Embryonic heart development primarily occurs during the first trimester, specifically between weeks 4–6, during which the primitive cardiovascular system develops rapidly. The system bends rightward, positioning the right ventricle on the right and the left ventricle on the left. It also bends backwards, situating the ventricles in front and the atria behind. Additionally, it bends upwards, positioning the atria superiorly and the ventricles inferiorly. This establishes the basic morphological structure of the right ventricular loop of the heart. Interference during this critical period of heart development, due to certain factors, can cause the primitive cardiovascular system to bend leftward, leading to the heart axis pointing to the lower right, with the heart apex located in the right chest, resulting in mirror-image dextrocardia.
After the COVID-19 pandemic, our research found a significant increase in the incidence of fetal mirror-image dextrocardia in Shaanxi Province. Most of these fetuses had mothers whose last menstrual period occurred in November 2022, within weeks 4 to 6 of COVID-19 infection. We validated our observational results by surveying the number of pregnant women with mirror-image dextrocardia in three hospitals in Shaanxi Province during three time periods: September-October 2022, November 2022, and December 2022-January 2023. The results confirmed a significantly higher incidence of mirror-image dextrocardia in fetuses whose mothers' last menstrual period occurred in November 2022, compared to those before or after this period (Fig. 1).
We performed further variance analysis comparing the gestational age at which pregnant women with fetuses without fetal mirror-image dextrocardia, infected with COVID-19 during their last menstrual cycle of September-October 2022, to that of pregnant women with fetal mirror-image dextrocardia infected with COVID-19 during their last menstrual cycle of November 2022. Our findings showed 80.2% of women in the positive dextrocardia group were infected with COVID-19 during weeks 4 to 6 of pregnancy, while 93% of women in the negative dextrocardia group were infected with COVID-19 outside of weeks 4 to 6 of pregnancy. This showed a significant difference between the two groups in terms of the gestational age at infection with COVID-19.
Further analysis was performed comparing the gestational age at which pregnant women with fetuses without fetal mirror-image dextrocardia, infected with COVID-19 during their last menstrual cycle of December 2022-January 2023, with that of pregnant women with fetal mirror-image dextrocardia who were infected with COVID-19 during their last menstrual cycle of November 2022. We found 80.2% of women in the positive dextrocardia group were infected with COVID-19 during weeks 4 to 6 of pregnancy, while 68.6% of women in the negative dextrocardia group were not pregnant at the time of infection. This showed a significant difference between the two groups in terms of the gestational age at infection with COVID-19.
Based on these findings, we suggest that COVID-19 infection during weeks 4 to 6 of pregnancy, when the heart is developing during a critical period of embryonic development, is strongly associated with mirror-image dextrocardia in fetuses. For pregnancies conceived before or after this critical period, the risk of mirror-image dextrocardia is not significantly different compared to preexisting rates.
In order to further investigate the risk factors, we searched the literature and found that less than 20% of congenital heart diseases are explained by chromosomal abnormalities and gene defects [7–8], while most are due to the interaction of genetic and environmental factors[9–12]. Factors such as maternal viral infection during pregnancy, metabolic diseases, use of teratogenic drugs, and exposure to teratogenic substances during early pregnancy, advanced maternal age (age ≥ 35 years), use of assisted reproductive technology, and adverse lifestyles can increase the risk of congenital heart disease [13–14].It is generally recognized that cold can cause fetal cardiac malformation. Cold is usually caused by virus, which replicates in cytotrophoblast cells and then enters fetal blood for infection; or it does not replicate and directly causes infection by overflowing into embryonic cells [15], thus causing congenital heart disease in the fetus. Therefore, virus is an important factor in congenital heart disease. Genetic factors such as single gene mutation and polygenic inheritance, as well as environmental factors such as infection, radiation, drugs, environmental pollution, food safety, pesticides, chemical plants, etc., are all risk factors for congenital heart disease [16–17].
To further explore risk factors for mirror-image dextrocardia, we conducted a single-factor and multi-factor logistic regression analysis through an online survey on pregnant women with a last menstrual cycle in November 2022, who had a history of COVID-19 infection, but without mirror-image dextrocardia, and pregnant women with a history of COVID-19 infection and with mirror-image dextrocardia. Our results showed that there was a statistically significant difference in the incidence of fever and duration of fever between the two groups. The main reason for the difference in outcomes between the two groups of pregnant women infected with COVID-19 was the duration of fever. Women who with fetal mirror-image dextrocardia with a fever duration of more than 3 days accounted for 70.00%, while those who without fetal mirror-image dextrocardia group accounted for 30.00%.Furthermore, other symptoms of COVID-19 infection, such as sore throat, diarrhea, cough, and expectoration, were more common in the right atrial appendage group than in the non-right atrial appendage group (Table 3). Therefore, we believe that the main reasons for the different outcomes between the two groups were the duration of fever and the severity of virus infection.