Stopping Folic Acid Supplementation in Hydroxyurea Treated Children with Sickle Cell Disease

Daily folic acid supplementation for all children with sickle cell disorders is a widely used preventative measure in UK practice. However, a Cochrane review in 2016 concluded there is little evidence for this practice (CD011130). The only randomised clinical trial of folate supplementation in children, conducted in 1983, showed no evidence of benefit. (Rabb et al. ,1983).

More convincing evidence as to the benefits of hydroxyurea and penicillin exists. However, adherence to these effective therapies can be a problem. We hypothesised that stopping folic acid could be clinically useful as this would reduce treatment burden on patients and allow them to focus on adherence to more effective medicines.

We reviewed the medical records of children receiving hydroxyurea for sickle cell disorders managed in our treatment centre. Children were selected for withdrawal from folic acid supplementation based on an absence of uncontrolled haemolysis; reticulocytes <200 x10⁹/L and bilirubin <80µmol/L, and an absence of low serum folate or low red cell folate. Clinical and laboratory monitoring was performed every 4 weeks to establish whether any benefit or adverse effect could be identified. This included monitoring Hb, HbF, MCV, neutrophils, platelets, reticulocytes, serum folate and red cell folate levels.

We withdrew folic acid supplementation from 30 children with sickle cell disorders (mean age 9.5 years (range 2-18)) and monitored clinical and laboratory parameters. At the time of this review, mean follow up time was 11.5 months (range 7-14).

Baseline investigations showed that serum folate levels in 14 children were so high in comparison to normal reference ranges that they were unquantifiable by standard laboratory analysis at our centre. The mean serum folate level in the other 16 children was 39.5 nmol/L (reference range 3.4-38.5 nmol/L). Similarly, red cell folate levels in 5 children were above maximum quantifiable levels. The mean red cell folate level in the other 25 children was 1445 nmol/L (reference range 272-1948 nmol/L).

On withdrawal of folic acid supplementation, all patients' serum folate and red cell folate levels returned to within the normal range. At the end of this observation period, mean serum folate level was 20.9 nmol/L and mean red cell folate level was 617.2 nmol/L, with no patients developing low serum folate or low red cell folate levels. No patients developed megaloblastic changes or any other clinical need to restart supplementation. Folic acid levels began to reduce immediately on withdrawal of supplementation and in most cases reached a plateau by 6 months. However, plateauing levels were not recorded in all patients and this is likely attributable to the shorter follow up time for some patients.

All patients were managed as per our standard protocol of escalating hydroxyurea therapy to maximum tolerated dose. An increase in mean dose from 27.0 mg/kg/day to 30.3 mg/kg/day ( p=0.0003) was recorded during the observation period. Other statistically significant changes in haematological parameters were: increased HbF (25.8% to 29.7%, p=0.0002 and increased MCV (91.2 to 94.7, p=0.026). No significant differences were recorded in haemoglobin, neutrophils, platelets or reticulocytes (statistical analysis was performed by paired T-test).

Stopping folic acid supplementation has caused no observable adverse effects either clinically or in laboratory haematological parameters. The significant increases in HbF and MCV observed here can be explained by the significant increase in hydroxyurea dose during the observation period and are not likely to be an effect of stopping folic acid.

Stopping folic acid is a minor change in patient management however, patients generally don't like taking medicines and stopping a medicine that is not required was seen as an improvement in quality of life. At the end of our observation period, laboratory parameters had improved and there was no evidence of any adverse effect of stopping folic acid supplementation in children with sickle cell disease.

Dixit et al., 2016. Cochrane Review, CD011130

Rabb et al., 1983. British Journal of Haematology 54(4):589-94