First trimester maternal infections and offspring congenital heart defects: a meta-analysis

Background and Aims Maternal infections have been proposed to play a role in the development of congenital heart defects (CHD). This study aims to synthesize contemporary evidence on the association between first-trimester maternal infection and risk of offspring CHD. Methods This systematic review and meta-analysis (PROSPERO number: CRD42024523638) used Embase, PubMed, Web of Science, Scopus, and the Cochrane Library to identify studies investigating first-trimester maternal infection and offspring CHD, published up until 30 September 2024. Human studies with a minimum of 50 cases were eligible. Inverse variance weighted random-effects models were conducted to pool estimates and stratify associations by infection type and heart defect type. Results A total of 30 studies (24 case-control, 3 cohort, and 3 cross-sectional studies) with 1 732 295 pregnancies were identified. Studies assessed maternal infectious status through self-reported questionnaires (n = 20, 66.7%), laboratory testing (n = 7, 23.3%) or medical records (n = 3, 10.0%). Overall, any first-trimester maternal infection was associated with higher risk of CHD in offspring, with a pooled odds ratio (OR) and 95% confidence interval (CI) of 1.63 (1.41, 1.88). Among specific types of infection, rubella virus, coxsackievirus, respiratory infections, and influenza presented higher risks of offspring CHD, with ORs (95% CI) of 2.78 (2.08, 3.72), 1.57 (1.12, 2.19), 1.57 (1.25, 1.96), and 1.50 (1.20, 1.87), respectively. Studies that reported associations by individual subtype of CHD relied on a comparatively modest number of cases. Pooled ORs for exposure to any first-trimester infection were 1.59 (1.16, 2.20) for ventricular septal defects, 1.55 (1.21, 1.99) for atrioventricular septal defects, and not statistically significant for other subtypes. Conclusions First-trimester maternal infections are associated with increased risk of offspring CHD and appear to extend beyond infections commonly tested for during routine pregnancy screening. Larger-scale studies are warranted to confirm these findings using laboratory antibody testing and explore underlying mechanisms.