Introduction: Recent studies have shown different associations between folate supplementation in pregnancy and gestational diabetes mellitus (GDM). Low folate intake can result in higher homocysteine levels, similar to individuals with a genetic polymorphism for the enzyme methylenetetrahydrofolate reductase (MTHFR 677C->T). We aimed to evaluate the impact of early pregnancy folic acid supplementation on the risk of GDM, with supplemental analysis on the associations of GDM with MTHFR genotypes and plasma homocysteine levels.
Methods: Participants were from a prospective cohort study that recruited pregnant women between 12-20 weeks’ gestation in Ottawa and Kingston, Canada, from September 1, 2002, to August 1, 2008. Log-binomial regression models were used to estimate the relative risk (RR) with 95% confidence intervals (CI) of GDM associated with folic acid supplementation, MTHFR genotypes, and homocysteine levels. The association of homocysteine levels and GDM was assessed by instrumental variable analysis by MTHFR genotypes.
Results: 7,552 women were included in the final analysis, with 84 (1.11%) diagnosed with GDM. Women with folate-containing multivitamins supplementation (mean dose=1.17 mg/day) had an RR (95% CI) of GDM of 0.64 (0.21, 2.01) compared with no folate supplementation. The RR (95% CI) for MTHFR 677 TT mutation (n=469) as compared with CC wildtype (n= 1747) was 1.36 (0.43, 4.27) and the RR (95% CI) for homocysteine levels higher than the 90th percentile was 1.47 (0.92, 2.34). Additionally, the RR (95% CI) for elevated homocysteine levels by MTHFR 677 TT was 2.07 (0.30, 14.39) compared with CC individuals.
Conclusion: Although we find no statistically significant associations for the risk of GDM, the genetic associations are not confounded by lifestyle or socioeconomic factors which may have biased previous studies. Further studies using genetic epidemiology and Mendelian randomization should be considered to answer the question if there are causal links between folate supplementation, homocysteine, and GDM.
Daniel Corsi– Adjunct Professor, School of Epidemiology and Public Health, University of Ottawa Faculty of Medicine, Ottawa, Canada
Ruth Rennicks White– Research Program & Operations Manager, OMNI Research Group, Department of Obstetrics, Gynecology, and Newborn Care, University of Ottawa Faculty of Medicine, Ottawa, Canada
Graeme Smith– Professor and Head, Obstetrics & Gynecology, Kingston Health Sciences Centre, Queen’s University, Ontario, Canada
Marc Rodger– Professor and Senior scientist, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada
Ravi Retnakaran– Professor of Medicine, Endocrinologist, Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, University of Toronto
Mark Walker– Professor and Chair, OMNI Research Group, Department of Obstetrics, Gynecology, and Newborn Care, University of Ottawa Faculty of Medicine, Ottawa, Canada
Shi Wu Wen– Professor and Senior Scientist, School of Epidemiology and Public Health, University of Ottawa Faculty of Medicine, Ottawa, Canada
Yanfang Guo– Adjunct Professor and Epidemiologist, School of Epidemiology and Public Health, University of Ottawa Faculty of Medicine, ON, CA