Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep.
Glucocorticoids regulate oligodendrocyte maturation and the myelin biosynthetic pathways. Synthetic glucocorticoids, the corticosteroids have been successfully used in clinical practice as a single course to enhance lung maturation and reduce mortality and morbidity in preterm infants with no long-term neurologic or cognitive side effects. However, a trend has arisen to use repeated courses despite an absence of safety data from clinical trials. We examined the effects of clinically appropriate, maternally administrated, repeated courses of corticosteroids on myelination of the corpus callosum using sheep as a large animal model. The corpus callosum is a major white matter tract that undergoes protracted myelination, underpins higher order cognitive processing and developmental damage to which is associated with, for example, cerebral palsy, mental retardation and attention deficit hyperactivity disorder. Pregnant ewes were given saline or betamethasone (0.5 mg/kg) at 104,111,118 and 124 days gestation, stages equivalent to the third trimester in humans. Lambs were delivered at 145 days (term), perfused and the corpus callosum examined light and electron microscopically. Total axon numbers were unaffected (P>0.05). However, myelination was significantly delayed. Myelinated axons were 5.7% in the experimental group and 9.2% in controls (P<0.05); conversely, unmyelinated axons were 88.3 and 83.7% (P<0.05). Myelinated axon diameter and myelin sheath thickness were also reduced (0.68 vs. 0.94 and 0.11 vs. 0.14 microm, P<0.05). Our data suggest that repeated prenatal corticosteroid administration delays myelination of the corpus callosum and that further safety data are needed to evaluate clinical practice.
Huang
W L
WL
Neurobiology Laboratory, Department of Zoology, The University of Western Australia, 6009, Crawley, Australia.
Harper
C G
CG
Evans
S F
SF
Newnham
J P
JP
Dunlop
S A
SA
D061085:Agenesis of Corpus Callosum; D000818:Animals; D001369:Axons / Q000473:pathology; D001623:Betamethasone / Q000008:administration & dosage / Q000633:toxicity*; D001925:Brain Damage, Chronic / Q000139:chemically induced* / Q000196:embryology; D002452:Cell Count; D003337:Corpus Callosum / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005325:Fetal Organ Maturity / Q000187:drug effects; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007273:Injections, Intramuscular; D008168:Lung / Q000187:drug effects / Q000196:embryology; D008431:Maternal-Fetal Exchange; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000502:physiology*; D009836:Oligodendroglia / Q000187:drug effects; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D012127:Respiratory Distress Syndrome, Newborn / Q000517:prevention & control; D012449:Safety; D012756:Sheep / Q000196:embryology
D001623:Betamethasone