Should we take another look at antenatal corticosteroids?
Despite Liggins’ landmark paper in 1972 and more than 44 years of active research, we are still at a loss to define which pregnancies are most likely to benefit from antenatal corticosteroids (ACS) and which may be harmed.1 While much attention has been focused on the impact of ACS on the preterm lung, the long-term impact of ACS on other organ systems has not been adequately studied in humans, even though glucocorticoids affect every human organ system.
The efficacy and relative safety of a single course of ACS in pregnancies delivered prior to 32–34 weeks is well established and one of the most powerful interventions in obstetric medicine.2,3 The value of ACS in late preterm pregnancies and before elective cesarean at term is less clear. Here I review the latest data from clinical trials on this topic and the risks of expanding use of ACS therapy.
What the evidence says
Use of ACS at ≥34 weeks’ gestation was evaluated in a 2016 meta-analysis that included 6 randomized controlled trials (RCTs).4 The RCTs looked at 2 groups: women who were candidates for ACS with delivery anticipated between 35 and 37 weeks’ gestation (N=3204) and women undergoing planned elective cesarean at term (≥37 weeks’ gestation, N=2498). The primary outcome of all the RCTs in the meta-analysis was neonatal respiratory outcomes and/or NICU admissions. Only 3 trials were blinded and long-term outcomes are available from one study.5,6 The group of women randomized between 34 and 36 6/7 weeks for “imminent preterm delivery” demonstrated statistically significant reductions in severe respiratory distress syndrome (1.4% vs 2.3%; RR 0.60, 95% CI 0.24–0.98) and transient tachypnea of the newborn (8.2% vs 10.9%; RR 0.72, 95% CI 0.50–0.98), but not RDS overall or mechanical ventilation. ACS treatment increased the risk for neonatal hypoglycemia (22.8% vs 14.2%; RR 1.61, 95% CI 1.16–2.12).4
The meta-analysis was dominated by the Antenatal Late Preterm Steroids Trial (ALPS),7 in which women at 34 0/7 to 36 5/7 weeks’ gestation at high risk for late preterm birth were randomly assigned to receive a first course of antenatal corticosteroids (2 injections of betamethasone 24 hrs apart) or placebo. No tocolytics were administered. The primary outcome was a composite of neonatal respiratory treatment in the first 72 hrs (continuous positive airway pressure [CPAP] or high-flow nasal cannula for ≥2 hours, supplemental oxygen with FIO2 ≥0.30 for ≥4 hrs, extracorporeal membrane oxygenation, or mechanical ventilation), stillbirth, or neonatal death within 72 hrs of delivery. See sidebar at left for major findings.
No data are available about the long-term neurodevelopmental outcomes of children exposed to corticosteroids between 34 0/7 and 36 5/7 weeks. A 2-year follow-up study is currently being performed.
Women randomized at term prior to cesarean received either betamethasone or dexamethasone administered 48 hrs before planned cesarean delivery at ≥37 weeks’ gestation. RDS (2.7% vs 6.7%; RR 0.40, 95% CI 0.27–0.59) and use of mechanical ventilation (0.7% vs 3.6%; RR 0.19, 95% CI 0.08–0.43) were reduced, as were time on oxygen, maximum inspired oxygen, and length of stay in the NICU.4
Long-term follow-up is available from the ASTECS (ACS for term cesarean section) and ASTECS2 trials.5,6 In ASTECS2, 998 women undergoing planned cesarean delivery at term were randomly assigned to receive a course of betamethasone (12 mg IM q 24 hrs x2) or usual treatment prior to delivery.6 The primary outcome was admission to a special care unit with respiratory problems.
The ASTECS-2 study provided follow-up data on participants of the ASTEC trial at ages 8 to 15 years.5 About 50% of participants were lost to follow-up; children available for study were disproportionately represented by the betamethasone group and those admitted to the special care nursery for respiratory complications (5% vs 2%, P=0.01). Long-term assessment was based on parental responses to the strengths and difficulties questionnaire (SDQ), standardized scholastic testing results, and teacher responses. Overall there was no difference in behavioral characteristics based on SDQ, school performance, health issues, asthma, or atopic disease. The authors concluded that “parents can be reassured that the administration of a single course of ACS is not only beneficial in the short term, but does not have any adverse long term consequences.” Based on these findings, use of ACS prior to term cesarean became accepted practice in the United Kingdom.