Prenatal, Intrapartum and Infant Antibiotic Use and Atopic Diseases in Childhood

 描述(申请人提供)：抗生素是怀孕和儿童早期最常用的药物之一。越来越多的证据表明，在产前和早期生命中破坏微生物区系的生态平衡可能会破坏免疫的轨迹。 系统发展对儿童免疫介导性疾病的发展有影响，包括哮喘、湿疹和花粉热，这些都是工业化社会中高度流行的慢性疾病。这项拟议的研究旨在阐明产前和出生后早期抗生素暴露对儿童特应性疾病的作用，明确考虑可能解释先前观察性流行病学研究中观察到的积极关联的偏见来源。我们将利用在大型健康维护组织北加州凯撒永久医院(KPNC)登记的552,000对母婴对的历史出生队列，来检验在怀孕期间、分娩期间和/或婴儿时期使用抗生素有助于特应性皮炎、过敏性鼻炎和儿童时期哮喘的病因的假设。关于1997年至2014年出生的儿童及其母亲的纵向数据将通过连接数据库收集起来，包括KPNC的电子医疗记录和药房配药记录，加州公共卫生部的出生记录，以及KPNC哮喘登记处，这是1996年成立的KPNC研究部的一个独特资源。超大的样本量将允许对抗生素使用的时间和类型进行精细评估，并检查关键的潜在影响因素，如分娩方式(阴道与剖腹产)、母乳喂养史以及母亲过敏或哮喘史。我们将采用创新的方法和统计方法来识别和减少此类研究中常见的偏差来源，包括反向因果关系、指示混淆以及未测量或测量不足的母婴因素(如求医行为)的混淆。方法将包括未来暴露方法的新应用，以加强对我们结果的因果解释，并扩大可用于检测和潜在纠正观察性流行病学研究中的偏差的工具 更广泛地说。使用这些方法，我们将回答以下问题：从产前到婴儿期的累计抗生素暴露对儿童特应性结局有什么影响；分娩方式、母乳喂养史、母亲哮喘或过敏史等因素是否改变了关系；时机、特征(例如，谱、类别、厌氧菌覆盖率、革兰氏阳性/革兰氏阴性覆盖率)和抗生素使用的适应症对儿童结局有什么影响；抗生素暴露是否与学龄期持续性疾病有关。高度翻译的结果将有助于指导最常用的早期处方药的临床安全使用。

 DESCRIPTION (provided by applicant): Antibiotics are among the most commonly used medications in pregnancy and early childhood. Increasing evidence suggests that disruption of the ecological balance of microbiota in prenatal and early life can derail the trajectory of immune system development, with implications for development of immune-mediated diseases in the child including asthma, eczema and hay fever, all chronic and highly prevalent diseases in industrialized societies. The proposed research seeks to elucidate the role of prenatal and early postnatal antibiotic exposure on childhood atopic diseases with explicit consideration of sources of bias that may account for the positive associations observed in previous observational epidemiologic studies. We will test the hypotheses that use of antibiotics during pregnancy, in the intrapartum period, and/or in infancy contributes to the etiology of atopic dermatitis, allergi rhinitis and asthma during childhood using a historical birth cohort of 552,000 mother-child pairs enrolled in Kaiser Permanente Northern California (KPNC), a large health maintenance organization. Longitudinal data on children born between 1997 and 2014 and their mothers will be assembled by linking across databases, including electronic medical records and pharmacy dispensing records at KPNC, birth records at the California Department of Public Health, and the KPNC Asthma Registry, a unique resource of KPNC Division of Research established in 1996. The exceptionally large sample size will allow for refined assessment of the timing and type of antibiotic use as well as examination of key potential effect modifiers such as delivery mode (vaginal versus Cesarean section), breastfeeding history, and maternal history of allergy or asthma. We will employ innovative methodological and statistical approaches to identify and reduce the sources of bias common in this kind of research, including reverse causality, confounding by indication, and confounding by unmeasured or poorly measured maternal and child factors such as healthcare-seeking behaviors. Methods will include novel application of a future exposure approach to strengthen causal interpretation of our results and expand the tools available for detection, and potentially correction, of bias in observational epidemiologic studies more broadly. Using these approaches we will answer the following questions: what is the effect of cumulative antibiotic exposures from the prenatal period through infancy on child atopic outcomes; are relationships modified by factors such as delivery mode, breastfeeding history, or maternal asthma or allergy history; what are the effects of the timing, characteristics (e.g., spectrum, class, anaerobe coverage, Gram-positive/Gram-negative coverage), and indication of the antibiotics taken on child outcomes; and are antibiotic exposures associated with persistent disease at school age. The highly translational results will help guide safe clinical use of the most commonly prescribed medications in early life.