A preconception cohort study of environmental chemicals, fertility, and miscarriage

摘要 不孕不育和自然流产(SAB)是严重的公共卫生问题，影响多达25% 美国的育龄夫妇。可归因于不孕不育和SAB的医疗费用超过5美元 每年10亿美元，几项研究表明不孕不育治疗和不良反应之间存在关联 妊娠结局。因此，确定不孕症和SAB的可改变的危险因素是一个重要的公众 健康目标。暴露于内分泌干扰性化学品(EDCs)对不育症和 SAB的研究还不够深入。现有的为数不多的人体研究存在样本量小、登记人数少等局限性 构思后，回溯性研究设计，暴露和结果的次优评估，不足 对潜在混杂变量的控制，以及有限的泛化。拟议的研究将前瞻性地 评估接触选定的内源性碳化物的关系，包括酚类、邻苯二甲酸盐、全氟烷基和多氟烷基 在950名怀孕规划师的先入为主的亚队列中，Pfas与不孕不育和SAB的风险有关。我们 将使用来自NICHD支持的北美和北美两个怀孕规划师预期队列的数据 丹麦。通过基于网络的招聘和数据收集，我们已经招募了17,000多名女性 把怀孕归入这些队列。在200名参与者中，我们成功地进行了面对面的试运行测试 收集怀孕前和怀孕早期的尿样和血样。在这 应用，我们建议扩大个人生物样本收集，增加患有 未孕和早孕的尿液和血液样本从200到950。在我们的三个生物展上 收集地点(波士顿、底特律和奥胡斯)，我们将招募250名女性，并收集3个尿样和1个 三份尿样和一份血样(怀孕早期)。我们会 将样品运往疾控中心进行尿邻苯二甲酸酯、尿酚和血清全氟辛烷磺酸的分析。至 为了提高成本效益，我们将在每个暴露窗口中汇集三个尿样，然后再进行检测 邻苯二甲酸盐和苯酚；我们将检测一个先入为主的血液样本的PFAS，一种持久的化学物质， 在不育症和SAB的分析中。最后，我们将在100名美国参与者中进行试点研究，以评估 通过邮寄收集尿液的可行性，这将使我们能够充分利用我们的地理多样性 未来的队列。此应用程序的优势包括前瞻性设计、先入为主的 怀孕计划者，在怀孕前和怀孕早期反复测量暴露，极好 通过对大范围协变量的双月前瞻性数据收集来控制混淆，并使用 用于混合物建模的最新分析方法。我们已经生成了令人信服的初步数据来支持我们的 目标。目前赠款在利用已建立的队列研究和数据收集方面具有成本效益 以及由其他赠款支持的后续行动。生成的结果将可通过直接通知未来进行翻译 关于EDC标准的监管决定，可以降低不孕不育和SAB的比率。

ABSTRACT Infertility and spontaneous abortion (SAB) are significant public health problems, affecting up to 25% of reproductive age couples in the United States. Health care costs attributable to infertility and SAB exceed $5 billion per year, and several studies have shown an association between infertility treatments and adverse pregnancy outcomes. Thus, identifying modifiable risk factors for subfertility and SAB is an important public health goal. The potential effects of exposure to endocrine-disrupting chemicals (EDCs) on risk of subfertility and SAB are understudied. The few existing human studies have limitations including small sample size, enrollment after conception, retrospective study design, suboptimal assessment of exposure and outcome, inadequate control for potential confounding variables, and limited generalizability. The proposed study will prospectively assess the relation of exposure to selected EDCs, including phenols, phthalates, and per- and poly-fluoroalkyl substances (PFAS), to risk of subfertility and SAB in a preconception subcohort of 950 pregnancy planners. We will use data from two NICHD-supported prospective cohorts of pregnancy planners in North America and Denmark. With web-based recruitment and data collection, we have enrolled over 17,000 women attempting pregnancy into these cohorts. In a subset of 200 participants, we have successfully pilot tested in-person collection of urine and blood specimens during the preconception and early pregnancy periods. In this application, we propose to expand in-person biospecimen collection, increasing the number of women with preconception and early pregnancy urine and blood samples from 200 to 950. At each of our three biospecimen collection sites (Boston, Detroit, and Aarhus), we will enroll 250 women and collect three urine samples and one blood sample (in preconception) and three urine samples and one blood sample (in early pregnancy). We will ship the samples to the CDC for the analysis of urinary phthalates, urinary phenols, and serum PFAS. To increase cost efficiency, we will pool three urine samples in each exposure window before assaying for phthalates and phenols; and we will assay one preconception blood specimen for PFAS, a persistent chemical, in analyses of subfertility and SAB. Finally, we will conduct a pilot study among 100 U.S. participants to assess the feasibility of collecting urine by mail, which would allow us to take advantage of our full geographically-diverse cohort in the future. Strengths of this application include the prospective design, preconception enrollment of pregnancy planners, repeated measurement of exposure during preconception and early pregnancy, excellent control for confounding via bimonthly prospective data collection on a wide range of covariates, and use of the latest analytic methods for mixtures modeling. We have generated compelling preliminary data to support our aims. The present grant is cost-effective in leveraging already-established cohort studies with data collection and follow-up supported by other grants. The results generated will be translatable by directly informing future regulatory decisions about EDC standards in a manner that could reduce rates of infertility and SAB.