Human placentation: foundations and implications for reproductive endocrinology and infertility

Human fetal development requires sustenance via the placenta, which mediates molecular transport between maternal and fetal circulations. Placental formation begins as cells of the trophoblast lineage differentiate and the extraembryonic mesoderm becomes vascularized, assembling a unique organ de novo that facilitates nutrient and gas exchange, waste removal, hormone production and immune modulation. We describe how placentation is orchestrated to keep pace with fetal growth, but is vulnerable to disruption by medical interventions for infertility. Initially, trophoblast stem cells differentiate into proliferating mononuclear cytotrophoblasts (CTBs) that fuse to form the multinucleated syncytiotrophoblast (STB). The STB ensheathes the chorionic villi, bathed in maternal blood. As fetal blood vessels develop within the mesodermal core of villi, the maternal-fetal interface is established. Where the villi meet the decidua, CTBs further differentiate into extravillous trophoblasts, which invade and remodel uterine arteries into high-conductance, low-resistance vessels, enhancing maternal blood flow to the placenta. Among the critical intercellular axes that govern trophoblast differentiation, invasion, and vascular remodeling hormonal cues, particularly those associated with the corpus luteum, are critical; their alteration in certain assisted reproductive technology (ART) protocols can contribute to incomplete arterial remodeling. Malplacentation is linked to miscarriage, fetal growth restriction, and preeclampsia, affecting over 10% of pregnancies, and occurring at higher rates in patients diagnosed with infertility, especially those who conceive through ART. Understanding the mechanisms driving these pathologies is essential for improving pregnancy outcomes. Strategies to optimize ART protocols and therapeutic interventions targeting key signaling pathways offer potential avenues to mitigate risks associated with malplacentation.