A preconception cohort study of air pollution, fertility, and miscarriage

摘要 不孕不育和自然流产(SAB)是重大的公共卫生问题，每个问题影响高达20%的 美国的育龄夫妇。随着越来越多的夫妇推迟生育， 在生育年份，许多人寻求不孕不育治疗，成功率相对较低，费用估计为 每年50亿美元，并与不良妊娠结局有关。因此，识别可修改的风险 不孕不育和SAB的因素是一个重要的公共卫生目标。空气污染对健康风险的潜在影响 不育症和SAB的研究还不够深入。现有的少数人体研究有很大的局限性，包括 回溯性研究设计，研究规模小，暴露和结果评估不够理想，不充分 对潜在混杂变量的控制，以及有限的泛化。拟议的研究将评估 两个相互关联的先入性前瞻性队列中几种空气污染物与不孕症和SAB风险的关系 在北美和丹麦学习。使用基于网络的招聘、数据收集和跟踪，我们拥有 招募了超过16,500名试图怀孕的女性，共同构成了最大的未孕队列 曾进行过与生育和SAB相关因素的研究。我们已经收集了关于时间的预期数据 怀孕、SAB、夫妻双方的潜在混杂因素，以及基线和双月住址 对所有参与者的跟踪调查问卷，为准确的时变评估提供基础 在怀孕前和怀孕早期暴露在空气污染中。我们的具体目标是 为感兴趣的病因时间段开发环境PM2.5、NO2和O3的时空模型，构建 使用地理信息系统软件测量每个住宅周围的交通和道路密度， 并对风险敞口进行适当的时变估计。在18,500名女性中，我们将检查 单项空气污染指标(PM2.5、NO2、O3和交通密度指标)与 受精率，受孕的特定周期概率。我们将评估同样的空气污染指标 有SAB的风险。我们还将利用最先进的统计方法，包括预测k-均值聚类， 检查污染物混合物的影响，重点是PM组分的形态。优势： 这一申请包括其庞大的研究规模，对地理和种族多样化的先入为主的招生 妊娠规划者队列，评估怀孕前和怀孕期间的重复暴露措施 早孕期，通过收集对个人和邻里层面的混淆进行出色的控制 对各种协变量的数据进行了分析，并使用了多种污染物模型技术。本申请 在利用NICHD资助的已经建立的队列研究方面具有成本效益。建议进行的研究 解决与空气有关的新的和重要的生殖健康结果 污染。研究结果可能为不孕不育和SAB的初级预防提供信息，并增加所用证据 监管机构为改善空气质量而采取的措施。

ABSTRACT Infertility and spontaneous abortion (SAB) are significant public health problems, each affecting up to 20% of reproductive-aged couples in the United States. As couples increasingly postpone childbearing to the later reproductive years, many seek infertility treatment, which has relatively low success rates, costs an estimated $5 billion per year, and is associated with adverse pregnancy outcomes. Therefore, identifying modifiable risk factors for subfertility and SAB is an important public health goal. The potential effects of air pollution on risk of subfertility and SAB are understudied. The few existing human studies have major limitations including retrospective study design, small study size, suboptimal assessment of exposure and outcome, inadequate control for potential confounding variables, and limited generalizability. The proposed study will assess the relation of several air pollutants to risk of subfertility and SAB in two interrelated preconception prospective cohort studies in North America and Denmark. Using web-based recruitment, data collection, and follow-up, we have enrolled over 16,500 women attempting pregnancy, collectively comprising the largest preconception cohort study ever conducted on factors related to fertility and SAB. We have collected prospective data on time-to- pregnancy, SAB, potential confounders in both partners, and residential addresses at baseline and on bi-monthly follow-up questionnaires for all participants, providing the foundation for accurate time-varying assessment of exposure to air pollution throughout the preconception and early pregnancy periods. Our specific aims are to develop spatio-temporal models of ambient PM2.5, NO2, and O3 for the etiologic time periods of interest, construct measures of traffic and roadway density around each residence using geographic information system software, and assign appropriate time-varying estimates of exposure. Among 18,500 women, we will examine the association between individual measures of air pollution (PM2.5, NO2, O3 and measures of traffic density) and fecundability, the cycle-specific probability of conception. We will evaluate the same measures of air pollution with risk of SAB. We will also utilize state-of-the-art statistical methods, including predictive k-means clustering, to examine the effects of pollutant mixtures, with an emphasis on speciation of PM components. Strengths of this application include its large study size, preconception enrollment of a geographically and ethnically diverse cohort of pregnancy planners, assessment of repeated measures of exposure during the preconception and early pregnancy periods, excellent control for individual-level and neighborhood-level confounding via collection of data on a wide range of covariates, and the use of multi-pollutant modeling techniques. The present application is cost-effective in leveraging already-established cohort studies funded by the NICHD. The proposed study addresses novel and important reproductive health outcomes that have had only limited study in relation to air pollution. Study results are likely to inform primary prevention of infertility and SAB, and add to evidence used by regulators to improve air quality.