Identifying susceptible exposure windows for ambient nitrogen dioxide before and during pregnancy and increased risks of small/large for gestational age
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摘要:[背景] 大气二氧化氮(NO2)暴露可能会增加小于胎龄儿(SGA)和大于胎龄儿(LGA)的发生风险。然而,既往研究在推测孕期大气污染暴露影响的易感窗口时,主要是将孕期划分为相对较长的暴露时期,如孕早、中、晚期或者妊娠月。目前尚无研究探索过怀孕前后大气NO2周均暴露水平与SGA和LGA发生风险的关联。
[目的] 评估孕前和孕期大气NO2暴露对SGA和LGA发生风险的影响,并细化暴露窗口为每周,以更为准确地分析NO2暴露的易感窗口。
[方法] 本研究依托在天津市开展的“环境和生活因素在人整个生命轨迹中对代谢健康的影响研究(ELEFANT)”项目建立出生队列,获取末次月经日期和分娩日期均在2014年6月至2016年6月期间且孕周为24~42周的10 916名单胎妊娠孕妇信息。基于中国空气质量再分析数据集(CAQRA),获得每名孕妇孕前和整个孕期NO2日均暴露水平。应用分布式滞后模型结合Cox比例风险回归模型,调整孕妇年龄、民族、文化程度、职业、孕前体重指数、居住地、怀孕次数、生产次数、吸烟和饮酒情况,丈夫吸烟情况,怀孕季节等潜在混杂因素,评估孕前12周和孕期NO2周均暴露水平与SGA和LGA发生风险的关系。回归结果以NO2每增加3 μg·m−3,SGA和LGA发生风险的危险比(HRs)及其95%置信区间(CIs)表示。
[结果] 研究对象孕前期、孕早期、孕中期、孕晚期和整个孕期NO2平均暴露水平分别为(39.6±10.8)、(42.7±10.5)、(44.8±12.7)、(37.7±11.1)和(41.6±4.8) μg·m−3。孕早期NO2暴露水平每增加3 μg·m−3,SGA发生风险升高19.0%(95%CI:8.0%~32.0%)。孕前、孕早期和整个孕期NO2暴露水平每增加3 μg·m−3,LGA发生风险分别升高7.0%(95%CI:1.0%~13.0%)、37.0%(95%CI:29.0%~46.0%)和19.0%(95%CI:9.0%~31.0%)。SGA的NO2暴露易感窗口为怀孕前第7~12周和孕期第6~12周,其中在怀孕前第12周的估计效应值最大,NO2暴露水平每增加3 μg·m−3,SGA发生风险升高6.0%(95%CI:3.2%~8.9%)。LGA的NO2暴露易感窗口为怀孕前第1~12周和孕期第1~6周,其中在怀孕前第12周的估计效应值最大,NO2暴露水平每增加3 μg·m−3,LGA发生风险升高6.1%(95%CI:4.5%~7.8%)。
[结论] 大气NO2暴露可增加SGA和LGA发生的风险,其细化到周的易感窗口期位于孕前12周和孕早期内。
Abstract:[Background] Exposure to ambient nitrogen dioxide (NO2) could increase the risks of small for gestational age (SGA) and large for gestational age (LGA). Nevertheless, previous published studies usually use a time period over relatively long durations as the exposure window, such as trimester-specific or gestational months, to identify adverse pregnancy outcomes related susceptible exposure windows for ambient air pollution. At present, no study has explored associations of weekly-specific ambient air NO2 exposure around pregnancy with SGA and LGA.
[Objective] To evaluate the associations of exposure to ambient NO2 over the preconception and entire pregnancy period with risks of SGA and LGA, as well as to explore critical windows of NO2 exposure by refining exposure period to specific weeks.
[Methods] Based on a birth cohort established by the project Environmental and LifEstyle FActors iN metabolic health throughout life-course Trajectories (ELEFANT) situated in Tianjin, 10 916 singleton pregnant women whose dates of the last menstrual period and delivery were both between June 2014 and June 2016, and whose gestational age were within 24-42 completed gestational weeks were included in this study. Each pregnant woman's exposures to ambient NO2 throughout 12 weeks before pregnancy and pregnancy period were matched with daily average NO2 concentrations obtained from the Chinese air quality reanalysis datasets (CAQRA). Distributed lag models incorporated in Cox proportional hazard regression models were applied to explore the associations of maternal exposure to weekly ambient NO2 throughout 12 weeks before pregnancy and pregnancy period with risks of SGA and LGA after controlling for potential confounders including maternal age, ethnicity, educational level, occupation, body mass index before pregnancy, residence, times of gravidity and parity, smoking, alcohol consumption, husband smoking, and season of conception. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated per 3 μg·m−3 increase in ambient NO2 concentrations.
[Results] The average levels of maternal exposure to NO2 over the preconception, first trimester, second trimester, third trimester, and entire pregnancy periods were (39.6±10.8), (42.7±10.5), (44.8±12.7), (37.7±11.1), and (41.6±4.8) μg·m−3, respectively. For a 3 μg·m−3 increase in NO2 over the first trimester, the risk of SGA increased by 19.0% (95%CI: 8.0%-32.0%). For a 3 μg·m−3 increase in NO2 over the preconception, first trimester, and entire pregnancy, the associated risks of LGA increased by 7.0% (95%CI: 1.0%-13.0%), 37.0% (95%CI: 29.0%-46.0%) and 19.0% (95%CI: 9.0%-31.0%), respectively. For SGA, the susceptible exposure windows for NO2 were observed during the 7th to 12th preconceptional weeks and the 6th to 12th gestational weeks, with the strongest association found at the 12th preconceptional week, when the risk of SGA increased by 6.0% (95%CI:3.2%-8.9%) for a 3 μg·m−3 increase in NO2. For LGA, the susceptible exposure windows for NO2 were observed during the 1st to 12th preconceptional weeks and the 1st to 6th gestational weeks, with the strongest association found at the 12th preconceptional week, when the risk of LGA increased by 6.1% (95%CI: 4.5%-7.8%) for a 3 μg·m−3 increase in NO2.
[Conclusion] Exposure to ambient NO2 is associated with increased risks of both SGA and LGA, and the most susceptible weekly exposure windows are nested within the 12 weeks before pregnancy and early pregnancy.
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大气污染可危害人体健康,引起心血管、呼吸、神经、内分泌、生殖等系统的损伤,增加人群死亡风险[1-4]。最新发表的全球疾病负担报告指出,2019年全球大气污染相关死亡人数达到546万,占全球总死亡人数的11.8%[5]。近二十年来,随着我国工业化和城镇化的快速发展,大气污染状况严重。《2019年中国生态环境状况公报》报道,中国337个城市中有180个城市环境空气质量超标(占比53.4%)[6]。二氧化氮(nitrogen dioxide, NO2)是环境空气质量监测的重要大气污染物之一,主要来源于高温燃烧过程的释放,如机动车尾气、燃料燃烧和工业生产排放等。暴露于NO2可刺激呼吸系统,诱发心肺疾病、全身炎症反应、神经性疾病等,增加人群死亡率和住院率[7-8]。而在我国NO2污染最严重的是京津冀地区[9]。
胎儿期对环境污染物的暴露较为敏感。小于胎龄儿(small for gestational age, SGA)是常用的反映胎儿宫内发育迟缓的指标。近些年环境流行病学调查研究发现,随着母亲孕期NO2暴露水平的增加,其新生儿出现SGA的风险也越高[10-11]。SGA是胎儿发育异常的表现,该类新生儿在幼儿期出现神经发育迟缓、代谢紊乱和免疫缺陷的风险要高于胎儿期正常发育的新生儿[12-16]。大于胎龄儿(large for gestational age, LGA)是反映胎儿宫内生长过度的指标,也是胎儿发育异常的表现之一。LGA会增加母亲生产过程中产道损伤、产后出血和难产的风险[17-18],也会增加新生儿成长过程中出现代谢紊乱、心血管疾病和癌症的风险[19-21]。但目前有关孕期NO2暴露和LGA发生风险之间的研究相对较少。
目前国内外有关大气污染和不良出生结局风险的研究在推测孕期大气污染暴露影响的易感窗口时,主要是将孕期划分为一些相对较长的暴露时期,例如孕早、中、晚期或者妊娠月。然而,有学者提出,较长暴露时期的划分忽略了可能跨越多个孕期的潜在窗口,其推测出来的易感暴露窗会存在偏差。越来越多研究已经开始尝试并建议进一步细化暴露时期以更准确地判断大气污染物产生健康损害的关键暴露窗口。然而目前国内外还没有对大气NO2暴露与SGA和LGA发生风险的暴露窗口进行细化研究。因此本研究基于在天津开展的出生队列研究,探索孕前和孕期大气NO2暴露与SGA和LGA发生风险的关系,并细化暴露时期以更为准确地判断NO2暴露影响的易感窗口。
1. 对象与方法
1.1 研究对象
本研究依托于在天津市开展的“环境和生活因素在人整个生命轨迹中对代谢健康的影响研究(Environmental and LifEstyle FActors iN metabolic health throughout life-course Trajectories, ELEFANT)”项目。该项目主要由3个队列人群构成:出生队列(Baby ELEFANT),成年队列(Young ELEFANT),老年队列(Elderly ELEFANT)。其中Baby ELEFANT出生队列人群由在天津市辖区内政府指定医院进行免费孕前健康检查的已婚夫妇及其新生儿组成。已婚夫妇进行孕前健康检查时由专业人员通过问卷调查,面对面询问获取其孕前信息,之后定期随访收集其出生结局信息。本研究选取了Baby ELEFANT出生队列中末次月经日期和分娩日期均在2014年6月至2016年6月期间的研究对象,在排除多胎妊娠、胎龄小于24周或者大于42周、治疗性分娩、胎儿为先天性畸形或死产、数据缺失、怀孕期间家庭住址发生变化的孕妇后,最终纳入10 916对母婴对。为了评估研究样本量是否足够,本研究应用PASS软件中Cox回归分析模块进行了统计学效能检验。结果显示,基于10916名研究对象,在检验水准为0.05(双侧)的情况下,得出SGA和LGA发生风险比为1.06的统计学效能接近于100%,说明研究样本量足够。本研究已通过天津医科大学伦理委员会(批准号:TMUhMEC2016022)审批,所有研究对象均自愿参加研究并签署知情同意书。
1.2 出生结局
新生儿胎龄根据母亲在第一次妊娠检查中报告的末次月经期的第一天至分娩时间的妊娠周数确定。SGA和LGA根据中国出生体重曲线,分别定义为出生体重低于同性别同胎龄平均体重的第10百分位数和高于同性别同胎龄平均体重的第90百分位数[22]。
1.3 环境暴露资料
大气污染物暴露评估基于中国空气质量再分析数据集(Chinese air quality reanalysis datasets, CAQRA)。CAQRA应用自行开发的化学数据同化系统,采用后处理模式将来自中国国家环境监测中心1000多个地面空气质量监测站点同化分析进而得出时空分辨率为15 km×15 km,时间分辨率为每小时的全国大气污染暴露数据集[23]。根据研究对象家庭住址经纬度,采用邻近模型,匹配CAQRA暴露数据中离研究对象家庭住址最近的大气污染物暴露数据,获得研究对象孕前12周和孕期NO2、细颗粒物(fine particulate matter, PM2.5)、粗颗粒物(coarse particulate matter, PM10)、二氧化硫(sulfur dioxide, SO2)、一氧化碳(carbon monoxide, CO)和最大8 h臭氧(ozone, O3)日均暴露水平。气象数据来源于国家气象数据中心,包括气温(℃)和平均露点(%),露点可作为衡量大气湿度的指标。根据研究对象家庭住址经纬度,采用邻近模型匹配获取研究对象日均气温和露点数据资料。
1.4 统计学分析
SGA和LGA均为二元分类变量。本研究首先运用Cox比例风险回归模型分别分析孕前期(末次月经日期前12周)、孕早期(1~13妊娠周)、孕中期(14~26妊娠周)、孕晚期(第27妊娠周至生产)和整个孕期NO2累积暴露与SGA和LGA发生风险的关联。随后运用分布滞后线性模型(distributed lag models, DLMs)结合Cox比例风险回归模型评估怀孕前12周和孕期NO2周均暴露水平与SGA和LGA发生风险之间的暴露-滞后-效应关系,识别其细化的暴露窗口。在滞后分布模型中,本研究假设NO2暴露与出生结局的关联随着每周的推移平稳变化,并采用自然立方样条函数,基于最小赤池量信息准则(Akaike Information Criteria, AIC),调整NO2的滞后分布,自由度最终设置为6[24-26]。参考既往文献[27-28],本研究所有模型中均校正了孕妇年龄、民族、文化程度、职业、孕前体重指数(body mass index, BMI)、居住地、怀孕次数、生产次数、吸烟和饮酒情况,丈夫吸烟情况和怀孕季节,并应用自然立方样条函数校正温度和露点的非线性混杂作用,自由度均设置为3。回归结果以NO2每增加3 μg·m-3,SGA和LGA发生风险的危险比(hazard ratios, HRs)及其95%置信区间(confidence intervals, CIs)表示。
为了验证模型结果的稳定性,本研究对细化暴露窗口的识别分析进一步进行了敏感性分析。首先应用双污染物模型探究单污染物模型结果的稳定性。其次,将孕前BMI≤18.50或者≥30.00 kg·m−2者(n=1047)、孕妇本身或丈夫吸烟(n=2286)、患有慢性或感染性疾病(n=50)的研究对象分别排除之后再进行分析。应用统计软件SAS 9.4和R 3.6.4进行数据整理与分析,使用的R包有“dlnm”“splines”和“survival”。检验水准均为α=0.05(双侧)。
2. 结果
2.1 基本特征
表1展示了10 916对母亲和新生儿的基本情况。募集的孕妇中,85.6%的孕妇年龄在19~34岁之间;98.8%是汉族;98.6%为高中学历及以下;68.7%的孕妇孕前BMI在18.51~23.99 kg·m−2之间;从事体力劳动的占81.3%;79.4%居住在农村;54.8%为首次怀孕;59.5%为首次生产。怀孕期间孕妇饮酒(2.7%)和吸烟(0.5%)均很少。不过有20.8%的丈夫在妻子怀孕期间吸烟。新生儿的出生体重( $ \bar{x}\pm s $)为(3 432.0±338.3)g,其中男孩占50.5%;SGA占1.8%,LGA占4.6%。
表 1研究对象基本信息(n=10 916)
Table 1.Basic information of participants (n=10 916)
变量(Variable) n(%) 变量(Variable) n(%) 孕妇年龄/岁
Maternal age/years孕妇民族
Maternal ethnicity19~34 9343(85.6) 汉族(Han) 10785(98.8) ≥35 1573(14.4) 少数民族(Minority) 131(1.2) 孕妇文化程度
Maternal educational level怀孕前体重指数/(kg·m−2)
Maternal BMI before
pregnancy/(kg·m−2)高中以下
Less than high school5489(50.3) ≤18.50 853(7.8) 高中(High school) 5275(48.3) 18.51~ 7502(68.7) 高中以上
Above high school152(1.4) ≥24 2561(23.5) 孕妇职业
Maternal employment孕妇家庭住址
Maternal residence体力劳动(Manual labor) 8880(81.3) 城市(Urban) 2249(20.6) 非体力劳动或无工作
Non manual labor
and unemployed2036(18.7) 农村(Rural) 8667(79.4) 孕妇怀孕次数
Maternal gravidity孕妇生产次数
Maternal parity1 5980(54.8) 1 6536(59.9) ≥2 4936(45.2) ≥2 4380(40.1) 孕妇吸烟
Maternal smoking丈夫吸烟
Husband smoking否(No) 10862(99.5) 否(No) 8644(79.2) 是(Yes) 54(0.5) 是(Yes) 2272(20.8) 孕妇饮酒
Maternal drinking新生儿性别
Neonatal sex否(No) 10621(97.3) 女性(Female) 5406(49.5) 是(Yes) 295(2.7) 男性(Male) 5510(50.5) 怀孕季节
Season of conception小于胎龄儿(SGA) 春季(Spring) 2621(24.0) 否(No) 10720(98.2) 夏季(Summer) 4990(45.7) 是(Yes) 196(1.8) 秋季(Autumn) 1572(14.4) 大于胎龄儿(LGA) 冬季(Winter) 1733(15.9) 否(No) 10412(95.4) 是(Yes) 504(4.6) 2.2 环境暴露情况
如表2所示,本研究孕妇孕前期、孕早期、孕中期、孕晚期和整个孕期NO2平均暴露水平分别为(39.6±10.8)、(42.7±10.5)、(44.8±12.7)、(37.7±11.1)和(41.6±4.8)μg·m−3。孕妇平均NO2暴露水平接近或超过国家日均二级标准限值(40 μg·m−3)。
表 2孕妇孕前和孕期NO2和气象因素暴露水平
Table 2.Summary levels of maternal exposure to NO2 and meteorological factors over the preconception and entire pregnancy periods
暴露窗口
Exposure window暴露物
Exposure$\bar{x}$ $ s $ 百分位数(Percentile) P5 P25 P50 P75 P95 孕前期(Preconception) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 39.6 10.8 25.2 31.2 38.0 46.9 60.8 温度(Temperature)/℃ 16.1 9.1 0.7 7.2 19.2 24.3 26.8 露点(Dew point)/% 5.0 10.2 −11.6 −4.7 7.2 13.8 18.7 孕早期(First trimester) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 42.7 10.5 24.5 34.7 43.9 50.7 58.6 温度(Temperature)/℃ 17.9 8.7 1.3 10.7 21.0 25.4 26.5 露点(Dew point)/% 8.0 10.4 −10.9 −0.9 11.4 17.8 18.5 孕中期(Second trimester) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 44.8 12.7 25.0 33.0 46.1 56.4 62.2 温度(Temperature)/℃ 12.3 9.3 −0.8 4.0 10.4 21.5 26.4 露点(Dew point)/% 2.8 10.0 −11.3 −6.5 1.6 12.2 18.4 孕晚期(Third trimester) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 37.7 11.1 23.8 28.3 35.1 44.6 60.0 温度(Temperature)/℃ 10.4 9.0 −0.4 2.5 8.6 18.6 25.7 露点(Dew point)/% −0.3 9.9 −11.2 −9.1 −3.3 8.3 17.5 整个孕期(Entire pregnancy) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 41.6 4.8 33.7 38.3 41.9 45.2 48.9 温度(Temperature)/℃ 13.4 2.6 10.4 11.3 12.5 15.8 17.8 露点(Dew point)/% 3.4 3.1 −0.7 0.8 2.7 6.0 8.3 [注] 孕前期数据是怀孕前12周数据。[Note] Data for the preconception period are obtained up to 12 weeks before pregnancy. 2.3 NO2累积暴露与SGA和LGA发生风险的关联
表3展示了研究期不同时间窗口NO2累积暴露与SGA和LGA发生风险的关联。校正潜在混杂因素后的结果显示,孕早期NO2累积暴露水平与SGA发生风险有关,NO2暴露水平每增加3 μg·m−3,SGA发生风险升高19.0%(95%CI:8.0%~32.0%)。孕前期、孕早期和整个孕期NO2累积暴露水平与LGA发生风险有关,NO2暴露水平每增加3 μg·m−3,LGA发生风险分别升高7.0%(95%CI:1.0%~13.0%)、37.0%(95%CI:29.0%~46.0%) 和 19.0%(95%CI:9.0%~31.0%)。
表 3研究期不同时间窗口NO2累积暴露与SGA和LGA发生风险的关联分析
Table 3.Associations of cumulative NO2 exposure over different exposure windows during study period with risks of SGA and LGA
暴露窗口(Exposure window) 小于胎龄儿(SGA) 大于胎龄儿(LGA) HRa(95%CI) HRb(95%CI) HRa(95%CI) HRb(95%CI) 孕前期(Preconception) 0.71(0.61~0.82) 0.86(0.78~0.95) 0.90(0.83~0.98) 1.07(1.01~1.13) 孕早期(First trimester) 0.91(0.80~1.04) 1.19(1.08~1.32) 1.06(0.97~1.15) 1.37(1.29~1.46) 孕中期(Second trimester) 1.19(1.06~1.33) 0.92(0.84~1.00) 1.15(1.07~1.23) 0.97(0.92~1.03) 孕晚期(Third trimester) 1.06(0.94~1.20) 0.81(0.73~0.91) 1.06(0.98~1.15) 0.93(0.87~1.00) 整个孕期(Entire pregnancy) 1.57(1.14~2.17) 0.89(0.77~1.03) 1.94(1.59~2.37) 1.19(1.09~1.31) [注] 孕前期数据是怀孕前12周数据;应用Cox比例风险回归模型计算NO2在不同时间窗口每增加3 μg·m−3的HR(95%CI);a:模型未校正混杂因素;b:模型校正了孕妇年龄、民族、文化程度、职业、孕前体重指数、居住地、怀孕次数、生产次数、吸烟和饮酒情况,丈夫吸烟情况,怀孕季节等因素,并应用自然立方样条函数校正温度和露点的影响。[Note] Data for the preconception are obtained up to 12 weeks before pregnancy; Cox proportional hazard regression model is used to calculate HR(95%CI) per 3 μg·m−3 increment in NO2 over different exposure windows; a: models are not adjusted any confounders; b: models are adjusted for maternal age, ethnicity, educational level, occupation, body mass index before pregnancy, residence, times of gravidity and parity, maternal smoking and alcohol consumption, husband smoking, season of conception, and natural cubic splines are used for mean ambient temperature and dew point. 2.4 NO2周均暴露与SGA和LGA发生风险的关联
DLMs结合Cox比例风险回归模型结果显示,孕前期和孕早期NO2周均暴露水平与SGA和LGA的发生风险有关。SGA的NO2暴露易感窗口为怀孕前第7~12周和孕期第6~12周,其中在孕前第12周的估计效应值最大,NO2暴露水平每增加3 μg·m−3,SGA发生风险将升高6.0%(95%CI:3.2%~8.9%)。LGA的NO2暴露易感窗口为怀孕前第1~12周和孕期第1~6周,其中在孕前第12周的估计效应值最大,NO2暴露水平每增加3 μg·m−3,LGA发生风险将升高6.1%(95%CI:4.5%~7.8%)。见图1。
图 1孕前期和孕期NO2周均暴露水平与SGA(A)和LGA(B)发生风险的关联
孕前期数据是怀孕前12周数据;应用DLMs结合Cox比例风险回归模型结合计算孕前期和孕期大气NO2每增加3 μg·m−3对应的HR(95%CI),并使用自然立方样条函数拟合NO2的滞后分布,自由度设置为6;所有模型均校正了孕妇年龄、民族、文化程度、职业、孕前体重指数、居住地、怀孕次数、生产次数、吸烟和饮酒情况,丈夫吸烟情况,怀孕季节等因素,并应用自然立方样条函数校正温度和露点的影响。 Figure 1.Associations of weekly NO2 exposure over the preconception and entire pregnancy periods with risks of SGA (A) and LGA (B)
Data for the preconception are obtained up to 12 weeks before pregnancy; DLMs incorporated in Cox proportional hazard regression model is used to calculate HR (95%CI) per 3 μg·m−3 increment in NO2 over the preconception and entire pregnancy period, and lag distribution for NO2 modelled as natural cubic splines with six degrees of freedom; all models are adjusted for maternal age, ethnicity, educational level, occupation, body mass index before pregnancy, residence, times of gravidity and parity, smoking and alcohol consumption, husband smoking, season of conception, and natural cubic splines are used for mean ambient temperature and dew point. 2.5 敏感性分析
在分别校正PM2.5、PM10、SO2、CO或O3周均暴露水平后,SGA和LGA的NO2暴露易感窗口出现些许改变,如校正PM2.5暴露水平之后,SGA的NO2暴露易感窗口改变为怀孕前第11~12周和孕期第5~15周,LGA的NO2暴露易感窗口改变为孕前第1~12周和孕期第1~4周,但整体上双污染物模型识别的NO2易感暴露窗口仍然在孕前期和孕早期范围内(具体分析结果见补充材料图S1~图S5)。分别剔除孕前BMI≤18.50或≥30.00 kg·m−2(n=1047)、孕妇本身或丈夫吸烟(n=2286)、诊断有慢性或感染性疾病(n=50)的研究对象,以及在原有模型上增加校正新生儿出生年份后,其结果与原模型结果相一致(具体分析结果见补充材料图S6~图S9)。
3. 讨论
本研究结果显示,孕前期和孕早期大气NO2暴露与SGA和LGA的发生有关。目前大多数研究在探索NO2与不良出生结局关系时,其研究暴露窗局限于全孕期,很少有研究探索孕前NO2暴露对不良出生结局的影响。受孕是女性在排卵期排出卵泡后,与进入体内的精子融合形成受精卵并成功植入子宫,发育形成胚胎的过程。因此精子与卵子的质量对于所形成胚胎质量具有决定性作用。有证据表明,NO2暴露会导致精子和卵子质量下降,影响所形成的胚胎质量,不利于胚胎发育[29-30]。本研究结果也显示孕前NO2暴露会增加SGA和LGA发生风险,这可能与孕前NO2暴露对卵子和精子质量的影响有关。
孕早期是胎儿着床和胎盘形成的关键时期,易受环境污染物的影响。在美国密歇根州底特律开展的一项研究报道,孕期第一个月NO2暴露浓度超过6.8 ppb(1 ppb=1.88 μg·m−3)将增加SGA的发生风险,其HR(95%CI)值为1.11(1.03~1.21)[13]。在广州市开展的一项出生队列研究发现,孕早期NO2暴露与SGA和LGA发生风险的增加显著相关,其HR(95%CI)值分别为1.04(1.01~1.09)和1.09(1.05~1.13)[11]。这与本研究结果得出的孕早期NO2暴露增加SGA和LGA的发生风险的结果相一致。
识别大气污染暴露对不良出生结局影响的关键易感暴露窗对于理解其危害产生的潜在生物学机制,以及优化相关产前保健的预防和管理策略具有重要意义。本研究首次探索了大气NO2周暴露与SGA和LGA发生风险关系,而目前已发表的研究主要是将孕期分为孕早、中、孕晚期三个暴露时间段以识别NO2暴露影响SGA和LGA发生的易感暴露窗[11]。本研究通过对较长时间窗口NO2累积暴露评估结果显示,孕早期NO2暴露与SGA发生风险的增加相关;孕前期和孕早期NO2暴露与LGA发生风险的增加相关。本研究进一步细化NO2暴露时间段,分析NO2周暴露与SGA和LGA发生风险关系,结果显示,NO2暴露影响SGA发生的易感窗口为怀孕前第7~12周和孕期第6~12周,影响LGA发生的易感窗口为怀孕前第1~12周和孕期第1~6周。可以看到,通过细化暴露时期,得到了更为精确的易感窗口,有助于识别由于划分的暴露时期较长而被忽略的潜在易感窗口。
NO2引起胎儿异常发育的具体机制目前还没有得出确切的结论。NO2引起的氧化应激可能是导致胎儿发育异常的主要机制之一。NO2可氧化组织成分,例如蛋白质和脂质,并抑制抗氧化保护系统[31]。有研究提出孕期NO2暴露会增加母体和脐带血中的脂质过氧化,进而通过氧化应激干扰子宫内胚胎的正常生长发育[32]。但其导致SGA和LGA发生的具体机制应该不同,前者可能是通过影响胎盘功能[33],后者可能是通过影响孕妇糖脂代谢[34]。后续需要进一步针对不同的效应终点,开展实验性研究以便为流行病学研究结果提供机制性支持。
目前,大部分研究主要关注大气污染暴露对宫内胎儿发育迟缓的影响,较少有研究关注大气污染暴露与宫内胎儿发育过速的关系。在本研究人群中,SGA的发生率仅为1.8%,而大于胎龄儿的发生率高达4.6%。本研究分析结果也显示,NO2暴露不仅与SGA的发生相关,还与LGA的发生相关,提示在关注NO2暴露对宫内胎儿发育迟缓的影响同时,同时也需要关注其对宫内胎儿发育过速的影响。
本研究存在一定局限性。第一,本研究环境暴露数据来自对环境监测站数据的模型转换,不能完全反映个体暴露情况,可能存在暴露错分问题。此外,女性在怀孕后,可能会采取一定防护措施以减少怀孕期间对空气污染的暴露程度,例如在空气污染严重的日子外出时戴口罩或在家中使用空气净化器。但是在本次研究中,本研究没有采集孕妇相关行为改变的信息。第二,孕妇体重增加可能会增加脐血瘦素水平,改变与胎儿生长加快有关的孕妇胰岛素样生长因子的表达[35-36]。在本次研究中,虽然没有获取到孕妇怀孕期间体重增加的信息,但在模型分析中对孕妇孕前的BMI进行了控制。第三,本研究选择的研究对象是计划怀孕的妇女,存在一定局限性。因此需要进行更大样本量和更大人群覆盖率的研究,以进一步来重复和证实本研究的发现。
综上,本研究应用DLMs细化NO2暴露时期为每周暴露,更为准确的鉴别了NO2暴露对SGA和LGA影响的易感窗口。分析结果显示,孕前期和孕早期NO2暴露可能增加SGA和LGA发生的风险。研究结果可为本地区及类似高污染地区制定大气污染健康危害防护措施提供一定科学依据。
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图 1
孕前期和孕期NO2周均暴露水平与SGA(A)和LGA(B)发生风险的关联
孕前期数据是怀孕前12周数据;应用DLMs结合Cox比例风险回归模型结合计算孕前期和孕期大气NO2每增加3 μg·m−3对应的HR(95%CI),并使用自然立方样条函数拟合NO2的滞后分布,自由度设置为6;所有模型均校正了孕妇年龄、民族、文化程度、职业、孕前体重指数、居住地、怀孕次数、生产次数、吸烟和饮酒情况,丈夫吸烟情况,怀孕季节等因素,并应用自然立方样条函数校正温度和露点的影响。 Figure 1.
Associations of weekly NO2 exposure over the preconception and entire pregnancy periods with risks of SGA (A) and LGA (B)
Data for the preconception are obtained up to 12 weeks before pregnancy; DLMs incorporated in Cox proportional hazard regression model is used to calculate HR (95%CI) per 3 μg·m−3 increment in NO2 over the preconception and entire pregnancy period, and lag distribution for NO2 modelled as natural cubic splines with six degrees of freedom; all models are adjusted for maternal age, ethnicity, educational level, occupation, body mass index before pregnancy, residence, times of gravidity and parity, smoking and alcohol consumption, husband smoking, season of conception, and natural cubic splines are used for mean ambient temperature and dew point. 表 1
研究对象基本信息(n=10 916)
Table 1
Basic information of participants (n=10 916)
变量(Variable) n(%) 变量(Variable) n(%) 孕妇年龄/岁
Maternal age/years孕妇民族
Maternal ethnicity19~34 9343(85.6) 汉族(Han) 10785(98.8) ≥35 1573(14.4) 少数民族(Minority) 131(1.2) 孕妇文化程度
Maternal educational level怀孕前体重指数/(kg·m−2)
Maternal BMI before
pregnancy/(kg·m−2)高中以下
Less than high school5489(50.3) ≤18.50 853(7.8) 高中(High school) 5275(48.3) 18.51~ 7502(68.7) 高中以上
Above high school152(1.4) ≥24 2561(23.5) 孕妇职业
Maternal employment孕妇家庭住址
Maternal residence体力劳动(Manual labor) 8880(81.3) 城市(Urban) 2249(20.6) 非体力劳动或无工作
Non manual labor
and unemployed2036(18.7) 农村(Rural) 8667(79.4) 孕妇怀孕次数
Maternal gravidity孕妇生产次数
Maternal parity1 5980(54.8) 1 6536(59.9) ≥2 4936(45.2) ≥2 4380(40.1) 孕妇吸烟
Maternal smoking丈夫吸烟
Husband smoking否(No) 10862(99.5) 否(No) 8644(79.2) 是(Yes) 54(0.5) 是(Yes) 2272(20.8) 孕妇饮酒
Maternal drinking新生儿性别
Neonatal sex否(No) 10621(97.3) 女性(Female) 5406(49.5) 是(Yes) 295(2.7) 男性(Male) 5510(50.5) 怀孕季节
Season of conception小于胎龄儿(SGA) 春季(Spring) 2621(24.0) 否(No) 10720(98.2) 夏季(Summer) 4990(45.7) 是(Yes) 196(1.8) 秋季(Autumn) 1572(14.4) 大于胎龄儿(LGA) 冬季(Winter) 1733(15.9) 否(No) 10412(95.4) 是(Yes) 504(4.6) 表 2
孕妇孕前和孕期NO2和气象因素暴露水平
Table 2
Summary levels of maternal exposure to NO2 and meteorological factors over the preconception and entire pregnancy periods
暴露窗口
Exposure window暴露物
Exposure$\bar{x}$ $ s $ 百分位数(Percentile) P5 P25 P50 P75 P95 孕前期(Preconception) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 39.6 10.8 25.2 31.2 38.0 46.9 60.8 温度(Temperature)/℃ 16.1 9.1 0.7 7.2 19.2 24.3 26.8 露点(Dew point)/% 5.0 10.2 −11.6 −4.7 7.2 13.8 18.7 孕早期(First trimester) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 42.7 10.5 24.5 34.7 43.9 50.7 58.6 温度(Temperature)/℃ 17.9 8.7 1.3 10.7 21.0 25.4 26.5 露点(Dew point)/% 8.0 10.4 −10.9 −0.9 11.4 17.8 18.5 孕中期(Second trimester) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 44.8 12.7 25.0 33.0 46.1 56.4 62.2 温度(Temperature)/℃ 12.3 9.3 −0.8 4.0 10.4 21.5 26.4 露点(Dew point)/% 2.8 10.0 −11.3 −6.5 1.6 12.2 18.4 孕晚期(Third trimester) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 37.7 11.1 23.8 28.3 35.1 44.6 60.0 温度(Temperature)/℃ 10.4 9.0 −0.4 2.5 8.6 18.6 25.7 露点(Dew point)/% −0.3 9.9 −11.2 −9.1 −3.3 8.3 17.5 整个孕期(Entire pregnancy) $\rho_{{\rm{NO}}_2} $/(μg·m−3) 41.6 4.8 33.7 38.3 41.9 45.2 48.9 温度(Temperature)/℃ 13.4 2.6 10.4 11.3 12.5 15.8 17.8 露点(Dew point)/% 3.4 3.1 −0.7 0.8 2.7 6.0 8.3 [注] 孕前期数据是怀孕前12周数据。[Note] Data for the preconception period are obtained up to 12 weeks before pregnancy. 表 3
研究期不同时间窗口NO2累积暴露与SGA和LGA发生风险的关联分析
Table 3
Associations of cumulative NO2 exposure over different exposure windows during study period with risks of SGA and LGA
暴露窗口(Exposure window) 小于胎龄儿(SGA) 大于胎龄儿(LGA) HRa(95%CI) HRb(95%CI) HRa(95%CI) HRb(95%CI) 孕前期(Preconception) 0.71(0.61~0.82) 0.86(0.78~0.95) 0.90(0.83~0.98) 1.07(1.01~1.13) 孕早期(First trimester) 0.91(0.80~1.04) 1.19(1.08~1.32) 1.06(0.97~1.15) 1.37(1.29~1.46) 孕中期(Second trimester) 1.19(1.06~1.33) 0.92(0.84~1.00) 1.15(1.07~1.23) 0.97(0.92~1.03) 孕晚期(Third trimester) 1.06(0.94~1.20) 0.81(0.73~0.91) 1.06(0.98~1.15) 0.93(0.87~1.00) 整个孕期(Entire pregnancy) 1.57(1.14~2.17) 0.89(0.77~1.03) 1.94(1.59~2.37) 1.19(1.09~1.31) [注] 孕前期数据是怀孕前12周数据;应用Cox比例风险回归模型计算NO2在不同时间窗口每增加3 μg·m−3的HR(95%CI);a:模型未校正混杂因素;b:模型校正了孕妇年龄、民族、文化程度、职业、孕前体重指数、居住地、怀孕次数、生产次数、吸烟和饮酒情况,丈夫吸烟情况,怀孕季节等因素,并应用自然立方样条函数校正温度和露点的影响。[Note] Data for the preconception are obtained up to 12 weeks before pregnancy; Cox proportional hazard regression model is used to calculate HR(95%CI) per 3 μg·m−3 increment in NO2 over different exposure windows; a: models are not adjusted any confounders; b: models are adjusted for maternal age, ethnicity, educational level, occupation, body mass index before pregnancy, residence, times of gravidity and parity, maternal smoking and alcohol consumption, husband smoking, season of conception, and natural cubic splines are used for mean ambient temperature and dew point. -
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