Real-World U.S. Data Back Azithromycin After Unscheduled C-Sections

Use of adjunctive azithromycin increased among women undergoing unscheduled cesarean deliveries and postpartum infection rates fell after a landmark trial showed the antibiotic’s benefits in this setting, according to a difference-in-differences analysis.

Use of azithromycin for cesarean deliveries — the most common surgical procedure in the U.S. — increased from 2.2% in January 2013 through September 2016 to 39.6% in January 2017 through December 2024, while use in vaginal births edged up from 0.01% to 0.04%, respectively, reported Taylor Freret, MD, of Beth Israel Deaconess Medical Center in Boston, and colleagues.

Meanwhile, postpartum infection rates within 6 weeks of delivery decreased from 9.2% of cesarean deliveries to 8%. For vaginal deliveries, rates were 2% and 2.7% over the two time frames, they wrote in JAMA.

The adjusted difference-in-differences estimate represents a 20% relative decrease, the authors noted. “Given that more than 300,000 individuals have an unscheduled cesarean delivery annually, a 20% reduction, if due to the use of azithromycin, would still represent a meaningful improvement in postpartum outcomes, potentially preventing 6,000 infections each year.”

Post-cesarean infection rates run from 10% to 20%, and having an unscheduled cesarean delivery can nearly double the risk of postpartum infection compared with scheduled cesarean deliveries.

The 2016 Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial showed that adding azithromycin to standard antibiotic prophylaxis in unscheduled cesarean deliveries reduced postpartum infections by nearly 50%. Those results prompted the American College of Obstetricians and Gynecologists (ACOG) in 2018 to update its guidelines with a call for azithromycin to be “considered” in unscheduled cesarean deliveries.

“These data strengthen the case for more consistent implementation of adjunctive azithromycin in appropriately selected patients and support a move in the ACOG guidelines from ‘consideration’ to ‘recommended use’ in unscheduled, high-risk cesarean deliveries,” wrote Alan Tita, MD, PhD, of the University of Alabama at Birmingham and an author of the C/SOAP trial, and colleagues in an accompanying editorial.

The prevention of maternal morbidity and mortality “remains an urgent global priority, yet progress has been unsatisfactory,” they noted, pointing out that despite maternal mortality declining globally, rates have increased in the U.S. and infections are among the top causes of preventable deaths.

The risk of infection after cesarean delivery is many times higher compared with vaginal delivery, “underscoring the importance of effective prophylaxis,” they added.

“Future work should refine patient selection and monitor the effects on maternal mortality and global antimicrobial resistance,” Tita and co-authors concluded. “The current evidence indicates that failure to implement this strategy represents a missed opportunity to reduce preventable maternal morbidity and potentially mortality.”

Freret and colleagues analyzed data on 1,696,535 births from the nationwide Epic Cosmos database from January 2013 to December 2024. The included pregnant women labored and gave birth to a live singleton infant at 24 to 43 weeks’ gestation.

The analysis compared two periods before and after the C/SOAP trial’s publication: January 2013 to September 2016 (294,594 deliveries), and January 2017 to December 2024 (1,368,847 deliveries). Among those two groups, 12.2% of deliveries (202,234) were cesarean.

During the study’s two periods, mean maternal ages were 29.6 and 30.2 years in the cesarean birth groups, and 28.7 and 29.3 years in the vaginal birth groups. Across all groups, the majority of women were white and had private health insurance.

The study’s composite postpartum infection outcome included endometriosis, meningitis, pneumonia, pyelonephritis, sepsis, urinary tract infection, wound disruption, wound infection, and other postpartum infections. In the period after C/SOAP, rates of endometriosis, sepsis, wound disruption, and wound infection fell significantly among cesarean deliveries. Rates of urinary tract infection were higher in this later period among both cesarean and vaginal births.

Study limitations included the use of vaginal births as the control group instead of scheduled cesarean births. In addition, patients in the database tend to be older and more likely to have private insurance versus the general U.S. population.