We found that exposure to antenatal corticosteroids during pregnancy did not appear to change the proportion of adverse respiratory outcomes in neonates born at 34 0/7 to 36 6/7 weeks when compared with offspring of unexposed parturients. Few prospective studies have evaluated respiratory outcomes in late-preterm neonates exposed to steroids. In the first randomized controlled trial of ACS to enhance fetal pulmonary maturation in 1972, Liggins and Howie found that exposure to betamethasone decreased the rate of RDS from 25.8% in controls to 9.0% in the treatment group, p=0.003(8
). When they performed a subgroup analysis evaluating neonates delivered between 32 to <37 weeks gestation, they found a lower rate of RDS from 6.9% in the control group to 4.7% in the treatment group; a similar risk reduction to that seen with delivery at earlier gestations, but statistical significance was not reached. Notably, there were only 4 cases of RDS in that cohort of 72 moderately preterm neonates. The most recent Cochrane systematic review evaluating the rates of RDS in fetuses exposed to steroids who delivered at 34 weeks gestation or beyond found a similar trend but significance was again not reached in control versus treatment groups, 4.7% versus 3.1%, Risk Ratio 0.66, 95% CI 0.38–1.16, p=0.15(9
). Of 1,261 included subjects, there were only 49 cases of RDS. The risk ratio for RDS among 189 newborns delivered at 35–36 weeks gestation was similar (Risk Ratio 0.61, 95% CI 0.11–3.26). Like Liggins’ study and this recent meta-analysis, our evaluation lacks the needed power to resolve this issue. However, it is reassuring that our multivariable analyses revealed similar results to those previously published.
Biologically, there is no good explanation supporting a cessation of benefit to ACS after 34 weeks gestation. Rather, it is more likely that a decrease in the disease burden makes demonstration of this benefit more difficult. Late-preterm neonates are less likely to have RDS than neonates born before 34 weeks; however, they are still at risk for respiratory morbidities from other causes. As a pregnancy approaches term, delivery is more likely to result in TTN than RDS. Rubaltelli et al, were one of the first groups to evaluate the etiologies of acute respiratory distress in the late-preterm cohort(11
). They found that the rate of TTN at 34 to 36 weeks was higher than that of babies born beyond 36 weeks, 6.2% versus 0.4%. Escobar and colleagues evaluated the need for respiratory support among late-preterm neonates compared with those delivered between 38 and 40 weeks gestation(6
). They found that babies born at 34, 35, and 36 weeks were 19.8-, 9.0-, and 5.2-fold more likely respectively to require assisted ventilation compared with the reference group born at 38 to 40 weeks. Other groups have also demonstrated higher respiratory morbidity in late-preterm compared with term neonates(4
). These data validate the suggestion that late-preterm neonates are at risk for serious respiratory morbidities other than RDS which impact their early neonatal management. What is currently unknown is whether ACS administration can decrease these other respiratory morbidities.
A limitation to our study is that we do not know the gestational age at which the steroids were given, and thus the time interval between ACS administration and delivery. This is an important confounder as the effects of ACS administration are believed to be of limited duration. None of the participating clinical centers in the parent study routinely administer ACS after 34 weeks gestation, so it is likely that the majority of exposed newborns had been exposed to ACS remote from delivery; and it is unlikely that ACS were administered beyond 34 weeks. Additionally, this secondary analysis evaluates the impact of ACS administration on those delivering at 34–36 weeks rather than the impact of steroids administered at 34–36 weeks on those delivering thereafter. Recently, a group of investigators evaluated the role of ACS to decrease respiratory morbidities including, but not limited to, RDS in a term population undergoing planned cesarean delivery(12
). They randomized women over 37 weeks gestation to betamethasone versus routine management and evaluated rates of admission of their neonates to a special care unit for respiratory distress. They found that the newborns of women who received steroids were less likely to require admission to a special care unit compared with neonates of women who did not, 0.024 versus 0.051%, (Relative Risk (RR) 0.46, 95% CI 0.23–0.93). They also found a lower rate of RDS in the treated group, 0.002% versus 0.011%, but statistical significance was not reached,(RR 0.32, 95% CI 0.03– 1.32). Based on these findings, it is plausible that ACS administration at 34–36 weeks to women at risk for late-preterm birth could also result in improved pulmonary outcomes. Finally, this is a secondary analysis of a prior completed trial and therefore, our sample size is fixed and limited.. Perhaps this difference would have been detectable with a larger sample size.
Our findings regarding the effect of ACS in the late-preterm period are consistent with prior reports, but highlight that adequate power to make clinical recommendations based on these studies is lacking. These studies support the need for well-designed trials of adequate size to evaluate the impact of antenatal corticosteroid administration in the late-preterm period for reduction of newborn respiratory complications.