The WHO ACTION-I (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns) Trial: A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries to improve newborn outcomes

1.     Executive Summary

1.1. Background

An estimated 14·9 million neonates were born preterm in 2010, accounting for 11·1% of live births worldwide. Complications of preterm birth (PTB) are the leading cause of under-5 mortality, and preterm neonates are at increased risk of numerous short- and long-term respiratory, infectious and neurological morbidities.

Antenatal corticosteroids (ACS) have long been regarded as a cornerstone intervention in mitigating the adverse effects of preterm birth. However, there are several important limitations that restrict generalizability of current evidence to ACS use in low- and middle-income countries (LMICs). Furthermore, serious concerns regarding whether ACS are safe and/or effective in low-resource settings have been raised by the recent Antenatal Corticosteroids Trial (ACT).

ACT was a community-based, cluster-randomized trial conducted in six low- and middle-income countries that aimed to evaluate the feasibility, effectiveness and safety of a multi-faceted intervention to increase the use of ACS at all levels of healthcare. The trial found that among the less-than-5th-percentile newborns (a proxy for preterm newborns), ACS use was not associated with a change in neonatal deaths before 28 days in the intervention group. Among all births, the risk of perinatal deaths in the intervention arm increased, driven by significant increases in both neonatal mortality by 28 days and stillbirth independently. The increased mortality appeared to be driven by increased mortality in infants above the 25th percentile for birthweight. Furthermore, the intervention was associated with an increased odds ratio of suspected maternal infection in women with births with less-than-5th-percentile, and all women.

WHO considered the available evidence on potential benefits of ACS largely derived from higher-level hospitals in high-resource countries and the possible harms of expanding ACS coverage in resource-limited countries to guide its 2015 recommendations on ACS. It recommends that ACS be used for women at risk of preterm birth from 24 weeks to 34 weeks gestation, in health facilities where a sufficient standard of maternal and newborn care is available, where the woman has no clinical evidence of infection, where the preterm birth is considered imminent, and where gestational age assessment can be accurately undertaken. The WHO recommendations acknowledge the limitations in the current evidence base regarding a lack of evidence on ACS efficacy from hospitals in low-resource countries, and the uncertainties around the preconditions that are critical to avoiding harms from ACS use in such settings.

The WHO guideline panel recognized that the safety and efficacy of ACS even in hospitals that can reasonably meet the ACS treatment preconditions in low-resource countries have not been established and therefore considered an efficacy trial of ACS in these settings an urgent research priority. The existence of a clinical equipoise regarding this research gap was further discussed and confirmed by a subsequent WHO technical consultation of obstetricians, neonatologists and researchers in preterm birth, who reviewed the available evidence and advised WHO to conduct an ACS efficacy trial.

1.2. Aims and Objectives

The aim of this trial is to determine whether antenatal corticosteroids are safe and efficacious for women and newborns, when given to pregnant women with a live fetus/es at risk of imminent preterm birth from 26 weeks 0 days to 33 weeks 6 days gestation in hospitals in low-resource countries, for the prevention of neonatal deaths. Specifically, the trial aims to assess ACS safety and efficacy in hospitals where the WHO proposed ACS treatment criteria can reasonably be met in participating countries.

Primary objectives:

1.      To compare the effect of dexamethasone to placebo on stillbirth and neonatal survival when given to pregnant women at risk of imminent preterm birth in  hospitals in low resource countries.

2.      To compare the effect of dexamethasone to placebo on possible maternal bacterial infections when given to pregnant women at risk of imminent preterm birth in  hospitals in low resource countries.

Secondary objectives:

1.      To compare the effect of dexamethasone to placebo on neonatal morbidity outcomes, when given to pregnant women at risk of imminent preterm birth in hospitals in low resource countries.

2.      To compare the effect of dexamethasone to placebo on maternal mortality and morbidity outcomes, when given to pregnant women at risk of imminent preterm birth in hospitals in low resource countries.

3.      To compare the effect of dexamethasone to placebo on maternal and newborn health care interventions and health service utilisation outcomes, when given to pregnant women at risk of imminent preterm birth in hospitals in low resource countries.

1.3. Methods

The trial design is a parallel, two-arm, double-blind, randomized, placebo-controlled trial of antenatal corticosteroids for women at risk of imminent preterm birth. Individual randomization will be used. The trial will be multi-country and multi-centre. The study sites are hospitals in Bangladesh, India, Kenya, Nigeria and Pakistan, where the WHO ACS treatment criteria can reasonably be met.  Trial activities will be facility-based, with community follow up of recruited women and newborns to 28 completed days.

Population: The population of interest is a) 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 hours, and b) their fetuses and newborns, who present at imminent risk of preterm birth (spontaneous or provider-initiated) to participating hospitals.

Intervention: The intervention regimen is based on the WHO recommendation for ACS use. That is:

·         A single course of IM dexamethasone for women in whom birth is planned or expected within 48 hours. The regimen will be 6mg IM dexamethasone administered every 12 hours, to a total of four (4) doses (or until delivery occurs, whichever comes first). If the full regimen is completed, the woman will have received a total of 24 mg.

·         If a woman has not delivered within 7 completed days after the initial dose, is still eligible (i.e. GA < 34 weeks) and a subsequent clinical assessment demonstrates that there is a high risk of preterm birth in the next 48 hours, a second course (repeat treatment pack) of IM dexamethasone (according to the same dosing regimen described above) should be administered. Hence, the use of a repeat course in eligible women shall be the same as the initial allocation (i.e. women initially randomized to dexamethasone will only receive dexamethasone as repeat course).

Comparison: Identical placebo, using same regimen as for intervention.

Primary Outcomes:

·         Neonatal death: death of a live birth within 28 completed days of life.

·         Stillbirth or neonatal death: Any death of a fetus (post enrollment), or death of a live birth within 28 completed days of life among all enrolled participants.

·         Possible maternal bacterial infection: Occurrence of maternal fever, or clinically suspected or confirmed infection, for which therapeutic antibiotics were used.

Secondary outcomes include a number of maternal and newborn adverse outcomes and health service outcomes.

Sample size: Based on a superiority hypothesis, a total of 5,416 women are needed to detect a reduction of 15% or more in neonatal deaths, from 25.0% deaths to 21.3%, among neonates of women who received ACS at <34 weeks, in a two-sided 5% significance test with 90% power. With 10% loss to follow-up, a total sample size of 6,018 women will be recruited.

For the possible maternal bacterial infection outcome, a non-inferiority hypothesis was used. A total sample size of 5,024 women are needed (including 10% loss to follow up) to demonstrate non-inferiority within that margin of 2.5% for the increase in the maternal infection outcome, assuming equal prevalence of 10% in the two arms, with a power of 80% and a significance level of 2.5%.

Study sites: 28 facilities in six sites from five countries (Bangladesh, India, Kenya, Nigeria-Ibadan, Nigeria-Ile Ife, and Pakistan) will participate in the trial.