Ultrasound Obstet Gynecol 2016; 47: 22–27 Published online 2 December 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14914

Predictive accuracy of second-trimester uterine artery Doppler indices for stillbirth: a systematic review and meta-analysis R. E. ALLEN*, M. MORLANDO†, B. THILAGANATHAN†, J. ZAMORA‡§, K. S. KHAN¶**, S. THANGARATINAM¶** and A. BHIDE† *Fetal Medicine Centre, Royal London Hospital, Barts Health NHS Trust, London, UK; †Fetal Medicine Unit, St George’s Healthcare NHS Trust, London, UK; ‡Clinical Biostatistics Unit, Hospital Ramon y Cajal (IRYCIS), Madrid, Spain; §CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain; ¶Women’s Health Research Unit, Multidisciplinary Evidence Synthesis Hub (mEsh), Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; **London School of Medicine and Dentistry, Queen Mary University of London, London, UK

K E Y W O R D S: second trimester; stillbirth; ultrasound; uterine artery Doppler

ABSTRACT Objective To assess the predictive accuracy for stillbirth of second-trimester uterine artery Doppler. Methods We searched MEDLINE, EMBASE and The Cochrane Library databases from inception until March 2015 without language restrictions. The included studies were those that assessed the association of abnormal uterine artery Doppler parameters and stillbirth. Two independent reviewers selected the studies, extracted data and assessed quality. Results for studies that were performed in the second trimester were pooled and summary estimates of sensitivity, specificity, likelihood ratios and their 95% confidence intervals were obtained. An overall summary of test accuracy was provided by the diagnostic odds ratio. Subgroup analysis was performed according to whether the study population was high risk or unselected. Results Literature searches returned 338 relevant citations with 32 considered in full. Thirteen studies met our search criteria (85 845 women, 508 stillbirths) and were included in the review. Bivariate pooled estimate for sensitivity was 65% (95% CI, 38–85%) and for specificity 82% (95% CI, 72–88%). The positive likelihood ratio was 3.5 (95% CI, 2.3–5.5) and negative likelihood ratio 0.43 (95% CI, 0.22–0.85). The diagnostic odds ratio was 8.3 (95% CI, 3.0–22.4). Heterogeneity was high in the studies of high-risk women. Conclusions Abnormal uterine artery Doppler indices are associated with a three- to four-fold increase in the risk of stillbirth. The heterogeneity was particularly

high in the high-risk group rendering it impossible to draw firm conclusions. In view of this, there is a role for individual patient data meta-analysis to define which Doppler parameter and threshold value should be measured. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

INTRODUCTION Stillbirth is defined as a baby born without signs of life after 23 + 6 weeks of pregnancy. There has been a downward trend in the rate of stillbirths in the UK over the past 10 years, and it is currently 5.1/10001 . The last Centre for Maternal and Child Enquiries (CMACE) report developed a new classification for conditions arising in pregnancy that caused or were associated with stillbirth1 . This classification enabled a reduction in the number of stillbirths being reported as unexplained from 50% to 23%. They found the main causes or associated factors of stillbirth were antepartum or intrapartum hemorrhage (13%), intrauterine growth restriction (IUGR) (10%) and specific placental conditions (9%). Pre-eclampsia was associated with 4.7% of stillbirths. All of these conditions are associated with impaired placentation1 . In normal pregnancy, the maternal spiral arteries are invaded by trophoblasts, converting narrow, high-resistance muscular vessels to wide, low-resistance non-muscular channels independent of maternal vasomotor control. In pregnancies complicated by pre-eclampsia, placental abruption and IUGR, there is histological evidence of impaired trophoblastic invasion. Abnormal

Correspondence to: Miss R. Allen, Fetal Medicine Centre, 8th Floor, South Tower, Royal London Hospital, Whitechapel, London E1 1BB, UK (e-mail: [email protected]) Accepted: 11 May 2015

Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

SYSTEMATIC REVIEW

Uterine artery Doppler and stillbirth (high resistance) uterine artery Doppler has been shown to be related to several defects in trophoblast invasion and function associated with the subsequent development of pre-eclampsia2 – 4 . More recently, studies have reported an association between elevated resistance in the uterine arteries and the later occurrence of stillbirth5 – 7 . Although promising, the performance of uterine artery Doppler for prediction of stillbirth has varied across these studies with variation in the reporting of outcomes and the Doppler measurements used. The objective of this systematic review was to identify studies reporting on the association of stillbirth with abnormal placental perfusion in order to quantify the extent of the risk.

23 Search results combined from databases: MEDLINE, EMBASE, Cochrane (n = 338)

Articles excluded (n = 308) Articles from other sources (n = 2)

Full-text articles assessed for eligibility (n = 32)

Articles excluded (n = 19) • Data not analyzable (n = 12) • Inappropriate outcome (n =2) • Duplicated data (n = 3) • First-trimester studies (n = 2)

METHODS We undertook the systematic review with a prospective protocol in line with current recommendations8 . We searched MEDLINE, EMBASE and The Cochrane Library databases from inception until March 2015 without language restrictions. We examined the reference lists of all known primary and review articles to capture articles missed by the electronic searches without language restrictions. We contacted the authors of primary studies if relevant data were not reported. We used the following combination of search terms: pregnan*, gravid*, ‘uterine artery Dopplers’, Doppler, stillbirth, IUD, ‘intra-uterine death’. Study selection was performed in two stages. Firstly the electronic searches were scrutinized and appropriate studies were identified. Secondly, two independent reviewers (R.E.A. and M.M.) reviewed the full text of the identified papers and selected the studies that fulfilled the inclusion criteria. We included those studies that evaluated the association between uterine artery Doppler and stillbirth. Data were extracted, in duplicate, by R.E.A. and M.M., in 2 × 2 tables for the incidence of stillbirth in women with abnormal uterine artery Doppler. The definition of abnormal uterine artery Doppler, as given in each individual study, was used for analysis. The quality of the study methodology was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria, which consist of four key domains: patient selection, index test, reference standard, and flow and timing9 . Each of these domains is assessed for risk of bias and classified as low or high risk or unclear. Data for true positives, true negatives, false positives and false negatives were extracted from primary studies and used to estimate sensitivities, specificities and likelihood ratios with their 95% confidence intervals for individual studies. We pooled the results for studies that were performed in the same trimester. To obtain summary estimates of sensitivity and specificity, a multilevel bivariate random-effects model was used as implemented in the mentandi user-written command developed for Stata statistical software10 . From these indices we derived corresponding likelihood ratios and their 95% confidence intervals for the subgroup of the

Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Second-trimester studies included in systematic review (n = 13)

Figure 1 Flowchart showing study selection in systematic review evaluating association of uterine artery Doppler indices and stillbirth.

second-trimester studies11 . This model also estimates the correlation between sensitivity and specificity as a random parameter to represent the counterbalance between sensitivity and specificity due to a threshold effect. Due to the low number of studies included in the review, we analyzed the effect of covariates (screening general population vs high-risk population) on diagnostic accuracy as measured by the diagnostic odds ratio (DOR) using meta-regression weighted by the inverse of withinstudy variance of log[DOR]. Meta-DiSc software was used for this analysis12 . We also performed an analysis dividing the studies into subgroups according to whether the study population was unselected or at high risk of developing pregnancy complications.

RESULTS Our initial search found 338 relevant citations; after reading through the titles and abstracts, we identified a total of 32 citations for further assessment. Full evaluation of these resulted in the identification of 13 studies (n = 85 845) in the review, which included 508 stillbirths (Figure 1 and Table 1).

Quality of the included studies The quality of the included studies is shown in Table 2 and Figure 2. All studies had a low risk of bias and low concerns regarding applicability for flow and timing, reference standard (stillbirth) and index test (uterine artery Doppler assessment). Six of the 13 (46%) studies had a high risk of bias and high concerns for applicability regarding patient selection.

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Table 1 Characteristics of studies included in systematic review evaluating association of uterine artery Doppler (UtAD) indices and stillbirth Stillbirths/women (n) Reference

Risk status

Definition of abn. UtAD

Madazli (2014)24

High

Jamal (2013)22

Low

Poon (2013)21 Singh (2012)5 Filippi (2011)18

Low Any High

Proctor (2009)13 Schwarze (2005)20

High Any

Axt-Fliedner (2005)16 Albaiges (2000)19

High Any

Coleman (2000)14 Bewley (1991)17 Steel (1990)23 Fleischer (1986)15

High Any Any High

SD ratio > 2.6 and bilateral notching Mean PI > 95th percentile and/or bilateral notching PI MoM > 90th centile Mean PI > 90th centile Mean PI > 1.45, bilateral or unilateral notching Mean PI > 1.45 Unilateral or bilateral notching Both RI > 0.58 Bilateral notching or mean PI > 1.45 Mean RI > 0.7 Mean RI > 95th centile Mean RI > 0.58 SD ratio > 2.6

Normal UtAD

Abn. UtAD

LR+ (95% CI)

Stillbirth rate (n/1000)

3/65

0/52

3/13

5.25 (2.70–10.2)

46.2

5/435

2/389

3/46

6.00 (2.78–12.96)

11.5

306/65 819 135/14 997 2/159

184/59 142 71/13 309 0/127

122/6677 64/1688 2/32

3.99 (3.47–4.58) 4.34 (3.61–5.21) 4.32 (2.37–7.85)

4.6 9.0 12.6

9/58 1/211

6/31 1/135

1.18 (0.59–2.38) 2.00 (1.19–3.37)

168.5 5.8

4/52 6/1757

1/38 2/1668

3/14 4/89

2.98 (1.39–6.41) 11.15 (7.31–17.00)

76.9 3.4

2/116 12/925 11/1014 5/71

0/38 9/871 8/896 0/43

2/78 3/54 3/118 5/28

1.25 (0.74–2.11) 4.47 (1.62–12.36) 2.38 (0.89–6.33) 2.61 (1.74–3.92)

17.2 12.9 10.8 70.4

Total

15/89 2/346

Only first author of each study is given. Abn., abnormal; LR+, positive likelihood ratio; MoM, multiples of the median; PI, pulsatility index; RI, resistance index; SD, systolic to diastolic. Table 2 Quality assessment of included studies using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria Risk of bias

Applicability concerns

Reference

Patient selection

Index test

Reference standard

Flow and timing

Patient selection

Index test

Reference standard

Madazli (2014)24 Jamal (2013)22 Poon (2013)21 Singh (2012)5 Filippi (2011)18 Proctor (2009)13 Schwarze (2005)20 Axt-Fliedner (2005)16 Albaiges (2000)19 Coleman (2000)14 Bewley (1991)17 Steel (1990)23 Fleischer (1986)15

High Low Low Low High High High High Low Low Low Low High

Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low

High Low Low Low Low High High High Low High Low Low High

Low Low Low Low Low Low Low Low Low Low Low Low Low

Low Low Low Low Low Low Low Low Low Low Low Low Low

Only first author of each study is given.

Characteristics of the included studies The included studies comprised 13 in the second trimester5,13 – 24 . Six studies were on high-risk women and included women with comorbidities such as hypertension, medical disorders, previous intrauterine growth restriction, placental abruption or stillbirth5,13 – 16,24 . Seven were on an unselected group of women. Two studies were in women with abnormal biochemistry when performed for Down syndrome screening, including low pregnancy-associated plasma protein A and estriol or high β-human chorionic gonadotropin/α-fetoprotein or inhibin A13,18 . The Doppler results were concealed from the clinicians in four of the studies16,17,20,23 and were open in seven5,13,14,16,18,19,21 , and there was no documentation

Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

in two22,24 . In four of the studies some of the women received aspirin or heparin13,14,21,24 . In one study women on these medications were excluded22 . There was no documentation regarding the use of these drugs in eight of the studies5,15 – 20,23 . The studies assessed various abnormal uterine artery parameters, which included notching (unilateral/bilateral) (five studies), mean pulsatility index (PI) > 1.45 (three studies), mean PI > 90th centile (two studies), mean PI > 95th percentile (one study), mean resistance index (RI) > 0.7 (one study), mean RI > 0.58 (two studies), mean RI > 95th centile (one study) and systolic to diastolic ratio > 2.6 (two studies). Although different uterine artery parameters were used, the various uterine artery Doppler indices cut-offs are highly correlated. For example, a PI of 1.45

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Uterine artery Doppler and stillbirth

25

QUADAS-2 domain

(a) Reference standard

13

Index test

13

Patient selection

7 0

6

100 20 40 60 80 Proportion of studies with concerns regarding applicability (%)

QUADAS-2 domain

(b) Flow and timing

13

Reference standard

13

Index test

13

The positive likelihood ratio was 2.9 (95% CI, 1.8–4.9), negative likelihood ratio 0.14 (95% CI, 0.1–1.8) and DOR 21.3 (95% CI, 1.2–380). However, the analysis demonstrated high heterogeneity, which, along with the small number of stillbirths, makes it impossible to draw any conclusions about sensitivity of the test (Figure 3b). The prediction ellipse and the confidence ellipse cover the whole ROC space. In the seven second-trimester studies that performed uterine artery Doppler in an unselected population, the prediction ellipse covers almost entirely the range of specificity, being narrower for sensitivity (Figure 3c). Pooled sensitivity is 46% (95% CI, 32–60%) and pooled specificity is 88% (95% CI, 82–93%). The positive likelihood ratio was 3.96 (95% CI, 3.1–5.0), negative likelihood ratio 0.62 (95% CI, 0.50–0.75) and DOR 6.4 (95% CI, 5.2–8.0).

DISCUSSION Patient selection

7

6

0 20 40 60 80 100 Proportion of studies with risk of bias (%)

Figure 2 Quality assessment of studies included in systematic review evaluating association of uterine artery Doppler indices and stillbirth, summarizing applicability concerns (a) and risk of bias (b). , low risk; , high risk.

corresponds to the 95th centile at 21–22 weeks25 , and mean RI of 0.73 and systolic to diastolic ratio of 4.05 at 20 weeks correspond to the 95th centile26 . In general, all the cut-offs used represent Doppler indices at the upper extreme of the reference range.

Performance of second-trimester uterine artery Doppler for predicting stillbirth The sensitivity of uterine artery Doppler in the 13 individual studies ranged from 25% to 100%. The specificity ranged from 33% to 94%. The bivariate pooled estimate for sensitivity was 65% (95% CI, 38–85%) and for specificity was 82% (95% CI, 72–88%). The positive likelihood ratio was 3.5 (95% CI, 2.3–5.5) and the negative likelihood ratio was 0.43 (95% CI, 0.22–0.85). Summary receiver–operating characteristics (ROC) curves and summary point are shown in Figure 3a. The prediction ellipse covers entirely the region of poor diagnostic performance (close to the diagonal of the ROC plane) denoting a high between-study heterogeneity in both accuracy indices, with smaller studies tending to give higher sensitivities but having almost no impact on pooled sensitivity given their small number of stillbirths. An overall summary for the accuracy of the test can be provided by means of the DOR, which is 8.3 (95% CI, 3.0–22.4). Subgroup analysis of the high-risk group (n = 6) showed that the average sensitivity was 90% (95% CI, 36–99%) with a pooled specificity of 69% (95% CI, 54–81%).

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This meta-analysis has shown that abnormal or high-resistance uterine artery Doppler indices in an unselected population increase the likelihood of stillbirth by a factor of three to four. Specificity for prediction of stillbirth was relatively high. Sensitivity varied widely between studies. This high heterogeneity could be caused by several factors, including the background risk of the populations recruited, differences in reported rates of stillbirth, different abnormal uterine artery parameters measured and different chosen positivity thresholds. A strength of this analysis is that we performed a literature search without language restrictions, and the included studies were of good quality, reducing the risk of bias. A limitation is the heterogeneity of the included studies. There was a large amount of variation between studies in the uterine artery Doppler parameters that were measured and their cut-off values. The populations tested also varied between those that were higher risk due to previous obstetric or medical history and those that underwent examinations performed on the general pregnant population. We performed a subgroup analysis in order to control for these as factors inducing heterogeneity. Unfortunately we were unable to include some studies in our analysis due to difficulty obtaining primary data despite contacting the authors. It is also clear that stillbirth has a variety of causes. Reasons such as congenital structural abnormalities and infections are unlikely to have placental failure as an underlying cause, and may therefore be deemed unavoidable. It is not likely that abnormal uterine artery Doppler findings would be associated with these causes. Therefore, the utility of uterine artery Doppler testing would be limited only to those potentially avoidable stillbirths with placental failure as the underlying cause for stillbirth. Previously, a meta-analysis of uterine artery Doppler for the prediction of perinatal death was reported in 200027 . This was based on four studies, and perinatal death rather than stillbirth was reported. It is interesting that the positive and negative likelihood ratios in that

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26

0.8

0.8

0.6

0.6

Sensitivity

(b) 1.0

Sensitivity

(a) 1.0

0.4

0.4

0.2

0.2

0

0 1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

Specificity

Specificity (c) 1.0

Figure 3 Summary receiver–operating characteristics (ROC) curves for performance of second-trimester uterine artery Doppler in predicting stillbirth. Summary ROC curves are presented for all studies included in the review (n = 13) (a), and for a subgroup analysis of studies evaluating performance in high-risk populations (n = 6) (b) and in unselected populations (n = 7) (c). Each individual study is represented by an open circle, the size of which is proportional to the sample size of the study such that larger studies are represented by larger circles. The filled square is the pooled mean estimate for sensitivity and specificity. The solid line represents the summary ROC curve fitted by the bivariate model. The dashed curve around the pooled result represents the 95% confidence ellipse and outer dotted curve represents the 95% prediction region.

Sensitivity

0.8

0.6

0.4

0.2

0 1.0

0.8

0.6

0.4

0.2

0

Specificity

study were 4.0 and 0.6, not too dissimilar to those reported here. The stillbirth rate in the UK is currently 5.1 per 1000. Whilst there has been a downward trend over the past 10 years, the UK still has one of the highest stillbirth rates in the developed world1 . There is an urgent need to reduce this rate, particularly focusing on those deaths occurring near or at term. There is currently no routine screening test for detecting pregnancies at higher risk of stillbirth. Even though the policy of routine induction of labor from 41 weeks’ gestation was specifically introduced by the National Institute of Clinical Excellence (NICE) to prevent stillbirth, it has not yet changed the prevalence of stillbirth at term28 . Other common associations with stillbirth include parity, racial origin, smoking, low educational level and previous adverse pregnancy outcome. These risk factors have modest adjusted odds ratios between

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1.6 and 2.9 for stillbirth with very low sensitivities. Furthermore, the high population prevalence of these risk factors means that their combined prevalence is likely to result in the majority of the population being identified as screen-positive. This limits the value of these risk factors for identification of stillbirth. Correspondingly, the positive likelihood ratios for such factors have been found to be in the 2–5 range, but the negative likelihood ratios were close to 1.0 and none was less than 0.529 . A combination of factors yielded a likelihood ratio of at least 5, but each applied to less than half a percent of the population, limiting sensitivity. Individual risk factors with higher odds ratios such as abruption (adjusted odds ratio of 18.9) have low (1%) population prevalence30 . Identification of a test with modest sensitivity, low false-positive rate and high positive likelihood ratio has the potential to be useful for possible intervention. This review has shown that uterine artery Doppler has these qualities if performed in the second trimester. Uterine artery Doppler assessment is a biologically plausible test given its strong association with impaired placental function (the most prevalent and potentially avoidable cause of stillbirth). Uterine artery Doppler indices are relatively easy to measure and can be performed at the

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Uterine artery Doppler and stillbirth time of the 20-week anomaly scan. It has been estimated that the additional cost would be £18–25 and an extra 5 min of examination time per patient31 . Pregnancies that are screen-positive could then be monitored more closely by means of regular scans to check growth, amniotic fluid volume and umbilical/fetal Doppler. Stillbirths occurring at the limits of viability are not preventable by elective delivery. Those occurring nearer term may well be preventable, since it is possible to deliver electively without increasing the risks of operative delivery32 . Therefore, detection of stillbirths at or near term is arguably more important than is detection of those that occur preterm. Unfortunately, except for the study of Poon et al.21 , insufficient data were provided in the other published individual studies to enable subgroup analysis based on timing of stillbirth. An individual patient data meta-analysis would allow this to be assessed. There is a role for an individual patient data meta-analysis to enable the best discriminator for detecting at-risk pregnancies and defining which Doppler parameter and threshold value should be measured. Subsequent studies should then focus on exploring if abnormal uterine artery Doppler is a predictor of term as well as preterm stillbirth, examining whether intervention in screen-positive women could lead to a reduction in stillbirths, and investigating if it is possible to improve the performance of uterine artery Doppler testing for stillbirth prediction by the addition of maternal serum biomarkers.

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