Preconception maternal infection-related exposures and risk of congenital heart disease in offspring: evidence from a large population-based cohort in South China

Background Maternal infections during pregnancy have been associated with congenital heart disease (CHD) in offspring. However, the associations of preconception maternal infection-related exposures with offspring CHD risk remain unclear. This study aimed to evaluate the independent and joint associations of reproductive tract infections and pathogen-specific immunoglobulin G (IgG) seropositivity assessed at the preconception examination with offspring CHD. Methods We conducted a population-based cohort study of 630,968 women planning pregnancy in Guangdong, China (2014–2018). Preconception maternal infection-related exposures comprised reproductive tract infections (candidiasis and Chlamydia trachomatis infection) and immunoglobulin G (IgG) seropositivity to cytomegalovirus, Toxoplasma gondii , and rubella virus. The primary outcome was offspring CHD recorded in the birth defects registry. Adjusted relative risks (RRs) and risk differences (RDs) per 1,000 births, with corresponding 95% confidence intervals (CIs), were estimated using multivariable modified Poisson regression with robust error variance. Results Among 630,968 pregnancies, 1,312 infants (0.21%) were diagnosed with CHD. In the expanded multivariable models, Chlamydia trachomatis infection was associated with increased offspring CHD risk (adjusted RR, 1.89; 95% CI, 1.14–3.15), as was cytomegalovirus (CMV) IgG seropositivity (adjusted RR, 2.70; 95% CI, 2.26–3.22). Associations were also observed for candidiasis (adjusted RR, 1.50; 95% CI, 1.12–2.02), rubella IgG seropositivity (adjusted RR, 1.59; 95% CI, 1.37–1.83), and Toxoplasma gondii IgG seropositivity (adjusted RR, 1.32; 95% CI, 1.01–1.74). Jointly exposed groups also had elevated risk, including Chlamydia trachomatis infection with CMV IgG seropositivity (adjusted RR, 5.14; 95% CI, 2.92–9.06) and candidiasis with CMV IgG seropositivity (adjusted RR, 3.72; 95% CI, 2.53–5.49). Results were consistent in sensitivity analyses. Conclusions In this large population-based cohort study, preconception maternal infection-related exposures, comprising reproductive tract infections and pathogen-specific IgG seropositivity, were associated with increased offspring congenital heart disease risk. Elevated estimates in jointly exposed groups describe joint exposure patterns and should not be interpreted as evidence of biological interaction.