Associated Maternal and Fetal Factors of Fetal Congenital Heart Diseases Diagnosed by Fetal Echocardiography

Associated Maternal and Fetal Factors of Fetal Congenital Heart Diseases Diagnosed by Fetal Echocardiography | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Associated Maternal and Fetal Factors of Fetal Congenital Heart Diseases Diagnosed by Fetal Echocardiography Yanping Ruan, Zan Xie, Xiaowei Liu, Yihua He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1408405/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jan, 2023 Read the published version in BMC Cardiovascular Disorders → Version 2 posted 10 You are reading this latest preprint version Show more versions Abstract Objective Current studies have suggested that fetal congenital heart diseases (CHDs) are caused by various factors. However, few data is available with respect to the aspect in China. This study aimed to detect associated maternal and fetal factors of fetal CHD in a large sample in China. Study Design: Pregnant women who underwent fetal echocardiography (N = 5024) were recruited in our hospital between May 2018 and September 2019. Of these, 875 pregnant women had fetuses with CHD. The maternal sociodemographic and lifestyle characteristics and some fetal factors were obtained. We used forward stepwise logistic regression analysis to assess the associations of fetal CHD with various factors. Results Among the fetal CHD group (N = 875), critical CHDs account for 27%, of which Tetralogy of Fallot is the most (7.1%), followed by coarctation of aorta (4.0%), Double-outlet right ventricle (2.9%). The forward stepwise logistic regression models revealed that gravidity (OR = 1.32, 95%CI 1.21–1.43, P = 0.000), upper respiratory tract infection during early pregnancy (OR = 1.30, 95%CI 1.04–1.63, P = 0.021), mental stress during early pregnancy (OR = 2.87, 95%CI 1.35–5.92, P = 0.006), single umbilical artery (OR = 2.46, 95%CI 1.24–4.85, P = 0.010), and parental smoking (OR = 1.20, 95%CI 1.00-1.45, P = 0.048) are positively associated with an increased risk of fetal CHD. Conclusion We identified two maternal factors and two fetal factors positively associated with fetal CHD.. These findings suggest that it is important to strengthen healthcare and prenatal counseling for women with these factors. Congenital heart diseases fetal Odd ratio Factor Introduction Congenital heart disease (CHD) results from a defect in the structure and function of the heart caused by abnormal heart development during the fetal period. CHD is a large, rapidly emerging global problem in child health; in the Global, regional, and national burden of CHD Study 2017, the global prevalence of CHD is estimated to be nearly 1.8‰ [ 1 ]. In China, the prevalence of CHD is 8.98 per 1000 live births [ 2 ], significantly higher than global level, definitely with much higher disease burden of CHD. It is also one of the leading causes of morbidity and mortality in the perinatal and infant periods [ 3 , 4 ]. As for fetal CHD, the prevalence cannot be reasonably estimated due to prenatal detection rates and intrauterine loss. Current research has shown that many factors are associated with an increased risk of CHD in the fetus, including genetic [ 5 ] and maternal or fetal factors, both of which are addressed for their associations with various risks in the Scientific Statement from the American Heart Association (AHA) [ 6 ]. However, available information about the association of maternal and fetal factors with CHD is limited in China, especially for fetal CHD. Therefore, this study is conducted to assess the factors that influence fetal CHD in a large sample size in China. Materials And Methods Study design and participants Our study was a retrospective population-based study of 5024 pregnant women who underwent fetal echocardiography from May 2018 to September 2019 at our center. All data are kept in our center's maternal-fetal medicine database. Fetal ages were calculated from the last menstrual period. Enrollment criteria included (1) relatively complete data, and (2) a fetal heart examination and diagnosis of fetal CHD meeting the specifications for the diagnosis and treatment of fetal cardiac disease released by AHA[ 6 ]. The exclusion criteria were including duplicate cases, subjects with more than 50% missing variables, variables with more than 50% missing data, and variables with only one assignment in the population, such as administration of angiotensin-converting enzyme inhibitors (ACEI), retinoic acid, lithium, anticonvulsants or selective serotonin reuptake inhibitors, and history of consanguinuous marriage. This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (2022060X), and written informed consent was signed by all participants. Data collection We acquired the following information through questionnaires while patients were waiting to be examined: (1) maternal sociodemographic and lifestyle characteristics: including age, comorbidities (diabetes, upper respiratory infection during early pregnancy, anemia, connective tissue diseases with anti-SSA/SSB positive and thyroid disease), mental stress during early pregnancy, medication exposure, history of CHD, consanguineous marriage, employment and bad habits of subjects and spouses, occupational radiation exposure, pet-keeping and indoor decoration. Early pregnancy usually refers to the first trimester of pregnancy. (2) pregnancy-related characteristics: including the gravidity, history of induced labor or spontaneous abortion, fertilization way, progesterone use and genetic testing of this pregnancy, and gestational weeks (GWs), (3)fetal factors, including single or twin fetuses, fetal hydrops, single umbilical artery (SUA), persistent right umbilical vein (PRUV), and results of fetal echocardiography. Anemia was defined as hemoglobin (g/dL) and hematocrit (percentage) levels below 11 g/dL and 33%, respectively, in the first trimester; 10.5 g/dL and 32%, respectively, in the second trimester; and 11 g/dL and 33%, respectively, in the third trimester [ 7 ]. Smokers were defined as smoking (≥ 10 cigarettes/d) and passive smoking status of pregnant women from the first 3 months before pregnancy to the first 3 months of pregnancy (with spouse’s smoking ≥ 10 cigarettes/d). Drinkers were defined as alcohol consumption of 3 drinks/week or 1 drink/d for 6 months prior to pregnancy for spouses or /and during pregnancy for pregnant women, and 1 drink was equivalent to 12g alcohol. Diagnosis of Fetal CHD The outcome variables were any form of fetal CHD. The diagnosis of fetal CHD was based on fetal echocardiography using a Voluson E8-RAB4-8 machine equipped with a 2- to 8-MHz transducer (GE Healthcare, Little Chalfont, United Kingdom). The acquisition of fetal echocardiographic images was performed according to the guidelines and standards of the AHA [ 6 ] and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) [ 8 ]. Fetal echocardiography was performed by experienced associate chief physicians and chief physicians, and diagnoses were then made by these individuals based on grayscale and color images and pulse wave Doppler according to multiple section screening, including four-chamber, left and right ventricular outflow tract (LVOT and RVOT), three-vessel (3V), and three vessels and trachea (3VT) views as well as sagittal views of the superior and inferior vena cavae, aortic arch, and ductal arch. In our center, we have been confirmed the diagnostic accuracy of fetal echocardiography by comparing with autopsy findings. The major cardiovascular malformations in about 98.8% of cases were accurately diagnosed by fetal echocardiography [ 9 ]. Statistical analysis Continuous variables with a Gaussian distribution are expressed as the mean ± standard deviation and were compared using a t-test between the two groups, while non-Gaussian variables are expressed as the median (interquartile range, IQR) and were compared using a non-parameter test between the groups. Noncontinuous variables are expressed as percentages (%). Chi-square tests were performed to compare the variables between the two groups. Multivariate logistic regression analyses using forward stepwise (likelihood ratio) were performed to evaluate the factors independently associated with the outcome variables. The independent variables included the maternal and fetal factors mentioned above. The odd ratio (OR) and 95% confidence interval (CI) were used to express the magnitude of the association between outcome and risk factors. Statistical significance was achieved with a two-tailed value of P < 0.05. The Statistical Package for Social Science, version 22 for Windows (SPSS22.0) was used for statistical analyses. Results Baseline characteristics in the normal group and the fetal CHD group Among all the participants, 875 pregnant women had fetal CHD fetuses, while 4149 women had normal fetuses. The mean age for the pregnant women and their spouses in the CHD group was 30.36, 31.79 years old, younger than that in the normal group, 31.03 or 32.65 years old, respectively (all P < 0.05). The gestational ages for both groups were about 26 weeks. The subjects in CHD group had more pregnancies than the normal group (all P < 0.05). The proportion of spontaneous abortion, induced labor, childbirth, progesterone use, upper respiratory tract infection in early pregnancy, mental stress during pregnancy, and spouse’s current smoking and drinking was higher in the CHD group than in the control group(all P < 0.05). In addition, CHD group had a higher rate of fetal hydrops and amniotic fluid abnormality than the control group (all P < 0.05) (Table 1 ). Table 1 Baseline characteristics of the normal group and the fetal CHD group Variables Normal group CHD group P-value N 4149 875 Age 31.03 (4.25) 30.36 (4.27) < 0.001 Gestational Weeks 26.08 (2.82) 26.77 (3.82) < 0.001 Parental age 32.65 (5.07) 31.79 (4.79) < 0.001 Gravidity 2.00 (1.00–2.00) 2.00 (1.00–3.00) 0.031 Spontaneous abortion < 0.001 No 2810 (70.51%) 533 (63.00%) Yes 1175 (29.49%) 313 (37.00%) Induced labor 0.003 No 3848 (98.46%) 795 (96.95%) Yes 60 (1.54%) 25 (3.05%) Delivery history 0.002 No 2775 (70.38%) 542 (64.83%) Yes 1168 (29.62%) 294 (35.17%) Fertilization way 0.735 Natural conception 3829 (95.87%) 818 (96.12%) In-Vitro Fertilization 165 (4.13%) 33 (3.88%) Progesterone use 0.026 No 3248 (83.30%) 664 (80.10%) Yes 651 (16.70%) 165 (19.90%) Down's or noninvasive DNA testing 0.419 Low risk 3219 (95.69%) 685 (95.01%) High risk 145 (4.31%) 36 (4.99%) Anemia 0.76 No 4129 (99.61%) 870 (99.54%) Yes 16 (0.39%) 4 (0.46%) Thyroid disorders 0.437 No 4113 (99.13%) 865 (98.86%) Yes 36 (0.87%) 10 (1.14%) Upper respiratory tract infection in early pregnancy < 0.001 No 3540 (85.32%) 707 (80.80%) Yes 609 (14.68%) 168 (19.20%) Autoimmune disease 0.603 No 4108 (99.01%) 868 (99.20%) Yes 41 (0.99%) 7 (0.80%) Diabetes mellitus 0.886 No 4104 (98.92%) 865 (98.97%) Yes 45 (1.08%) 9 (1.03%) Nonsteroidal anti-inflammatory drugs 0.925 No 4129 (99.57%) 871 (99.54%) Yes 18 (0.43%) 4 (0.46%) Vitamin K–antagonist 0.961 No 4140 (99.88%) 874 (99.89%) Yes 5 (0.12%) 1 (0.11%) Maternal smoking 0.987 No 4138 (99.78%) 873 (99.77%) Former smokers 5 (0.12%) 1 (0.11%) Current smokers 4 (0.10%) 1 (0.11%) Maternal drinking 0.087 No 4139 (99.83%) 873 (99.77%) Former drinkers 7 (0.17%) 1 (0.11%) Current drinkers 0 (0.00%) 1 (0.11%) Parental smoking 0.013 No 3897 (93.97%) 800 (91.43%) Former smokers 30 (0.72%) 12 (1.37%) Current smokers 220 (5.31%) 63 (7.20%) Parental drinking 0.031 No 3986 (96.12%) 824 (94.17%) Former drinkers 40 (0.96%) 14 (1.60%) Current drinkers 121 (2.92%) 37 (4.23%) Spouse's medication use during preparation for pregnancy 0.014 No 4102 (99.11%) 857 (98.17%) Yes 37 (0.89%) 16 (1.83%) Mental stress during early pregnancy < 0.001 No 4120 (99.32%) 858 (98.17%) Yes 28 (0.68%) 16 (1.83%) Occupational radiation exposure 0.099 No 4132 (99.61%) 868 (99.20%) Yes 16 (0.39%) 7 (0.80%) Family history of CHD 0.828 No 4140 (99.81%) 872 (99.77%) Yes 8 (0.19%) 2 (0.23%) Multifetation 0.238 No 4060 (97.90%) 851 (97.26%) Yes 87 (2.10%) 24 (2.74%) Fetal hydrops < 0.001 No 4135 (99.81%) 867 (99.09%) Yes 8 (0.19%) 8 (0.91%) amniotic fluid volume 0.009 Normal 4103 (99.37%) 860 (98.51%) Abnormal 26 (0.63%) 13 (1.49%) Pet-keeping 0.608 No 3974 (95.85%) 842 (96.23%) Yes 172 (4.15%) 33 (3.77%) Indoor decoration during pregnancy 0.147 No 4130 (99.81%) 871 (99.54%) Yes 8 (0.19%) 4 (0.46%) Single umbilical artery 0.108 No 4112 (99.11%) 862 (98.51%) Yes 37 (0.89%) 13 (1.49%) Persistent right umbilical vein 0.41 No 4114 (99.16%) 870 (99.43%) Yes 35 (0.84%) 5 (0.57%) CHD: congenital heart disease Different types of fetal CHD in the case group Among the cases of fetal CHD, the top three types are congenital anomaly of a ventricle or the ventricular septum, ventriculo-arterial connection and the great arteries, including the arterial duct. In addition, critical CHDs account for 27%, of which Tetralogy of Fallot is the most (7.1%), followed by coarctation of aorta (4.0%), Double-outlet right ventricle (2.9%), D-transposition of the great arteries (2.5%), and Pulmonary atresia with intact septum (2.1%) (Table 2 ). Table 2 Different types of fetal critical CHD in the case group Types of fetal CHD N(%) Overall CHD 875(100%) Critical CHDs 236(27.0%) Tetralogy of Fallot 62(7.1%) Coarctation of the aorta 35(4.0%) Double-outlet right ventricle 25(2.9%) D-transposition of the great arteries 22(2.5%) Pulmonary atresia with intact septum 18(2.1%) Single ventricle 16(1.8%) Total anomalous pulmonary venous connection 15(1.7%) Hypoplastic left heart syndrome 11(1.3%) Interrupted aortic arch 11(1.3%) Truncus arteriosus 9(1.0%) Ebstein anomaly 8(0.9%) Tricuspid atresia 4(0.5%) CHD: congenital heart disease Logistic regression analysis of factors related to fetal congenital heart disease Forward stepwise regression analysis has shown that there are several factors positively related to the increased risk of fetal heart disease, namely gravidity (OR = 1.32, 95%CI 1.21–1.43, P = 0.000), upper respiratory tract infection during early pregnancy (OR = 1.30, 95%CI 1.04–1.63, P = 0.021), mental stress during early pregnancy (OR = 2.87, 95%CI 1.35–5.92, P = 0.006), single umbilical artery (OR = 2.46, 95%CI 1.24–4.85, P = 0.010), and spouse smoking (OR = 1.20, 95%CI 1.00-1.45, P = 0.048)(Table 3 ). Table 3 Logistic regression analysis of factors related to fetal congenital heart disease Variables B SE Wald OR 95% CI P-value Lower Upper Gravidity 0.274 0.043 40.164 1.315 1.208 1.432 0.000 Upper respiratory tract infection in early pregnancy 0.263 0.114 5.342 1.301 1.041 1.626 0.021 Mental stress during early pregnancy 1.039 0.377 7.604 2.827 1.351 5.918 0.006 Spouse smoking 0.186 0.094 3.905 1.204 1.002 1.447 0.048 Fetal single umbilical artery 0.898 0.347 6.684 2.455 1.243 4.851 0.010 Constant -0.411 0.326 1.586 0.663 - - 0.208 Discussions This cross-sectional study analyzes factors related to fetal CHD based on our maternal-fetal database, with 875 cases of CHD fetuses among 5024 subjects from May 2018 to September 2019. The results of this research have revealed that there are several factors independently associated with an increased risk of fetal CHD, including gravidity, upper respiratory tract infection during early pregnancy, mental stress during early pregnancy, parental smoking, and fetal single umbilical artery. Among them, mental stress of pregnant women during pregnancy is associated with higher risk of CHD, followed by fetal single umbilical artery and gravidity. Mental stress and upper respiratory tract infection during pregnancy are common maternal comorbidities associated with fetal CHD, which has also been reported in previous studies. One of the studies was from Shandong, China, which pointed out several environmental risk factors related to CHD, including maternal upper respiratory tract infection (OR = 4.12) and maternal mental stress (OR = 3.93) during early pregnancy, as well as number of previous pregnancies (OR = 2.68) [ 10 ]. In 2019, another study has reported that these three factors can increase the risk of CHD by about 2 times using an artificial neural network prediction model [ 11 ]. In other research on the association between mental stress and CHD, the evaluation of mental stress is often based on several questions. However, the mental stress mentioned in this study is only derived from the self-experience of the respondents in the questionnaire, so it is not clear to define the degree of mental stress experienced by pregnant women. Although the role of maternal stress needs to be validated by additional studies, and the biological mechanisms by which maternal stress causes CHD are not clear, we strongly suggest that psychological management for pregnant women be strengthened, especially during early pregnancy. As for maternal viral infection, we first talk about another study, which provide new enforced evidence that maternal upper respiratory tract infection/influenza during early pregnancy, in general, play an important role in the occurrence of CHD [ 12 ]. In addition, there is a meta-analysis [ 13 ] of maternal viral infection and increased risk of fetal CHD, which suggested that mothers who had a history of viral infection in early pregnancy had a significantly higher risk of having offspring with CHD (RR = 2.28), and this risk was more significant in mothers with rubella and cytomegalovirus. The effect of nonspecific maternal infection is difficult to definitively separate from the effects of medications used to treat the illness, including maternal fever and infection. Jenkins et al reported an up to 1.9-fold increase in the risk of aggregate cardiac defects in patients with maternal febrile illness and a 1.1-fold increase in the rate of any heart defects among subjects with maternal influenza infection in early pregnancy[ 14 ]. The results of these studies are consistent with ours. However, the viruses were not classified in detail in our study. Regarding the number of pregnancy related to the increased risk of fetal CHD, although the exact mechanism is unknown, it might be related to spontaneous abortion. China has opened the second child policy in 2016. Before that, multiparity has been limited. However, the causal relationship between spontaneous abortion and CHD could not be inferred according to current knowledge, and these results only indicate that a history of miscarriage is a predictor of having an infant born with CHD or an increased risk of tetralogy of Fallot [ 15 ]. In any case, these findings suggest that the management of obstetric healthcare and counseling for women with a history of miscarriages should be strengthened to reduce the incidence of CHD. The correlation between paternal smoking and congenital cardiovascular defects has been studied, but too little information is available to determine the associated risk. Of the many congenital defects observed in a nursery, there was a significantly higher incidence of cardiovascular system abnormalities in the tobacco-exposed group [ 16 ]. A case-control study [ 17 ] suggested that there is an association between periconceptional tobacco exposure and an increased risk of CHD during the neonatal period and that there may be a dose effect; however, this needs to be confirmed in a larger population. Unfortunately, in our study, we were not able to verify this dose-effect relationship, although our results do suggest that paternal smoking is a risk factor for CHD. The potential mechanisms underlying the teratogenicity associated with periconceptional tobacco exposure remain unclear. One possible reason is that nicotine and carbon monoxide damage placental functions, leading to fetal hypoxia [ 18 , 19 ]. The association between maternal diabetes and an increased risk of CHD has been clearly described in many studies [ 6 , 20 , 21 ]. However, no similar finding was achieved in our research. This may be because of selection bias in the population recruited in our center because many pregnant women with diabetes are referred to our center from local hospitals for fetal echocardiography, and most of these fetuses are normal, resulting in a nonrandomly selected population. This could further affect our conclusions. With regard for fetal factors, we found that there was a correlation between single umbilical artery and fetal CHD. Single umbilical artery is one of the most common human umbilical malformations, with an incidence of 0.55–4.85% [ 22 ], while the proportion in our population is 1%. Previous studies have demonstrated an increased prevalence of CHD in fetuses with an single umbilical artery in the presence of additional risk factors for CHD[ 23 , 24 ]. All these results have suggested the indication of fetal echocardiography for the fetuses with single umbilical artery. Compared with existing research, our conclusions are consistent with it, but the sample size of our study is much larger than that of related studies. There are several advantages and limitations in this study. We analyzed factors related to fetal CHD for the first time with such a complete and huge database in China. The large sample size makes the conclusions of this study more stable and more convincing. We did consider as many factors as possible with CHD. As is known to us that CHD is a multifactorial complex disease, but we have to admit that we have not refined the assessment of the interactions between the various factors and also failed to take into account all the factors that cause CHD. Another strength of the study is the fact that we examine fetal CHD as opposed to only live births and thus would capture pregnancies who would go on to have intrauterine demise or termination that would not be captured in a neonatal/live birth registry. We acknowledge that although it was based on a large population, the data were mainly obtained from self-reported questionnaires, and the accuracy of information collection is therefore a problem that needs to be considered. Moreover, this is a cross-sectional study that demonstrates only the correlations between these factors and fetal CHD but does not provide causal relationships. One additional limitation is that our center is a referral center for fetal heart disease. The fetuses referred to our center come from all over the country. Therefore, some of the patients coming to our center are pregnant women with known risk factors or with a fetus previously found to have CHD at a local hospital, and this may have led to selection bias in the population. In addition, fetal CHD was diagnosed by fetal echocardiography and we didn't make postnatal verification for every case. But our findings can be credible, because fetal echocardiographic diagnoses were mostly consistent with autopsy findings in our center, which has shown that fetal cardiovascular anomalies disclosed by FE were completely in line with autopsy findings in nearly 99% of cases[ 9 ]. A final limitation may be that the relationships between genetic factors and fetal CHD were not considered in this study, which is solely focused on clinical characteristics. Considering the above factors, our findings should be interpreted cautiously and may not be generalizable to all patients. In conclusion, we have found that there were several factors independently associated with fetal CHD, including gravidity, upper respiratory tract infection and mental stress during early pregnancy, parental smoking and fetal single umbilical artery. Thus, the CHD risk can be alleviated by reducing the exposure to environmental risk factors. Augmenting maternal mental healthcare, obtaining regular health counseling and testing during pregnancy, preventing upper respiratory tract infections and mental stress, offering health promotion and health education to women of childbearing age (especially those with less formal education), and improving obstetric procedures and techniques may lower the occurrence of CHD. Abbreviations CHD Congenital heart disease AHA American Heart Association GW gestational weeks ISUOG International Society of Ultrasound in Obstetrics and Gynecology LVOT left ventricular outflow tract RVOT right ventricular outflow tract IQR interquartile range OR odd ratio CI confidence interval Declarations Acknowledgement Not applicable. Authors ’ contributions YH supervised the study and performed statistical analysis of the data. YR was conceived the study and wrote the main body of the manuscript. ZX participated in the discussion on the interpretation of the research content and involved in the procedure. XL revised the paper. All authors read and approved the final manuscript. Funding The work was supported by National Key R&D Program of China (2018YFC1002300) and Yantai Science and Technology Innovation Development Project (2021YD018). Availability of data and materials The datasets used during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate All participants provided written consent before entering the study. The study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University，with the ethical Approval Number: 2022060X. We can confirm that all methods for the acquisition of fetal echocardiographic images was performed according to the guidelines and standards of the AHA [6] and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) [8]. Consent for publication Not applicable. Competing interests All authors declare that they have no competing interests. References GBD 2017 Congenital Heart Disease Collaborators.Global, regional, and national burden of congenital heart disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Child Adolesc Health. 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Cite Share Download PDF Status: Published Journal Publication published 27 Jan, 2023 Read the published version in BMC Cardiovascular Disorders → Version 2 posted Editorial decision: Major revision 24 Aug, 2022 Reviewers agreed at journal 06 Aug, 2022 Reviewers agreed at journal 16 May, 2022 Reviews received at journal 25 Apr, 2022 Reviewers agreed at journal 19 Apr, 2022 Reviewers invited by journal 06 Apr, 2022 Editor assigned by journal 06 Apr, 2022 Editor invited by journal 06 Apr, 2022 Submission checks completed at journal 06 Apr, 2022 First submitted to journal 17 Mar, 2022 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-1408405","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[{"code":1,"date":"2022-03-07 23:51:06","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}}],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":99463898,"identity":"b004170a-8f15-4f74-9bfb-d458fbfff8ab","order_by":0,"name":"Yanping Ruan","email":"","orcid":"","institution":"Department of Ultrasound, Maternal-fetal Medicine Research Consultation Center, Beijing Anzhen Hospital, Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yanping","middleName":"","lastName":"Ruan","suffix":""},{"id":99463899,"identity":"10297a0e-6f95-4024-a9bc-6727b0e580b9","order_by":1,"name":"Zan Xie","email":"","orcid":"","institution":"the Affiliated Yantai Yuhuangding Hospital of Qingdao University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zan","middleName":"","lastName":"Xie","suffix":""},{"id":99463900,"identity":"6bc78ccc-da26-4ef7-9cd9-06e35b963a53","order_by":2,"name":"Xiaowei Liu","email":"","orcid":"","institution":"Department of Ultrasound, Maternal-fetal Medicine Research Consultation Center, Beijing Anzhen Hospital, Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaowei","middleName":"","lastName":"Liu","suffix":""},{"id":99463901,"identity":"7039f3e0-0214-44dd-9416-4b2255dc6e09","order_by":3,"name":"Yihua He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBACAyA+DGZJMDA+BjOYmRuI1sJsDOYzMxLWwgzVwiYN4RPQYs7eY3i4sM1Ojn9287Hqgoo/0fztQC0/Krbh1GLZc8bg8My2ZGOJO8fSbs84Y5A74zBjA2PPmdu4HXYjx+Awbxtz4gaJHLPbvG0GuQ1ALcyMbXi03H8D0lJfD9JSDNIyn6CWGzwgLYcTDIBamEFaNhDUciat4DDPueOGM26kJUvznDHO3QjUchCvX44f3vyZp6xann9G8sHPPBVyufPOHz744EcFbi0MDBwGmGIH8KgHAvYH+OVHwSgYBaNgFAAA90JZK8h1c40AAAAASUVORK5CYII=","orcid":"","institution":"Department of Ultrasound, Maternal-fetal Medicine Research Consultation Center, Beijing Anzhen Hospital, Capital Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yihua","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2022-03-01 14:29:02","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-1408405/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-1408405/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12872-022-02981-3","type":"published","date":"2023-01-27T18:32:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44717848,"identity":"a7e75163-576a-4c20-925e-90f513182559","added_by":"auto","created_at":"2023-10-16 18:40:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":380400,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1408405/v2/61e1ef7f-1be6-4077-b2ac-5084a82577ad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Associated Maternal and Fetal Factors of Fetal Congenital Heart Diseases Diagnosed by Fetal Echocardiography","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCongenital heart disease (CHD) results from a defect in the structure and function of the heart caused by abnormal heart development during the fetal period. CHD is a large, rapidly emerging global problem in child health; in the Global, regional, and national burden of CHD Study 2017, the global prevalence of CHD is estimated to be nearly 1.8\u0026permil; [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In China, the prevalence of CHD is 8.98 per 1000 live births [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], significantly higher than global level, definitely with much higher disease burden of CHD. It is also one of the leading causes of morbidity and mortality in the perinatal and infant periods [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As for fetal CHD, the prevalence cannot be reasonably estimated due to prenatal detection rates and intrauterine loss.\u003c/p\u003e \u003cp\u003eCurrent research has shown that many factors are associated with an increased risk of CHD in the fetus, including genetic [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and maternal or fetal factors, both of which are addressed for their associations with various risks in the Scientific Statement from the American Heart Association (AHA) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, available information about the association of maternal and fetal factors with CHD is limited in China, especially for fetal CHD. Therefore, this study is conducted to assess the factors that influence fetal CHD in a large sample size in China.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eOur study was a retrospective population-based study of 5024 pregnant women who underwent fetal echocardiography from May 2018 to September 2019 at our center. All data are kept in our center's maternal-fetal medicine database. Fetal ages were calculated from the last menstrual period. Enrollment criteria included (1) relatively complete data, and (2) a fetal heart examination and diagnosis of fetal CHD meeting the specifications for the diagnosis and treatment of fetal cardiac disease released by AHA[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The exclusion criteria were including duplicate cases, subjects with more than 50% missing variables, variables with more than 50% missing data, and variables with only one assignment in the population, such as administration of angiotensin-converting enzyme inhibitors (ACEI), retinoic acid, lithium, anticonvulsants or selective serotonin reuptake inhibitors, and history of consanguinuous marriage. This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (2022060X), and written informed consent was signed by all participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eWe acquired the following information through questionnaires while patients were waiting to be examined: (1) maternal sociodemographic and lifestyle characteristics: including age, comorbidities (diabetes, upper respiratory infection during early pregnancy, anemia, connective tissue diseases with anti-SSA/SSB positive and thyroid disease), mental stress during early pregnancy, medication exposure, history of CHD, consanguineous marriage, employment and bad habits of subjects and spouses, occupational radiation exposure, pet-keeping and indoor decoration. Early pregnancy usually refers to the first trimester of pregnancy. (2) pregnancy-related characteristics: including the gravidity, history of induced labor or spontaneous abortion, fertilization way, progesterone use and genetic testing of this pregnancy, and gestational weeks (GWs), (3)fetal factors, including single or twin fetuses, fetal hydrops, single umbilical artery (SUA), persistent right umbilical vein (PRUV), and results of fetal echocardiography. Anemia was defined as hemoglobin (g/dL) and hematocrit (percentage) levels below 11 g/dL and 33%, respectively, in the first trimester; 10.5 g/dL and 32%, respectively, in the second trimester; and 11 g/dL and 33%, respectively, in the third trimester [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Smokers were defined as smoking (\u0026ge;\u0026thinsp;10 cigarettes/d) and passive smoking status of pregnant women from the first 3 months before pregnancy to the first 3 months of pregnancy (with spouse\u0026rsquo;s smoking\u0026thinsp;\u0026ge;\u0026thinsp;10 cigarettes/d). Drinkers were defined as alcohol consumption of 3 drinks/week or 1 drink/d for 6 months prior to pregnancy for spouses or /and during pregnancy for pregnant women, and 1 drink was equivalent to 12g alcohol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDiagnosis of Fetal CHD\u003c/h2\u003e \u003cp\u003eThe outcome variables were any form of fetal CHD. The diagnosis of fetal CHD was based on fetal echocardiography using a Voluson E8-RAB4-8 machine equipped with a 2- to 8-MHz transducer (GE Healthcare, Little Chalfont, United Kingdom). The acquisition of fetal echocardiographic images was performed according to the guidelines and standards of the AHA [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFetal echocardiography was performed by experienced associate chief physicians and chief physicians, and diagnoses were then made by these individuals based on grayscale and color images and pulse wave Doppler according to multiple section screening, including four-chamber, left and right ventricular outflow tract (LVOT and RVOT), three-vessel (3V), and three vessels and trachea (3VT) views as well as sagittal views of the superior and inferior vena cavae, aortic arch, and ductal arch. In our center, we have been confirmed the diagnostic accuracy of fetal echocardiography by comparing with autopsy findings. The major cardiovascular malformations in about 98.8% of cases were accurately diagnosed by fetal echocardiography [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables with a Gaussian distribution are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and were compared using a t-test between the two groups, while non-Gaussian variables are expressed as the median (interquartile range, IQR) and were compared using a non-parameter test between the groups. Noncontinuous variables are expressed as percentages (%). Chi-square tests were performed to compare the variables between the two groups. Multivariate logistic regression analyses using forward stepwise (likelihood ratio) were performed to evaluate the factors independently associated with the outcome variables. The independent variables included the maternal and fetal factors mentioned above. The odd ratio (OR) and 95% confidence interval (CI) were used to express the magnitude of the association between outcome and risk factors. Statistical significance was achieved with a two-tailed value of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The Statistical Package for Social Science, version 22 for Windows (SPSS22.0) was used for statistical analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics in the normal group and the fetal CHD group\u003c/h2\u003e \u003cp\u003eAmong all the participants, 875 pregnant women had fetal CHD fetuses, while 4149 women had normal fetuses. The mean age for the pregnant women and their spouses in the CHD group was 30.36, 31.79 years old, younger than that in the normal group, 31.03 or 32.65 years old, respectively (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The gestational ages for both groups were about 26 weeks. The subjects in CHD group had more pregnancies than the normal group (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The proportion of spontaneous abortion, induced labor, childbirth, progesterone use, upper respiratory tract infection in early pregnancy, mental stress during pregnancy, and spouse\u0026rsquo;s current smoking and drinking was higher in the CHD group than in the control group(all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). In addition, CHD group had a higher rate of fetal hydrops and amniotic fluid abnormality than the control group (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eBaseline characteristics of the normal group and the fetal CHD group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" 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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCHD group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.03 (4.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.36 (4.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eGestational Weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.08 (2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.77 (3.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eParental age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.65 (5.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.79 (4.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eGravidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.00 (1.00\u0026ndash;2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.00 (1.00\u0026ndash;3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.031\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous abortion\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=\"char\" char=\".\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e2810 (70.51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e533 (63.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e1175 (29.49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e313 (37.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduced labor\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e3848 (98.46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e795 (96.95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (1.54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (3.05%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelivery 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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e2775 (70.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e542 (64.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e1168 (29.62%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e294 (35.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFertilization way\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.735\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNatural conception\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3829 (95.87%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e818 (96.12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn-Vitro Fertilization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e165 (4.13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (3.88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgesterone use\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.026\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e3248 (83.30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e664 (80.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e651 (16.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e165 (19.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDown's or noninvasive DNA testing\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3219 (95.69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e685 (95.01%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145 (4.31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (4.99%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.76\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4129 (99.61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e870 (99.54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (0.39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (0.46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid disorders\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.437\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4113 (99.13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e865 (98.86%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (0.87%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (1.14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper respiratory tract infection in early 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=\"char\" char=\".\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e3540 (85.32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e707 (80.80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e609 (14.68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e168 (19.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAutoimmune\u0026nbsp;disease\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.603\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4108 (99.01%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e868 (99.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (0.99%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (0.80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.886\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4104 (98.92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e865 (98.97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (1.08%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (1.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNonsteroidal anti-inflammatory drugs\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.925\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4129 (99.57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e871 (99.54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (0.43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (0.46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin\u0026nbsp;K\u0026ndash;antagonist\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.961\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4140 (99.88%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e874 (99.89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0.12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal smoking\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.987\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4138 (99.78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e873 (99.77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer smokers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (0.12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smokers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (0.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal drinking\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.087\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4139 (99.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e873 (99.77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer drinkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (0.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent drinkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParental smoking\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e3897 (93.97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e800 (91.43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer smokers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (0.72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (1.37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smokers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e220 (5.31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (7.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParental drinking\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.031\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e3986 (96.12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e824 (94.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer drinkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (0.96%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (1.60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent drinkers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e121 (2.92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (4.23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpouse's medication use during preparation for 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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.014\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4102 (99.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e857 (98.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (0.89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (1.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMental stress during early 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=\"char\" char=\".\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4120 (99.32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e858 (98.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (0.68%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (1.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOccupational radiation exposure\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.099\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4132 (99.61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e868 (99.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (0.39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (0.80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of CHD\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.828\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4140 (99.81%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e872 (99.77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (0.19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultifetation\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.238\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4060 (97.90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e851 (97.26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (2.10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (2.74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal hydrops\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=\"char\" char=\".\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4135 (99.81%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e867 (99.09%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (0.19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (0.91%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eamniotic fluid volume\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4103 (99.37%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e860 (98.51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (0.63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (1.49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePet-keeping\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.608\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e3974 (95.85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e842 (96.23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e172 (4.15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (3.77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndoor decoration 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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.147\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4130 (99.81%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e871 (99.54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (0.19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (0.46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle umbilical artery\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.108\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4112 (99.11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e862 (98.51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (0.89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (1.49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersistent right umbilical vein\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=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.41\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4114 (99.16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e870 (99.43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (0.84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (0.57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCHD: congenital heart disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eDifferent types of fetal CHD in the case group\u003c/h2\u003e \u003cp\u003eAmong the cases of fetal CHD, the top three types are congenital anomaly of a ventricle or the ventricular septum, ventriculo-arterial connection and the great arteries, including the arterial duct. In addition, critical CHDs account for 27%, of which Tetralogy of Fallot is the most (7.1%), followed by coarctation of aorta (4.0%), Double-outlet right ventricle (2.9%), D-transposition of the great arteries (2.5%), and Pulmonary atresia with intact septum (2.1%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003eDifferent types of fetal critical CHD in the case group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of fetal CHD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\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\u003eOverall CHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e875(100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCritical CHDs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e236(27.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTetralogy of Fallot\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62(7.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoarctation of the aorta\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35(4.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDouble-outlet right ventricle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(2.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD-transposition of the great arteries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22(2.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary atresia with intact septum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18(2.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle ventricle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(1.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal anomalous pulmonary venous connection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(1.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypoplastic left heart syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterrupted aortic arch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTruncus arteriosus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(1.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEbstein anomaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(0.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTricuspid atresia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(0.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eCHD: congenital heart disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eLogistic regression analysis of factors related to fetal congenital heart disease\u003c/h2\u003e \u003cp\u003eForward stepwise regression analysis has shown that there are several factors positively related to the increased risk of fetal heart disease, namely gravidity (OR\u0026thinsp;=\u0026thinsp;1.32, 95%CI 1.21\u0026ndash;1.43, P\u0026thinsp;=\u0026thinsp;0.000), upper respiratory tract infection during early pregnancy (OR\u0026thinsp;=\u0026thinsp;1.30, 95%CI 1.04\u0026ndash;1.63, P\u0026thinsp;=\u0026thinsp;0.021), mental stress during early pregnancy (OR\u0026thinsp;=\u0026thinsp;2.87, 95%CI 1.35\u0026ndash;5.92, P\u0026thinsp;=\u0026thinsp;0.006), single umbilical artery (OR\u0026thinsp;=\u0026thinsp;2.46, 95%CI 1.24\u0026ndash;4.85, P\u0026thinsp;=\u0026thinsp;0.010), and spouse smoking (OR\u0026thinsp;=\u0026thinsp;1.20, 95%CI 1.00-1.45, P\u0026thinsp;=\u0026thinsp;0.048)(Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\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\u003e\u003cb\u003eLogistic regression analysis of factors related to fetal congenital heart disease\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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 \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 \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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWald\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLower\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUpper\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGravidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper respiratory tract infection in early pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.626\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMental stress during early pregnancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.377\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.604\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.827\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.351\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.918\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpouse smoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.447\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFetal single umbilical artery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.898\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.347\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.455\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.326\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.586\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.663\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussions","content":"\u003cp\u003eThis cross-sectional study analyzes factors related to fetal CHD based on our maternal-fetal database, with 875 cases of CHD fetuses among 5024 subjects from May 2018 to September 2019. The results of this research have revealed that there are several factors independently associated with an increased risk of fetal CHD, including gravidity, upper respiratory tract infection during early pregnancy, mental stress during early pregnancy, parental smoking, and fetal single umbilical artery. Among them, mental stress of pregnant women during pregnancy is associated with higher risk of CHD, followed by fetal single umbilical artery and gravidity.\u003c/p\u003e \u003cp\u003eMental stress and upper respiratory tract infection during pregnancy are common maternal comorbidities associated with fetal CHD, which has also been reported in previous studies. One of the studies was from Shandong, China, which pointed out several environmental risk factors related to CHD, including maternal upper respiratory tract infection (OR\u0026thinsp;=\u0026thinsp;4.12) and maternal mental stress (OR\u0026thinsp;=\u0026thinsp;3.93) during early pregnancy, as well as number of previous pregnancies (OR\u0026thinsp;=\u0026thinsp;2.68) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In 2019, another study has reported that these three factors can increase the risk of CHD by about 2 times using an artificial neural network prediction model [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In other research on the association between mental stress and CHD, the evaluation of mental stress is often based on several questions. However, the mental stress mentioned in this study is only derived from the self-experience of the respondents in the questionnaire, so it is not clear to define the degree of mental stress experienced by pregnant women. Although the role of maternal stress needs to be validated by additional studies, and the biological mechanisms by which maternal stress causes CHD are not clear, we strongly suggest that psychological management for pregnant women be strengthened, especially during early pregnancy. As for maternal viral infection, we first talk about another study, which provide new enforced evidence that maternal upper respiratory tract infection/influenza during early pregnancy, in general, play an important role in the occurrence of CHD [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In addition, there is a meta-analysis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] of maternal viral infection and increased risk of fetal CHD, which suggested that mothers who had a history of viral infection in early pregnancy had a significantly higher risk of having offspring with CHD (RR\u0026thinsp;=\u0026thinsp;2.28), and this risk was more significant in mothers with rubella and cytomegalovirus. The effect of nonspecific maternal infection is difficult to definitively separate from the effects of medications used to treat the illness, including maternal fever and infection. Jenkins et al reported an up to 1.9-fold increase in the risk of aggregate cardiac defects in patients with maternal febrile illness and a 1.1-fold increase in the rate of any heart defects among subjects with maternal influenza infection in early pregnancy[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The results of these studies are consistent with ours. However, the viruses were not classified in detail in our study.\u003c/p\u003e \u003cp\u003eRegarding the number of pregnancy related to the increased risk of fetal CHD, although the exact mechanism is unknown, it might be related to spontaneous abortion. China has opened the second child policy in 2016. Before that, multiparity has been limited. However, the causal relationship between spontaneous abortion and CHD could not be inferred according to current knowledge, and these results only indicate that a history of miscarriage is a predictor of having an infant born with CHD or an increased risk of tetralogy of Fallot [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In any case, these findings suggest that the management of obstetric healthcare and counseling for women with a history of miscarriages should be strengthened to reduce the incidence of CHD.\u003c/p\u003e \u003cp\u003eThe correlation between paternal smoking and congenital cardiovascular defects has been studied, but too little information is available to determine the associated risk. Of the many congenital defects observed in a nursery, there was a significantly higher incidence of cardiovascular system abnormalities in the tobacco-exposed group [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A case-control study [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] suggested that there is an association between periconceptional tobacco exposure and an increased risk of CHD during the neonatal period and that there may be a dose effect; however, this needs to be confirmed in a larger population. Unfortunately, in our study, we were not able to verify this dose-effect relationship, although our results do suggest that paternal smoking is a risk factor for CHD. The potential mechanisms underlying the teratogenicity associated with periconceptional tobacco exposure remain unclear. One possible reason is that nicotine and carbon monoxide damage placental functions, leading to fetal hypoxia [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe association between maternal diabetes and an increased risk of CHD has been clearly described in many studies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, no similar finding was achieved in our research. This may be because of selection bias in the population recruited in our center because many pregnant women with diabetes are referred to our center from local hospitals for fetal echocardiography, and most of these fetuses are normal, resulting in a nonrandomly selected population. This could further affect our conclusions.\u003c/p\u003e \u003cp\u003eWith regard for fetal factors, we found that there was a correlation between single umbilical artery and fetal CHD. Single umbilical artery is one of the most common human umbilical malformations, with an incidence of 0.55\u0026ndash;4.85% [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], while the proportion in our population is 1%. Previous studies have demonstrated an increased prevalence of CHD in fetuses with an single umbilical artery in the presence of additional risk factors for CHD[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. All these results have suggested the indication of fetal echocardiography for the fetuses with single umbilical artery. Compared with existing research, our conclusions are consistent with it, but the sample size of our study is much larger than that of related studies.\u003c/p\u003e \u003cp\u003eThere are several advantages and limitations in this study. We analyzed factors related to fetal CHD for the first time with such a complete and huge database in China. The large sample size makes the conclusions of this study more stable and more convincing. We did consider as many factors as possible with CHD. As is known to us that CHD is a multifactorial complex disease, but we have to admit that we have not refined the assessment of the interactions between the various factors and also failed to take into account all the factors that cause CHD. Another strength of the study is the fact that we examine fetal CHD as opposed to only live births and thus would capture pregnancies who would go on to have intrauterine demise or termination that would not be captured in a neonatal/live birth registry. We acknowledge that although it was based on a large population, the data were mainly obtained from self-reported questionnaires, and the accuracy of information collection is therefore a problem that needs to be considered. Moreover, this is a cross-sectional study that demonstrates only the correlations between these factors and fetal CHD but does not provide causal relationships. One additional limitation is that our center is a referral center for fetal heart disease. The fetuses referred to our center come from all over the country. Therefore, some of the patients coming to our center are pregnant women with known risk factors or with a fetus previously found to have CHD at a local hospital, and this may have led to selection bias in the population. In addition, fetal CHD was diagnosed by fetal echocardiography and we didn't make postnatal verification for every case. But our findings can be credible, because fetal echocardiographic diagnoses were mostly consistent with autopsy findings in our center, which has shown that fetal cardiovascular anomalies disclosed by FE were completely in line with autopsy findings in nearly 99% of cases[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. A final limitation may be that the relationships between genetic factors and fetal CHD were not considered in this study, which is solely focused on clinical characteristics. Considering the above factors, our findings should be interpreted cautiously and may not be generalizable to all patients.\u003c/p\u003e \u003cp\u003eIn conclusion, we have found that there were several factors independently associated with fetal CHD, including gravidity, upper respiratory tract infection and mental stress during early pregnancy, parental smoking and fetal single umbilical artery. Thus, the CHD risk can be alleviated by reducing the exposure to environmental risk factors. Augmenting maternal mental healthcare, obtaining regular health counseling and testing during pregnancy, preventing upper respiratory tract infections and mental stress, offering health promotion and health education to women of childbearing age (especially those with less formal education), and improving obstetric procedures and techniques may lower the occurrence of CHD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCHD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCongenital heart disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAHA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAmerican Heart Association\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGW\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egestational weeks\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eISUOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Society of Ultrasound in Obstetrics and Gynecology\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLVOT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eleft ventricular outflow tract\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRVOT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eright ventricular outflow tract\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodd ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYH supervised the study and performed statistical analysis of the data. YR was conceived the study and wrote the main body of the manuscript. ZX participated in the discussion on the interpretation of the research content and involved in the procedure. XL revised the paper. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by National Key R\u0026amp;D Program of China (2018YFC1002300) and Yantai Science and Technology Innovation Development Project (2021YD018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants provided written consent before entering the study. The study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University，with the ethical Approval Number: 2022060X. We can confirm that all methods for the acquisition of fetal echocardiographic images was performed according to the guidelines and standards of the AHA\u0026nbsp;[6]\u0026nbsp;and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) [8].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2017 Congenital Heart Disease Collaborators.Global, regional, and national burden of congenital heart disease, 1990\u0026ndash;2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Child Adolesc Health. Lancet Child Adolesc Health 2020;4(3):185\u0026ndash;200.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao QM, Liu F, Wu L, et al. Prevalence of Congenital Heart Disease at Live Birth in China. J Pediatr 2019; 204:53\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTennant PW, Pearce MS, Bythell M, et al. 20-year survival of children born with congenital anomalies: a population-based study. Lancet 2010;375(9715):649\u0026ndash;656.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWren C, Irving CA, Griffiths JA, et al. Mortality in infants with cardiovascular malformations. Eur J Pediatr 2012;171(2):281\u0026ndash;287.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBruneau BG. The developmental genetics of congenital heart disease. Nature 2008 21;451(7181):943\u0026ndash;948.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDonofrio MT, Moon-Grady AJ, Hornberger LK, et al. Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. Circulation 2014;129(21):2183\u0026ndash;2242.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 95: anemia in pregnancy. Obstet Gynecol 2008;112(1):201\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInternational Society of Ultrasound in Obstetrics and Gynecology, Carvalho JS, Allan LD, Chaoui R, et al. ISUOG Practice Guidelines (updated): sonographic screening examination of the fetal heart. Ultrasound Obstet Gynecol 2013;41(3):348\u0026ndash;359.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao S, Han J, Yu S, et al. Comparison of fetal echocardiogram with fetal cardiac autopsy findings in fetuses with congenital heart disease. J Matern Fetal Neonatal Med 2019; 12:1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu S, Liu J, Tang J, et al. Environmental risk factors for congenital heart disease in the Shandong Peninsula, China: a hospital-based case-control study. J Epidemiol 2009;19(3):122\u0026ndash;130.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi H, Luo M, Zheng J, et al. An artificial neural network prediction model of congenital heart disease based on risk factors: A hospital-based case-control study. Medicine (Baltimore) 2017;96(6):e6090.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXia YQ, Zhao KN, Zhao AD, et al.Associations of maternal upper respiratory tract infection/influenza during early pregnancy with congenital heart disease in offspring: evidence from a case-control study and meta-analysis. BMC Cardiovasc Disord. 2019;19(1):277.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe Z, Wang L, Yang T, et al. Maternal Viral Infection and Risk of Fetal Congenital Heart Diseases: A Meta-Analysis of Observational Studies. J Am Heart Assoc 2019;8(9):e011264.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.Circulation 2007;115(23):2995\u0026ndash;3014.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTikkanen J, Heinonen OP. Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy. Teratology 1992; 46(5):447\u0026ndash;454.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWoods SE, Raju U. Maternal smoking and the risk of congenital birth defects: a cohort study.J Am Board Fam Pract 2001;14(5):330\u0026ndash;334.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaratza AA, Giannakopoulos I, Dassios TG, Belavgenis G, Mantagos SP, Varvarigou AA. Periconceptional tobacco smoking and isolated congenital heart defects in the neonatal period. Int J Cardiol 2011;148(3):295\u0026ndash;299.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRogers JM. Tobacco and pregnancy. Reprod Toxicol 2009; 28(2):152\u0026ndash;160.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShi M, Wehby GL, Murray JC. Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects. Birth Defects Res C Embryo Today 2008;84(1):16\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChou HH, Chiou MJ, Liang FW, et al. Association of maternal chronic disease with risk of congenital heart disease in offspring. CMAJ 2016;188(17\u0026ndash;18):E438-E46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu S, Joseph KS, Lisonkova S, et al. Association between maternal chronic conditions and congenital heart defects: a population-based cohort study.Circulation 2013;128(6):583\u0026ndash;589.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThummala MR, Raju TN, Langenberg P. Isolated single umbilical artery anomaly and the risk for congenital malformations: A meta-analysis. J Pediatr Surg 1998; 33: 580\u0026ndash;585.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen K, Akoma U, Anderson A, Mertz H, Quartermain MD.Prenatally diagnosed single umbilical artery: The role and relationship of additional risk factors in the fetus for congenital heart disease. J Clin Ultrasound 2016;44(2):113\u0026ndash;117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang J, Ye Y, Xin T, et al.Is echocardiography necessary for all single umbilical artery fetuses? A retrospective study in a selected Chinese population. J Obstet Gynaecol Res 2019;45(4):803\u0026ndash;809.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Congenital heart diseases, fetal, Odd ratio, Factor","lastPublishedDoi":"10.21203/rs.3.rs-1408405/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1408405/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eCurrent studies have suggested that fetal congenital heart diseases (CHDs) are caused by various factors. However, few data is available with respect to the aspect in China. This study aimed to detect associated maternal and fetal factors of fetal CHD in a large sample in China.\u003c/p\u003e\u003ch2\u003eStudy Design:\u003c/h2\u003e \u003cp\u003ePregnant women who underwent fetal echocardiography (N\u0026thinsp;=\u0026thinsp;5024) were recruited in our hospital between May 2018 and September 2019. Of these, 875 pregnant women had fetuses with CHD. The maternal sociodemographic and lifestyle characteristics and some fetal factors were obtained. We used forward stepwise logistic regression analysis to assess the associations of fetal CHD with various factors.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the fetal CHD group (N\u0026thinsp;=\u0026thinsp;875), critical CHDs account for 27%, of which Tetralogy of Fallot is the most (7.1%), followed by coarctation of aorta (4.0%), Double-outlet right ventricle (2.9%). The forward stepwise logistic regression models revealed that gravidity (OR\u0026thinsp;=\u0026thinsp;1.32, 95%CI 1.21\u0026ndash;1.43, P\u0026thinsp;=\u0026thinsp;0.000), upper respiratory tract infection during early pregnancy (OR\u0026thinsp;=\u0026thinsp;1.30, 95%CI 1.04\u0026ndash;1.63, P\u0026thinsp;=\u0026thinsp;0.021), mental stress during early pregnancy (OR\u0026thinsp;=\u0026thinsp;2.87, 95%CI 1.35\u0026ndash;5.92, P\u0026thinsp;=\u0026thinsp;0.006), single umbilical artery (OR\u0026thinsp;=\u0026thinsp;2.46, 95%CI 1.24\u0026ndash;4.85, P\u0026thinsp;=\u0026thinsp;0.010), and parental smoking (OR\u0026thinsp;=\u0026thinsp;1.20, 95%CI 1.00-1.45, P\u0026thinsp;=\u0026thinsp;0.048) are positively associated with an increased risk of fetal CHD.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWe identified two maternal factors and two fetal factors positively associated with fetal CHD.. These findings suggest that it is important to strengthen healthcare and prenatal counseling for women with these factors.\u003c/p\u003e","manuscriptTitle":"Associated Maternal and Fetal Factors of Fetal Congenital Heart Diseases Diagnosed by Fetal Echocardiography","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2022-04-19 14:22:28","doi":"10.21203/rs.3.rs-1408405/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-08-24T12:51:50+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"9e5840f2-4054-4a9b-a582-0b337adaacbe","date":"2022-08-07T01:06:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10ad2346-1626-406f-a28f-6da2bea871f9","date":"2022-05-16T22:46:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-04-25T16:18:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ef216a11-5923-4365-82fb-ac185a448361","date":"2022-04-19T20:32:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-04-06T08:58:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-04-06T08:54:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-04-06T07:37:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-04-06T07:33:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2022-03-17T14:42:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"da97ffca-22dd-4e10-a584-94feb1f358da","owner":[],"postedDate":"April 19th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T18:37:57+00:00","versionOfRecord":{"articleIdentity":"rs-1408405","link":"https://doi.org/10.1186/s12872-022-02981-3","journal":{"identity":"bmc-cardiovascular-disorders","isVorOnly":false,"title":"BMC Cardiovascular Disorders"},"publishedOn":"2023-01-27 18:32:40","publishedOnDateReadable":"January 27th, 2023"},"versionCreatedAt":"2022-04-19 14:22:28","video":"","vorDoi":"10.1186/s12872-022-02981-3","vorDoiUrl":"https://doi.org/10.1186/s12872-022-02981-3","workflowStages":[]},"version":"v2","identity":"rs-1408405","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1408405","identity":"rs-1408405","version":["v2"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}