First trimester mechanisms of gestational sac placental and foetal teratogenicity: a framework for birth cohort studies

Author:

Adibi Jennifer J12ORCID,Layden Alexander J12,Birru Rahel L1,Miragaia Alexandra1,Xun Xiaoshuang1,Smith Megan C3,Yin Qing4,Millenson Marisa E5ORCID,O’Connor Thomas G678,Barrett Emily S9,Snyder Nathaniel W10,Peddada Shyamal4,Mitchell Rod T11ORCID

Affiliation:

1. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

2. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA

3. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

4. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

5. School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

6. Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, USA

7. Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA

8. Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA

9. Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, NJ, USA

10. Department of Microbiology and Immunology, Center for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

11. MRC Centre for Reproductive Health, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, UK

Abstract

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.

Funder

National Institute of Environmental Health Sciences

National Center for Advancing Translational Sciences

Department of Epidemiology

University of Pittsburgh Graduate School of Public Health

Publisher

Oxford University Press (OUP)

Subject

Obstetrics and Gynecology,Reproductive Medicine

Reference223 articles.

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