In Utero Infection: Child Health and Neurodevelopment

描述(申请人提供)：早产是脑性瘫痪的最高风险因素，其他不利的神经后果(如失明、耳聋和智力低下)，以及长期的不利儿童健康后果占这些不利后遗症的50%。大多数这种发病率集中在妊娠不到32周的早产儿中。由于美国早产率的上升和早产婴儿存活率的提高，不良长期后遗症的发生率正在上升。现已证实，临床上无症状的上生殖道细菌感染与大多数发生在32周前的早产密切相关。此外，新出现的数据表明，胎儿在宫内暴露于细菌感染/炎症是发生脑性瘫痪和其他不良健康后果的独立危险因素，推测促炎细胞因子暴露可能代表了这些不良后果的联系。大多数将感染与不良神经结局联系起来的研究仅限于短期新生儿结局，包括脑室周围白质软化症等脑性瘫痪后续发展的标志物。这一领域的长期随访研究很少，主要局限于脑性瘫痪作为主要结果，提供的关于母亲/新生儿临床过程的信息有限。目前的文献缺乏关于母婴配对的广泛的母婴临床、实验室、微生物学和组织学数据的纵向研究，这些母婴配对的长期结果评估不仅包括脑性瘫痪，而且还包括其他重要的神经发育和健康结果。我们假设，在子宫内暴露于感染/炎症与4-7岁儿童不良神经发育和儿童健康结局的风险增加有关。我们建议在424对母婴配对的队列中检验这一假设，这些母婴配对在24周、0天和31周、6天妊娠期间在本机构分娩。这一队列已经被研究，形成了一个广泛的数据库，几乎包括产前、产中和新生儿临床数据的每一个细节。该队列还提供了组织学、微生物学和生化数据，包括脐带血和新生儿培养、脐带血细胞因子数据、胎盘组织学和胎盘培养。我们建议对这一早产儿队列进行一项纵向跟踪研究，以便系统地评估母婴感染、胎儿暴露于炎症、新生儿短期结局和4-7岁最终神经发育结局之间的关系(目标1和2)，包括环境因素和照顾者特征等效应调节剂的潜在影响(目标3)。我们还将确定神经元损伤的脐带血标志物是否与短期或长期结果相关(目标4)，以及宫内感染/炎症、支气管肺发育不良与肺功能障碍的长期指标之间的关联强度(目标5)。

DESCRIPTION (provided by applicant): Preterm birth is the highest risk factor for cerebral palsy, other adverse neurological outcomes (such as blindness deafness, and mental retardation), and long-term adverse child health outcomes accounting for up to 50% of these adverse sequelae. Most of this morbidity is concentrated among the subset of preterm births that deliver at less than 32 weeks' gestation. Because of the increasing rate of preterm birth in the United States and the increased survival of infants delivered at the earlier gestational ages, the incidence of adverse long-term sequelae is rising. It is now well established that clinically silent upper genital tract intrauterine bacterial infection is strongly associated with a majority of preterm births that occur prior to 32 weeks' gestation. Additionally, emerging data implicate fetal in utero exposure to bacterial infection/inflammation as an independent risk factor for development of cerebral palsy and other adverse health outcomes, it is speculated that proinflammatory cytokine exposure may represent the link to these adverse outcomes. Most of the studies linking infection to adverse neurological outcomes have been limited to short-term neonatal outcomes including markers for subsequent development of cerebral palsy such as periventricular leukomalacia. Long-term follow-up studies in this area are sparse, are largely limited to cerebral palsy as the primary outcome, and provide limited information regarding the maternal/neonatal clinical course. The current literature lacks a longitudinal study with extensive maternal and neonatal clinical, laboratory, microbiological, and histological data on a cohort of maternal-infant pairs on whom long-term outcome evaluation is available including not only cerebral palsy but also other important neurodevelopmental and health outcomes. We hypothesize that in utero exposure to infection/inflammation is associated with increased risk of adverse neurodevelopmental and child health outcomes at age 4-7 years. We propose to test this hypothesis in a cohort of 424 maternal-infant pairs that delivered at our institution between 24 weeks 0 days and 31 weeks 6 days gestation. This cohort has already been studied resulting in an extensive database that includes almost every detail of antepartum, intrapartum, and neonatal clinical data. Also already available from this cohort are histological, microbiological, and biochemical data including umbilical cord blood and neonatal cultures, umbilical cord blood cytokine data, placental histology, and placental cultures. We propose a longitudinal follow-up study of this preterm cohort in order to systematically evaluate the relationship between maternal/fetal infection, fetal exposure to inflammation, neonatal short-term outcomes and ultimate neurodevelopmental outcomes at age 4 to 7 years (Aims 1 and 2) including the potential influence of effect modifiers such as environmental factors and caregiver characteristics (Aim 3). We will also determine if umbilical cord blood markers of neuronal damage are associated with short-term or long-term outcomes (Aim 4) and the strength of association between in utero infection/inflammation, bronchopulmonary dysplasia and long-term indicators of pulmonary dysfunction (Aim 5).