Adoption of Adjunctive Azithromycin for Unscheduled Cesarean Delivery and Postpartum Infections

Importance Cesarean delivery is the most common surgery in the US and the most significant risk factor for postpartum infection. Although trial evidence demonstrated that adjunctive azithromycin use at the time of birth reduces postpartum infection in pregnant persons who undergo an unscheduled cesarean delivery, use of azithromycin outside that trial has not been reported. Objective To determine the adoption of trial evidence in clinical practice and describe postpartum infection trends among US pregnant persons undergoing unscheduled cesarean delivery. Design, Setting, and Participants Data from Epic Cosmos were used to conduct a difference-in-differences analysis including pregnant individuals who received prenatal care, labored, and gave birth to a liveborn singleton infant at 24 to 43 weeks’ gestation from 2013 to 2024. Cesarean birth was considered the treatment group and vaginal birth was considered the control group. The analysis was conducted from July 2025 to June 2026. Exposure Relative to the publication of trial evidence in 2016, births that occurred from January 1, 2013, to September 28, 2016, were compared with births that occurred from January 1, 2017, to December 31, 2024. Main Outcomes and Measures The primary outcomes were perioperative administration of azithromycin and postpartum infection within 6 weeks of delivery. Patient-level linear regression was used to obtain the difference-in-differences estimate. Results Of the 1 663 441 infant deliveries included in the analysis, there were 202 234 cesarean births and 1 461 207 vaginal births (mean age of pregnant individuals, 29.3 [SD, 5.7] years; median body mass index at time of delivery, 31.8 [IQR, 28.2-36.5]). From January 1, 2013, to September 28, 2016, azithromycin was administered during 2.2% of cesarean births (721/32 970) vs 0.01% of vaginal births (15/261 624) compared with 39.6% (67 094/169 264) vs 0.04% (421/1 199 583), respectively, from January 1, 2017, to December 31, 2024 (adjusted difference-in-differences estimate, 37.6 percentage points [95% CI, 33.1 to 42.2]). From January 1, 2013, to September 28, 2016, postpartum infection occurred after 9.2% of cesarean births (3048/32 970) vs 2.0% of vaginal births (5311/261 624) compared with 8.0% (13 555/169 264) vs 2.7% (32 581/1 199 583), respectively, from January 1, 2017, to December 31, 2024 (adjusted difference-in-differences estimate, −2.0 percentage points [95% CI, −2.6 to −1.4]). Conclusions and Relevance After publication of the trial evidence in 2016, azithromycin use for pregnant persons undergoing unscheduled cesarean delivery increased and postpartum infection rates decreased in the US.