Title: A Randomised Placebo-Controlled Trial of Antenatal Corticosteroids for Planned Birth in Twins: STOPPIT-3
Funder: Chief Scientist Office, Scotland

Abstract: This study aims to find out if the drug antenatal corticosteroids (ACS) given to women with a twin pregnancy prior to planned birth of twins reduces breathing difficulties in the twin babies._x000D_ _x000D_ Twin pregnancies have a higher risk of complications than singleton pregnancy, carrying a tenfold increase in death compared to singleton pregnancies. The rate of twin pregnancies is increasing, mainly due to the increased use of in vitro fertilisation (IVF) techniques. National guidance recommends that twins who share a placenta (monochorionic twins) should be born from 36 weeks of pregnancy if there are no medical problems requiring earlier birth, whilst twins with two placentae (dichorionic twins) should be born from 37 weeks of pregnancy. This slightly early birth means that twins with planned birth 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, treatments to support breathing and their complications. However, it is not clear if ACS work in twins as their use in twins has not been studied. ACS may also have harmful side effects such as lowering babies’ blood sugars, and affecting babies’ growth. Thus, before all women with twin pregnancy in the UK are offered a course of ACS prior to planned birth we need to be certain about the benefits and the risks of this approach._x000D_ _x000D_ Current practice and use of ACS in twins in the UK varies significantly across the country with nearly all women with twin pregnancy receiving ACS routinely in some maternity units, whilst in other maternity units ACS are not given to women with twins having planned birth due to concerns about the lack of evidence of benefits in this group. The study we propose here will resolve uncertainty about whether ACS given to women with a twin pregnancy reduces breathing complications in twin babies. We will build in mechanisms for follow-up studies, so we can look at the longer-term safety of ACS, as ACS may have effects on childhood brain development. The study will also calculate the costs of the drug for the NHS._x000D_ _x000D_ We will involve 50 UK NHS Centres. We will ask women with a twin pregnancy who have a planned birth after 35 weeks of pregnancy if they will participate in the study. Women who agree to take part in the study will be treated with either ACS or a placebo (dummy drug). These will be administered by injection prior to the planned birth around 36 weeks in monochorionic and 37 weeks in dichorionic twins. We will look at the number of babies who are born (or die) in each group and look at the complications that happen to babies when we compare the two groups. If we find that the use of ACS improves outcomes in twin babies it could be used in the NHS straight away. If it works we hope it will reduce healthcare costs and will perform an economic evaluation for the NHS to confirm this. _x000D_ We need to recruit and randomise 1552 women to ACS or placebo treatment to be able to show a difference in complications in the babies between the groups, if one truly exists._x000D_ _x000D_ The trial team we propose in this application is very experienced in trials in twin pregnancy and have patient advocates who are involved and help us in the design of this trial. The team is also experienced in conducting trials in pregnant women and we are confident we can succeed in carrying out this study in the time and budget requested.

Lay abstract: Research question: Do antenatal corticosteroids (ACS) reduce the need for respiratory support in twins born after scheduled late preterm or early term birth and are they cost effective?_x000D_ _x000D_ Background: Women with twin pregnancy are recommended to have scheduled birth in the late preterm (35-36 weeks gestation) or early term (37 weeks gestation) period to reduce the risk of perinatal mortality. Rates of neonatal unit admission in twins after late preterm/early term birth are disproportionately high (up to 30%), and ACS use has potential to reduce morbidity. However, there is currently little evidence of ACS effectiveness in twins, and ACS are not devoid of harm. Late preterm/early term ACS can neonatal hypoglycaemia and reduce birthweight, and may be associated with detrimental effects on childhood educational attainment._x000D_ _x000D_ Aims and Objectives: Our aim is to determine the clinical and cost effectiveness of ACS prior to planned birth of twins in a multi-centre placebo-controlled trial with internal pilot. Specific objectives are:_x000D_ i) To determine the effect of ACS on neonatal morbidity including the need for respiratory support within 72 hours of birth (primary outcome), and severe respiratory morbidity, NNU admission and Apgar score (secondary outcomes)_x000D_ ii) To determine the effect of ACS on perinatal mortality, newborn hypoglycaemia, birthweight and head circumference, and sepsis (safety outcomes)_x000D_ iii) To determine the effect of ACS on maternal outcomes including infection and breastfeeding_x000D_ iv) To determine the cost-effectiveness of treatment with ACS compared to placebo _x000D_ v) To explore the effects of ACS on childhood cognitive and language development at two years of age compared to placebo, in a subset of twins, using a validated questionnaire (PARCA-R) _x000D_ vi) To establish a platform for future studies of the effects of ACS on childhood neurodevelopmental outcomes compared to placebo using record linkage of maternity data to school census data aged 4-18._x000D_ vii) Within the internal pilot, to confirm our sample size, recruitment and outcome frequency estimates._x000D_ _x000D_ Design and setting: Multicentre, double-blinded, randomised, placebo-controlled trial with an internal pilot phase and economic evaluation in at least 50 UK Obstetric units._x000D_ _x000D_ Target population and sample size: 1552 women with a twin pregnancy and a planned birth between 35 and 38+6 weeks’ gestation recruited from antenatal clinics._x000D_ _x000D_ Health Technology being assessed: Women will be randomised (1:1) to Dexamethasone Phosphate (24mg) given by 2 IM injections 24 hours apart, or placebo, 24-72 hours prior to scheduled birth._x000D_ _x000D_ Outcomes: The primary outcome is respiratory support within 72 hours of birth. A number of secondary and safety outcomes will be included. Cognitive and language development at age two years will be assessed in a subset of participants using the Parent report of Children’s Abilities- Revised [PARCA-R] questionnaire._x000D_ _x000D_ Timelines for delivery: 48 months from February 2021 with 6 months set up, a total of 36 months recruitment over 50 sites and 6 months to final outcomes, analysis and reports. We will include an internal pilot of 10 months (159 patients)._x000D_ _x000D_ Anticipated impact and dissemination: The proposed research will inform national guidance on the use of ACS in twin pregnancies. The results will be communicated to the scientific community via publication and conference presentation, and to the public via links with charity partners and social media.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH