Fetal and umbilical Doppler ultrasound in high‐risk pregnancies

Zarko Alfirevic; Tamara Stampalija; Therese Dowswell

doi:10.1002/14651858.CD007529.pub4

. 2017 Jun 13;2017(6):CD007529. doi: 10.1002/14651858.CD007529.pub4

Fetal and umbilical Doppler ultrasound in high‐risk pregnancies

Zarko Alfirevic ^1,^✉, Tamara Stampalija ², Therese Dowswell ³

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC6481396 PMID: 28613398

Abstract

Background

Abnormal blood flow patterns in fetal circulation detected by Doppler ultrasound may indicate poor fetal prognosis. It is also possible that false positive Doppler ultrasound findings could lead to adverse outcomes from unnecessary interventions, including preterm delivery.

Objectives

The objective of this review was to assess the effects of Doppler ultrasound used to assess fetal well‐being in high‐risk pregnancies on obstetric care and fetal outcomes.

Search methods

We updated the search of Cochrane Pregnancy and Childbirth's Trials Register on 31 March 2017 and checked reference lists of retrieved studies.

Selection criteria

Randomised and quasi‐randomised controlled trials of Doppler ultrasound for the investigation of umbilical and fetal vessels waveforms in high‐risk pregnancies compared with no Doppler ultrasound. Cluster‐randomised trials were eligible for inclusion but none were identified.

Data collection and analysis

Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Data entry was checked. We assessed the quality of evidence using the GRADE approach.

Main results

Nineteen trials involving 10,667 women were included. Risk of bias in trials was difficult to assess accurately due to incomplete reporting. None of the evidence relating to our main outcomes was graded as high quality. The quality of evidence was downgraded due to missing information on trial methods, imprecision in risk estimates and heterogeneity. Eighteen of these studies compared the use of Doppler ultrasound of the umbilical artery of the unborn baby with no Doppler or with cardiotocography (CTG). One more recent trial compared Doppler examination of other fetal blood vessels (ductus venosus) with computerised CTG.

The use of Doppler ultrasound of the umbilical artery in high‐risk pregnancy was associated with fewer perinatal deaths (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.52 to 0.98, 16 studies, 10,225 babies, 1.2% versus 1.7 %, number needed to treat (NNT) = 203; 95% CI 103 to 4352, evidence graded moderate). The results for stillbirths were consistent with the overall rate of perinatal deaths, although there was no clear difference between groups for this outcome (RR 0.65, 95% CI 0.41 to 1.04; 15 studies, 9560 babies, evidence graded low). Where Doppler ultrasound was used, there were fewer inductions of labour (average RR 0.89, 95% CI 0.80 to 0.99, 10 studies, 5633 women, random‐effects, evidence graded moderate) and fewer caesarean sections (RR 0.90, 95% CI 0.84 to 0.97, 14 studies, 7918 women, evidence graded moderate). There was no comparative long‐term follow‐up of babies exposed to Doppler ultrasound in pregnancy in women at increased risk of complications.

No difference was found in operative vaginal births (RR 0.95, 95% CI 0.80 to 1.14, four studies, 2813 women), nor in Apgar scores less than seven at five minutes (RR 0.92, 95% CI 0.69 to 1.24, seven studies, 6321 babies, evidence graded low). Data for serious neonatal morbidity were not pooled due to high heterogeneity between the three studies that reported it (1098 babies) (evidence graded very low).

The use of Doppler to evaluate early and late changes in ductus venosus in early fetal growth restriction was not associated with significant differences in any perinatal death after randomisation. However, there was an improvement in long‐term neurological outcome in the cohort of babies in whom the trigger for delivery was either late changes in ductus venosus or abnormalities seen on computerised CTG.

Authors' conclusions

Current evidence suggests that the use of Doppler ultrasound on the umbilical artery in high‐risk pregnancies reduces the risk of perinatal deaths and may result in fewer obstetric interventions. The results should be interpreted with caution, as the evidence is not of high quality. Serial monitoring of Doppler changes in ductus venosus may be beneficial, but more studies of high quality with follow‐up including neurological development are needed for evidence to be conclusive.

Plain language summary

Doppler ultrasound of fetal vessels in pregnancies at increased risk of complications

What is the issue?

Most babies in high‐income countries grow well in the womb. However, when the mother has a medical problem such as diabetes, high blood pressure, heart or kidney problems, or the placenta does not develop properly, this may affect the growth of the baby. Also, sometimes babies do not grow well for reasons we do not fully understand. Babies with poor growth are more likely to have complications, resulting in babies being ill or dying. Doppler ultrasound detects changes in the pattern of blood flow through the baby's circulation. These changes may identify babies who have problems.

Why is this important?

If babies with growth problems are identified, interventions such as early delivery might help to prevent serious illness and death. However, using Doppler ultrasound could increase interventions such as caesarean section.

What evidence did we find?

We searched for evidence in March 2017. We found 19 trials involving over 10,000 women. Eighteen of these studies compared the use of Doppler ultrasound of the umbilical artery of the unborn baby with no Doppler or with cardiotocography (CTG, sometimes called electronic fetal monitoring). One more recent trial compared Doppler examination of other fetal blood vessels (ductus venosus) with computerised CTG (short‐term variation).

Evidence from included studies was assessed as moderate to very low‐quality due to incomplete reporting of methods and uncertainty of findings; when the strength of the evidence is low or very low, this means future research may change the results and we cannot be certain about them.

Results showed that Doppler ultrasound of the umbilical artery may decrease the number of babies who die, and may lead to fewer caesarean sections and inductions of labour. There was no clear difference in the number of stillbirths, births using forceps or ventouse, or babies with a low Apgar score five minutes after birth. Findings for serious problems in the neonate were not consistent in different studies. In babies with growth restriction, when the decision to deliver was based on late ductus venosus changes or abnormalities on computerised CTG, this appeared to improve long‐term (two‐year) developmental outcome.

What does this mean?

Doppler ultrasound in high‐risk pregnancies appears to reduce the number of babies who die, and may also lead to fewer obstetric interventions. However, the evidence was of moderate to very low‐quality. Further studies of high‐quality with long‐term follow‐up would help us to be more certain.

Summary of findings

Summary of findings for the main comparison. Umbilical artery Doppler ultrasound compared to no Doppler ultrasound in high‐risk pregnancies.

Umbilical artery Doppler ultrasound compared to no Doppler ultrasound in high‐risk pregnancies
Patient or population: pregnant women at increased risk of fetal complications  Setting: antenatal clinics or inpatient wards in hospitals in Australia (3) UK (6) US (2) Sweden (1) South Africa (2) Ireland (1) The Netherlands (1) France (1) Canada (1)  Intervention: umbilical artery Doppler ultrasound  Comparison: no Doppler ultrasound
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with no Doppler ultrasound	Risk with umbilical artery Doppler ultrasound
Any perinatal death after randomisation	Study population		RR 0.71  (0.52 to 0.98)	10225  (16 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	17 per 1000	12 per 1000  (9 to 17)
Serious neonatal morbidity	Study population			1098  (3 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 3 4}	We did not pool the data for this outcome due to high heterogeneity (the direction of effect in the 2 studies contributing data were not consistent).

Stillbirth	Study population		RR 0.65  (0.41 to 1.04)	9560  (15 RCTs)	⊕⊕⊝⊝  LOW ^{1 2 5}
	9 per 1000	6 per 1000  (4 to 9)
Apgar < 7 at 5 minutes	Study population		RR 0.92  (0.69 to 1.24)	6321  (7 RCTs)	⊕⊕⊝⊝  LOW ^{1 5}
	29 per 1000	26 per 1000  (20 to 36)
Caesarean section (elective and emergency)	Study population		RR 0.90  (0.84 to 0.97)	7918  (14 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	263 per 1000	237 per 1000  (221 to 255)
Induction of labour	Study population		RR 0.89  (0.80 to 0.99)	5633  (10 RCTs)	⊕⊕⊕⊝  MODERATE ^{1 2}
	334 per 1000	298 per 1000  (268 to 331)
Long‐term infant neurodevelopmental outcome (impairment at 2 years)	Study population		‐	(0 studies)	‐	There has been no comparative long‐term follow‐up of babies exposed to Doppler ultrasound in pregnancy in women at increased risk of complications.
	see comment	see comment
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Date	Event	Description
31 March 2017	New citation required but conclusions have not changed	One study previously in ongoing section was included in this update (Lees 2013). The conclusions remain the same.
31 March 2017	New search has been performed	Search updated and no new studies identified. The quality of the evidence was assessed using the GRADE approach and a 'Summary of findings' table was incorporated.

Date	Event	Description
30 September 2013	New citation required but conclusions have not changed	No new trials identified.
30 September 2013	New search has been performed	Search updated. Methods updated.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any perinatal death after randomisation	16	10225	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.52, 0.98]
1.1 Singleton pregnancy	9	4661	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.35, 1.01]
1.2 Multiple pregnancy	1	1052	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.32, 2.41]
1.3 Singleton plus multiple pregnancies, or not stated	6	4512	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.51, 1.19]
2 Serious neonatal morbidity	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Singleton pregnancy	1	500	Risk Ratio (M‐H, Random, 95% CI)	0.13 [0.02, 0.99]
2.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Singleton plus multiple pregnancies, or not stated	2	598	Risk Ratio (M‐H, Random, 95% CI)	2.95 [0.31, 28.14]
3 Stillbirth	15	9560	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.41, 1.04]
3.1 Singleton pregnancy	8	3996	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.31, 1.19]
3.2 Multiple pregnancy	1	1052	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.11, 4.00]
3.3 Singleton plus multiple pregnancy, or not stated	6	4512	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.35, 1.39]
4 Neonatal death	13	8167	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.53, 1.24]
4.1 Singleton pregnancy	7	2656	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.31, 1.53]
4.2 Multiple pregnancy	1	1052	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.29, 3.46]
4.3 Singleton plus multiple pregnancies, or not stated	5	4459	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.48, 1.45]
5 Any potentially preventable perinatal death*	16	10225	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.46, 0.98]
5.1 Singleton pregnancy	9	4661	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.30, 1.13]
5.2 Multiple pregnancy	1	1052	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.32, 2.41]
5.3 Singleton plus multiple pregnancies or not stated	6	4512	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.41, 1.15]
6 Apgar < 7 at 5 minutes	7	6321	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.69, 1.24]
6.1 Singleton pregnancy	4	2555	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.45, 1.09]
6.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Singleton plus multiple pregnancies or not stated	3	3766	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.77, 1.73]
7 Caesarean section (elective and emergency)	14	7918	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.84, 0.97]
7.1 Singleton pregnancy	7	2929	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.75, 0.95]
7.2 Multiple pregnancy	1	526	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.77, 1.19]
7.3 Singleton plus multiple pregnancies or not stated	6	4463	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.84, 1.05]
8 Caesarean section ‐ elective	11	6627	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.93, 1.22]
8.1 Singleton pregnancy	6	1934	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.90, 1.38]
8.2 Multiple pregnancy	1	526	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.77, 1.47]
8.3 Singleton plus multiple pregnancies or not stated	4	4167	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.84, 1.26]
9 Caesarean section ‐ emergency	10	6175	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.67, 0.98]
9.1 Singleton pregnancy	5	1482	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.43, 0.78]
9.2 Multiple pregnancy	1	526	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.57, 1.23]
9.3 Singleton plus multiple pregnancies or not stated	4	4167	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.77, 1.20]
10 Spontaneous vaginal birth	5	2504	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.98, 1.10]
10.1 Singleton pregnancy	2	576	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.96, 1.18]
10.2 Multiple pregnancy	1	526	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.90, 1.19]
10.3 Singleton plus multiple pregnancies or not stated	2	1402	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.95, 1.12]
11 Operative vaginal birth	4	2813	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.80, 1.14]
11.1 Singleton pregnancy	3	1916	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.78, 1.22]
11.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 Singleton plus multiple pregnancies or not stated	1	897	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.68, 1.25]
12 Induction of labour	10	5633	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.80, 0.99]
12.1 Singleton pregnancy	5	1784	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.64, 0.97]
12.2 Multiple pregnancy	1	526	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.80, 1.50]
12.3 Singleton plus multiple pregnancies or not stated	4	3323	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.86, 1.04]
13 Infant requiring intubation/ventilation	6	3136	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.87, 2.30]
13.1 Singleton pregnancy	4	1539	Risk Ratio (M‐H, Random, 95% CI)	2.89 [1.40, 5.96]
13.2 Multiple pregnancy	1	1052	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.59, 1.25]
13.3 Singleton plus multiple pregnancies or not stated	1	545	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.79, 1.98]
14 Neonatal fitting/seizures	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.49]
14.1 Singleton pregnancy	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.49]
14.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Preterm labour	2	626	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.72, 1.75]
15.1 Singleton pregnancy	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.51, 2.07]
15.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.3 Singleton plus multiple pregnancy or not stated	1	476	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.66, 2.11]
16 Gestational age at birth (weeks)	8	4066	Mean Difference (IV, Random, 95% CI)	0.21 [‐0.02, 0.43]
16.1 Singleton pregnancy	3	1043	Mean Difference (IV, Random, 95% CI)	0.54 [‐0.00, 1.09]
16.2 Multiple pregnancy	1	1052	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.24, 0.44]
16.3 Singleton plus multiple pregnancies or not stated	4	1971	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.19, 0.31]
17 Infant respiratory distress syndrome (RDS)	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.07, 16.48]
17.1 Singleton pregnancy	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.07, 16.48]
17.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Neonatal admission to SCBU and/or NICU	12	9334	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.89, 1.03]
18.1 Singleton pregnancy	8	4511	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.80, 1.06]
18.2 Multiple pregnancy	1	1052	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.88, 1.05]
18.3 Singleton plus multiple pregnancies or not stated	3	3771	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.85, 1.14]
19 Hypoxic ischaemic encephalopathy	2	1045	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.01, 33.07]
19.1 Singleton pregnancy	1	500	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.01, 1.64]
19.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
19.3 Singleton plus multiple pregnancies or not stated	1	545	Risk Ratio (M‐H, Random, 95% CI)	4.91 [0.24, 101.79]
20 Intraventricular haemorrhage	4	2008	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.47, 4.30]
20.1 Singleton pregnancy	3	1463	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.38, 4.16]
20.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
20.3 Singleton plus multiple pregnancies or not stated	1	545	Risk Ratio (M‐H, Fixed, 95% CI)	2.95 [0.12, 71.99]
21 Birthweight (grams)	7	3887	Mean Difference (IV, Fixed, 95% CI)	31.33 [‐8.70, 71.37]
21.1 Singleton pregnancy	3	1916	Mean Difference (IV, Fixed, 95% CI)	49.34 [‐0.62, 99.31]
21.2 Multiple pregnancy	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.3 Singleton plus multiple pregnancies or not stated	4	1971	Mean Difference (IV, Fixed, 95% CI)	‐0.95 [‐67.84, 65.95]
22 Length of infant hospital stay (days)	3	1076	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.28 [‐0.40, ‐0.16]
22.1 Singleton pregnancy	3	1076	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.28 [‐0.40, ‐0.16]
22.2 Multiple pregnancy	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.3 Singleton plus multiple pregnancies or not stated	0	0	Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23 Birth < 34 weeks (not prespecified)	2	976	Risk Ratio (M‐H, Random, 95% CI)	2.04 [0.62, 6.69]
23.1 Singleton pregnancy	1	500	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.40, 3.42]
23.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
23.3 Singleton plus multiple pregnancies or not stated	1	476	Risk Ratio (M‐H, Random, 95% CI)	3.90 [1.11, 13.65]
24 Antenatal admissions (not prespecified)	2	893	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.60, 0.88]
24.1 Singleton pregnancy	2	893	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.60, 0.88]
24.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
25 Phototherapy for neonatal jaundice (not prespecified)	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.87]
25.1 Singleton pregnancy	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.87]
25.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
25.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
26 Abnormal neurological development at 9 months (not prespecified)	1	137	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.26, 1.45]
26.1 Singleton pregnancy	1	137	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.26, 1.45]
26.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
26.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
27 Hospitalisation for IUGR neonatal (not prespecified)	1	142	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.75, 1.41]
27.1 Singleton pregnancy	1	142	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.75, 1.41]
27.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28 Fetal distress in labour (not prespecified)	1	289	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.10, 1.22]
28.1 Singleton pregnancy	1	289	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.10, 1.22]
28.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29 Birthweight < 5 percentile (not prespecified)	1	289	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.51, 2.64]
29.1 Singleton pregnancy	1	289	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.51, 2.64]
29.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29.3 Singleton plus multiple pregnancies or not stated	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30 Periventricular leucomalacia (not prespecified)	1	545	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.00]
30.1 Singleton pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.2 Multiple pregnancy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.3 Singleton plus multiple pregnancies or not stated	1	545	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.00]
31 Antenatal hospital stay (days) (not prespecified)	1	426	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐2.39, 1.19]
31.1 Singleton pregnancy	1	426	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐2.39, 1.19]
31.2 Multiple pregnancy	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.3 Singleton plus multiple pregnancies or not stated	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any perinatal death after randomisation	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.39, 1.82]
1.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.39, 1.82]
2 Survival following severe neonatal morbidity	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.75, 1.61]
3 Stillbirth	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.37, 10.71]
3.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.37, 10.71]
4 Neonatal death	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.22, 1.60]
4.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.22, 1.60]
5 Any potentially preventable perinatal death*	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.37, 1.86]
5.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.37, 1.86]
6 Fetal acidosis	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.20]
6.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.03, 2.20]
7 Apgar < 7 at 5 minutes	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.44, 1.72]
7.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.44, 1.72]
8 Infant requiring intubation/ventilation	1	333	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.67, 1.13]
8.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.67, 1.13]
9 Intraventricular haemorrhage	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	8.95 [0.49, 164.87]
9.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	8.95 [0.49, 164.87]
10 Bronchopulmonary dysplasia	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.55, 1.38]
10.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.55, 1.38]
11 Necrotising enterocolitis	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.15]
11.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.03, 3.15]
12 Infant birthweight (grams)	1	333	Mean Difference (IV, Fixed, 95% CI)	38.0 [‐31.53, 107.53]
12.1 Singleton pregnancy	1	333	Mean Difference (IV, Fixed, 95% CI)	38.0 [‐31.53, 107.53]
13 Long‐term infant neurodevelopmental outcome (impairment at 2 years)	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.30, 1.18]
13.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.30, 1.18]
14 Long‐term infant neurodevelopmental outcome (cerebral palsy at 2 years)	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 1.68]
14.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 1.68]
15 Infant survival at 2 years without neurodevelopmental impairment (not prespecified)	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.92, 1.23]
15.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.92, 1.23]
16 Sepsis (proven) (not prespecified)	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.60, 1.45]
16.1 Singleton pregnancy	1	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.60, 1.45]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any perinatal death after randomisation	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.64, 2.55]
1.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.64, 2.55]
2 Survival following severe neonatal morbidity	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.66, 1.45]
3 Stillbirth	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [0.60, 14.31]
3.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [0.60, 14.31]
4 Neonatal death	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.47, 2.46]
4.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.47, 2.46]
5 Any potentially preventable perinatal death*	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.59, 2.53]
5.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.59, 2.53]
6 Fetal acidosis	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 2.00]
6.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 2.00]
7 Apgar < 7 at 5 minutes	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.69, 2.37]
7.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.69, 2.37]
8 Infant requiring intubation/ventilation	1	336	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.73, 1.20]
8.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.73, 1.20]
9 Intraventricular haemorrhage	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	16.60 [0.97, 285.35]
9.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	16.60 [0.97, 285.35]
10 Bronchopulmonary dysplasia	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.61, 1.48]
10.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.61, 1.48]
11 Necrotising enterocolitis	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.20, 4.77]
11.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.20, 4.77]
12 Infant birthweight (grams)	1	336	Mean Difference (IV, Fixed, 95% CI)	25.0 [‐40.06, 90.06]
12.1 Singleton pregnancy	1	336	Mean Difference (IV, Fixed, 95% CI)	25.0 [‐40.06, 90.06]
13 Long‐term infant neurodevelopmental outcome (impairment at 2 years)	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.15, 0.79]
13.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.15, 0.79]
14 Long‐term infant neurodevelopmental outcome (cerebral palsy at 2 years)	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.00, 1.59]
14.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.00, 1.59]
15 Infant survival at 2 years without neurodevelopmental impairment (not prespecified)	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [1.02, 1.34]
15.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [1.02, 1.34]
16 Sepsis (proven) (not prespecified)	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.42, 1.11]
16.1 Singleton pregnancy	1	336	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.42, 1.11]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any perinatal death after randomisation	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.32, 1.36]
1.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.32, 1.36]
2 Survival following severe neonatal morbidity	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.77, 1.65]
3 Stillbirth	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.20, 2.36]
3.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.20, 2.36]
4 Neonatal death	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.21, 1.47]
4.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.21, 1.47]
5 Any potentially preventable perinatal death*	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.31, 1.47]
5.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.31, 1.47]
6 Fetal acidosis	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [0.13, 74.43]
6.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [0.13, 74.43]
7 Apgar < 7 at 5 minutes	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.36, 1.29]
7.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.36, 1.29]
8 Infant requiring intubation/ventilation	1	337	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.71, 1.21]
8.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.71, 1.21]
9 Intraventricular haemorrhage	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.16, 1.66]
9.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.16, 1.66]
10 Bronchopulmonary dysplasia	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.58, 1.46]
10.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.58, 1.46]
11 Necrotising enterocolitis	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.04, 3.23]
11.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.04, 3.23]
12 Infant birthweight (grams)	1	337	Mean Difference (IV, Fixed, 95% CI)	13.0 [‐59.31, 85.31]
12.1 Singleton pregnancy	1	337	Mean Difference (IV, Fixed, 95% CI)	13.0 [‐59.31, 85.31]
13 Long‐term infant neurodevelopmental outcome (impairment at 2 years)	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [0.70, 4.32]
13.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [0.70, 4.32]
14 Long‐term infant neurodevelopmental outcome (cerebral palsy at 2 years)	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [0.13, 74.43]
14.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	3.05 [0.13, 74.43]
15 Infant survival at 2 years without neurodevelopmental impairment (not prespecified)	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.80, 1.03]
15.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.80, 1.03]
16 Sepsis (proven) (not prespecified)	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.84, 2.25]
16.1 Singleton pregnancy	1	337	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.84, 2.25]

Methods	2‐arm prospective RCT; randomised block design; individual women.
Participants	Singleton pregnancies with suspected IUGR at 31 completed weeks of pregnancy. IUGR if fetal weight < 2 SD below the mean at 31 weeks. N = 427 women.
Interventions	Intervention: Doppler of umbilical artery only every 2 weeks till birth unless: fetal weight 28% to 33% below mean, then every week; fetal weight > 34% below the mean, then twice a week and admission to hospital. Comparison: CTG (NST).
Outcomes	Primary: GA at delivery, frequency of CS, frequency of operative delivery for fetal distress, CS, vacuum, forceps, length of stay at NICU. Secondary: number of fetal monitoring occasions, duration of antenatal hospital stay, frequency of labour induction, birthweight, frequency of small‐for‐dates infants, Apgar score at 1 min and 5 min, need for respiratory support.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised block design. No information about how the randomisation was performed.
Allocation concealment (selection bias)	Unclear risk	Sealed numbered envelopes according to a randomisation block design. This may mean separate randomisation schedules for the 4 different hospitals. No mention of whether the envelopes were opaque.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No women were lost to follow‐up. 3 women declined to take part in the trial. 1 woman in the CTG group had to be excluded from data analysis since all her records were mislaid before evaluation. All women seemed to get their allocated Doppler or CTG, so this was an ITT analysis.
Selective reporting (reporting bias)	Unclear risk	All outcomes were described in results section, but we did not assess the trial protocol.
Other bias	High risk	The study was not stopped earlier. Baseline imbalance: significantly more operations (elective CS) due to breech presentation and suspected feto‐pelvic disproportion in the Doppler group; the proportion of smokers was higher in the Doppler group than in the CTG group. Differential diagnosis: Almstrom 1995 concluded that obstetricians may have been influenced by the knowledge of a normal umbilical Doppler examination when assessing the CTG in labour. This might have contributed bias to the finding of fewer emergency CS for fetal distress in the Doppler group than in the CTG group.

Methods	Randomised controlled study.
Participants	Women with high‐risk singleton pregnancies. N = 674 women randomised.
Interventions	Intervention: Doppler of umbilical artery revealed. N = 338. Comparison: no Doppler. N = 336.
Outcomes	Elective births; GA at birth; birthweight; Apgar scores, admissions to NICU, length of time in NICU, number of babies ventilated, length of ventilation, perinatal mortality.
Notes	The information came only from the 2 conference abstracts and personal communication (ZA). Sadly, Dr Biljan has died, so further detailed information on the study is not available. The information on the number of women randomised to each group was obtained from previous published version of this systematic review (Alfirevic 1995), and data on 'potentially preventable perineal deaths' was calculated from data in a previous version of this Cochrane review (Neilson 1996).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"...were randomised..."
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information provided in the conference abstract to assess this.
Selective reporting (reporting bias)	High risk	Only gave data for the significant findings and reported the nonsignificant findings just as lower but not statistically significant.
Other bias	Unclear risk	Insufficient information provided in the conference abstract to assess this.

Methods	Prospective RCT, individual women, 2 trial arms.
Participants	Women with high‐risk pregnancies (suspected IUGR, hypertensive disorders, previous baby < 2.5 kg, antepartum haemorrhage, previous perinatal death, diminished fetal movements, post maturity, diabetes, and others). N = 476 women.
Interventions	Intervention: Doppler of umbilical artery and fetal biometry and BPP scoring. Comparison: fetal biometry and BPP scoring.
Outcomes	Primary outcomes: induction of labour, elective and emergency CS, preterm delivery, and perinatal loss.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation by a random number sequence but it was unclear whether this was made by a third independent person.
Allocation concealment (selection bias)	Unclear risk	Sealed numbered envelopes but there was no information whether the envelopes were opaque and whether there was an ordered numbered sequence.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No exclusions after randomisation. Reported as ITT.
Selective reporting (reporting bias)	Unclear risk	All outcomes were described in the results section, but we did not assess the trial protocol.
Other bias	Low risk	The study was not stopped early. Baseline imbalance: "Doppler examinations were not carried out in the control group unless specifically requested by the consultant in charge of patients" ‐ 2 women in the control group had a Doppler and were not excluded.

Methods	2‐arm RCT of individual women.
Participants	Women with singleton post‐term pregnancies (40 + 3 weeks to 42 + 3 weeks). N = 107 women.
Interventions	Intervention: Doppler US of umbilical artery. Comparison: no Doppler US, and standard care (FHR).
Outcomes	CS, RDS and post maturity.
Notes	Paper in French with English abstract, paper was translated. Most of the data were missing.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Women "...were randomly divided...". No information on how the random sequence was generated.
Allocation concealment (selection bias)	Unclear risk	Not described.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Describe any loss of participants to follow‐up at each data collection point: none reported. Describe any exclusion of participants after randomisation: there appeared to be none. Was the analysis ITT? If not, have the data been able to be reincluded? probably.
Selective reporting (reporting bias)	Unclear risk	There was no list of prespecified outcomes as far as we could ascertain and we did not assess the trial protocol.
Other bias	Unclear risk	If the study was stopped early, explain the reasons: no. Describe any baseline imbalance: no information provided. Describe any differential diagnosis: unclear.

Study	Reason for exclusion
Davies 1992	Participants were an "unselected population".
Gonsoulin 1991	Full report not available.
Mason 1993	Participants were "low‐risk primigravid women".
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 was never reported in full although it has been partly reported in a review article (McParland 1988) and a full manuscript was 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.
Newnham 1993	Participants were an "unselected population".
Omtzigt 1994	Participants were a "non‐selected University Hospital population".
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 reviewers to be sufficiently reliable to be retained within this review.
Schneider 1992	Participants were an "unselected pregnant population".
Whittle 1994	Participants were an "unselected population".

Methods	Multi‐centred RCT; block randomisation, block of 20. Individual women, 2‐arm trial.
Participants	Women with twin pregnancies (monochorionic and dichorionic) at 25 weeks. 2 viable apparently normally formed fetuses seen on US scan. Exclusions: fetal anomalies; polyhydramnios/oligohydramnios; demise of 1 twin before 25 weeks. Significance of chorionicity not realised at time randomisation began so no attempt was made to assess chorionicity. N = 539 women.
Interventions	Intervention: Doppler and biometry US. Doppler + biometry at 25, 30 and 35 weeks; “the clinicians were advised to undertake interventions if there was an abnormal umbilical artery Doppler study (> 95th centile systolic diastolic ratio) or abnormal ultrasound biometry indicating discordant growth. The suggested intervention was intensive surveillance by obstetrics caregivers...if other indicators of fetal well‐being (lack of serial growth, decreased amniotic fluid or abnormal fetal monitoring) were abnormal, the early delivery was advised after 25 weeks; “An abnormality of Doppler waveforms themselves was not considered an indication for immediate delivery unless there was absence of diastolic flow velocity at > 32 weeks of gestation”. Comparison: biometry US. Biometry only at 25, 30 and 35 weeks.
Outcomes	Maternal: antenatal admission, presence of hypertension, gestation at delivery, indication for delivery and mode of delivery. Fetal: US biometry measurements, umbilical artery doppler systolic diastolic ratios and the occurrence of fetal death and causative factors. Neonatal: birthweight, Apgar scores, admission to NICU, admission to special care nursery, requirements for ventilation and occurrence of neonatal death (up to 28 days of life).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	“....opaque sealed envelopes containing the randomisation code the envelope being opened by an observer remote from patient care”.
Allocation concealment (selection bias)	Low risk	“....opaque sealed envelopes containing the randomisation code the envelope being opened by an observer remote from patient care".
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Describe any loss of participants to follow‐up at each data collection point: 539 women were randomised in Doppler Assessment in Multiple Pregnancy (DAMP) study: Doppler 268 and control 271. 13 were lost to follow‐up after randomisation at 25 weeks and were not included in the results. This left 526 women with complete follow‐up: 262 in Doppler and 264 in no Doppler. Describe any exclusion of participants after randomisation: Was the analysis ITT? If not, have the data been able to be reincluded? 7 women in the no Doppler group had Doppler.
Selective reporting (reporting bias)	Unclear risk	There seemed to be no evidence of selective reporting bias, but we did not assess the trial protocol.
Other bias	Low risk	If the study was stopped early, explain the reasons: not stopped early, but PNM findings in study much lower than expected. Power calc was based on 85.7/1000 (but PNM in study was 11/1000), so study significantly underpowered ‐ needed 3300 per arm. Describe any baseline imbalance: no imbalances.

Methods	2‐arm RCT with stratified block randomisation producing 4 groups: Caucasian primiparous and multiparous women, and Asian primiparous and multiparous women. Randomised in blocks of 8 using table of random numbers. However, the results are not reported by any of these subgroups ‐ only Doppler vs CTG overall. Randomisation was of individual women.
Participants	Women with singleton fetuses with US examination showing the abdominal circumference < 2 SD of the mean for the GA FHR on charts recommended by British Medical Ultrasound Society. There was no GA constraint although all women were > 26 weeks' gestation. N = 150 women.
Interventions	Intervention: Doppler of umbilical artery and no CTG. Comparison: CTG.
Outcomes	Primary: duration of hospital antenatal admission, induction of labour rates. Secondary: number of investigations (CTG or Doppler), number of outpatient visits to hospital, emergency CS rate, length of stay on the NICU, birthweight, and 1 min and 5 min Apgar score. All women were sent a questionnaire asking their views on the process of their care.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocks of 8 using a table of random numbers.
Allocation concealment (selection bias)	Low risk	"...randomisation only possible by telephone .... sequentially numbered sealed opaque envelopes..."
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No loss of participants at follow‐up. No exclusion after the randomisation. ITT analysis.
Selective reporting (reporting bias)	Unclear risk	We did not assess the trial protocol. Also, despite the stratified randomisation to look at ethnicity and parity, the results are not reported by any of these subgroups, only Doppler vs CTG overall.
Other bias	Low risk	Study went to completion. Baseline imbalance: more women had no live‐in support at home in the CTG group. Differential diagnosis: "...there was not a rigid protocol except that clinicians usually felt that a CTG record gave reassurance for 48 to 72 hours and a Doppler examination for a week or more ...".

Methods	2‐arm RCT, but with additional evaluation by the nonallocated technique. Randomisation was of individual women.
Participants	Women undergoing evaluation of fetal well‐being in the high‐risk obstetric unit. 867 women randomised. N = 897 women.
Interventions	Intervention: Doppler US of umbilical artery. Comparison: computerised CTG.
Outcomes	Number and duration of tests; perinatal outcomes. “Our objective was to determine whether the experimental policy of Doppler study followed when necessary by FHR testing would take less time than routine FHR testing alone".
Notes	We contacted the authors to ask for clarification of the phrase, "computer generated algorithm based on the hospital number". They kindly responded with an explanation: "allocation was done automatically by a computer programme. Although the algorithm made use of the woman's hospital number, it was impossible for the midwife performing the fetal assessment to predict to which group the women would be allocated. The 'algorithm' was simply a mathematical sequence which was applied to the woman's hospital number to generate an allocation".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"...computer generated algorithm based on the hospital number...". We sought clarification from the authors who kindly responded: "allocation was done automatically by a computer programme".
Allocation concealment (selection bias)	Low risk	Not described in the paper but we wrote for clarification from the authors who kindly responded: "although the algorithm made use of the woman's hospital number, it was impossible for the midwife performing the fetal assessment to predict to which group the women would be allocated. The 'algorithm' was simply a mathematical sequence which was applied to the woman's hospital number to generate an allocation".
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Describe any loss of participants to follow‐up at each data collection point: none apparent. Describe any exclusion of participants after randomisation: none apparent. Was the analysis ITT? If not, have the data been able to be reincluded? it would appear so.
Selective reporting (reporting bias)	Unclear risk	There was no list of prespecified outcomes from the protocol, and we did not assess the trial protocol.
Other bias	High risk	If the study was stopped early, explain the reasons: not stopped early as far as could ascertain. Describe any baseline imbalance: imbalance in numbers in each group: 439 Doppler vs 459 FHR; unspecified number of women in CTG group had also Doppler evaluation ‐ assessment by the alternate nonallocated method was required on 1241 (66%) of 1869 occasions in which the allocated method was Doppler, and 804 (39%) of 2069 occasions when the allocated method was FHR testing.

Methods	2‐arm RCT. Randomisation by Zelen method ‐ only those randomised to Doppler were invited to participate in the trial. Those allocated to CTG were being given normal care so their permission was regarded as not required. Randomisation was of individual women.
Participants	Women with pregnancies identified clinically as being at increased risk (N = 2289 out of the 8018 women giving birth at the hospital during the time of the study). Doppler or CTG or BPP was given to pregnant women where there was concern by medical staff about antenatal fetal well‐being by random allocation. Women were admitted to the trial if there was a wish for Doppler studies or a referral for AN fetal monitoring (CTG or BPP). So, all women meeting these criteria were randomised regardless of risk. N = 2289 women.
Interventions	Intervention: Doppler US of umbilical artery (and other monitoring). Comparison: no Doppler ‐ but other monitoring used (CTG/BPP).
Outcomes	Fetal mortality and morbidity; obstetric interventions; use of other tests of fetal monitoring; impact on obstetric decision making; health and personal costs; women’s satisfaction (to be presented in a separate report).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Just described as randomised.
Allocation concealment (selection bias)	Low risk	“Sequentially numbered opaque sealed envelopes were attached by stapling to the case notes of all women attending this hospital. Randomisation was carried out by opening the envelope for every woman who met the criteria described above.”
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Describe any loss of participants to follow‐up at each data collection point: all women seemed to have data collected. Describe any exclusion of participants after randomisation: of the 1114 women allocated to Doppler, 24 did not have Doppler assessment (2%); 3 women got 'Doppler' though they were randomised to 'no Doppler'; uneven, but numbers were small relative to the size of the study. Was the analysis ITT? If not, have the data been able to be reincluded? “data analysis was on an ITT basis".
Selective reporting (reporting bias)	Unclear risk	They seemed to report on their prespecified outcomes but we did not assess the trial protocol.
Other bias	Low risk	If the study was stopped early, explain the reasons: no. Describe any baseline imbalance: none reported in the text. Describe any differential diagnosis: seemed okay. Receiving the other intervention: 24 women allocated to Doppler did not have it performed; 3 women in No Doppler had Doppler.

Methods	3‐arm prospective randomised controlled study of individual women.
Participants	Study in 20 tertiary care hospitals in 5 European countries (Austria, Germay, Italy, The Netherlands, UK). Women over 18 years capable of giving consent. Singleton pregnancy at 26 + 0 to 31 + 6 weeks’ gestation with FGR (defined as abdominal circumference below the 10^th percentile based on local standards and abnormal umbilical artery Doppler pulsatility index (PI) above the 95^th percentile based on local standards irrespective of the presence or absence of reversed end‐diastolic flow). In all cases, estimated fetal weight was > 500 g. Short‐term variation after 1 hour of CTG tracing had to be > 3.5 ms at 26 to 28 weeks and > 4 at 29 to 31 weeks with ductus venosus PI < 95^th percentile. (GA determined by US at 14 and between 14 to 21 + 6 weeks). Women with known or planned impending delivery, major structural abnormality or fetal karyotype abnormality were excluded. N = 511 randomised (8 subsequently excluded).
Interventions	Randomisation groups: 1. Cardiotocograph short term variation (CTG STV) and timing of delivery was assessed with a criterion for reduced STV. Umbilical artery Doppler measurements were taken but no waveform measurements of the ductus venosus were recorded. (166 allocated, 21 lost to follow‐up, 1 missing neonatal data, 144 in primary analysis). 2. Early abnormality of ductus venosus prompted delivery (early changes pulsatility index > 95^th percentile) (n = 167, 25 lost to follow‐up, 142 in primary analysis). 3. Late ductus venosus changes (a wave indicated no or reversed flow) (n = 170, 13 lost to follow‐up, 157 in primary analysis). All measurements were confirmed by a second measurement at least 24 hours later. Monitoring in all groups included umbilical artery Doppler and CTG was recommended at least once a week but could be more frequent depending on local protocol. Irrespective of randomised group, there was a cutoff rescue value for STV based on CTG at 26 to 28.9 weeks that prompted delivery. At 32 weeks, deliveries were according to local protocol. In all groups, delivery could be undertaken based on a maternal indication such as severe pre‐eclampsia or clear CTG abnormalities such as recurrent late decelerations.
Outcomes	Primary outcome: survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85 at 2 years of age. Secondary outcomes: composite of adverse neonatal outcome defined as fetal or postnatal death (between trial entry in‐utero and discharge home from neonatal services) or 1 or more of the following severe morbidities: BPD (defined as supplemental oxygen to maintain SATs > 90% at 36 weeks), severe cerebral haemorrhage (IVH grade III or IV) cystic periventricular leukomalacia, proven neonatal sepsis (blood culture and requiring antibiotics) or NEC (presence of pneumatosis or perforation on X‐ray or disease present on laparotomy).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Through central randomisation website. Random block design, stratified by gestation (< 29 vs > 29 weeks) and centre.
Allocation concealment (selection bias)	Low risk	Through central randomisation website.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	It was not feasible to blind clinicians to intervention group. Women may have been aware of randomisation group.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Neonatal outcome data entered directly from records and entered into database. Not possible to blind outcome assessment for all outcomes, however, the assessor of the primary outcome was blinded. “Concealment of the allocated monitoring regime was not possible, and clinicians responsible for the care of the women entered in the study and women themselves were aware of the treatment allocation. However, the paediatrician doing the follow‐up examination was masked to follow‐up assessment and data entry allocation”.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Of 511 randomised, missing data for 8 women and babies for the primary outcome. There was some attrition at 2‐year follow‐up (59 lost to follow‐up). ITT analysis.
Selective reporting (reporting bias)	Low risk	Protocol available and no evidence of outcome reporting bias.
Other bias	Low risk	Demographic data given for whole sample and those with poor composite outcome. Groups appeared similar at baseline.

Methods	2‐arm randomised controlled study of individual women.
Participants	Women of 24 weeks or greater gestation with a singleton pregnancy, and ultrasonic evidence of IUGR (abdominal circumference on or below 5^th centile for GA). N = 467 women.
Interventions	Intervention: Doppler US of umbilical artery revealed, weekly or more often if indicated. Documented in notes. Discussed with registrar. Comparison: Doppler US weekly but recorded in separate file and not disclosed to clinicians.
Outcomes	Obstetric management: gestation at birth, time from enrolment to birth, mode of birth/onset of labour, fetal distress in labour. Neonatal outcome: perinatal mortality, birthweight, admission to NICU, neonatal outcome.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information other than 'randomised'.
Allocation concealment (selection bias)	Unclear risk	Sealed envelopes but there was no information as to whether the envelopes were opaque and whether they were distributed in a sequential order.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Describe any loss of participants to follow‐up at each data collection point: no withdrawals reported. Describe any exclusion of participants after randomisation: no exclusion: no withdrawals reported. Was the analysis ITT? If not, have the data been able to be reincluded? ITT as far as able to assess. Not specifically stated as such.
Selective reporting (reporting bias)	High risk	Not all outcomes available and we did not assess the trial protocol.
Other bias	Unclear risk	If the study was stopped early, explain the reasons: not stopped early for benefit, but underpowered due to 'cannot do a large enough study'.

Methods	2‐arm RCT, stratified for twin pregnancies. Randomisation was of individual women.
Participants	Women with high‐risk pregnancies, singletons and twins. Defined as those disorders of pregnancy in which an increased risk of retarded fetal growth or impaired fetal well‐being were considered likely. N = 505 women.
Interventions	Intervention: Doppler of umbilical and utero‐placental (within the placental bed) artery. N = 254, including 21 twins. Performed immediately after randomisation and then frequency by clinical judgement. "The ratio of peak systolic (S) to least diastolic (D) Doppler shift frequency was calculated from waveforms obtained from an umbilical artery and from a maternal uteroplacental artery within the placental bed. These ratios were not adjusted to standard fetal or maternal heart rates”. Comparison: no Doppler. N = 251, including 19 twins.
Outcomes	Primary: duration of neonatal stay in hospital. Secondary: number and type of fetal heart monitoring studies, obstetric interventions, frequency of fetal distress, birthweight, Apgar score, and need for NICU.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Just described as random.
Allocation concealment (selection bias)	Low risk	Numbered opaque sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Assessors of neonatal outcomes were blind to Doppler results.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Describe any loss of participants to follow‐up at each data collection point: no loss reported. Describe any exclusion of participants after randomisation: none described. Was the analysis ITT? If not, have the data been able to be reincluded? apparently yes.
Selective reporting (reporting bias)	Unclear risk	Reported outcomes were the same as those prespecified but we did not assess the trial protocol.
Other bias	Low risk	If the study was stopped early, explain the reasons: no. Describe any baseline imbalance: groups comparable for maternal age, height, parity, smoking and GA. No 'P' values given but looked alright. Describe any differential diagnosis: seemed alright.

Methods	Randomised controlled study ‐ stratified randomisation and block randomisation. Stratification by GA (< 32 weeks and > 32 weeks) and smoking (regardless of number of cigarettes smoked). Randomisation by individual women, 2‐arm trial.
Participants	Women with clinically suspected IUGR of > 2 weeks diagnosed by fundal height measurements at the outpatient clinic. Singleton pregnancies. Exclusions: multiple pregnancies, uncertain GA, nonCaucasian origin, maternal or fetal conditional requiring immediate hospitalisation or intervention. N = 161 women.
Interventions	Intervention: Doppler US of umbilical artery revealed: done weekly until birth; maintaining outpatient management while the Doppler was in the normal range, in a setting whereby hospitalisation was the management of choice where significant IUGR was suspected. Comparison: Doppler US of umbilical artery concealed: the PIs were not calculated until after birth and the results were concealed from the clinicians in charge; standard clinical management for suspected IUGR.
Outcomes	Effect on costs in terms of hospitalisation, perinatal outcome, neurological development and postnatal catchup growth, onset and mode of birth, birthweight, and GA at birth.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised numbers from a published table of random numbers from a person not involved in patient management. However, study stated “....even number allocated the participant to the intervention group....uneven numbers were allocated to the control group” (Nienhuis 1995). A block size of 10 was used.
Allocation concealment (selection bias)	Low risk	“A randomisation number was requested over the telephone from an independent person not involved in patient management”. After the stratification, the next number of 1 of the 4 randomisation lists was read.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Assessors of neonatal outcomes were blind to Doppler results.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Describe any loss of participants to follow‐up at each data collection point: 11 women refused to participate in the study. Describe any exclusion of participants after randomisation: 8 cases were excluded (4 in intervention group and 4 in control group) because of congenital defects. Was the analysis ITT? If not, have the data been able to be reincluded? not for some outcomes ‐ not able to reinclude; authors took out protocol violation and re‐evaluated because they said: “14 participants were admitted during pregnancy despite a normal Doppler. Suspected IUGR was the sole reason and they should not have been admitted. The authors recalculated excluding these 14 and this is inappropriate as it is likely to reflect real life".
Selective reporting (reporting bias)	Unclear risk	All the outcomes were reported but we did not assess the trial protocol.
Other bias	High risk	If the study was stopped early, explain the reasons: not reported as stopping early. Describe any baseline imbalance: slight difference in primipara: Doppler 34/74 (46%) and control 43/76 (57%) but reported as NS; 58.1% boys in intervention group and 36.8% boys in control group; 4.1% breech in intervention group and 18.4% breech in control group; in the analysis, the possible influence of the skewed distribution of sex was reduced by using sex‐specific growth reference.

Methods	RCT; 2‐arm trial randomising individual women.
Participants	Pregnant women seen at the 'Fetal Assessment Unit' over 40 weeks' gestation.
Interventions	Intervention: pulsed Doppler revealed. Fetal aorta and umbilical artery assessed. BPP and NST also undertaken. Comparison: pulsed Doppler concealed. BPP and NST were reported.
Outcomes	CS; gestation at birth; meconium in amniotic fluid; need for phototherapy.
Notes	Conference abstract available, but no full publication.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information available.
Allocation concealment (selection bias)	Unclear risk	No information available.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No information available.
Selective reporting (reporting bias)	Unclear risk	Very limited data in the conference abstract. We did not assess the trial protocol.
Other bias	Unclear risk	No information available on which to judge this aspect.

Methods	RCT. Individual women randomised in 2 arms.
Participants	Women with high‐risk pregnancies with recurrent pregnancy loss (2 or more mid trimester or early third trimester losses which resulted in IUFD, stillbirth or neonatal death) at least 24 weeks' pregnant. 54 women randomised. N = 54 women.
Interventions	Intervention: Doppler velocimetry of umbilical artery revealed. Comparison: Doppler velocimetry of umbilical artery concealed.
Outcomes	Maternal intervention, hospital stay, induction of labour, CS, perinatal mortality and morbidity.
Notes	A conference poster (incomplete data).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Women were randomly allocated.
Allocation concealment (selection bias)	Unclear risk	Sealed envelope, but no mention of how they were distributed nor whether they were opaque.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Describe any loss of participants to follow‐up at each data collection point: 1 woman lost to follow‐up, but no explanation. Describe any exclusion of participants after randomisation: no information. Was the analysis ITT? If not, have the data been able to be reincluded? no information.
Selective reporting (reporting bias)	Unclear risk	No information in the poster to enable this to be assessed. Also we did not assess the trial protocol.
Other bias	Low risk	If the study was stopped early, explain the reasons: was not stopped early. Describe any baseline imbalance: “...both groups were comparable at study entry as regards maternal age, number of previous losses and GA”. Describe any differential diagnosis: seemed fine.

PERMALINK

Fetal and umbilical Doppler ultrasound in high‐risk pregnancies

Zarko Alfirevic

Tamara Stampalija

Therese Dowswell

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings for the main comparison. Umbilical artery Doppler ultrasound compared to no Doppler ultrasound in high‐risk pregnancies.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Comparisons

Types of outcome measures

Main outcomes

Additional outcomes of interest

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

(5) Selective reporting (checking for reporting bias)

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

(7) Overall risk of bias

Assessment of the quality of the evidence using the GRADE approach

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Cross‐over trials

Multiple pregnancies

Studies with multiple treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Risk of bias in included studies

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Sensitivity analyses

Effects of interventions

1) Umbilical artery Doppler ultrasound versus no Doppler ultrasound (18 studies, 10,156 women)

Main outcomes

Any perinatal mortality after randomisation (16 studies, 10,225 babies)

1.1. Analysis.

Methods	RCT; block randomisation of individual women: 2‐arm RCT but with 3 subgroups: group 1. women with fetuses with AEDV; group 2: women with hypertension but fetuses with EDV and group 3: women with fetuses suspected of being SGA but with EDV present; 3 groups were created based on clinical picture and Doppler results; if the woman was hypertensive and fetus had EDV and was suspected of being small, then she went to HT group; each subset was managed differently; balanced block randomisation in blocks of 10 for AEDV and 20 for other groups. There were equal numbers of women in each group; data analysed at completion of each block; in each group, Doppler revealed and Doppler concealed.
Participants	Women > 28 weeks' pregnant with hypertension and/or suspected SGA fetuses were referred for Doppler US. 212 women with singleton pregnancies. N = 212 women.
Interventions	Intervention: Doppler velocimetry of umbilical artery revealed: other tests available, e.g. sonar and AN FHR. Comparison: Doppler velocimetry of umbilical artery concealed: other test available, e.g. sonar and AN FHR.
Outcomes	Perinatal mortality and morbidity, antenatal hospitalisation, maternal intervention, admission to the NICU, and hospitalisation until discharge from the neonatal wards.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	“...randomisation was performed by the person doing the Doppler velocity .......”
Allocation concealment (selection bias)	Unclear risk	“......opaque sealed envelopes......”, but no mention of numbered and sequentially ordered envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Describe any loss of participants to follow‐up at each data collection point: none were lost. Describe any exclusion of participants after randomisation: not apparent. Was the analysis ITT? If not, have the data been able to be reincluded? probably.
Selective reporting (reporting bias)	Unclear risk	All the outcomes were reported but we did not assess the trial protocol.
Other bias	High risk	If the study was stopped early, explain the reasons: in the group of AEDV (20 women), there were 6 perinatal deaths in the control group and 1 perinatal death in the study group. The trial was stopped at this point because significantly more fetuses had died in the control group. Describe any differential diagnosis: if AEDF detected, then Doppler was repeated the following day. In the control group, Doppler was repeated weekly if the woman was in hospital and fortnightly if the woman was an outpatient; in the AEDV group, the authors stated that "by giving the responsible clinician a management guideline for a fetus with ADEV we might have biased the outcome because the clinician was aware we were specifically interested in the outcome and so more care might have been taken"; women in the control group were managed by consultants who might have had an infertility or gynaecology speciality, where women with problems identified were managed with a specific management plan. So it is possible that there might not have been a difference in a hospital where all high‐risk pregnancies were managed by clinicians who were subspecialists in perinatal medicine.

Methods	RCT; pragmatic 2‐arm trial.
Participants	Women with high‐risk singleton pregnancies. Specifically, 500 pregnant women at high risk of growth retardation or stillbirth. IUGR clinically suspected or by US scan, previous SGA baby, previous antepartum haemorrhage, hypertension. Exclusions: women with diabetes, twin pregnancies. N = 500 women.
Interventions	Intervention: routine use of Doppler and BPP testing + other tests: Doppler of umbilical and uteroplacental arteries; testing at 28 weeks' gestation, or at the time of presentation if risk factors appeared later than this. Thereafter, they had weekly Doppler and fetal biophysical assessment for 3 weeks, followed by fortnightly examinations until delivery. Comparison: no Doppler and no biophysical assessment but other tests only: "clinicians responsible for the care of women in the selectively investigated arm could only obtain Doppler and biophysical assessment on special request, and this happened in only 12 pregnancies”.
Outcomes	Total number of days of antenatal admission, rate of induction of labour (by any method), mode of birth (elective CS and emergency CS), 1 and 5 min Apgar, birthweight, admission to NICU.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"...random number sequence...” though it is not clear how this was generated; "...the randomisation was performed by the 2 ultrasonographers involved in the study neither of whom knew anything about the patients or was involved in their clinical management...".
Allocation concealment (selection bias)	Unclear risk	"...sealed, sequentially numbered envelopes..” though it is not clear whether these were opaque.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Describe any loss of participants to follow‐up at each data collection point: "...the data on duration of antenatal stay and induction of labour were obtained retrospectively, and the case notes could not be traced in 15% of the women". Describe any exclusion of participants after randomisation: no exclusion. Was the analysis ITT? If not, have the data been able to be reincluded? 12 women in 'no Doppler' group had Doppler and BPP at specific request of obstetrician. These seemed to be assessed in the group to which women were randomised, so appeared to be ITT.
Selective reporting (reporting bias)	Unclear risk	Not all outcomes were reported, emergency CS just reported in the text. We did not assess the trial protocol.
Other bias	Unclear risk	If the study was stopped early, explain the reasons: not reported; the registered study aimed for 28,000 over 7 years, but this was probably impractical. Describe any baseline imbalance: "clinicians responsible for the care of women in the selectively investigated arm could only obtain Doppler and biophysical assessment on special request, and this happened in only 12 pregnancies". Describe any differential diagnosis: seemed alright.

Methods	Randomised controlled study; block randomisation (block of 4 and 6). Individual women.
Participants	Women with high‐risk pregnancies: singletons (IUGR 7%, hypertension 10%, diabetes 11%, prolonged pregnancy 43%, decreased fetal movements 22%). GA > 32 weeks. N = 1360 women.
Interventions	Intervention: umbilical artery Doppler: if Doppler normal, then women seen twice a week; if equivocal, then amniotic fluid index done; if abnormal, then proceeded to induction/delivery within 24 hours. Comparison: electronic FHR with NST: twice a week; Kulbi score (5 components). If equivocal (identified Kulbi = 6), then assessment of amniotic fluid volume; if abnormal (identified Kulbi = 4), then induction/delivery within 24 hours.
Outcomes	Primary outcome: incidence of CS for fetal distress in labour (nonreassuring FHR). Secondary outcome: total CS, Apgar score 1 and 5 min, the incidence of stillbirth, the presence of meconium, and the incidence of transfer to the NICU with severe neonatal morbidity.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table with a variable block size of 4 and 6.
Allocation concealment (selection bias)	Unclear risk	Sequentially numbered opaque envelopes although no information as to whether they were sealed. “...envelopes were kept in a locked drawer that was accessible only to the unit clerk. The envelops was opened by the nurse/sonographer in the presence of the patient”.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Blinding women and/or staff in these trials was not generally feasible.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Describe any loss of participants to follow‐up at each data collection point: no final outcome data were available for 16 women (10 in NST group and 6 in Doppler group). Describe any exclusion of participants after randomisation: 4 women were assigned in error, did not have the identified high‐risk condition, and were removed from further analysis; 1356 women in study. Was the analysis ITT? “once assigned randomly to particular group, the patient remained in that group for any subsequent assessment that took place in that pregnancy".
Selective reporting (reporting bias)	Unclear risk	All the outcomes were reported but we did not assess the trial protocol.
Other bias	Low risk	If the study was stopped early, explain the reasons: study not stopped early for benefit. Describe any baseline imbalance: this seemed fine. Describe any differential diagnosis: this seemed alright.