Adoption and Real-World Effectiveness of Adjunctive Azithromycin for Unscheduled Cesarean Delivery: A National Difference-in-Differences Analysis

ImportanceCesarean delivery is the most common surgery in the US with more than 1 million performed each year; it is also the most significant risk factor for postpartum infection. The Cesarean Section Optimal Antibiotic Prophylaxis trial demonstrated that the addition of azithromycin at the time of cesarean birth performed in labor reduces postpartum infection. ObjectiveTo determine the real-world adoption and effect of this trial on clinical practice and postpartum infections among U.S. pregnant persons undergoing cesarean delivery in labor. DesignDifference-in-differences analysis from 2013-2024. SettingPopulation-based, patient-level analysis using Epic Cosmos, a large longitudinal national electronic health record database of patients seen in health systems using Epic. ParticipantsPregnant individuals who received outpatient prenatal care in the system, who labored and gave birth to a liveborn singleton infant at 24-43 weeks of gestation were included. Exclusion criteria included unknown mode of delivery and intraamniotic infection. ExposuresThe treatment group included those delivered by cesarean and the control group included those who delivered vaginally. The pre-period was defined as 2013-2016, excluding a washout period from trial publication until December 31, 2016, and the post-period was defined from 2017-2024. Main Outcomes and MeasuresThe primary outcomes were perioperative azithromycin administration and postpartum infection within 6 weeks of delivery. Results1,663,341 participants were included in the final analysis. In the pre- and post-periods, azithromycin was administered in 0.01% and 0.04% of vaginal births and in 2.2% and 39.6% of cesarean births, respectively. In the pre- and post-periods, postpartum infection occurred in 2.0% and 2.7% of vaginal births and 9.2% and 8.0% of cesarean births. In the adjusted difference-in-difference analysis, the trial resulted in an absolute increase in azithromycin use by 37.6 percentage points (pp) (95% CI: 33.1 to 42.2 pp); postpartum infection decreased by 2.0 pp (95% CI: -2.5 to -1.4 pp), a relative decrease of 20%. Conclusions and RelevanceOutside the clinical trial setting, this study provides evidence that azithromycin significantly reduces postpartum infection among pregnant persons undergoing a cesarean delivery in labor. Key PointsO_ST_ABSQuestionC_ST_ABSDid evidence from the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial change real-world clinical practice and decrease postpartum infections among U.S. pregnant persons who underwent a cesarean delivery in labor? FindingsIn this difference-in-differences analysis of 1.6 million births, azithromycin use increased 37.6 percentage points and postpartum infections decreased by 2.0 percentage points following the C/SOAP trial. MeaningOutside the clinical trial setting, this study provides evidence that azithromycin significantly reduces postpartum infection among individuals having a cesarean delivery in labor.