Scientific basis and therapeutic regimens for use of antenatal glucocorticoids

Abstract

The scientific basis for use of prenatal steroid therapy in preparing the human fetus for premature delivery is extensive and convincing. Studies in numerous animal species have documented precocious maturation of lung and other tissues after administration of glucocorticoids to the fetus, and ablation experiments indicate delayed organ maturation with a deficiency of endogenous corticosteroid. The timing of lung differentiation correlates well with the developmental increase in circulating corticosteroid, supporting the concepts that endogenous corticosteroids, interacting with other hormones, are important physiologic modulators of tissue maturation and that prenatal steroid therapy mimics the effect of endogenous glucocorticoids. In fetal lung the response to glucocorticoid involves induction of a limited number of proteins, including all the components of surfactant, as well as key lipogenic enzymes. These effects are mediated by glucocorticoid receptors, occur with physiologic concentrations of hormone, are primarily exerted at the level of gene activation, and are reversible on removal of hormone from cultured tissue. These various observations predict that a relatively brief exposure of the human fetus to glucocorticoid accelerates the normal developmental process in lung and other tissues and reduces disease resulting from developmental immaturity. Prenatal treatment with either betamethasone or dexamethasone at the recommended doses provides similar physiologic stress levels of glucocorticoid activity in fetal plasma sufficient to provide a near-maximal occupancy of receptors and induction of target proteins. Elevated glucocorticoid levels are maintained during the course of treatment and values return to normal by 2 days after the last dose. Treatment causes a transient suppression of maternal and fetal adrenal function; however, treated infants respond to newborn stress with a near-normal cortisol surge. However, there is little information, and reason for concern, regarding the safety of higher or repeated dose of prenatal steroid, and accordingly, routine retreatment of women who are not in active labor is not advised. The recommendation of the consensus panel that corticosteroid therapy is indicated for women at risk of premature delivery with few exceptions is thus well supported by evidence relating to glucocorticoid effects, mechanisms, and pharmacokinetics.