Title: Mechanisms of action of intervention in the PHOENIX trial: in women with preterm pre-eclampsia does planned delivery improve postpartum maternal cardiac function through attenuation of myocardial ischaemia at time of disease (PHOEBE study)?
Funder: Department of Health and Social Care

Abstract: Background: Cardiovascular disease remains the leading cause of mortality in women in the United Kingdom. Pre-eclampsia is a disease of placental aetiology and is characterised by endothelial dysfunction, increased vascular permeability, reduced peripheral blood flow, increased arterial stiffness and hypertension. We and others have shown that women with preterm pre-eclampsia (<37 weeks’ gestation) demonstrate evidence of cardiac dysfunction at the time of pre-eclampsia and that these changes are evident one to two years after pregnancy. We have recently demonstrated that women with pre-eclampsia have higher levels of the cardiac necrosis markers highly sensitive cardiac troponin I and cardiac myosin binding protein C. The underlying mechanism for this long term dysfunction is unclear and is a novel research question. Aims: In women with pre-eclampsia recruited to the PHOENIX study we aim to evaluate the mechanisms of action of disease underlying the association between pre-eclampsia and the development of cardiovascular dysfunction. Hypothesis: That prolongation of pregnancy complicated by pre-eclampsia, with attendant myocardial ischaemia, may increase the risk of the development of cardiovascular dysfunction following pregnancy. Design: Mechanistic study of women recruited to a multi-centre randomised controlled trial. Population: Women with pre-eclampsia between 34+0 and 36+6 weeks’ gestation. Intervention/ exposure: Women will be randomised in the main PHOENIX trial to planned immediate delivery or expectant management (usual care arm) Outcomes: The primary outcome will be a measure of diastolic and systolic dysfunction classified according to the American College of Cardiology as assessed by echocardiography with tissue Doppler studies at 6 months postpartum. Assessment of myocardial ischaemia in the two trial arms will be by measurement of high-sensitivity cardiac troponin I and cardiac myosin-binding protein C to investigate whether these measures of cardiac necrosis provide further mechanistic insight into maternal long term increased cardiovascular risk. Assessments: Echocardiography 6 months postpartum. Blood sampling at recruitment and serially at the time of routine blood collection, (for expectant arm), within 48 hours following delivery and at 6 months postpartum. Sample size: We aim to detect a 25% relative risk (from 70% to 52.5%) in the primary outcome defined as evidence of diastolic and systolic dysfunction in the planned delivery group compared with those managed expectantly. To have a 90% chance of detecting this at the 5% significance level, complete data on 322 women (161 per groups) are needed. We will approach and enrol at least 404 women with the expectation that at least 80% will return for the echocardiogram at six months. Duration of the study: 1st January 2016 for 32 months until 31st August 2018. Statistical analysis: Risk ratios will be estimated for binary outcomes. For continuous measures, log transformations will be used as appropriate, and multiple regression, adjusting for key baseline predictors used to estimate the effect of the treatment. Impact: This study will provide critical insight into the mechanisms of disease between pre-eclampsia and cardiovascular dysfunction.

Lay abstract: Heart disease is the leading cause of death in the UK. Pre-eclampsia causes high blood pressure and protein in the urine in pregnancy. It affects 3-5% of pregnancies. The only cure is delivery of the baby and placenta. This causes many babies to be born early. Babies born early may have long term problems with their health or social development. Women with pre-eclampsia also have long term health problems. They are at risk of high blood pressure and heart problems later in life. We do not understand why this occurs. We want to do a study to answer this important question: why do women with pre-eclampsia have long term heart problems and can we reduce their risk of it happening? We have recently started a clinical trial that is examining the ideal timing for delivery of mothers with pre-eclampsia. This is called the PHOENIX study. In this study one group of women with pre-eclampsia are delivered straight away (called immediate delivery). The other half with pre-eclampsia wait until either the mother or baby becomes unwell (called expectant management), then they are delivered. We want to ask women who are in this trial if we can examine their heart after the pregnancy. This will allow us to tell if having pre-eclampsia for a longer time has a long term effect on their hearts. First of all we will ask these women if they wish to take part in our study. If they agree, we will ask for a blood sample to test for a protein in the blood at the time of pre-eclampsia. We will repeat this test roughly every three days until they deliver, taken at the same time as their routine blood tests for pre-eclampsia. We will take one further sample after delivery. We will ask all these women to come back six months after they have their baby. At this visit we will perform a special ultrasound of their heart, called an echo. The echo will tell us how well their heart is working. We will also take one final blood sample at this time. The samples will be checked for a protein in the blood that measures stress in the heart. These results will be combined with the ultrasound scan findings and may explain the link between pre-eclampsia and heart disease. We think this research is very important. This current trial gives us the ideal chance to examine two similar groups of women who receive two different treatments. This will help us examine the effect of these two treatments (immediate delivery or expectant management) on their hearts six months later. If we can show that having pre-eclampsia for a longer time leads to changes in the heart six months later, it will help us decide how to manage pre-eclampsia. It may also show that we need future research to see what treatments we could give women who have had pre-eclampsia to reduce the risk of them getting heart disease later in life.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH