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广州市出生队列(BIGCS)研究方案

2011年9月8日


1.介绍

    近30年是中国经济飞速发展的时代,同时,西式饮食和城市生活方式也日渐盛行,这些因素都有可能增加非传染性慢性疾病的发生,如糖尿病和恶性肿瘤等。中国目前的年长一代(中年及以上)的成人在出生时的社会环境仍相对艰苦,甚至处于计划经济时期,对他们来说,这种社会和疾病转型的经历可能会对目前的健康状况产生显著的影响。相反,年轻一代一直处于物资丰富时期,但他们仍受到一些传统价值观的影响,如强烈的家庭价值观取向和唯成绩论。
   广州是中国南部经济最为发达的城市之一。从1978年到2011年期间,广州市常住人口从480万增加至1270万,人均国民生产总值从不到1000元上升至97588元。在社会飞速发展的背景下,为了考察生命早期暴露对健康结局的短期和长期影响,完全有必要建立一个大规模的前瞻性出生队列。因此,广州市出生队列(BIGCS)作为中国南部的第一个出生队列研究,于2011年应运而生。

2.主办方和协作方

    广州市妇女儿童医疗中心作为广州市出生队列(BIGCS)的主办方,是中国最大的三级妇女儿童专科医院之一,年分娩量达18000~20000。英国伯明翰大学参与研究的部分工作。

3.目的

   广州市出生队列(BIGCS)旨在考察遗传、营养、环境和社会等多方面因素对于孕产妇、儿童和青少年健康结局的影响。研究成果将有助于促进和改善中国下一代儿童及其家庭的健康状况,甚至可能推广到其他国家或地区。
   研究主要考察以下五个研究领域:
   1) 孕妇健康和妊娠结局
   2) 胎儿宫内生长发育
   3) 儿童早期免疫系统和功能发育
   4) 神经认知发育
   5) 影响婴幼儿和儿童健康结局的父系/母系危险因素

4.研究人群

   广州市出生队列(BIGCS)分别在广州市妇女儿童医疗中心的两个院区招募初次产检的孕妇(一般为孕16周左右)、配偶及其子女。
   纳入标准:
   1) 妊娠20周前的孕妇
   2) 计划在广州市妇女儿童医疗中心分娩
   3) 常住广州且在儿童3岁以内无搬迁计划

5.研究流程

   由受过培训的研究人员在孕妇进行早孕期检查时邀请其加入广州市出生队列(BIGCS)。
   所有的参与者均需要签署知情同意书。研究将分别在入组、孕24~27周和孕35~38周时收集孕妇及其配偶的基本情况、临床评估、体格测量等信息并进行生物样本采集。临床评估信息主要是通过常规产科记录获取产前筛查结果(如口服葡萄糖耐量实验、生化检查等)、超声检查、产科并发症和处方药物使用等信息。分娩后对产妇的随访则主要集中在生活习惯、体格测量和心理生理健康相关情况。
   广州市出生队列(BIGCS)也收集儿童相关的数据。其中,新生儿信息主要通过医疗记录获取分娩信息、出生特征(如出生体重、Apgar评分)和围产结局。绝大多数的婴幼儿和学龄前儿童的随访由广州市妇女儿童医疗中心的儿童保健医生进行,分别在出生后6周、6个月、12个月和36个月在门诊实行面对面访谈。从儿童6岁开始可通过相关连接记录获取常规体检和学校成绩等信息。所有的队列儿童都将被随访至18岁。具体的随访流程详见表1。

6.统计学方法

1)分析方法

   采用如下统计方法描述孕妇和儿童的基本特征:对于连续型变量,如为正态分布采用均值和标准差,如为非正态分布则采用中位数和四分位间距进行描述。对于分类变量则采用频数和百分比进行描述。采用线性/非线性混合效应回归、生存分析和结构方程模型等分析方法进行因果推断。采用纵向结构方程模型或生长曲线分析评价时间效应。对于基因数据,则采用回归树分析基因与基因之间、基因与环境之间的交互作用。当P值<0.05时判定为有统计学意义。

2)样本量和检验效能

   队列目标样本量为30000对母子,在考察一些常见的环境、社会和生物学暴露因素与健康结局之间的关联时,具备充足的检验效能以发现中等强度的因果效应(表2)。

7.可能存在的问题

   与广州市平均水平相比,在广州市妇女儿童医疗中心接受产检的孕妇往往受教育程度更高、年龄更大,社会经济地位更好,这在一定程度上限制了研究成果的外推性。但从另一个角度来讲,即使研究人群不是全人口的代表性样本,对于暴露和关键的母儿健康结局之间关联的探寻仍然具备其有效性。

8.预期结果


   1)识别疾病转型和遗传因素等对妊娠结局的影响,如死胎、早产和低出生体重。
   2)发掘影响儿童生长和神经行为发育过程的关键因素。
   3)获取可能影响儿童早期免疫系统发育的相关因素。

9. 队列注册网页链接

https://clinicaltrials.gov/ct2/show/NCT02526901

 

 

 

Study Protocol for the Born in Guangzhou Cohort Study (BIGCS)

September 8, 2011


1.Introduction

Over the past three decades, China is undergoing rapidly economic development. At the same time, the Western diet and urban lifestyle has been more common than before, which may lead to an increase of incidence of non-communicable chronic diseases, such as diabetes and malignancies. Notably, the current generation of Chinese adults, particularly those in their middle age or older, were born in an era where hardship and rationing was the norm and witnessed a social and epidemiological transition that might have a profound effect on their present health. In contrast, the younger generation is raised in relative material abundance, under the influence of traditional Chinese values such as a strong family orientation and an emphasis on academic success. Guangzhou is one of the most economically developed regions of in China, located in south of China. From 1978 to 2011, the population growth has accelerated from 4.8 million to 12.7 million, meanwhile during the same period the Per Capita Gross Domestic Product increased from <1000 yuan to 97 588 yuan. In the context of rapid development, it is necessary to set up a large-scale prospective birth cohort to provide an opportunity to examine the short- and long-term effects of exposure in early life on health consequences in this younger generation. Accordingly, the Born in Guangzhou Cohort Study, the first birth cohort study in South China, has been designed in 2011.

2.Sponsor and Collaborator

Guangzhou Women and Children’s Medical Center (GWCMC) is the sponsor of BIGCS, one of the largest tertiary hospitals in China, with 18 000-20 000 annual deliveries of 220 000 total births in the Guangzhou municipality. University of Birmingham partially participates in present study.

3.Objectives

The objectives of BIGCS are to examine the effects of genetic, nutritional, environmental and social factors on maternal, child and adolescent health outcomes. The findings from this study will improve the health of future generations of children and their families in China and even other countryside. Five major research topics will be explored:
1) Mother’s health and pregnancy outcomes
2) Fetal growth and development
3) Immune development in early life
4) Neural development
5) Parents’ risk factors for infant and child health outcomes

4.Study Population

The BIGCS will recruit pregnant women attending their first routine antenatal examinations (usually around week 16) and their partners and offspring at two campuses of the GWCMC. Inclusion Criteria:
1) Pregnant women with <20 weeks of gestation
2) Pregnant women intended to eventually deliver in Guangzhou Women and Children's Medical Center
3) Permanent residents or families intended to remain in Guangzhou with their child for ≥3 years

5.Study Procedures

For the pregnant women, during early pregnancy examinations, will be identified and ask for consent to take part in BIGCS by trained study personnel. Informed consent is signed by all study participants. Pregnant women and their partners’ information, clinical assessment, anthropometry and biological samples are obtained at recruitment, 24-27 and 35-38 gestation weeks. Clinical information including antenatal screening test results (e.g. Oral Glucose Tolerance Test, Coagulation test, and maternal biochemistry), ultrasound findings, and obstetric complications and prescribed medication will be obtained from routine maternity records. After delivery, maternal information including living habits, anthropometric measures and physical and mental health-related information are scheduled to be followed up. For children in BIGCS, neonatal birth information including the details of the delivery, birth characteristics (e.g. birth weight, Apgar scoring) and perinatal outcomes are extracted from medical records. Most infants and pre-school aged children are interviewed by doctors in GWCMC’s child health care clinics at ~6 weeks, 6, 12 and 36 months. All cohort children will be followed up until 18 years old, with routine health and academic performance information is obtained from 6 years old through record linkage. Follow up flow of the BIGCS is summarized in the table 1 below.

6.Statistical Considerations

1)Analysis methods

We will describe maternal and child characteristics by statistics characterizing. Means and SD will be used to repent continuous variables for the normally distributed variables otherwise median and inter-quartile ranges will be calculated. Frequencies of categorical will be showed using percentages. Linear/Non-Linear mixed effects regression models, survival analysis model and structural equations models etc., will be used to explore the causal inference. Longitudinal Structural Equation Modeling or Growth Curve Analysis will be used to evaluate temporal effects. For analysis of genomic data, regression tree approaches to the analysis of interactions between genes and between genes and the environment will be used. All analysis will be considered statistically significant at 5% level.

2)Sample Size and Power

The overall cohort sample size target is 30 000 mother-child pairs, which provide adequate power to detect moderately strong causal effects of common environmental, social and biological exposures (table 2).

7.Possible Problems

Mothers receiving antenatal care in the GWCMC are more likely to be higher levels of education, older and higher socio-economic status than the average level of pregnant women in Guangzhou, hence limiting generalisability of our research outputs. However, exploring potential associations between exposure and key maternal and child health outcomes provide validity even when estimated within a non-representative sample of the entire study population.

8.Anticipated Results and Conclusions


1) We will identify the influence of epidemiological transition and genetic factors on pregnancy outcomes (e.g. stillbirth, preterm birth and low birth weight).
2) We will explore some key factors in children's growth and neurodevelopmental processes.
3) We will examine related factors that affect children’s immune system development early life.

9.Linkage to the cohort registers web site

https://clinicaltrials.gov/ct2/show/NCT02526901