Summary of findings 1. Summary of findings.

Folic acid compared with calcium lactate for sickle cell (SS) disease
Patient or population: 117 children with homozygous sickle cell (SS) disease Settings: hospital Intervention: folic acid 5 mg Comparison: calcium lactate (placebo)
Outcomes1	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	calcium lactate (placebo)	folic acid 5 mg
Folate concentration Serum folate levels, measured between 6 and 12 months after entry to the study	1. values in excess of 18 pg/L occurring in 6/39 (15%) children in the placebo group. 2. levels below 5 pg/L occurring in 15/39 (39%)	1. values in excess of 18 pg/L occurring in 33/41 (81 %) in the folic acid group. 2. levels below 5 pg/L None in the folic acid group.	NA	80/115 (70%) (1 study)	⊕⊕⊝⊝ low2	There were marked differences between trial groups in the distribution of serum folate levels.
Haemoglobin concentration Haematological analyses were performed in the 100/115 (87%) children in whom baseline (within 2 months of entry to study) and 1 year (between 10 and 14 months after entry)	See comment	See comment	NA	100/115 (87%) (1 study)	⊕⊕⊝⊝ low2	There were no significant differences in total haemoglobin (Hb) either at baseline or after 1 year.
Adverse events ‐ acute splenic sequestration Clinical events experienced by children during the 1 year period commencing at entry to the trial	8/56 Total episodes 15	9/59 Total episodes 12	RR 1.07 (95% CI 0.44 to 2.57)	115 (1 study)	⊕⊕⊝⊝ low2	There were no significant differences in these measures of growth between the folic acid and placebo groups.
Adverse events ‐ painful episodes Clinical events experienced by children during the 1 year period commencing at entry to the trial	18/56 Total episodes 27	22/59 Total episodes 39	RR 1.16 (95% CI 0.70 to 1.92)	115 (1 study)	⊕⊕⊝⊝ low2	There were no significant differences in painful episodes between the folic acid and placebo groups.
Adverse events ‐ minor Infections Clinical events experienced by children during the 1 year period commencing at entry to the trial	48 out of 56 children Total episodes/child: 2.3	50 out of 59 children Total episodes/child: 2.7	RR 0.99 (95% CI 0.85 to 1.15)	115 (1 study)	⊕⊕⊝⊝ low2	There were no differences in minor infections between the folic acid and placebo groups.
Adverse events ‐ major infections Clinical events experienced by children during the 1 year period commencing at entry to the trial	15 out of 56 children Total episodes/child: 19	14 out of 59 children Total episodes/child: 18	RR 0.89 (95% CI 0.47 to 1.66)	115 (1 study)	⊕⊕⊝⊝ low2	There were no differences in major infections between the folic acid and placebo group.
Adverse events ‐ dactylitis Clinical events experienced by children during the 1 year period commencing at entry to the trial	17 out of 56 children Total episodes: 32	12 out of 59 children Total episodes:15	RR 0.67 (95% CI 0.37 to 1.27)	115 (1 study)	⊕⊕⊝⊝ low2	There were no differences in dactylitis events between the folic acid and placebo group.
*The basis for the assumed risk is the risk in the control group. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.

1. Pre‐specified adverse events of 'Increased incidence of priapism' and 'The risk of masking cobalamin deficiency with consequent neuropsychiatric manifestations (nanogram per litre (ng/L))' were not assessed in the included trial (Rabb 1983). In the included trial, there was no difference between the folic acid and placebo groups for growth, determined by height‐for‐age and weight‐for‐age as well as height and growth velocity.

2. Reason for downgrading evidence to low ‐ very serious risk of bias (two domains of high risk of bias).