Adjunctive azithromycin use may have increased substantially among patients undergoing unscheduled cesarean delivery in the United States following publication of trial evidence.
Investigators conducted a retrospective difference-in-differences analysis using Epic Cosmos electronic health record data from 2013 to 2024. They included nearly 1.7 million deliveries among patients with live-born singleton pregnancies at 24 to 43 weeks’ gestation, 202,234 of which were cesarean deliveries and 1.5 million of which were vaginal deliveries serving as the control. The investigators compared outcomes prior to publication of the C/SOAP randomized trial in September 2016 with outcomes from 2017 to 2024.
The co–primary outcomes were perioperative azithromycin administration and postpartum infection within 6 weeks postdelivery. The infection composite included endometritis, meningitis, other postpartum infection, pneumonia, pyelonephritis, sepsis, urinary tract infection (UTI), wound disruption, and wound infection. Analyses accounted for patient and pregnancy characteristics, including age, body mass index, parity, prior cesarean delivery, gestational age, prolonged rupture of membranes, and diabetes.
Among cesarean deliveries, perioperative azithromycin use increased from 2% prior to publication of the trial to 40% afterward. Azithromycin use remained uncommon with vaginal delivery, increasing from 0.01% to 0.04%.
During the same periods, postpartum infection following cesarean delivery decreased from 9% to 8%, whereas infection following vaginal delivery increased from 2% to 3%. The adjusted difference-in-differences estimate was a 2-percentage-point reduction in postpartum infection, corresponding to an estimated 20% relative decrease.
Several components of the composite outcome declined following cesarean delivery, including endometritis, sepsis, wound infection, and wound disruption. UTIs increased over time in both delivery groups. The primary findings remained consistent across sensitivity analyses addressing changes in participating sites and outcome definitions.
The real-world reduction in infection was smaller than what was reported in the C/SOAP trial, which found 6% of patients assigned to adjunctive azithromycin compared with 12% of those assigned to placebo experienced infection following unscheduled cesarean delivery. The investigators noted that fewer than 50% of patients undergoing cesarean delivery received azithromycin during the postpublication period compared with all patients assigned to azithromycin in the trial, and antibiotic administration in clinical practice was less standardized than under the trial protocol.
In an accompanying editorial, Alan T. N. Tita, MD, PhD, of the University of Alabama at Birmingham, and colleagues, noted that azithromycin use continued to rise during the study period, reaching about 60% of cesarean deliveries by 2024. They highlighted incomplete adoption as one potential explanation for the smaller real-world effect and noted that differences in the patient population and infection ascertainment may have contributed. Other changes in clinical practice may have played a role in the declining infection rate.
The study had several limitations. Scheduled and unscheduled cesarean deliveries could not be reliably distinguished, requiring the investigators to use clinical proxies for labor and vaginal deliveries as the control group. The analysis could not account for contemporaneous infection-prevention measures, leaving the potential for residual confounding. Epic Cosmos did not capture all clinical information or care received outside participating systems, and the study population and participating hospitals differed in some respects from the broader US population and health care system. Changes in site participation and reliance on diagnosis codes to identify infections may also have affected the results. Neither the current study nor the original trial was designed to evaluate maternal mortality.
“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 [United States],” wrote lead study author Taylor S. Freret, MD, EdM, of Beth Israel Deaconess Medical Center, and colleagues.
Full disclosures of the study authors can be found in the study.
