Introduction: Periconceptional supplementation with 400ug/day of folic acid (FA) is recommended for reducing the primary occurrence of neural tube defects. Women often exceed daily FA intake recommendations when they consume over-the-counter or prescribed supplements containing >1mg FA. Our objective was to evaluate the impact of high-dose FA supplementation in pregnancy on markers of folate status and one-carbon metabolism.
Methods: This study was nested in FACT, a randomized, double-blinded, placebo-controlled, phase III trial. For FACT, women were randomized at 8-16 gestational weeks to receive daily supplementation of either high-dose (4.0-5.1 mg) or low-dose (≤1.1 mg) FA. Fifty participants were randomly recruited from three Canadian FACT centres and provided non-fasting blood samples at 24-26 weeks gestation. Red blood cell (RBC) and total serum folate concentrations were measured as were individual serum folate vitamers (unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, MeFox), homocysteine, and vitamins B12 and B6. Differences between groups were determined using Chi-Squared and Fisher-Exact tests for categorical variables. Wilcoxon rank-sum tests were used for continuous variables.
Results: Nineteen (38%) women received high-dose and 31 (62%) received low-dose FA. The median age was 32 years (IQR:30-35). Samples were collected at a median 25.1 weeks gestation (IQR:24.6-26.3), a median 11.5 weeks (IQR:10.1-12.7) post-randomization. The median RBC folate concentration was 2700.6nmol/L (IQR:2242.9-3032.2) and did not differ between the treatment arms. Total serum folate was higher in the high-dose FA supplementation group (median=148.44nmol/L, IQR:110.40-181.24) than in the low-dose group (median=122.76nmol/L, IQR:99.49-136.04). This difference was driven by higher circulating UMFA (median=4.6nmol/L (IQR:2.5-33.8) versus median=1.9nmol/L (IQR:0.9-4.1), p=0.008) and 5-methylTHF (median=126.6nmol/L (IQR:98.8-158.6) versus median=108.6nmol/L (IQR:96.4-123.2), p=0.03).
Conclusion: High-dose FA supplementation in early pregnancy significantly increases maternal serum folate concentrations by 24-26 weeks gestation. Higher UMFA concentrations in women receiving high-dose FA relative to low-dose supplementation suggests that these doses are supraphysiological.
Katherine Muldoon– Research Associate, OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute
Yvonne Lamers– Associate Professor, Food, Nutrition and Health, Faculty of Land and Food Systems, University of British Columbia; and British Columbia Children’s Hospital Research Institute
Natalie Rybak– Chief administrative officer, OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute; and the Department of Obstetrics, Gynecology & Newborn Care, The Ottawa Hospital
Laura Gaudet– Doctor of Medicine, Maternal Fetal Medicine. Associate Scientist and Professor., Queen's University
Graeme Smith– Professor and Head, Obstetrics & Gynecology, Kingston Health Sciences Centre, Queen’s University, Ontario, Canada
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
Amanda MacFarlane– Scientist, Nutrition Research Division, Health Canada; and the Department of Biology, Carleton University