Prevention of stillbirth

Key content: • Most of the variability in stillbirth risk is not due to maternal risk factors. Hence, modifying maternal risk factors, or screening women using maternal risk factors to assess risk has limited potential impact. • The only intervention that prevents stillbirth is delivery. The overall risk of perinatal death is lowest at 39 weeks gestational age, and induction of labour at term does not increase a woman's risk of emergency caesarean section. • The most promising approach to screening low risk women for stillbirth risk may be to improve identification of small for gestational age infants. However, there is an absence of high quality evidence around the optimal approach to achieving this goal. Learning objectives • To understand the relationship between maternal risk factors, obstetric complications and fetal size in relation to stillbirth risk. • To understand the approach to fetal assessment and elective delivery as methods to prevent stillbirth. Ethical issues • Screening for stillbirth risk has the potential to do good by preventing deaths. However, if programmes of screening and intervention are developed, many more women may be harmed due to high false positive rates.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1111/tog.12197/abstrac

Variation in caesarean section rates in the US: outliers, damned outliers, and statistics.

Gordon C. Smith discusses the study by Katy Kozhimannil and colleagues that examines variations in cesarean section rates in the US and argues for the need for high-quality routine data collection to better understand the reasons for these variations. Please see later in the article for the Editors' Summary.This is the final version. It was first published by PLoS Medicine at http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001746

The STRIDER trial: one step forward, one step back.

Severe, early onset fetal growth restriction (FGR) is characterised by a fetus presenting at a gestational age at the borderline of viability which is extremely small for gestational age by ultrasonic biometry and exhibits other signs of utero-placental insufficiency, such as abnormal patterns of uterine or umbilical blood flow. Following diagnosis, there is, currently, no disease modifying therapy other than medically indicated delivery, which carries a high risk of neonatal death or, if the infant survives, severe neurodisability in later life. Conversely, expectant management carries a substantial risk of intra-uterine fetal death. Balancing these conflicting risks is a day to day element of practice in Maternal-Fetal Medicine. Practitioners looks to a future of disease modifying therapies other than delivery. Unfortunately, the STRIDER trial suggests that one of the promising candidates, sildenafil citrate, is very unlikely to offer hope in this dismal situation. The study was powered to detect a 7 day prolongation in pregnancy. In reality, the trend was towards a reduction in the duration of pregnancy and the 95% confidence interval indicates that the best one could expect is a 1.3 day prolongation. In reality, it is more likely that the drug hastens delivery rather than postpones it.GCSS reports grants from Scottish Government (Chief Scientist Office Division), Medical Research Council, Stillbirth and Neonatal Death Society, and National Institute of Health Research (UK), grants and personal fees from GlaxoSmithKline Research and Development Limited, and personal fees and non-financial support from Roche Diagnostics International Limited, outside of the submitted work, and has a patent pending (PCT/EP2014/062602)

Screening and prevention of stillbirth.

Stillbirth is delivery of a baby at or after 24 weeks of gestational age (UK definition) not showing any signs of life. It affects almost one in 200 pregnancies and is the single major cause of perinatal death. Stillbirth is associated with a wide range of maternal demographic characteristics, but most of the variations in stillbirth risk are independent of these characteristics. Stillbirth is the end point of multiple processes, but the single most common cause is probably placental dysfunction. Stillbirth is associated with a wide range of biochemical and ultrasonic predictors, but there is limited evidence to support population-based screening. However, the evidence based is weak due to the use of poorly characterised screening tests, the failure to couple risk assessment with a clearly effective intervention for those who screen positive and inadequate study sample sizes. Basic research needs to identify better predictors, and clinical trials need to adopt more rigorous methodologies.This is the author accepted manuscript. The final version is available from Elsevier via https://doi.org/10.1016/j.bpobgyn.2016.08.00

Quantifying the Risk of Different Types of Perinatal Death in Relation to Gestational Age: Researchers at Risk of Causing Confusion.

This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/ppe.1225

AGAINST: The increased PNMR over weekends is proof that we require a 7 day maternity service

Palmer et al. (BMJ 2015;351:h5774) demonstrated that perinatal mortality was 5–10% higher at weekends than weekdays and this was widely reported by UK news media. About two‐thirds of perinatal deaths are stillbirths and about 90% of stillbirths follow prelabour death of the baby (Smith and Fretts Lancet 2007;370:1715–25). Hence, most babies stillborn on a Saturday will have died on a weekday. Hence, it is difficult to draw firm conclusions about the quality of out of hours care using analyses of all‐cause perinatal mortality. However, a previous study using nationally collected Scottish data from 1985 to 2004, focused on neonatal deaths attributed to intrapartum anoxia and actually showed stronger associations, with a ~50% increase in the risk of this type of neonatal death at the weekend (Pasupathy et al. BMJ 2010;341:c3498). Does this prove that we require a 7‐day maternity service

Birth weight percentile and the risk of term perinatal death.

OBJECTIVE: To estimate the association between birth weight percentile and the risk of perinatal death at term in relation to the cause of death. METHODS: We performed a retrospective cohort study of all term singleton births in delivery units in Scotland between 1992 and 2008 (n=784,576), excluding perinatal deaths ascribed to congenital anomaly. RESULTS: There were 1,700 perinatal deaths in the cohort, which were not the result of congenital anomaly (21.7/10,000 women at term). We observed a reversed J-shaped association between birth weight percentile and the risk of antepartum stillbirth in all women, but the associations significantly differed (P<.001) according to smoking status. The highest risk (adjusted odds ratio referent to 21st-80th percentile, 95% confidence interval) among nonsmokers was for birth weight third or less percentile (10.5, 8.2-13.3), but there were also positive associations for birth weight percentiles 4th-10th (3.8, 3.0-4.8), 11th-20th (1.9, 1.5-2.4), and 98th-100th (1.8, 1.3-2.4). Among smokers, the associations with being small were weaker and the associations with being large were stronger. We also observed a reversed J-shaped association between birth weight percentile and the risk of delivery-related perinatal death (ie, intrapartum stillbirth or neonatal death), but there was no interaction with smoking. The highest risk was for birth weight greater than the 97th percentile (2.3, 1.6-3.3), but there were also associations with third or less percentile (2.1, 1.4-3.1), 4th-10th (1.8, 1.4-2.4), and 11th-20th (1.5, 1.2-2.0). Analysis of the attributable fraction indicated that approximately one in three antepartum stillbirths and one in six delivery-related deaths at term could be related to birth weight percentile outside the range 21st-97th percentile. CONCLUSION: Effective detection of variation in fetal size at term has potential as a screening test for the risk of perinatal death. LEVEL OF EVIDENCE: II.Supported by the NIHR Cambridge Comprehensive Biomedical Research Centre.This version is the author accepted manuscript. This article can also be viewed in advanced access form on the publisher's website at: http://journals.lww.com/greenjournal/pages/articleviewer.aspx?year=9000&issue=00000&article=99411&type=abstract © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins

Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study.

BACKGROUND: Fetal growth restriction is a major determinant of adverse perinatal outcome. Screening procedures for fetal growth restriction need to identify small babies and then differentiate between those that are healthy and those that are pathologically small. We sought to determine the diagnostic effectiveness of universal ultrasonic fetal biometry in the third trimester as a screening test for small-for-gestational-age (SGA) infants, and whether the risk of morbidity associated with being small differed in the presence or absence of ultrasonic markers of fetal growth restriction. METHODS: The Pregnancy Outcome Prediction (POP) study was a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan. Women participating had clinically indicated ultrasonography in the third trimester as per routine clinical care and these results were reported as usual (selective ultrasonography). Additionally, all participants had research ultrasonography, including fetal biometry at 28 and 36 weeks' gestational age. These results were not made available to participants or treating clinicians (universal ultrasonography). We regarded SGA as a birthweight of less than the 10th percentile for gestational age and screen positive for SGA an ultrasonographic estimated fetal weight of less than the 10th percentile for gestational age. Markers of fetal growth restriction included biometric ratios, utero-placental Doppler, and fetal growth velocity. We assessed outcomes for consenting participants who attended research scans and had a livebirth at the Rosie Hospital (Cambridge, UK) after the 28 weeks' research scan. FINDINGS: Between Jan 14, 2008, and July 31, 2012, 4512 women provided written informed consent of whom 3977 (88%) were eligible for analysis. Sensitivity for detection of SGA infants was 20% (95% CI 15-24; 69 of 352 fetuses) for selective ultrasonography and 57% (51-62; 199 of 352 fetuses) for universal ultrasonography (relative sensitivity 2·9, 95% CI 2·4-3·5, p<0·0001). Of the 3977 fetuses, 562 (14·1%) were identified by universal ultrasonography with an estimated fetal weight of less than the 10th percentile and were at an increased risk of neonatal morbidity (relative risk [RR] 1·60, 95% CI 1·22-2·09, p=0·0012). However, estimated fetal weight of less than the 10th percentile was only associated with the risk of neonatal morbidity (pinteraction=0·005) if the fetal abdominal circumference growth velocity was in the lowest decile (RR 3·9, 95% CI 1·9-8·1, p=0·0001). 172 (4%) of 3977 pregnancies had both an estimated fetal weight of less than the 10th percentile and abdominal circumference growth velocity in the lowest decile, and had a relative risk of delivering an SGA infant with neonatal morbidity of 17·6 (9·2-34·0, p<0·0001). INTERPRETATION: Screening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of SGA infants. Combined analysis of fetal biometry and fetal growth velocity identified a subset of SGA fetuses that were at increased risk of neonatal morbidity. FUNDING: National Institute for Health Research, Medical Research Council, Sands, and GE Healthcare.This work was supported by the National Institute for Health Research (NIHR) Cambridge Comprehensive Biomedical Research Centre and the Stillbirth and Neonatal Death Society. DP was supported by a Medical Research Council (MRC) Clinical Training Fellowship. IRW is supported by a MRC Unit Programme (number U105260558). GE Healthcare (Fairfield, CT, USA) donated two Voluson i ultrasound systems for this study. This study was also supported by the NIHR Cambridge Clinical Research Facility, where all visits at about 20, 28, and 36 weeks took place. No direct or indirectly supporting bodies for the project were involved in any aspect of preparation of this paper for publication. We thank the Perinatal Institute for providing a bulk calculator for customised percentiles of estimated fetal weight. We thank all the women who participated in the study, and all the staff in the Rosie Hospital (Cambridge, UK) and NIHR Cambridge Clinical Research Facility who provided direct or indirect assistance for the study.This is the final published version of the article. It was originally published in The Lancet (Sovio U, White IR, Dacey A, Pasupathy D, Smith GCS, The Lancet, 2015, doi:10.1016/S0140-6736(15)00131-2). The final version is available at http://dx.doi.org/10.1016/S0140-6736(15)00131-2

The Effect of an Oxytocin Receptor Antagonist (Retosiban, GSK221149A) on the Response of Human Myometrial Explants to Prolonged Mechanical Stretch.

Multiple pregnancy is a major cause of spontaneous preterm birth, which is related to uterine overdistention. The objective of this study was to determine whether an oxytocin receptor antagonist, retosiban (GSK221149A), inhibited the procontractile effect of stretch on human myometrium. Myometrial biopsies were obtained at term planned cesarean delivery (n = 12). Each biopsy specimen was dissected into 8 strips that were exposed in pairs to low or high stretch (0.6 or 2.4 g) in the presence of retosiban (1 μM) or vehicle (dimethylsulfoxide) for 24 hours. Subsequently, we analyzed the contractile responses to KCl and oxytocin in the absence of retosiban. We found that incubation under high stretch in vehicle alone increased the response of myometrial explants to both KCl (P = .007) and oxytocin (P = .01). However, there was no statistically significant effect of stretch when explants were incubated with retosiban (P = .3 and .2, respectively). Incubation with retosiban in low stretch had no statistically significant effect on the response to either KCl or oxytocin (P = .8 and >.9, respectively). Incubation with retosiban in high stretch resulted in a statistically significant reduction (median fold change, interquartile range, P) in the response to both KCl (0.74, 0.60-1.03, P = .046) and oxytocin (0.71, 0.53-0.91, P = .008). The greater the effect of stretch on explants from a given patient, the greater was the inhibitory effect of retosiban (r = -0.65, P = .02 for KCl and r= -0.73, P = .007 for oxytocin). These results suggest that retosiban prevented stretch-induced stimulation of human myometrial contractility. Retosiban treatment is a potential approach for preventing preterm birth in multiple pregnancy.This is the author accepted manuscript. The final version is available from the Endocrine Society via http://dx.doi.org/10.1210/en.2015-137