Glucocorticoids in pregnancy: a master-switch for fetal maturation

The prepartum surge in plasma glucocorticoids is a critical signal for fetal organ maturation, facilitating the transition from fetal reliance on the placenta for functions such as respiration, nutrition, and waste removal to newborn use of their own physiological systems. The fetal glucocorticoid surge is conserved across mammalian species, but mechanisms driving the surge differ. Preterm birth interrupts fetal maturation because babies are born before the rise in endogenous glucocorticoids occurs, placing the newborn at greater risk of morbidity and mortality. In particular, lung immaturity increases risk of short-term and long-term respiratory disease. Antenatal corticosteroids (ACS) are routinely administered to women at risk of preterm birth to mimic the missed maturational signal of elevated glucocorticoids. Consequently, ACS improve neonatal survival and respiratory outcomes. Clinical guidelines universally recommend ACS use, but recommended regimens, gestational age limits, and use in settings of preexisting maternal conditions vary. Importantly, preterm infants have variable responsiveness to ACS treatment, and do not benefit equally. While male fetal sex and fetal growth restriction may be associated with lower ACS responsiveness, there is limited understanding of underlying factors. Emerging evidence points to differential glucocorticoid receptor isoform expression and elevated pretreatment plasma cortisol concentrations as potential contributors to variable ACS response. Improved insight into underlying mechanisms is crucial for identifying responsive subgroups and optimizing ACS treatment beyond the current one-size-fits-all approach to enhance health outcomes for preterm infants.