?Childhood Pulmonary and Related Outcomes after Perinatal Exposure to Adjunctive Azithromycin Prophylaxis for Cesarean Delivery? is a large multi-center non-inferiority follow-up cohort study designed to evaluate long- term microbiome-mediated childhood pulmonary and gastrointestinal (GI) effects after perinatal exposure to adjunctive azithromycin as compared with placebo (plus standard cephalosporin) prior to incision to prevent surgical site infections at cesarean delivery. The parent C/SOAP randomized trial of adjunctive azithromycin (4/2011?11/2014) demonstrated a significant reduction in maternal infections (endometritis and wound infection) without any significant effect on short-term neonatal outcomes in the azithromycin group. This reduction in maternal infection (a major cause of death) was so significant that azithromycin use was found to be cost-saving ? saving ~$360 for each use in unscheduled cesareans, corresponding to $270 million dollars annually in US healthcare costs. However, enthusiasm for adjunctive azithromycin has been tempered given reports of changes induced by azithromycin on the newborn gut microbiome (dysbiosis) that may be associated with immune/inflammatory diseases affecting respiratory and GI function (asthma, wheezing, atopy, inflammatory bowel disease [IBD]). In September 2018, ACOG suggested ?consideration? of adjunctive azithromycin, but emphasized the need for studies of its effect on microbiome-mediated long-term outcomes. In this study, we hypothesize that perinatal exposure to adjunctive azithromycin compared to standard cesarean prophylaxis alone is not associated with increased childhood pulmonary or GI morbidity (i.e. is non- inferior). We propose a long-term follow-up study of the offspring of the C/SOAP trial cohort at optimal target age of 7 years (range 6-8) at the 14 sites that participated in the parent C/SOAP trial. We expect at least 1410 of 2013 children (70% follow-up) whose mothers were enrolled in C/SOAP will undergo a single study visit incorporating assessment of pulmonary and GI health. We will address the following specific aims: 1) To compare the incidence of childhood respiratory morbidity, specifically physiologic pulmonary impairment, based on a primary composite outcome of abnormal pulmonary function testing, physician diagnosis of asthma, or use of respiratory rescue medications in the previous year at age 7 (range 6-8) after perinatal exposure to adjunctive azithromycin versus placebo (standard prophylaxis alone) 2) To compare the incidence of childhood gastrointestinal (GI) morbidity based on a primary composite outcome of physician diagnosis of GI disease (eosinophilic esophagitis or IBD) OR an abnormal score on a validated GI questionnaire (Rome IV) between cohort offspring aged 7 (range 6-8) after perinatal exposure to adjunctive azithromycin versus placebo This study is the only opportunity to provide long-term safety data from a large US trial to inform and strengthen the newly recommended use of adjunctive azithromycin for cesarean delivery.
Cesarean delivery, the most common major surgical procedure in the US, is the strongest risk factor for maternal infection (a top 3 cause of death during childbirth). Adjunctive azithromycin compared to standard antibiotic prophylaxis alone is proven (through our large C/SOAP trial and other studies) to be highly effective in preventing infection after cesarean - with authorities now recommending consideration of its use while calling for more information on long-term health outcomes after exposure at birth. We propose a US multi-center long-term follow- up study of children from the parent C/SOAP trial at age 6-8 years to evaluate childhood respiratory and gastrointestinal health effects after perinatal exposure to adjunctive azithromycin; findings from this study will be used to inform and strengthen national and global health care policy regarding the use of adjunctive azithromycin to reduce maternal infection after cesarean delivery.
