In a landmark paper, Liggins and Howie showed that a single course of antenatal corticosteroid therapy administered to women at risk for preterm delivery (PTD) reduced the incidence and severity of respiratory distress syndrome (RDS) and mortality in offspring . More than a dozen randomized trials have confirmed these findings . Subsequent trials have also shown that antenatal corticosteroid therapy improves circulatory stability in preterm neonates, resulting in lower rates of intraventricular hemorrhage (IVH) and necrotizing enterocolitis compared with unexposed preterm neonates.
This topic will review evidence supporting the use of antenatal corticosteroids to improve neonatal outcomes in women at risk for preterm delivery, pharmacological issues, and clinical concerns about administration of this therapy.
Mechanism of action — Corticosteroid stimulation of developmentally regulated gene expression and physiologic functions result in maturation of the lungs and some other tissues . Antenatal steroids accelerate development of type 1 and type 2 pneumocytes, leading to structural and biochemical changes that improve both lung mechanics (maximal lung volume, compliance) and gas exchange [4-8]. Induction of type 2 pneumocytes increases surfactant production by inducing production of surfactant proteins and enzymes necessary for phospholipid synthesis. Antenatal steroid exposure also enhances the neonatal response to postnatal surfactant treatment. Other effects of antenatal corticosteroids include induction of pulmonary beta-receptors, which play a role in surfactant release and absorption of alveolar fluid when stimulated ; induction of fetal lung antioxidant enzymes ; and upregulation of gene expression for the epithelial Na+ channel, which is important for absorption of lung fluid after birth . For these changes to occur, however, the lungs need to have reached a stage of development that is biologically responsive to corticosteroids. (See 'Gestational age at administration' below.)
The biologic rationale for repeating antenatal corticosteroid therapy is based upon the observation that biochemical stimulation of surfactant production appears to be reversible in cell culture models (eg, surfactant protein mRNA levels decline to control levels after cortisol is removed) [5,11]. However, other beneficial effects, such as cytostructural maturation, persist (in rhesus monkeys) after steroid exposure is withdrawn . (See 'Use of repeated courses of therapy' below.)
Evidence of short-term clinical efficacy
Reduction of RDS — In the landmark study by Liggins and Howie, 282 gravida at high risk for preterm delivery before 37 weeks of gestation were randomly assigned to receive betamethasone (two doses of 12 mg given intramuscularly 24 hours apart) or placebo (cortisone acetate 6 mg) . Administration of betamethasone resulted in a lower incidence of respiratory distress syndrome (RDS) (9.0 versus 25.8 percent in controls) . The maximum benefit occurred in the subgroup of infants delivered more than 48 hours but less than seven days after maternal treatment (incidence of RDS: 3.6 versus 33.3 percent in controls), and when the drug was given between 26 and 32 weeks of gestation (incidence of RDS: 11.8 versus 69.6 percent in controls).