Rheumatoid arthritis and adverse pregnancy outcomes: a bidirectional two-sample mendelian randomization study

There is growing evidence of bidirectional associations between rheumatoid arthritis and adverse pregnancy outcomes (APOs) in observational studies, but little is known about the causal direction of these associations. Therefore, we explored the potential causal relationships between rheumatoid arthritis and APOs using a bidirectional two-sample Mendelian randomization (MR) in European and Asian populations. We conducted a bidirectional two-sample Mendelian randomization analysis using available summary statistics from released genome-wide association studies. Summary statistics for instrument-outcome associations were retrieved from two separate databases for rheumatoid arthritis and adverse pregnancy outcomes, respectively. The inverse-variance weighted method was used as the primary MR analysis, and cML-MA-BIC was used as the supplementary analysis. MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran Q statistic method were implemented as sensitivity analyses approach to ensure the robustness of the results. Our study showed that a higher risk of rheumatoid arthritis in the European population was associated with gestational hypertension (OR: 1.04, 95%CI: 1.02-1.06), pre-eclampsia (OR: 1.06, 95%CI: 1.01-1.11), fetal growth restriction (OR: 1.08, 95%CI: 1.04-1.12), preterm delivery (OR:1.04, 95%CI: 1.01-1.07). Furthermore, we found no evidence that APOs had causal effects on rheumatoid arthritis in the reverse MR analysis. No association between rheumatoid arthritis and APOs was found in East Asian population. There was no heterogeneity or horizontal pleiotropy. This MR analysis provides the positive causal association from rheumatoid arthritis to gestational hypertension, pre-eclampsia, fetal growth restriction and preterm delivery genetically. It highlights the importance of more intensive prenatal care and early intervention among pregnant women with rheumatoid arthritis to prevent potential adverse obstetric outcomes.