The Pharmacology of Periconceptional Folic Acid Supplementation

Periconceptional folic acid supplementation is associated with a reduction in the risk of neural tube defects, other birth defects, as well as positive maternal outcomes during pregnancy. Current healthcare recommendations regarding the timing and dosage of prenatal supplementation are based on studies in non-pregnant women of childbearing age. The overall objective of this thesis is to characterize risk factors associated with the periconceptional period, validate the effectiveness of folic acid supplementation based on pregnancy-related pharmacokinetics, analyze the current folate status of women in Toronto, as well as explore recruitment strategies for clinical trials in pregnant women. The first study was a two-arm, randomized, clinical trial assessing the long-term folate kinetics in pregnant women supplementing with either 1.1mg (regular dose) or 5mg (high dose) of folic acid. This study evaluated dose-dependent and gestational age-dependent changes in the pharmacokinetics among pregnant women, which have not been previously studied at these doses of supplementation. We found non-linear folate pharmacokinetics in the 5mg group, as well as altered pharmacokinetics in both dose-groups due to pregnancy-related changes. The second study was based on secondary analysis emerging from the randomized clinical trial, where we tackled the challenges associated with recruitment of pregnant women (a vulnerable population) into a study on folic acid supplementation at a time when a high degree of supplementation awareness already exists among women in Toronto. We used social media as a novel tool for recruitment, and found a 12-fold increase in recruitment rate. The third study was a systematic review and meta-analysis investigating the effect of oral contraceptive use on blood folate concentrations among women. We found that oral contraceptives had a folate-lowering effect and recommended continued folate supplementation among oral contraceptive users. Finally, in our fourth population-based cohort study, we evaluated blood folate concentrations among women in Toronto and found that 93% of women of childbearing age had optimally protective blood folate concentrations against neural tube defects.Recommendations for periconceptional folic acid supplementation should be re-evaluated based on population-level data, and be tailored to individual risk factors such oral contraceptive use or altered folate demands during pregnancy.Ph.D