Title: Bp response Assessment BY Pregnancy ANtihypertensive Drug treAtment: (Mechanism of Action of Health Intervention): BABY PANDA study
Funder: Medical Research Council

Abstract: What is the aim of the study?_x000D_ The aim of this study is to compare how well blood pressure medicines used to treat high blood pressure in pregnancy work over a short time frame. _x000D_ _x000D_ Why is this study important?_x000D_ Around one in ten women will have high blood pressure in pregnancy. Without treatment, high blood pressure in pregnancy can damage a woman’s heart, kidneys and brain, and cause harm to her baby. We know that controlling high blood pressure in pregnancy with medicines is important to protect the health of the woman and her baby. There haven’t been enough studies to know which is the best blood pressure medicine to use in pregnancy. Previous studies have shown that the medicines commonly used do not work well in all women. _x000D_ _x000D_ We are doing a large study (Giant PANDA study) of the two main blood pressure medicines, called labetalol and nifedipine to find out which one works best to treat high blood pressure, and to check if there are any effects on the baby. Now we also want to see if there are differences in how well how these two medicines control blood pressure over a short time frame (12-24 hours), and to see if this helps us understand how these medicines work throughout pregnancy. We will also look at whether women’s ethnic background and kidney markers in her blood are related to how well blood pressure is controlled by these medicines. This may help us better understand why some blood pressure medicines do not work well in some pregnant women. _x000D_ _x000D_ We also want to see if monitoring blood pressure over 12-24 hours can identify which women will go on to have well-controlled blood pressure throughout their pregnancy. If we can identify which women are unlikely to have good blood pressure control on a particular medicine early, this would allow early switching of their medicine to one that may work better. _x000D_ _x000D_ What does the study involve?_x000D_ We will ask a minimum of 274 women taking part in our larger study to take part in this study. We will provide these women with a monitor that automatically measures their blood pressure and heart rate every 30-60 minutes. They will be asked to wear the blood pressure monitor for 12-24 hours on up to three occasions during their pregnancy, coinciding with scheduled antenatal appointments where possible. Each time women complete this monitoring they will be asked to provide a urine and blood sample. Women will also be provided with a diary to record: the times they take their blood pressure medicine, any side-effects from the medicine, and times they wake up and go to sleep, during these monitoring periods. _x000D_ _x000D_ What do women think of this study? _x000D_ We have involved women with lived experience of high blood pressure in pregnancy, including 1:1 interviews and workshops, and the national support charity Action on Pre-eclampsia (APEC), to design this study. Women have told us that finding out how best to control their blood pressure in pregnancy is an important priority because uncontrolled blood pressure affects what happens to them and their baby during pregnancy and can include being admitted to hospital, and when their baby will be born. _x000D_ _x000D_ How will we share our findings?_x000D_ We will continue to work in partnership with women with experience of high blood pressure in pregnancy throughout this study through focus groups and surveys, and with APEC. This will include creating a plan to share the findings of the study with other researchers, medical professionals, pregnant women and the public.

Lay abstract: Research question_x000D_ In women with pregnancy hypertension, what is the short-term blood pressure (BP) response to antihypertensive agents and how is this related to clinical effectiveness?_x000D_ _x000D_ Aims_x000D_ 1) To determine short-term BP response of nifedipine versus labetalol._x000D_ 2) To explore the association between short-term BP response and long-term BP control (Giant PANDA primary outcome)._x000D_ 3) To assess whether maternal characteristics, disease markers or drug metabolites provide mechanistic insight into differing responses to antihypertensive agents between individuals._x000D_ _x000D_ Background_x000D_ Achieving timely and sustained BP control in pregnancy hypertension reduces the risk of maternal severe hypertension, organ dysfunction and adverse perinatal outcomes. Systematic reviews have revealed the paucity of evidence to inform optimal antihypertensive agent choice in pregnancy. Current NICE Guidelines (2019) recommend labetalol as a ‘safe’ first-line treatment for all pregnancy hypertension, despite varying response rates. The Giant PANDA study (funded by the NIHR HTA programme) will compare the clinical effectiveness of nifedipine versus labetalol for treatment of pregnancy hypertension, recruiting 2300 women. In this Mechanisms of Action study, 24-hour ambulatory BP response data, along with maternal characteristics, plasma markers of renin-angiotensin system activation and urinary drug metabolites (assessing adherence) will provide mechanistic insight into differing responses to nifedipine and labetalol across individuals and the relationship between short-term BP response and clinical effectiveness. _x000D_ _x000D_ Methods_x000D_ Design: Observational study at 10 recruiting sites within Giant PANDA study._x000D_ _x000D_ Inclusion & recruitment criteria: Women enrolled in Giant PANDA study, a minimum of 274 women on labetalol or nifedipine monotherapy. _x000D_ _x000D_ Study procedures: After consent, women will be provided with a pregnancy-validated ambulatory BP monitor to measure up to a 24-hour BP profile (every 30-60 mins) on up to three occasions across pregnancy. Drug ingestion times, sleep and wake times and side-effects will be self-reported. Urine and blood samples will be collected for renin-angiotensin system markers and drug metabolite levels. _x000D_ _x000D_ Outcomes: Short-term BP response, including 8-hour BP post-dose response to labetalol or nifedipine (proportion of systolic BP readings =140mmHg), BP variability and short-term side-effects. _x000D_ _x000D_ Sample size: Assuming 90% power, 5% two-sided alpha, 24% standard deviation in the outcome measure and 10% loss to follow up, a total of 274 women will detect a clinically meaningful absolute difference of 10% in 8-hour BP post-dose response between labetalol and nifedipine monotherapy groups e.g. 20% versus 30%._x000D_ _x000D_ Timelines for delivery_x000D_ Months -1 to 3: Set up and approvals _x000D_ Months 4 to 18: Main recruitment period (7-10 sites, recruitment rate of 1.8-2.6 per site/ month for 15 months, aligned with Giant PANDA recruitment)_x000D_ Months 19 to 24: Follow up_x000D_ Months 25 to 27: Analysis and write up_x000D_ _x000D_ Anticipated impact and dissemination_x000D_ Greater understanding of determinants of clinical response to labetalol and nifedipine may provide mechanistic insight into clinical effectiveness and differing drug responses across individuals, informing treatment optimisation. A dissemination plan will be co-created with our PPIE co-applicant and partners to reach an academic and lay audience including publication in high-impact journals, presentations, lay summarie

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH