Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency

Haiyan Wang; Linyi Li; Ling Ling Qin; Yanan Song; Josep Vidal‐Alaball; Tong Hua Liu

doi:10.1002/14651858.CD004655.pub3

Cochrane Database of Systematic Reviews

Vitamina B₁₂ oral versus vitamina B₁₂ intramuscular para la deficiencia de vitamina B₁₂

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DOI:

https://doi.org/10.1002/14651858.CD004655.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

15 marzo 2018see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Trastornos metabólicos y endocrinos

Copyright:

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Haiyan Wang

Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
Linyi Li

Key Laboratory of Upper Airway Dysfunction‐related Cardiovascular Diseases, Beijing Anzhen Hospital，Capital Medical University，Beijing Institute of Heart，Lung and Blood Vessel Diseases, Beijing, China
Ling Ling Qin

Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
Yanan Song

Dongfang Hospital Affiliated to Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
Josep Vidal‐Alaball

Gerència Territorial Catalunya Central, Catalan Health Institute, St Fruitós de Bages, Spain
Tong Hua Liu

Correspondencia a: Graduate Campus, Beijing University of Chinese Medicine, Beijing, China

[email protected]

Contributions of authors

All review authors read and approved the final review draft.

Hai Yan Wang (HYW): trial selection, data analysis, data interpretation, quality of evidence assessment, and review writing.

Linyi Li (LYL): data extraction and 'Risk of bias' assessment.

Ling Ling Qin (LLQ): data extraction and 'Risk of bias' assessment.

Yanan Song (YNS): trial selection, 'Risk of bias' assessment, data analysis, data interpretation, and review update.

Josep Vidal‐Alaball (JVA): protocol draft, search strategy development, acquiring trial reports, trial selection, data extraction, data analysis, data interpretation, review draft, and future review updates.

Tong Hua Liu (THL): trial selection, data analysis, quality of evidence assessment, and data interpretation.

Sources of support

Internal sources

Department of General Practice, Wales College of Medicine, Cardiff University, UK.
National Public Health Service for Wales, Wales, UK.
Department of General Practice and Elderly Care Medicine, VU University Medical Center, Amsterdam, Netherlands.

External sources

No sources of support supplied

Declarations of interest

HYW: none known

LYL: none known.

LLQ: none known.

YNS: none known.

JVA: none known.

THL: none known.

Acknowledgements

Christopher C Butler, Rebecca Cannings‐John, Andrew Goringe, Kerry Hood, Andrew McCaddon, Ian McDowell, Alexandra Papaioannou, Johannes C van der Wouden, and Rianne Langeveld (original Cochrane Review).
The search strategies for this review update were designed and run by the CMED Group's Information Specialist, Maria‐Inti Metzendorf.
We thank Ms Sai Zhao from Systematic Review Solution Ltd for being our methodology and reporting consultant.

Version history

Published

Title

Stage

Authors

Version

2018 Mar 15

Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency

Review

Haiyan Wang, Linyi Li, Ling Ling Qin, Yanan Song, Josep Vidal‐Alaball, Tong Hua Liu

https://doi.org/10.1002/14651858.CD004655.pub3

2005 Jul 20

Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency

Review

Josep Vidal‐Alaball, Christopher Butler, Rebecca Cannings‐John, Andrew Goringe, Kerry Hood, Andrew McCaddon, Ian McDowell, Alexandra Papaioannou

https://doi.org/10.1002/14651858.CD004655.pub2

2004 Jan 26

Oral vitamin B12 versus parenteral vitamin B12 for vitamin B12 deficiency.

Protocol

Josep Vidal‐Alaball, Chris Butler, Kerry Hood, Rebecca Cannings, Andrew McCaddon, Alexandra Papaioannou

https://doi.org/10.1002/14651858.CD004655

Differences between protocol and review

The review authors' team changed for this update: Christopher C Butler, Rebecca Cannings‐John, Andrew Goringe, Kerry Hood, Andrew McCaddon, Ian McDowell, Alexandra Papaioannou, Johannes C van der Wouden, and Rianne Langeveld are no longer review authors.

Since the last publication of this review (Issue 3, 2005), multiple changes such as new methods and other standards were introduced, leading to a complete renewal of this Cochrane Review. We have revised the search strategies for this review update. The following sections have also been changed.

We used a cut‐off point below 200 pg/mL (below 148 pmol/L) as a threshold serum level for vitamin B₁₂ deficiency to better differentiate vitamin B₁₂ deficiency from borderline deficiency.
Types of outcomes: we added the section 'Method and timing of outcome measurement' to define each outcome and group the timing of outcome measurement.
Types of outcomes: we added a 'Summary of findings' table.
We updated the 'Assessment of risk of bias of included studies' section to provide further details about our judgements.
We revised the 'Data extraction and management' section by specifying data items we planned to extract; adding two sections: 'Unit of analysis issues' and ' Dealing with missing data'; and other minor amendments.

Notes

We included a total of three trials in this update (one additional trial compared to the first published version in 2005).

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Aged; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 1 Serum vitamin B12 levels.

Analysis 1.1

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 1 Serum vitamin B₁₂ levels.

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 2 Number of participants with normalisation of serum vitamin B12 deficiency.

Analysis 1.2

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 2 Number of participants with normalisation of serum vitamin B₁₂ deficiency.

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 3 Adverse events.

Analysis 1.3

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 3 Adverse events.

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 4 Haemoglobin.

Analysis 1.4

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 4 Haemoglobin.

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 5 Mean corpuscular volume.

Analysis 1.5

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 5 Mean corpuscular volume.

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 6 Total homocysteine.

Analysis 1.6

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 6 Total homocysteine.

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Comparison 1 Oral versus intramuscular vitamin B12, Outcome 7 Serum methylmalonic acid.

Analysis 1.7

Comparison 1 Oral versus intramuscular vitamin B₁₂, Outcome 7 Serum methylmalonic acid.

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Summary of findings for the main comparison. Oral versus intramuscular vitamin B12 for vitamin B12 deficiency

Oral versus intramuscular vitamin B₁₂ for vitamin B₁₂ deficiency
Patient: people with vitamin B₁₂ deficiency Setting: outpatients Intervention: oral versus IM vitamin B₁₂
Outcomes	IM vitamin B₁₂	Oral vitamin B₁₂	Relative effect (95% CI)	No. of participants (trials)	Quality of the evidence (GRADE)	Comments
Serum vitamin B₁₂ levels Normal value: > 300 pg/mL (> 221 pmol/L) Follow‐up: 90 days and 4 months	See comment	See comment	Not estimable	153 (3)	⊕⊕⊝⊝ low^a	1 trial (60 participants) used 1000 μg/day oral or IM vitamin B₁₂ (total dose 15 mg): MD was ‐11.7 pg/mL (95% CI ‐29.5 to 6.1) (Bolaman 2003). 1 trial (33 participants) used 2000 μg/day vitamin B₁₂ (total dose 240 mg) or 1000 μg/day IM vitamin B₁₂ (total dose 9 mg): MD was 680 pg/mL (95% CI 392.7 to 967.3) in favour of oral vitamin B₁₂ (Kuzminski 1998). 1 trial (60 participants) (using 1000 μg/day oral or IM vitamin B₁₂ (total dose 90 mg and 15 mg, oral and IM respectively) reported that 27/30 in the IM vitamin B₁₂ group (90%) and 20/30 in the oral vitamin B₁₂ group (66.7%) achieved normalisation of serum vitamin B₁₂, defined as ≥ 200 pg/mL (Saraswathy 2012).
Clinical signs and symptoms	Not reported
Adverse events Follow‐up: 90 days and 3 months	See comment	See comment	Not estimable	120 (2)	⊕⊝⊝⊝ very low^b	Bolaman 2003 reported no treatment‐related adverse events in both the oral and IM vitamin B₁₂ groups. Saraswathy 2012 reported that 2/30 participants (6.7%) in the oral vitamin B₁₂ group left the trial early due to adverse events.
Health‐related quality of life	Not reported
Acceptability	Not reported
Socioeconomic effects Follow‐up: 90 days	See comment	See comment	Not estimable	60 (1)	⊕⊕⊝⊝ low^c	Only 1 trial reported data for this outcome (Bolaman 2003). The costs per treatment were USD 80 per person in the oral vitamin B₁₂ group compared with USD 220 per person in the IM group.
CI: confidence interval; IM: intramuscular; MD: mean difference
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.
^aDowngraded by two levels due to serious imprecision (low numbers of trials and participants); see Appendix 12. ^bDowngraded by three levels due to risk of bias (performance bias, detection bias) and serious imprecision (low numbers of trials and participants); see Appendix 12. ^cDowngraded by two levels due to serious imprecision (low numbers of trials and participants); see Appendix 12.

Summary of findings for the main comparison. Oral versus intramuscular vitamin B12 for vitamin B12 deficiency

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Table 1. Overview of trial populations

	Intervention(s) and comparator(s)	Description of power and sample size calculation	Screened/eligible (N)	Randomised (N)	Analysed (N)	Finishing trial (N)	Randomised finishing trial (%)	Follow‐up (extended follow‐up)^a
Bolaman 2003 (parallel RCT)	I: 1000 µg oral vitamin B₁₂	—	—	26	26	26	100	90 days (none)
	C: 1000 µg IM vitamin B₁₂	—	—	34	34	34	100
	Total:			60^b	60	60	100
Kuzminski 1998 (parallel RCT)	I: 2000 µg oral vitamin B₁₂	—	138	18	18	18	100	4 months (none)
	C: 1000 µg IM vitamin B₁₂	—	138	15	15	15	100
	Total:			33^c	33	33	100
Saraswathy 2012 (parallel RCT)	I: 1000 μg oral vitamin B₁₂	"Sample size was estimated to be 23 in each study arm, assuming equal response of 90% and non inferiority margin of 25% /alpha = 0.25, 1‐beta = 80%)"	—	30	22	22	73	3 months (none)
	C: 1000 μg IM vitamin B₁₂		—	30	27	27	90
	Total:			60	49	49	82
*Grand total*	*All interventions*			74		66
	*All comparators*			79		76
	*All interventions and comparators*			*153*		*142*
— denotes not reported C: comparator; I: intervention; IM: intramuscular; RCT: randomised controlled trial ^aFollow‐up under randomised conditions until end of trial (= duration of intervention + follow‐up postintervention or identical to duration of intervention); extended follow‐up refers to follow‐up of participants once the original trial was terminated as specified in the power calculation. ^bOf 70 participants enrolled in the trial, 10 were excluded because of failure to appear for follow‐up after 10 days of treatment. ^c38 participants were randomised; after completion of the trial 5 participants were judged to have primary folate deficiency rather than vitamin B₁₂ deficiency and were excluded from the final analysis.

Table 1. Overview of trial populations

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Comparison 1. Oral versus intramuscular vitamin B12

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum vitamin B₁₂ levels Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Totals not selected

2 Number of participants with normalisation of serum vitamin B₁₂ deficiency Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4 Haemoglobin Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5 Mean corpuscular volume Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

6 Total homocysteine Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7 Serum methylmalonic acid Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

Comparison 1. Oral versus intramuscular vitamin B12

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Vitamina B₁₂ oral versus vitamina B₁₂ intramuscular para la deficiencia de vitamina B₁₂

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