ABSTRACT We propose a large randomized clinical trial within the MFMU Network designed to evaluate the benefits and safety of azithromycin-based prophylaxis (azithromycin plus standard cephalosporin) relative to standard cephalosporin alone prior to surgical incision to prevent post-cesarean (CD) infection. In contrast to cephalosporin, azithromycin is effective against additional pathogens encountered in polymicrobial post-CD infections. We demonstrated adjunctive azithromycin, compared to standard prophylaxis, reduced maternal infections by 50% with remarkable cost-savings in unscheduled CDs. The American College of Obstetricians and Gynecologists (ACOG) now recommends routine use in unscheduled CDs. Our preliminary studies suggest azithromycin may also lower infection risk in the 40-50% that are scheduled/pre-labor CDs, but there are safety concerns regarding the adverse neonatal and long-term microbiome-mediated effects of perinatal exposure. During the project period of 5 years, we will randomize up to 8000 women undergoing scheduled/pre-labor CD to either 500mg of intravenous azithromycin or identical placebo initiated prior to surgery. Both groups will also receive standard single-dose cefazolin prophylaxis (or alternative in the 5% allergic to cephalosporin). Women will be followed for 6 weeks according to adapted Centers for Disease Control and Prevention (CDC) recommendations for ascertaining surgical site infections. The following specific aims will be addressed: Primary Aim (Efficacy): Test in patients undergoing scheduled/prelabor CD if pre-incision adjunctive azithromycin prophylaxis reduces the risk of post-CD infections compared to placebo. Primary Hypothesis: Compared to standard prophylaxis (i.e. placebo + cefazolin alone), azithromycin (+ cefazolin) reduces the incidence of post-CD infections (primary composite outcome of endometritis, wound and other severe infections). Secondary Aim 1 (Safety): Assess the perinatal and maternal safety of pre-incision adjunctive azithromycin. Hypothesis: Compared to standard prophylaxis (cefazolin alone), the use of azithromycin for scheduled CD does not increase adverse perinatal outcomes including a perinatal composite of death, neonatal morbidities, cardiac resuscitation, and hypertrophic pyloric stenosis. We will also examine maternal and neonatal adverse events. Secondary Aim 2 (Resource use): Test the hypothesis that compared to standard cefazolin prophylaxis alone, adjunctive azithromycin reduces a secondary maternal composite outcome (postpartum readmission or ER or unscheduled clinic visits), maternal hospital stay, neonatal ICU admission and neonatal hospital stay. We will collect and store biological specimens including maternal and umbilical cord blood for future mechanistic and biomarker studies. We also plan a separate microbiome sub-study proposal. Completion of this trial, ranked #1/28 by MFMU, will likely change policy, extending the benefits of azithromycin prophylaxis to scheduled CDs faster than the 20 years it took to for standard prophylaxis.

NARRATIVE Our prior studies demonstrated efficacy of adjunctive azithromycin to further reduce maternal infections by 50% and remarkable cost-savings in unscheduled cesareans (CDs), leading ACOG to recommend its routine use in unscheduled CDs. Given additional promising preliminary data, we propose a large randomized trial (N=8000) within the MFMU Network to evaluate the benefits of adjunctive azithromycin in scheduled/pre-labor CDs and further assess the safety of this innovative antibiotic prophylaxis strategy to reduce the incidence of infection, one of the top 3 causes of pregnancy-related death and illness in the US. The trial will likely lead to a rapid policy change to extend this promising intervention to scheduled CDs, with significant health and cost benefits.