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Neurocognitive sequelae of antenatal corticosteroids in a late preterm rabbit model
American Journal of Obstetrics and Gynecology ( IF 9.8 ) Pub Date : 2021-12-04 , DOI: 10.1016/j.ajog.2021.11.1370
Johannes van der Merwe 1 , Lennart van der Veeken 1 , Annalisa Inversetti 2 , Angela Galgano 2 , Ignacio Valenzuela 2 , Thomas Salaets 3 , Sebastiano Ferraris 4 , Tom Vercauteren 5 , Jaan Toelen 3 , Jan Deprest 6
Affiliation  

Background

Late preterm birth is associated with short-term respiratory and adaptive problems. Although antenatal corticosteroids seem to reduce the respiratory burden, this may come at the cost of adverse neuropsychological outcomes later in life. This impact has not been investigated.

Objective

Herein, we investigate what the short- and long-term neurodevelopmental effects of a single course of betamethasone in simulated late preterm birth.

Study Design

Time-mated pregnant does received 0.1 mg/kg betamethasone (n=8) or 1 mL saline intramuscular (n=6) at the postconceptional ages of 28 and 29 days. The antenatal corticosteroid dose and scheme were based on previous studies and were comparable with routine clinical use. Cesarean delivery was done on postconceptional age 30 days (term=31 days), and new-born rabbits were foster-cared for 28 days and were thereafter cared for in group housing. Neonatal lung function testing and short-term neurobehavioral testing was done. Open field, spontaneous alternation, and novel object recognition tests were subsequently performed at 4 and 8 weeks of age. On postnatal day 1 and at 8 weeks, a subgroup was euthanized and transcardially perfuse fixated. Ex vivo high-resolution Magnetic Resonance Imaging was used to calculate the Diffusion Tensor Imaging-derived fractional anisotropy and mean diffusivity. Fixated brains underwent processing and were serial sectioned, and a set of 3 coronal sections underwent anti-NeuN, Ki67, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining.

Results

Antenatal corticosteroid exposure was associated with improved neonatal lung function, yet resulted in a long-term growth deficit that coincided with a persistent neurobehavioral deficit. We demonstrated lower neonatal motor scores; a persistent anxious behavior in the open field test with more displacements, running, and self-grooming episodes; persistent lower alternation scores in the T-Maze test; and lower discriminatory indexes in the novel object recognition.

On neuropathological assessment, antenatal corticosteroid exposure was observed to result in a persistent lower neuron density and fewer Ki67+ cells, particularly in the hippocampus and the corpus callosum. This coincided with lower diffusion tensor imaging-derived fractional anisotropy scores in the same key regions.

Conclusion

Clinical equivalent antenatal corticosteroid exposure in this late preterm rabbit model resulted in improved neonatal lung function. However, it compromised neonatal and long-term neurocognition.



中文翻译:

晚期早产兔模型中产前皮质类固醇的神经认知后遗症

背景

晚期早产与短期呼吸和适应问题有关。尽管产前皮质类固醇似乎可以减轻呼吸负担,但这可能以在以后的生活中产生不良的神经心理学后果为代价。这种影响尚未调查。

客观的

在此,我们研究了单一疗程倍他米松在模拟晚期早产中的短期和长期神经发育影响。

学习规划

时间交配的孕妇在受孕后 28 天和 29 天接受 0.1 mg/kg 倍他米松 (n=8) 或 1 mL 生理盐水肌肉注射 (n=6)。产前皮质类固醇剂量和方案基于以前的研究,与常规临床使用相当。剖宫产在受孕后 30 天(足月 = 31 天)进行,新生兔被寄养 28 天,之后在集体饲养中进行护理。进行了新生儿肺功能测试和短期神经行为测试。随后在 4 周龄和 8 周龄时进行了开放视野、自发交替和新物体识别测试。在出生后第 1 天和第 8 周,对一个亚组实施安乐死并经心脏灌注固定。离体高分辨率磁共振成像用于计算扩散张量成像衍生的分数各向异性和平均扩散率。固定的大脑经过处理和连续切片,一组 3 个冠状切片经过抗 NeuN、Ki67 和末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色。

结果

产前皮质类固醇暴露与新生儿肺功能改善有关,但会导致长期生长缺陷,同时伴有持续的神经行为缺陷。我们展示了较低的新生儿运动评分;在旷场测试中出现持续的焦虑行为,出现更多的位移、跑步和自我修饰;T-Maze 测试中持续较低的交替分数;并且在新颖的对象识别中具有较低的判别指数。

在神经病理学评估中,观察到产前皮质类固醇暴露导致神经元密度持续降低和 Ki67+ 细胞减少,特别是在海马和胼胝体中。这与相同关键区域中较低的扩散张量成像衍生的分数各向异性分数相吻合。

结论

在这种晚期早产兔模型中临床等效的产前皮质类固醇暴露导致新生儿肺功能改善。然而,它损害了新生儿和长期神经认知。

更新日期:2021-12-04
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