This is a phase-III multi-center double-blind randomized controlled trial of 8,000 individuals undergoing a scheduled or prelabor cesarean delivery who are randomized to either adjunctive azithromycin prophylaxis or to placebo. Both groups also will receive standard of care preoperative antibiotics (excluding azithromycin). The primary endpoint is a maternal infection composite defined as any one of the following up to 6 weeks postpartum: endometritis, wound infection, abscess, septic thrombosis, sepsis, pneumonia, pyelonephritis and breast infection.

This is a phase-III multi-center double-blind randomized controlled trial of 8,000 individuals undergoing a scheduled or prelabor cesarean delivery who are randomized to either azithromycin prophylaxis or to placebo. All participants will receive standard of care preoperative antibiotics. The primary objective is to evaluate in patients undergoing scheduled/prelabor cesarean if pre-incision adjunctive azithromycin prophylaxis reduces the risk of post-cesarean infections compared with placebo. Secondary objectives include 1) to assess the perinatal and maternal safety of pre-incision adjunctive azithromycin, 2) to evaluate whether adjunctive azithromycin prophylaxis reduces maternal and neonatal resource use outcomes compared with placebo, and 3) to evaluate whether adjunctive azithromycin influences maternal and neonatal infection with resistant organisms compared with placebo.

Individuals will be randomized prior to the start of the cesarean to either 500mg of intravenous azithromycin or to placebo (normal saline). Maternal blood and cord blood will be collected on a subset of the population. Research staff will abstract maternal and neonatal outcomes following delivery and discharge from the hospital. A single maternal follow-up study visit at 6 weeks (4-8 weeks) postpartum will be scheduled to ascertain maternal and neonatal outcomes.

Inclusion Criteria:

• ≥ 23 weeks' gestation (ACOG dating criteria)
• Scheduled or prelabor cesarean delivery
• Singleton or twin gestation

Exclusion Criteria:

• Allergy or contraindication to azithromycin or macrolide antibiotics, including those with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin
• Chorioamnionitis
• Bacterial infection (e.g., pyelonephritis) requiring ongoing antibiotic treatment after delivery
• Premature rupture of membranes (PROM) or labor (i.e., contractions with ongoing cervical change)
• Fetal demise or known major congenital anomaly
• Azithromycin treatment within 7 days
• Planned use of antimicrobial prophylaxis after delivery for any reason
• Known structural heart disease or active cardiomyopathy (current ejection fraction<40%)
• Known arrhythmia with QT prolongation or taking scheduled medications known to prolong the QT interval such that it would preclude the use of azithromycin
• Refusal or unable to obtain consent (e.g., language barrier)
• Participating in another intervention study that influences the primary outcome in this study
• Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, do not have to be excluded.

Data will be shared via NICHD DASH in accordance with NIH policy.

The study medication will be prepared by the center research pharmacies from a list provided by the independent data coordinating center, with the active and placebo medication having identical appearance. No other individuals, including the participant or any other clinical or research staff will be informed of the study assignment.