Title: Placental growth factor to Assess and diagnose hypeRtensive pRegnant wOmen: a stepped wedge Trial (PARROT)
Funder: Department of Health and Social Care

Abstract: Background: Hypertensive disorders of pregnancy affect around 15% of pregnant women (&asymp;120,000 women/year in the UK)(WHO 2005). Pre-eclampsia is characterised by hypertension and other features of multi-organ disease and complicates around 5% of all pregnancies. Presentation is varied and overlaps with gestational hypertension making diagnosis difficult which may result in a delay in treatment, or in healthy women being over-investigated. Rationale: One of the key research recommendations of the NICE Hypertension in Pregnancy guidelines (NICE 2010) includes the investigation of biochemical parameters. In 2013, our group published the PELICAN study (Chappell 2013) the first multicentre prospective study evaluating the use of PlGF in women presented with suspected pre-eclampsia prior to 37 weeks gestation, in which we reported high sensitivity (95-96%) and negative predictive value (95-98%) for low PlGF in determining need for delivery for confirmed pre-eclampsia within 14 days. The aim this trial is to evaluate implementation of PlGF as a diagnostic test by evaluating whether PlGF measurement in women presenting with hypertension between 20 and 37 weeks' gestation decreases the time to clinician-recognised pre-eclampsia. This will enable appropriate stratification of antenatal management for women presenting with suspected pre-eclampsia, such that those at highest risk receive greater surveillance with a decrease in maternal and perinatal adverse outcomes, and those at lower risk can be managed without unnecessary admission with considerable cost savings to the NHS. Objectives: 1. to evaluate whether the use of PlGF testing decreases the time to clinician recognised pre-eclampsia. 2. to determine if knowledge of PlGF improves perinatal morbidity, and has an impact on health economics. Methodology: We propose a stepped-wedge designed randomised controlled trial, in which we compare the time it takes from presentation with suspected pre-eclampsia to a confirmed diagnosis with the addition of PlGF testing as compared to conventional practice. We will obtain institutional level consent to adopt PlGF testing at randomly allocated timepoints. Before transition to PlGF testing all women presenting with suspected pre-eclampsia will be managed according to NICE guidelines (NICE 2010) on the management of hypertensive disorders of pregnancy. After transition to PlFG testing at the randomly allocated timepoint, we will use modified consent (Zelen 1979) to consent women additionally to PlGF testing. A blood sample will be taken and a PlGF measurement obtained. Women will be risk stratified as having VERY LOW, LOW or NORMAL PlGF values and antenatal care determined according to the PARROT algorithm incorporated into NICE guidelines with those at high risk of adverse events streamlined for intensive assessment and admission, and those at low risk reassured and returned to routine antenatal surveillance. The impact on time to diagnosis, along with adverse maternal and fetal/neonatal adverse outcomes and health economic impacts recorded. Collaborations: we will collaborate with Action on Pre-eclampsia (patient support group), NIHR PPI group, Mr Paul Seed (medical statistician) and King's College London. The trial will be undertaken in six consultant-led maternity units; Guy s and St Thomas NHS Foundation Trust (Prof A Shennan); Oxford University Hospitals (Dr L Mackillop); Central Manchester University Hospitals (Dr J Myers); Leeds Teaching Hospitals (Dr N Simpson); University Hospitals Bristol (Dr R Bahl); West Middlesex University Hospitals (Dr J Girling). Impact: the project, if successful, has the potential to substantively improve pregnancy care for women presenting with suspected pre-eclampsia, enabling more accurate and timely diagnosis and appropriate risk stratification in order that those at highest risk are intensively monitored and minimising attendance or admission for those at low risk. We anticipate cost savings to the NHS due to the high number and length of hospital admissions.

Lay abstract: Pre-eclampsia is a condition occurring only in pregnancy. It is thought to be caused by the way the placenta implants into the wall of the womb. Mothers with pre-eclampsia can suffer from high blood pressure, problems with their kidneys, liver and blood clotting. The problems with the placenta can mean that the baby s growth is affected; in some cases the baby can be stillborn. All women have their blood pressure and urine monitored during pregnancy. Once diagnosed, the only cure is to deliver the baby. If it occurs before 37 weeks of pregnancy, mothers 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. It is not always possible to identify women at high risk of the severe complications of pre-eclampsia needing early delivery. The PARROT trial aims to look at levels of a protein produced by the placenta called Placenta Growth Factor (PlGF). Women with suspected pre-eclampsia would have a simple blood test for this protein. Studies have shown that women with very low PlGF levels are at greater risk of severe pre-eclampsia and stillbirth. Women with normal PlGF levels are at low risk and can return to normal antenatal care. PARROT aims to tackle the complex nature of Pre-eclampsia. When suspected, it is difficult to predict how severely mother and baby will be affected. By testing for PlGF, care can be concentrated in women with genuine pre-eclampsia. It will help identify those at risk, whilst reducing long hospital stays for those who are not. Reducing hospital admissions has the potential to improve outcomes for patients and save NHS costs.

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