Fetal exposure to maternal stress and inflammation: Effects on neurodevelopment

描述（由申请人提供）：拟议的项目旨在调查怀孕期间的母亲压力，怀孕期间的母亲炎症和胎儿缺氧（胎儿缺氧）如何影响后代青春期抑郁症状的风险。第二个目标是绘制这些产前风险因素如何导致一连串事件的轨迹，导致儿童时期情感，认知和行为结果的发展轨迹改变以及随后的青春期抑郁症。该项目基于一项大型出生队列研究，即儿童健康与发育研究（CHDS），该研究从1959年至1966年前瞻性地跟踪了妇女的整个怀孕过程，并获得了有关母亲在怀孕和分娩期间的经历，健康风险行为和医疗并发症的详细信息。这些信息包括母亲对过去一年中有关担忧或担忧的开放式问题的回答以及对怀孕的感受。在整个妊娠期间从母亲收集多个血清样品，并在-20 ℃下存档。后代在5岁、9岁和15岁时进行认知、行为和心理评估。本研究将包括750名母亲及其后代，他们在每个时间点都有完整的数据。将对妊娠早期和中期的存档产前血清进行血清学分析，以测量妊娠期间母体应激的生物标志物（即皮质醇）、称为细胞因子的炎症蛋白（IL-1和TNF-α的可溶性受体以及细胞因子IL-8和IL-6）的母体水平以及胎儿缺氧标志物（VEGF）。此外，前瞻性收集的分娩和分娩信息将用于胎儿缺氧的额外测量。此外，本研究将定性编码的压力相关的主题，从获得的叙述，在回答上述开放式问题和地理编码的邻里水平的背景因素为每个主题。具体目标如下：1）调查胎儿暴露于母体压力和压力激素对青少年后代抑郁风险的贡献，2）调查是否存在中间的儿童期情绪和行为表型，以及胎儿在怀孕期间暴露于母体压力和随后的青春期抑郁之间的认知轨迹改变，和3）调查胎儿暴露于高水平的母体压力是否增加了其他产前和围产期并发症或与其他产前和围产期并发症相互作用，以增加神经发育后遗症和青少年精神病理学的风险。这项研究的独特之处在于回答了关于产前风险因素如何在抑郁症的神经发育过程中起作用的关键问题。本研究有可能影响早期干预和预防策略的制定，以及确定青春期后续困难的早期风险标志物。 公共卫生相关性：拟议的项目旨在调查母亲的心理社会和神经内分泌指标的压力在怀孕期间，母亲在怀孕期间的炎症和胎儿缺氧（缺氧）有助于抑郁症的神经发育过程中的青少年后代。

DESCRIPTION (provided by applicant): The proposed project aims to investigate how maternal stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen to the fetus) influence the risk of symptoms of depression during adolescence in offspring. A secondary aim is to map trajectories of how these prenatal risk factors result in a cascade of events, leading to altered developmental trajectories in emotional, cognitive, and behavioral outcomes during childhood and subsequent depression during adolescence. The proposed project is based on a large birth cohort study, the Child Health and Development Study (CHDS), that followed women prospectively throughout their pregnancies from 1959-1966 and acquired detailed information on the mothers' experiences, health-risk behaviors, and medical complications during pregnancy and delivery. This information included maternal responses to open-ended questions about concerns or worries within the past year and feelings about the pregnancy. Multiple sera samples were collected from mothers throughout their pregnancies and archived at -20oC. Offspring were administered cognitive, behavioral, and psychological assessments at ages 5, 9, and 15. The present study will include 750 mothers and their offspring who have complete data at each time point. Serological analyses will be conducted on archived prenatal sera from the first and second trimesters of pregnancy in order to measure biomarkers of maternal stress during pregnancy (i.e. cortisol), maternal levels of inflammatory proteins, termed cytokines, (the soluble receptors for IL-1¿ and TNF-¿ and the cytokines IL-8 and IL-6), and markers of fetal hypoxia (VEGF). Further, prospectively collected labor and delivery information will be used for additional measures of fetal hypoxia. In addition, the present study will qualitatively code stress-related themes from narratives acquired in response to the aforementioned open- ended questions and geocode neighborhood-level contextual factors for each subject. The specific aims are as follows: 1) to investigate the contributions of fetal exposure to maternal stress and stress hormones to risk of depression in adolescent offspring, 2) to investigate whether there are intermediate childhood emotional and behavioral phenotypes, as well as altered cognitive trajectories between fetal exposure to maternal stress during pregnancy and subsequent depression in adolescence, and 3) to investigate whether fetal exposure to elevated levels of maternal stress adds to or interacts with other pre- and perinatal complications to increase risk for neurodevelopmental sequelae and adolescent psychopathology. The proposed study is uniquely positioned to answer key questions about how prenatal risk factors operate within the neurodevelopmental course of depression. The present study has the potential to influence the development of early intervention and prevention strategies, as well as to identify early risk markers for subsequent difficulties in adolescence. PUBLIC HEALTH RELEVANCE: The proposed project aims to investigate how maternal psychosocial and neuroendocrine indicators of stress during pregnancy, maternal inflammation during pregnancy and fetal hypoxia (lack of oxygen) contribute to the neurodevelopmental course of depression in adolescent offspring.