Abstract: One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with SCD. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children). Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/L and values below 5 µg/L (low-quality evidence). In the folic acid group, values above 18 µg/L were observed in 33 of 41 (81%) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/L, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year (low-quality evidence). It is important to note that none of the raw data for the outcomes listed above were available for analysis. The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio (RR) 0.99 (95% confidence interval (CI) 0.85 to 1.15) (low-quality evidence); major infections, RR 0.89 (95% CI 0.47 to 1.66) (low-quality evidence); dactylitis, RR 0.67 (95% CI 0.35 to 1.27) (low-quality evidence); acute splenic sequestration, RR 1.07 (95% CI 0.44 to 2.57) (low-quality evidence); or episodes of pain, RR 1.16 (95% CI 0.70 to 1.92) (low-quality evidence). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05). Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups. The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low. There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet). One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with SCD was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear. If further trials were conducted, these may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to SCD-related morbidity. Such trials should include people with SCD of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow-up, than the trial currently included in 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.

Plain-language summary: 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). 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. 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.