Effects of antenatal corticosteroids on the hypothalamic-pituitary-adrenocortical axis of the fetus and newborn: experimental findings and clinical considerations

Abstract

The hypothalamic-pituitary-adrenocortical (HPA) axis is a major neuroendocrine pathway that modulates the stress response. The glucocorticoid, cortisol, is the principal end product of the HPA axis in humans and plays a fundamental role in maintaining homeostasis and in fetal maturation and development. Antenatal administration of synthetic glucocorticoids (GCs) accelerates fetal lung maturation and has significantly decreased neonatal mortality and morbidity in infants born before 34 weeks of gestation. Exposure to excess levels of endogenous GCs and exogenous GCs (betamethasone and dexamethasone) has been shown to alter the normal development trajectory. The development and regulation of the fetal HPA axis is discussed and the experimental animal evidence presented suggests long-term adverse consequences of altered HPA function. The clinical data in infants exposed to GCs also suggest altered HPA axis function over the short term. The longer-term consequences of antenatal GC exposure on HPA axis function and subtler neurodevelopmental outcomes including adaptation to stress, cognition, behavior, and the cardiovascular and immune responses are poorly understood. Emerging clinical strategies and interventions may help in the selection of mothers at risk for preterm delivery who would benefit from existing or future formulations of antenatal GCs with a reduction in the associated risk to the fetus and newborn. Detailed longitudinal long-term follow-up of those infants exposed to synthetic GCs are needed.

Figure 1

Neuroendocrine interactions among the maternal, placental and fetal compartments. The top panel depicts the activation (+) and negative feedback inhibition (−) pathways of the HPA system. 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. Because of this positive feedback between cortisol and placental CRH the effects of GCs on the fetus may be amplified. In addition to its effects on placental CRH, maternal cortisol passes through the placenta. However, the effects of maternal cortisol on the fetus are modulated by the presence of a placental enzyme 11βHSD2 which oxidizes it into an inactive form, cortisone. Synthetic GCs used for fetal lung maturation (betamethasone and dexamethasone) cross the placenta more easily because they are not readily metabolized by 11β-HSD2. Structures of the HPA axis begin their development early in gestation and become increasingly functional with the progression towards term. See text for description. GCs= glucocorticoids, CRH=corticotropin releasing hormone, ACTH=adrenocorticotropic hormone, 11βHSD2=11β-hydroxysteroid dehydrogenase type 2