Academy of Medical Sciences of I.R. Iran Archives of Iranian Medicine 1029-2977 28 2 2025 02 01 Pregestational Diabetes and Adverse Pregnancy Results: A Mendelian Randomization Study 81 87 10.34172/aim.33461 EN Sedigheh Hantoushzadeh https://orcid.org/0000-0003-3779-9218 Majid Zaki-Dizaji Danial Habibi Leyla Sahebi Amir Hesam Saeidian Mohadese Dashtkoohi https://orcid.org/0000-0003-3579-4181 Mostafa Saeedinia Hanifeh Mirtavoos-Mahyar Zohreh Heidary https://orcid.org/0000-0003-0966-7795 Journal Article 10.34172/aim.33461 2024 11 10 2024 12 24 Background: Hyperglycemia in pregnancy is believed to be associated with negative pregnancy outcomes. However, establishing a causal connection between diabetes mellitus (DM) and adverse pregnancy results is challenging due to the limitations inherent in traditional observational studies. Methods: Our study used a two-sample Mendelian randomization (MR) technique to examine the possible influence of pregestational diabetes mellitus (PGDM) on adverse pregnancy outcomes. Summary-level data were obtained from genome-wide association studies (GWAS) of European ancestry and FinnGen biobank. The primary analysis employed the random-effects multiplicative inverse variance weighted (IVW) technique to appraise causal relationships between PGDM and adverse outcomes. Heterogeneity and pleiotropy were assessed using Cochran’s Q statistic, Rucker’s Q statistic, and the I² statistic. Sensitivity analyses were conducted using MR-Egger and weighted median methods. Additionally, outlier detection techniques, including MR-PRESSO and RadialMR, were applied. Results: The results from the IVW method indicated no significant causal association between PGDM and stillbirth (SB) (OR (SE)=0.99 (0.001); P value=0.992), miscarriage (MIS) (OR (SE)=0.97 (0.016); P value=0.125), and preterm birth (PTB) (OR (SE)=1.072 (0.028); P value=0.014). Pleiotropy and heterogeneity tests revealed no evidence of pleiotropy for SB, MIS, and PTB (MR–Egger intercept P value=0.296, 0.525, and 0.532, respectively), with no observed heterogeneity for SB, MIS, and PTB (Q- P values of IVW were 0.929, 0.999, and 0.069, and MR–Egger were 0.931, 0.999, and 0.065, respectively). Conclusion: Our findings indicate that there is no direct causal link between PGDM and the likelihood of MIS, SB, and PTB.