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

Abstract

OBJECTIVE-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.METHODS-Doses of 170 (n = 6) and 110 µg/kg (n = 6) betamethasone phosphate equivalent to 12 or 8mg, respectively, administered to a 70kg pregnant woman or 170 µg/kg (n = 6) of a depot formulation (50% betamethasone phosphate and 50% betamethasone acetate) were injected intramuscularly to chronically instrumented pregnant sheep.RESULTS-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.CONCLUSION-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.Administration of synthetic glucocorticoids to women in premature labor has a clearly proven clinical benefit in decreasing the incidence of respiratory distress syndrome and Although it has been shown in sheep that repeated treatments may be of benefit for the lung, 12 to our knowledge there has never been a study designed to examine a broad range of doses at the clinical level to determine the dose of maternal glucocorticoid that is optimal for the effects on the fetus in rodents, sheep, nonhuman primates or humans (PubMed, January 1966-January 2006; no language restrictions; search terms: antenatal or prenatal; glucocorticoids, steroids or betamethasone; dose or pharmacokinetics; lung or blood pressure). Recommendations 1 for dose and timing of treatments are mainly based on the study of Liggins and Howie 13 who chose the dose for clinical trials partly from the doses used in experiments with sheep. Retrospective data collected on mothers who received only a partial course of steroids, however, suggests that any exposure to an appropriate corticosteroid has beneficial effects on postnatal outcome. 14 The present study was designed to estimate the time course of maternal and fetal betamethasone concentrations after maternal exposure to two doses and two different betamethasone preparations frequently used clinically i...

Betamethasone Attenuates Oxidant Stress in Endothelial Cells from Fetal Lambs with Persistent Pulmonary Hypertension

“…Since clinical use of this drug consists of two doses, we chose to add twice the measured concentration initially without addition of subsequent doses during the 48-h period. The fetal plasma concentrations reported in a recent study with a single dose of betamethasone given to the pregnant sheep are 10% of the maternal concentrations (21). Therefore, the concentration we used for PAEC is approximately 20-fold higher than fetal plasma levels measured after administration to the mother.…”

“…The medium was then replaced with either 20% FBS-DMEM or 20% FBS-DMEM with betamethasone (Sigma Chemical Co.) at a concentration of 400 ng/mL (10 -6 M) for 48 h. The concentration of betamethasone in media is based on plasma concentrations measured in pregnant sheep plasma (20) following a single injection of 0.25 mg/kg (approximately 12 mg for a 50-kg sheep) and are 10 -20 fold higher than concentrations measured in fetal lambs (21).…”

Dose-response effects of betamethasone on maturation of the fetal sheep lung

“…Since synthetic glucocorticoids rapidly cross the placenta6 their administration to the pregnant mother inevitably exposes the fetus to glucocorticoid concentrations that are inappropriate for the current stage of fetal maturation. Indeed this is the purpose of the treatment.…”

“…We have evaluated the relationship of the fetal hypertension produced when betamethasone is administered to the pregnant ewe to the resulting fetal plasma betamethasone concentration6. We administered equal total amounts of betamethasone, either as the fast releasing form, betamethasone phosphate or as the slow-release betamethasone depot preparation, consisting of 50% betamethasone phosphate and 50% betamethasone acetate.…”

Measurement of betamethasone concentration in maternal serum treated for fetal lung maturity; Is it feasible?

“…The current dosage of betamethasone was determined by Liggins and Howie during the 1970s, and since then a fixed dosage is administered to all pregnant women regardless of gestational age, maternal body mass index, and whether a singleton or multiple gestation is present [8]. Additionally, betamethasone rapidly crosses the placenta [13]. Its administration to the pregnant mother inevitably exposes the fetus to glucocorticoid concentrations that may be inappropriate for the current stage of fetal development [14].…”