Does Maternal Smoking Affect the Efficacy of Antenatal Betamethasone in Reducing Respiratory Distress Syndrome? A Secondary Analysis of the Antenatal Late Preterm Steroids (ALPS) Trial

Background: The Antenatal Late Preterm Steroids (ALPS) Trial demonstrated that antenatal betamethasone reduces respiratory morbidity among infants delivered between 34 0/7 and 36 5/7 weeks of gestation. Maternal smoking is a known risk factor for adverse neonatal outcomes; paradoxically, some studies report lower rates of respiratory distress syndrome (RDS) among very preterm infants born to smokers, possibly due to accelerated fetal lung maturation (Curet et al. AJOG 1983). Proposed mechanisms include increased cortisol in amniotic fluid promoting surfactant production, nicotine-induced structural and functional lung changes via nicotinic acetylcholine receptors, and enhanced surfactant gene expression (Rehan et al. Lung 2009). The EPIPAGE study noted reduced antenatal steroid benefits among smokers delivering between 27–32 weeks’ gestation (Burguet et al. ADC Fetal Neonatal Ed 2005). Late preterm infants inherently have lower RDS rates compared to very preterm infants, with gestational age remaining the primary predictor of respiratory outcomes (Lorenzo et al. Neonatology 2021). Whether maternal smoking modifies the respiratory benefit of betamethasone in late preterm newborns remains unclear. Objective: To determine whether maternal smoking during pregnancy affects the efficacy of antenatal betamethasone in reducing a composite of respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), and apnea in late preterm infants. Methods: This secondary analysis was limited to participants randomized to the active treatment arm (N=1,428) of the ALPS Trial. Seven participants were excluded due to missing data on neonatal resuscitation (N=1,421). All participants were assigned to receive two intramuscular injections containing 12mg of betamethasone 24 hours apart. Analyses for both the ALPS Trial and this secondary analysis were performed according to the intention-to-treat principle. Maternal smoking status was determined at enrollment and defined as any cigarette use during pregnancy; frequency and amount were not recorded. The primary respiratory outcome was a composite of neonatal respiratory morbidity: RDS, TTN, and apnea. RDS was defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis), with a requirement for supplemental oxygen with a FiO2>0.21 and a chest radiograph showing hypoaeration and reticulogranular infiltrates. TTN was diagnosed when tachypnea occurred in the absence of chest radiography or with a radiograph that was normal or showed signs of increased perihilar interstitial markings and resolved within 72 hours. Secondary outcomes included a composite of CPAP or high-flow nasal cannula (HFNC) use for ≥2 hours, inspired oxygen ≥30% for ≥4 hours, mechanical ventilation (MV), or extracorporeal membrane oxygenation (ECMO) within 72 hours after birth; and the need for neonatal resuscitation within the first 30 minutes of life, defined as the use of blow-by oxygen, cannula, oxyhood, mask, bag-mask ventilation, CPAP, intubation, chest compressions, or administration of cardiac medications. Baseline clinical and maternal characteristics were compared using chi-square tests for categorical variables. Logistic regression was performed to account for confounding factors identified on univariate analysis: mode of delivery, maternal age, race or ethnicity, marital status, and primary source of medical payment for prenatal care. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for unadjusted group comparisons. Adjusted odds ratios (aORs) were derived using multiple logistic regression. Results: Compared to non-smokers, smokers were more likely to deliver via cesarean, be Caucasian or African American, under age 35, unmarried or not living with a partner, and use government-assisted health insurance. The primary composite respiratory outcome occurred in 14.4% of neonates born to smokers and 13.9% of those born to non-smokers. After adjusting for potential confounders, smoking was not associated with increased rates of RDS, TTN, or apnea in late preterm infants (aOR 1.04; 95% CI:0.65–1.62). The secondary outcome of a composite of CPAP or high-flow nasal cannula (HFNC) use for ≥2 hours, inspired oxygen ≥30% for ≥4 hours, mechanical ventilation (MV), or extracorporeal membrane oxygenation (ECMO) within 72 hours after birth occurred in 10.4% of neonates born to smokers and 11.8% of those born to non-smokers. After logistic regression, maternal smoking did not increase these risks (aOR 0.82; 95% CI:0.47–1.35). Resuscitation within the first 30 minutes of life occurred in 22.3% of neonates born to smokers and 21.4% of those born to non-smokers. Similarly, maternal smoking was not significantly associated with receiving any resuscitative intervention within 30 minutes of birth, including blow-by oxygen, oxygen by cannula/oxyhood/mask, bag-mask ventilation, CPAP, intubation, chest compressions, or cardiac medications (aOR 1.00; 95% CI:0.68–1.45). Conclusion: In this secondary analysis of the ALPS Trial, maternal smoking during pregnancy was not significantly associated with a composite of neonatal morbidity, including RDS, TTN, apnea, or the need for neonatal resuscitation after antenatal betamethasone. Although prior studies suggest smoking may accelerate fetal lung maturation, it did not appear to alter the protective effect of corticosteroids in this late preterm infant population.