Exploring potential causal links between air pollutants and congenital malformations: A two-sample Mendelian Randomization study

Observational studies have suggested an association between air pollutants and congenital malformations; however, conclusions are inconsistent and the causal associations have not been elucidated. In this study, based on publicly available genetic data, a two-sample Mendelian randomization (MR) was applied to explore the associations between particulate matter 2.5 (PM2.5), NO_X, NO₂ levels and 11 congenital malformations. Inverse variance weighted (IVW), MR-Egger and weighted median were used as analytical methods, with IVW being the main method. A series of sensitivity analyses were used to verify the robustness of the results. For significant associations, multivariable MR (MVMR) was utilized to explore possible mediating effects. The IVW results showed that PM2.5 was associated with congenital malformations of digestive system (OR = 7.72, 95 %CI = 2.33–25.54, P = 8.11E⁻⁴) and multiple systems (OR = 8.63, 95 %CI = 1.02–73.43, P = 0.048) risks; NO_X was associated with circulatory system (OR = 4.65, 95 %CI = 1.15–18.86, P = 0.031) and cardiac septal defects (OR = 14.09, 95 %CI = 1.62–122.59, P = 0.017) risks; NO₂ was correlated with digestive system (OR = 27.12, 95 %CI = 1.81–407.07, P = 0.017) and cardiac septal defects (OR = 22.57, 95 %CI = 2.50–203.45, P = 0.005) risks. Further MVMR analyses suggest that there may be interactions in the effects of these air pollutants on congenital malformations. In conclusion, this study demonstrated a causal association between air pollution and congenital malformations from a genetic perspective.