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Williams, Brock Alexander

University of British Columbia

Supplementation with 1-5 mg/d folic acid, a synthetic form of folate, is the routine recommendation for Canadian individuals with sickle cell disease (SCD), an inherited hemoglobin disorder thought to increase requirements for folate due to chronic hemolysis and increased folate-dependent erythropoiesis. There is concern about whether children with SCD need such high doses of folic acid following mandatory folic acid fortification of refined grains and advancements in medical therapies for SCD in Canada. Thus, I conducted a double-blind randomized cross-over trial to determine the efficacy of folic acid supplementation by measuring the effect of folic acid, compared to placebo, on the primary outcome of red blood cell (RBC) folate concentrations in children with SCD. Children with SCD (n=31) in British Columbia were randomized to either 1 mg/d folic acid (current standard of care), or a placebo for 12 ± 1 weeks. After a 12 ± 1 week washout period, treatments were reversed. RBC folate concentrations were measured via microbiological assay and serum folate concentrations were measured via LC-MS/MS at baseline and after treatment periods. Mean differences in RBC and serum folate concentrations by treatment were evaluated using generalized linear regression models. Dietary intake was collected and analyzed from non-consecutive 24-hour dietary recalls. Inadequate dietary folate intake, defined as below the Estimated Average Requirement, was observed in 31% (n=8/26) of participants. In intention-to-treat analyses, the adjusted mean difference in RBC folate concentrations across treatments (placebo vs. folic acid) was -248 (95% CI: -367, -129) nmol/L (p<0.001). In per-protocol analyses (excluding periods with >1 RBC transfusion), the mean adjusted difference was -224 (95% CI: -336, -111) nmol/L (p<0.001). As per the ‘a priori’ defined non-inferiority margin of -227 nmol/L, the results were equivocal regarding non-inferiority of placebo in comparison to folic acid for the maintenance of RBC folate concentrations over 12 weeks. There was no significant difference in adjusted mean serum folate concentrations across treatments (-7 [95% CI: -35, 21] nmol/L, p=0.610). Future in vitro work in which the folate capacity of sickled red blood cells is tested could further inform interpretation of folate status in this population with abnormally shaped RBCs.

Text

2025-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86122

Human Nutrition

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/