The duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation

Kemp, M.W., Saito, M., Schmidt, A.F., Usuda, H., Watanabe, S., Sato, S., Hanita, T., Kumagai, Y., Takahashi, T., Musk, G.C., Furfaro, L., Stinson, L., Fee, E.L., Eddershaw, P.J., Payne, M.S., Smallwood, K., Bridges, J., Newnham, J.P. and Jobe, A.H. (2019) The duration of fetal antenatal steroid exposure determines the durability of preterm ovine lung maturation. American Journal of Obstetrics and Gynecology . In Press.

Abstract

Objective
Antenatal corticosteroids (ACS) are the standard of care for maturing the fetal lung and improving outcomes for preterm infants. ACS dosing remains un-optimized, and there is little understanding of how different treatment to delivery intervals may affect treatment efficacy. The durability of a lung maturational response is important because the majority of women treated with ACS do not deliver within the widely accepted 1-7 day window of treatment efficacy. We used a sheep model to test duration of fetal exposures for efficacy at delivery intervals from 1 to 10 days.

Methods
For infusion studies, ewes with single fetuses were randomised to receive an intravenous bolus and maintenance infusion of betamethasone phosphate to target 1-4ng/mL fetal plasma betamethasone for 36 hours, with delivery at either 2, 4 or 7 days-post treatment or sterile saline as control. Animals receiving the clinical treatment were randomised to receive either:i) a single injection of 0.25mg/kg with a 1:1 mixture of betamethasone phosphate + betamethasone acetate with delivery at either 1 or 7 days post treatment; or ii) two treatments of 0.25 mg/kg betamethasone phosphate + betamethasone acetate spaced at 24 hours (giving approximately 48 hours of fetal steroid exposure) with delivery at 2, 5, 7 or 10 days post-treatment. Negative control animals were treated with saline. All lambs were delivered at 121±3 days gestational age and ventilated for 30 minutes to assess lung function.

Results
Preterm lambs delivered at 1 or 2 days post-ACS treatment had significant improvements in lung maturation for both intravenous and single dose intramuscular treatments. After 2 days the efficacy of 36 hour betamethasone phosphate infusions was lost. The single dose of 1:1 betamethasone phosphate + betamethasone acetate also was ineffective at 7 days. In contrast, animals treated with two doses had significant improvements in lung maturation at 2, 5 and 7 days, with treatment efficacy reduced by 10 days.

Conclusion
In preterm lambs, the durability of ACS treatment depends on the duration of fetal exposure and is independent of the IV or IM maternal route of administration. For acute 24-48 hour post-treatment deliveries, a 24 hour fetal ACS exposure was sufficient for lung maturation. A fetal exposure duration of at least 48 hours was necessary to maintain long-term treatment durability. A single dose ACS treatment should be sufficient for women delivering within <48 hours of ACS treatment.

Item Type:	Journal Article
Murdoch Affiliation(s):	School of Veterinary and Life Sciences
Publisher:	Mosby Inc
Copyright:	© 2019 Published by Elsevier Inc.
URI:	http://researchrepository.murdoch.edu.au/id/eprint/51069

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