Currently, 8 to 10 percent of all live births are premature and contribute to more than 60 percent of perinatal morbidity and mortality. Annually, this accounts for almost a quarter million low birth weight infants. Despite many advances in perinatal care the incidence of preterm birth has not declined. Until the prevention of premature birth becomes a reality, the consideration of alternative therapies is necessary. The purpose of this article is to discuss the impact of antenatal steroid therapy on neonatal outcomes. This article will focus on studies of antenatal steroid use for lung maturation and the prevention of respiratory distress syndrome (RDS), as well as two other common neonatal problems--patent ductus arteriosus and periventricular/intraventricular hemorrhage.
Antenatal Steroids and Lung Maturity
The landmark clinical trial of antenatal steroid therapy reported by Liggins and Howie (1972), involved 268 women between 24 and 36 weeks gestation. The subjects were given betamethasone 12 mg IM twice, 24 hours apart or a placebo. The study suggested that infants born to mothers treated with betamethasone prior to delivery had a decreased incidence of RDS. In a subsequent study, Murphy (1974) demonstrated low cortisol and cortisone levels in the cord blood of infants who subsequently developed RDS.
In 1976, the National Heart, Lung, and Blood Institute of the National Institutes of Health sponsored a collaborative project to investigate the safety and efficacy of antenatally administered steroids. During the study, 720 participants were enrolled in a randomized, double-blind, placebo trial with gestational ages ranging from 26 to 37 weeks gestation. The collaborative group reported that prenatal steroid administration was effective in reducing the overall incidence of RDS, however the group advised that antenatal steroids should be used selectively and with caution. The reason was because the study found no difference in the incidence of RDS among the offspring of women with prolonged rupture of the membranes, among blacks, and among female infants. The most significant decrease in incidence of RDS was in infants born between 30 and 34 weeks. However, only 17 infants below 30 weeks gestation were enrolled in the study.
Regarding the safety of antenatal steroids in women with premature rupture of the membranes, the collaborative group study found no differences in rates of maternal or fetal infections. Subsequent studies (Papageorgiou, 1979; Doran, 1980; and Schmidt, 1984; Ferguson, 1984) also reported no differences in the rate of maternal infections, however one study (Taeusch, 1975) found a higher rate of infection in those mothers that had rupture of the membranes for longer than 24 hours. Hypoglycemia has been reported, and particularly in conjunction with betamimetics and in diabetics. Pulmonary edema associated with steriods has been cited in case reports, mainly with concurrent tocolytic therapy or in twin pregnancies. A controlled trial failed to show an association.
In the 22 years since the Liggins and Howie study, there have been 11 other prospective randomized controlled clinical trials. Eleven of these twelve trials demonstrated a decline in RDS with an overall reduction of over 50 percent. A recent meta-analysis (Crowley, 1990) also demonstrated an overall reduction in neonatal deaths, cerebral hemorrhage, and necrotizing enterocolitis. The infants that benefited most were born 24 hours to 7 days after steroid therapy, but infants born outside this time frame were also helped. Infants did better at all gestational ages at which RDS occurs. The meta-analysis revealed no evidence that gender influenced the protective effects of corticosteroids. A separate analysis of steroid administration after premature rupture of the membranes also suggested a significant reduction in RDS.
Betamethasone is the most commonly used corticosteroid preparation (66 per cent of centers). According to Liggins, steroids should be used at 26 to 34 weeks gestation, and beyond 34 weeks only if the L/S ratios is immature. He recommends betamethasone 5 mg every 12 hours times 4.
Effects on Patent Ductus Arteriosus
A PDA in the preterm infant is associated with an increased incidence of bronchopulmonary dysplasia and intraventricular hemorrhage. The delayed closure of the PDA seen in premature infants may be the result of a combination of factors, including ineffective contractile response of the ductus to high oxygen levels after birth or poor response to circulating prostaglandin.
One of the reasons that some infants do not develop a PDA is because of induced glucocorticoid synthesis brought on by intrauterine stress. During chronic intrauterine stress, such as pre-eclampsia, glucocorticoid synthesis increases. In both human and animal studies an increase in cortisol levels has been associated with accelerated ductal muscle maturity. During the initial surfactant replacement therapy clinical trials, investigators found that the infants with the lowest incidence of PDA were those infants whose mothers were treated antenatally with steroids. Thus it appears that the protective effect of steroid therapy extends to decreasing the incidence and complications of PDA.
Effects on Periventricular/Intraventricular Hemorrhage
Periventricular/intraventricular hemorrhage (PIVH) in the preterm infant continues to produce significant neonatal morbidity and mortality. There are known associations between RDS and PIVH. Hypoxic/ischemic brain injury, which is thought to be a major determinant of PIVH, may occur as a consequence of RDS. Infants with RDS have fluctuations in blood pressure associated with their physiologic instability and therapeutic interventions such as mechanical ventilation. In addition, infants with RDS are at increased risk of pneumothoraces which cause dramatic changes in cerebral pressure, markedly increasing risk for PIVH. Since antenatal steroids decrease the incidence and severity of RDS and thus the need for mechanical ventilation, this, in theory, would decrease the incidence of PIVH. The effect of steroids on decreasing the incidence of PDA may also have a positive outcome in decreasing PIVH. It is also possible that in the same way antenatal steroids enhance ductal maturity, they may have an effect on the maturity of intracerebral vessels and provide protection against PIVH.
Summary
In selected patients, antenatal steroid therapy decreases the incidence, severity and complications of RDS, and decreases overall neonatal mortality and morbidity. In addition, antenatal steroids may decrease the incidence of PDA and PIVH. Not discussed in this article are possible maturational effects on other organs systems such as the GI tract, kidneys and skin. Used appropriately, corticosteroid therapy provides these benefits with minimal complications to the mother and infant.
