围孕期微营养素干预对先天性心脏病发生的一级预防作用及其机制

Congenital heart diseases (CHD) have become the most common of all birth defects in recent decades. It is a serious disease with a high burden of clinical treatments but the causes remain unclear. At present there are no effective primary prevention measures. Based on our previous studies of community-based micronutrient interventions to prevent preterm birth, low birth weight and neonatal mortality, the present study will be conducted in high risk areas of CHD in China and focus on an in-depth analysis of epidemiological characteristics of CHD, the identification of specific risk factors and the investigation of the impact of periconceptional deficiency of micronutrients on the occurrence of CHD by a range of approaches including cross-sectional and case-control studies, nutritional and molecular epidemiological studies assisted with meta analysis and a focus group study. Further, a large-scale community-based trial with three interventions, the first randomized controlled intervention study targeted on CHD primary prevention registered in the international clinic trial registry, will be conducted among periconceptional women. The three intervention arms will be iron/folic acid, multiple micronutrients containing iron/folic, and folic acid only (as control). Simultaneously a basic intervention will delivered in each of the treatment arms to control potential risk factor exposures. The study aims to verify the preventive effect of periconceptional iron and/or multiple micronutrient supplements on CHD occurrence using a randomized trial study design to control for potential risk factors. The relationship of CHD with polymorphism of susceptible genes, nutrients and active elements will be clarified. The mechanisms by which multiple micronutrients containing iron/folic acid play roles in preventing CHD will also be explored at the population and molecular levels. This project has the potential to establish the first model of primary prevention against CHD.

先天性心脏病是威胁胎婴儿生存的首位出生缺陷,其病因不明,治疗成本高，目前尚无有效的一级预防措施。在既往研究预防新生儿死亡、早产与低出生体重的基础上，该项目拟在高发区采用现况与病例对照、营养与分子流行病学方法，结合meta分析与专家访谈，深入分析其流行特征，识别特异危险因素谱，探讨围孕期微营养素缺乏在该病发生中的作用；以围孕期妇女为干预对象，以叶酸为对照，"叶酸+铁"、"叶酸+铁+多微营养素"为研究干预，三组同时接受控制多种危险因素暴露的基础干预，实施在国际临床试验注册体系注册的针对先天性心脏病的第一个社区随机对照干预试验，验证围孕期以补充含叶酸与铁的多微营养素为核心并控制多种危险因素暴露的预防措施的效果；分析易感基因多态性、营养素和活性成分与先天性心脏病的关系，从人群水平、分子水平阐明围孕期补充铁、多微营养素对预防先天性心脏病发生的作用及机制；构建国内外首个先天性心脏病一级预防模式。

背景：先天性心脏病（CHD）是威胁胎婴儿生存的首位出生缺陷,其病因不明,治疗成本高，目前尚无有效的一级预防措施。方法：本项目采用横断面调查、病例对照研究、营养与分子流行病学方法，深入分析CHD的流行特征及危险因素，探讨围孕期微营养素缺乏在CHD发生中的作用；以围孕期妇女为干预对象，以叶酸为对照，“叶酸+铁”、“叶酸+复合B族维生素”为研究干预，实施针对CHD的社区随机对照干预试验，验证围孕期以补充微营养素为核心并控制多种危险因素暴露的预防措施的效果；分析易感基因多态性、营养素和活性成分与CHD的关系，阐明围孕期补充铁、复合B族维生素对预防CHD发生的作用及机制；构建国内外首个CHD一级预防模式。结果：（1）陕西省2010-2013年CHD的发生率为61.7/万，占所有出生缺陷的32.46%，为第1顺位的出生缺陷类型，居前三位的亚型是室间隔缺损（19.0/万）、房间隔缺损（14.4/万）和动脉导管未闭（11.0/万）；CHD发生率由北到南逐渐升高（陕北46.2/万、关中58.3/万、陕南90.7/万），在早产（256.1/万）、有CHD家族史（658.7/万）的新生儿中较高。（2）除孕期患病、用药、不良行为习惯、环境污染物暴露等因素外，特别证明了膳食营养情况差以及遗传多样性均为CHD的危险因素。（3）孕期合理膳食结构、足量叶酸和铁摄入与低CHD发生风险有关，首次发现铁营养状况、铁代谢相关基因多态性与CHD有关；（4）首次证实围孕期增补复合B族维生素有效预防子痫前期的发生；围孕期增补铁和复合B族维生素有效预防早产、低体重等不良出生结局，或可预防CHD。（5）提出以构建出生缺陷防控三级平台为基础，以完善人员培训与体制搭建、规范化管理育龄妇女、加强出生缺陷人群动态监测为辅助，以推广包含健康教育、风险评估、行为指导、膳食营养干预等措施为核心的CHD一级预防策略。结论：本研究获得了CHD在陕西的流行病学规律及高风险因素,建立和推广了CHD的一级预防网络；证实了以围孕期微营养素补充为核心的一级预防策略有助于预防CHD及子痫前期为代表的母婴疾病，其机制有待进一步研究。