Non-study post-partum antibiotics use and risk of maternal and neonatal infection: A secondary analysis of the A-PLUS randomized controlled trial

Objective: The randomized trial of azithromycin to reduce maternal and neonatal sepsis (the A-PLUS Trial) found substantial reduction in maternal sepsis among women receiving azithromycin and substantial non-study antibiotic use. This secondary analysis explored the effect modification of non-study antibiotics on azithromycin versus placebo on maternal and newborn infection among A-PLUS participants. Methods: Women ≥28 weeks gestation in labor and planning a vaginal delivery at a study hospital in seven low- and middle-income countries (Bangladesh, India [two sites], Pakistan, Guatemala, Kenya, Democratic Republic of Congo, and Zambia) were eligible for inclusion. Non-study antibiotic use was collected prospectively. We estimated the interaction of non-study antibiotics with azithromycin versus placebo on maternal and newborn sepsis. Results: A total of 29 287 participants were randomized (14 590 to azithromycin; 14 688 to placebo). Maternal infection was reduced among the azithromycin group compared to placebo among those who did not receive non-study antibiotics, with estimated relative risk (RR) 0.58 (95% confidence interval [CI] 0.48, 0.70), and among those who received non-study antibiotics, with RR 0.80 (95% CI 0.70, 0.91). Similar results were observed for maternal sepsis. Neonatal infection was not significantly reduced in any group. These results were similar when stratified by African and Asian region but not statistically significant. Conclusion: Our results suggest a benefit of azithromycin in reducing maternal infection or sepsis across all groups, with a larger reduction in risk among participants who had not received other antibiotics. Given the concerns of inappropriate use of antibiotics, further research is warranted to determine the most effective strategies of reducing risk of infection.