Greenness exposure mitigate PM2.5-associated congenital heart defects in China: A mediation analysis of chemical composition and seasonal-spatial vulnerability.

While prenatal PM2.5 exposure constitutes an established risk factor for congenital heart defects (CHDs), the modifying role of greenness exposure in this association remains underexplored. We conducted a retrospective cohort study analyzed 1,356,420 birth records (11,803 CHD cases) from Zhejiang Province, China (2018-2023). Prenatal exposure to PM2.5 and its major constituents was estimated using satellite-derived speciation models, and greenness was assessed via the normalized difference vegetation index (NDVI). Generalized additive models (GAMs) with a quasibinomial logit link and restricted maximum likelihood were used to model non-linear associations and interactions. Mixture effects and joint exposure-response surfaces were estimated using fast Bayesian kernel machine regression (fbKMR). Causal mediation analysis under a counterfactual framework was used to assess indirect effects of PM2.5 in the greenness-CHD relationship. We identified predominantly J-shaped exposure-response relationships between key PM2.5 constituents and CHD risk, with organic matter (OM) and black carbon (BC) exhibiting the steepest risk increases. Mixture modeling via fbKMR revealed a monotonic increase in CHD risk with joint pollutant exposure. NDVI showed a robust U-shaped association with CHDs, with lowest risk at moderate greenness. Seasonal analysis highlighted strong BC and OM effects in autumn and winter, sulfate in spring and winter, and a threshold pattern for ammonium in summer. Spatial heterogeneity was evident, with eastern coastal cities (e.g., Ningbo, Jiaxing) showing pronounced risk increases above 35 μg/m3. Septal-type CHDs exhibited consistent positive associations with PM2.5, while complex subtypes showed weaker patterns. Mediation analysis indicated that PM2.5 accounted for 5.6-15.7 % of the greenness-CHD association, with BC showing the strongest mediation effect. Our findings underscore the cumulative toxicity of PM2.5 mixtures and the protective yet nonlinear role of greenness. Region- and season-specific strategies that integrate pollution control and green infrastructure may help mitigate CHD risk.