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

摘要 不孕症和自然流产（SAB）是严重的公共卫生问题，影响到多达25%的 美国的育龄夫妇。不孕症和SAB导致的医疗保健费用超过5美元 一些研究表明，不孕症治疗与不良反应之间存在关联。 妊娠结局。因此，确定低生育力和SAB的可改变的风险因素是一个重要的公共 健康目标。暴露于内分泌干扰物（EDCs）对生育力低下风险的潜在影响， SAB是备用的。现有的少数人体研究存在局限性，包括样本量小，招募 受孕后，回顾性研究设计，暴露和结局的次优评估，不充分 控制潜在的混杂变量，以及有限的概括性。这项研究将前瞻性地 评估暴露于选定的内分泌干扰物的关系，包括苯酚、邻苯二甲酸酯、全氟烷基和多氟烷基 在950名怀孕计划者的孕前子队列中，使用PFAS对生育力低下和SAB的风险进行评估。我们 将使用来自北美两个NICHD支持的怀孕计划者前瞻性队列的数据， 丹麦。通过网络招聘和数据收集，我们已经招募了17，000多名女性， 怀孕到这些人群中。在200名参与者的子集中，我们成功地进行了现场试点测试 在孕前和怀孕早期采集尿液和血液样本。在这 应用，我们建议扩大在人的生物标本收集，增加妇女的数量， 怀孕前和怀孕早期的尿液和血液样本从200到950。我们的三个生物样本 收集地点（波士顿，底特律和奥胡斯），我们将招募250名妇女，并收集三个尿液样本和一个 血液样本（孕前）和三个尿液样本和一个血液样本（怀孕早期）。我们将 将样本运送至CDC进行尿邻苯二甲酸盐、尿酚和血清PFAS分析。到 为了提高成本效益，我们将在每个暴露窗口合并三个尿液样本，然后进行分析， 邻苯二甲酸盐和苯酚;我们将检测一个孕前血液样本的PFAS，一种持久性化学物质， 在低生育力和SAB的分析中。最后，我们将在100名美国参与者中进行一项试点研究， 通过邮寄收集尿液的可行性，这将使我们能够利用我们的地理多样性， 未来的cohort该申请的优势包括前瞻性设计、 妊娠计划者，在孕前和妊娠早期重复测量暴露，极好 通过每两个月收集一次关于广泛协变量的前瞻性数据来控制混杂因素，并使用 混合物建模的最新分析方法。我们已经产生了令人信服的初步数据，以支持我们的 目标。现时的拨款是具成本效益的，可利用已建立的有数据收集的群组研究 后续工作由其他赠款支持。产生的结果将通过直接通知未来的翻译 关于EDC标准的监管决定，以降低不孕症和SAB的发生率。

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.