BMJ  2005;330:871 (16 April), doi:10.1136/bmj.38399.495648.8F (published 31 March 2005)

Paper

Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials

Alia El-Kadiki, specialist registrar1, Alexander J Sutton, senior lecturer in medical statistics2

1 Chemical Pathology Department, Royal Hallamshire Hospital, Sheffield S10 2JF, 2 Department of Health Sciences, University of Leicester, Leicester LE1 6TP

Correspondence to: A El-Kadiki alia{at}elkadiki.fsnet.co.uk

Abstract

Objective To evaluate the effectiveness of multivitamins and mineral supplements in reducing infections in an elderly population.

Design Systematic review and meta-analysis of randomised controlled trials.

Data sources Medline and other databases. Reference lists of identified articles were inspected for further relevant articles.

Selection of studies Trials were included if they evaluated the effect of multivitamins and mineral supplements on infections in an elderly population.

Review methods Studies were assessed for the methodological quality by using the Jadad instrument. If the data required for the analyses were not available from the published articles we requested them from the original study authors. Meta-analysis was undertaken on three outcomes: the mean difference in number of days spent with infection, the odds ratio of at least one infection in the study period, and the incidence rate ratio for the difference in infection rates. Data on adverse events were also extracted.

Results Eight trials met our inclusion criteria. Because the outcomes reported were inconsistent, only a proportion of the trials could be included in each meta-analysis. Multivitamins and mineral supplements were found to reduce the mean annual number of days spent with infection (three studies) by 17.5 (95% confidence interval 11 to 24, P < 0.001). The odds ratio for at least one infection in the study period (three studies) was 1.10 (0.81 to 1.50, P = 0.53). The infection rate ratio (four studies) was 0.89 (0.78 to 1.03, P = 0.11). Reporting of adverse events was poor.

Conclusion The evidence for routine use of multivitamin and mineral supplements to reduce infections in elderly people is weak and conflicting. Study results are heterogeneous, and this is partially confounded by outcome measure.

Introduction

Ageing is associated with physiological and economical changes that compromise nutritional status, and also with an increased susceptibility to infections. Public interest in vitamin supplements is enormous: 20-30% of the population in developed countries currently use such supplements.1 Few studies have documented their benefits, which has raised concern recently.1 2 In elderly people, supplementation with different nutrients improves immune status. Most of these studies looked at the effect of micronutrients on vaccine responses and other surrogate markers of immune response. The clinical importance of these findings is still a subject of debate; some believe that the micronutrients have a major role3 and others believe that they have only a minor role4 in reducing the frequency of infections in elderly people.

We undertook a systematic review and meta-analysis of randomised controlled trials evaluating the use of multivitamin and mineral supplements to prevent infections in an elderly population.

Methods

We searched computerised databases to identify relevant randomised controlled trials covering the period from 1966 to the first week of January 2004. We supplemented this search by examining published reviews, guidelines, and conference abstracts (for details of the specific search strategies used, see appendix 1 on bmj.com). We scrutinised the reference lists of identified relevant articles to identify any further studies.

Selection
Studies had to be randomised placebo controlled trials, evaluating a combination of multivitamins and mineral supplements in an elderly population. Studies also had to report an infection related outcome.

Data extraction and quality assessment
We focused our attention on the three most widely used and reported outcomes: the mean difference in number of days spent with infection, the odds ratio of at least one infection in the study period, and the incidence rate ratio for the difference in infection rates. Additionally, we extracted any data on adverse events. The authors extracted all outcome data relating to infections and disagreements were resolved by consensus. If data were not available from the published reports, we wrote requesting the information. We used the Jadad scoring system to assess the methodological quality.5

Quantative data synthesis
We used random effects models to perform meta-analyses if the heterogeneity between studies was estimated to be greater than zero; otherwise we used the model reduced to a fixed effect model. The continuous outcome (the mean difference in number of days of infection over 12 months) was combined on the mean difference scale, the binary outcome (one or more infections during the study period) on the (log) odds ratio scale and the incidence rate (the rate of infections during the study period) using weighted (fixed effect) Poisson regression. The relatively small number of studies reporting each outcome precluded the use of funnel plots to assess the possibility of publication bias and meant that using meta-regression to assess heterogeneity between studies was also not possible.

Results

We screened a total of 1490 abstracts from the combined searches. This identified 36 potentially relevant studies, but on obtaining and reading the articles, only eight met the inclusion criteria (see bmj.com for details on design characteristics and quality assessment scores). Variability between studies is considerable with respect to duration of follow-up, infections assessed, and number of subjects. Jadad scores were reasonable for all studies except one, but this probably, at least in part, reflects the brevity of the study report. Three of the trials used a 2x2 factorial trial, and only the two most relevant arms are included in this meta-analysis.

Meta-analysis of first outcome
Figure 1 shows that all three trials individually show a significant reduction in days of infection for the multivitamin and mineral group and the pooled estimate of a benefit of approximately 17.5 days (95% confidence interval 11 to 24) is highly significant (P < 0.001). Although the direction of results is consistent, studies are heterogeneous (the I2 statistic is estimated to be 97.3%, which is considered very large6). We had a concern that the reported standard deviations for this outcome seemed to be very small and may in fact be standard errors. Hence we performed an extreme sensitivity analysis in which we re-analysed the data under the assumption that this error had been made in all three trials; the pooled estimate remained similar and still significant (14 day benefit, 10 to 18, P < 0.001).



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  		Fig 1 Random effects meta-analysis of outcome: mean difference in number of days of infection between multivitamin+supplement and placebo groups in 12 months

 

Meta-analysis of second outcome
Figure 2 shows that the odds ratios for two of the three studies are greater than one, and the pooled odds ratio is 1.10 (0.81 to 1.50). Hence this meta-analysis provides little support for the benefit of multivitamin, and minerals; however, the wide confidence interval makes the findings inconclusive (P = 0.53).



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  		Fig 2 Fixed effects meta-analysis of outcome: odds ratio for at least one infection during the study period between multivitamin+supplement and placebo groups

 

Meta-analysis of third outcome
Figure 3 shows that the pooled incidence risk ratio for the fixed effect model is 0.89 (0.78 to 1.03). Hence there is an indication that multivitamins and minerals may reduce the number of infections, but this does not reach conventional significance levels (P = 0.11).



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  		Fig 3 Fixed effects meta-analysis of outcome: incidence rate ratio for infection between multivitamin+supplement and placebo groups

 

Reporting of adverse events
Reporting of adverse event outcomes for the trials was so incomplete that meta-analysis was not possible. One trial reported some dropouts (four in the treatment group and one in the placebo group) because of nausea, which in our interpretation could be attributable to the intervention. Two further trials indirectly implied that no adverse events causing dropout occurred. Two more trials stated clearly that there were no dropouts owing to the effects of the intervention. No mention of adverse events was given in the remaining three trials.

Discussion

The evidence for the effectiveness of the routine use of multivitamins in an elderly population to reduce infections is of poor to moderate quality, heterogeneous, and conflicting. We found little evidence of adverse events due to the intervention, but this may be due to poor reporting. It is worth noting that other studies using excessive micronutrient supplements (in larger doses than implemented in any of the trials reviewed here) have been shown to have toxic effects and may impair cellular function.15

The potential underlying mechanism by which multivitamins and minerals generally and specifically prevent infections is still uncertain; we do not know whether it is related to improvement in immunity, improvement of the underlying deficiency, or other reasons.

We have qualitatively considered potential factors that may influence the observed heterogeneity. The exact composition of multivitamin and mineral supplements may in part be responsible; two studies used dosages of nutrients that were close to recommended dietary allowances in France and the United States, three studies used nutrient dosages similar to the recommended dietary allowance in the United States, with the exception of vitamin E and {beta} carotene, two studies used a daily oral tablet that contained amounts of vitamins and minerals similar to those found in most commercial multivitamin and mineral supplements, and one study used dosages at the level of recommended dietary allowances for vitamins and 25-50% of recommended dietary allowances for minerals.

A further potential explanation for heterogeneous results is variability in the baseline nutritional status of study participants. Differences were considerable in the baseline rates of infection in the control groups of the four trials reporting infection rates (fig 3). Further, two trials even had marked imbalances in nutrient deficiencies at baseline. The subject populations recruited differed between studies. Two trials recruited exclusively from nursing homes, and one trial included a much higher proportion of people with type 2 diabetes (39%) than any of the others. In the original trial report, a subgroup analysis by diabetes status was carried out, and nearly all the intervention effect was found to the attributed to the diabetic patients. The most beneficial effect sizes were observed in small studies, which may mean this literature is subject to publication bias. Loss to follow-up in some trials was considerable, which could induce bias in those studies. Other factors that may influence outcome include the length of study follow-up and the seasonal changes it covered, which infections were being investigated and how they were measured, and the quality of the studies.

Limitations of the study
We identified only a modest number of relevant studies. This limited the assessments of publication bias and the formal exploration of the considerable heterogeneity between studies. Considerable variability existed in the outcome definitions used to report infections. However, it is noteworthy that in the two instances when two outcomes were reported by a single trial, they gave similar results, implying, perhaps, that definition of outcome is not the most important source of variation. Disappointingly, no more than four studies reported any one outcome.


What is already known on this topic

Ageing is associated with an increased susceptibility to infection

Currently, interest is great in the use of multivitamins and mineral supplements, with the hope of preventing infections

What this study adds

The evidence for routine use of multivitamin and mineral supplements to reduce infections in the elderly is weak and conflicting

Therefore the evidence does not support a policy recommending the routine use of such supplements in all elderly people

Further randomised controlled trials using consistent outcome measures are needed before routine use can be recommended


Comparison with previous studies
Although one previous paper has reviewed the role of micronutrients in preventing infections in elderly people,16 to the best of our knowledge no previous systematic review or meta-analysis of the use of micronutrients in preventing infections in elderly people has ever been undertaken.

Implications for practice
Currently, not enough evidence exists to recommend the routine use of micronutrient supplements for an elderly population. However, the results of this review are sufficiently encouraging to warrant further and more expansive studies.

{webplus.f1}Search strategies are on bmj.com

{elps.f1}This is the abridged version of an article that was posted on bmj.com on 31 March 2005: http://bmj.com/cgi/doi/10.1136/bmj.38399.495648.8F

We thank Catherine Beverly, systematic reviews information officer, University of Sheffield, and Mary Edmunds Otter, clinical effectiveness information librarian, University of Leicester, for assistance and advice on literature searching and for updating the literature search; Nicola Cooper for helpful comments on an earlier draft of this paper; and Trevor Sheldon for very insightful review comments.

Contributors: See bmj.com Funding: None.

Competing interests: None declared.

Ethical approval: Not required.

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