The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- and middle-income countries

Abstract

Abstract Background: Preterm birth complications are the leading cause of newborn and under-5 mortality. Over 85% of all preterm births occur in the late preterm period i.e., between 34 and <37 weeks of gestation. Antenatal corticosteroids (ACS) prevent mortality and respiratory morbidity when administered to women at high risk of an early preterm birth i.e. < 34 weeks’ gestation. However, the benefits and risks of ACS in the late preterm period are less clear; both guidelines and practices vary between settings. Emerging evidence suggests that the benefits of ACS may be achievable at lower doses than presently used. This trial aims to determine the efficacy and safety of two ACS regimens compared to placebo, when given to women with a high probability of late preterm birth, in hospitals in low-middle income countries (LMICs). Methods: WHO ACTION III trial is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens: dexamethasone phosphate 4x6 mg q12h or betamethasone phosphate 4x2 mg q 12h. The trial is being conducted across seven sites in five countries- Bangladesh, India, Kenya, Nigeria and Pakistan. Eligible women are those with a gestational age between 34 weeks 0 days and 36 weeks 5 days, who have a high probability of preterm birth in next 12 hours to 7 days (up to 36 weeks 6 days gestation). The primary outcome is a composite of stillbirth or neonatal death within 72 hours of birth, or use of newborn respiratory support within 72 hours of birth or prior to discharge from hospital, whichever is earlier. Secondary outcomes include safety and health utilization measures for both women and newborns The sample size is 13,500 women. Discussion: This trial will evaluate the benefits and possible harms of ACS when used in women likely to have a late preterm birth. It will also evaluate a lower-dose ACS regimen based on literature from pharmacokinetic studies. The results of this trial will provide robust critical evidence on the safe and appropriate use of ACS in the late preterm period internationally. Trial registration: ISRCTN11434567. Registered on 7 June 2021; https://doi.org/10.1186/ISRCTN11434567.