Antenatal Dexamethasone: Why NEJM Published a New Trial of a Drug with Longstanding Evidence of Benefit

For decades, antenatal dexamethasone has been the gold standard in pregnant women at risk for preterm birth in the United States. In 1972, the first trial of the efficacy of antenatal glucocorticoids in at-risk mothers reported a reduction in respiratory distress syndrome and neonatal mortality. However, the use of antenatal glucocorticoids did not become established practice until the 1990s because of concerns about adverse effects. A 1990 meta-analysis of 12 trials conducted in high-resource countries changed practice by demonstrating that antenatal corticosteroids decreased neonatal mortality. Based on these data, a 1994 National Institute of Health Consensus Statement recommended antenatal glucocorticoids in women at risk of preterm birth (<34 weeks of gestation).

In 2015, the Antenatal Corticosteroids Trial (ACT) sought to expand the use of antenatal glucocorticoids in six low-to-middle income countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) using a multifaceted intervention that included training on identifying at-risk mothers and administering glucocorticoids. In this community-based, cluster-randomized trial, the intervention increased the number of at-risk mothers who received antenatal glucocorticoids. However, the intervention did not reduce neonatal mortality and showed evidence of harm due to increased rates of neonatal mortality and maternal infections. Based on these data, the World Health Organization (WHO) recommended further research before corticosteroids were used in low-resource settings. 

Now, in a new study published in NEJM, the WHO ACTION Trials Collaborators demonstrated the efficacy of antenatal corticosteroids in low-resource populations (Bangladesh, India, Kenya, Nigeria, and Pakistan) similar to those included in ACT. In this randomized trial, women between 26 and 33 weeks and 6 days of gestation who were at risk for preterm birth received intramuscular dexamethasone or placebo. Test sites also were supplied with CPAP machines, pulse oximeters, glucometers, and ultrasound machines. The results indicated that neonatal mortality was significantly lower in the dexamethasone group, compared with the placebo group (19.6% vs. 23.5%). Neither maternal nor neonatal infection rates differed between the two groups.

This history of glucocorticoid use in obstetrics raises important research questions: What factors are at play when findings vary in different settings? Is the intervention itself harmful or are other factors such as lack of support structures responsible for the different results? Also, should one study (e.g., ACT) overturn decades of evidence? 

The following NEJM Journal Watch summary provides more details of the study:

Robert L. Barbieri, MD reviewing Oladapo OT et al. N Engl J Med 2020 Oct 23

The benefits of dexamethasone or betamethasone administration in pregnant women at risk for preterm birth are well known in high-resource countries — but what about in low-resource countries? Researchers randomized 2852 pregnant women at risk for preterm birth in Bangladesh, India, Kenya, Nigeria, and Pakistan to dexamethasone (6 mg intramuscularly every 12 hours for at most 4 doses) or placebo injections. A repeat course could be given if the woman had not delivered within 7 days. Mean gestational age at trial entry was approximately 31 weeks. About 70% of participants delivered within 1 week of entry.

Neonatal death occurred less often with dexamethasone than with placebo (19.6% vs. 23.5%; relative risk, 0.84); similarly, likelihood of stillbirth or neonatal death was lower with dexamethasone (25.7% vs. 29.2%; RR, 0.88). Compared with newborns whose mothers received placebo, neonates of dexamethasone-treated women were less likely to need major resuscitation at birth (RR, 0.70) and required less continuous positive airway pressure (CPAP) ventilation support (RR, 0.78). Incidence of maternal or neonatal infections or other adverse outcomes was similar between groups.

Comment: This trial extends the beneficial findings seen in high-resource nations to birth centers in low-resource nations with access to newborn oxygen and CPAP support. Notably, the study's dexamethasone dose (12 mg daily for 2 days) far exceeds the amount of cortisol produced daily by an adult. Substantial effort is currently focused on studying the impact on long-term neurocognitive outcomes in children of pregnant women at risk for preterm birth who received antenatal glucocorticoids.

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Siri is a 2020-2021 NEJM Editorial Fellow. She graduated from Internal Medicine Residency at Indiana University.