van der Merwe Johannes, van der Veeken Lennart, Inversetti Annalisa, Galgano Angela, Valenzuela Ignacio, Salaets Thomas, Ferraris Sebastiano, Vercauteren Tom, Toelen Jaan, Deprest Jan
Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium; Division Woman and Child, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.
Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium.
Am J Obstet Gynecol. 2022 Jun;226(6):850.e1-850.e21. doi: 10.1016/j.ajog.2021.11.1370. Epub 2021 Dec 4.
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.
Herein, we investigate what the short- and long-term neurodevelopmental effects of a single course of betamethasone in simulated late preterm birth.
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.
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.
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.
晚期早产与短期呼吸和适应问题相关。尽管产前使用皮质类固醇似乎能减轻呼吸负担，但这可能会以日后出现不良神经心理结果为代价。这种影响尚未得到研究。
在此，我们研究在模拟晚期早产中单次使用倍他米松的短期和长期神经发育影响。
在受孕后28天和29天，对经时间匹配的怀孕母兔分别肌肉注射0.1mg/kg倍他米松（n = 8）或1mL生理盐水（n = 6）。产前皮质类固醇的剂量和方案基于先前的研究，与常规临床使用相当。在受孕后30天（足月为31天）进行剖宫产，新生兔寄养28天，之后群居饲养。进行了新生儿肺功能测试和短期神经行为测试。随后在4周和8周龄时进行旷场试验、自发交替试验和新物体识别试验。在出生后第1天和8周时，对一个亚组实施安乐死并经心脏灌注固定。使用离体高分辨率磁共振成像计算扩散张量成像衍生的分数各向异性和平均扩散率。对固定的大脑进行处理并连续切片，对一组3个冠状切片进行抗NeuN、Ki67和末端脱氧核苷酸转移酶dUTP缺口末端标记染色。
产前暴露于皮质类固醇与新生儿肺功能改善相关，但导致长期生长发育迟缓，同时伴有持续的神经行为缺陷。我们发现新生儿运动评分较低；在旷场试验中存在持续的焦虑行为，表现为更多的位移、奔跑和自我梳理行为；在T型迷宫试验中持续的交替评分较低；在新物体识别试验中辨别指数较低。在神经病理学评估中，观察到产前暴露于皮质类固醇导致神经元密度持续降低且Ki67 +细胞减少，尤其是在海马体和胼胝体中。这与相同关键区域中扩散张量成像衍生的分数各向异性评分较低一致。
在这个晚期早产兔模型中，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。
