Maternal inflammation during pregnancy and neurodevelopmental disorders

摘要 神经发育障碍（NDD）是一组中枢神经系统发育障碍， 系统受到干扰。在美国，大约六分之一的儿童受到NDD的影响， 支持一个NDD患者的费用超过200万美元。常见的NDD包括自闭症 谱系障碍（ASD）、脑瘫（CP）和发育迟缓（DD）。NDD的原因是 大多数情况下是未知的，很少有可改变的风险因素被确定。越来越多的证据表明， 遗传和环境因素的关键作用，特别是在妊娠期和产后早期 期常见的免疫介导和代谢疾病以及免疫和代谢水平 生物标志物已显示与NDD风险相关。此外，免疫和代谢 系统相互影响，反过来又受到基因的影响。我们的核心假设是， 怀孕期间由于免疫或代谢失调引起的炎症会对孩子产生不利影响。 神经发育以前的NDD风险的妊娠标志物的研究主要集中在一个特定的 NDD只在怀孕期间的一个时间点测量免疫生物标志物，并且没有考虑母亲的 遗传学或环境暴露。我们试图克服以往研究的局限性， 早期发现将妊娠期间母体免疫和代谢功能与NDD风险增加联系起来 通过利用以前为凯撒永久研究计划收集的全面数据， 基因环境与健康（RPGEH）妊娠队列，其中包括约15，000名孕妇， 存档的第一和第二个三个月的血液样本，人口统计学特征的综合信息， 母亲在怀孕前和怀孕期间的临床状况，以及电子健康记录的儿童结局。我们 寻求资金，对怀孕早期和中期的血液样本进行免疫和代谢检测， 患有ASD（N=150）、CP（N=60）、DD（N=1500）或无ASD的母亲 NDD（N=1000），并生成全基因组母体SNP数据，以支持解决以下问题的分析 目的：1）描述妊娠期母体免疫和代谢状况，并评估是否存在 是与后代神经发育结果相关的特定纵向模式， 2)确定与改变的母亲因素（人口统计学和临床特征，遗传学） 母亲在怀孕期间的免疫或代谢功能和不同的神经发育结果的风险。 我们的研究有可能确定怀孕期间的免疫和代谢特征，这些特征表明 具体NDD。这将支持NDD产前筛查的发展，从而更早地 因此，我们认为，这是一项非常重要的干预措施，也是预防未来发病和提高生活质量的潜力所在。而且 产前生物标志物的鉴定将阐明异常妊娠的生物学机制。 神经发育，并为制定预防策略提供机会。

ABSTRACT Neurodevelopmental disorders (NDD) are a group of disorders in which the development of the central nervous system is disturbed. Approximately one in six children in the United States is affected by NDD, and the lifetime cost of supporting one individual with NDD exceeds $2 million. Commonly known NDD include autism spectrum disorders (ASD), cerebral palsy (CP), and developmental delays (DD). The causes of NDD are largely unknown, and few modifiable risk factors have been identified. A growing body of evidence supports a critical role for both genetic and environmental factors, particularly during gestation and the early postnatal period. Common immune-mediated and metabolic conditions as well as levels of immune and metabolic biomarkers have been shown to be associated with NDD risk. Furthermore, the immune and metabolic systems influence each other, and are in turn genetically-influenced. Our central hypothesis is that maternal inflammation during pregnancy stemming from immune or metabolic dysregulation will adversely impact child neurodevelopment. Previous studies of gestational markers of NDD risk primarily focused on one specific NDD, measured immune biomarkers at only one point in pregnancy, and didn't take into account maternal genetics or environmental exposures. We seek to overcome the limitations of previous studies and extend earlier findings linking maternal immune and metabolic function during pregnancy with increased risk of NDD by leveraging the comprehensive data previously collected for the Kaiser Permanente Research Program on Genes Environment and Health (RPGEH) Pregnancy Cohort, which includes ~15,000 pregnant women with archived first and second trimester blood samples, comprehensive information on demographic characteristics, maternal clinical status before and during pregnancy, and child outcomes from electronic health records. We seek funds to perform immune and metabolic assays on first and second trimester blood samples from mothers who gave birth to children diagnosed with ASD (N=150), CP (N=60), DD (N=1500), or who have no NDD (N=1000) and generate genome-wide maternal SNP data to support analyses addressing the following aims: 1) Characterize the maternal immune and metabolic profiles over pregnancy and evaluate whether there are specific longitudinal patterns that are associated with neurodevelopmental outcomes in the offspring, and 2) Identify maternal factors (demographic and clinical characteristics, genetics) that are associated with altered maternal immune or metabolic function during pregnancy and risk of different neurodevelopmental outcomes. Our study has the potential to identify immune and metabolic profiles during pregnancy that indicate risk for specific NDD. This would support the development of prenatal screening for NDD, leading to earlier intervention and the potential for preventing future morbidity and improving quality of life. Furthermore, the identification of prenatal biomarkers will illuminate the biologic mechanisms underlying aberrant neurodevelopment and provide an opportunity for developing preventive strategies.