Exploring genetic causal relationship between antidepressants use and congenital malformations

Existing studies have demonstrated that the use of antidepressants is associated with congenital malformations; however, the conclusions are inconsistent, and the potential causal relationship remains unclear. Based on large-scale genetic data, we conducted a two-sample Mendelian randomization (MR) study. The exposure datasets included the use of antidepressants, responses to selective serotonin reuptake inhibitors (SSRIs), and the use of four SSRIs-related antidepressants: fluoxetine, citalopram, paroxetine, and sertraline. The outcome datasets encompassed congenital malformations across 12 major organ systems, as well as overall congenital malformations. All datasets were of European ancestry. We employed inverse variance weighting (IVW), MR-Egger, and weighted median methods as our MR analytical approaches. Additionally, the robustness of the MR results was evaluated through a series of sensitivity analyses. After Bonferroni multiple comparisons, MR results did not reveal a significant association between the use of all antidepressants and any congenital malformations. However, IVW provided a suggestive positive association between antidepressants use and congenital digestive malformations (OR = 1.28, 95% CI = 1.01-1.62, P = 0.039), as well as between SSRIs response and respiratory system malformations (OR = 1.21, 95% CI = 1.02-1.44, P = 0.033), and fluoxetine use and nervous system malformations (P = 0.026). This study did not find evidence of an association between the use of citalopram, paroxetine, or sertraline and any congenital malformations. Our study provides evidence of a causal association between exposure to antidepressants and certain specific congenital malformations. However, further in-depth research is needed to confirm this association and explore the underlying biological mechanisms.