Increased Early Severe Lung Disease (ESLD) and mortality in preterm neonates following multiple courses of antenatal corticosteroids (ANCS)

In a post-hoc analysis of preterm neonates in the North American TRH trial, we previously reported (Pediatr Res 43[4]:165A, 1998) no benefit but increased mortality among infants who received ≥ 3 courses of ANCS (≥3 ANCS) compared with 1-2 courses (1-2 ANCS). To evaluate the cause of death and potential confounding variables, we analyzed maternal factors including race, multiple gestation, prolonged rupture of membranes, infection, bleeding, maternal illness, substance abuse, and tocolytic use. No infant <26wk GA received ≥3 ANCS. Among the 595 neonates 26-32wk GA. 13 of 141 ≥ 3 ANCS died (9.2%) compared to 22 of 454 (48%) 1-2 ANCS. Using a best subset model selection approach, a multiple logistic regression model predicting mortality was fit. Only increased gestational age at delivery (OR = 0.48/week, p<0.001), multiple gestation (OR = 2.8, p = 0.008), and ≥ 3 ANCS (OR = 3.2. p = 0.003) were associated with mortality. Infants with ≥ 3 ANCS had a shorter survival time after birth by Kaplan-Meier analysis (p = 0.04). We evaluated condition at birth, the incidence of preterm morbidities, and cause of death in the ≥ 3 ANCS vs 1-2 ANCS infants. There was no difference between groups in Clinical Risk Index for Babies (CRIB) scores or incidence of RDS, PDA, IVH, NEC, infection, or need for pharmacologic blood pressure support. However, infants with ≥ 3 ANCS were more likely to have early severe lung disease (ESLD). defined as pulmonary hypoplasia or severe RDS (mean airway pressure x FiO2 > 5 during 1_st 24 hrs) Fourteen of 141 ≥ 3 ANCS infants (9.9%) had ESLD with 10 deaths compared to 14/454 1-2 ANCS (3.1%) with 6 deaths (odds ratio for ESLD = 3.5, p < 0.001). Using further log linear modeling, ≥ 3 ANCS was associated with an increased incidence of ESLD, which was associated with mortality. Treatment with ≥ 3 ANCS was no longer associated with mortality after accounting for the effects of ESLD. We conclude in this post-hoc analysis that the increased mortality among preterm neonates receiving ≥ 3 ANCS could not be explained by confounding maternal risk factors, increased infection or other morbidities of prematurity, but was associated with an increased incidence of early severe lung disease at birth.