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Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over
Brock A Williams1, Heather McCartney2, Joel Singer3
1Food, Nutrition, and Health Program, Faculty of Land and Food Systems, The University of British Columbia, Vancouver, British Columbia, Canada; BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Insights
Folic acid supplementation may benefit children with sickle cell disease (SCD) despite food fortification. However, this study found no significant improvement in clinical outcomes or folate deficiency rates.
Area of Science:
- Pediatric Hematology
- Nutritional Science
- Sickle Cell Disease Research
Background:
- Children with sickle cell disease (SCD) in Canada receive folic acid supplements for increased erythropoiesis.
- Mandatory folic acid fortification and improved SCD treatments question the necessity of routine supplementation.
Purpose of the Study:
- To evaluate the efficacy of 1 mg/d folic acid supplementation versus placebo in children with SCD.
- To measure the impact on red blood cell (RBC) folate, serum folate, 1-carbon metabolites, and clinical outcomes.
Main Methods:
- A double-blind, randomized controlled crossover trial involving 31 children with SCD (aged 2-19 years).
- Participants received either 1 mg/d folic acid or placebo for 12 weeks, followed by a washout period and then switched treatments.
Main Results:
- While RBC folate levels differed significantly between treatments, RBC folate deficiency rates did not.
- No significant differences were observed in serum folate, 1-carbon metabolites, hematological measures, or clinical outcomes (pain episodes, megaloblastic changes).
Conclusions:
- Some children with SCD might still benefit from folic acid supplementation, even with food fortification and advanced therapies.
- The clinical benefit of folic acid supplementation in this population remains uncertain.
Background:
Children with sickle cell disease (SCD) in Canada are routinely supplemented with folic acid to provide sufficient folate for the increased demands of erythropoiesis. However, with the mandatory folic acid fortification of refined grains and pharmacotherapies that extend the lifespan of sickled red blood cells (RBC), this clinical practice is in question.
Objectives:
This study aims to determine the efficacy of folic acid supplementation by measuring the effect of 12 ± 1 wk of 1 mg/d folic acid, compared with placebo, on concentrations of RBC folate (primary outcome), serum folate, and 1-carbon-related metabolites, and clinical outcomes in children with SCD.
Methods:
In this double-blind randomized controlled noninferiority cross-over trial, 31 children with SCD, aged 2-19 y, were enrolled and randomly assigned (1:1 with blocks of 4) to 1 mg/d folic acid, the current standard of care, or a placebo for 12 ± 1 wk. After a 12 ± 1 wk washout period, treatments were reversed.
Results:
The mean [95% confidence interval (CI)] difference in endline RBC folate concentrations across treatments was -179 (-260, -99) nmol/L, with the lower boundary of the CI exceeding noninferiority 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 1-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 with placebo.
Conclusions:
Despite mandatory food fortification and advances in the medical treatment of SCD, 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).
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