Adverse Effects of Antenatal Glucocorticoids on Cerebral Myelination in Sheep

OBJECTIVE: To determine in fetal sheep the effect of betamethasone on myelination in relation to stage of myelination, number of treatment courses, dose, and route of administration. METHODS: Fetal expression of myelin basic protein (MBP), a marker of mature oligodendrocytes and myelin, was determined between 0.27 and 0.93 gestation. Shortterm betamethasone effects were examined 24 hours after one maternal intramuscular treatment course (weight adjusted to equal the clinical dose of 2x8 mg betamethasone to a 70-kg woman) at 0.63, 0.75, and 0.87 gestation or after continuous 48-hour fetal intravenous infusion at 0.75 and 0.87 gestation. Lasting effects were examined 20 days after one and two treatment courses weight-adapted to the clinical dose of 2x8 mg or 2x12 mg betamethasone at 0.75 gestation. RESULTS: Myelin basic protein immunoreactivity was first detected in the internal capsule at 0.53 gestation, followed by the centrum semiovale, the superficial white matter, and corpus callosum at 0.63 gestation. Within 24 hours after treatment, betamethasone reduced the number of mature oligodendrocytes and MBP immunoreactivity. The effect decreased with gestational age. Maternal and fetal betamethasone administration had similar effects. Loss of MBP immunoreactivity was not reversed 20 days after two treatment courses, independent of dose. CONCLUSION: Betamethasone-induced delayed cerebral myelination is dependent on the stage of brain development in sheep. Beta methasone-related disturbances in myelination and any potential contribution to childhood behavior deficits need to be confirmed in clinical studies.