Title: Infant hypothalamic-pituitary-adrenal axis responses following antenatal corticosteroids and perinatal outcomes: a mechanism of action of health intervention study
Funder: Medical Research Council

Abstract: What is the study aim?_x000D_ _x000D_ STOPPIT-3 is a clinical trial which aims to understand how the drug antenatal corticosteroids (ACS) given to pregnant women prior to planned birth of twins reduces breathing difficulties in the twin babies._x000D_ _x000D_ In this proposal we aim to understand why some babies still have breathing difficulties despite their mothers receiving ACS. _x000D_ _x000D_ Why is this study important?_x000D_ _x000D_ The use of ACS in babies that are born slightly early (from 36 weeks of pregnancy) is highly controversial. Babies born slightly early are at high risk of admission to neonatal units for support with their breathing, separating mothers and babies at a crucial time. ACS may reduce breathing difficulties, and so may reduce neonatal unit admission and need for treatments to support breathing. However, ACS may also have harmful side effects such as lowering baby’s blood sugar, and affecting baby’s growth and brain development. This controversy is a particular problem in twin pregnancy as national guidance recommends that twins who share a placenta should be born from 36 weeks of pregnancy, whilst twins with two placentae should be born from 37 weeks of pregnancy. _x000D_ _x000D_ Current practice and use of ACS in twins varies significantly across the UK with nearly all women with twin pregnancy receiving ACS routinely in some maternity units, whilst in other units ACS are not given to women with twins having planned birth. The STOPPIT-3 clinical trial will resolve uncertainty about whether ACS given to women with a twin pregnancy reduces breathing complications in twin babies._x000D_ _x000D_ In this proposal we want to understand why ACS work for some babies, but other babies still develop problems. We know that ACS can directly cross the placenta and reach the baby. We propose that ACS damp down the babies own ‘stress response’ systems and that this leads to problems such as breathing difficulties and low blood sugar._x000D_ _x000D_ What does the study involve?_x000D_ _x000D_ We are inviting 543 women who are taking part in the STOPPIT-3 trial and have been treated with either ACS or a placebo (dummy drug) prior to the planned birth of their twins by a caesarean section to take part. At birth we will take blood samples from the mother and the baby’s cord. We will collect some of the fluid that surrounded the baby in the womb and a sample of the placenta. We will use the cord blood samples to measure the levels of the baby’s stress hormone levels. We will also measure the stress hormones and levels of ACS in the other samples to further understand the baby’s stress responses. In a subgroup of babies we will also collect a saliva sample before and after a routine ‘heel prick’ blood test and we will sample a small section of the baby’s hair. These samples will allow us to measure the baby’s ‘stress response’ and overall stress hormone release._x000D_ _x000D_ What do women think about the study?_x000D_ _x000D_ We have worked with two charities who represent twins to design the study. We have also worked with women to decide on which biological samples to collect to cause minimum inconvenience to both the mother and her babies. Women agree that better understanding of the way that ACS work will be helpful for decision making about whether ACS will be of benefit for their baby._x000D_ _x000D_ How we will share our findings?_x000D_ _x000D_ We will work in partnership with women with twin pregnancy throughout this study. We will create a plan to share the findings of the study with other researchers, medical professionals, pregnant women and the public

Lay abstract: RESEARCH QUESTION_x000D_ Does infant hypothalamic-pituitary-adrenal (HPA) axis activity underpin respiratory morbidity and responses to antenatal corticosteroids (ACS) in later preterm and early term infants?_x000D_ _x000D_ BACKGROUND_x000D_ The use of ACS in later preterm (35-36 weeks gestation) and early term (37 weeks gestation) is an area of substantial controversy in obstetrics. There is evidence that ACS reduce serious respiratory morbidity and neonatal unit admission but there is potential for both short (e.g. hypoglycaemia) and long-term harms (e.g. neurodevelopment). Practice is highly variable regarding ACS administration at later preterm and early term gestations._x000D_ _x000D_ STOPPIT-3 is a multicentre placebo-controlled trial to evaluate the effectiveness of ACS (dexamethasone phosphate) prior to planned birth of twins in an NHS setting. The primary outcome is respiratory support within 72 hours of birth. We propose a nested cohort study to explore the mechanisms underlying ACS effects on the infant’s endogenous HPA axis responses, and resultant effects on neonatal outcomes._x000D_ _x000D_ AIM_x000D_ To compare the HPA axis in infants with_x000D_ i) early neonatal morbidity (need for respiratory support; low APGAR score; hypoglycaemia; jaundice), in babies exposed and non-exposed to ACS (after unblinding)_x000D_ ii) developmental delay aged 2 years_x000D_ _x000D_ A secondary aim is to explore sex-specific effects given observational data suggesting that there is sexual dimorphism in responses to ACS and in neonatal outcomes per se._x000D_ _x000D_ METHODS_x000D_ DESIGN Observational study within STOPPIT-3._x000D_ INCLUSION CRITERIA STOPPIT-3 participants undergoing elective caesarean section (exclusion of women with planned vaginal birth will avoid known confounding of mode of delivery on infant HPA responses)._x000D_ PROTOCOL Paired maternal and cord blood samples, amniotic fluid and placenta collected at delivery for measurement of_x000D_ i) endogenous glucocorticoids, dexamethasone and its metabolites (glucocorticoid release and response to ACS)_x000D_ ii) glucocorticoid receptor in cord blood leukocytes (glucocorticoid signalling)_x000D_ iii) placental genes regulating glucocorticoids (glucocorticoid metabolism and transfer)_x000D_ iv) in a subset of infants_x000D_ a. salivary cortisol pre and post heel-prick (glucocorticoid stress response)_x000D_ b. hair cortisol (overall glucocorticoid secretion)_x000D_ _x000D_ OUTCOMES Understanding of glucocorticoid secretion, signalling and responsiveness following ACS through detailed phenotyping of fetal/placental/infant HPA axis._x000D_ _x000D_ SAMPLE SIZE Our data indicate 70% (n=1086) of the sample (n=1552) will have elective caesarean section and be eligible for inclusion. The study is powered assuming samples are collected from ~50% of eligible women._x000D_ _x000D_ TIMELINES FOR DELIVERY_x000D_ Months -6 to 0: Set up_x000D_ Months 1 to 10: Internal pilot of STOPPIT-3, demonstrate sample quality, refine collection procedures_x000D_ Months 11 to 36: Main recruitment_x000D_ Months 27 to 39: Laboratory analyses_x000D_ Months 39 to 42: Complete data analysis, write up and final report._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ Gaining a better understanding of the mechanisms of action of ACS is essential to improve targeted delivery of ACS – ensuring administration to mothers and babies who need ACS, but avoiding harm in those who do not. The results will be communicated to the scientific community via publication and conference presentation alongside the main STOPPIT-3 trial, and to the public via links with charity partners, the University of Edinburgh press office, and social medi

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