An analysis of more than 1.6 million US childbirths indicates that use of azithromycin during unscheduled cesarean deliveries has risen, and postpartum infections have declined over the past decade, researchers reported today in JAMA.
The aim of the study was to determine the adoption of prophylactic azithromycin use into clinical practice in the wake of a 2016 randomized controlled trial that found a 50% reduction in postpartum infections in women who received a dose of adjunctive azithromycin (in addition to routine pre-incision surgical antibiotics) prior to cesarean incision compared with those who received placebo.
Those results, along with follow-up studies that confirmed fetal safety and cost-effectiveness, led the American College of Obstetricians and Gynecologists to endorse the practice in 2018.
A team led by researchers with Beth Israel Deaconess Medical Center in Boston also wanted to see whether the reductions in postpartum infections demonstrated in the trial were observed in real-world settings.
“Although randomized clinical trials are the gold standard for determining the efficacy of an intervention, their translation into clinical practice can be limited by issues of generalizability outside highly controlled environments,” they wrote.
Cesarean section is the most common major surgical procedure in the United States. The researchers note that nearly one-third of all US births occur by C-section, and approximately 30% of the 1 million cesarean births in 2024 were unscheduled.
Postpartum infection rates after C-sections range from 10% to 20% and are nearly two-fold higher in unscheduled C-sections. Infections can range from non–life-threatening conditions like endometritis (inflammation of the inner lining of the uterus) to more severe conditions like sepsis.
20% relative reduction in postpartum infections
For the study, the researchers used Epic Cosmos, a large database of electronic health records from hospitals in all 50 states and Washington, DC, to analyze data on all pregnant individuals who received prenatal care and gave birth from 2013 through 2024.
They compared perioperative administration of azithromycin and postpartum infection within six weeks of delivery in two periods: January 2013 to September 2016 (before the publication of the trial) and January 2017 through December 2024.
Women who underwent unscheduled C-sections were considered the intervention group, and women who gave birth vaginally were the control group, as the researchers could not identify scheduled C-sections with certainty.
During the study period, 202,234 cesarean births and nearly 1.5 million vaginal births met the criteria for inclusion. From January 1, 2013, to September 28, 2016, azithromycin was administered in 2.2% of cesarean births, compared with 0.01% of vaginal births. From January 1, 2017, to December 31, 2024, azithromycin was used in 39.6% of cesarean births, compared with 0.04% of vaginal births. The adjusted difference-in-difference estimate was 37.6 percentage points.
The current study suggests that perioperative azithromycin use at the time of unscheduled cesarean delivery is associated with decreased infection in a large, real-world cohort outside the clinical trial setting that is representative of the US population.
Postpartum infection occurred in 9.2% of cesarean and 2.0% of vaginal births in the pre-trial period, and in 8.0% of cesarean and 2.7% of vaginal births in the post-trial period—an absolute reduction of 2.0 percentage points and a relative reduction of 20%, which would translate to roughly 6,000 fewer postpartum infections a year.
The researchers said significant reductions were observed across a variety of postpartum infections, including endometritis, sepsis, and surgical site infections.
“The current study suggests that perioperative azithromycin use at the time of unscheduled cesarean delivery is associated with decreased infection in a large, real-world cohort outside the clinical trial setting that is representative of the US population,” the authors wrote. “These findings support the external validity of the 2016 trial.”
A smaller, but substantial, benefit
The authors say the smaller relative reduction in postpartum infections observed in the study (20% vs 50% in the trial) can be attributed to the fact that less than half of pregnant individuals in the study received adjunctive azithromycin. In the trial, all participants in the azithromycin group received the antibiotic.
But in an accompanying editorial, the lead investigators of the 2016 trial say the population benefits “remain substantial” and strengthen the case for more consistent implementation of adjunctive azithromycin.
“Given that up to 60% (n = 720 000) of cesarean deliveries are unscheduled (occur after labor) annually in the US, even the modest relative reduction translates into thousands of infections prevented each year, with downstream reductions in hospital readmissions, antibiotic use, and health care costs,” they wrote. “The current evidence indicates that failure to implement this strategy represents a missed opportunity to reduce preventable maternal morbidity and potentially mortality.”
