对镰状细胞病患者进行叶酸补充
Appendices
Appendix 1. Embase search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| Embase | 2 August 2015 | 1. exp sickle cell/ 2. sickle cell*:tw 3. haemoglobin S*:tw 4. HbS disease:tw 5. 1 OR 2 OR 3 OR 4 6. exp folic acid/ 7. exp folic acid deficiency/ 8. folic acid*:tw 9. folate:tw 10. vitamin B9:tw 11. B9 vitamin:tw 12. vitamin B‐9:tw 13. metafolin:tw 14. levomefolate:tw 15. folvite:tw 16. folacin:tw 17. 5‐methyltetrahydrofolate:tw 18. 5‐methylTHF:tw 19. 5‐MTHF:tw 20. L‐5‐MTHF:tw 21. 6 OR 7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19 OR 20 22. randomized controlled trial:tw 23. controlled clinical trial:tw 24. randomized:tw 25. placebo:tw 26. drug therapy/ 27. randomly:tw 28. trial:tw 29. groups [tiab] 30. 22 OR 23 OR 24 OR 25 OR 26 OR 27 OR 28 OR 29 31. 5 AND 21 AND 30 Results: 10 |
Appendix 2. PubMed search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| PubMed | 31 July 2015 | #1 folic acid[MeSH] OR Folic Acid Deficiency [Mesh] OR folic acid[tw] OR folate[tw] OR vitamin B9[tw] OR B9 vitamin[tw] OR vitamin B‐9[tw] OR metafolin[tw] OR levomefolate[tw] OR folvite [tw] OR folacin [tw] OR 5‐methyltetrahydrofolate[tw] OR 5‐methylTHF[tw] OR 5‐MTHF[tw] OR L‐5‐MTHF[tw] #2 anaemia, sickle cell[MeSH] OR sickle cell[tw] OR haemoglobin S*[tw] OR HbS disease[tw] #3 (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]) #1 AND #2 AND #3 Results: 73 |
Appendix 3. CINAHL search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| CINAHL database | 31 July 2015 | #1 folic acid OR folate OR vitamin B9 OR B9 vitamin OR vitamin B‐9 OR metafolin OR levomefolate OR folvite OR folacin OR 5‐methyltetrahydrofolate OR 5‐methylTHF OR 5‐MTHF OR L‐5‐MTHF #2 sickle cell OR haemoglobin S dis* OR HbS dis* #3 randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR drug therapy OR randomly OR trial OR groups #1 AND #2 AND #3 Results: 7 |
Appendix 4. CABI, Web of Science search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| CABI database | 31 July 2015 | TS = (("sickle cell" OR "haemoglobin S disease" OR "haemoglobin S disorder" OR "HbS disease") AND ("folic acid" OR folate OR "vitamin B9" OR "vitamin B‐9" OR metafolin OR levomefolate OR folvite OR folacin OR 5‐methyltetrahydrofolate OR 5‐methylTHF) AND (“randomized controlled trial” OR “controlled clinical trial” OR randomized OR placebo OR “drug therapy” OR randomly OR trial OR groups)) Results: 27 |
Appendix 5. ISRCTN search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| ISRCTN | 2 August 2015 | #1 folic acid OR folate OR vitamin B9 OR B9 vitamin OR vitamin B‐9 OR metafolin OR levomefolate OR folvite OR folacin OR 5‐methyltetrahydrofolate OR 5‐methylTHF OR 5‐MTHF OR L‐5‐MTHF #2 sickle cell OR haemoglobin S OR HbS disease #1 AND #2 Results: 0 |
Appendix 6. ClinicalTrials.gov search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| ClinicalTrials.gov | 31 July 2015 and 02 February 2018 | #1 "sickle cell" OR "haemoglobin S disease" OR "haemoglobin S disorder" OR "HbS disease" #2 "folic acid" OR folate OR "vitamin B9" OR "vitamin B‐9" OR metafolin OR levomefolate OR folvite OR folacin OR 5‐methyltetrahydrofolate OR 5‐methylTHF #1 AND #2 Results: 9 |
Appendix 7. ICTRP search strategy
| Database | Date of Search | Search terms |
|---|---|---|
| ICTRP Database | 3 Aug 2015 and 02 Fberuary 2018 | #1 folate #2 sickle cell #1 AND #2 Results: 202 |
Appendix 8. Glossary
| Term | Definition |
|---|---|
| Bioavailability | The extent to which a nutrient or medication can be used by the body. |
| Electrophoretic mobility | The migration of charged colloidal particles or molecules through a solution under the influence of an applied electric field usually provided by immersed electrodes. |
| Erythropoiesis | The formation or production of red blood cells. |
| Megaloblastic anaemia | A type of anaemia characterised by enlarged red cells and a relative reduction in leukocytes and platelets. |
| Neoplastic foci | Microscopic visualisation of the tumour cells. |
| Polyglutamates | A polymer of glutamic acid residues in the usual peptide linkage. |
| Mean cell volume | It is a measure of the average volume of a red blood corpuscle (or red blood cell). The measure is attained by multiplying a volume of blood by the proportion of blood that is cellular (the haematocrit (or hematocrit)), and dividing that product by the number of erythrocytes (red blood cells) in that volume. |
| Femtolitres (fL) | The femtolitre (US femtoliter) is the metric unit of volume equal to 10 −15 litres, or one thousand trillionth (European) or one quadrillionth (American) litre. It is abbreviated fL or fl. One femtolitre is the same as one cubic micrometre (μm). |
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 | |
