Kozik Valeska, Schwab Matthias, Thiel Sandra, Hellwig Kerstin, Rakers Florian, Dreiling Michelle
Department of Neurology, Jena University Hospital, Jena, Germany.
Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
Front Neurol. 2022 Apr 26;13:830057. doi: 10.3389/fneur.2022.830057. eCollection 2022.
Multiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the fetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitization of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of fetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behavior.
Eighty children aged 8-18 years of mothers with MS will be recruited. Forty children, exposed to GC in will be compared to 40 children without fetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioral difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analyzed using linear regression models. Time-variant outcomes of the stress test will be analyzed in two mixed linear models exploring overall activity and change from baseline.
This study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement.
https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130.
多发性硬化症（MS）是育龄女性中最常见的神经免疫性疾病。目前的MS治疗包括使用疾病修正疗法（DMTs）进行免疫调节以预防复发，以及使用合成糖皮质激素（GC）甲泼尼龙（MP）进行急性复发治疗。由于大多数DMTs未被批准在孕期使用，治疗通常会中断，这增加了复发风险。虽然孕期使用MP治疗对胎儿相对安全，但可能对后期的认知和神经精神功能有害。其潜在机制被认为是GC受体的表观遗传介导的脱敏、随后应激敏感性的增加以及GC介导的脑发育受损。本研究的目的是调查在MS复发治疗背景下胎儿暴露于MP与后期认知功能、脑发育、应激敏感性和行为之间的关联。
将招募80名患有MS的母亲的8至18岁儿童。将40名在孕期暴露于GC的儿童与40名未暴露于胎儿GC的儿童进行比较。智商将作为主要结局。次要结局将包括注意力、运动发育、情绪兴奋性、注意力缺陷多动障碍相关症状和行为困难。特里尔社会应激测试将测试应激敏感性，脑电图（EEG）和磁共振成像（MRI）将评估脑功能和结构发育。为了确定潜在机制，将研究GC受体基因和H19/IGF2基因座的DNA甲基化以及微生物组和代谢组的变化。主要和次要结局将使用线性回归模型进行分析。应激测试的时变结局将在两个混合线性模型中进行分析，以探索总体活动和相对于基线的变化。
本研究已获得参与机构伦理委员会的批准，结果将根据2007年《加强流行病学观察性研究报告规范（STROBE）声明》进行呈现。
