Neurodevelopmental Effect of Acetaminophen Exposures

项目摘要 推荐对乙酰氨基酚（N-乙酰基-对氨基苯酚或APAP）作为一种安全的治疗方法， 怀孕期间发烧据估计，在美国，45-65%的孕妇报告摄入了APAP，但 关于产前暴露对后代的潜在健康影响的安全性数据很少。APAP 胎盘 可以穿过 屏障到达胎儿，其在早期发育中代谢化合物的能力有限。 最近的实验研究表明，令人信服的证据表明，APAP可以诱导抗雄激素 可能影响胎儿大脑发育。母胎医学与美国食品协会 和药物管理局呼吁进行更彻底的调查和更好的数据，以指导安全性， APAP在怀孕期间的使用。我们经验丰富的多学科团队建议利用收集的丰富数据 丹麦国家出生队列（DNBC）和丹麦人口医疗登记处的记录， 研究APAP暴露对胎儿发育的潜在影响。在目标1中，我们将研究64，322名母亲- 在DNBC登记的儿童对，并调查产前暴露于APAP对广谱 从婴儿期到18岁的多个时间点确定的神经发育结果。六个领域 的结果将进行检查，包括婴儿期的里程碑，颅面标志物，神经行为障碍， 运动功能、学校表现和心理健康。一组丰富的混杂因素，包括母亲 疾病和家族/遗传风险，将在一个强有力的多阶段分析框架中进行审查。另外我们 将评估出生后APAP暴露对神经发育的影响（目的1a），APAP的影响 暴露于儿童ADHD，调整ADHD的遗传风险（目的1b），并探讨APAP是否 暴露影响不同的神经精神表型和/或整个童年的行为轨迹， 青春期（目标1c）。在目标2中，我们将研究产前联合用药暴露对APAP的影响 以及它们对神经发育的影响。我们将检查与APAP使用同时发生的药物是否 在怀孕期间，研究人员混淆了APAP暴露与儿童神经发育之间的联系。我们还将 检查合并用药暴露的联合效应。我们将重点介绍常见药物列表（7大 和15个亚类），其影响文献中记载的胎儿生长和/或脑发育。这一及时 一项研究项目将提供强有力的科学严谨的数据，以告知早期生活的长期健康影响 APAP对儿童神经发育的影响这也是最广泛的队列研究， 母体多药暴露对子代神经发育的影响我们的发现将有助于 APAP是一种广泛使用的妊娠期药物， 以及相关的联合用药。

Project Summary Acetaminophen (N-acetyl-p-aminophenol or APAP) is recommended as a safe treatment to reduce pain and fever during pregnancy. An estimated 45-65% of pregnant people reported intake of APAP in the U.S., but there has been little data on safety for potential health effects in the prenatally exposed offspring. APAP placental can cross the barrier reaching the fetus which has limited capacity to metabolize the compound in early development. Recent experimental studies demonstrated compelling evidence suggesting APAP can induce anti-androgenic effects potentially affecting fetal brain development. The Society for Maternal-Fetal Medicine and the U.S. Food and Drug Administration have called for a more thorough investigation and better data to guide the safety of APAP use in pregnancy. Our experienced and multidisciplinary team proposes to leverage the rich data collected in the Danish National Birth Cohort (DNBC) and records from the Danish population medical registries to investigate the potential effects of APAP exposures on fetal development. In Aim 1, we will study 64,322 mother- child pairs enrolled in the DNBC and investigate the effects of prenatal exposure to APAP on a wide spectrum of neurodevelopmental outcomes, ascertained at multiple time points from infancy through age 18. Six domains of outcomes will be examined, including milestones in infancy, craniofacial markers, neurobehavioral disorders, motor function, school performance, and mental health. A rich set of confounding factors, including maternal illnesses and familial/genetic risks, will be examined in a robust multi-stage analytical framework. In addition, we will evaluate the effect of post-natal APAP exposure on neurodevelopment (aim 1a), the effect of APAP exposures on childhood ADHD, adjusting for the genetic risk of ADHD (aim 1b), and explore whether APAP exposures affect distinct neuropsychiatric phenotypes and/or behavioral trajectories across childhood and adolescence (aim 1c). In Aim 2, we will investigate the influence of prenatal co-medication exposures with APAP and their impacts on neurodevelopment. We will examine whether medications that co-occur with APAP use during pregnancy confound the associations between APAP exposure and child neurodevelopment. We will also examine the joint effects of co-medications exposures. We will focus on a list of common medications (7 major and 15 subclasses) that impact fetal growth and/or brain development documented in the literature. This timely research project will provide strong and scientifically rigorous data to inform long-term health effects of early life exposure to APAP on child neurodevelopment. This is also the most extensive cohort study investigating maternal polypharmacy exposure effects on offspring neurodevelopment. Our findings will contribute to regulatory recommendations and policymaking decisions for APAP, a widely consumed medication in pregnancy, as well as related co-medication use.