妊娠期SDB对母婴健康的前瞻性流行病学研究及分子生物和表观遗传机制探讨

Our previous research indicated that the prevalence of sleep-disordered breathing (SDB) increases as pregnancy progresses and severe symptoms may occur gradually which result in both a state of oxidative stress and inflammatory responses. Based on these findings, a prospective cohort longitudinal study is specifically designed to observe the prevalence and severity of SDB at the first, second and third trimester of pregnancy. The present study also attempts to examine the associations between SDB and several outcome measurements including pregnancy complications, birth outcomes and infant neurobehavioral development status. The following research questions will be specifically concerned: whether or not the above associations are dose-dependent, and whether or not there is a susceptible period to SDB exposure with different research outcomes. Furthermore, the biological mechanisms underlying these associations would be comprehensively explored: ① How exposure to SDB during pregnancy affects the state of oxidative stress, inflammatory reaction and hemodynamic changes; and ② potential epigenetic modifications of cortisol-related signaling pathway and the methylation status of key genes on this pathway. In summary, this study systematically examines the impact of SDB exposure during pregnancy on maternal and child health which could be potentially explained by biological mechanisms. All of the above evidence may be significant to prenatal care which can be used in clinical practices in order to enhance aristogenesis and stirpiculture.

课题组前期发现，随着妊娠的进展，孕妇睡眠呼吸障碍（Sleep-Disordered Breathing, SDB）的发生率逐步上升，症状逐渐加重，使机体处于氧化应激和炎症反应状态。基于此发现，本项目分别于孕早、中、晚期纵向随访SDB的发病及病情分级评分，前瞻性评估其与妊娠合并症、分娩结局和婴幼儿神经行为发育之间的关联，评价可能的剂量-效应关系，寻找SDB暴露危险窗口。以氧化应激、炎症反应和心血管、胎盘血流动力学为生物效应指标，探讨妊娠SDB对母婴围产健康影响的生物学机制，构建妊娠SDB-生物效应-围产结局之间的数学模型；以婴幼儿神经行为发育水平为远期健康结局，阐述妊娠SDB在胎儿下丘脑-垂体-肾上腺轴发育宫内编程和表观遗传修饰中的作用及远期效应。本研究关注到妊娠这一孕育生命的特定阶段，比较系统阐述妊娠SDB对母婴健康的影响及潜在生物学机制，对于丰富孕期保健理论知识和促进优生优育意义重要。

本课题组较早关注到孕期睡眠健康，在预实验发现随着妊娠的进展，睡眠呼吸障碍（Sleep-Disordered Breathing, SDB）的发生率逐步上升的基础上，着手研究孕期睡眠特征及健康效应。本项目以SDB为观察重点，全面动态评估孕期睡眠特征。分别于孕早、中、晚期纵向随访包括SDB在内的各类睡眠参数，随访其与妊娠合并症和分娩结局之间的关联。同时，以婴幼儿睡眠模式的建立和过敏性疾病易感性为效应指标观察孕期睡眠的远期健康效应，并通过Hippo信号通路和Jun基因表达初步分析了睡眠影响胚胎发育的生物学机制。.研究取得如下成果：.一.采用国际标准化评估工具分别于孕早、中、晚期纵向评估了单胎和双胎孕期孕期睡眠的多个参数，首次获得了中国人孕期睡眠特征的前瞻性流行病学资料。其中，有关双胎孕妇睡眠特征的数据有望填补国际研究空白。.二.包括SDB在内的多个睡眠参数均与孕期合并症（如妊娠期糖尿病、妊高症）及不良分娩结局（如早产）相关。睡眠质量差可导致孕期体重增长速率过快，该发现可部分解释睡眠问题与妊娠期糖尿病、妊高症发病高风险之间的关联。.三.初步证实孕期睡眠问题可对子代出生后的生长发育带来远期危害，从两个视角提供了研究数据支持：1孕期母亲睡眠可影响子代睡眠模式的建立；2.孕期睡眠与运动模式与子代过敏性疾病的易感性相关。.四.围孕期睡眠问题可通过褪黑素分泌异常为介导干扰胚胎发育，Hippo信号通路可能参与其中，使细胞周期在G1至S期发生阻滞。此外，与妊娠睡眠正常人群相比，妊娠SDB暴露人群皮质醇信号通路关键基因11β-HSD2中的9个CpG位点平均甲基化水平上升，提示睡眠问题可导致甲基化修饰发生改变。.本研究首次动态描述了中国人孕期睡眠特征，其中，在双胎孕妇中的研究为首次。比较系统阐述了包括SDB在内的多个睡眠参与胚胎发育调控，且会带来出生后远期健康效应，研究结果对于丰富孕期保健理论知识和促进优生优育意义重要。