Abstract
BackgroundAntenatal corticosteroids are commonly used to reduce neonatal mortality, but most research to date has been in high-resource settings and few studies have evaluated its impact on stillbirth. In the Antenatal Corticosteroids Trial (ACT), a multi-country trial to assess impact of a multi-faceted intervention including antenatal corticosteroids to reduce neonatal mortality associated with preterm birth, we found an overall increase in 28-day neonatal mortality and stillbirth associated with the intervention.MethodsThe ACT was a cluster-randomized trial conducted in 102 clusters across 7 research sites in 6 countries (India [2 sites], Pakistan, Zambia, Kenya, Guatemala and Argentina), comparing an intervention to train birth attendants at all levels of the health system to identify women at risk of preterm birth, administer corticosteroids and refer women at risk. Because of inadequate gestational age dating, the <5th percentile birth weight was used as a proxy for preterm birth. A pre-specified secondary outcome of the trial was stillbirth.ResultsAfter adjusting for the pre-trial imbalance in stillbirth rates, the ACT intervention was associated with a non-significant increased risk of stillbirth (aRR 1.08, 95 % CI, 0.99–1.17, p–0.073). Additionally, the stillbirth rate was higher in the term births (1.20 95 % CI 1.06–1.37, 0.004) and among those with signs of maceration (RR 1.18 (1.04–1.35), p = 0.013) in the intervention vs. control clusters. Differences in obstetric care favored the control clusters and maternal infection was likely more common in the intervention clusters.ConclusionsIn this pragmatic trial, limited data were available to identify the causes of the increase in stillbirths in the intervention clusters. A higher rate of stillbirth in the intervention clusters prior to the trial, differences in obstetric care and an increase in maternal infection are potential explanations for the observed increase in stillbirths in the intervention clusters during the trial.Trial registrationclinicaltrials.gov (NCT01084096)
Highlights
Antenatal corticosteroids are commonly used to reduce neonatal mortality, but most research to date has been in high-resource settings and few studies have evaluated its impact on stillbirth
We explored potential reasons for the higher stillbirth rate in the intervention clusters compared to the control clusters in the Antenatal Corticosteroids Trial (ACT) trial
There was no consistent increase in stillbirths in the intervention clusters in the lighter more preterm infants and there may have been a small reduction in stillbirths in some birth weight and gestational age groups
Summary
Antenatal corticosteroids are commonly used to reduce neonatal mortality, but most research to date has been in high-resource settings and few studies have evaluated its impact on stillbirth. The Antenatal Corticosteroid Trial (ACT) was a cluster randomized trial performed in 7 sites in 6 low and middle income countries (LMIC) [1, 2]. ACT was a “pragmatic” trial and not designed to evaluate mechanisms leading to specific pregnancy outcomes, especially those such as stillbirth that were not a primary endpoint. We emphasize that compared to prior trials demonstrating efficacy of ACS which were all individually randomized and conducted in in high and some middle income country hospitals with good obstetric and neonatal care, this cluster randomized trial enrolled more than 100,000 subjects in countries where half the women delivered at home or in low-level community clinics [3, 4]
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