胎儿生长模式与3岁儿童肥胖关系的前瞻性队列研究

Childhood obesity is a strong predictor of cardiovascular and metabolic diseases during adulthood. Previous studies showed fetal growth is related to childhood obesity. Most of these studies used birth weight as a proxy of fetal growth, while these indicators cannot reflect the pattern of intrauterine growth at different trimeste. In the pilot study, we observed the association between fetal growth indicators measured at different trimesters (including crown-rump length, head circumference, biparietal diameter, abdomen circumference, femur length and fetal estimated weight) and infant weight for age, bady mass index and weight gain at age of 1 (well-established risk factors of childhood obesity) were different, suggesting there may be a trimester- and indicator-specific effect of fetal growth on childhood obesity. The present study will be based on the Born in Guangzhou Cohort Study. Using the collected fetal growth data at different trimester and physical growth at age of 3, we will examine the associations of fetal growth indicators at different trimester with childhood obesity. We will also detect the metabolic factors (blood sugar, insulin, leptin, adiponectin and lipid) in child blood, and examine the relationship between fetal growth and these metabolic factors. Finally, we explore the pathways between fetal growth, metabolic factors and childhood obesity using path analysis. We aim to determine the relationship between the fetal growth patterns and childhood obesity and the related pathway. This study will provide scientific evidence for improving antenatal care and for the prevention of childhood obesity in later life.

儿童肥胖与成年期慢性非传染性疾病风险密切相关，多哈（DOHaD）理论认为胎儿生长可影响其发生。既往研究多采用出生体重作为胎儿生长的评价指标，不能反映宫内生长的变化过程。我们前期利用孕期超声测量数据发现，出生体重相近婴儿的宫内生长轨迹存在明显差异，且不同妊娠阶段、不同胎儿生长指标与1岁婴儿的年龄别体重、体质指数及体重增长速率（儿童肥胖的重要预测因素）存在不同的关联性，提示胎儿生长对儿童肥胖的影响可能存在关键时点和敏感指标。本课题将基于广州出生队列，采用前瞻性研究设计，分析胎儿生长模式（孕早、中、晚期的超声测量径线指标水平及增长速率、生长轨迹）与3岁儿童肥胖的关联，并检测3岁儿童外周血代谢因子水平（血糖、胰岛素、瘦素、脂联素、血脂），采用通径分析模型探讨胎儿生长、代谢因子对儿童肥胖影响的作用路径。本课题旨在明确胎儿生长模式与儿童肥胖的关系及作用通路，为制定儿童肥胖的早期防治策略提供依据。

儿童肥胖是成年慢性疾病（糖尿病、高血压）的重要风险因子，且近年来我国发生率大幅攀升。胎儿生长可能是儿童肥胖的影响因素，但过往研究未明确宫内动态生长模式与儿童肥胖的关系，且未探讨其作用路径。基于大型出生队列，本课题纳入4818对母子，采用fractional polynomial model及multilevel linear spline models，将胎儿生长分为4个阶段：早期妊娠阶段（22周）胎儿大小、孕中期（22-27周; mid-pregnancy）增重速率、孕晚期第一阶段（28-36周; early-third trimester）增重速率，以及孕晚期第二阶段（37周及以上; late-third trimester）增重速率。泊松回归模型分析显示，在妊娠早期（孕22周）胎儿体重、孕中期（22-27周）、孕晚期的第一阶段（28-36周）的生长速率与儿童超重/肥胖风险呈正相关，风险比值 （RR） 从 1.25 到 1.45 之间；而孕晚期第二阶段（37周及以后）的生长速率无关联。本课题进一步分析了不同妊娠阶段的胎儿生长与脐血代谢因子的关联性，发现各阶段的胎儿体重、腹围均与脐血胰岛素水平呈正相关，胎儿体重、腹围与甘油三酯呈负相关，关联性在孕晚期的第一阶段和第二阶段最为明显；孕晚期胎儿体重、腹围与脐血HDL呈正相关；而各阶段的胎儿股骨长与甘油三酯呈正相关，孕37周前股骨长与LDL呈负相关。最后，采用结构方程模型分析了孕妇代谢因素、胎儿生长、脐血代谢因子、婴儿生长速率对3岁儿童BMI的作用关系，构建了作用路径，发现与脐血甘油三脂相关的代谢通路可能是胎儿生长影响3岁儿童BMI的中介因素。综上所述，本课题利用多时点的超声测量数据，全面探讨了胎儿生长模式对儿童肥胖的影响，并首次探讨了胎儿生长、脐血代谢因子对儿童肥胖的作用路径。本课题的研究发现一方面为阐明儿童肥胖的发生机制提供新线索，另一方面为儿童肥胖的预测及早期预防提供科学依据，具有一定的科学价值和应用前景。