Retinal maturation is delayed by repeated, but not single, maternal injections of betamethasone in sheep

Quinlivan, Julie A.; Beazley, Lyn; Evans, Sharon F.; Newnham, John P.; Dunlop, Sarah

doi:10.1038/eye.2000.20

Cited by 44 publications

(23 citation statements)

References 19 publications

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“…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]. …”

Section: Introductionsupporting

confidence: 79%

“…Although the effects of repeated steroid exposure on the developing fetal optic nerve are well established in sheep [13], much remains to be understood about the impact of ACS administration on auditory nerve development. We hypothesized that single and repeated administration of corticosteroids would disrupt auditory myelination in an ovine model of pregnancy.…”

Section: Introductionmentioning

confidence: 99%

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

Rittenschober-Böhm

Rodger²,

Jobe

et al. 2018

Neonatology

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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.

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Section: Introductionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

Rittenschober-Böhm

Rodger²,

Jobe

et al. 2018

Neonatology

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“…(B) The oxidative stress caused by excessive fetal or neonatal exposure to AC has been implicated in damage to the cochlea [11] and brain [10]. (C) Excessive fetal or neonatal AC exposure causes adverse effects on the nervous system which include the inhibition of neural growth and myelination [6,23,29,58,63,73,74,93], the inhibition of cell division and DNA synthesis [47], epigenetic modifications [51,85], cell death [47], decreased cerebral blood flow [63] and “steroid diabetes” with all its negative sequelae for sensory and neurological morbidities [68,72,84,85]. …”

Section: Discussionmentioning

confidence: 99%

“…The offspring effects include impaired brain myelination and impaired neurologic development [6,23,29,33,47,58,63], altered hypothalamic-pituitary-adrenal axis function [9,30], decreased hippocampus neuron numbers [93], hyperglycemia [68], impaired sciatic axonal growth [73], impaired retinal maturation [73,74], impaired myelination of optic nerve axons [29], altered behaviors [9,33,45], reduced fecundity [30] and reduced brain weights [33,48,54]. In addition, recent animal studies found abnormal auditory function as a result of fetal overexposure to glucocorticoids [11,44,50].…”

Section: Introductionmentioning

confidence: 99%

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

Church

Adams

Anumba

et al. 2012

Neurotoxicology and Teratology

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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.

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“…Repeated AC also decreases human placental growth [32], may increase the incidence of cerebral palsy [38] and may cause attention problems [11]; although not all studies have found these effects [14,24,37]. Animal studies of repeated AC treatment have found impaired brain myelination and neurologic development [8,13,29,30], reduced fetal brain [17,20,22] and birth weights [18,19], altered postnatal cortisol and thyroid levels [18] and altered neural growth [4,33]. …”

Section: Introductionmentioning

confidence: 99%

Repeated courses of antenatal corticosteroids: Are there effects on the infant's auditory brainstem responses?

Church

Wapner

Mele

et al. 2010

Neurotoxicology and Teratology

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Our objective was to assess the effects of repeated antenatal corticosteroid treatments on the neonatal auditory brainstem response (ABR), a sensitive measure of neonatal brain maturity and auditory function. To achieve this, we performed and blindly evaluated neonatal ABRs on a subset of infants delivering within a multicenter randomized placebo-controlled clinical trial comparing single versus repeated courses of antenatal corticosteroid treatments for women at 23–31 weeks gestation who remained at increased risk for preterm birth. The women were randomly assigned to either the single or the repeated antenatal corticosteroid treatment group. Women in the repeated antenatal corticosteroid group received weekly antenatal corticosteroid treatments until 34 weeks gestation or until they reached a study-determined limited number of courses, whereas women in the single antenatal corticosteroid group received an initial course of corticosteroid followed by weekly placebo injections. We performed ABR testing on their infants prior to discharge. The latencies of waves I, III and V and the peak-to-trough amplitudes of waves I and V were compared between those in the single (n=27) and repeated antenatal corticosteroid treatment (n=24) groups. The majority of repeated antenatal corticosteroid infants (20 of 24) were exposed to ≥4 antenatal corticosteroid treatments. Even though gestational age was similar between our subset of single and repeated antenatal corticosteroid treatment groups, infant birth weight and length and head circumference were significantly smaller in the repeated antenatal corticosteroid group (p<0.05). Despite these differences in birth sizes, there were no significant group differences in the ABR wave latencies or amplitudes. We concluded that our repeated antenatal corticosteroid treatments, in comparison to a single treatment, did not significantly benefit or harm the neonatal ABR despite significant effects on birth size.

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Retinal maturation is delayed by repeated, but not single, maternal injections of betamethasone in sheep

Cited by 44 publications

References 19 publications

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

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

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

Repeated courses of antenatal corticosteroids: Are there effects on the infant's auditory brainstem responses?

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