Maternal Chorioamnionitis and Hypoxic-Ischemic Encephalopathy: The MATCH Study

项目总结 缺氧缺血性脑病(HIE)是一种严重的神经综合征，影响超过12,000名新生儿 每年在美国。HIE导致约一半患者死亡或神经发育障碍 新生儿。新生儿缺氧缺血性脑病的病因是多种多样的，人们对此知之甚少。绒毛膜羊膜炎，或宫内 感染/炎症，会引起胎儿炎症反应综合征，从而降低胎儿的 能耐受分娩过程中的缺氧缺血。绒毛膜羊膜炎与增加4倍的风险有关。 而且可能还会降低治疗性亚低温的疗效，这是治疗HIE的唯一方法。然而， 绒毛膜羊膜炎是一种不准确的临床诊断，指的是一系列疾病。临床证据表明 分娩和分娩期间的炎症(“临床性绒毛膜羊膜炎”)依赖于母体发热，而母体发热 是非特定的。发热发生在5%的分娩母亲身上，也可能是由硬膜外等其他因素引起的 止痛药。更好地了解绒毛膜羊膜炎、母体发热和HIE之间的关系是至关重要的 提高我们预防和治疗HIE的能力。NICHD最近的一份共识报告建议了更准确的 临床绒毛膜羊膜炎(“绒毛膜-NICHD”)的定义基于母亲体温的特定界值， 母血白细胞计数，胎儿心动过速。但绒毛膜缺乏症与HIE风险之间的关系尚不清楚。是否 绒毛膜NICHD的存在降低了治疗性低温的神经保护作用也没有得到 学习。为了填补这些知识空白，我将检验绒毛膜-NICHD独立相关的假设 儿童患HIE的风险较高，并且与尽管接受治疗但HIE脑损伤的风险增加有关 治疗体温过低。通过利用具有丰富数据的大型出生队列，涵盖围产期、新生儿和 童年时期，我会：1。量化绒毛膜-NICHD之间的联系，包括临床特征，如 母亲发热的高度和持续时间、白细胞增多的程度、胎儿心动过速的程度和新生儿缺氧缺血性脑病。 2.确定临床或组织学标准定义的绒毛膜羊膜炎是否与MRI脑的严重程度有关 治疗性亚低温治疗新生儿缺氧缺血性脑病的损伤3.量化绒毛膜之间的联系- NICHD与儿童神经发育障碍作为一名新生儿专家和临床研究人员，我的职业生涯 目标是成为一名独立的医生-流行病学家，产生可操作的证据，优化 新生儿脑疾病的诊断和治疗。有了这台K23，我将继续接受新生儿的高级培训 脑部疾病流行病学，发展电子健康数据管理和纵向数据分析的技能。 我将接受分析新生儿脑部核磁共振结果和胎盘组织学方面的培训。这个事业奖， 凭借严格的培训计划和优秀的指导团队，我将成为该领域的领导者 新生儿神经病学教授和一位独立的内科科学家。在这个奖项的第四年到第五年，我将做好准备 提交R01以研究预防和治疗宫内环境下新生儿缺氧缺血性脑病的新策略 发炎。 1

PROJECT SUMMARY Hypoxic-ischemic encephalopathy (HIE) is a severe neurologic syndrome affecting more than 12,000 newborns in the United States each year. HIE results in death or neurodevelopmental disabilities in about half of affected neonates. The causes of HIE are heterogeneous and poorly understood. Chorioamnionitis, or intrauterine infection/inflammation, gives rise to a fetal inflammatory response syndrome that may reduce a fetus’ ability to tolerate hypoxia-ischemia during delivery. Chorioamnionitis has been associated with a 4-fold increased risk of HIE, and may also reduce the efficacy of therapeutic hypothermia, the only available therapy for HIE. However, chorioamnionitis is an imprecise clinical diagnosis that refers to a spectrum of conditions. Clinical evidence of inflammation (“clinical chorioamnionitis”) during labor and delivery relies on the presence of maternal fever which is non-specific. Fever occurs in 5% of laboring mothers and can be caused by other factors such as epidural analgesia. A better understanding of the relationship between chorioamnionitis, maternal fever and HIE is crucial to improving our ability to prevent and treat HIE. A recent NICHD consensus report recommended a more precise definition of clinical chorioamnionitis (“Chorio-NICHD”) based on specific cut-offs for maternal temperature, maternal white cell count, and fetal tachycardia. But how Chorio-NICHD relates to HIE risk is unknown. Whether the presence of Chorio-NICHD reduces the neuroprotective effect of therapeutic hypothermia has also not been studied. To fill these gaps in knowledge, I will test the hypothesis that Chorio-NICHD is independently associated with a higher risk of HIE in the child, and is associated with increased risk of HIE brain injury despite treatment with therapeutic hypothermia. By leveraging a large birth cohort with rich data spanning perinatal, neonatal, and childhood periods, I will: 1. Quantify the association between Chorio-NICHD, including clinical features such as height and duration of maternal fever, degree of leukocytosis, and degree of fetal tachycardia, and HIE. 2. Determine if chorioamnionitis defined by clinical or histologic criteria is associated with severity of MRI brain injury in neonates with HIE treated with therapeutic hypothermia. 3. Quantify the association between Chorio- NICHD and childhood neurodevelopmental impairment. As a neonatologist and clinical researcher, my career objective is to become an independent physician-epidemiologist generating actionable evidence that optimizes diagnosis and treatment of neonatal brain disorders. With this K23, I will pursue advanced training in neonatal brain disease epidemiology, develop skills in electronic health data management and longitudinal data analyses. I will receive training in the analysis of neonatal brain MRI findings and placental histology. This career award, with its rigorous training program and outstanding mentorship team, will allow me to become a leader in the field of neonatal neurology and an independent physician-scientist. In years 4-5 of this award, I will be poised to submit an R01 to study novel strategies for preventing and treating neonates with HIE in the setting of intrauterine inflammation. 1