Timing of Prophylactic Intrapartum Azithromycin Administration and Efficacy in Prevention of Maternal and Infant Infections: A Secondary Analysis of a Randomized Controlled Trial

Objective: A multi-centre international trial (A-PLUS), demonstrated that a single dose of 2 g oral azithromycin in labour reduced the risk of maternal sepsis or death, but not neonatal mortality. We aimed to determine whether the efficacy of azithromycin in prevention of any maternal infection or neonatal infection varied by time interval from azithromycin administration to delivery. Design: This is a secondary analysis of a randomized controlled trial. Setting: Multi-centre international randomized controlled trial. Population: Pregnant patients ≥ 28 weeks gestation (singleton or multiple gestation) presenting in labour for planned vaginal delivery. Outcomes: The primary outcome for this secondary analysis was maternal infection and the secondary outcome was any neonatal infection. Methods: The estimated relative risks (and 95% confidence interval) of any maternal or neonatal infection comparing azithromycin to placebo were obtained by fitting a Poisson model adjusting for site, treatment arm, hours between drug administration and delivery (as continuous measure, and ≤ 12 or > 12 h for maternal and ≤ 9 or > 9 h for neonatal), and the two-way interaction between treatment arm and hours between drug administration and delivery. Results: Included in the analysis were n = 14 569 randomized to azithromycin and n = 14 667 to placebo. There was no evidence that the benefit of azithromycin on reducing the risk of any maternal infection varied by time from dose to delivery (RR 0.71 (0.64–0.79) and RR 0.71 (0.54–0.94) for ≤ 12 and > 12 h respectively, interaction p = 0.987), although there was an observed interaction in Sub-Saharan Africa subgroup with reduced risk observed with administration > 12 vs. ≤ 12 (RR 0.21 (0.08–0.54) vs. RR 0.52 (0.41–0.66), interaction p = 0.03). There was no benefit observed in prevention of infant infection regardless of time from dose to delivery (≤ 9 or > 9 h) (RR 1.00 (0.95–1.06) and RR 1.01 (0.88–1.15) interaction p = 0.997). Conclusion: The benefit observed with a single intrapartum dose of azithromycin for prevention of any maternal infection in the setting of planned vaginal delivery was not observed to vary by time interval from azithromycin administration to delivery, although in some populations there may be greater benefit with delivery > 12 h from administration. Pregnant patients presenting for planned vaginal birth benefit from a single dose of 2 g azithromycin regardless of how soon delivery is anticipated.