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

项目摘要/摘要 我们提出了一项大型多中心非劣势随访队列研究，旨在评估长期 围产期服用辅助性阿奇霉素后肥胖/生长和神经发育的比较 安慰剂(加标准头孢菌素)预防剖宫产手术部位感染。父辈 辅助性阿奇霉素的C/Soap随机试验(4/2011-11/2014)显示， 母体感染(子宫内膜炎和伤口感染)对新生儿短期无明显影响 阿奇霉素组的结果。产妇感染(死亡的一个主要原因)的减少就是如此 值得注意的是，阿奇霉素的使用被发现是节省成本的-节省约360美元/次非计划剖腹产和270美元 美国医疗保健成本为百万美元/年。然而，人们对辅助剂阿奇霉素的热情有所减弱。 已有报道称阿奇霉素对新生儿肠道微生物群的影响可能与 儿童体重增加/肥胖和神经发育障碍。2018年9月，奥组委建议 “考虑”辅助性阿奇霉素，但强调有必要对其长期疗效进行研究 童年的结局。为了回应这些担忧，我们提出了一项R01研究，评估肺和 围产期接触阿奇霉素后的胃肠(GI)健康状况(第6个百分位数)。评审员强调 评估肥胖/生长和神经发育的必要性(NIH官员建议单独申请，因为 上限限制)。因此，在这项建议中，我们假设围产期接触辅助性阿奇霉素 与标准剖腹产相比，单独进行预防并不会增加肥胖/体重增加的风险 或神经发育障碍(即非劣质)。我们建议对黑猩猩的后代进行后续研究 父母试验中14个地点的目标年龄为7岁(6-9岁)的C/SOAP试验队列。我们预计至少 在2013名母亲参加C/SOAP的儿童中，有1410名(70%随访)将接受一项单一研究 访问包含生长/生物测量和神经发育评估的网站，以实现以下具体目标： 1)比较肥胖/超重儿童的发生率(主要结果)和其他生物物理指标 围产期暴露在7岁(6-9岁)的队列后代之间的测量 辅助性阿奇霉素与安慰剂(单独标准预防) 2)比较神经发育结果，包括认知能力(主要结果)、功能和 7岁(6-9岁)的队列之间的行为障碍和运动熟练程度 围产期应用辅助性阿奇霉素与安慰剂的比较 这项研究以及评估肺部和胃肠道结果的配套研究(获奖通知待定)是 有效提供来自美国大型试验的全面长期安全数据的唯一机会是 并加强新推荐的剖宫产辅助性阿奇霉素的使用。

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.