Prenatal programming of human neurological function

Abstract

The human placenta expresses the genes for proopiomelanocortin and the major stress hormone, corticotropin-releasing hormone (CRH), profoundly altering the "fight or flight" stress system in mother and fetus. As pregnancy progresses, the levels of these stress hormones, including maternal cortisol, increase dramatically. These endocrine changes are important for fetal maturation, but if the levels are altered (e.g., in response to stress), they influence (program) the fetal nervous system with long-term consequences. The evidence indicates that fetal exposure to elevated levels of stress hormones (i) delays fetal nervous system maturation, (ii) restricts the neuromuscular development and alters the stress response of the neonate, (iii) impairs mental development and increases fearful behavior in the infant, and (iv) may result in diminished gray matter volume in children. The studies reviewed indicate that fetal exposure to stress peptides and hormones exerts profound programming influences on the nervous system and may increase the risk for emotional and cognitive impairment.

Figure 1

The regulation of the HPA axis changes dramatically over the course of gestation with profound implications for the mother and the fetus. One of the most significant changes during pregnancy is the development of the placenta, a fetal organ with significant endocrine properties. During pregnancy, CRH is released from the placenta into both the maternal and fetal compartments. In contrast to the negative feedback regulation of hypothalamic CRH, cortisol increases the production of CRH from the placenta. Placental CRH (pCRH) concentrations rise exponentially over the course of gestation. In addition to its effects on pCRH, maternal cortisol passes through the placenta. However, the effects of maternal cortisol on the fetus are modulated by the presence of p11βHSD2 which oxidizes it into an inactive form, cortisone. Activity of this enzyme increases as pregnancy advances and then drops precipitously so that maternal cortisol is available to promote maturation of the fetal lungs, central nervous system, as well as other organ systems.

Figure 2

Schematic representation of the psychobiological stress, fetal programming model that guides our research program. Fetal exposure to stress can influence infant/child development directly or indirectly (through fetal behavior, birth outcomes, and neonatal functioning).