Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Neurotoxicol Teratol. 2012 Jan-Feb;34(1):196-205. doi: 10.1016/j.ntt.2011.09.004. Epub 2011 Sep 22.
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 0.2mg/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 to 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.
产前皮质类固醇（AC）治疗用于有早产风险的孕妇，以通过增强肺和脑成熟度来降低婴儿发病率和死亡率。然而，目前尚无关于 AC 治疗应多频繁给予的公认方案，并且一些研究发现重复 AC 治疗会导致生长迟缓和脑损伤。我们的目标是评估重复 AC 治疗的剂量依赖性效应，并估计引起听觉脑干反应（ABR）有害影响的关键 AC 疗程数，ABR 是脑发育、神经传递和听力损失的敏感测量指标。我们假设，只有给予超过 3 次 AC 治疗疗程，重复 AC 治疗才会对后代的 ABR 和生长产生有害影响。为了验证这一假设，我们给怀孕的 Wistar 大鼠分别给予高剂量 AC（HAC）、中剂量 AC（MAC）、低剂量 AC（LAC）或生理盐水（SAL）。还使用了未经处理的对照（CON）组。模拟临床情况，HAC 孕鼠在妊娠第 17-22 天期间每天接受 0.2mg/kg 倍他米松（IM）两次，共 6 天。MAC 孕鼠分别在妊娠第 17-19 天和第 20-22 天接受 3 天 AC 治疗，然后接受 3 天生理盐水治疗。LAC 孕鼠分别在妊娠第 17 天和第 18-22 天接受 1 天 AC 治疗，然后接受 5 天生理盐水治疗。SAL 孕鼠从妊娠第 17 天到第 22 天每天接受 6 天生理盐水治疗（两次，与 HAC 注射等容，IM）。在出生后第 24 天对后代进行 ABR 测试。结果表明，与 CON 幼鼠相比，HAC 幼鼠的 ABR 的 P4 潜伏期（神经传递时间）明显延长（更差），而 HAC 和 MAC 幼鼠的 ABR 阈值明显升高（更差）。HAC 和 MAC 幼鼠的生长也受到抑制，且死亡率高于 CON 幼鼠。SAL 和 LAC 幼鼠表现出很少或没有不良反应。总之，重复 AC 治疗对大鼠后代的 ABR、出生后生长和存活有不良影响。延长的 ABR 潜伏期反映了听觉神经和脑干听觉通路中神经传递时间的减慢。升高的 ABR 阈值反映了听力缺陷。我们得出结论，重复 AC 治疗会对大鼠后代的神经系统、感觉和发育产生有害影响。在权衡重复 AC 治疗的益处和风险以及监测和管理产前暴露儿童可能的不良反应时，应考虑这些影响。
