Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter

Background: Antenatal steroid therapy is standard of care for women at imminent risk of preterm delivery. Current dosing regimens employ supra-pharmacological doses to achieve extended fetal steroid exposures. Objective: We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation. Study design: Ewes with singles fetuses underwent surgery to install a fetal jugular catheter. Adopting a step-wise design, ewes were randomised to either a saline-only group (Negative Control Group; n=9), or one of four betamethasone-treatment groups. Each betamethasone group fetus received a fetal intravenous infusion to target a constant plasma betamethasone levels of either: i) 2 ng/ml (2 ng/ml Positive Control Group, n=9); ii) 1 ng/ml, (1 ng/ml Group, n=10); iii) 0.5 ng/ml (0.5 ng/ml Group, n=10); or iv) 0.25 ng/ml Group (0.25 ng/ml Group, n=10). Fetuses were infused for 48 hours, delivered and ventilated. The Positive Control Group, Negative Control Group and mid-point 0.5 ng/ml Group animals were tested first. An interim analysis informed the final betamethasone group tested. Results: Positive Control Group animals had large, statistically significant improvements in respiratory function. Based on an interim analysis, the 1.0 ng/ml Group was studied in favour of the 0.25 ng/ml Group. Treatment efficacy was progressively lost at plasma betamethasone concentrations lower than 2 ng/ml. Conclusion: We demonstrated that the acute respiratory benefit conveyed by antenatal steroid exposure in the fetal sheep is progressively lost when constant fetal plasma betamethasone concentrations are reduced below a targeted value of 2 ng/ml.