Long Term Antibiotic Use and Weight Gain in Children and Adolescents

描述（由申请人提供）：儿童肥胖和超重已迅速成为流行病。可能导致这种现象的一个因素是感染，无论是特定暴露的变化还是定植植物群的变化，抗生素（ABX）的使用也可能起作用。ABX在农场动物中的生长促进作用自20世纪40年代以来就已为人所知。人类长期使用ABX的类似影响似乎越来越合理。1950年在新兵中进行的一项试验表明，接受ABX治疗的人比安慰剂对照组体重增加更多。最近，接受ABX治疗的心内膜炎患者与未接受ABX治疗的对照组相比，体重明显增加。研究人员假设肥胖和肠道微生物群之间存在关联，ABX也可以通过改变肠道微生物群来影响体重。在幼儿中，通过在配方奶粉中添加益生菌来改变肠道微生物群，导致体重显著增加。研究ABX对体重的作用具有挑战性，因为服用ABX的患者通常生病，然后在改善健康的过程中体重增加。然而，一些相对健康的受试者确实接受了ABX，这一组是我们研究的重点。假设：在健康儿童和青少年中长期使用ABX会促进体重增加，这比基于ABX前生长的预期更大。目的：1.研究健康儿童和青少年长期口服ABX是否会导致体重增加超过基于正常生长的预期。2.评估ABX类的特定类是否比其他类更影响体重。3.研究ABX效应的持续时间。设计：首先，我们将使用过去10年的数据进行回顾性队列研究，这些数据来自大型初级保健机构的患者。约6，700名儿童和青少年接受了为期4周的长期口服ABX处方（并在ABX前/后获得了药房填充数据和体重）。在我们的初步分析中，我们将重点关注青少年痤疮，最健康和同质的群体。其中大约500人有体重和身高前/后ABX。我们还将分析儿童，以研究ABX对更广泛年龄范围的影响。在我们的主要分析中，每例患者将作为其自身对照。我们将使用标准t检验测量末次ABX前BMI Z评分与首次ABX后（主要结局）之间的变化，以及BMI Z评分变化e0.5的比例。在二次分析中，我们还将捕获每个受试者的数据轨迹，并探索其他变量对研究关联的影响。其次，我们将进行一项巢式病例对照研究，比较口服ABX的青少年痤疮患者与仅外用药物的痤疮患者的对照组。通过这些分析，我们将消除个体间的变异性，最大限度地减少个体内的变异性，并解释与正常生长相关的变化。潜在影响：ABX促进生长作用的文献将为肠道微生物群和感染在儿童肥胖中的作用提供进一步的经验支持，并为新的预防策略开辟新的视野。我们想研究在健康儿童和青少年中长期使用ABX是否具有生长促进作用，这种作用是否特异于某些抗生素，以及在抗生素停止后是否会持续体重增加。找到抗生素和体重之间的联系可能会为预防儿童肥胖症的策略开辟新的视野。

DESCRIPTION (provided by applicant): Obesity and overweight in children have rapidly become epidemic. One factor that may contribute to this phenomenon is infection, either changes in specific exposures or in colonizing flora, and use of antibiotics (ABX) may also play a role. The growth promoting effects of ABX in farm animals have been known since the 1940's. A similar effect of prolonged ABX use in humans seems increasingly plausible. A 1950's trial in army recruits showed that those treated with ABX gained more weight than did placebo controls. More recently, endocarditis patients receiving ABX had marked weight gain compared to matched controls without ABX. Investigators hypothesize that there is an association between obesity and gut microbiota and that ABX can affect weight also by altering gut microbiota. In young children, changes in gut microbiota by adding probiotics to formula have resulted in marked weight increase. Studying the role of ABX on weight is challenging because patients who take ABX are usually ill and then gain weight in the course of improving their health. Some relatively healthy subjects however, do receive ABX and this group is the focus of our study. HYPOTHESIS: Prolonged ABX use in healthy children and adolescents promotes weight gain that is greater from what would be expected based on their pre-ABX growth. OBJECTIVES:1. To study whether prolonged oral ABX in healthy children and adolescents results in greater weight gain than expected based on their normal growth. 2. To assess whether specific classes of ABX classes affect weight more than others. 3. To study the duration of such ABX effect. DESIGN: First, we will do a retrospective cohort study using data from the past 10 years, from patients in a large primary care setting. About 6,700 children and adolescents were prescribed prolonged oral ABX for e4 weeks (and had pharmacy fill data AND weights pre/post-ABX). In our primary analysis we will focus on adolescents with acne, the most healthy and homogeneous group. About 500 of those had weights AND heights pre/post- ABX. We will analyze also children, to study the effect of ABX on a broader spectrum of ages. In our primary analysis each patient will serve as his/her own control. We will measure the change between last pre-ABX BMI Z-score and first post-ABX (primary outcome) using standard t-test AND also the proportion that had a BMI Z-score change e0.5. In secondary analyses we will also capture the trajectory of data for each subject and explore the effect of additional variables on the studied association. Second, we will do a nested case-control study to compare adolescents with acne on oral ABX with a matched control group of acne patients only on topicals. With these analyses we will eliminate between-individuals variability, minimize within-individual variability and account for changes associated with normal growth. POTENTIAL IMPACT: Documentation of growth promoting effects of ABX will provide further empiric support for the role of gut microbiota and infection in childhood obesity and open new horizons for novel preventive strategies. We want to study whether prolonged ABX use in healthy children and adolescents has a growth promoting effect, whether this effect is specific to certain antibiotics and whether any weight gain is sustained after antibiotic cessation. Finding a link between antibiotics and weight may open new horizons for strategies to prevent childhood obesity.