Antenatal steroids enhance long-term neonatal lung outcomes and are associated with placental alterations in experimental chorioamnionitis.

Abstract

Intrauterine inflammation from chorioamnionitis (CA) is associated with placental dysfunction and increased risk of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity. Antenatal steroid (ANS) treatment improves early respiratory outcomes for premature infants. However, it remains unclear whether ANS improves long-term respiratory outcomes, and whether these effects are mediated through the improvement of placental dysfunction and/or direct impact on the fetal lung. We hypothesized that maternal ANS therapy preserves long-term lung development and impacts placental structural changes and gene expression in experimental CA with features of BPD. Pregnant rat dams were administered either saline (CTL), intra-amniotic (IA) endotoxin (ETX), ETX plus intramuscular (IM) betamethasone (ETX + BETA), or IM BM alone (BETA) on embryonic day 20 (E20). We collected placental tissue at delivery (E22) and infant lung tissue on the day of life (DOL) 14. In comparison with controls, IA ETX had impaired infant lung growth and function. Maternal BM treatment of ETX-exposed pregnant dams reduced infant total lung resistance by 15.3% (P < 0.05), improved infant lung compliance by 9.5% (P < 0.05), preserved alveolar and vascular growth (P < 0.05), and improved right ventricular hypertrophy (RVH) by 42.4% (P < 0.05). ETX + BETA pregnancies were also associated with normalization of placental spiral artery modification and altered placental gene expression. These included the upregulation of placental prolactin, which has regulatory effects on pregnancy homeostasis and has been clinically associated with decreased BPD risk. The current study identifies parallel lung and placental changes associated with ANS treatment, providing a foundation for future studies to identify alternate antenatal therapies with more specific efficacy for BPD prevention.NEW & NOTEWORTHY We performed parallel neonatal lung and placental analyses in a preclinical model to characterize the impact of antenatal betamethasone in experimental chorioamnionitis. Antenatal steroids improved long-term respiratory outcomes and were associated with concurrent structural and molecular changes in the placenta. This study establishes an important model system for future analyses to evaluate mechanistic links determining whether the long-term impact of antenatal steroids on lung development may be through alteration of placental function.