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

doi:10.19723/j.issn.1671-167X.2026.03.009

摘要/Abstract

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6 322 635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1 478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。

关键词: 冷暴露, 热暴露, 先天性心脏病, 队列研究, 发病风险

Abstract:

Objective: To investigate the associations between maternal exposure to cold and heat exposure 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 distribution during each exposure window. Cox proportional hazards models were used to analyze the associations 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 6 322 635 women aged 20-49 years with complete pregnancy outcome follow-up were included, and 1 478 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 pregnancy 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 associated with heat exposure during the three months before pregnancy was increased in women aged ≥30 years (HR=2.18, 95%CI: 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 BMI ≥24 kg/m² (HR=1.86, 95%CI: 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.

Key words: Cold exposure, Heat exposure, Congenital heart disease, Cohort, Risk

中图分类号:

R122.2

徐慧颖, 何兴侯, 黄薇, 张彬, 李梦瑶, 刘家辉, 方言, 赵二璐, 魏相睿, 马旭, 杨英. 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[J]. 北京大学学报（医学版）, 2026, 58(3): 503-512.

Huiying XU, Xinghou HE, Wei HUANG, Bin ZHANG, Mengyao LI, Jiahui LIU, Yan FANG, Erlu ZHAO, Xiangrui WEI, Xu MA, Ying YANG. Association between periconception maternal cold and heat exposure and the risk of congenital heart disease in offspring in China[J]. Journal of Peking University (Health Sciences), 2026, 58(3): 503-512.

图/表 10

图1

图2

表1

按孕前3个月及孕早期冷热暴露状态分组的研究对象基本特征"

Characteristic	Total (n=6 322 635)	Heat exposure group (n=632 260)	Cold exposure group (n=632 264)	Reference group (n=5 058 111)	P value
Maternal age					＜0.001/＜0.001
≤25 years	2 954 301 (46.73)	277 919 (43.96)	311 376 (49.25)	2 365 006 (46.76)
26-30 years	2 340 674 (37.02)	245 876 (38.89)	223 325 (35.32)	1 871 473 (37.00)
31-35 years	753 035 (11.91)	80 159 (12.68)	71 573 (11.32)	601 303 (11.89)
36-40 years	237 627 (3.76)	24 609 (3.89)	22 264 (3.52)	190 754 (3.77)
＞40 years	36 998 (0.59)	3 697 (0.58)	3 726 (0.59)	29 575 (0.58)
Parity					＜0.001/＜0.001
0	3 187 438 (50.41)	310 842 (49.16)	321 770 (50.89)	2 554 826 (50.51)
≥1	2 710 740 (42.87)	278 429 (44.04)	273 172 (43.21)	2 159 139 (42.69)
Missing	424 457 (6.71)	42 989 (6.80)	37 322 (5.90)	344 146 (6.80)
Ethnicity					＜0.001/＜0.001
Han Chinese	5 786 746 (91.52)	591 045 (93.48)	557 828 (88.23)	4 637 873 (91.69)
Ethnic minority	368 979 (5.84)	21 064 (3.33)	60 055 (9.50)	287 860 (5.69)
Missing	166 910 (2.64)	20 151 (3.19)	14 381 (2.27)	132 378 (2.62)
Pre-pregnancy BMI, kg/m²					＜0.001/＜0.001
＜18.5	836 772 (13.23)	86 856 (13.74)	78 230 (12.37)	671 686 (13.28)
≥18.5-＜24	4 406 391 (69.69)	436 429 (69.03)	447 815 (70.83)	3 522 147 (69.63)
≥24-＜28	835 383 (13.21)	83 607 (13.22)	82 809 (13.10)	668 967 (13.23)
≥28	206 453 (3.27)	20 878 (3.30)	20 345 (3.22)	165 230 (3.27)
Missing	37 636 (0.60)	4 490 (0.71)	3 065 (0.48)	30 081 (0.59)
Education					＜0.001/＜0.001
Junior high school or below	3 381 720 (53.49)	311 218 (49.22)	381 363 (60.32)	2 689 139 (53.16)
Senior high school	1 352 056 (21.38)	140 163 (22.17)	119 920 (18.97)	1 091 973 (21.59)
College or above	1 262 756 (19.97)	138 245 (21.87)	108 629 (17.18)	1 015 882 (20.08)
Missing	326 103 (5.16)	42 634 (6.74)	22 352 (3.54)	261 117 (5.16)
Residence					＜0.001/＜0.001
Rural	5 653 361 (89.41)	555 060 (87.79)	580 233 (91.77)	4 518 068 (89.32)
Urban	667 753 (10.56)	76 839 (12.15)	51 989 (8.22)	538 925 (10.65)
Missing	1 521 (0.02)	361 (0.06)	42 (0.01)	1 118 (0.02)
Occupation					＜0.001/＜0.001
Farmer	3 945 602 (62.40)	371 929 (58.83)	435 849 (68.93)	3 137 824 (62.04)
Worker	726 121 (11.48)	73 792 (11.67)	64 321 (10.17)	588 008 (11.63)
Other	1 273 756 (20.15)	139 527 (22.07)	104 656 (16.55)	1 029 573 (20.35)
Missing	377 156 (5.97)	47 012 (7.44)	27 438 (4.34)	302 706 (5.98)
Smoking					＜0.001/＜0.001
No	6 266 975 (99.12)	625 940 (99.00)	627 715 (99.28)	5 013 320 (99.11)
Yes	12 613 (0.20)	1 169 (0.18)	1 220 (0.19)	10 224 (0.20)
Missing	43 047 (0.68)	5 151 (0.81)	3 329 (0.53)	34 567 (0.68)
Passive smoking					＜0.001/＜0.001
No	5 639 696 (89.20)	558 973 (88.41)	573 912 (90.77)	4 506 811 (89.10)
Yes	639 714 (10.12)	68 164 (10.78)	55 031 (8.70)	516 519 (10.21)
Missing	43 225 (0.68)	5 123 (0.81)	3 321 (0.53)	34 781 (0.69)
Drinking					＜0.001/＜0.001
No	6 111 037 (96.65)	608 280 (96.21)	616 308 (97.48)	4 886 449 (96.61)
Yes	162 586 (2.57)	18 247 (2.89)	12 034 (1.90)	132 305 (2.62)
Missing	49 012 (0.78)	5 733 (0.91)	3 922 (0.62)	39 357 (0.78)
Folic acid supplementation					＜0.001/＜0.001
No	1 132 478 (17.91)	114 881 (18.17)	97 806 (15.47)	919 791 (18.18)
Regular	4 868 152 (77.00)	487 320 (77.08)	501 073 (79.25)	3 879 759 (76.70)
Irregular	219 736 (3.48)	20 366 (3.22)	21 481 (3.40)	177 889 (3.52)
Missing	102 269 (1.62)	9 693 (1.53)	11 904 (1.88)	80 672 (1.59)
Season of conception					＜0.001/＜0.001
Spring	1 834 270 (29.01)	25 875 (4.09)	60 516 (9.57)	1 747 879 (34.56)
Summer	1 537 980 (24.32)	574 307 (90.83)	3 518 (0.56)	960 155 (18.98)
Autumn	1 311 823 (20.75)	27 260 (4.31)	38 083 (6.02)	1 246 480 (24.64)
Winter	1 638 562 (25.92)	4 818 (0.76)	530 147 (83.85)	1 103 597 (21.82)
Year of birth					＜0.001/＜0.001
2014	355 234 (5.62)	2 602 (0.41)	112 108 (17.73)	240 524 (4.76)
2015	1 386 551 (21.93)	126 373 (19.99)	108 391 (17.14)	1 151 787 (22.77)
2016	1 430 994 (22.63)	105 069 (16.62)	139 850 (22.12)	1 186 075 (23.45)
2017	1 514 811 (23.96)	184 651 (29.20)	111 367 (17.61)	1 218 793 (24.10)
2018	1 010 052 (15.98)	126 048 (19.94)	99 094 (15.67)	784 910 (15.52)
2019	571 710 (9.04)	84 100 (13.30)	60 911 (9.63)	426 699 (8.44)
2020	53 283 (0.84)	3 417 (0.54)	543 (0.09)	49 323 (0.98)
Neonate’s gender					＜0.001/＜0.001
Male	3 271 381 (51.74)	327 550 (51.81)	326 282 (51.61)	2 617 549 (51.75)
Female	3 023 385 (47.82)	302 247 (47.80)	302 746 (47.88)	2 418 392 (47.81)
Missing	27 869 (0.44)	2 463 (0.39)	3 236 (0.51)	22 170 (0.44)
Mode of delivery					＜0.001/＜0.001
Vaginal delivery	4 517 758 (71.45)	455 719 (72.08)	450 798 (71.30)	3 611 241 (71.40)
Cesarean section	1 787 130 (28.27)	174 968 (27.67)	179 490 (28.39)	1 432 672 (28.32)
Missing	17 747 (0.28)	1 573 (0.25)	1 976 (0.31)	14 198 (0.28)
Geographic region					＜0.001/＜0.001
Northern	380 976 (6.03)	29 319 (4.64)	73 873 (11.68)	277 784 (5.49)
Northeast	73 447 (1.16)	6 514 (1.03)	8 741 (1.38)	58 192 (1.15)
Eastern	1 563 946 (24.74)	137 595 (21.76)	186 272 (29.46)	1 240 079 (24.52)
Central	2 335 185 (36.93)	295 028 (46.66)	133 708 (21.15)	1 906 449 (37.69)
Southern	1 002 141 (15.85)	119 162 (18.85)	68 741 (10.87)	814 238 (16.10)
Southwest	501 732 (7.94)	20 424 (3.23)	41 613 (6.58)	439 695 (8.69)
Northwest	465 208 (7.36)	24 218 (3.83)	119 316 (18.87)	321 674 (6.36)
Climate zone					0.999/>0.999
Tropic humid	1 056 022 (16.70)	105 603 (16.70)	105 603 (16.70)	844 816 (16.70)
Subtropical humid	2 793 125 (44.18)	279 313 (44.18)	279 313 (44.18)	2 234 499 (44.18)
Qinghai-Xizang Plateau	51 951 (0.82)	5 195 (0.82)	5 195 (0.82)	41 561 (0.82)
Warmtemperate humid and subhumid	2 147 904 (33.97)	214 785 (33.97)	214 791 (33.97)	1 718 328 (33.97)
Temperate humid and subhumid	129 444 (2.05)	12 945 (2.05)	12 945 (2.05)	103 554 (2.05)
Temperate grassland	75 508 (1.19)	7 551 (1.19)	7 549 (1.19)	60 408 (1.19)
Temperate and warmtemperate desert	68 681 (1.09)	6 868 (1.09)	6 868 (1.09)	54 945 (1.09)

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表3

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Climate zone	Mean/℃	P₅/℃	P₁₀/℃	P₁₅/℃	P₈₅/℃	P₉₀/℃	P₉₅/℃
Subtropical humid	16.51	8.55	9.49	10.31	23.15	23.78	24.48
Warmtemperate humid and subhumid	14.31	4.10	5.78	6.88	22.55	23.29	23.93
Temperate and warmtemperate desert	6.09	-7.73	-6.11	-4.75	16.64	17.46	18.43
Temperate humid and subhumid	8.62	-3.41	-1.56	-0.31	18.03	19.32	21.56
Temperate grassland	8.73	-3.67	-1.57	0.15	18.22	19.19	20.20
Tropic humid	21.82	16.05	17.11	17.76	26.10	26.56	27.05
Qinghai-Xizang Plateau	3.34	-6.83	-4.89	-3.60	10.83	11.91	13.12

Climate zone	Mean/%	Minimum/%	P₂₅/%	Median/%	P₇₅/%	Maximum/%
Subtropical humid	75.90	37.21	72.85	76.51	79.44	92.22
Warm-temperate humid and sub-humid	62.25	32.49	57.78	63.15	67.54	83.02
Temperate and warm-temperate desert	61.92	31.21	56.46	62.94	68.21	82.37
Temperate humid and sub-humid	45.35	17.06	37.68	44.41	53.00	78.69
Temperate grassland	45.43	27.54	39.19	44.55	50.79	74.52
Tropic humid	79.77	44.98	76.90	80.37	83.21	92.83
Qinghai-Xizang Plateau	57.54	22.63	49.76	57.17	64.59	91.02

Exposure window	Exposure threshold	Exposure type	HR (95%CI)	P value
Three months before pregnancy	P₅	Cold exposure	0.91 (0.70-1.20)	0.513
Three months before pregnancy	P₁₅	Cold exposure	0.85 (0.72-1.02)	0.076
Three months before pregnancy	P₈₅	Heat exposure	1.29 (1.08-1.55)	0.006
Three months before pregnancy	P₉₅	Heat exposure	1.31 (1.03-1.69)	0.031
First trimester	P₅	Cold exposure	0.75 (0.56-0.99)	0.041
First trimester	P₁₅	Cold exposure	0.90 (0.75-1.07)	0.222
First trimester	P₈₅	Heat exposure	1.15 (0.96-1.38)	0.131
First trimester	P₉₅	Heat exposure	1.01 (0.76-1.34)	0.931

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