A Barrier to Understanding Teratogenicity: The Critical Periods of Sensitivity for Most Structural Birth Defects Precede the Established Hemochorial Placenta

Abstract

Background

Teratogens and other environmental factors influence human birth defect risk, but our understanding of how they reach the developing conceptus is surprisingly limited. The placenta is often invoked as a key mediator of teratogenicity by acting as a physical barrier that can block or regulate the transfer of harmful substances to the embryo or fetus.

Methods

In this review, we compare the timing of teratogen susceptibility with the development of the placenta. Teratogenicity data from multiple published studies were plotted on a unified multi-species developmental timeline to relate findings from animal models to human developmental timing.

Results

The critical periods for most teratogen-induced structural birth defects, including fetal alcohol syndrome-related defects, neural tube defects, orofacial clefts, and limb malformations translate to the 3rd to 6th week of human embryonic development, while the human hemochorial placenta matures later, between 8 and 12 weeks of pregnancy.

Conclusions

This developmental chronology challenges the seemingly pervasive notion that placental transfer capacity plays a major role in mediating teratogenicity and highlights the need to further investigate the barrier capacity of the structures that surround and protect the developing embryo (e.g., trophoblast, yolk sac) prior to formation of the definitive placenta, and when the embryo is most sensitive to teratogenic insult.