Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birth weights when administered to pregnant sheep in combination with betamethasone acetate

Background Antenatal corticosteroid (ACS) therapy is standard of care for women at imminent risk of preterm labour. Despite this, much remains to be understood regarding an optimal (maximum benefit, minimal risk of side effects) ACS dosing strategy. Although conveying overall benefit when given to the right patient at the right time, ACS treatment efficacy is highly variable, and is not risk-free. Building on earlier findings, we hypothesized that when administered in combination with slow-release betamethasone acetate, betamethasone phosphate and the high materno-fetal betamethasone concentrations it generates are redundant for fetal lung maturation. Objective Using an established sheep model of prematurity and post-natal ventilation of the preterm lamb, we aimed to compare the pharmacodynamic effects of a low-dose treatment with betamethasone acetate only against a standard dose of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynaecologists for women at risk of imminent preterm delivery between 24 and 35+6 weeks’ gestation. Methods Ewes carrying a single fetus at 122±1 d gestational age (term=150d) were randomized to receive either: i) maternal intramuscular injections of sterile saline (the Saline Negative Control Group, n=12), ii) two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + acetate spaced by 24h (the Beta-P+Ac Group, n=12); or iii) two maternal intramuscular injections of 0.125 mg/kg betamethasone acetate spaced by 24h (the Beta-Ac Group, n=11). Fetuses were surgically delivered 48h after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. Fetuses were euthanized after ventilation and lung were collected for analysis using quantitative polymerase chain reaction and western blot assays. Fetal plasma ACTH levels were measured in the cord blood samples taken at delivery. Results Preterm lambs were defined as either ACS treatment responders or non-responders using an arbitrary cut-off, being a PaCO2 level at 30 minutes of ventilation being more extreme than two standard deviations from the mean value of the normally-distributed Saline Control Group values. Relative to Saline Control Group animals, both ACS treatment group animals showed significantly improved lung physiological responses (blood gas and ventilation data) and had a biochemical signature (mRNA and surfactant protein assays) consistent with functional maturation. However, the Beta-Ac Group had a significantly higher treatment response rate than the Beta-P+Ac Group. These physiological results were strongly correlated to the amount of surfactant protein A. Birth weight was lower in Beta-P+Ac Group and the fetal HPA axis was supressed to a greater extent in the Beta-P+Ac Group. Conclusion Low dose ACS therapy solely employing Beta-Ac was sufficient for fetal lung maturation. The elevated materno-fetal betamethasone concentrations associated with the co-administration of betamethasone phosphate did not additionally improve lung maturation, but were associated with greater HPA axis suppression, a lower ACS treatment response rate, and lower birth weight – outcomes not desirable in a clinical setting. These data warrant a clinical investigation of sustained, low-dose ACS treatments that avoid high materno-fetal betamethasone exposures