Children with SCD may benefit from folic acid supplementation
However, supplementation was found not to affect clinical outcomes in trial
Some children with sickle cell disease (SCD) may benefit from supplementing with folic acid, according to a clinical trial.
Supplementation was found to significantly increase the levels of red blood cell folate, a molecule important for the production of red blood cells, compared with a placebo.
However, no differences were reported in the clinical outcomes of the patients.
“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,” researchers wrote. “Whether this translates to improved clinical outcomes remains uncertain.”
The study, “Folic acid supplementation in children with sickle cell disease: A randomized double-blind non-inferiority crossover trial,” was published in The American Journal of Clinical Nutrition.
SCD is caused by the production of a faulty version of hemoglobin, the protein that carries oxygen in red blood cells, which makes red blood cells take on a sickle-like shape. The disease is marked by anemia (low red blood cell counts) and problems associated with blood vessel blockage.
Folic acid supplementation commonly recommended for SCD
In Canada, clinicians commonly recommend supplementing with folic acid, an artificial form of folate, which is a compound that plays an essential role in erythropoiesis, or the production of red blood cells.
“There is evidence that folic acid supplementation increases serum folate concentrations, but limited evidence that it improves hematological or clinical outcomes,” the researchers wrote.
In the study, researchers in Vancouver, Canada, conducted a clinical trial (NCT04011345) to determine the efficacy of folic acid supplementation in improving the levels of folate in red blood cells and patient clinical outcomes.
The study enrolled a total of 31 people living with SCD, ages 2 to 19 years, who were randomly assigned to receive folic acid (1 mg/day), or a placebo, for 12 weeks (about three months). After a washout period of 12 weeks, the treatments were reversed, meaning patients who initially received folic acid were then given a placebo, and vice versa.
Participants were a median age of 10 years and more than half were female (55%).
Before the study, all patients were on folic acid supplementation, and the majority were also receiving hydroxyurea (94%) and antibiotics to prevent infections (90%).
At baseline, or the study’s start, the concentration of red blood cell folate was of 562.3 nanomoles per liter (nmol/L).
When comparing the 25 participants who completed both treatment regimens, patients treated with folic acid had significantly higher levels of red blood cell folate than those who received a placebo (541.6 vs. 362.2 nmol/L).
Although seven patients had red blood cell folate deficiency after treatment (six patients after the placebo and one after folic acid supplementation), none of them had folate deficiency in their blood (levels below 7 nmol/L) after either treatment.
Difference in proportion of patients with detectable unmetabolized folic acid
However, there was a significant difference in the proportion of patients with detectable levels (above 0.27 nmol/L) of unmetabolized folic acid (UMFA), which was most commonly observed after folic acid treatment. UMFA refers to the presence of folic acid in the bloodstream that the body cannot fully utilize.
Specifically, eight patients had detectable levels of UMFA after folic acid supplementation, while two had detectable levels after both folic acid and placebo treatments, and one had detectable levels only after the placebo.
Although the biological effects of UMFA are not fully understood, there is “an emerging need for research to determine whether UMFA produces any adverse effects and the associated biological pathways,” the researchers noted.
Overall, no differences were found in the levels of vitamin B12, hemoglobin levels, the proportion of red blood cells in the blood, or the average size of red blood cells.
There were also no differences in clinical outcomes, including acute pain episodes, the need for red blood cell transfusions, or changes in the size of red blood cell precursors associated with a folate deficiency, when participants were given folic acid or a placebo.
“Future … research to examine the capacity of sickled [red blood cells] to reflect folate status would be helpful to inform the assessment and interpretation of folate status in this population,” the researchers wrote.
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