Folic acid supplementation in children with sickle cell disease: A randomized double-blind non-inferiority crossover trial.

Abstract

Background: Children with sickle cell disease in Canada are routinely supplemented with folic acid to provide sufficient folate for the increased demands of erythropoiesis. However, with mandatory folic acid fortification of refined grains and pharmacotherapies which extend the lifespan of sickled red blood cells (RBC), this clinical practice is in question.

Objective: To determine the efficacy of folic acid supplementation by measuring the effect of 12±1 weeks of 1mg/d folic acid, compared to placebo, on concentrations of RBC folate (primary outcome), serum folate and one-carbon-related metabolites, and clinical outcomes in children with SCD.

Methods: In this double-blind randomized controlled non-inferiority crossover trial, 31 children with sickle cell disease, aged 2-19 years, were enrolled and randomly assigned (1:1 with blocks of 4) to 1mg/d folic acid, the current standard of care, or a placebo for 12±1 weeks. Following a 12±1 week washout period, treatments were reversed.

Results: The mean (95% CI) difference in endline RBC folate concentrations across treatments was -179 (-260, -99) nmol/L, with the lower boundary of the confidence interval exceeding non-inferiority but the upper boundary not (p=0.0001; modified intention-to-treat). There was no significant difference in the number of participants who had RBC folate deficiency after each treatment (p=0.059). No participants presented with serum folate deficiency (<7 nmol/L). There were no significant differences observed in one-carbon metabolite concentrations (total homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, vitamin B12, or methylmalonic acid), hematological measures, nor clinical outcomes (specifically acute pain episodes or megaloblastic changes) when individuals were supplemented with folic acid in comparison to placebo.

Conclusions: Despite mandatory food fortification and advances in the medical treatment of sickle cell disease, it appears that some children with this condition may still benefit from daily folic acid supplementation. Whether this translates to improved clinical outcomes remains uncertain. This trial was registered at ClinicalTrials.gov as NCT04011345 (https://clinicaltrials.gov/study/NCT04011345).