Genetically proxied TNF inhibition and pregnancy-related maternal and fetal outcomes in the general population: a Mendelian randomization study

Objectives Evidence on the safety of TNF inhibitors (TNFi) for pregnancy-related maternal and fetal outcomes remains limited. While some studies report increased rates of preterm delivery, others have suggested a possible protective role for gestational diabetes. We used population-level data to examine the effect of genetically proxied TNFi on these outcomes. Methods We proxied TNFi using rs1800693, a splicing variant within the TNFRSF1A gene, which is strongly associated with C-reactive protein (CRP) in a genome-wide association study of 575,531 individuals of European ancestry. CRP was selected as the biomarker because TNFi is recognised to suppression CRP. Genetic association data for pregnancy-related outcomes were taken from FinnGen and UK Biobank, including the outcomes of spontaneous abortion, ectopic pregnancy, hyperemesis gravidarum, gestational diabetes, pre-eclampsia or eclampsia, preterm birth, and offspring birthweight. Colocalization analysis was used to examine genetic confounding. Results We found no strong association between genetically proxied TNFi and any adverse pregnancy-related outcome, including spontaneous abortion (OR 1.07, 95% CI: 0.41, 2.81), preterm birth (OR 0.48, 95% CI 0.14, 1.60), hyperemesis gravidarum (OR 0.20, 95% CI 0.02, 2.57), pre-eclampsia or eclampsia (OR 0.59, 95% CI 0.13, 2.65). Genetically proxied TNFi was associated with lower risk of gestational diabetes (OR 0.16, 95% CI 0.05, 0.52). There was no statistical evidence to suggest genetic confounding through linkage disequilibrium. Conclusions This genetic investigation found no evidence linking TNFi to adverse pregnancy-related outcomes. The suggestive association with a reduced risk of gestational diabetes warrants further research and may support its consideration for at-risk pregnant women.