孕期应激/端粒-端粒酶系统与婴儿神经认知行为发育滞后的相关性研究

The prevalence of abnormal neurocognitive and behavioral development has up to 10%, which brings heavily social-psychological and economic burden for society and family. However, the etiology is still unclear. According to the “DOHaD” hypothesis and previous studies, prenatal stress exposure has a negative effect on neuroendocrine system development in utero, then increases the risk of mental disorders in childhood and adulthood. In addition, it has been proposed that the alternative telomere length is shorter among children with autism spectrum disorder compared with children without the disorder. Hence, we plan to build a mother-infant cohort and perform a prospective study to evaluate the source of increasing stress exposure during pregnancy, and follow up their offspring until 12 months ages to examine the neurocognitive and behavioral development status. Based on this, we will perform a nested case-control study. The cases are identified by Bayley scales of infant development (BSID-Chinese version), which are matched with children without a diagnosis of development retardation. By detecting the alternatively telomere length and telomerase activity in the offspring's buccal mucosa, and cortisol and α-amylase quantity in mother's saliva sample, we explore the associations among prenatal stress, telomere and telomerase system and neurocognitive and behavioral development retardation. The study will make substantial contribution to disclosing the mechanism of association between prenatal stress and neurocognitive and behavior development and will play work ground for the early intervention.

目前我国很多地区儿童及青少年神经认知行为异常总患病率已超过10%，给家庭及社会造成了沉重社会心理及经济负担，而其病因仍不明确。根据“胎源性成人疾病”理论及前期研究结果提示，母亲孕期应激水平上升可能影响胎儿神经内分泌系统发育，进而影响儿童及成人期精神疾病发生风险。另外近期有研究提示孤独症患儿的端粒相对长度较同龄正常儿短。本课题通过建立孕婴队列，孕早、中、晚期定期随访孕妇以明确应激水平及来源，前瞻性随访婴儿在不同月龄的神经认知行为的发育情况。另外嵌套开展巢式病例对照研究，选择经贝利婴幼儿发展量表筛查为神经认知行为发育迟滞婴儿作为病例，随机选择正常婴儿按性别和月龄1：1匹配，通过比较两组婴儿颊粘膜组织中端粒相对长度和端粒酶活性及母亲唾液中皮质醇和α淀粉酶水平，明确孕期应激水平及端粒-端粒酶系统与婴儿神经认知行为发育滞后的相关性，为揭示孕期应激对神经认知行为发育异常的生物学机制及早期干预奠定基础。

孕期应激水平的上升可能会影响胎儿神经内分泌系统的发育，进而影响儿童及成人期精神疾病发生风险，且动物实验研究提示应激与端粒长度缩短也存在相关性。本课题组借助于国际规范化量表开展流行病学调查，探讨了妊娠期应激水平的主要来源和及可能高危人群的特征，并评估孕期应激发展轨迹，及其与神经认知行为发育的相关性；并分析新生儿相对端粒长度与应激及神经认知行为发育之间的相关性。本次研究分两部分完成：（1）建立孕妇队列，借助于《匹兹堡睡眠质量指数量表（PSQI）》、《SAS焦虑自评量表》、《SDS抑郁自评量表》对1636名孕妇在孕早、中、晚期的睡眠质量、焦虑、抑郁水平进行评估，结果显示：孕妇在孕期焦虑/抑郁水平发展轨迹平稳，孕妇所处的家庭结构为单亲家庭或者扩展家庭时，孕妇应激水平相对较高；另外文化程度较低的孕妇在孕期出现睡眠障碍的可能性也更高。（2）选择在我院产检的309名孕妇，借助于包括《妊娠压力量表》、《特质应对方式问卷》、《社会支持评定量表》等在内9个国际规范化量表，全面调查应激及应激相关环境情况，并完成了部分新生儿脐血中相对端粒长度的监测，随访其神经认知行为发育滞后的发育情况。结果显示：消极应对特质评分与孕期睡眠障碍及自评焦虑水平之间存在正相关，孕妇在孕早期睡眠障碍与新生儿脐带血中相对端粒长度缩短存在相关，而关于相对端粒长度与神经认知行为发育迟滞的相关性有待后期巢式病例对照结果的验证。