维生素D缺乏介导炎症反应在孕期抑郁与幼儿认知损伤关联中的作用

Prenatal depressive symptoms is significantly associated with abnormal cognitive and neurobehavioral development in offspring, however the biological mechanism is unclear. Our previous study suggested that vitamin D deficiency is more prevalent in depressive pregnant women and could promote the placental inflammation. Thus, we hypothesized that vitamin D deficiency inducing inflammation mediated the effect of prenatal depressive symptoms on cognitive impairment in offspring. We will establish Hefei Cohort of Maternal-Infant Pairs(HCMIP) including 1 500 maternal-infant pairs. Maternal depressive symptoms, the levels of 25(OH)D and serum inflammatory markers including IL-6, TNF-alpha? and CRP will be investigated at 12-16, and 28-32 weeks of gestation, respectively. The levels of inflammatory markers in cord blood and the placental mRNA expression of vitamin D receptor, CYP27B1, IL-6, TNF-alpha and CRP will be measured after delivery. The cognitive development, executive function and multimode MRI index will be evaluated during toddlerhood. Based on the longitudinal cohort study, we will evaluated the dose-response relationshiop between maternal and fetal inflammation and cognitive development in toddlers, and investigate the potential role for maternal and fetal inflammation in the association between prenatal depressive symptoms and cognitive impairment. Using orthogonal design, we will assess the moderating role of prenatal vitamin D in the association between prenatal depressive symptoms and cognitive impairment in toddlers. The study will extent the understanding on the biological mechanism by which prenatal depressive symptoms impact neural development in offspring, and will support the possibility that vitamin D supplements in depressive pregnant women would promote the cognitive and neurobehavioral development in offspring.

孕期抑郁与子代异常神经发育关联密切，其生物学机制有待揭示。前期研究发现，维生素D缺乏在抑郁孕妇中更普遍，并可促进胎盘炎症反应，因此推论：维生素D缺乏介导的炎症反应可能是联结孕期抑郁与儿童认知发育损伤的生物学中介因素。本研究拟招募1500名孕妇建立合肥母婴队列，在孕期进行2次抑郁症状、外周血25(OH)D和炎症标志物（IL-6、TNF-a和CRP）的监测，分娩后检测脐血炎症标志物和胎盘滋养层维生素D受体、活化酶及炎症标志物mRNA表达。在幼儿期进行认知发育、执行功能评价和多模态脑MRI检查。基于前瞻性队列，阐明母－胎炎症反应影响幼儿认知发育的剂量－反应关系及其在联结孕期抑郁与幼儿认知损伤中的中介作用；正交设计分析，探讨孕期充足的维生素D对孕期抑郁暴露幼儿认知损伤的修饰效应。研究结果将为孕期抑郁与子代脑发育关联的生物学基础提供新思路，并为抑郁孕妇补充维生素D保护子代脑发育提供依据。

孕期抑郁与子代异常神经发育关联密切，其生物学机制有待揭示。前期研究显示，维生素D 缺乏在抑郁孕妇中更普遍，并可促进胎盘炎症反应，因此推论：维生素D 缺乏介导的炎症反应可能是联结孕期抑郁与儿童认知发育损伤的生物学中介因素。本项目建立了合肥母婴队列，在孕期进行2 次抑郁症状评价，检测母婴25(OH)D 和炎症标志物，在幼儿期进行认知发育和执行功能评价。研究结果显示：（1）生命早期维生素D缺乏可显著增加子代炎症因子水平。维生素D缺乏的新生儿与非缺乏新生儿相比，高炎症风险显著增加，调整后OR= 3.06, 95% CI: 2.00-4.69；（2）孕期抑郁可能通过干扰胎盘转运功能影响胎儿维生素D水平。抑郁孕妇分娩新生儿维生素D缺乏风险相对于非抑郁孕妇的新生儿显著增加，调整后OR=1.56; 95% CI: 1.01-2.40；（3）生命早期维生素D参与神经发育，维生素D缺乏将严重影响神经发育结局。脐血25(OH)D处于最低五分位组的新生儿，其在幼儿期时（16～18月龄）的精神发育指数（MDI）和运动发育指数（PDI）与脐血25(OH)D较高的对照组相比，分别低7.60分（95 % CI：-12.4, -2.82）和8.04（95 % CI：-12.9, -3.11）；（4）出生时较高的维生素D水平可显著降低孕期抑郁介导的幼儿神经发育损伤风险。孕期抑郁显著增加学龄前儿童的ADHD风险（RR= 1.85, 95% CI: 1.17-2.93,）。分层分析显示，这种风险在出生时维生素D缺乏的儿童中存在（RR=3.10, 95% CI 1.44-6.63），但在出生时维生素D充足的儿童中并未观察到（RR=1.53, 95% CI 0.86-2.72）。本项目基于前瞻性队列，初步阐明孕期维生素D缺乏介导的高炎症反应在联结孕期抑郁与幼儿认知损伤中的中介作用，为抑郁孕妇补充维生素D保护子代脑发育提供依据。