Review question

We wanted to assess how effective and safe folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) is in people with sickle cell disease (SCD).

Background

SCD is a group of disorders affecting haemoglobin (the molecule in red blood cells that delivers oxygen to cells throughout the body), leading to distorted sickle or crescent-shaped red blood cells. It is characterized by anaemia (the blood cannot carry enough oxygen around the body), repeated infections and episodes of pain. While SCD was originally found in the tropics and subtropics, due to migration, it is now common worldwide. There are three widely-used preventative measures for managing SCD, these include penicillin, immunisation against pneumococcal infection and folate supplementation. Folate is a water-soluble B vitamin needed for erythropoiesis (the process which produces red blood cells). Given there is increased erythropoiesis in people with SCD, it is thought they may require increased folate intake, by supplements or through diet. However, a lack of evidence-based research means it is still not clear whether the benefits of supplementation outweigh the risk of possible adverse effects.

Search date

The evidence is current to: 17 November 2017.

Study characteristics

We included one trial with 117 children with SCD aged between six months and four years. This was a one-year doubIe-blind (both participants and doctors did not know which treatment group the participants were allocated to) controlled triaI comparing children taking folic acid supplements to those taking a placebo (a ‘dummy’ treatment).

Key results

The trial investigators reported that folic acid supplementation led to higher levels of folic acid measured in the blood. However, there were no differences in haemoglobin concentrations at the end of one year.

The trial also reported on clinical factors linked to treatment, including growth, major and minor infections, acute splenic sequestration, episodes of bone or abdominal pains. The investigators reported no differences in these outcomes from baseline to the end of the trial; however, the trial was not large enough to detect any possible differences reported between the folic acid group and the placebo group.

Quality of the evidence

In the included trial it was not clear how participants were allocated to receive folic acid or placebo. The method of making sure that participants and trial staff did not know what treatment each person was receiving (called allocation concealment) was also not described. These two factors mean that the trial had a high risk of biased results.

The trial did not contain many participants. For many of its clinical endpoints, it was not designed to show differences between people taking folic acid and those taking a placebo. This means that the results from this trial are imprecise, and therefore hard to interpret.

Finally, our review was meant to investigate folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in children and adults. Because we only identified one trial that investigated one form of supplementation in children, the results are not useful for other populations.

Therefore, we judged the evidence from the included trial to be of low quality. Based on just one low quality study with evidence only to show that folate supplementation raises the blood levels of folic acid, we cannot state whether this treatment is effective or not.

More trials with more people and longer treatment duration (and follow-up) of folate supplementation in people with SCD are needed to strengthen this review; however, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.