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 Library2010, 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.

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 2.1. Comparison 2 Uterine artery Doppler ultrasound versus no Doppler ultrasound, 2nd trimester, Outcome 1

Any perinatal death after randomisation. . . . . . . . . . . . . . . . . . . . . . . . . 33


Hypertensive disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34


Stillbirth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35


Neonatal death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36


Any potentially preventable perinatal death after randomisation. . . . . . . . . . . . . . . . . 37


Intrauterine growth restriction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38


Neonatal resuscitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39


Apgar score < 7 at 5 min. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40


Neonatal admission to SCBU or NICU. . . . . . . . . . . . . . . . . . . . . . . . . 41


Iatrogenic preterm birth (< 37 weeks). . . . . . . . . . . . . . . . . . . . . . . . . . 42


Caesarean section (both elective and emergency). . . . . . . . . . . . . . . . . . . . . . 43


Elective caesarean section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44


Emergency caesarean section. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45


Gestational age at birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46


Infant birthweight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

47HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

48INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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


[Intervention Review]

Utero-placental Doppler ultrasound for improving pregnancyoutcome

Tamara Stampalija1, Gillian ML Gyte2, Zarko Alfirevic3

1Department of Obstetrics and Gynaecology, Childrens Hospital V. Buzzi, Milano, Italy. 2Cochrane Pregnancy and Childbirth

Group, School of Reproductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine, The University of

Liverpool, Liverpool, UK. 3School 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. [email protected].

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. CochraneDatabase of Systematic Reviews 2010, Issue 9. Art. No.: CD008363. DOI: 10.1002/14651858.CD008363.pub2.


A B S T R A C T

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 utero-

placental 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.

1Utero-placental Doppler ultrasound for improving pregnancy outcome (Review)


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.

P L A I N L A N G U A G E S U M M A R Y

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.

B A C K G R O U N D

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 an-

tibody 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 ul-

trasound, the emitted ultrasound frequency will change when ul-

trasound beam encounters moving blood. The principle can be

applied using different ultrasound modalities such as continuous-

wave 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 di-

rection, 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 down-

stream resistance (Owen 2001).

Physiological process of the trophoblastic invasion of spiral arter-

ies takes place between six and 24 weeks of gestation in normal

pregnancies. The blood flow from the uterine arteries to the pla-

centa will progressively increase during that time. By studying the

uterine arteries with pulse Doppler ultrasound, it is possible to as-

sess the progressive decrease in resistance to blood flow. The ratio-

nale 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-eclamp-

sia 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 de-

scription 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 as-

sessment of flow velocity waveform - Harrington 1996). Numer-

ous 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 re-

ported specificity is around 95%, which means that most women

with normal uterine artery Doppler will not develop pre-eclamp-

sia. 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 be-

fore 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 uter-

ine artery Doppler in the first trimester is the possibility to in-

tervene with some prophylactic therapy such as antithrombotic

drugs while the trophoblastic invasion is still ongoing. The uterine

arteryDoppler has been found tobe less predictivewhen 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 thematernal characteristics,

history and/or biochemical markers have been proposed. In fact,

uterine artery Doppler in the first and second trimester, in com-

bination 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 cost-

effectiveness remains to be proven.

How the intervention might work

It is hoped that early detection of abnormal placental vascula-

ture, before maternal and fetal complications develop, would al-

low 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 utero-

placental 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-eclamp-

sia and IUGR is undoubtedly appealing. Early recognition of pre-

eclampsia and IUGR could improve maternal and perinatal out-

come by administration antiplatelet therapy, appropriate antihy-

pertensive therapy, medication for fetal lung maturation and early

delivery. Nevertheless, labelling woman as at risk could cause sig-

nificant anxiety and increase the number of unnecessary examina-

tions and interventions (blood tests, hospital admission and pos-

sibly early delivery).



This review will complement two other Cochrane reviews that

focus on the fetal and umbilical Doppler ultrasound in high-

risk populations (Alfirevic 2010a), and in low-risk populations

(Alfirevic 2010b).

O B J E C T I V E S

To assess whether the use of utero-placental Doppler ultrasound

(uterine arteries and placental vessels) improves the outcome of

low- and high-risk pregnancies.

M E T H O D S

Criteria for considering studies for this review

Types of studies

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.Wehave considered cluster trials, thoughwe foundnone,

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 sec-

ond trimester of pregnancy. We planned to include twin preg-

nancies 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 andumbilicalDoppler 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

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 outcome measures

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, termina-

tion of pregnancies, birth before fetal viability (as defined by tri-

alists) and fetal death before use of the intervention.

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 edito-

rial 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.

Data collection and analysis

Themethodology for data collection and analysis was based on the

Cochrane Handbook of Systematic Reviews of Interventions (Higgins2008).

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

We designed a form to extract data. For eligible studies, two re-

view authors (TS, GG) extracted the data using the agreed form,

with additional help at times (Stephania Livio). We resolved dis-

crepancies through discussion or, if required, we consulted the

third author (ZA).We entered data into ReviewManager 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 theCochraneHandbookfor Systematic Reviews of Interventions (Higgins 2008).We resolvedany 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 non-

opaque 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 theywere 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 ex-

clusions from the analysis. We state whether attrition and exclu-

sions were reported, the numbers included in the analysis at each

stage (compared with the total randomised participants), reasons

for attrition or exclusionwhere reported, andwhethermissing 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.

(5) Selective reporting bias

We describe for each included study how we investigated the pos-

sibility of selective outcome reporting bias and what we found.


adequate (where it was clear that all of the studys pre-

specified 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

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 Hand-book for Systematic Reviews of Interventions (Higgins 2008). Withreference to (1) to (6) above, we assessed the likely magnitude and

direction of the bias and whether we considered it is likely to im-

pact 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 sameway between trials.We used the standardised

mean difference to combine trials that measure the same outcome,

but used different methods.

Unit of analysis issues

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 co-

efficient (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 cluster-

randomised 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 ran-

domisation 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 miss-

ing data in the overall assessment of treatment effect by using sen-

sitivity 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 partici-

pants 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 encoun-

tered such data.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using

the T (tau-squared), I and Chi statistics. We regarded hetero-

geneity 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 vi-

sually, and use formal tests for funnel plot asymmetry. For contin-

uous 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 soft-

ware (RevMan 2008).We used fixed-effect meta-analysis for com-

bining 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 ef-

fects differ between trials, or if substantial statistical heterogeneity

was detected, we would have used random-effects analysis to pro-

duce an overall summary, if this was considered clinically mean-

ingful. 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-analy-

ses, we would have assessed differences between subgroups by in-

spection 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 out-

comes 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 ade-

quate sequence generation and allocation concealment.

R E S U L T S

Description of studies

See:Characteristics of included studies; Characteristics of excluded

studies; Characteristics of studies awaiting classification.



Results of the search

The searchwas designed to identify all randomised controlled trials

on assessing the effectiveness of Doppler ultrasound, whether us-

ing fetal-umbilical or utero-placental (maternal) vessels. We iden-

tified 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 fe-

tal 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 classi-

fication 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 utero-

placental 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

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 stud-

ies, low-dose aspirin was administrated in cases of abnormal uter-

ine 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 preg-

nancies (Subtil 2003), while the other did not state specifically if

it included multiple pregnancies, although reported numbers sug-

gest only singleton pregnancies were included (Goffinet 2001).

Excluded studies

We excluded 30 studies, mostly because they assessed umbilical

arteryDoppler ultrasound. SeeCharacteristics of excluded studies.

Risk of bias in 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 fea-

sible. Some outcomes like induction of labour and caesarean sec-

tion may be influenced by the knowledge of Doppler results, but

it may be possible to avoid bias in neonatal assessment. Unfortu-

nately, the information on the attempts to protect against biased

assessment was not available.

Incomplete outcome data

The two studies had adequate outcomedata (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.

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 ad-

equate labelled sequence generation and adequate allocation con-

cealment as essential criteria for high quality. Two of three stud-

ies 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)

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 ultra-

sound in the second trimester in women at low risk for hyperten-

sive disorders (Goffinet 2001; Subtil 2003). Both were full pub-

lications (Goffinet 2001; Subtil 2003). Overall the quality of the

included studies was good for the main criteria of randomisa-

tion, 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 underpow-

ered to detect clinically important differences in serious maternal

and neonatal morbidity.

Any perinatal death after randomisation

The difference in perinatal mortality between two groups was not

statistically significant (average risk ratio (RR) 1.61, 95% confi-

dence 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 con-

tributed to by 17 abortions or medically indicated terminations of

pregnancy in the 1253 women in the Doppler group (1.4%) com-

pared with three out of 617 in the control group (0.5%). In addi-

tion, 78 of the 1253 women randomised toDoppler group (6.2%)

did not receive their allocated treatment. The reason was termina-

tion 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 doc-

umented. 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

There was no difference identified in maternal hypertensive dis-

orders between two groups (RR 1.08, 95% CI 0.87 to 1.33, two

studies, 4987 women, Analysis 2.2).

Secondary outcomes

We found no significant difference in the pooled estimate of the in-

tervention effect for the range of secondary outcomeswith lowhet-

erogeneity where a fixed-effect meta-analysis was used. Most pre-

specified secondary outcomes had high heterogeneity and there-

fore 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 RR1.29, 95%CI 0.21 to 7.94,

two studies, 5009babies, random-effectsT 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

pretermbirth (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 fiveminutes (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 admis-

sion to special care.

Non-prespecified outcomes

We did not include any non-prespecified outcomes.

Sensitivity analysis

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.

D I S C U S S I O N

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).

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 out-

comes. 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 pre-

ventable perinatal death 0.4%, hypertensive disorders 7%, IUGR

11%).

In both studies (Goffinet 2001; Subtil 2003), the finding of patho-

logical 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 par-

ticipants that makes our review underpowered rare events such as

perinatal mortality and severe maternal outcomes.

Suprisingly, lower perinatal mortality was observed in the con-

trol group in one study (Subtil 2003: risk ratio 3.14, 95% confi-

dence 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 disor-

ders versus controls. There were no studies of women in the first

trimester.

Overall completeness and applicability ofevidence



There were only two studies involving 4993 women, and clearly

the meta-analysis remains underpowered to show clinically im-

portant 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. Eachworked 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 otherstudies 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.

A U T H O R S C O N C L U S I O N S

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 hy-

pertensive disorders provides benefit for the baby or mother.

Uterine arteryDoppler ultrasound is widely used in high-risk preg-

nancy 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-riskwomen for hypertensive disorders.Moreover, randomised

controlled trials of uterine artery Doppler in the first and second

trimester, in combination with womans history and/or biochemi-

cal serummarkers, are needed to evaluate the benefit of combined

models.

A C K N OW L E D G E M E N T S

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 reviewhas 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 Statis-

tical Adviser.

R E F E R E N C E S

References to studies included in this review

Goffinet 2001 {published data only}

Goffinet F, Aboulker D, Paris-Llado J, Bucourt M, Uzan

M, Papiernik E, et al.Screening with a uterine doppler in

low risk pregnant women followed by low dose aspirin in

women with abnormal results: a multicenter randomised

controlled trial. British Journal of Obstetrics and Gynaecology2001;108:5108.

Subtil 2003 {published data only} Subtil D, Goeusse P, Houfflin-Debarge V, Puech F,

Lequien P, Breart G, et al.Randomised comparison of

uterine artery doppler and aspirin (100 mg) with placebo

in nulliparous women: the Essai Regional Aspirine Mere-

Enfant study (part 2). BJOG: an International Journal of

Obstetrics & Gynaecology 2003;110(5):48591.Subtil D, Truffert P, Goeusse P, Dufour P, Uzan S, Breart

G, et al.Value of systematic doppler +/- low dose aspirin

to prevent vascular complications in primigravidae.

Hypertension in Pregnancy 2000;19(Suppl 1):9.

References to studies excluded from this review

Almstrom 1992 {published data only} Almstrom H, Axelsson O, Cnattingius S, Ekman G,

Maesel A, Ulmsten U, et al.Comparison of umbilical-artery

velocimetry and cardiotocography for surveillance of small-

for-gestational-age fetuses. Lancet 1992;340:93640.

Almstrom H, Axelsson O, Ekman G, Ingemarsson I,

Maesel A, Arstrom K, et al.Umbilical artery velocimetry

may influence clinical interpretation of intrapartum



cardiotocograms. Acta Obstetricia et Gynecologica

Scandinavica 1995;74:5269.Marsal K, Almstrom H, Axelsson O, Cnattingius S, Ekman

G, Maesel A, et al.Umbilical artery velocimetry is more

effective than cardiotocography for surveillance of growth

retarded fetuses. Journal of Perinatal Medicine 1991;19(Suppl 2):84.

Ben-Ami 1995 {published data only}

Ben-Ami M, Battino S, Geslevich Y, Shalev E. A random

single Doppler study of the umbilical artery in the evaluation

of pregnancies complicated by diabetes. American Journal of

Perinatology 1995;12(6):4378.

Biljan 1992 {published data only} Biljan M, Haddad N, McVey K, Williams J. Efficiency of

continuous-wave Doppler in screening high risk pregnancies

in a district general hospital (a prospective randomized

study on 674 singleton pregnancies). Proceedings of 26th

British Congress of Obstetrics and Gynaecology; 1992 July

7-10; Manchester, UK. 1992:6.

Biljan MM, McVey KP, Haddad NG. The value of

continuous wave doppler assessment of fetal umbilical artery

in management of at risk pregnancies. Proceedings of 2nd

European Congress on Prostaglandins in Reproduction;

1991 April 30-May 3; The Hague, Netherlands. 1991:189.

Burke 1992 {published data only} Burke G, Stuart B, Crowley P, Ni Scanaill S, Drumm J.

Does Doppler ultrasound alter the management of high-risk

pregnancy?. Care concern and cure in perinatal medicine.

13th European Congress of Perinatal Medicine; 1992 May;

Amsterdam, The Netherlands. Parthenon, 1992:597604.

Burke G, Stuart B, Crowley P, Ni Scanaill S, Drumm J.

Does Doppler ultrasound alter the management of high-risk

pregnancy?. Journal of Perinatal Medicine 1992;20(Suppl1):266.

Davies 1992 {published data only}

Breart G, Uzan S, Uzan M. Doppler ultrasound screening

during pregnancy [Letter; comment]. Lancet 1993;341(8843):5012.

Davies J, Spencer J, Gallivan S. Randomised trial of Doppler

screening in a general obstetric population. Proceedings of

26th British Congress of Obstetrics and Gynaecology; 1992

July 7-10; Manchester, UK. 1992:316. Davies JA, Gallivan S, Spencer JAD. Randomised

controlled trial of doppler ultrasound screening of placental

perfusion during pregnancy. Lancet 1992;340:1299303.Spencer JAD, Davies JA, Gallivan S. Randomised trial of

routine Doppler screening during pregnancy. Journal ofMaternal Fetal Investigation 1992;1:126.

de Rochambeau 1992 {published data only}

de Rochambeau B, Jabbour N, Mellier G. Umbilical doppler

velocimetry in prolonged pregnancies [La velocimetrie

Doppler ombilicale dans les grossesses prolongees.]. RevueFrancaise de Gynecologie et d Obstetrique 1992;87(5):

28994.

Doppler 1997 {published data only}

Doppler French Study Group. A randomised controlled

trial of Doppler ultrasound velocimetry of the umbilical

artery in low risk pregnancies Doppler French Study Group.

British Journal of Obstetrics and Gynaecology 1997;104(4):

41924.

Giles 2003 {published data only}

Giles W, Bisits A, OCallaghan S. The doppler assessment

in multiple pregnancy study (damp) and metaanalyses

of doppler and twins. American Journal of Obstetrics andGynecology 2000;182(1 Pt 2):S17. Giles W, Bisits A, OCallaghan S, Gill A. The doppler

assessment in multiple pregnancy randomised controlled

trial of ultrasound biometry versus umbilical artery doppler

ultrasound and biometry in twin pregnancy. BJOG: an

international journal of obstetrics and gynaecology 2003;110(6):5937.

Gonsoulin 1991 {published data only}

Gonsoulin W. Umbilical artery Doppler waveform analysis:

a randomized study on effect on outcome. American Journal

of Obstetrics and Gynecology 1991;164:370.

Haley 1997 {published data only}

Haley J, Tuffnell DJ, Johnson N. Randomised controlled

trial of cardiotocography versus umbilical artery Doppler in

the management of small for gestational age fetuses. BritishJournal of Obstetrics and Gynaecology 1997;104(4):4315.

Hofmeyr 1991 {published data only}

Hofmeyr GJ, Pattinson R, Buckley D, Jennings J, Redman

CWG. Umbilical artery resistance index as a screening

test for fetal well-being. II. Randomized feasibility study.

Obstetrics & Gynecology 1991;78:35962.

Johnstone 1993 {published data only}

Johnstone FD, Prescott R, Hoskins P, Greer IA, McGlew

T, Compton M. The effect of introduction of umbilical

Doppler recordings to obstetric practice. British Journal of

Obstetrics and Gynaecology 1993;100:73341.

Mason 1993 {published data only}

Mason GC, Lilford RJ, Porter J, Nelson E, Tyrell S.

Randomised comparison of routine vs highly selective use of

Doppler ultrasound in low risk pregnancies. British Journal

of Obstetrics and Gynaecology 1993;100:1303.

McCowan 1996 {published data only}

McCowan LME, Harding J, Roberts AB, Barker S,

Townend K. Perinatal morbidity in small for gestational age

fetuses in relation to umbilical doppler. Proceedings of the

14th Annual Congress of the Australian Perinatal Society in

conjunction with the New Zealand Perinatal Society; 1996

March 24-27; Adelaide, Australia. 1996:P10.

McParland 1988 {published data only}

McParland P, Pearce JM. Doppler blood flow in pregnancy.

Placenta 1988;9:42750.

Neales 1994 {published data only}

Neales K. A randomised controlled study to assess the use

of Doppler ultrasound in the management of patients with

intrauterine growth retardation. Personal communication

1994.



Newnham 1991 {published data only}

Newnham JP, ODea MRA, Reid KP, Diepeveen DA.

Doppler flow velocity waveform analysis in high risk

pregnancies: a randomized controlled trial. British Journalof Obstetrics and Gynaecology 1991;98:95663.

Newnham 1993 {published data only}

Evans S, Newnham J, MacDonald W, Hall C.

Characterisation of the possible effect on birthweight

following frequent prenatal ultrasound examinations. EarlyHuman Development 1996;45(3):20314.

Newnham J, Macdonald W, Gurrin L, Evans S, Landau L,

Stanley F. The effect of frequent prenatal ultrasound on

birthweight: follow-up at one year of age. Proceedings

of the 14th Annual Congress of the Australian Perinatal

Society in conjunction with the New Zealand Perinatal

Society; 1996 March 24-27; Adelaide, Australia. 1996:A26.

Newnham JP, Doherty DA, Kendall GE, Zubrick SR,

Landau LL, Stanley FJ. Effects of repeated prenatal

ultrasound examinations on childhood outcome up to 8

years of age: follow-up of a randomised controlled trial.

Lancet 2004;364:203844. Newnham JP, Evans SF, Michael CA, Stanley FJ, Landau

LI. Effects of frequent ultrasound during pregnancy: a

randomised controlled trial. Lancet 1993;342:88791.

Nienhuis 1997 {published data only}

Nienhuis SJ. Costs and effects of Doppler ultrasound

measurements in suspected intrauterine growth retardation.

A randomised clinical trial. Thesis. Maastricht: UniversitairePers Maastricht, 1995.

Nienhuis SJ, Ruissen CJ, Hoogland HJ, Gerver JW, Vles

J, de Haan J. Cost-effectiveness of a doppler policy in

suspected intrauterine growth retardation - a randomized

controlled trial. International Journal of Gynecology and

Obstetrics 1991;36 Suppl:32. Nienhuis SJ, Vles JS, Gerver WJ, Hoogland HJ.

Doppler ultrasonography in suspected intrauterine growth

retardation: a randomized clinical trial. Ultrasound in

Obstetrics & Gynecology 1997;9(1):613.Ruissen CJ, Nienhuis SJ, Hoogland HJ, Vles JFH, Gerver

WJ, De Haan J. Cost-effectiveness of a Doppler based policy

of suspected intrauterine growth retardation - a randomised

controlled trial. Journal of Maternal Fetal Investigation 1992;1:126.

Nimrod 1992 {published data only}

Nimrod C, Yee J, Hopkins C, Pierce P, Lange I, Fick G, et

al.The utility of pulsed Doppler studies in the evaluation of

postdate pregnancies. Journal of Maternal Fetal Investigation

1992;1:127.

Norman 1992 {published data only}

Norman K, Pattinson RC, Carstens E. Doppler velocimetry

in recurrent pregnancy loss: is there a role?. Proceedings of

11th Conference on Priorities in Perinatal Care in South

Africa; 1992 March; Caledon, South Africa. 1992:714.

Omtzigt 1994 {published data only}

Omtzigt AWJ. Clinical value of umbilical doppler velocimetry.Utrecht: University of Utrecht, 1990.

Omtzigt AWJ, Bruinse HW, Reuwer PJHM. A randomized

controlled trial on the clinical value of umbilical Doppler

velocimetry: neonatal outcome. Proceedings of 12th

European Congress of Perinatal Medicine; 1990 Sept 11-

14; Lyon, France. 1990:189.

Omtzigt AWJ, Bruinse HW, Reuwer PJHM. A randomized


velocimetry. I. Obstetrical management. Proceedings of

12th European Congress of Perinatal Medicine; 1990 Sept

11-14; Lyon, France. 1990:210. Omtzigt AWJ, Reuwer PJHM, BruinseHW. A randomized


velocimetry in antenatal care. American Journal of Obstetricsand Gynecology 1994;170:62534.

Pattinson 1994 {published data only}

Pattinson R, Norman K, Odendaal HJ. Management of

fetuses suspected of IUGR but with EDVs of the umbilical

artery: a randomised controlled trial. Proceedings of 26th

British Congress of Obstetrics and Gynaecology; 1992 July

7-10; Manchester, UK. 1992:5. Pattinson RC, Norman K, Odendaal HJ. The role of

Doppler velocimetry in the management of high risk

pregnancies. British Journal of Obstetrics and Gynaecology1994;101:11420.

Pattinson RC, Norman K, Odendaal HJ. The role of

doppler velocimetry in the management of pregnancies:

a randomized controlled trial. Proceedings of 11th

Conference on Priorities in Perinatal Care in South Africa;

1992 March; Caledon, South Africa. 1992:5963.

Pearce 1992 {published data only}

Pearce JM. The application of uteroplacental waveforms to

complicated pregnancies. In: Pearce JMP editor(s). Dopplerultrasound in perinatal medicine. Oxford: Oxford University

Press, 1992:15977.

Schneider 1992 {published data only}

Schneider KT, Amberg-Wendland D, Renz S, Furstenau

U. Prospective randomized study of the clinical value

of Doppler sonography as a screening procedure

[Prospektiv randomisierte Untersuchung zum klinischen

Wert der Dopplersonographie als Screeningverfahren].

Gynakologische Rundschau 1991;31(Suppl 1):13940.

Schneider KTM, Renz S, Furstenau U, Amberg-Wendland

D, Prochaska D, Graeff H. Doppler flow measurements as a

screening method during pregnancy: is it worth the effort?.

Journal of Maternal Fetal Investigation 1992;1:125.

Scholler 1993 {published data only}

Scholler J, Putz M, Sainz HG, Altrichter R, Philipp

K. Value of Doppler sonography in management of

non-risk pregnancies at term [Der Stellenwert der

Dopplersonographie bei der Betreuung von Nicht

Risikoschwangerschaften amGeburtstermin]. Gynakologisch

Geburtshilfliche Rundschau 1993;33(1 Suppl):1189.

Trudinger 1987 {published data only}

Trudinger BJ, Cook CM, Giles WB, Connelly AJ,

Thompson RS. Umbilical artery flow velocity waveforms in

high-risk pregnancy: randomised controlled trial. Lancet

1987;1:18890.



Tyrrell 1990 {published data only}

Lilford RJ. Fetal assessment in laboratory vs standard

management of high risk pregnancy. Personal

communication 1989. Tyrrell SN, Lilford RJ, MacDonald HN, Nelson EJ,

Porter J, Gupta JK. Randomized comparison of routine vs

highly selective use of Doppler ultrasound and biophysical

scoring to investigate high risk pregnancies. British Journalof Obstetrics and Gynaecology 1990;97:90916.

Whittle 1994 {published data only}

Hanretty KP. Randomized study of doppler waveforms in

umbilical and uterine arteries as a screening method to

identify the compromised fetus. Personal communication

1988.

Whittle MJ, Hanretty KP, Primrose MH, Neilson JP.

Screening for the compromised fetus: a randomized trial

of umbilical artery velocimetry in unselected pregnancies.

American Journal of Obstetrics and Gynecology 1994;170:5559.

Williams 2003 {published data only}

Williams K, Farquharson D, Bebbington M, Dansereau J,

Galerneau F, Wilson RD, et al.A randomized controlled

clinical trial comparing non stress testing versus doppler

velocimetry as a screening test in a high risk population

[abstract]. American Journal of Obstetrics and Gynecology

2000;182(1 Pt 2):S109. Williams KP, Farquharson DF, Bebbington M, Dansereau

J, Galerneau F, Wilson RD, et al.Screening for fetal well-

being in a high-risk pregnant population comparing the

nonstress test with umbilical artery doppler velocimetry: a

randomized controlled clinical trial. American Journal of

Obstetrics and Gynecology 2003;188(5):136671.

References to studies awaiting assessment

Ellwood 1997 {published data only}

Ellwood D. Predicting adverse pregnancy outcomes with

ultrasound. Personal communication 1997.

Snaith 2006 {published data only}

Snaith V. Support and reassurance in antenatal care (ongoing

trial). Current Controlled Trials (http://controlled-

trials.com/mrct) (accessed 21 March 2006).

Additional references

Aardema 2001

Aardema MW, Oosterhof H, Timmer A, van Rooy

I, Aarnoudse JG. Uterine artery Doppler flow and

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Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Goffinet 2001

Methods Multicentre randomised trial. Stratified by centre and parity (nulliparous ormultiparous)

. Blocks of 4. Randomisatioin numbers were established using tables of order 4 permu-

tations

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



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 randomisa-

tion:

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.



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 second-

trimester 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 gesta-

tional 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 gen-

erated by themanufacturer of the treatment



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 ran-

domisation 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 con-

nection to an always available server.... Af-

ter verifying the inclusion criteria and the

patients consent, the server provided ei-

ther a treatment box number or the word

Doppler to the physician investigator. At

the end of prenatal consultation the physi-

cian 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 arteryDoppler.

Blinding?

All outcomes

No It was not possible to blind participants and

clinicians with regard t

Documents

Utero-placental Doppler Ultrasound for Improving Pregnancy Outcome (Review)