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

项目摘要/摘要 围产期接触辅助性阿奇霉素预防后的儿童肺及相关结局 剖宫产“是一项大型多中心非劣势随访队列研究，旨在评估长期的 围产期接触尘埃对儿童肺脏和胃肠(GI)的影响 切开前辅助性阿奇霉素与安慰剂(加标准头孢菌素)的比较 剖宫产手术部位感染。辅助剂阿奇霉素的亲本C/Soap随机试验 (4/2011-11/2014)显示产妇感染(子宫内膜炎和伤口)显著减少 感染)，而阿奇霉素组对新生儿短期预后没有任何显著影响。这 产妇感染(死亡的主要原因)的减少是如此显著，以至于阿奇霉素的使用被发现 节约成本-非计划剖腹产每次使用可节省约360美元，相当于2.7亿美元 美国每年的医疗成本。然而，人们对辅助剂阿奇霉素的热情有所缓和 关于阿奇霉素对新生儿肠道微生物群的影响的报道可能是 与影响呼吸和胃肠道功能的免疫/炎症性疾病(哮喘、喘息、过敏症、 炎症性肠病[IBD])。2018年9月，北京奥组委建议“考虑”使用附加语 阿奇霉素，但强调需要研究其对微生物组介导的长期结果的影响。 在这项研究中，我们假设围产期接触辅助性阿奇霉素与标准阿奇霉素相比 单独的剖宫产预防与儿童肺部或胃肠道疾病发病率的增加无关(即，非 次等)。我们建议对C/SOAP试验队列的后代进行长期跟踪研究，以达到最佳目标 年龄为7岁(6-8岁)，在14个参与母公司C/SOAP试验的地点。我们预计至少有1410人 在2013年中，母亲参加C/SOAP课程的儿童(70%随访)将接受一次学习访问 纳入对肺部和胃肠道健康的评估。我们将解决以下具体目标： 1)比较儿童呼吸道疾病，特别是生理性肺病的发病率 基于肺功能异常测试的主要综合结果的损害，医生 7岁时诊断为哮喘或前一年使用呼吸抢救药物(6-8岁) 围产期接触辅助性阿奇霉素与安慰剂(单独标准预防) 2)比较基于主要成分的儿童胃肠道(GI)发病率 医生诊断为胃肠道疾病(嗜酸性食管炎或IBD)或A 围产期暴露后7岁(范围6-8)队列子女的有效GI问卷(罗马第四版) 辅助性阿奇霉素与安慰剂 这项研究是提供来自美国大型试验的长期安全数据的唯一机会，以告知和 加强新推荐的剖宫产辅助性阿奇霉素的使用。

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.