Infections Fall With Azithromycin for Unscheduled Cesarean Deliveries

Use of adjunctive azithromycin during unscheduled cesarean delivery climbed sharply in the decade after a randomized trial demonstrated its benefit, and postpartum infection rates among those patients fell over the same span, according to a study published in JAMA. The analysis drew on more than 1.6 million births recorded in the Epic Cosmos electronic health record database and is the first report on how widely the trial evidence was adopted into routine US practice.^1,2

Cesarean delivery is the most common surgery performed in the United States and remains the single most significant risk factor for postpartum infection. Overall infection rates after cesarean delivery range from 10% to 20% and are nearly double among unscheduled procedures compared with scheduled ones. In 2024, more than 1 million US births involved cesarean delivery, and the study authors estimate approximately 30% were unscheduled.¹

Uptake Climbed From Rare to Routine

The 2016 trial, known as the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP; NCT01235546) trial, randomized 2013 women undergoing unscheduled cesarean delivery to adjunctive intravenous azithromycin or placebo on top of routine preincision prophylaxis.¹

That trial found a 50% reduction in postpartum infection, 6% in the azithromycin group compared with 12% in the placebo group, and the American College of Obstetricians and Gynecologists endorsed considering azithromycin for unscheduled cesarean delivery in a 2018 practice bulletin update.¹

The new study, led by researchers at Beth Israel Deaconess Medical Center, used a difference-in-differences design comparing cesarean births (the treatment group) with vaginal births (the control group) before and after the trial's September 2016 publication.¹

Before publication, azithromycin was administered in 2.2% of cesarean births (721 of 32,970) compared with 0.01% of vaginal births (15 of 261,624). After publication, use climbed to 39.6% of cesarean births (67,094 of 169,264) versus 0.04% of vaginal births (421 of 1,199,583), an adjusted difference-in-differences estimate of 37.6 percentage points (95% CI, 33.1-42.2).¹

Infection Rates Declined Even With Partial Adoption

Postpartum infection within 6 weeks of delivery occurred in 9.2% of cesarean births before the trial's publication compared with 8.0% afterward, versus a comparatively stable 2.0% to 2.7% among vaginal births over the same periods. The adjusted difference-in-differences estimate was –2.0 percentage points (95% CI, –2.6 to –1.4), representing a 20% relative decrease against the study's counterfactual rate. The authors noted significant reductions across several infection types among cesarean deliveries, including endometritis, sepsis, and surgical site infections.¹

"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 study authors wrote, adding that the findings support the external validity of the 2016 trial.¹

The authors also pointed out that the relative reduction observed in practice (20%) was smaller than in the original trial (50%), which they attributed largely to the fact that fewer than half of eligible patients received azithromycin during the 2017-2024 period compared with 100% of the trial's intervention arm.¹

In an accompanying editorial, the lead investigators of the original 2016 trial wrote that "the current evidence indicates that failure to implement this strategy represents a missed opportunity to reduce preventable maternal morbidity and potentially mortality," according to CIDRAP's coverage of the study.²

What the Findings Mean for Pharmacists

For pharmacists involved in surgical antibiotic stewardship, the timing of azithromycin administration relative to incision is a practical detail worth reinforcing. A secondary analysis of the original C/SOAP trial data, published separately in Obstetrics & Gynecology, examined outcomes by timing of the single 500-mg intravenous dose among the trial's 2013 participants.³

Azithromycin was associated with significantly reduced risk of the composite maternal infection outcome when given 0 to 30 minutes before skin incision (risk ratio [RR], 0.62; 95% CI, 0.44-0.89), more than 30 to 60 minutes before incision (RR, 0.31; 95% CI, 0.13-0.66), or after incision at a median of 3 minutes (RR, 0.31; 95% CI, 0.13-0.76).³

Risk reduction was not statistically significant when the dose was given more than 60 minutes before incision (RR, 0.59; 95% CI, 0.10-3.36), a group with a small sample size. Neonatal outcomes did not differ significantly across timing groups.³

Because azithromycin is typically infused over 60 minutes alongside a separate, rapidly administered cephalosporin, pharmacists coordinating perioperative order sets can use this timing evidence to support protocols that keep azithromycin administration within roughly an hour of incision, even when cesarean delivery proceeds faster than anticipated.³

The adoption study's authors noted their own analysis could not confirm whether patients who did not receive azithromycin had a documented contraindication, an unmeasured antibiotic allergy, or simply were not offered it, leaving room for pharmacy-led protocols to help close the remaining gap in uptake.¹

REFERENCES

1. Freret TS, Litman E, Wen T, Guise J, Little SE, Clapp MA. Adoption of Adjunctive Azithromycin for Unscheduled Cesarean Delivery and Postpartum Infections. JAMA. Published online September 14, 2026. doi:10.1001/jama.2026.15010

2. Dall C. Analysis bolsters case for using azithromycin for unscheduled C-sections. CIDRAP News. September 14, 2026. Accessed September 22, 2026. https://www.cidrap.umn.edu/antimicrobial-stewardship/analysis-bolsters-case-using-azithromycin-unscheduled-c-sections

3. Sanusi A, Ye Y, Boggess K, et al. Timing of Adjunctive Azithromycin for Unscheduled Cesarean Delivery and Postdelivery Infection. Obstet Gynecol. 2022;139(6):1043-1049. doi:10.1097/AOG.0000000000004788