Repeated antenatal corticosteroid treatments adversely affect neural transmission time and auditory thresholds in laboratory rats

Abstract

Antenatal corticosteroid (AC) treatment is given to pregnant women at risk for preterm birth to reduce infant morbidity and mortality by enhancing lung and brain maturation. However, there is no accepted regimen on how frequently AC treatments should be given and some studies found that repeated AC treatments can cause growth retardation and brain damage. Our goal was to assess the dose-dependent effects of repeated AC treatment and estimate the critical number of AC courses to cause harmful effects on the auditory brainstem response (ABR), a sensitive measure of brain development, neural transmission and hearing loss. We hypothesized that repeated AC treatment would have harmful effects on the offspring’s ABRs and growth only if more than 3 AC treatment courses were given. To test this hypothesis, pregnant Wistar rats were given either a high regimen of AC (HAC), a moderate regimen (MAC), a low regimen (LAC), or saline (SAL). An untreated control (CON) group was also used. Simulating the clinical condition, the HAC dams received 0.2 mg/kg Betamethasone (IM) twice daily for 6 days during gestation days (GD) 17-22. The MAC dams received 3 days of AC treatment followed by 3 days of saline treatment on GD 17-19 and GD 20-22, respectively. The LAC dams received 1 day of AC treatment followed by 5 days of saline treatment on GD 17 and GD 18-22, respectively. The SAL dams received 6 days of saline treatment from GD 17-22 (twice daily, isovolumetric to the HAC injections, IM). The offspring were ABR-tested on postnatal day 24. Results indicated that the ABR’s P4 latencies (neural transmission time) were significantly prolonged (worse) in the HAC pups and that ABR’s thresholds were significantly elevated (worse) in the HAC and MAC pups when compared to the CON pups. The HAC and MAC pups were also growth retarded and had higher postnatal mortality than the CON pups. The SAL and LAC pups showed little or no adverse effects. In conclusion, repeated AC treatment had harmful effects on the rat offspring’s ABRs, postnatal growth and survival. The prolonged ABR latencies reflect slowed neural transmission times along the auditory nerve and brainstem auditory pathway. The elevated ABR thresholds reflect hearing deficits. We concluded that repeated AC treatment can have harmful neurological, sensory and developmental effects on the rat offspring. These effects should be considered when weighing the benefits and risks of repeated AC treatment and when monitoring and managing the prenatally exposed child for possible adverse effects.

Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5)

“…Dunlop and Quinlivan examined the effect of repeated injections of corticosteroids on the development of the optic nerve and reported a disrupted retinal development that persisited days after cessation of treatment and a significant delay in the myelination of the optic axons and thinning of the retina [ 15 , 16 ]. Church et al demonstrated that neonatal rats exhibited prolonged auditory brainstem response latencies reflecting slower neural transmission times along the auditory nerve and brainstem auditory pathway, and associated hearing deficits [ 17 ]. Similar effects may be present to account for the differences seen in the term group of this study.…”

Prenatal Anti‐Ro Antibody Exposure, Congenital Complete Atrioventricular Heart Block, and High‐Dose Steroid Therapy: Impact on Neurocognitive Outcome in School‐Age Children

“…Animal studies have demonstrated a variety of deleterious effects of antenatal administration of highdose dexamethasone on the developing brain, including alteration of nuclear transcription factors and neurotransmitter systems, reduced brain growth, and delayed myelination and maturation of astrocytes (19)(20)(21)(22)(23)(24)(25). Experiments in pregnant non-human primates exposed to betamethasone have also showed delayed myelination of the fetal brain and hippocampal damage (26,27).…”

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

“…In MACS-5, infants born at term who were exposed as fetuses to multiple courses of ACS had a higher risk of the composite outcome of death or survival with a neurodevelopmental or neurosensory disability [10]. These findings are consistent with animal studies where repeated ACS treatment was associated with impairment of axonal myelination in the optic nerve, prolonged auditory brainstem responses, and slower neural transmission times [11-13]. …”

“…Several animal studies have shown harmful effects of fetal ACS exposure on auditory function [11, 20]. Church et al [11] demonstrated that repeated ACS treatment in rats resulted in a significantly prolonged neuronal transmission time along the auditory nerve and significantly elevated auditory brainstem response thresholds.…”

“…Church et al [11] demonstrated that repeated ACS treatment in rats resulted in a significantly prolonged neuronal transmission time along the auditory nerve and significantly elevated auditory brainstem response thresholds. They hypothesized that 1 possible mechanism for these results could be impaired myelination due to ACS overexposure.…”