Abstract

Introduction: Antenatal steroid (ANS) therapy accelerates preterm lung maturation. Clinical and experimental data show current regimens disrupt placental function and transport and impact fetal growth. We have previously shown that higher materno-fetal steroid exposures increase fetal glucocorticoid clearance. Using a sheep model, we aimed to determine whether: (i) placental transcriptomic changes correlate with fetal glucocorticoid exposure; (ii) these changes persist below the threshold for lung maturation; and (iii) transcriptomic changes explain altered steroid clearance and fetal growth. Methods: This secondary analysis included singleton fetuses delivered at 123 ± 1 days’ gestation (n = 6/group), ventilated for 30-min, then euthanized. Fetuses received a 48-h infusion targeting plasma betamethasone levels of 2, 1, or 0.5 ng/mL, a control group received saline. Placental tissue was collected for RNA sequencing, fetal liver for qPCR and betamethasone concentrations were measured by LCMS. Results: Maximal lung maturation occurred at 2 ng/mL. Placental transcriptome changes were dose-dependent, with 2052, 408, and 498 differentially expressed genes in the 2, 1, and 0.5 ng/mL groups, respectively. KEGG analysis showed suppression of DNA replication, nucleocytoplasmic transport, and cell cycle (p < 0.001), and activation of steroid hormone biosynthesis pathways, including upregulation of UGT1A4 and CYP17A1. Placental transporters SLC4A10, SLC7A3, SLC36A3, SLC46A1 and SLC6A3 were downregulated at 2 ng/mL. In the fetal liver, expression of transport protein ABCB1 increased across all treatment groups. Discussion: Placental transcriptomic disruption persisted at and below the ANS exposure necessary for lung maturation. These findings suggest placental involvement in both impaired fetal growth and steroid clearance and underscore the need to optimize ANS dosing. © 2025 The Authors