Maternal Environmental Tobacco Smoke Exposure During Pregnancy and the Risk of Congenital Heart Defects: a Case-control Study in Sichuan, China

Maternal Environmental Tobacco Smoke Exposure During Pregnancy and the Risk of Congenital Heart Defects: a Case-control Study in Sichuan, China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Maternal Environmental Tobacco Smoke Exposure During Pregnancy and the Risk of Congenital Heart Defects: a Case-control Study in Sichuan, China Min Luo, Yuci Liu, Gang Zhang, Weixin Liu, Yan Gao, Tianjin Zhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5357930/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Studies on the association between maternal environmental tobacco smoke (ETS) exposure during pregnancy and congenital heart defects (CHD) in offspring are limited. In this case-control study, we collected data from 116 fetuses with CHD and 3744 fetuses without any congenital anomalies to examine the association between maternal ETS exposure during different weeks of pregnancy and the duration of exposure with offspring CHD. Our results showed that maternal ETS exposure during pregnancy was associated with an increased risk of CHD in a dose-response gradient. The adjusted odds ratios (AOR) and corresponding 95% confidence intervals (CIs) were 2.97(1.42, 6.17) and 3.19(1.35, 7.50) for ETS exposure of 2-5h/week and >5h/week, respectively. Compared to the unexposed group, the AORs for maternal ETS exposure only in the first trimester and continuous exposure throughout pregnancy were 2.32 and 4.89, respectively. Our findings suggest that maternal ETS exposure during pregnancy may increase the risk of offspring CHD in a dose-response manner, and that ETS exposure during different weeks of pregnancy is associated with an increased risk of CHD among non-smoking pregnant women. These results highlight the importance of preventing ETS exposure throughout pregnancy, particularly during the early stages. environmental tobacco smoke congenital heart defect a case-control study. Figures Figure 1 1. Introduction Congenital heart defect (CHD) is a condition resulting from abnormal development of the heart and large blood vessels in the fetus. It’s one of the most common and severe birth defects, and is the leading cause of death among children under 5 years of age in many regions of China. According to the 2012 China Birth Defect Prevention Report [ 1 ] , over 130,000 infants are born with CHD in China each year, resulting in a total economic burden exceeding 12.6 billion yuan. Most CHDs are not caused by a single factor, but rather result from the interaction of multiple genetic and environmental factors. Genetic factors account for about 35% of CHD cases, while environmental factors account for approximately 65% [ 2 – 3 ] . Due to differences in living environments, lifestyles, and exposures among countries, regions, and populations, it is necessary to conduct research on the environmental impact of CHD in different regions [ 4 ] . Studies have shown that several environmental factors are closely associated with the occurrence of CHD, including first-trimester drug use, gestational diabetes mellitus, living in a house for less than half a year, active/passive smoking, mental stress, exposure to chemical agents, first-trimester colds and fevers, living within 50 meters of a road during the first trimester, and maternal and paternal alcohol and cigarette use during pregnancy [ 5 – 11 ] . China is the world's largest producer and consumer of tobacco, with a high prevalence of active smoking among men. It is estimated that approximately 4.2% of women aged 15–69 are current smokers, while over 70% of women are exposed to secondhand smoke [ 12 ] . Environmental tobacco smoke (ETS) exposure among Chinese women ranges from 68–71.6%, with passive smoking rates in homes, indoor workplaces, and public places being 67.3%, 63.3%, and 72.7%, respectively [ 13 ] . Research on the toxicity and carcinogenicity of tobacco smoke has shown that the health risks associated with inhaling tobacco smoke are not limited to the smoker but also extend to those exposed to ETS [ 14 ] . It is reported that ETS during pregnancy are linked to a host of deleterious effects on the pregnancy, fetus, and infant. Furthermore, researches show an association between maternal tobacco exposure, both active and passive, and congenital heart defects in offspring [ 15 ] .In fact, the association between active maternal cigarette smoking and CHDs has been reviewed. The relationship between maternal ETS during pregnancy and birth defects, however, has been examined to a lesser extent [ 16 ] . A recent meta-analysis on the association of prenatal tobacco exposure to CHDs found that maternal passive smoking were significantly associated with CHDs risks, with relative risks (RRs) of 1.57 However, the results of this study must be interpreted with caution. 68% of the included studies did not adjust for any confounding factors [ 17 ] . Accordingly, the study could not determine whether the observed association between maternal cigarette smoking and CHDs reflected the magnitude of a causal effect or was biased by confounding factors. Considering that the critical development period of CHDs is from the 3rd to the 8th week of gestation, studies on risk factors for CHDs should focus on the critical period, that is, from 3 months before pregnancy to the end of the first trimester. However, 70.4% of the studies within the meta-analysis did not explicitly define the time of tobacco exposure, which may further confound the observed associations between maternal cigarette smoking and risks of CHDs in offspring [ 17 ] . Given the relatively high prevalence of prenatal tobacco exposure and the potential severity of CHDs, it is important to investigate the association between maternal passive smoking during different weeks of pregnancy, the duration of exposure, and offspring CHD, as this may help to elucidate causality. Compared to previous studies, this case-control aims to clarify the association between passive smoking during pregnancy and offspring CHDs with adjusting potential confounding factors, and the relationship between tobacco exposure at different stages of pregnancy, the duration of exposure, and CHD. 2. Materials and Methods Study Population This study is based on data from the Southwest Region Birth Cohort Construction Study. Participants in this birth cohort were pregnant women who underwent their first prenatal examination at the survey site before 13 + 6 weeks' gestation. To ensure the accurate identification and uniqueness of all participant information, each participant was assigned a unique study number that was matched with their identity number. This number was shared by the mother and baby throughout the study. The study was approved by the Institutional Review Board at Sichuan University (approval number: K2016038), and written informed consent was obtained from all participating women. For the present study, we included 18816 pregnant women who delivered between January 2019 and June 2021. The inclusion criteria were as follows:(1) no history of smoking and no smoking during pregnancy, (2) singleton live birth, (3) availability of ETS exposure information during the first and last trimesters, (4) follow-up until one-year postpartum, (5) no diagnosis or co-occurrence of other types of birth defects, and (6) availability of CHD status information. A total of 3,860 pregnant women were ultimately included in this study, comprising 116 cases and 3,744 controls (Fig. 1 ). Case and Control Definitions Case fetuses were defined as fetuses diagnosed with congenital heart disease (CHD) via prenatal systematic echocardiography at participating hospitals, with no recognized or suspected single gene condition or chromosomal abnormality. To ensure the accuracy of the final diagnosis and that the patients met the inclusion criteria in the analysis, all live birth CHD cases were confirmed via routine examination, heart auscultation, and thorough neonatal echocardiography performed by pediatric cardiologists after delivery. These cases were followed until the end of the child’s first year of age, and the diagnosis of CHD was made in strict accordance with the ICD-10 classification standard. Controls were defined as fetuses without birth defects, as assessed by prenatal systematic echocardiography at participating hospitals. Live birth controls were confirmed via routine physical examination, heart auscultation, and thorough neonatal echocardiography, and were followed up to one year after delivery. Any controls exhibiting heart defects or extracardiac defects identified after delivery were excluded from our analysis. Data Measurement Detailed and structured questionnaires were used to collect information from participants. These included five questionnaires for pregnant women (baseline survey at the time of recruitment, first trimester, second trimester, third trimester, and birth information) and three questionnaires for parents of children (maternal and infant surveys at 42 days postpartum, 6 months, and 12 months of age). The questionnaires covered a range of topics, including basic sociodemographic information (e.g., age, marital status, education level, family income), lifestyle factors (e.g., living environment, smoking, drinking, work and home conditions), personal fertility history and anthropometric indicators (e.g., height, weight), medication and nutritional supplementation, common disease history, and child growth and health. ETS exposure was defined as passive exposure to environmental tobacco smoke for any duration in any setting. Questions related to maternal ETS exposure were included in the first- and third-trimester questionnaires. Mothers were asked to answer the following questions: (1) Have you ever smoked? If so, (2) When did you start smoking regularly? (3) How often do you smoke (cigarettes/day)? (4) Did you quit smoking? (5) Have you been exposed to smoking since becoming pregnant? If yes, continue to answer (6) Does anyone in your family smoke in front of you? If yes, continue to answer (7) How long does this person usually smoke in front of you each day? (8) Are people smoking in front of you in your work environment or public places? (9) How many hours per week are you exposed to smoking on average? ETS exposure status during pregnancy was categorized into two groups: NO ETS and Ever ETS. Based on the stage of pregnancy, the ETS group was further divided into first-trimester ETS (mothers exposed only during the first trimester), last-trimester ETS (mothers exposed only during the last trimester), and continuous ETS (mothers exposed throughout pregnancy). ETS exposure was also classified by duration ( 5 hours/week). Data Collection Each participating institution in the birth cohort construction study selected at least one pregnant woman investigator and one child investigator to be responsible for the specific project work. A project manager was also designated to oversee project organization and coordination, regularly review questionnaire completion, and supervise implementation. Pregnant women who participated in the questionnaire and were included in the study did not have any mental illness or intellectual disability, had normal expression and comprehension abilities, underwent unified training, used an appropriate questionnaire, and voluntarily signed an informed consent form agreeing to cooperate in completing the entire follow-up survey. Participants were ultimately enrolled based on their cooperative number. Covariates and potential confounders Based on previous reports, several important perinatal social and environmental factors may affect the occurrence of CHD. This study controlled for 11 potential confounding variables, including maternal age at enrollment (in years), maternal residence (rural/urban), maternal and paternal education level (< 12 or ≥ 12 completed years of school), parity (nulliparous/multiparous), history of abortion, maternal alcohol use during pregnancy, perinatal folic acid intake, exposure to adverse environments during pregnancy, exposure to harmful substances during pregnancy, and use of an air purifier during pregnancy (yes/no). Abortion history included spontaneous abortion, medication-induced abortion, and induced abortion. Exposure to adverse environments referred to working night shifts or being exposed to noise during pregnancy, while exposure to harmful substances included exposure to dust, harmful gases, fumes, decoration odors, and hair perms during pregnancy. Statistical analysis Statistical analysis was carried out using SPSS version 23. Categorical variables were represented as frequencies and percentages, and differences in characteristics between case and control participants were evaluated using the Chi-square test. To assess the association between CHD and ETS exposure, binary logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using both unadjusted and adjusted models. Covariates were selected for adjustment based on Chi-square tests with p-values less than 0.1. These covariates included maternal age at enrollment, maternal residence, maternal education level, parity, abortion history, maternal alcohol use during pregnancy, perinatal folic acid intake, exposure to harmful substances and adverse environments during pregnancy, and use of an air purifier during pregnancy. Risks were reported as unadjusted and adjusted ORs with 95% CIs. All tests were two-sided, and p-values less than 0.05 were considered statistically significant. 3. Results Table 1 presents the basic characteristics of the case and control participants. Compared to the control group, mothers of fetuses with CHD were more likely to be younger, reside in rural areas, be nulliparous, have completed fewer than 12 years of school, and have used air purifiers during pregnancy. Mothers who reported perinatal folic acid intake and had no history of miscarriage were less likely to have offspring with CHD than case mothers. Mothers who consumed alcohol or were exposed to harmful substances or adverse environments during pregnancy were more likely to have offspring with CHD than controls. However, there was no significant difference between the case and control groups with regard to paternal education level. Table 1 The Maternal and Paternal Characteristics of Case and Control Participants Characteristics Case participants(N = 116) Control participants(N = 3744) P a N(%) N(%) Maternal age(years) 0.001 < 30 48(41.4) 1012(27.0) ≥ 30 68(58.6) 2732(73.0) Maternal residence < 0.001 rural 71(61.2) 1285(34.3) urban 45(38.8) 2459(65.7) Paternal education level(years) 0.943 < 12 34(34.3) 1109(29.6) ≥ 12 82 (70.7) 2635(70.4) Maternal leducation level(years) 0.002 < 12 52(44.8) 1167(31.2) ≥ 12 64(55.2) 2577(68.8) Parity < 0.001 nulliparous 11(9.5) 52(1.4) multiparous 105(90.5) 3692(98.6) Abortion history 0.017 yes 43(37.1) 1011(27.0) no 73(62.9) 2733(73.0) Maternal alcohol use during pregnancy yes 19(16.4) 60(1.6) < 0.001 no 97(83.6) 3684(98.4) Folic acid intake during perinatal period < 0.001 yes 84(72.4) 3715(99.2) no 32(27.6) 29(0.8) Exposure to adverse environments during pregnancy 0.005 yes 59(50.9) 1421(38.0) no 57(49.1) 2323(62.0) Exposure to harmful substances during pregnancy 0.019 yes 69(59.5) 1813(48.4) no 47(40.5) 1931(51.6) Using air purifiers during pregnancy < 0.001 yes 55(47.4) 855(22.8) no 61(52.6) 2889(77.2) a Chi-square test, N: number, P : P value Table 2 shows the association between maternal passive smoking levels during pregnancy and CHD in offspring. Of the 3860 subjects, 469 pregnant women reported passive smoking during pregnancy, including 37 cases (31.9%) in the case group and 432 cases (11.5%) in the control group. Overall, a significantly increased risk of CHD in offspring was observed among mothers exposed to passive smoking compared to the No ETS group (AOR: 2.53; 95% CI: 1.50–4.27). An association was found between mothers exposed to ETS for 2–5 hours/week during pregnancy and offspring with CHD (AOR: 2.97; 95% CI: 1.42–6.17). Compared to the No ETS group, mothers exposed to ETS for > 5 hours/week during pregnancy had an increased risk of CHD, with an adjusted OR (95% CI) of 3.19 (1.35–7.50). However, no significant association was found between ETS exposure for > 1 hour/week and CHD (AOR: 1.68; 95% CI: 0.70–4.05). ETS exposure rates during the first trimester, last trimester, and continuously throughout pregnancy were 12.9%, 12.1%, and 6.9%, respectively, in the case group, and 6.3%, 3.0%, and 2.2%, respectively, in the control group. When participants were categorized according to the stage of exposure, the first-trimester ETS group was more likely to have offspring with CHD compared to the No ETS group (AOR: 2.32; 95% CI: 1.17–4.60), while a stronger association was observed for the continuous ETS group (AOR: 4.89; 95% CI: 1.96–12.21). No significant association was found between last-trimester ETS exposure and CHD in offspring (AOR: 1.82; 95% CI: 0.73–4.50). Table 2 Logistic regression analysis of the relationship between maternal ETS exposure during pregnancy and CHD in offspring Characteristics Case participants (N = 116) Control participants (N = 3744) ORs(95%CI) N(%) N(%) COR(95%CI) AOR(95%CI) b Maternal ETS exposure during pregnancy no 79(68.1) 3312(88.5) 1.00(Ref.) 1.00(Ref.) yes 37(31.9) 432(11.5) 3.59(2.40,5.37) 2.53(1.50,4.27) Duration, hours/week 79(68.1) 3312(82.9) 1.00(Ref.) 1.00(Ref.) 5h 12(10.3) 62(1.7) 8.11(4.21,15.66) 3.19(1.35,7.50) Exposure stage no ETS 79(68.1) 3312(88.5) 1.00(Ref.) 1.00(Ref.) first trimester ETS 15(12.9) 234(6.3) 3.05(1.77,5.23) 2.32(1.17,4.60) last trimester ETS 14(12.1) 114(3.0) 4.41(2.34,8.33) 1.82(0.73,4.50) a continuous ETS 8(6.9) 84(2.2) 3.99(1.87,8.53) 4.89(1.96,12.21) a P >0.05, b ORs were adjusted by the following convariates: maternal age at enrollment, maternal residence, maternal education level, parity, abortion history, maternal alcohol use during pregnancy, folic acid intake during the perinatal period, exposure to harmful substances and adverse environments during pregnancy, using air purifiers during pregnancy. N: number; COR: crude odds ratio; AOR: adjusted odds ratio; CI: confidence interval. Table 3 presents the results of subgroup analyses for risk estimates between maternal passive smoking during pregnancy and CHD in offspring. After controlling for confounding factors, a statistically significant association was observed between the Ever ETS group during pregnancy and offspring CHD in all subgroups. In each subgroup, except for exposure to adverse environments during pregnancy, a significant association was found, including maternal age over 30 years, residence in rural areas, completion of over 12 years of school, multiparity, no history of abortion, no history of alcohol consumption during pregnancy, folic acid intake during pregnancy, and use of an air purifier during pregnancy. However, the association was not statistically significant in the corresponding stratum. In the subgroup exposed to adverse environments during pregnancy, a statistically significant association was observed between maternal passive smoking during pregnancy and offspring CHD. Overall, the direction of the association between passive smoking during pregnancy and offspring CHD remained consistent across all subgroups, suggesting a stable relationship between these factors. Table 3 Subgroup analysis of the relationship between maternal ETS exposure during pregnancy and CHD in offspring Characteristics AOR(95%CI) P value Maternal age(years) < 30 0.80(0.29,2.17) 0.654 ≥ 30 3.46(1.81,6.59) < 0.001 Maternal residence rural 5.55(2.80,11.00) < 0.001 urban 1.87(0.98,3.55) 0.058 Maternal education level(years) < 12 1.90(0.85,4.24) 0.117 ≥ 12 2.66(1.29,5.48) 0.008 Parity nulliparous 1.72(0.89,3.20) 0.999 multiparous 2.67(1.45,4.20) 0.003 Abortion history yes 0.37(0.02,67.80) 0.718 no 3.10(1.64,5.87) < 0.001 Maternal alcohol use during pregnancy yes 0.66(0.06,7.85) 0.738 no 2.72(1.59,4.69) < 0.001 Folic acid intake during the perinatal period yes 1.99(1.14,3.47) 0.015 no 0.67(0.04,12.03) 0.785 Exposure to adverse environments during pregnancy yes 2.28(1.12,4.62) 0.022 no 2.61(1.07,6.39) 0.036 Exposure to harmful substances during pregnancy yes 1.17(0.62,2.22) 0.633 no 4.98(1.86,13.32) 0.001 Using air purifiers during pregnancy yes 2.78(1.02,7.60) 0.047 no 1.86(0.97,3.57) 0.061 AOR: adjusted odds ratio; CI: confidence interval. 4. Discussion In this study, after adjusting for potential confounders, we observed that maternal ETS exposure during pregnancy may increase the risk of CHD in offspring in a dose-response manner. We also found that maternal ETS exposure only during the first trimester increased the risk of CHD, while continuous maternal ETS exposure throughout pregnancy was associated with an even stronger increase in CHD risk. Our findings are consistent with previous studies [ 18 – 20 ] . Tobacco smoke contains numerous chemical carcinogens, including nicotine, carbon monoxide, polycyclic aromatic hydrocarbons, and carbonyls. Nicotine and carbon monoxide can rapidly cross the placenta and interfere with fetal cardiac development [21 . Furthermore, passive smoking can expose individuals to elevated concentrations of harmful substances, potentially even higher than those associated with active smoking [ 22 – 23 ] . Both spermatozoa and oocytes can be vulnerable to DNA damage due to exposure to tobacco smoke [ 20 , 24 ] . There is growing evidence that maternal smoking before and after pregnancy, as well as passive smoking, can increase the risk of miscarriage, stillbirth, low birth weight, childhood asthma, and offspring CHD [ 13 , 16 , 25 – 26 ] . A recent meta-analysis of nearly 140,000 CHD cases reported positive associations between maternal cigarette smoking and the risk of CHD in offspring, with an increased risk of 25% for active smoking and 124% for passive smoking [ 17 ] .Our study provides further evidence of the dose-response relationship between maternal ETS exposure during pregnancy and CHD in offspring. Previous studies have also identified a dose-dependent relationship between maternal passive smoking and the risk of CHD [ 6 , 27 , 28 ] . For example, Li et al. found that the association between CHD risk and maternal passive smoking was significantly stronger in the high hair nicotine concentration (HNC) group compared to the low HNC group [ 29 ] . In our study, we found that maternal exposure to ETS only during the first trimester or continuously throughout pregnancy was associated with an increased risk of CHD in offspring. However, no such association was observed for maternal ETS exposure only during the last trimester of pregnancy. Similarly, a National Birth Defect Prevention Study found a modest positive association between maternal exposure to secondhand smoke during early pregnancy and certain CHD subtypes [ 16 ] .The first trimester is a critical period for fetal heart development and malformation, during which the placental barrier is not fully impermeable to environmentally harmful chemical contaminants, potentially leading to cardiovascular abnormalities. Most CHDs occur in fetuses between 2 and 9 weeks of gestation, but many women are unaware of their pregnancy during this period [ 30 ] . Avoiding smoking or tobacco exposure early in pregnancy can improve fetal and newborn health outcomes. Our findings indicate that fetuses exposed to maternal ETS during pregnancy have a significantly increased risk of CHD, highlighting the importance of preventing smoking among women of childbearing age before or during early pregnancy. This is particularly important in China, where smoking rates during pregnancy are significantly lower than in the United States or Europe [ 31 ] . Current guidelines focus on quitting smoking rather than reducing it [38], which may deter women who find it difficult to quit [ 32 ] . Adequate information should be provided to these women about not only the risks of continuing to smoke but also the benefits of reducing smoking. Additionally, as early pregnancy is a critical period for fetal heart growth and development, exposure to smoke should be minimized during this time. The main strength of our study is its design. Our subjects in the nested case-control study and the control group come from the same cohort, which is more representative of the source population of the population study, and can better control selection bias and better comparability. Additionally, the time sequence is from the past to the present, and the time sequence of causal inference is clear, which can better control the recall bias. Furthermore, Compared with the traditional cohort study, thisl study does not need to detect the biological samples of all members of the cohort, which is more time-saving and labor-saving than the cohort study. However, our study also has some limitations. Information on ETS exposure was self-reported, and the intensity of exposure was not accurately known. We also excluded many cases due to missing information, which may have introduced bias. Finally, we were unable to analyze the association between ETS exposure and specific CHD subtypes due to the small number of cases in the case group. In conclusion, our study provides prospective evidence that maternal ETS exposure during pregnancy may increase the risk of CHD in offspring in a dose-response manner. Maternal ETS exposure during the first trimester or continuously throughout pregnancy also increases the risk of CHD. These findings highlight the importance of preconception planning and prevention, including folic acid supplementation, avoidance of ETS exposure at home or in the workplace, and avoidance of toxic and harmful environments to reduce the risk of CHD and other adverse outcomes in offspring. Preventive strategies to reduce the occurrence of major CHDs are necessary for pregnant women exposed to ETS in the presence of other risk factors. Abbreviations ETS, environmental tobacco smoke; CHD, congenital heart defect; AOR, adjusted odds ratio. Declarations The authors decare no conficts of interest statement. Fundings This work was supported by the National Key R&D Program of China[2019YFC0840703], the Project of Chengdu Municipal Health Commission [2022222]. Author Contribution A-G wrote the main manuscript text. All authors reviewed the manuscript." References http://www.gov.cn/gzdt/2012-09/12/content_2223371.htm Azhar M, Ware SM. Genetic and Developmental Basis of Cardiovascular Malformations. Clin Perinatol. 2016 ;43(1):39-53. doi: 10.1016/j.clp.2015.11.002. Ou Y, Mai J, Zhuang J, Liu X, Wu Y, Gao X, et al. Risk factors of different congenital heart defects in Guangdong. China. Pediatr Res. 2016 ;79(4):549-58. Bouma BJ, Mulder BJ. Changing Landscape of Congenital Heart Disease. Circ Res. 2017 ;120(6):908-922. Hackshaw A, Rodeck C, Boniface S. 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Li X, Liu Z, Deng Y, Li S, Mu D, Tian X, et al. Modification of the association between maternal smoke exposure and congenital heart defects by polymorphisms in glutathione S-transferase genes. Sci. Rep. 2015;5:14915. Cresci M, Foffa I, Ait-Ali L, Pulignani S, Gianicolo EA, Botto N, et al. Maternal and paternal environmental risk factors, metabolizing GSTM1 and GSTT1 polymorphisms, and congenital heart disease. Am. J. Cardiol. 2011;108:1625–1631. Lange S, Probst C, Rehm J, Popova S.National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis. Lancet Glob Health. 2018;6:e769-76. Wang T, Chen L, Ni B, Sheng X, Huang P, Zhang S, et al. Maternal pre-pregnancy/early-pregnancy smoking and risk of congenital heart diseases in offspring: A prospective cohort study in Central China. J Glob Health. 2022;12:11009. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5357930","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":375899182,"identity":"23e01c5e-2048-4ac3-b71a-585530f0fb0c","order_by":0,"name":"Min Luo","email":"","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Luo","suffix":""},{"id":375899184,"identity":"b71a6419-5899-4f39-a350-8542bee5bc2a","order_by":1,"name":"Yuci Liu","email":"","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuci","middleName":"","lastName":"Liu","suffix":""},{"id":375899187,"identity":"2ead84dd-8b64-4852-9aea-386a78cc9ae3","order_by":2,"name":"Gang Zhang","email":"","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Zhang","suffix":""},{"id":375899191,"identity":"6076893b-047f-4785-8968-ea42b87fc7be","order_by":3,"name":"Weixin Liu","email":"","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Weixin","middleName":"","lastName":"Liu","suffix":""},{"id":375899192,"identity":"97ec88fd-da47-4c19-a7c5-2cfd46fb2b1f","order_by":4,"name":"Yan Gao","email":"","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Gao","suffix":""},{"id":375899193,"identity":"df09a729-d6d3-4673-8dd5-c6f3424b804e","order_by":5,"name":"Tianjin Zhou","email":"","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tianjin","middleName":"","lastName":"Zhou","suffix":""},{"id":375899194,"identity":"1ffa76ea-aea2-4b4e-b58a-324ee94537c9","order_by":6,"name":"Ziling Zhao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYNCCCgk5NmbGxsd/gAx+4rScsTHmZ2c+bMBzxsJYsoEYHYxtaYkz+9nSJHjbKhI3ENJizn724OMKtsOMGw7zGEhIzpNg3MDA/PDRDTxaLHvykg3P8BxmNgBqMTDcJsFszsBmbJyDR4vBgRwzyQaJw2wgLQmJ2yTYLBt42KTxajn/xvxnA0g9EB04OEcCSBLSciPHjLEhIU1CspktsbGxQUKCoBbLGe+SJRsO2BjwMzMfZmY4JmEA1IvfL+b8uQc/Nv6TqG/jP9j+m6Gmrr6fvfnhY7wOY+BBF2LGoxyHllEwCkbBKBgFaAAA0ZBKCrzXe9EAAAAASUVORK5CYII=","orcid":"","institution":"Sichuan Provincial Maternity and Child Health Care Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ziling","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2024-10-30 03:23:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5357930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5357930/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70401869,"identity":"95032a66-0f7f-458e-bc15-8193e9be207b","added_by":"auto","created_at":"2024-12-02 22:23:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":114591,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study population.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5357930/v1/817d90463b9a0de05038144b.png"},{"id":70402258,"identity":"8ed0cd60-00af-47fd-908b-d8eb433dbb01","added_by":"auto","created_at":"2024-12-02 22:31:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":696362,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5357930/v1/16326c4e-9e4e-45a5-98b9-0e6cbcd9c21d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Maternal Environmental Tobacco Smoke Exposure During Pregnancy and the Risk of Congenital Heart Defects: a Case-control Study in Sichuan, China","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCongenital heart defect (CHD) is a condition resulting from abnormal development of the heart and large blood vessels in the fetus. It\u0026rsquo;s one of the most common and severe birth defects, and is the leading cause of death among children under 5 years of age in many regions of China. According to the 2012 China Birth Defect Prevention Report \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e, over 130,000 infants are born with CHD in China each year, resulting in a total economic burden exceeding 12.6\u0026nbsp;billion yuan.\u003c/p\u003e \u003cp\u003eMost CHDs are not caused by a single factor, but rather result from the interaction of multiple genetic and environmental factors. Genetic factors account for about 35% of CHD cases, while environmental factors account for approximately 65% \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Due to differences in living environments, lifestyles, and exposures among countries, regions, and populations, it is necessary to conduct research on the environmental impact of CHD in different regions \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Studies have shown that several environmental factors are closely associated with the occurrence of CHD, including first-trimester drug use, gestational diabetes mellitus, living in a house for less than half a year, active/passive smoking, mental stress, exposure to chemical agents, first-trimester colds and fevers, living within 50 meters of a road during the first trimester, and maternal and paternal alcohol and cigarette use during pregnancy \u003csup\u003e[\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eChina is the world's largest producer and consumer of tobacco, with a high prevalence of active smoking among men. It is estimated that approximately 4.2% of women aged 15\u0026ndash;69 are current smokers, while over 70% of women are exposed to secondhand smoke \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Environmental tobacco smoke (ETS) exposure among Chinese women ranges from 68\u0026ndash;71.6%, with passive smoking rates in homes, indoor workplaces, and public places being 67.3%, 63.3%, and 72.7%, respectively\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Research on the toxicity and carcinogenicity of tobacco smoke has shown that the health risks associated with inhaling tobacco smoke are not limited to the smoker but also extend to those exposed to ETS \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. It is reported that ETS during pregnancy are linked to a host of deleterious effects on the pregnancy, fetus, and infant. Furthermore, researches show an association between maternal tobacco exposure, both active and passive, and congenital heart defects in offspring\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.In fact, the association between active maternal cigarette smoking and CHDs has been reviewed. The relationship between maternal ETS during pregnancy and birth defects, however, has been examined to a lesser extent\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA recent meta-analysis on the association of prenatal tobacco exposure to CHDs found that maternal passive smoking were significantly associated with CHDs risks, with relative risks (RRs) of 1.57 However, the results of this study must be interpreted with caution. 68% of the included studies did not adjust for any confounding factors\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Accordingly, the study could not determine whether the observed association between maternal cigarette smoking and CHDs reflected the magnitude of a causal effect or was biased by confounding factors. Considering that the critical development period of CHDs is from the 3rd to the 8th week of gestation, studies on risk factors for CHDs should focus on the critical period, that is, from 3 months before pregnancy to the end of the first trimester. However, 70.4% of the studies within the meta-analysis did not explicitly define the time of tobacco exposure, which may further confound the observed associations between maternal cigarette smoking and risks of CHDs in offspring\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eGiven the relatively high prevalence of prenatal tobacco exposure and the potential severity of CHDs, it is important to investigate the association between maternal passive smoking during different weeks of pregnancy, the duration of exposure, and offspring CHD, as this may help to elucidate causality. Compared to previous studies, this case-control aims to clarify the association between passive smoking during pregnancy and offspring CHDs with adjusting potential confounding factors, and the relationship between tobacco exposure at different stages of pregnancy, the duration of exposure, and CHD.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e \u003cb\u003eStudy Population\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis study is based on data from the Southwest Region Birth Cohort Construction Study. Participants in this birth cohort were pregnant women who underwent their first prenatal examination at the survey site before 13\u003csup\u003e+\u0026thinsp;6\u003c/sup\u003e weeks' gestation. To ensure the accurate identification and uniqueness of all participant information, each participant was assigned a unique study number that was matched with their identity number. This number was shared by the mother and baby throughout the study. The study was approved by the Institutional Review Board at Sichuan University (approval number: K2016038), and written informed consent was obtained from all participating women.\u003c/p\u003e \u003cp\u003eFor the present study, we included 18816 pregnant women who delivered between January 2019 and June 2021. The inclusion criteria were as follows:(1) no history of smoking and no smoking during pregnancy, (2) singleton live birth, (3) availability of ETS exposure information during the first and last trimesters, (4) follow-up until one-year postpartum, (5) no diagnosis or co-occurrence of other types of birth defects, and (6) availability of CHD status information. A total of 3,860 pregnant women were ultimately included in this study, comprising 116 cases and 3,744 controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eCase and Control Definitions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eCase fetuses were defined as fetuses diagnosed with congenital heart disease (CHD) via prenatal systematic echocardiography at participating hospitals, with no recognized or suspected single gene condition or chromosomal abnormality. To ensure the accuracy of the final diagnosis and that the patients met the inclusion criteria in the analysis, all live birth CHD cases were confirmed via routine examination, heart auscultation, and thorough neonatal echocardiography performed by pediatric cardiologists after delivery. These cases were followed until the end of the child\u0026rsquo;s first year of age, and the diagnosis of CHD was made in strict accordance with the ICD-10 classification standard.\u003c/p\u003e \u003cp\u003eControls were defined as fetuses without birth defects, as assessed by prenatal systematic echocardiography at participating hospitals. Live birth controls were confirmed via routine physical examination, heart auscultation, and thorough neonatal echocardiography, and were followed up to one year after delivery. Any controls exhibiting heart defects or extracardiac defects identified after delivery were excluded from our analysis.\u003c/p\u003e \u003cp\u003e \u003cb\u003eData Measurement\u003c/b\u003e \u003c/p\u003e \u003cp\u003eDetailed and structured questionnaires were used to collect information from participants. These included five questionnaires for pregnant women (baseline survey at the time of recruitment, first trimester, second trimester, third trimester, and birth information) and three questionnaires for parents of children (maternal and infant surveys at 42 days postpartum, 6 months, and 12 months of age). The questionnaires covered a range of topics, including basic sociodemographic information (e.g., age, marital status, education level, family income), lifestyle factors (e.g., living environment, smoking, drinking, work and home conditions), personal fertility history and anthropometric indicators (e.g., height, weight), medication and nutritional supplementation, common disease history, and child growth and health.\u003c/p\u003e \u003cp\u003eETS exposure was defined as passive exposure to environmental tobacco smoke for any duration in any setting. Questions related to maternal ETS exposure were included in the first- and third-trimester questionnaires. Mothers were asked to answer the following questions: (1) Have you ever smoked? If so, (2) When did you start smoking regularly? (3) How often do you smoke (cigarettes/day)? (4) Did you quit smoking? (5) Have you been exposed to smoking since becoming pregnant? If yes, continue to answer (6) Does anyone in your family smoke in front of you? If yes, continue to answer (7) How long does this person usually smoke in front of you each day? (8) Are people smoking in front of you in your work environment or public places? (9) How many hours per week are you exposed to smoking on average?\u003c/p\u003e \u003cp\u003eETS exposure status during pregnancy was categorized into two groups: NO ETS and Ever ETS. Based on the stage of pregnancy, the ETS group was further divided into first-trimester ETS (mothers exposed only during the first trimester), last-trimester ETS (mothers exposed only during the last trimester), and continuous ETS (mothers exposed throughout pregnancy). ETS exposure was also classified by duration (\u0026lt;\u0026thinsp;2 hours/week, 2\u0026ndash;5 hours/week, and \u0026gt;\u0026thinsp;5 hours/week).\u003c/p\u003e \u003cp\u003e \u003cb\u003eData Collection\u003c/b\u003e \u003c/p\u003e \u003cp\u003eEach participating institution in the birth cohort construction study selected at least one pregnant woman investigator and one child investigator to be responsible for the specific project work. A project manager was also designated to oversee project organization and coordination, regularly review questionnaire completion, and supervise implementation. Pregnant women who participated in the questionnaire and were included in the study did not have any mental illness or intellectual disability, had normal expression and comprehension abilities, underwent unified training, used an appropriate questionnaire, and voluntarily signed an informed consent form agreeing to cooperate in completing the entire follow-up survey. Participants were ultimately enrolled based on their cooperative number.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCovariates and potential confounders\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBased on previous reports, several important perinatal social and environmental factors may affect the occurrence of CHD. This study controlled for 11 potential confounding variables, including maternal age at enrollment (in years), maternal residence (rural/urban), maternal and paternal education level (\u0026lt;\u0026thinsp;12 or \u0026ge;\u0026thinsp;12 completed years of school), parity (nulliparous/multiparous), history of abortion, maternal alcohol use during pregnancy, perinatal folic acid intake, exposure to adverse environments during pregnancy, exposure to harmful substances during pregnancy, and use of an air purifier during pregnancy (yes/no). Abortion history included spontaneous abortion, medication-induced abortion, and induced abortion. Exposure to adverse environments referred to working night shifts or being exposed to noise during pregnancy, while exposure to harmful substances included exposure to dust, harmful gases, fumes, decoration odors, and hair perms during pregnancy.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analysis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStatistical analysis was carried out using SPSS version 23. Categorical variables were represented as frequencies and percentages,\u003c/p\u003e \u003cp\u003eand differences in characteristics between case and control participants were evaluated using the Chi-square test. To assess the association between CHD and ETS exposure, binary logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using both unadjusted and adjusted models. Covariates were selected for adjustment based on Chi-square tests with p-values less than 0.1. These covariates included maternal age at enrollment, maternal residence, maternal education level, parity, abortion history, maternal alcohol use during pregnancy, perinatal folic acid intake, exposure to harmful substances and adverse environments during pregnancy, and use of an air purifier during pregnancy.\u003c/p\u003e \u003cp\u003eRisks were reported as unadjusted and adjusted ORs with 95% CIs. All tests were two-sided, and p-values less than 0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the basic characteristics of the case and control participants. Compared to the control group, mothers of fetuses with CHD were more likely to be younger, reside in rural areas, be nulliparous, have completed fewer than 12 years of school, and have used air purifiers during pregnancy. Mothers who reported perinatal folic acid intake and had no history of miscarriage were less likely to have offspring with CHD than case mothers. Mothers who consumed alcohol or were exposed to harmful substances or adverse environments during pregnancy were more likely to have offspring with CHD than controls. However, there was no significant difference between the case and control groups with regard to paternal education level.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe Maternal and Paternal Characteristics of Case and Control Participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase participants(N\u0026thinsp;=\u0026thinsp;116)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl participants(N\u0026thinsp;=\u0026thinsp;3744)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e48(41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1012(27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68(58.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2732(73.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal residence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e71(61.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1285(34.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eurban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45(38.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2459(65.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePaternal education level(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.943\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34(34.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1109(29.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e82 (70.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2635(70.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal leducation level(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52(44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1167(31.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64(55.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2577(68.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enulliparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52(1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emultiparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e105(90.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3692(98.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbortion history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43(37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1011(27.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73(62.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2733(73.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal alcohol use during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e60(1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e97(83.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3684(98.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolic acid intake during perinatal period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e84(72.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3715(99.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32(27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29(0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure to adverse environments during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e59(50.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1421(38.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e57(49.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2323(62.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure to harmful substances during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e69(59.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1813(48.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47(40.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1931(51.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUsing air purifiers during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55(47.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e855(22.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61(52.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2889(77.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003eChi-square test, N: number, \u003cem\u003eP\u003c/em\u003e: \u003cem\u003eP\u003c/em\u003e value\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the association between maternal passive smoking levels during pregnancy and CHD in offspring. Of the 3860 subjects, 469 pregnant women reported passive smoking during pregnancy, including 37 cases (31.9%) in the case group and 432 cases (11.5%) in the control group. Overall, a significantly increased risk of CHD in offspring was observed among mothers exposed to passive smoking compared to the No ETS group (AOR: 2.53; 95% CI: 1.50\u0026ndash;4.27). An association was found between mothers exposed to ETS for 2\u0026ndash;5 hours/week during pregnancy and offspring with CHD (AOR: 2.97; 95% CI: 1.42\u0026ndash;6.17). Compared to the No ETS group, mothers exposed to ETS for \u0026gt;\u0026thinsp;5 hours/week during pregnancy had an increased risk of CHD, with an adjusted OR (95% CI) of 3.19 (1.35\u0026ndash;7.50). However, no significant association was found between ETS exposure for \u0026gt;\u0026thinsp;1 hour/week and CHD (AOR: 1.68; 95% CI: 0.70\u0026ndash;4.05).\u003c/p\u003e \u003cp\u003eETS exposure rates during the first trimester, last trimester, and continuously throughout pregnancy were 12.9%, 12.1%, and 6.9%, respectively, in the case group, and 6.3%, 3.0%, and 2.2%, respectively, in the control group. When participants were categorized according to the stage of exposure, the first-trimester ETS group was more likely to have offspring with CHD compared to the No ETS group (AOR: 2.32; 95% CI: 1.17\u0026ndash;4.60), while a stronger association was observed for the continuous ETS group (AOR: 4.89; 95% CI: 1.96\u0026ndash;12.21). No significant association was found between last-trimester ETS exposure and CHD in offspring (AOR: 1.82; 95% CI: 0.73\u0026ndash;4.50).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLogistic regression analysis of the relationship between maternal ETS exposure during pregnancy and CHD in offspring\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase participants\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;116)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl participants\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3744)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eORs(95%CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCOR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAOR(95%CI)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal ETS exposure during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79(68.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3312(88.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00(Ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.00(Ref.)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37(31.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e432(11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.59(2.40,5.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.53(1.50,4.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration, hours/week\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79(68.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3312(82.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00(Ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.00(Ref.)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;2h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e202(5.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.70(1.48,4.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.68(0.70,4.05)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u0026thinsp;~\u0026thinsp;5h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e168(4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.00(1.60,5.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.97(1.42,6.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;5h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(10.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62(1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.11(4.21,15.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.19(1.35,7.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno ETS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e79(68.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3312(88.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.00(Ref.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.00(Ref.)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efirst trimester ETS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(12.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e234(6.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.05(1.77,5.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.32(1.17,4.60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elast trimester ETS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e114(3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.41(2.34,8.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.82(0.73,4.50)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003econtinuous ETS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e84(2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.99(1.87,8.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.89(1.96,12.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cem\u003ea\u003c/em\u003e \u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026gt;0.05, \u003csup\u003eb\u003c/sup\u003eORs were adjusted by the following convariates: maternal age at enrollment, maternal residence, maternal education level, parity, abortion history, maternal alcohol use during pregnancy, folic acid intake during the perinatal period, exposure to harmful substances and adverse environments during pregnancy, using air purifiers during pregnancy.\u003c/p\u003e \u003cp\u003eN: number; COR: crude odds ratio; AOR: adjusted odds ratio; CI: confidence interval.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results of subgroup analyses for risk estimates between maternal passive smoking during pregnancy and CHD in offspring. After controlling for confounding factors, a statistically significant association was observed between the Ever ETS group during pregnancy and offspring CHD in all subgroups. In each subgroup, except for exposure to adverse environments during pregnancy, a significant association was found, including maternal age over 30 years, residence in rural areas, completion of over 12 years of school, multiparity, no history of abortion, no history of alcohol consumption during pregnancy, folic acid intake during pregnancy, and use of an air purifier during pregnancy. However, the association was not statistically significant in the corresponding stratum. In the subgroup exposed to adverse environments during pregnancy, a statistically significant association was observed between maternal passive smoking during pregnancy and offspring CHD. Overall, the direction of the association between passive smoking during pregnancy and offspring CHD remained consistent across all subgroups, suggesting a stable relationship between these factors.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analysis of the relationship between maternal ETS exposure during pregnancy and CHD in offspring\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAOR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.80(0.29,2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.654\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.46(1.81,6.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal residence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003erural\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.55(2.80,11.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eurban\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.87(0.98,3.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal education level(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.90(0.85,4.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.66(1.29,5.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enulliparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.72(0.89,3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emultiparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.67(1.45,4.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbortion history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.37(0.02,67.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.718\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.10(1.64,5.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal alcohol use during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.66(0.06,7.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.72(1.59,4.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolic acid intake during the perinatal period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.99(1.14,3.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.67(0.04,12.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.785\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure to adverse environments during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.28(1.12,4.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.61(1.07,6.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure to harmful substances during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.17(0.62,2.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.633\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.98(1.86,13.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUsing air purifiers during pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.78(1.02,7.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.86(0.97,3.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAOR: adjusted odds ratio; CI: confidence interval.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, after adjusting for potential confounders, we observed that maternal ETS exposure during pregnancy may increase the risk of CHD in offspring in a dose-response manner. We also found that maternal ETS exposure only during the first trimester increased the risk of CHD, while continuous maternal ETS exposure throughout pregnancy was associated with an even stronger increase in CHD risk.\u003c/p\u003e\n\u003cp\u003eOur findings are consistent with previous studies \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. Tobacco smoke contains numerous chemical carcinogens, including nicotine, carbon monoxide, polycyclic aromatic hydrocarbons, and carbonyls. Nicotine and carbon monoxide can rapidly cross the placenta and interfere with fetal cardiac development \u003csup\u003e[21\u003c/sup\u003e. Furthermore, passive smoking can expose individuals to elevated concentrations of harmful substances, potentially even higher than those associated with active smoking \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Both spermatozoa and oocytes can be vulnerable to DNA damage due to exposure to tobacco smoke \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. There is growing evidence that maternal smoking before and after pregnancy, as well as passive smoking, can increase the risk of miscarriage, stillbirth, low birth weight, childhood asthma, and offspring CHD \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. A recent meta-analysis of nearly 140,000 CHD cases reported positive associations between maternal cigarette smoking and the risk of CHD in offspring, with an increased risk of 25% for active smoking and 124% for passive smoking \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e .Our study provides further evidence of the dose-response relationship between maternal ETS exposure during pregnancy and CHD in offspring. Previous studies have also identified a dose-dependent relationship between maternal passive smoking and the risk of CHD \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. For example, Li et al. found that the association between CHD risk and maternal passive smoking was significantly stronger in the high hair nicotine concentration (HNC) group compared to the low HNC group \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn our study, we found that maternal exposure to ETS only during the first trimester or continuously throughout pregnancy was associated with an increased risk of CHD in offspring. However, no such association was observed for maternal ETS exposure only during the last trimester of pregnancy. Similarly, a National Birth Defect Prevention Study found a modest positive association between maternal exposure to secondhand smoke during early pregnancy and certain CHD subtypes\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e .The first trimester is a critical period for fetal heart development and malformation, during which the placental barrier is not fully impermeable to environmentally harmful chemical contaminants, potentially leading to cardiovascular abnormalities. Most CHDs occur in fetuses between 2 and 9 weeks of gestation, but many women are unaware of their pregnancy during this period \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Avoiding smoking or tobacco exposure early in pregnancy can improve fetal and newborn health outcomes.\u003c/p\u003e\n\u003cp\u003eOur findings indicate that fetuses exposed to maternal ETS during pregnancy have a significantly increased risk of CHD, highlighting the importance of preventing smoking among women of childbearing age before or during early pregnancy. This is particularly important in China, where smoking rates during pregnancy are significantly lower than in the United States or Europe \u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Current guidelines focus on quitting smoking rather than reducing it [38], which may deter women who find it difficult to quit\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Adequate information should be provided to these women about not only the risks of continuing to smoke but also the benefits of reducing smoking. Additionally, as early pregnancy is a critical period for fetal heart growth and development, exposure to smoke should be minimized during this time.\u003c/p\u003e\n\u003cp\u003eThe main strength of our study is its design. Our subjects in the nested case-control study and the control group come from the same cohort, which is more representative of the source population of the population study, and can better control selection bias and better comparability.\u003c/p\u003e\n\u003cp\u003eAdditionally, the time sequence is from the past to the present, and the time sequence of causal inference is clear, which can better control the recall bias. Furthermore, Compared with the traditional cohort study, thisl study does not need to detect the biological samples of all members of the cohort, which is more time-saving and labor-saving than the cohort study.\u003c/p\u003e\n\u003cp\u003eHowever, our study also has some limitations. Information on ETS exposure was self-reported, and the intensity of exposure was not accurately known. We also excluded many cases due to missing information, which may have introduced bias. Finally, we were unable to analyze the association between ETS exposure and specific CHD subtypes due to the small number of cases in the case group.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study provides prospective evidence that maternal ETS exposure during pregnancy may increase the risk of CHD in offspring in a dose-response manner. Maternal ETS exposure during the first trimester or continuously throughout pregnancy also increases the risk of CHD. These findings highlight the importance of preconception planning and prevention, including folic acid supplementation, avoidance of ETS exposure at home or in the workplace, and avoidance of toxic and harmful environments to reduce the risk of CHD and other adverse outcomes in offspring. Preventive strategies to reduce the occurrence of major CHDs are necessary for pregnant women exposed to ETS in the presence of other risk factors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eETS, environmental tobacco smoke; CHD, congenital heart defect; AOR, adjusted odds ratio.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors decare no conficts of interest statement.\u003c/p\u003e\n\u003ch2\u003eFundings\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Key R\u0026amp;D Program of China[2019YFC0840703], the Project of Chengdu Municipal Health Commission [2022222].\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA-G wrote the main manuscript text. All authors reviewed the manuscript.\"\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003ehttp://www.gov.cn/gzdt/2012-09/12/content_2223371.htm\u003c/li\u003e\n \u003cli\u003eAzhar M, Ware SM. 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J Glob Health. 2022;12:11009.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"environmental tobacco smoke, congenital heart defect, a case-control study.","lastPublishedDoi":"10.21203/rs.3.rs-5357930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5357930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStudies on the association between maternal environmental tobacco smoke (ETS) exposure during pregnancy and congenital heart defects (CHD) in offspring are limited. In this case-control study, we collected data from 116 fetuses with CHD and 3744 fetuses without any congenital anomalies to examine the association between maternal ETS exposure during different weeks of pregnancy and the duration of exposure with offspring CHD. Our results showed that maternal ETS exposure during pregnancy was associated with an increased risk of CHD in a dose-response gradient. The adjusted odds ratios (AOR) and corresponding 95% confidence intervals (CIs) were 2.97(1.42, 6.17) and 3.19(1.35, 7.50) for ETS exposure of 2-5h/week and \u0026gt;5h/week, respectively. Compared to the unexposed group, the AORs for maternal ETS exposure only in the first trimester and continuous exposure throughout pregnancy were 2.32 and 4.89, respectively. Our findings suggest that maternal ETS exposure during pregnancy may increase the risk of offspring CHD in a dose-response manner, and that ETS exposure during different weeks of pregnancy is associated with an increased risk of CHD among non-smoking pregnant women. These results highlight the importance of preventing ETS exposure throughout pregnancy, particularly during the early stages.\u003c/p\u003e","manuscriptTitle":"Maternal Environmental Tobacco Smoke Exposure During Pregnancy and the Risk of Congenital Heart Defects: a Case-control Study in Sichuan, China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 22:23:28","doi":"10.21203/rs.3.rs-5357930/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9e1f044f-d73e-4bc6-9c32-44ae177b5e65","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-02T22:23:41+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-02 22:23:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5357930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5357930","identity":"rs-5357930","version":["v1"]},"buildId":"CiT4i_kKBbxQbnFL0ufpk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}