Abstract

BACKGROUND

The function of the gestational sac (GS) and the placenta in the closely related processes of embryogenesis and teratogenicity in the first trimester has been minimally described. The prevailing assumption is that direct teratogenic effects are mediated by the critical extraembryonic organ, the placenta, which either blocks or transfers exposures to the foetus. Placental transfer is a dominant mechanism, but there are other paradigms by which the placenta can mediate teratogenic effects. Knowledge of these paradigms and first trimester human developmental biology can be useful to the epidemiologist in the conduct of biomarker-based studies of both maternal and child health.

OBJECTIVE AND RATIONALE

Our aim is to provide a causal framework for modelling the teratogenic effects of first trimester exposures on child health outcomes mediated by the GS and placenta using biomarker data collected in the first trimester. We initially present first trimester human developmental biology for the sake of informing and strengthening epidemiologic approaches. We then propose analytic approaches of modelling placental mechanisms by way of causal diagrams using classical non-embryolethal teratogens (diethylstilboestrol [DES], folic acid deficiency and cytomegalovirus [CMV]) as illustrative examples. We extend this framework to two chronic exposures of particular current interest, phthalates and maternal adiposity.

SEARCH METHODS

Information on teratogens was identified by a non-systematic, narrative review. For each teratogen, we included papers that answered the five following questions: (i) why were these exposures declared teratogens? (ii) is there a consensus on biologic mechanism? (iii) is there reported evidence of a placental mechanism? (iv) can we construct a theoretical model of a placental mechanism? and (v) can this knowledge inform future work on measurement and modelling of placental-foetal teratogenesis? We prioritized literature specific to human development, the organogenesis window in the first trimester and non-embryolethal mechanisms.

OUTCOMES

As a result of our review of the literature on five exposures considered harmful in the first trimester, we developed four analytic strategies to address first trimester placental mechanisms in birth cohort studies: placental transfer and direct effects on the foetus (DES and maternal adiposity), indirect effects through targeted placental molecular pathways (DES and phthalates), pre-placental effects through disruptions in embryonic and extraembryonic tissue layer differentiation (folic acid deficiency), and multi-step mechanisms that involve maternal, placental and foetal immune function and inflammation (DES and CMV).

WIDER IMPLICATIONS

The significance of this review is to offer a causal approach to classify the large number of potentially harmful exposures in pregnancy when the exposure occurs in the first trimester. Our review will facilitate future research by advancing knowledge of the first trimester mechanisms necessary for researchers to effectively associate environmental exposures with child health outcomes.

中文翻译：

---

妊娠早期妊娠囊胎盘和胎儿致畸机制：出生队列研究框架

摘要

背景

妊娠囊（GS）和胎盘在妊娠早期密切相关的胚胎发生和致畸过程中的功能很少被描述。普遍的假设是，直接致畸作用是由关键的胚胎外器官胎盘介导的，胎盘可以阻止或将暴露转移给胎儿。胎盘转移是一种主要机制，但胎盘还可以通过其他方式介导致畸作用。这些范例和妊娠早期人类发育生物学的知识对于流行病学家进行基于生物标志物的孕产妇和儿童健康研究很有用。

目标和理由

我们的目标是提供一个因果框架，利用妊娠早期收集的生物标志物数据来模拟妊娠早期暴露对 GS 和胎盘介导的儿童健康结果的致畸影响。我们最初介绍妊娠早期的人类发育生物学，是为了提供信息和加强流行病学方法。然后，我们提出使用经典非胚胎致畸剂（二乙基己烯雌酚 [DES]、叶酸缺乏和巨细胞病毒 [CMV]）作为说明性示例，通过因果图来模拟胎盘机制的分析方法。我们将这个框架扩展到当前特别感兴趣的两种长期暴露：邻苯二甲酸盐和母亲肥胖。

搜寻方法

关于致畸剂的信息是通过非系统的叙述性审查确定的。对于每种致畸因素，我们纳入了回答以下五个问题的论文：(i) 为什么这些暴露被宣布为致畸因素？(ii) 生物学机制是否有共识？(iii) 是否有胎盘机制的报道证据？（iv）我们能否构建胎盘机制的理论模型？(v) 这些知识能否为未来胎盘-胎儿畸形发生的测量和建模工作提供信息？我们优先考虑针对人类发育、妊娠早期的器官发生窗口和非胚胎机制的文献。

结果

根据我们对关于妊娠早期被认为有害的五种暴露的文献的回顾，我们制定了四种分析策略来解决出生队列研究中妊娠早期胎盘机制：胎盘转移和对胎儿的直接影响（DES和母亲肥胖），通过靶向胎盘分子途径（DES和邻苯二甲酸盐）产生间接影响，通过破坏胚胎和胚胎外组织层分化（叶酸缺乏）产生胎盘前影响，以及涉及母体、胎盘和胎儿免疫功能和炎症的多步骤机制（DES）和巨细胞病毒）。

更广泛的影响

本次综述的意义在于提供一种因果方法，对妊娠早期发生的大量潜在有害暴露进行分类。我们的审查将通过增进对研究人员有效地将环境暴露与儿童健康结果联系起来所需的前三个月机制的了解来促进未来的研究。