women
21 Gestational age at birth
of complications
complications
women
22 Infant birthweight
of complications
complications
women
23 Length of infant hospital stay
of complications
complications
women
24 Length of maternal hospital
stay
of complications
complications
women
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0
Mean Difference (IV, Fixed, 95% CI)

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Comparison 2. Uterine artery Doppler ultrasound versus no Doppler ultrasound, 2nd trimester
Outcome or subgroup title

1 Any perinatal death after
randomisation
No. of
studies
No. of
participants
5009
Statistical method
Risk Ratio (M-H, Random, 95% CI)

Effect size
1.61 [0.48, 5.39]
28

of complications
complications
women
2 Hypertensive disorders
of complications
complications
women
3 Stillbirth
of complications
complications
women
4 Neonatal death
of complications
complications
women
5 Any potentially preventable
perinatal death after
randomisation
of complications
complications
women
6 Serious neonatal morbidity composite
of complications
complications
women
7 Intrauterine growth restriction
of complications
complications
women
Not estimable
5009
1.61 [0.48, 5.39]
Not estimable
2
0
4987
0

1.08 [0.87, 1.33]

Not estimable
4987
1.08 [0.87, 1.33]
Not estimable
2
0
5003
0

1.44 [0.38, 5.49]

Not estimable
5003
1.44 [0.38, 5.49]
Not estimable
2
0
5009
0

2.39 [0.39, 14.83]

Not estimable
5009
2.39 [0.39, 14.83]
Not estimable
5009
1.29 [0.21, 7.94]
Not estimable
5009
1.29 [0.21, 7.94]
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
2
0
5006
0
Odds Ratio (M-H, Random, 95% CI)

0.98 [0.64, 1.50]

Not estimable
5006
0.98 [0.64, 1.50]
Not estimable

29
8 Fetal distress
of complications
complications
women
9 Neonatal resuscitation
of complications
complications
women
10 Infant requiring intubation/
ventilation
of complications
complications
women
11 Infant respiratory distress
syndrome
of complications
complications
women
12 Apgar score < 7 at 5 min
of complications
complications
women
13 Neonatal admission to SCBU
or NICU
of complications
complications
women
14 Spontaneous preterm birth (<
37 weeks)
of complications
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
1
0
3133
0

0.94 [0.75, 1.19]

Not estimable
3133
0.94 [0.75, 1.19]
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
1
0
3133
0

1.08 [0.48, 2.45]

Not estimable
3133
1.08 [0.48, 2.45]
Not estimable
5001
1.12 [0.92, 1.37]
Not estimable
5001
1.12 [0.92, 1.37]
Not estimable
Not estimable
Not estimable

30

complications
women
15 Iatrogenic preterm birth (< 37
weeks)
of complications
complications
women
16 Caesarean section (both elective
and emergency)
of complications
complications
women
17 Elective caesarean section
of complications
complications
women
18 Emergency caesarean section
of complications
complications
women
19 Serious maternal morbidity and
mortality
of complications
complications
women
20 Mothers admission to special
care or intensive care unit
of complications
complications
women
21 Gestational age at birth
Not estimable
Not estimable
4982
0.92 [0.51, 1.65]
Not estimable
4982
0.92 [0.51, 1.65]
Not estimable
3133
1.09 [0.91, 1.29]
Not estimable
3133
1.09 [0.91, 1.29]
Not estimable
1
0
3133
0

1.05 [0.82, 1.34]

Not estimable
3133
1.05 [0.82, 1.34]
Not estimable
1
0
3133
0

1.13 [0.87, 1.46]

Not estimable
3133
1.13 [0.87, 1.46]
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
3133
-0.10 [-0.24, 0.04]

31

of complications
complications
women
22 Infant birthweight
of complications
complications
women
23 Length of infant hospital stay
of complications
complications
women
24 Length of maternal hospital
stay
of complications
complications
women
Not estimable
3133
-0.10 [-0.24, 0.04]
Not estimable
1
0
3133
0

-34.0 [-68.63, 0.63]

Not estimable
3133
-34.0 [-68.63, 0.63]
Not estimable
0
0
0
0

Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable
Not estimable

32
Analysis 2.1. Comparison 2 Uterine artery Doppler ultrasound versus no Doppler ultrasound, 2nd
trimester, Outcome 1 Any perinatal death after randomisation.
Review:
Utero-placental Doppler ultrasound for improving pregnancy outcome
Comparison: 2 Uterine artery Doppler ultrasound versus no Doppler ultrasound, 2nd trimester
Outcome: 1 Any perinatal death after randomisation
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
1 Women at increased risk of complications
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
Total events: 0 (Doppler US), 0 (No Doppler US)

Heterogeneity: not applicable
Test for overall effect: not applicable
2 Women at low risk of complications
Goffinet 2001
13/1572
14/1561
54.6 %
0.92 [ 0.43, 1.96 ]
Subtil 2003
25/1249
4/627
45.4 %
3.14 [ 1.10, 8.98 ]
2821
2188
100.0 %
1.61 [ 0.48, 5.39 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2188
100.0 %
1.61 [ 0.48, 5.39 ]
Subtotal (95% CI)

Heterogeneity: Tau2 = 0.55; Chi2 = 3.54, df = 1 (P = 0.06); I2 =72%
Test for overall effect: Z = 0.77 (P = 0.44)
3 Unselected population of women
Subtotal (95% CI)

Total (95% CI)
2821

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
33
trimester, Outcome 2 Hypertensive disorders.
Review:
Outcome: 2 Hypertensive disorders
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
83/1572
81/1561
51.2 %
1.02 [ 0.76, 1.37 ]
133/1238
58/616
48.8 %
1.14 [ 0.85, 1.53 ]
2810
2177
100.0 %
1.08 [ 0.87, 1.33 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2177
100.0 %
1.08 [ 0.87, 1.33 ]

Goffinet 2001
Subtil 2003
Subtotal (95% CI)

Heterogeneity: Chi2 = 0.29, df = 1 (P = 0.59); I2 =0.0%
Subtotal (95% CI)

Total (95% CI)
2810

0.5
0.7
Favours Doppler

1.5
Favours no Doppler
34
trimester, Outcome 3 Stillbirth.
Review:
Outcome: 3 Stillbirth
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]

Subtil 2003
24/1253
4/617
47.0 %
2.95 [ 1.03, 8.48 ]
Goffinet 2001
10/1572
13/1561
53.0 %
0.76 [ 0.34, 1.74 ]
2825
2178
100.0 %
1.44 [ 0.38, 5.49 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2178
100.0 %
1.44 [ 0.38, 5.49 ]
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2825

0.05
0.2
Favours Doppler

20
Favours no Doppler
35
trimester, Outcome 4 Neonatal death.
Review:
Outcome: 4 Neonatal death
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]

Goffinet 2001
3/1572
1/1561
60.1 %
2.98 [ 0.31, 28.61 ]
Subtil 2003
1/1249
0/627
39.9 %
1.51 [ 0.06, 36.94 ]
2821
2188
100.0 %
2.39 [ 0.39, 14.83 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2188
100.0 %
2.39 [ 0.39, 14.83 ]
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2821

0.01
0.1
Favours Doppler
10
100
Favours no Doppler

36
trimester, Outcome 5 Any potentially preventable perinatal death after randomisation.
Review:
Outcome: 5 Any potentially preventable perinatal death after randomisation
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]

Goffinet 2001
5/1572
8/1561
61.0 %
0.62 [ 0.20, 1.89 ]
Subtil 2003
8/1249
1/627
39.0 %
4.02 [ 0.50, 32.04 ]
2821
2188
100.0 %
1.29 [ 0.21, 7.94 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2188
100.0 %
1.29 [ 0.21, 7.94 ]
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2821

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
37
trimester, Outcome 7 Intrauterine growth restriction.
Review:
Outcome: 7 Intrauterine growth restriction
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]

Goffinet 2001
162/1572
135/1561
51.1 %
1.21 [ 0.95, 1.54 ]
Subtil 2003
158/1246
98/627
48.9 %
0.78 [ 0.60, 1.03 ]
2818
2188
100.0 %
0.98 [ 0.64, 1.50 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2188
100.0 %
0.98 [ 0.64, 1.50 ]
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2818

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
38
trimester, Outcome 9 Neonatal resuscitation.
Review:
Outcome: 9 Neonatal resuscitation
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
127/1572
134/1561
100.0 %
0.94 [ 0.75, 1.19 ]
1572
1561
100.0 %
0.94 [ 0.75, 1.19 ]
0.0 %
0.0 [ 0.0, 0.0 ]
1561
100.0 %
0.94 [ 0.75, 1.19 ]

Goffinet 2001
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
1572

Test for subgroup differences: Not applicable
0.01
0.1
Favours Doppler

10
100
Favours no Doppler
39
trimester, Outcome 12 Apgar score < 7 at 5 min.
Review:
Outcome: 12 Apgar score < 7 at 5 min
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
12/1572
11/1561
100.0 %
1.08 [ 0.48, 2.45 ]
1572
1561
100.0 %
1.08 [ 0.48, 2.45 ]
0.0 %
0.0 [ 0.0, 0.0 ]
1561
100.0 %
1.08 [ 0.48, 2.45 ]

Goffinet 2001
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
1572

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
40
trimester, Outcome 13 Neonatal admission to SCBU or NICU.
Review:
Outcome: 13 Neonatal admission to SCBU or NICU
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
142/1572
121/1561
74.0 %
1.17 [ 0.92, 1.47 ]
63/1242
32/626
26.0 %
0.99 [ 0.66, 1.50 ]
2814
2187
100.0 %
1.12 [ 0.92, 1.37 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2187
100.0 %
1.12 [ 0.92, 1.37 ]

Goffinet 2001
Subtil 2003
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2814

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
41
trimester, Outcome 15 Iatrogenic preterm birth (< 37 weeks).
Review:
Outcome: 15 Iatrogenic preterm birth (< 37 weeks)
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]

Goffinet 2001
16/1572
24/1561
46.3 %
0.66 [ 0.35, 1.24 ]
Subtil 2003
44/1237
18/612
53.7 %
1.21 [ 0.70, 2.07 ]
2809
2173
100.0 %
0.92 [ 0.51, 1.65 ]
0.0 %
0.0 [ 0.0, 0.0 ]
2173
100.0 %
0.92 [ 0.51, 1.65 ]
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
2809

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
42
trimester, Outcome 16 Caesarean section (both elective and emergency).
Review:
Outcome: 16 Caesarean section (both elective and emergency)
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
232/1572
212/1561
100.0 %
1.09 [ 0.91, 1.29 ]
1572
1561
100.0 %
1.09 [ 0.91, 1.29 ]
0.0 %
0.0 [ 0.0, 0.0 ]
1561
100.0 %
1.09 [ 0.91, 1.29 ]

Goffinet 2001
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
1572

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
43
trimester, Outcome 17 Elective caesarean section.
Review:
Outcome: 17 Elective caesarean section
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
117/1572
111/1561
100.0 %
1.05 [ 0.82, 1.34 ]
1572
1561
100.0 %
1.05 [ 0.82, 1.34 ]
0.0 %
0.0 [ 0.0, 0.0 ]
1561
100.0 %
1.05 [ 0.82, 1.34 ]

Goffinet 2001
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
1572

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
44
trimester, Outcome 18 Emergency caesarean section.
Review:
Outcome: 18 Emergency caesarean section
Study or subgroup
Doppler US
No Doppler US
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
115/1572
101/1561
100.0 %
1.13 [ 0.87, 1.46 ]
1572
1561
100.0 %
1.13 [ 0.87, 1.46 ]
0.0 %
0.0 [ 0.0, 0.0 ]
1561
100.0 %
1.13 [ 0.87, 1.46 ]

Goffinet 2001
Subtotal (95% CI)

Subtotal (95% CI)

Total (95% CI)
1572

0.01
0.1
Favours Doppler

10
100
Favours no Doppler
45
trimester, Outcome 21 Gestational age at birth.
Review:
Outcome: 21 Gestational age at birth
Study or subgroup
Doppler US
N
Mean
Difference
No Doppler US
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
100.0 %
-0.10 [ -0.24, 0.04 ]

Goffinet 2001
Subtotal (95% CI)
1572
1572
39 (2)
1561
39.1 (2)
100.0 % -0.10 [ -0.24, 0.04 ]
1561

Subtotal (95% CI)
1572
1561
0.0 %
0.0 [ 0.0, 0.0 ]

Total (95% CI)
100.0 % -0.10 [ -0.24, 0.04 ]

-100
-50
Favours no Doppler

50
100
Favours Doppler
46
trimester, Outcome 22 Infant birthweight.
Review:
Outcome: 22 Infant birthweight
Study or subgroup
Doppler US
Mean
Difference
No Doppler US
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
Subtotal (95% CI)
0.0 %
0.0 [ 0.0, 0.0 ]
100.0 %
-34.00 [ -68.63, 0.63 ]

Goffinet 2001
Subtotal (95% CI)
1572
3282 (503)
1572
1561
3316 (486)
100.0 % -34.00 [ -68.63, 0.63 ]
1561

Subtotal (95% CI)
1572
1561
0.0 %
0.0 [ 0.0, 0.0 ]

Total (95% CI)
100.0 % -34.00 [ -68.63, 0.63 ]

-100
-50
Favours no Doppler
50
100
Favours Doppler
HISTORY
Protocol first published: Issue 2, 2010
Review first published: Issue 9, 2010

47
CONTRIBUTIONS OF AUTHORS
T Stampalija drafted the background section and Z Alfirevic added further suggestions. G Gyte drafted the methodology section. T
Stampalija and G Gyte decided on the studies to include and extracted the data. T Stampalija entered the data into RevMan (RevMan
2008) and G Gyte checked this. T Stampalija drafted the text of the findings and all authors agreed with the final version of the review.
DECLARATIONS OF INTEREST
No known conflicts of interest.
SOURCES OF SUPPORT
Internal sources
The University of Liverpool, UK.
External sources
National Institute for Health Research, UK.
NIHR NHS Cochrane Collaboration Programme Grant Scheme award for NHS-prioritised centrally-managed, pregnancy and
childbirth systematic reviews: CPGS02
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

There were no differences between the protocol and review.
INDEX TERMS
Medical Subject Headings (MeSH)
Pregnancy Outcome; Aspirin [administration & dosage]; Fibrinolytic Agents [administration & dosage]; Placenta [ ultrasonography];
Platelet Aggregation Inhibitors [administration & dosage]; Pregnancy Trimester, Second; Randomized Controlled Trials as Topic;
Regional Blood Flow; Ultrasonography, Prenatal; Uterine Artery [ ultrasonography]
MeSH check words

Female; Humans; Pregnancy

48

Utero-Placental Doppler Ultrasound For Improving Pregnancy Outcome (Review)

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Utero-placental Doppler ultrasound for improving pregnancy

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Utero-placental Doppler ultrasound for improving pregnancy

PLAIN LANGUAGE SUMMARY

Description of the condition

is replacement of the muscular and elastic arterial layer by collagen

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Description of the intervention

How the intervention might work

Why it is important to do this review

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Criteria for considering studies for this review

revealed versus Doppler of utero-placental vessels concealed) in

Types of outcome measures

This review will complement two other Cochrane reviews that

All randomised trials and quasi-randomised studies comparing

1. Doppler ultrasound of utero-placental vessels versus no

1. Any perinatal death after randomisation.

1. Stillbirth (as defined by trialists).

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

15. Caesarean section - emergency.

Data collection and analysis

Data extraction and management

Search methods for identification of studies

Searching other resources

Assessment of risk of bias in included studies

(1) Sequence generation (checking for possible selection

We describe for each included study the method used to generate

(2) Allocation concealment (checking for possible selection

We describe for each included study the method used to conceal

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

We assessed the methods as:

(3) Blinding (checking for possible performance bias)

We describe for each included study the methods used, if any, to

(4) Incomplete outcome data (checking for possible attrition

incompletely and so cannot be used; study fails to include results

(6) Other sources of bias

We describe for each included study any important concerns we

(7) Overall risk of bias

We made explicit judgements about whether studies were at high

For dichotomous data, we present results as summary risk ratio

For continuous data, we used the mean difference if outcomes are

(5) Selective reporting bias

We would have included cluster-randomised trials in the analyses

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

We considered cross-over designs inappropriate for this research

Dealing with missing data

Assessment of reporting biases

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Results of the search

Included studies compared uterine artery Doppler assessments in

Risk of bias in included studies

The quality of the three included studies was reasonable, although

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

We found no studies assessing uterine artery Doppler ultrasound

2. Uterine artery Doppler ultrasound versus no

1. Uterine artery Doppler ultrasound versus no

Any perinatal death after randomisation

Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)

Since we assessed both studies as adequate for sequence generation

Increasing interest in maternal Doppler in first and second

We did not include any non-prespecified outcomes.