Maternal Depression and Antidepressant Use During Pregnancy and Risk of Childhood Autism Spectrum Disorders in Offspring: Population-Based Cohort and Bidirectional Case-Crossover Sibling Study

 描述(由申请人提供)：我们建议对母亲抑郁和产前抗抑郁药物的使用进行药物流行病学研究，以解决他们与儿童自闭症谱系障碍(ASD)风险的关系。这项研究将花费 通过使用大型电子病历数据库--临床实践研究数据链接(CPRD)，有效地评估这种关系。CPRD是世界上使用最广泛的药物安全研究资源，能够将母亲和婴儿的记录联系起来，研究怀孕期间的暴露情况和后代的结局。在初步分析中，我们确定了约471,000对符合条件的母婴和~4,500例自闭症病例，母亲平均有6.5年有记录的病史，孩子平均随访10年。这项拟议的研究将是迄今为止就这一主题进行的最大规模的研究，将包括两个部分：1)队列研究和2)嵌套的双向病例交叉同胞研究。为了将药物效应与潜在疾病的效果区分开来，我们将考虑三种暴露类别：1)暴露于抗抑郁药物和抑郁(约16,400对母婴)，2)仅暴露于抑郁(约34,000对母婴)，以及3)仅暴露于抗抑郁药(约9,000对母婴)，与之相比，匹配的(4：1)未暴露于抑郁和抗抑郁药物的女性队列。以这种方式确定暴露的队列将使我们能够独立评估抑郁的影响，抗抑郁药物和抑郁的联合作用，以及在没有抑郁的情况下抗抑郁药物对后代患ASD风险的影响。我们还将进行一项新的“母亲孕期内”嵌套病例交叉同胞分析，以比较ASD病例和同一母亲所生的非ASD兄弟姐妹产前抗抑郁药物的暴露情况。这项兄弟姐妹分析将控制ASD的遗传和环境风险因素，以及母亲患抑郁症的易感性。我们将使用匹配、分层和多变量分析来检验CPRD中可用的各种医学和行为协变量的混杂。我们的研究团队由药物流行病学药物安全研究方面的专家组成，在抑郁症、抗抑郁药物、产前暴露和后代结局方面的研究方面具有丰富的经验。我们可以立即访问CPRD的数据，并且PI在使用CPRD的研究方面拥有25年的经验。我们建议的研究的其他优势包括大量的母婴配对和长时间的随访，使用现有的医疗记录(避免患者回忆的担忧)，用于混杂控制的丰富的协变量信息，以及嵌套的病例交叉同胞分析，以密切控制遗传和环境风险因素。这一项目对公共卫生的贡献是迅速告知 抗抑郁药物的安全性概况以及关于在怀孕期间使用这些药物的更广泛的辩论，涉及到越来越多的被诊断为自闭症的儿童。

 DESCRIPTION (provided by applicant): We propose a pharmacoepidemiology study of maternal depression and prenatal antidepressant medication use to address concerns regarding their association with the risk of autism spectrum disorder (ASD) in children. This study will cost efficiently evaluate this relationship via use of a large, electronic medical record database, the Clinical Practice Research Datalink (CPRD). The CPRD is the most widely used resource for drug safety research in the world and has the ability to link mother and baby records to study exposures during pregnancy and outcomes in the offspring. In a preliminary analysis, we identified ~471,000 eligible mother-baby pairs and ~4,500 ASD cases, with a mean of 6.5 years of recorded history for the mothers and mean of 10 years of follow-up for the children. The proposed study, which will be the largest study conducted on this topic to date, will have two parts: 1) a cohort study and 2) a nested bidirectional case-crossover sibling study. To separate the drug effect from that of underlying disease, we will consider three exposure categories; 1) Antidepressant and Depression Exposed (~16,400 mother-baby pairs), 2) Depression Only Exposed (~34,000 mother-baby pairs), and 3) Antidepressant Only Exposed (~9,000 mother-baby pairs), compared to a matched (4:1) unexposed cohort of women who have neither depression nor antidepressant medications. Defining the exposed cohort in this way will allow us to independently evaluate the effects of depression, the combined effect of antidepressants and depression, and the effect of antidepressants in the absence of depression on the risk of ASD in offspring. We will also conduct a novel 'within-mother-between-pregnancy' nested case-crossover sibling analysis to compare prenatal antidepressant medication exposure among ASD cases to that of non-ASD siblings born to the same mother. This sibling analysis will control for genetic and environmental risk factors for ASD, as well as maternal predisposition to depression. We will examine confounding for the wide variety of medical and behavioral covariates available in the CPRD using matching, stratification, and multivariable analysis. Our research team is comprised of experts in pharmacoepidemiology drug safety studies, with demonstrated experience in studies on depression, antidepressants, prenatal exposures and outcomes in offspring. We have immediate access to the CPRD data and the PI has >25 years of experience in studies using the CPRD. Other strengths of our proposed research include its large number of mother-baby pairs with long follow-up time, use of existing medical records (avoiding concerns of patient recall), the richness of covariate information for confounder control, and the nested case-crossover sibling analysis to closely control for genetic and environmental risk factors. The public health contribution of this project is to quickly inform the safety profile of antidepressant medications and the broader debate on the use of these medications during pregnancy with respect to the growing number of children diagnosed with ASD.