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Randomized Controlled Trial
. 2025 Apr;121(4):910-920.
doi: 10.1016/j.ajcnut.2025.02.001. Epub 2025 Feb 5.

Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over trial

Brock A Williams  1 , Heather McCartney  2 , Joel Singer  3 , Angela M Devlin  4 , Suzanne Vercauteren  5 , Ali Amid  4 , John K Wu  4 , Crystal D Karakochuk  6
Affiliations
Randomized Controlled Trial

Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over trial

Brock A Williams et al. Am J Clin Nutr. 2025 Apr.

Abstract

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).

Keywords: folic acid; micronutrient supplementation; one carbon metabolism; pediatrics; randomized control trial; sickle cell disease.

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Conflict of interest statement

Conflict of interest The authors report no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
CONSORT flow diagram.
FIGURE 2
FIGURE 2
Red blood cell (RBC) folate trends by treatment order among children with sickle cell disease. (A) Red blood folate trends among participants who received placebo-folic acid treatment order (n = 14). (B) RBC folate trends among participants who received folic acid-placebo treatment order (n = 12).
FIGURE 3
FIGURE 3
Mean difference (95% CI) in red blood cell folate concentration (nmol/L) between treatments (placebo compared with folic acid) using modified intention-to-treat and per-protocol analysis.
FIGURE 4
FIGURE 4
Serum folate trends by treatment order among children with sickle cell disease. (A) Serum folate trends among participants who received treatment order placebo-folic acid (n = 14). (B) Serum folate trends among participants who received treatment order folic acid-placebo (n = 12).
See this image and copyright information in PMC

References

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