Childhood follow-up study of obesity and neurodevelopment after perinatal exposure to adjunctive azithromycin prophylaxis for cesarean delivery

项目概要/摘要 我们提出了一项大型多中心非劣效性随访队列研究，旨在评估长期 围产期暴露于阿奇霉素后的肥胖/生长和神经发育， 安慰剂（加标准头孢菌素），以预防剖腹产手术部位感染。母 C/SOAP随机试验（2011年4月-2014年11月）显示， 母体感染（尿道炎和伤口感染）对短期新生儿无任何显著影响 阿奇霉素组的结果。产妇感染（死亡的一个主要原因）的减少， 使用阿奇霉素可节省费用- 美国每年的医疗费用为100万美元。然而，对阿奇霉素的热情已经有所缓和， 鉴于有报道称阿奇霉素对新生儿肠道微生物组引起的变化可能与 儿童期体重增加/肥胖和神经发育障碍。2018年9月，ACOG建议 “考虑”阿奇霉素的替代性，但强调需要研究其对长期 童年的成果。针对这些问题，我们提出了一项R 01研究，评估肺和 围产期阿奇霉素暴露后的胃肠道（GI）健康（第6百分位数评分）。评论家强调， 需要评估肥胖/生长和神经发育（NIH官员建议单独申请， 上限限制）。因此，在本研究中，我们假设围产期接触阿奇霉素 与标准剖宫产预防相比，单独剖宫产预防与肥胖/体重增加风险增加无关 或神经发育障碍（即非劣效性）。我们提出了一个后续研究的后代的 在母试验的14家研究中心，目标年龄为7岁（范围6-9岁）的C/SOAP试验队列。我们希望至少 2013名母亲入组C/SOAP的儿童中有1410名（70%随访）将接受一项研究 访问包括生长/生物统计学和神经发育评估，以解决以下具体目标： 1)比较肥胖/超重儿童的发生率（主要结局）和其他生物物理学指标， 测量，在围产期暴露后7岁（范围6-9岁）的队列后代之间， 阿奇霉素与安慰剂的对比（单独标准预防） 2)比较神经发育结局，包括认知能力（主要结局）、功能和 行为障碍和运动熟练度，在7岁时（范围6-9岁）， 围产期暴露于连续性阿奇霉素与安慰剂的比较 这项研究，沿着评价肺和胃肠道结局的伴随研究（奖励通知待定）， 这是从美国大型试验中有效提供全面的长期安全性数据的唯一机会， 加强新推荐的阿奇霉素在剖宫产术中的应用。

PROJECT SUMMARY/ABSTRACT We propose a large multi-center non-inferiority follow-up cohort study designed to evaluate long-term obesity/growth and neurodevelopment after perinatal exposure to adjunctive azithromycin as compared with placebo (plus standard cephalosporin) 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/unscheduled cesarean and $270 million/year in US healthcare costs. However, enthusiasm for adjunctive azithromycin has been tempered given reports of changes induced by azithromycin on the newborn gut microbiome that may be associated with childhood weight gain/obesity and neurodevelopmental impairment. In September 2018, ACOG suggested “consideration” of adjunctive azithromycin, but emphasized the need for studies of its effect on long-term childhood outcomes. In response to these concerns, we proposed an R01 study evaluating pulmonary and gastrointestinal (GI) health after perinatal azithromycin exposure (6th percentile score). Reviewers emphasized the need to evaluate obesity/growth and neurodevelopment (NIH officers advised a separate application due to cap limitations). Thus, in this proposal, we hypothesize that perinatal exposure to adjunctive azithromycin compared to standard cesarean prophylaxis alone is not associated with increased risk of obesity/weight gain or neurodevelopmental impairment (i.e. is non-inferior). We propose a follow-up study of the offspring of the C/SOAP trial cohort at target age of 7 years (range 6-9) at the 14 sites in the parent 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 growth/biometry and neurodevelopment assessments to address the following specific aims: 1) To compare the incidence of obese/overweight children (primary outcome), and other biophysical measurements, between cohort offspring aged 7 (range 6-9 years) after perinatal exposure to adjunctive azithromycin versus placebo (standard prophylaxis alone) 2) To compare neurodevelopmental outcomes including cognitive ability (primary outcome), functional and behavioral impairment, and motor proficiency, between cohorts at age 7 (range 6-9 years) after perinatal exposure to adjunctive azithromycin versus placebo This study, along with the companion study evaluating pulmonary and GI outcomes (award notice pending), is the only opportunity to efficiently provide comprehensive long-term safety data from a large US trial to inform and strengthen the newly recommended use of adjunctive azithromycin for cesarean delivery.