Title: Pre-eclampsia in Hospital: Early Induction or Expectant management (PHOENIX)
Funder: Department of Health and Social Care

Abstract: Women with pre-eclampsia are at risk of morbidity or in severe cases, maternal or fetal death. Delivery after 37 weeks' gestation is routinely indicated, and does not significantly increase operative morbidity in the mother. In contrast, the risk/ benefit of delivery between 34+0 and 36+6 weeks gestation is not clear, as reduced risks to the mother and infant associated with pregnancy cessation, and therefore disease progression, must be balanced against risks of immaturity due to premature birth. In the UK, approximately 10,000 women per year will present with mild to moderate disease during this gestational 'window'; equivalent to approximately 33% of all women who develop pre-eclampsia. Our team, which has extensive experience in the design and implementation of multi-centre clinical trials and pre-eclampsia research, will conduct a randomised controlled trial to determine whether delivery or expectant management leads to better outcomes in both mother and baby (including at two year follow up) in pregnancies affected by pre-eclampsia between 34 and 37 weeks' gestation. Women with confirmed pre-eclampsia between 34+0 and 36+6 weeks' gestation will be randomised to delivery (commencement within 48 hours) or to expectant management. We have selected a composite maternal morbidity outcome measure that clinicians recognise as important, and with sufficient prevalence to allow the trial to be delivered in a feasible timeframe, while aiming to detect a meaningful and plausible relative risk reduction. It would not be feasible to power the study on rare permanent morbidity to the mother. The primary outcome measure will be a composite of maternal morbidity adapted from the fullPIERS model for prediction of pre-eclampsia adverse events (von Dadelszen et al, Lancet 2011) which will include central nervous system, cardiorespiratory, haematological, hepatic and renal outcomes together with placental abruption, intensive care unit admission as well as confirmed severe systolic hypertension (>=160mmHg). All these outcomes are included in the recently completed Dutch HYPITAT II trial and will allow prospective meta-analysis (we have collaborated with the CI Professor Ben Mol to ensure this). Taking into account a 5% loss to follow-up and a two-sided significance level of 5%, 900 women will be required to determine at 90% power a 25% relative risk reduction from 43% in the expectant management group to 32.25% in the planned delivery group. For the neonatal outcome, these numbers will give sufficient power (93%) to demonstrate a non-inferiority difference between the group proportions of no less than 10% based on the neonatal admission rate of 24% in the expectant group. The long term outcome at two years will use the revised Parent Report of Children's Abilities (PARCA-R), and 345 women in each arm (assuming a 20% loss to follow up) will achieve 94% power to detect a non-inferiority difference in mean of no less than 4 points. Other outcome measures will include complications of planned delivery, including sepsis, thromoembolism and operative vaginal delivery. Health service use outcomes will include antenatal and postnatal inpatient days, as well as maternal and fetal intensive care unit admissions. Patient reported outcome measures that have been developed in our unit will be used. Health economic outcome data will be collected until the infants are two years old, and include tests and procedures on both mother and infants. If clinically important differences between randomised groups are observed at two years, further funding will be sought to examine longer term effects on intelligence quotient at 5 years and other neuropsychological outcomes.

Lay abstract: Background: Pre-eclampsia affects approximately one in twenty-five pregnancies and is diagnosed by doctors when the mother develops high blood pressure and protein in her urine. The complications of this disorder are potentially very serious. Pre-eclampsia, particularly when it occurs early on in pregnancy, can result in severe problems for the mother such as fits, bleeding, and may even result in her death. The baby can be affected by a poorly functioning placenta, which leads to reduced blood flow, inadequate nutrition and poor oxygen supply which can result in reduced growth so that the infant may be born with a low birthweight and may even die. Timely delivery of the baby will prevent many of these complications, but can also increase the risk of short and longer term problems for the baby related to premature birth and immaturity. In women who develop raised blood pressure or mild pre-eclampsia at the end of pregnancy, bringing on labour has been shown to reduce the risk of problems to the mother and also lower the caesarean section rate, without any detriment to the baby. Pre-eclampsia which occurs before 37 weeks of pregnancy is known to be more complicated, but the risk/benefit of routinely delivering the baby between the 34th and 37th week of pregnancy is less clear. Delivery may prevent complications in the mother but might increase risks to the baby compared with delivery at term. Methods/Design: Pregnant women with pre-eclampsia who come into hospital between the 34th and 37th week of pregnancy but do not require immediate delivery will be allocated by a computer (i.e. by chance, like tossing a coin) to delivery (by bringing on labour within 48 hours or by caesarean section if necessary) or to what doctors call 'expectant management'. 'Expectant management' simply means 'wait and watch' i.e. these pregnant women will be observed closely and only be delivered if complications arise. If the mother or baby's condition deteriorates, or if the 37th week of pregnancy is reached then delivery will also be initiated in the women allocated to the group who are not immediately delivered. We shall determine if there are fewer complications in the mother if we adopt the policy of immediate delivery. The study will also find out if this strategy leads to fewer babies being admitted to hospital, less frequent admission to a baby intensive care unit and if there are fewer deaths in this group when compared to those babies born to women in the 'wait and watch' group. At 2 years old, the babies will be assessed for normal brain development using a questionnaire which the mother will help us fill in regarding their behaviour. We will also find out about parents' experiences, breathing difficulties in the baby, the way in which the baby was delivered (e.g. normal vaginal delivery, forceps, caesarean section), and the cost to the NHS of looking after the mother and baby, all of which may may be affected by the strategy adopted.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH