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) . 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 . 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 . In addition, there is a meta-analysis  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. 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 . 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 . A case-control study  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% , 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. 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.