中国育龄女性围孕期冷热暴露与先天性心脏病发病风险的关联

Association between periconception maternal cold and heat exposure and the risk of congenital heart disease in offspring in China

摘要

目的：系统评估母亲在孕前3个月及孕早期冷热暴露对子代先天性心脏病发病风险的影响，并识别潜在的暴露敏感窗口及影响因素。方法：研究对象为2014年1月1日至2020年4月21日纳入国家免费孕前优生健康检查项目队列中20~49岁有完整妊娠结局追踪的女性。气象数据来源于欧洲中期天气预报中心第五代再分析数据集，根据研究对象居住地匹配孕期温度。为反映区域热适应性，冷热暴露采用相对阈值法定义：依据气候带对研究人群进行分层，计算每位个体在特定暴露时间窗内的平均温度；热暴露定义为该温度高于其所在气候带所有个体温度分布的第90百分位数；冷暴露则定义为低于第10百分位数。采用 Cox 比例风险模型分析孕前3个月及孕早期冷热暴露与先天性心脏病发病风险的关联，校正母亲年龄、体重指数（body mass index，BMI）、教育水平、地理区域、受孕季节、相对湿度等混杂因素后计算风险比（hazard ratio，HR）及其 95% 置信区间（confidence interval，CI）。通过分层分析探讨年龄、体重指数、胎儿性别因素对冷热暴露与先天性心脏病发病风险关联的影响。结果：共纳入6322635例20~49岁有完整妊娠结局追踪的女性，其子代共确诊先天性心脏病1478例。分析显示，在孕前3个月，热暴露与子代先天性心脏病发病风险升高显著相关（HR=1.49,95\%CI:1.23∼1.80）；而孕早期热暴露与子代先天性心脏病发病风险无显著关联。孕前 3 个月及孕早期的冷暴露均未发现与先天性心脏病发病风险存在显著关联（孕前 3 个月：HR=0.93,95\%CI:0.77∼1.14 ；孕早期：HR=0.95,95\%CI:0.79∼1.16）。分层分析显示，孕前 3个月热暴露导致先天性心脏病发病风险在30岁及以上孕产妇（HR=2.18,95\%CI:1.54∼3.10）和男性胎儿（HR=1.73,95\%CI:1.31∼2.29）中更高；孕早期热暴露导致先天性心脏病发病风险在 BMI⩾24 kg/m² 的孕产妇中显著升高（HR=1.86,95\%CI:1.21∼2.87）。结论：孕前3个月热暴露可增加子代先天性心脏病的发病风险，该风险在30岁及以上孕产妇和男性胎儿中更高。此外，孕早期热暴露导致先天性心脏病发病风险在 BMI⩾24 kg/m² 的孕产妇中显著升高。未发现冷暴露与先天性心脏病发病风险存在显著关联。

Abstract

Objective：To investigate the associations between maternal exposure to cold and heat expo- sure during the three months before pregnancy and early pregnancy and the risk of congenital heart disease（CHD）in offspring，and to identify critical exposure windows and modifying factors. Methods： This nationwide cohort study included women aged 20-49 years with complete pregnancy outcome follow- up from the National Free Pre-pregnancy Check-ups Project（NFPCP）database between January 1， 2014 and April 21，2020.Meteorological data from the European Centre for Medium-Range Weather Forecasts Reanalysis v5（ERA5）dataset were linked to residential addresses.Cold and heat exposure were defined based on relative thresholds stratified by climate zone：heat and cold were defined as temperatures above the 90th percentile or below the 10th percentile，respectively，of the location-specific temperature distri- bution during each exposure window.Cox proportional hazards models were used to analyze the associa- tions between cold and heat exposure during the three months before pregnancy and early pregnancy and the risk of CHD，and to calculate hazard ratios (HR) and 95% confidence intervals (CI) after adjusting for maternal age，body mass index（BMI），education level，geographical region，conception season，and relative humidity.Stratified analyses were performed to examine the effects of age，BMI，and fetal sex on the associations between cold and heat exposure and the risk of CHD. Results：A total of 6322635 women aged 20-49 years with complete pregnancy outcome follow-up were included，and 1478 cases of CHD were diagnosed among their offspring.The analysis showed that heat exposure during the three months before pregnancy was significantly associated with an increased risk of CHD in offspring（HR= 1.49,95\%CI:1.23-1.80) ；while no significant association was found for heat exposure during early pregnancy.No significant association was observed for cold exposure during the three months before preg- nancy and early pregnancy（three months before pregnancy：HR=0.93,95\%CI:0.77-1.14 ；early pregnancy：HR=0.95,95\%CI:0.79-1.16）.Stratified analyses showed that the risk of CHD associ- ated with heat exposure during the three months before pregnancy was increased in women aged ⩾30 years（$\mathit{H}\mathit{R}=\mathrm{2.18,95}\mathrm{\%}\mathit{C}\mathit{I}:1.54-3.10)$ and in male fetuses（HR=1.73,95\%CI:1.31-2.29）； the risk of CHD associated with heat exposure during early pregnancy was significantly increased in women with $\mathrm{B}\mathrm{M}\mathrm{I}⩾24\text{ }\mathrm{k}\mathrm{g}/{\mathrm{m}}^{2}(\mathit{H}\mathit{R}=\mathrm{1.86,95}\mathrm{\%}\mathit{C}\mathit{I}:1.21-2.87)$. Conclusion：Heat exposure during the three months before pregnancy might increase the risk of congenital heart disease in offspring，and this risk was elevated in both women aged ⩾30 years and male fetuses.Furthermore，heat exposure during early pregnancy significantly increased the risk of congenital heart disease in offspring among women with BMI ⩾24 kg/m².No significant association was observed between cold exposure and the risk of congenital heart disease.

关键词

冷暴露 / 热暴露 / 先天性心脏病 / 队列研究 / 发病风险

Key words

Cold exposure / Heat exposure / Congenital heart disease / Cohort / Risk

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基金资助

国家自然科学基金(82273589)

国家重点研发计划(2016YFC1000307)

北京市自然科学基金(7222246)