Fetal exposure to corticosteroids: how low can we go?

Dosing regimens of corticosteroids to women who threaten premature delivery involve maternal intramuscular injections of the synthetic glucocorticoids betamethasone or dexamethasone. Treatment typically employs a course totalling 24 mg of drug administered as two or four injections over 2 days. There is no adjustment for patient body weight. Following each injection the fetus is exposed to an initially high level of glucocorticoid followed by a decline in concentration, the time course of which is affected by several factors including the volume of distribution and the pharmacokinetic properties of the drug used. Following the NIH Consensus Statement on the use of antenatal glucocorticoids in 1994 (NIH, 1995), patients have been exposed to many times the single course recommended. This practice occurs in spite of a lack of evidence for improved outcome following multiple courses, and has led to widely voiced concern today, including opposition to repeat courses by a second NIH Consensus panel (Crane et al. 2003). The net effect, however, has been to expose human fetuses to a range of glucocorticoid doses over varying lengths of time. The beneficial effects of a single course of corticosteroids for the premature infant are without question. These include well-documented decreases in the incidence of respiratory distress syndrome, intracerebroventricular haemorrhage and necrotizing enterocolitis. More recently, a neuroprotective function has been ascribed to antenatal steroid administration to very low-birthweight infants (Agarwal et al. 2002). Conversely, antenatal corticosteroid exposure is also associated with decreased fetal heart rate variability, decreased incidence of fetal breathing and body movements (Mulder et al. 1997) and increased fetal blood pressure (Derks et al. 1997; Koenen et al. 2002). There are also reports of postnatal adrenal suppression, altered lung growth and altered cerebral myelination. While follow-up studies of children 12 years or younger who received at least one course of corticosteroids indicate no apparent risk of adverse neurodevelopmental outcome, the long-term consequences of fetal exposure to corticosteroids are yet to be fully revealed. In this issue of The Journal of Physiology, Fletcher et al. describe the fetal cardiovascular and endocrine responses to acute hypoxaemia during and following dexamethasone infusion in sheep. Their observations follow a previous paper published in The Journal of Physiology in 2002 in which the same group describe how the fetal cardiac baroreflex is altered during dexamethasone exposure in sheep (Fletcher et al. 2002). These papers, and those of others before them (e.g. Derks et al. 1997), utilize a methodology that both distinguishes their experiments from the approach used in clinical practice and provides insights into the issue of corticosteroid dosing. The corticosteroid is administered via direct intravascular infusion to the fetus over 48 h and at a weight-adjusted dose that achieves circulating levels one-fifth of that found in umbilical cord blood at delivery in humans. By infusing dexamethasone directly to the fetus, Fletcher et al. (2003) avoid the potentially confounding influences of steroid-induced changes in maternal cardiovascular status, metabolic status and placental morphology and function. Direct fetal infusion also largely negates species-specific differences in the transplacental passage of steroids resulting from differences in placental architecture. While Fletcher et al. (2003) do not attempt to draw conclusions regarding dosing, their work clearly demonstrates that circulating dexamethasone levels approximately 20 % of those achieved clinically have significant and persistent physiological effects. During dexamethasone treatment, acute hypoxaemia leads to a prolonged fetal bradycardia, an increase in plasma levels of neuropeptide Y and lower levels of plasma catecholamines and vasopressin when compared to saline-treated controls. Two days after the cessation of dexamethasone infusion, the cardiovascular and endocrine responses to acute hypoxaemia were all increased relative to the responses of the control group. The authors therefore demonstrate persistent modification of fetal cardiovascular and endocrine responses to acute hypoxaemia resulting from a relatively low dose of dexamethasone. Some evidence, primarily from studies in the rat, suggests that there are dose-dependent differences in the impact of dexamethasone on the fetus. Slotkin et al. showed a dose-dependent effect of dexamethasone in the rat that induces fetal growth inhibition at high doses, whereas at low doses enhancement of noradrenergic synaptogenesis occurs without growth inhibition. Furthermore, the same low-dose dexamethasone to the pregnant rat has a promotional effect on kidney development, whereas the higher, growth-inhibiting doses do not (Slotkin et al. 1992). Rebello et al. (1996) have reported dose dependence in lung maturation following betamethasone administration in sheep. Finally, maternal administration of dexamethasone at levels above the threshold for promoting lung maturation in the rat suppresses myocardial sensitivity to β-adrenergic stimulation, while doses below the threshold enhance β-adrenoreceptor transduction (Bian et al. 1993). Since Fletcher et al. (2003) report persistent bradycardia in response to acute hypoxaemia during and following dexamethasone administration (probably a result of depressed myocardial β-adrenergic sensitivity), it seems appropriate to conclude that the dose of dexamethasone used does not qualify as low. This then leads to the question. ‘How low can we go?’ Perhaps it is time to take a cost-benefit approach to define a stratagem that minimizes fetal antenatal steroid exposure without losing the beneficial effects for the preterm baby.