Childhood Pulmonary and Related Outcomes after Perinatal Exposure to Adjunctive Azithromycin Prophylaxis for Cesarean Delivery (C/SOAP Follow-Up Study)

项目概要/摘要 “围产期暴露于辅助阿奇霉素预防后的儿童肺部和相关结局 ”是一项大型多中心非劣效性随访队列研究，旨在评估长期 围产期暴露于以下物质后，长期微生物组介导的儿童期肺和胃肠道（GI）影响 与安慰剂（加标准头孢菌素）相比，切开前预防阿奇霉素 剖腹产手术部位感染。阿奇霉素连续治疗的C/SOAP随机对照试验 （2011年4月至2014年11月）显示，孕产妇感染（肠炎和伤口感染）显著减少 感染）对阿奇霉素组的短期新生儿结局无任何显著影响。这 母亲感染（死亡的主要原因）的减少是如此显著，以致发现阿奇霉素的使用 节省费用-每次用于计划外剖腹产节省约360美元，相当于2.7亿美元 美国每年的医疗费用。然而，对阿奇霉素的热情有所缓和， 阿奇霉素对新生儿肠道微生物组（生态失调）引起的变化的报告， 与影响呼吸和GI功能的免疫/炎性疾病（哮喘，喘息，特应性， 炎症性肠病[IBD]）。2018年9月，ACOG建议“考虑” 阿奇霉素，但强调需要研究其对微生物群介导的长期结果的影响。 在这项研究中，我们假设，与标准阿奇霉素相比， 单纯预防剖宫产与儿童期肺部或胃肠道发病率增加无关（即， 劣）。我们建议在最佳目标下对C/SOAP试验队列的后代进行长期随访研究 在参与母C/SOAP试验的14个研究中心，年龄为7岁（范围6-8岁）。我们预计至少1410 2013例母亲入组C/SOAP的儿童（70%随访）将接受一次研究访视 包括肺部和胃肠道健康评估。我们将致力于实现以下具体目标： 1)比较儿童呼吸系统疾病的发病率，特别是生理性肺部疾病， 基于肺功能检查异常的主要复合结局，医师 7岁时诊断为哮喘，或在前一年使用呼吸救援药物（范围6-8） 在围产期暴露于阿奇霉素与安慰剂（单独标准预防）后 2)基于主要复合指标比较儿童胃肠道（GI）发病率 医生诊断的GI疾病（嗜酸性粒细胞性食管炎或IBD）或 在围产期暴露后7岁（范围6-8）的队列后代之间进行经验证的GI问卷调查（罗马IV） 阿奇霉素与安慰剂的对比 这项研究是提供美国大型试验的长期安全性数据的唯一机会， 加强新推荐的剖腹产辅助使用阿奇霉素。

PROJECT SUMMARY/ABSTRACT “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.