Maternal Chorioamnionitis and Hypoxic-Ischemic Encephalopathy: The MATCH Study

母亲绒毛膜羊膜炎和缺氧缺血性脑病：MATCH 研究

• 批准号: 10507551
• 负责人: Marie Cornet
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507551
• 关键词: Accounting; Affect; Animal Model; Award; Azithromycin; Biometry; Birth; Blood; Blood flow; Brain; Brain Diseases; Brain Hypoxia-Ischemia; Brain Injuries; Brain imaging; California; Cell Count; Cerebral Palsy; Cessation of life; Child; Childhood; Clinical; Consensus; Data; Data Analyses; Development; Diagnosis; Early treatment; Electronic Health Record; Epidemiologist; Epidemiology; Epidural Analgesia; Epilepsy; Etiology; Exhibits; Exposure to; Fetus; Fever; Future; Height; Histologic; Histology; Human Development; Infant; Inflammation; Inflammatory Response; Intellectual functioning disability; Knowledge; Lead; Leukocytes; Leukocytosis; Link; Magnetic Resonance Imaging; Mediating; Mentorship; Mission; Mothers; National Institute of Child Health and Human Development; Neonatal; Neurodevelopmental Disability; Neurodevelopmental Impairment; Neurologic; Neurology; Newborn Infant; Outcome; Outcome Study; Oxygen; Pathologist; Perinatal; Physicians; Placenta; Pregnancy; Reporting; Research Personnel; Risk; Risk Factors; Scientist; Services; Severities; Syndrome; System; Tachycardia; Temperature; Testing; Therapeutic; Therapeutic Effect; Therapy Clinical Trials; Training; Training Programs; Treatment Efficacy; United States; administrative database; autism spectrum disorder; base; brain magnetic resonance imaging; career; clinical diagnosis; cohort; data management; disability; fetal; fetal inflammatory response syndrome; health data; high risk; improved; infant brain injury; intraamniotic infection; intrauterine infection; intrauterine inflammation; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; novel; novel strategies; placental infection; prevent; skills; targeted therapy trials; targeted treatment; therapeutic effectiveness

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

项目摘要 缺氧缺血性脑病（HIE）是一种严重的神经系统综合征，影响超过12，000名新生儿 在美国每年。新生儿缺氧缺血性脑病导致约一半的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，而且人们对其了解甚少。绒毛膜炎，或宫内炎 感染/炎症，引起胎儿炎症反应综合征，可能会降低胎儿的能力， 耐受分娩过程中的缺氧缺血。绒毛膜炎与4倍的风险增加有关， 此外，还可能降低治疗性低温的疗效，而治疗性低温是治疗HIE的唯一有效疗法。然而，在这方面， 绒毛膜炎是一种不精确的临床诊断，涉及一系列的病症。的临床证据 分娩和分娩期间的炎症（“临床绒毛膜炎”）依赖于母体发热的存在， 是非特异性的。发热发生在5%的临产母亲，可由其他因素引起，如硬膜外 analgesia.更好地了解绒毛膜炎、母体发热和HIE之间的关系至关重要 提高我们防治HIE的能力。NICHD最近的一份共识报告建议， 基于母体体温的特定截止值的临床绒毛膜炎（“Chorio-NICHD”）的定义， 母体白色细胞计数和胎儿心动过速。但Chorio-NICHD与HIE风险的关系尚不清楚。是否 Chorio-NICHD的存在降低了治疗性低温的神经保护作用， 研究了为了填补这些知识空白，我将检验Chorio-NICHD独立相关的假设 儿童发生缺氧缺血性脑病的风险更高，并且尽管接受了治疗， 治疗性低温通过利用具有涵盖围产期、新生儿和 童年时期，我会：1。量化脉络膜-NICHD之间的关联，包括临床特征，如 母体发热的高度和持续时间、白细胞增多的程度和胎儿心动过速的程度以及HIE。 2.确定临床或组织学标准定义的绒毛膜炎是否与MRI脑部严重程度相关 亚低温治疗新生儿缺氧缺血性脑病损伤3.量化Chorio之间的关联- NICHD和儿童神经发育障碍。作为一名临床医学家和临床研究者，我的职业生涯 目标是成为一名独立的流行病学医生，产生可操作的证据，优化 新生儿脑部疾病的诊断和治疗。有了这个K23，我将继续进行新生儿的高级培训， 脑疾病流行病学，发展电子健康数据管理和纵向数据分析的技能。 我将接受新生儿脑MRI结果和胎盘组织学分析的培训。这个职业奖， 凭借其严格的培训计划和优秀的导师团队，将使我成为该领域的领导者 新生儿神经病学和独立的医学科学家。在这个奖项的第4-5年，我将准备 提交R 01，研究在宫内环境下预防和治疗新生儿HIE的新策略 炎症 1