Kinetics of Betamethasone and Fetal Cardiovascular Adverse Effects in Pregnant Sheep After Different Doses

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Abstract
To study the pharmacokinetics of different betamethasone doses and preparations used to enhance fetal lung maturation in the maternal and fetal circulation of sheep and the adverse effects on fetal blood pressure. Doses of 170 (n = 6) and 110 microg/kg (n = 6) betamethasone phosphate equivalent to 12 or 8 mg, respectively, administered to a 70 kg pregnant woman or 170 microg/kg (n = 6) of a depot formulation (50% betamethasone phosphate and 50% betamethasone acetate) were injected intramuscularly to chronically instrumented pregnant sheep. Both betamethasone preparations produced highest maternal concentrations after 15 min followed by an exponential decline with a t(1/2) of about 3 hours. The drug fell below the limit of detection at 8 to 12 hours. Betamethasone was first detectable in the fetal circulation at 1 hour, peaked at 3 hours, and decreased below the limit of detection at 8 hours independently of the dose or preparation. Maternal and fetal betamethasone concentrations achieved with the phosphate and acetate formulation were one half of those obtained with betamethasone phosphate, suggesting that very little betamethasone is released from the acetate within the first 8 hours when the effect on lung maturation is needed. Betamethasone led to a maximal increase of mean fetal blood pressure from 42+/-1 to 51+/-1 mm Hg (P < .05) and did not differ between the doses and preparations, although plasma concentrations showed a clear dose-concentration relationship. The doses of betamethasone used in obstetrics are supramaximal in terms of cardiovascular effects in sheep. Risk-benefit studies are needed to find the effective steroid dose with the least adverse effects.