Dosing and formulation of antenatal corticosteroids for fetal lung maturation and gene expression in rhesus macaques

Augusto F Schmidt,Dakota Lipps,Jeffrey A Whitsett,Lisa A Miller,Yan Xu,Alan H Jobe,Alyssa Filuta,Matthew Kemp,Paranthaman S Kannan,James P Bridges,Suhas G Kallapur

doi:10.1038/s41598-019-45171-6

Abstract

Antenatal corticosteroids (ANS) are the major intervention to decrease respiratory distress syndrome and mortality from premature birth and are standard of care. The use of ANS is expanding to include new indications and gestational ages, although the recommended dosing was never optimized. The most widely used treatment is two intramuscular doses of a 1:1 mixture of betamethasone-phosphate (Beta-P) and betamethasone-acetate (Beta-Ac) – the clinical drug. We tested in a primate model the efficacy of the slow release Beta-Ac alone for enhancing fetal lung maturation and to reduce fetal corticosteroid exposure and potential toxic effects. Pregnant rhesus macaques at 127 days of gestation (80% of term) were treated with either the clinical drug (0.25 mg/kg) or Beta-Ac (0.125 mg/kg). Beta-Ac alone increased lung compliance and surfactant concentration in the fetal lung equivalently to the clinical drug. By transcriptome analyses the early suppression of genes associated with immune responses and developmental pathways were less affected by Beta-Ac than the clinical drug. Promoter and regulatory analysis prediction identified differentially expressed genes targeted by the glucocorticoid receptor in the lung. At 5 days the clinical drug suppressed genes associated with neuronal development and differentiation in the fetal hippocampus compared to control, while low dose Beta-Ac alone did not. A low dose ANS treatment with Beta-Ac should be assessed for efficacy in human trials.

Highlights

Antenatal corticosteroids (ANS) are the major perinatal intervention to reduce the incidence of respiratory distress syndrome and neonatal mortality associated with preterm birth[1]
To compare Beta-Ac with the clinical drug for fetal lung maturation, pregnant Rhesus macaques were treated with a single IM injection of either Beta-Ac (0.125 mg/kg or 0.06 mg/kg), saline or the clinical drug (0.25 mg/kg) and delivered 5 days after treatment (Table 1)
The main lipid component of surfactant is saturated phosphatidylcholine (SatPC), which can be used as a marker of lung surfactant content and indicator of biochemical lung maturation[24]

Summary

Introduction

Antenatal corticosteroids (ANS) are the major perinatal intervention to reduce the incidence of respiratory distress syndrome and neonatal mortality associated with preterm birth[1]. While ANS are considered to be safe, expanding treatments to gestations beyond 24 to 34 weeks may change the risk to benefit ratio[2]. A recent large trial demonstrated that ANS decreased the respiratory complications and the need for respiratory support for infants between 34 and 37 weeks gestational age[3]. ANS decreased neonatal respiratory morbidity for elective C-section deliveries at term gestation[4,5]. ANS exposure in late preterm newborns (with gestational ages between 340 and 366 weeks)[3]. In experimental studies ANS caused hippocampal degeneration and HPA axis dysfunction in macaques[11,12,13] and decreased fetal and brain growth in sheep and rats[14,15,16]. We evaluated a lower dosing strategy using Beta-Ac for fetal lung maturation and transcriptional effects on the fetal lung and brain in the Rhesus macaque

Methods

Results

Conclusion