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: 10670862
• 负责人: Marie Cornet
• 金额: $ 17.32万
• 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/10670862
• 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; 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; Leukocytes; Leukocytosis; Link; Magnetic Resonance Imaging; Mediating; Melatonin; 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; Recommendation; Reporting; Research Personnel; Risk; Risk Factors; Scientist; Services; Severities; Syndrome; System; Tachycardia; Temperature; Term Birth; Testing; Therapeutic; Therapeutic Effect; Therapy Clinical Trials; Training; Training Programs; Treatment Efficacy; United States; administrative database; autism spectrum disorder; brain magnetic resonance imaging; career; clinical diagnosis; cohort; data management; demographics; disability; electronic health data; electronic health record system; fetal; fetal inflammatory response syndrome; high risk; improved; infant brain injury; intraamniotic infection; intrauterine infection; intrauterine inflammation; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonate; neuroprotection; 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

项目概要 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 每年在美国。 HIE 导致约一半受影响者死亡或神经发育障碍 新生儿。 HIE 的病因多种多样且知之甚少。绒毛膜羊膜炎，或宫内 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。绒毛膜羊膜炎与以下疾病的风险增加 4 倍相关： HIE，还可能降低低温治疗的功效，低温治疗是 HIE 的唯一可用疗法。然而， 绒毛膜羊膜炎是一种不精确的临床诊断，涉及一系列病症。临床证据 临产和分娩期间的炎症（“临床绒毛膜羊膜炎”）依赖于产妇发烧的存在， 是非特定的。 5% 的产妇会出现发烧现象，可能是由硬膜外麻醉等其他因素引起的 镇痛。更好地了解绒毛膜羊膜炎、产妇发烧和 HIE 之间的关系至关重要 提高我们预防和治疗 HIE 的能力。最近的 NICHD 共识报告建议采用更精确的方法 基于产妇体温的特定临界点的临床绒毛膜羊膜炎（“Chorio-NICHD”）的定义， 母体白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。无论 Chorio-NICHD 的存在会降低治疗性低温的神经保护作用，但尚未被证实 研究过。为了填补这些知识空白，我将检验 Chorio-NICHD 独立相关的假设 儿童患 HIE 的风险较高，并且尽管接受治疗，仍与 HIE 脑损伤的风险增加相关 与治疗性低温。通过利用庞大的出生队列以及涵盖围产期、新生儿和新生儿的丰富数据 童年时期，我将： 1. 量化 Chorio-NICHD 之间的关联，包括临床特征，例如 母亲发烧的高度和持续时间、白细胞增多程度、胎儿心动过速程度以及 HIE。 2. 确定临床或组织学标准定义的绒毛膜羊膜炎是否与 MRI 脑部严重程度相关 新生儿 HIE 损伤的治疗性低温治疗。 3. 量化 Chorio-之间的关联 NICD 和儿童神经发育障碍。作为一名新生儿科医生和临床研究员，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 新生儿脑部疾病的诊断和治疗。有了这台 K23，我将继续进行新生儿高级培训 脑疾病流行病学，培养电子健康数据管理和纵向数据分析技能。 我将接受新生儿脑部 MRI 结果和胎盘组织学分析的培训。这个职业奖， 以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 新生儿神经病学博士和独立医师科学家。在该奖项的第 4-5 年，我将做好准备 提交 R01 研究预防和治疗宫内新生儿 HIE 的新策略 炎。 1