鎌状赤血球症の患者における葉酸補充
Referencias
References to studies included in this review
References to studies excluded from this review
References to ongoing studies
Additional references
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Double‐blind quasi‐RCT. | |
| Participants | 117 children admitted to the trial (115 analysed). Children with homozygous SCD aged 6 months to 4 years. | |
| Interventions | 5 mg folic acid (treatment B) versus a placebo of calcium lactate (treatment A) | |
| Outcomes | Folate concentration, haemoglobin concentration, recurrent infections, minor infections, major infections, acute splenic sequestration, dactylitis or episodes of bone or abdominal pain. | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | "A trial of pneumococcal vaccine and prophylactic penicillin, involving four treatment regimes. was already underway in this same group of children and it was important to ensure that the groups receiving tablets A and B were similarly distributed between these regimes. This was achieved by allocating the children alternately to tablets A and B within each of the four treatment regimes". |
| Allocation concealment (selection bias) | Unclear risk | Not mentioned in the text. |
| Blinding of participants and personnel (performance bias) | Low risk | "Tablets A and B were identical in appearance and neither the participants nor the paediatricians involved in the clinical management of the study were aware of the code." |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not mentioned in the text. |
| Incomplete outcome data (attrition bias) | High risk | There was a large proportion of missing data for one of our primary outcomes (folate measurements, only 70% data available) and a somewhat substantial proportion of missing data for other primary and secondary outcomes (haemoglobin, growth). Out of 117 children admitted to the trial, only 115 were analysed, and further no reason cited for missing numbers. |
| Selective reporting (reporting bias) | Unclear risk | There was no protocol or resource outlining previously defined outcomes. |
| Other bias | Low risk | No other biases were detected. |
RCT: randomized controlled trial
SCD: sickle cell disease
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| RCT with 133 child participants with SCD (HbSS) in Nigeria. Participants were randomly allocated into 3 comparison groups, all of which took 1 to 2 tablets containing various therapeutic agents, either alone or in a specific formula preparation, including anti‐malarials, vitamins, and/or steroids. All 3 groups' treatment regimens included 5 mgm of folic acid. Outcomes included efficacy in malaria control, prevention of folic acid deficiency, infection control, growth indicators, and "overall course of the disease." The study did not contain a control group without folic acid supplementation, even at a different dosage, and was therefore not included in our analyses. | |
| Non‐randomised, single‐arm trial with 61 children and adult participants with SCA and 2 socio‐economically matched control groups (61 with sickle cell trait, HbAS, and 69 race‐matched controls without sickle cell trait, HbAA). Participants did not take folic acid supplements had not experienced an infection or pain crisis within 2 weeks of enrolment. 24 participants with SCA who had low baseline serum or erythrocyte folate levels (or both) were supplemented with 1 mg folic acid per day for 3 to 12 months. Clinical and laboratory measures were taken for all participants with SCA twice prior to folate therapy and for 24 participants with SCA, twice after therapy. This study was not a RCT and was therefore not included in our review. | |
| Randomised placebo‐controlled trial with 51 adult participants (23 controls, 28 cases) in Iran with β‐thalassemia major on regular blood transfusions. Participants were stratified by baseline serum folate levels and then randomised to receive folic acid tablets (1 mg) or placebo, taken once daily for 4 weeks, at which point serum folate and other hematological indices were measured. Exclusion criteria included pregnant or lactating women, those with chronic liver disease, or those using folic acid supplements or medications interfering with folic acid metabolism. The study participants did not match our study eligibility criteria and was therefore not included in our analyses. | |
| RCT with 119 child participants with SCD (HbSS) in Tanzania. Children received in random order a daily RUSF providing 500 kcal, 1 RDA of vitamins and minerals & 1mg folate (Nutriset, France), plus weekly anti‐malarial prophylactic chloroquine syrup (150/225 mg base) (Wallace manufacturing chemicals, UK), or a vascular‐RUSF (RUSFv) fortified with arginine and citrulline (average 0.2 g/kg/d & 0.1 g/kg/d) plus daily chloroquine syrup (3 mg base/kg/d). Both the groups’ treatment regimens included 1 mg of folate. Outcomes included endothelium‐dependent and ‐independent vasodilatation, height, and weight and body composition. The study did not contain a control group without folic acid supplementation, even at a different dosage, and was therefore not included in our review. |
RCT: randomised controlled trial
RDA: recommended daily allowance
RUSF: ready‐to‐use supplementary food
SCA: sickle cell anaemia
SCD: sickle cell disease
Characteristics of ongoing studies [ordered by study ID]
| Study name | Study of Beet Juice for Patients With Sickle Cell Anemia (NCT02162225). |
| Methods | Phase 2 clinical trial. Single group assignment. |
| Participants | Adults with sickle cell anaemia. |
| Interventions | Beet juice (dietary provision of folate). |
| Outcomes | Safety of intervention. |
| Starting date | June 2014. |
| Contact information | Natalia Dixon, MD [email protected]. |
| Notes | While we were unable to identify any ongoing randomised controlled trials involving folic acid supplementation or folate provision through diet, we did identify a Phase 2 clinical trial investigating the safety of beet juice (“Unbeetable”) in adults with sickle cell anemia (Kim‐Shapiro NCT02162225). The trial is focused on the provision of nitrates through the beet juice, however, the beet juice also contains a substantial quantity of folate (23% ‐ 46% of daily value, depending on amount consumed). As the trial may ultimately progress to a Phase 3 RCT, it is important to document in this review as potential future research. Note: on 08 November 2017 this trial was suspended due to the fact that enrolment was very slow. The investigators hope to reopen as multi‐site study. |
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Acute splenic sequestration Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.1  Comparison 1: Folic acid supplementation versus placebo, Outcome 1: Acute splenic sequestration | ||||
| 1.2 Painful episodes Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.2  Comparison 1: Folic acid supplementation versus placebo, Outcome 2: Painful episodes | ||||
| 1.3 Minor Infections Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.3  Comparison 1: Folic acid supplementation versus placebo, Outcome 3: Minor Infections | ||||
| 1.4 Major Infection Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.4  Comparison 1: Folic acid supplementation versus placebo, Outcome 4: Major Infection | ||||
| 1.5 Dactylitis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Analysis 1.5  Comparison 1: Folic acid supplementation versus placebo, Outcome 5: Dactylitis | ||||
Study flow diagram
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Folic acid supplementation versus placebo, Outcome 1: Acute splenic sequestration
Comparison 1: Folic acid supplementation versus placebo, Outcome 2: Painful episodes
Comparison 1: Folic acid supplementation versus placebo, Outcome 3: Minor Infections
Comparison 1: Folic acid supplementation versus placebo, Outcome 4: Major Infection
Comparison 1: Folic acid supplementation versus placebo, Outcome 5: Dactylitis
| 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 | No of Participants | Quality of the evidence | 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 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 |
| 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 |
| 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 |
| 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 |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 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). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Acute splenic sequestration Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.2 Painful episodes Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.3 Minor Infections Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4 Major Infection Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Dactylitis Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
