Fetal exposure to placental corticotropin-releasing hormone (pCRH) programs developmental trajectories

• Placental CRH organizes human neurobehavioral development.
• Elevated placental CRH is associated with preterm birth.
• Elevated placental CRH is associated with fearful temperament in children.
• Fetal exposure to CRH remodels the nervous system.
• Conservation of function across species.

The maternal endocrine stress system is profoundly altered during the course of human pregnancy. The human placenta expresses the genes for CRH as early as the seventh week of gestation and it is the expotential increase in placental CRH (pCRH) over the course of human gestation that is responsible for the greatest modification in the maternal stress system. The bi-directional placental release of hormones into the maternal and fetal compartments has profound influences for both. The influential Fetal Programming model predicted that early or fetal exposures to maternal signals of threat or adverse conditions have lifelong consequences for health outcomes. A basic assumption of this model was that developing organisms play a dynamic role in their own construction. Data are reviewed and new data are presented that elevated pCRH over the course of human gestation plays a fundamental role in the organization of the fetal nervous system, modifies birth phenotype (the timing of the onset of spontaneous labor and delivery), and influences developmental, temperamental and metabolic trajectories. Evidence for sex differences and conserved function across species is presented. Finally, a model is presented that proposes several pathways that pCRH can program risk for health and disease.