Antenatal Corticosteroid Exposure Disrupts Myelination in the Auditory Nerve of Preterm Sheep

Abstract

Background: Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. Objectives: We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. Methods: Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA; (ii) betamethasone on day 104 and saline on days 111 and 118 GA; or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. Results: Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group (p < 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value (p < 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas (p = 0.005; OR = 2.14, 95% CI 1.26–3.63; 31.6 vs. 18.2% in controls) and irregular myelin deposition (p = 0.001; OR = 5.91, 95% CI 2.16–16.19; 49.0 vs. 16.8% in controls) in the myelin sheath. Conclusions: In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition.

Neurodevelopmental disorders among term infants exposed to antenatal corticosteroids during pregnancy: a population-based study

“…In animal studies, exposure to ACS has been associated with delay in brain growth and development11–14 and with persistent changes in the hypothalamic–pituitary–adrenal (HPA) axis 15–20. Data regarding the long-term effects of ACS on human fetuses are less clear.…”

“…Currently available human data raise concerns that prior exposure to ACS, in term infants, might increase the risk of adverse neurodevelopmental outcome, specifically neurosensory disability 39 44. These concerns are supported by animal studies demonstrating neurosensory susceptibility to ACS in the form of delayed optic and auditory nerve myelination,14 45 decreased eye growth,46 decreased retinal thickness and maturation46 47 and abnormal auditory function 48. Other concerning long-term observations in term infants exposed to ACS include lower academic ability at school age,49 long-term dysfunction of the HPA axis42 43 and abnormal brain anatomical findings such as cortical thinning which persist to early childhood 41…”

Prenatal programming of stress responsiveness and behaviours: Progress and perspectives

“…6 For example, prenatal sGC in late gestation resulted in reduced hippocampal volume in juvenile vervet monkeys, 67 as well as in adult rats. 70 This latter finding is relevant to the human study cited above 59 that reported an increased incidence of neurosensory disability in children exposed to multiple courses of sGC in utero. 69 A very recent study in foetal sheep has demonstrated that multiple courses but not a single course of sGC resulted in changes in auditory nerve myelination, consistent with disruption of normal myelin deposition.…”

“…69 A very recent study in foetal sheep has demonstrated that multiple courses but not a single course of sGC resulted in changes in auditory nerve myelination, consistent with disruption of normal myelin deposition. 70 This latter finding is relevant to the human study cited above 59 that reported an increased incidence of neurosensory disability in children exposed to multiple courses of sGC in utero.…”

Conserved DNA Methylation Signatures in The Prefrontal Cortex of Newborn and Juvenile Guinea Pigs Following Antenatal Corticosteroid Exposure

“…Neuron ensheathment or myelination, has been reported to be dysregulated in association with ACS exposure. Sheep fetuses exposed to ACS demonstrated dysfunctional myelination, evidenced by reduced number of myelinated axons, reduced axon diameter, thinner myelination in the corpus callosum [40] and optic nerve [41], and improper myelin compaction in the auditory nerve [42]. Mbp is one gene that regulates myelination that has been shown to be downregulated at 24h, as well as 20 days following ACS treatment [43].…”