The World Health Organization ACTION-I (Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns) Trial: a multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries

Abstract

Background: Antenatal corticosteroids (ACS) have long been regarded as a cornerstone intervention in mitigating the adverse effects of a preterm birth. However, the safety and efficacy of ACS in hospitals in low-resource countries has not been established in an efficacy trial despite their widespread use. Findings of a large cluster-randomized trial in six low- and middle-income countries showed that efforts to scale up ACS use in low-resource settings can lead to harm. There is equipoise regarding the benefits and harms of ACS use in hospitals in low-resource countries. This randomized controlled trial aims to determine whether ACS are safe and efficacious when given to women at risk of imminent birth in the early preterm period, in hospitals in low-resource countries.

Methods/design: The trial design is a parallel, two-arm, double-blind, individually randomized, placebo-controlled trial of ACS (dexamethasone) for women at risk of imminent preterm birth. The trial will recruit 6018 women in participating hospitals across five low-resource countries (Bangladesh, India, Kenya, Nigeria and Pakistan). The primary objectives are to compare the efficacy of dexamethasone with placebo on survival of the baby and maternal infectious morbidity. The primary outcomes are: 1) neonatal death (to 28 completed days of life); 2) any baby death (any stillbirth postrandomization or neonatal death); and 3) a composite outcome to assess possible maternal bacterial infections. The trial will recruit eligible, consenting pregnant women from 26 weeks 0 days to 33 weeks 6 days gestation with confirmed live fetuses, in whom birth is planned or expected within 48 h. The intervention comprises a regimen of intramuscular dexamethasone sodium phosphate. The comparison is an identical placebo regimen (normal saline). A total of 6018 women will be recruited to detect a reduction of 15% or more in neonatal deaths in a two-sided 5% significance test with 90% power (including 10% loss to follow-up).

Discussion: Findings of this trial will guide clinicians, programme managers and policymakers on the safety and efficacy of ACS in hospitals in low-resource countries. The trial findings will inform updating of the World Health Organization's global recommendations on ACS use.

Trial registration: ACTRN12617000476336 . Registered on 31 March 2017.

Fig. 1

SPIRIT figure for the Antenatal Corticosteroids for Improving Outcomes in preterm Newborns (ACTION)-I trial. ¹ Data will be collected from randomized women from time of randomization to day 28 postpartum. Data will be collected on all newborn babies (single or multiple) from time of birth to day 28 postnatal or death. ² Data will be collected from time of randomization. Some randomized women may be discharged without giving birth; however, data collection continues when they are readmitted later in the pregnancy for birth. ³ Data will be collected for women and newborn babies during admission until discharge. If the length of admission exceeds 28 days, data will be collected to 28 completed days only. ⁴ Women or newborn babies who experience a readmission to hospital during the follow-up period (postdischarge from hospital following birth) will have data collected. ⁵ Day 7 and day 28 follow-up visits will be performed, regardless of location (hospital or community). ⁶ The regimen is described in the study protocol. A full course (four doses) takes a total of 36 h to administer. In the event that a randomized woman does not give birth within 7 days, she may be eligible for a repeat course (four doses). ⁷ Baseline variables are collected after the first dose has been administered. Baseline variables include: age, education, marital status, gravidity, parity, maternal history of preterm birth, weight, height, mid-upper arm circumference, medical conditions (chronic hypertension, diabetes mellitus, HIV/AIDS, tuberculosis, pyelonephritis, anaemia, malaria), obstetric conditions (gestational diabetes, preterm prelabour rupture of membranes, pre-eclampsia or eclampsia, gestational hypertension, oligohydramnios, polyhydramnios, intrauterine growth restriction (known or suspected), macrosomia, abruptio placentae, placenta praevia, other obstetric haemorrhage), gestational, use of tocolysis, symptoms of imminent preterm birth. ⁸ All outcome variables are described in Additional file 2. IM intramuscular

Fig. 2

Study boxes and dispensers