Kinetics of betamethasone and fetal cardiovascular adverse effects in pregnant sheep after different doses.

Administration of synthetic glucocorticoids to women in premature labor has a clearly proven clinical benefit in decreasing the incidence of respiratory distress syndrome and intraventricular hemorrhage in the offspring if they are born prematurely.1 On the other hand, this treatment exposes the fetus to glucocorticoid concentrations higher than those that would normally be present in fetal blood at that stage of development. Fetal exposure at critical developmental stages to glucocorticoid concentrations that are inappropriate for that stage has been shown to have acute adverse effects on the central nervous2–6 and cardiovascular systems in the fetal sheep and baboon.7–11 In the cardiovascular system of sheep and nonhuman primates, synthetic glucocorticoids increase peripheral7–9,11 and cerebral vascular resistance,10 leading to increased mean fetal arterial blood pressure and decreased cerebral blood flow. Although the increased blood pressure may have harmful effects, the increase of cerebral vascular resistance may protect the brain from postasphyxic blood pressure peaks and intraventricular hemorrhage (Schwab M, Muller T, Loehle M, Coksaygan T, Antonow-Schlorke I, Wood CE, et al. Glucocorticoid induced maturation of cerebral autoregulation may explain the decreased incidence of intraventricular hemorrhage and increased risk of periventricular leukomalacia [abstract]. J Soc Gynecol Investig 2004;11 suppl: 355). 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). Recommendations1 for dose and timing of treatments are mainly based on the study of Liggins and Howie13 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 in women in premature labor. Secondly, we evaluated the fetal arterial blood pressure responses to the different betamethasone doses and preparations as an index of cardiovascular adverse effects. Fetal arterial blood pressure changes in their time course are a sensitive measure of the biological activity of glucocorticoids.7–11 We hypothesized that the clinical doses of betamethasone produce supramaximal effects on the fetal cardiovascular system as an indicator that the doses used clinically may also need evaluation in relation to lung maturation.