孕妇炎症反应对胎婴儿生长轨迹影响的出生队列研究

Global studies have demonstrated that the abnormal growth pattern during fetal and infancy increased the risk of emergence of obesity, type 2 diabetes and cardiovascular disease in childhood and early adulthood. Our preliminary findings, based on the Born in Guangzhou Cohort study, showed that (1) the small for gestational age (SGA) newborns were already significant smaller than other babies in the early stage of second trimester, (2) the SGA babies had significant higher rate of accelerated growth than the other babies, and (3) maternal inflammation (white blood cell >13×10＾9/L) during pregnancy was associated with an increased risk of the offspring with SGA. Evidence suggested that the insulin pathway played an important role in regulating the SGA’s growth during pre- and postnatal stages. Thus, we hypothesis that maternal inflammation in specific period during pregnancy could change the fetal growth pattern by changing the insulin sensitivity and metabolism of the fetus, and then reduce the birth weight, which subsequently increase the risk of accelerated infant growth. The present study is aim to investigate the association between increased level of TNF-α, IL-6, IL-1β in maternal serum during pregnancy and neonatal insulin sensitivity, birth weight and infant growth trajectory. The second aim is to examine the interaction effect of maternal inflammation and other risk factors on infant growth trajectory, providing neonatal insulin sensitivity and birth weight as mediator variables. The third aim is to determine the sensitivity period and the persistence effect of maternal inflammation on fetal and infant growth. The study will provide population evidence for the association between maternal inflammation and infant growth as well as for establishing new strategy for prevention of childhood obesity in early life.

胎婴儿生长速率异常会增加儿童期和成年早期肥胖、糖尿病和心血管疾病的风险。本课题组基于广州出生队列研究发现，小于胎龄儿（SGA）的主要径线在孕早中期既已落后于其他胎儿，且其婴儿期发生追赶生长比例最高；此外孕期母体炎症反应增加SGA发生风险。其他研究提示SGA可能在宫内已存在代谢模式改变。由此提出假设，孕妇在作用敏感期发生的炎症可改变胎儿生长及其胰岛素敏感性，降低出生体重，代谢模式的延续增加婴儿期追赶生长风险。本课题拟通过大规模出生队列研究探讨孕妇炎症因子TNF-α、IL-6、IL-1β水平升高对胎儿胰岛素敏感性、出生体重、婴儿期生长轨迹的影响。进一步以胎儿胰岛素敏感性和出生体重作为中间变量，研究孕妇炎症和其他因素的交互作用对婴儿期生长轨迹的影响，并分析孕期炎症因子作用的敏感期。本项目将为孕期炎症改变婴儿期生长轨迹提供重要的人群证据，为建立合理的儿童肥胖早期防治方案提供新的思路和途径。

胎婴儿生长速率异常会增加儿童期和成年早期肥胖、糖尿病和心血管疾病的风险。孕期母血炎性因子可能通过影响出生体重进而对婴儿期生长速率产生影响，然而尚缺乏人群研究证据。本课题通过大规模出生队列研究阐明了以下内容：（1）孕期母体外周血和脐血炎症因子水平均可影响子代出生体重和代谢；新发现孕中期母血IL-15水平升高与小于胎龄儿(Small for gestational age, SGA)风险增加和脐血胰岛素水平降低相关；（2）明确了胎儿生长和出生体重可影响婴儿期体格生长速率、追赶生长发生风险和超重肥胖风险；SGA婴儿期追赶生长发生风险增加；（3）明确脐血胰岛素水平与SGA的关系，验证了本研究中SGA在胎儿期的组织胰岛素敏感性存在代偿性增加的研究假设。（4）阐明脐血胰岛素是影响婴儿期追赶生长的最重要的因素，与追赶生长呈负相关。验证了SGA 胎儿期的组织胰岛素敏感性代偿性增加这一模式持续到婴儿期，增加婴儿期追赶生长风险的研究假设。（5）通过综合分析孕期、脐血炎症因子、脐血胰岛素、血糖对婴儿期追赶生长的影响发现，母血IL15、TNFa等炎症因子可增加SGA的风险，降低脐血胰岛素水平；而脐血胰岛素水平降低的婴儿，在婴儿期追赶生长的风险增加，这些结果验证了孕妇炎症反应在孕中期通过改变胎儿生长和代谢，降低新生儿出生体重，胎儿期的代谢模式持续到出生后，增加婴儿期追赶生长风险。本研究虽然发现脐血炎症因子可影响胎儿生长和代谢、婴儿期生长，但是影响三个结局的因子不太一致，有待进一步研究。本研究同时建立预测效能良好的SGA、脐血胰岛素和婴儿期追赶生长的预测模型。本项目为孕期炎症是否改变胎婴儿期生长轨迹提供重要的人群证据，为儿童肥胖早期防治提供精准的预测预警系统，有助于干预前移和有效降低儿童肥胖发生率。