The effect of once weekly folic acid supplementation on red blood cell folate concentrations in women to determine the potential to prevent neural tube defects

In populations where the prevalence of anemia is >20% in women of reproductive age, the World Health Organization (WHO) recommends weekly supplementation with 60 mg iron and 2.8 mg folic acid as an anemia prevention strategy. Folic acid was included in this weekly supplement not only for anemia prevention, but also to reduce the risk of neural tube defects (NTD) should a woman become pregnant. The dose of folic acid is equivalent to seven times the daily dose of folic acid shown to reduce the risk of NTDs in controlled trials (0.4 mg x 7 days = 2.8 mg). However, the majority of currently-used weekly supplements contain 0.4 mg of folic acid (the daily recommended dose in pregnancy). There is a lack of evidence to support if a weekly 2.8 mg dose of folic acid is more effective at raising red blood cell (RBC) folate concentrations to a level associated with a reduced risk of NTD (>748 nmol/L) than the current practice of weekly 0.4 mg folic acid. In this three-arm randomized controlled trial, we randomized n=331 non-pregnant Malaysian women (18-45 y) to receive 60 mg iron and either 2.8, 0.4, or 0 mg folic acid. RBC and plasma folate were measured at baseline, 16 weeks, and 4 weeks after the discontinuation of the intervention. Following 16 weeks of intervention, the primary outcome of mean RBC folate in the 2.8 mg folic acid per week group was significantly higher than the 0.4 mg and 0 mg groups [mean difference (95% CI) 271 (234, 309) and 355 (316, 394) nmol/L, respectively (P<0.0001)]. Mean plasma folate in the 2.8 mg group was also higher than the 0.4 mg and 0 mg groups [mean difference (95% CI) 14.9 (12.0, 17.8) and 19.6 (16.9, 22.4) nmol/L, respectively (P<0.0001)]. At 20 weeks, mean plasma and RBC folate were still significantly higher in the 2.8 mg group than the 0.4 mg and 0 mg groups (P