Maternal Viral Infection in Early Pregnancy and Risk of Congenital Heart Disease in Offspring: A Prospective Cohort Study in Central China

PURPOSE: To examine the associations of maternal virus infection in early pregnancy with risk of offspring congenital heart disease (CHD) and its seven common subtypes including atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, Tetralogy of Tallot, pulmonary stenosis, and transposition of the great arteries. PATIENTS AND METHODS: A prospective cohort study was conducted in Central China. A total of 44,048 pregnant women with singleton pregnancies at 8–14 gestational weeks were finally included and followed to 3 months postpartum. Serum was tested for virus infection including hepatitis B virus (HBV), coxsackievirus-B, human cytomegalovirus (HCMV), herpes simplex virus (HSV), and rubella virus. Multivariable modified Poisson regression models were used to estimate the relative risks (RRs) of all CHDs as well as seven common subtypes of CHD in offspring of pregnant women with different types of virus infection in early pregnancy, adjusting for confounders identified by directed acyclic graphs. RESULTS: At the end of follow-up, 564 births were diagnosed with CHD. Multivariable analyses showed that the presence of maternal viral infection in early pregnancy was independently associated with increased risks of CHD in offspring, with an adjusted relative risk of 2.21 (95% CI: 1.66–2.95) for HBV infection, 2.21 (95% CI: 1.63–3.00) for coxsackievirus-B infection, 3.12 (95% CI: 2.44–3.98) for HCMV infection, and 2.62 (95% CI: 1.95–3.51) for rubella virus infection. More specifically, the offspring of pregnant women with HCMV infection had the highest increased risk of patent ductus arteriosus (RR=10.50, 95% CI: 6.24–17.66). These findings persisted in analyses that were further adjusted for the other virus of interest in this study. CONCLUSION: Our study proposed evidence that maternal virus infection in early pregnancy, including HBV, coxsackievirus-B, HCMV, and rubella virus, was implicated in CHD, although more studies remain needed to verify the results, especially associations in specific CHD phenotypes.