Title: Preventing adverse pregnancy outcome in women at increased risk of stillbirth by detecting placental dysfunction
Funder: Department of Health and Social Care

Abstract: In the UK, 1 in 200 pregnancies after 24 weeks gestation end in stillbirth; this rate has not decreased significantly for 20 years and the UK ranks 33rd out of 35 high-income countries (HICs). Importantly, one third of stillbirths occur after 36 weeks gestation in babies with no structural abnormality when appropriate delivery would prevent stillbirth, with minimal associated neonatal morbidity. The most common abnormality seen in late stillbirth in HICs is placental insufficiency. This may be manifest clinically as fetal growth restriction or a small for gestational age infant. However, identification of placental insufficiency is complex and current methods used in clinical practice have not reduced perinatal mortality. Several recent studies have demonstrated that measurement of placental markers including: human placental lactogen, placental protein 13 and placental growth factor may effectively identify placental dysfunction and thus identify fetuses which are at increased risk of complications. The central hypothesis of this research programme is that a combination of measurement of placental factors in maternal biofluid(s) with current ultrasound assessment of fetal size will better identify placental insufficiency in women at increased risk of stillbirth and when combined with appropriate intervention, this strategy would reduce the incidence of stillbirth. However, large studies are needed to assess stillbirth as a primary outcome; depending on the methodology employed between 11,000 and 250,000 participants would be required. Thus, robust evidence is required that any such study is feasible, economically viable and likely to show a reduction in stillbirth. To generate high-quality evidence to inform a study of placental markers two systematic reviews will be carried out, i) to determine whether measurement of placental markers improves pregnancy outcome and ii) to determine the accuracy of placental markers in prediction of stillbirth and adverse pregnancy outcome. The clinical accuracy and analytical performance of these markers will be confirmed in a cohort of 660 women with reduced fetal movements in late pregnancy. Women with reduced fetal movements are at significantly increased risk of adverse pregnancy outcomes related to placental insufficiency, including stillbirth. The reviews and experimental data will inform a multi-centre pilot randomised controlled trial of 750 women to determine whether intervention based upon the measurement of placental factors reduces poor pregnancy outcomes related to placental insufficiency in women presenting with reduced fetal movements. In addition to clinical outcomes, data will be collected to allow economic analysis and modelling and to describe participants' and clinicians' views of the study. This strategy will to provide useful data regarding the efficacy of measuring placental factors. It will also address the need for evidence to inform the management of reduced fetal movements, a common reason to attend maternity services. This pilot study will inform a definitive trial to determine whether this approach will reduce stillbirth. Critically, if there is a reduction in adverse pregnancy outcomes related to placental insufficiency in this pilot study, this strategy could potentially reduce stillbirth resulting from placental insufficiency. This study will also provide data regarding the cost and acceptability of an intervention which are essential components in determining the feasibility of a definitive trial. Currently, the stillbirth rate in women presenting with reduced fetal movements is approximately (1.5%). It is estimated that 6% of pregnant women attend with reduced fetal movements in late pregnancy, totalling approximately 45,000 women in the UK, of which 675 would go on to have a stillbirth. Identification of placental insufficiency leading to fetal compromise in this group could reduce this figure by 50%, preventing 340 stillbirths annually; this would represent an 8% reduction in stillbirths - the first significant reduction in the UK stillbirth rate for over two decades.

Lay abstract: Combining a test which reliably identifies babies at risk of stillbirth with delivery of the baby could reduce the number of stillbirths. This research will analyse results from all studies that measure how well the placenta (afterbirth) works to see which of these tests best identifies infants at risk of stillbirth. To investigate whether using placental tests to determine delivery is effective, the outcome of pregnancy in women who had an additional placental test will be compared with those who did not. This will determine whether a trial of placental tests to reduce stillbirth would be possible and desirable.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH