Title: Prognostic indicators of severe disEAse in women with late preterm pre-eClampsia tO guide deCision-maKing on timing of delivery (PEACOCK study)
Funder: Department of Health and Social Care

Abstract: Aim: To establish a prognostic model to inform optimal timing of delivery in women with late preterm pre-eclampsia (34+0 to 36+6 weeks' gestation), comparing novel candidate biomarkers (e.g. plasma placental growth factor; PlGF) with clinical and routinely collected blood/ urinary parameters to determine clinically indicated need for delivery for pre-eclampsia (or related complications) within seven days of assessment. Design: Prospective observational cohort study Setting: Consultant-led maternity units in England and Wales Target population: Women with late preterm pre-eclampsia eligible for the PHOENIX study Inclusion criteria (as for PHOENIX trial): Pregnant women between 34+0 and 36+6 weeks of gestation with late preterm pre-eclampsia, singleton or DCDA twin pregnancy, viable fetus and 18 years of age or over Exclusion criterion (as for PHOENIX trial): Women for whom a decision has already been made to deliver within the next 48 hours Outcomes: Primary: clinically indicated need for delivery for pre-eclampsia (or related complications) within seven days of assessment, in women from the expectant management arm of the PHOENIX trial. Delivery is most commonly triggered by the development of maternal or fetal complications that are indicators of severe pre-eclampsia. Secondary: clinically indicated need for delivery for pre-eclampsia within 48 hours (using both arms of the PHOENIX trial), and within 14 days of assessment, as well as perinatal death and neonatal unit admission for more than 48 hours. Predictors: PlGF measurement and clinical, blood/ urinary parameters included in the final PREP model (include maternal age, gestational age at diagnosis, medical history, systolic blood pressure, urine protein creatinine ratio, platelet count, serum urea, oxygen saturation, baseline treatment with antihypertensive and administration of magnesium sulphate) evaluated separately and in combination. Sample size: Based on our previous work and other literature, we estimate that the primary outcome occurs in 40% of cases with expectant management. The sample size for estimation of the sensitivity (within 7%) and specificity (within 7%), assuming a sensitivity of 0.90, specificity 0.70, and 95% confidence intervals (2-tailed) requires 120 women with the primary outcome (and 180 without) in the expectant management arm, giving a minimum of 10 events per candidate variable. Data analysis: Receiver Operating Characteristic plots will be used to report the performance of individual parameters on the primary and secondary outcomes. Logistic regression techniques will be used to build prognostic models for the primary and secondary outcomes. Resampling techniques will be used to evaluate the performance of the developed models. Care pathways: There is no current prognostic model in use in UK clinical practice. A novel prognostic model will enable enhanced identification of women and babies who experience complications within seven days of assessment to guide decision-making around timing of delivery. Project timetables: We plan to enrol 600 women into this study between Feb 2016 and Aug 2017 (of 700 women recruited to the PHOENIX trial) and we are currently meeting all PHOENIX recruitment milestones. Expertise: We have a strong multidisciplinary team assembled, nested within the wider PHOENIX trial including clinical, operational, statistical and lay involvement

Lay abstract: Pre-eclampsia is a condition occurring only in pregnancy. It is thought to arise from poor attachment of the placenta to the wall of the womb. A woman with pre-eclampsia can suffer from high blood pressure, problems with her kidneys, liver and blood clotting. The problem with the placenta can mean the baby's growth is affected: in severe cases sometimes the baby can be stillborn. Once diagnosed, the only cure is to deliver the baby. If pre-eclampsia occurs before 37 weeks of pregnancy, a woman may need to be admitted to hospital to have blood pressure treatment and monitoring for complications, whilst planning for safe delivery of the baby. Some women become unwell very quickly and need to have their babies delivered. Others have long stays in hospital for monitoring their condition. It is often not possible to identify women and babies at high risk of the severe complications of pre-eclampsia who would benefit from early delivery. Sometimes the decision whether to deliver is very difficult: women can remain well for long periods of time, but in some cases they can become very unwell - suffering consequences such as fitting, kidney failure, strokes and needing admission to the intensive care unit. Sadly women still die from the complications of pre-eclampsia. If the baby is going to be born prematurely it may suffer consequences of early delivery such as long term disability – but babies who are not delivered can also become very unwell, sometimes dangerously. We therefore need to know when it is best to deliver the baby for both the woman and the baby’s health. We do not know whether it best to always deliver or to deliver only when complications occur in women with pre- eclampsia. In this study, we are planning to investigate 600 women affected by pre-eclampsia to try to improve our assessment of which women will become unwell, and to help detect which babies are struggling the most. If we are able to define better the risks for the woman and baby, it will help doctors and women make decisions about when the baby should be born. We want to use promising new ways of looking at the woman with pre-eclampsia and her baby by measuring substances in the blood. We want to look at markers in the blood, such as placental growth factor and others, which have been shown to be useful for diagnosing pre-eclampsia. We will use information from this blood test, together with the woman’s medical history, blood pressure, and other measures of her kidney/ liver function, to see if we can tell which women are likely to need delivery soon. Patient and Public Involvement Pregnant women have been consulted in all stages of planning this project. The study was planned with the national charity and support group called Action on Pre-eclampsia (APEC). The charity has told us what women want to know about pre-eclampsia, and what research they think is important in this disease. Dissemination Once the project is finished, we will give talks about the findings to other doctors and midwives who work in this field. We will write up the study for publication in a scientific journal which can be read by anyone, whether they are a health care professional or a member of the public. We will work with the charity Action on Pre-eclampsia charity to provide information about the findings of the study in a way that women find easy to read.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH