孕期过度增重与儿童内外化行为和神经发育障碍关联的出生队列研究

There has been an increased interest in the research of adverse effect of the excess weight gain during pregnancy on childhood neurodevelopment. Animal findings suggest that chronic low-grade inflammation might program inflammation in offspring tissues through placenta inflammation, which might ultimately damage fetal brain development. However, dose-dependent relationship and critical window that excess gestational weight gain may affect childhood neurodevelopment, as well as possible mediation role of placenta inflammation involved in this process still remains a challenge and could only be deciphered through birth cohort study. This project will identify dose-dependent relation between extents of weight gain in different gestation with internalizing and externalizing behavioral problems among 3500 children followed-up in 5-7 year-old and 7-9 year-old in China-Anhui Birth Cohort Study (C-ABC study), with demographic characteristics, pre-pregnancy weight, pregnancy implications, birth outcomes controlled. Four types of neurodevelopmental disorders including attention deficit hyperactivity disorder will be diagnosed at 7-9 year-old and its association with gestational weight gain and possible critical period of gestation will be explored further based on nested case-control design. Ma’anshan Birth Cohort Study will be used to determine relation of gestational weight gain with maternal, placenta and neonatal inflammation, possible mediation effects of placenta inflammation in the association between gestational excess weight gain and internalizing and externalizing behaviors among 3000 children aged 4-5 years will be revealed. Evidence from this study will elucidate dose-effect relationship between gestational weight gain and childhood neurodevelopment and possible role of placenta inflammation, which could help to navigate the pathway of translational research for discipline of Maternal and Child Health /Child and Adolescent Health.

孕期过度增重致儿童神经发育损害近年来开始关注，动物实验显示慢性低度炎症可能介导了胎盘炎症并编程子代组织炎症，致胎儿脑发育受损。但不同孕期过度增重与儿童神经发育损伤量效关系及关键期有待揭示，胎盘炎症中介作用需要以母婴队列加以验证。利用已建立中国-安徽出生队列随访3500名5～7岁、7～9岁内外化行为及孤独症行为，控制人口统计学变量、孕前肥胖、妊娠并发症、出生结局等混杂因素分析孕期增重量、过度增重孕期与5～9岁儿童行为问题关联效应；在7～9岁诊断注意缺陷多动障碍等3种神经发育障碍，基于巢氏病例对照研究分析其与孕期增重量及关键孕期的关系。利用马鞍山优生优育队列研究孕期增重与孕妇、胎盘炎症反应，评价胎盘炎症在联接孕期过度增重与3000名4～5岁儿童内外化行为关联的意义。以揭示孕期过度增重对儿童神经精神发育影响的量效关系、关键期及胎盘炎症的中介作用，为妇幼保健和儿少卫生学科架起研究与转化桥梁。

研究依托项目负责人建立的中国—安徽出生队列（China-Anhui Birth Cohort, C-ABC）和马鞍山优生优育队列（Ma，anshan Birth Cohort, MABC），目前C-ABC已经随访到学龄前和小学阶段，MABC建立了18次随访（孕早期～6岁儿童），研究对象配合度高、生物样本采集及实验室检测标准严格，已形成成熟、系统的研究队列运作模式。.C-ABC发现学龄前儿童多种内外化行为的影响因素，孕前肥胖比孕期增与学龄前儿童的内外化行为问题的关联强度更大，妊娠相关焦虑、孕期不良饮食模式和多种环境化学物与学龄前儿童内外化行为问题以及孤独症样行为均呈统计学显著关联。进一步利用MABC孕母和脐带血样本，通过多重磁珠酶免分析仪（MILLIPLEX®MAP）检测孕早期、孕中期、孕晚期和脐带血清的8种孕期炎症因子，采用RT-qPCR方法检测胎盘14个指标。基于大样本队列数据，对孕期增重及孕期炎症标志物进行纵向分析，采用重复测量方法对孕期增重及孕期炎症因子分布进行描述。结果发现，研究发现不同孕期增重均可增加儿童神经发育障碍的发生风险，并且具有性别差异，女童风险高于男童。机制研究发现，肥胖及孕期过度增重引起孕期慢性炎症反应，孕期炎症部分介导了孕期过度增重与儿童神经发育障碍的关联。.研究首次在大样本人群中开展各孕期、分娩及分娩后胎盘炎症标志物检测，研究应用可视化轨迹描述孕期增重与孕期炎症标志物的变化趋势，建立中国孕妇适宜的孕期增重范围提供了科学依据，填补了我国研究孕期免疫应答的时间变化方向的空白。.本课题共发表论文18篇，其中SCI论文10篇，中文核心期刊论文8篇，累积影响因子为49.24。项目负责人主编出版专著1部，获得软件著作权1项（2019SR0466793），以第一完成人获得安徽省科技进步二等奖1项。共培养博士研究生毕业4人，硕士研究生毕业4人，在读博士研究1名和硕士研究生2名。课题组成员3人获得副高职称或校聘副高职称；外展参与人员（均是实足性参与者，参与项目研究并以第一作者或者参与者发表论文）晋升教授和副教授各1人；研究现场主要合作者晋升正高职称1人。