The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference

Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States (1). According to the National Health and Nutrition Examination Survey 19992000, 35% of adults reported recent use of multivitamin supplements (1). Most persons use multivitamin and mineral supplements to ensure adequate intake and to prevent or mitigate diseases. The commonly used over-the-counter multivitamin and mineral supplements contain at least 10 vitamins and 10 minerals. Many chronic diseases share common risk factors, including cigarette smoking, unhealthy diet, sedentary lifestyle, and obesity. Important underlying mechanisms for these factors to increase risk for disease include oxidative damage, inflammation, and 1-carbon metabolism (27). Numerous in vitro studies and animal studies have suggested favorable effects of several vitamins and minerals on these processes and on angiogenesis, immunity, cell differentiation, proliferation, and apoptosis (810). The U.S. Food and Nutrition Board has established tolerable upper intake levels for several nutrients. An upper intake level is defined as the highest level of daily nutrient intake that is likely to pose no risk for adverse effects to almost all persons in the general population (11). The strength of the evidence used to determine an upper intake level depends on data availability. Hence, an update of the data on adverse effects will help researchers to evaluate the appropriateness of upper intake levels. We performed a systematic review to synthesize the published literature on 1) the efficacy of multivitamin and mineral supplements and certain commonly used single vitamin or mineral supplements in the primary prevention of cancer and chronic disease in the general adult population and 2) the safety of multivitamin and mineral supplements and certain commonly used single vitamin or mineral supplements in the general population of adults and children (12). The review was done for a National Institutes of Health State-of-the-Science Statement for health care providers and the general public. This report is from the systematic review and focuses on 2 questions: What is the efficacy determined in randomized, controlled trials of multivitamin and mineral supplements (each at a dose less than the upper intake level) in the general adult population for the primary prevention of cancer and chronic diseases or conditions, and what is known about the safety of multivitamin and mineral supplement use in the general population of adults and children, on the basis of data from randomized, controlled trials and observational studies? Methods We defined multivitamin and mineral supplements as any supplements that contain 3 or more vitamins or minerals without herbs, hormones, or drugs. We defined the general population as community-dwelling persons who do not have special nutritional needs. (Examples of persons with special nutritional needs are those who are institutionalized, hospitalized, pregnant, or clinically deficient in nutrients.) A disease or condition was defined as chronic if it persists over an extended period, is not easily resolved, often cannot be cured by medication (although symptoms may be controlled or ameliorated with medication), frequently worsens over time, causes disability or impairment, and often requires ongoing medical care (13). The following chronic diseases were considered: breast cancer, colorectal cancer, lung cancer, prostate cancer, gastric cancer, or any other cancer (including colorectal polyps); myocardial infarction, stroke, hypertension, or other cardiovascular diseases; type 2 diabetes mellitus; Parkinson disease, cognitive decline, memory loss, or dementia; cataracts, macular degeneration, or hearing loss; osteoporosis, osteopenia, rheumatoid arthritis, or osteoarthritis; nonalcoholic steatohepatitis; chronic renal insufficiency or chronic nephrolithiasis; HIV infection, hepatitis C, or tuberculosis; and chronic obstructive pulmonary disease. We focused on primary prevention trials in adults because primary prevention is the main purpose of multivitamin supplement use in the general adult population (14). Primary prevention was defined as an action taken to prevent the development of a disease in persons who are well and do not have the disease in question (15). Using this definition, we included studies for prevention of chronic disease (for example, cardiovascular disease) in persons with risk factors (for example, type 2 diabetes mellitus or hypertension) for that disease. We also included studies for prevention of malignant disorders (such as colon cancer) in persons with selected precursors of disease (such as polyps). We did not include studies in persons with carcinoma in situ or similar malignant conditions. Literature Sources We searched the MEDLINE, EMBASE, and Cochrane databases, including Cochrane Reviews and the Cochrane Central Register of Controlled Trials, for articles published from 1966 through February 2006. Additional articles were identified by searching references in pertinent articles, querying experts, and hand-searching the tables of content of 15 relevant journals published from January 2005 through February 2006. Search Terms and Strategies We developed a core strategy for searching MEDLINE, accessed through PubMed, that was based on analysis of the Medical Subject Heading terms and text words of key articles identified a priori. This strategy formed the basis for the strategies developed for the other databases (see the complete evidence report for additional details) (12). Inclusion and Exclusion Criteria We focused on trials that ascertained clinical end points. Biomarker data were considered if data were presented in a way that permitted ascertainment of incident cases of chronic disease. Because users of multivitamin supplements were more likely than nonusers to be women, to be older, to have higher levels of education, to have a healthier lifestyle (more physical activities, more fruit and vegetable intake, and less likely to be smokers), and to more frequently use nonsteroidal anti-inflammatory drugs (1, 16), residual confounding would limit the internal validity of observational studies. Hence, for assessment of efficacy, we focused on data from randomized, controlled trials as the strongest source of evidence. However, for assessment of safety, we included data from randomized, controlled trials and observational studies in adults and children to minimize the risk for missing any potential safety concerns. An article was excluded if it was not written in English; presented no data in humans; included only pregnant women, infants, persons 18 years of age or younger (except if a study of persons 18 years of age presented data on the safety of multivitamin and mineral supplements), patients with chronic disease, patients receiving treatment for chronic disease, or persons living in long-term care facilities; studied only nutritional deficiency; did not address the use of supplements; did not address the use of supplements separately from dietary intake; did not cover any pertinent diseases; or was an editorial, commentary, or letter. Each article underwent title review, abstract review, and assessment of inclusion or exclusion by paired reviewers. Differences in opinion were resolved through consensus adjudication. Article review, organization, and tracking were performed by using Web-based SRS, version 3.0 (TrialStat! Corp., Ottawa, Ontario, Canada). Assessment of Study Quality Each eligible article was reviewed by paired reviewers who independently rated its quality according to 5 domains: the description of how study participants were representative of the source population (4 items), bias and confounding (12 items), descriptions of study supplements and supplementation (1 item), adherence to treatment and follow-up (7 items), and statistical analysis (6 items). Reviewers assigned a score of 0 (criterion not met), 1 (criterion partially met), or 2 (criterion fully met) to each item. The score for each quality domain was the proportion of the maximum score available in each domain. The overall quality score of a study was the average of the 5 scores for the 5 domains. The quality of each study in each domain was classified as good (score 80%), fair (score of 50% to 79%), or poor (score < 50%). For data on adverse effects, causality was evaluated with respect to temporal relationship, lack of alternative causes, doseresponse relationship, evidence of increased circulating levels of the nutrient under investigation, disappearance of adverse effects after cessation of supplement use, and response to rechallenge. Data Extraction Paired reviewers abstracted data on study design, participant characteristics, study supplements, and results. Data abstraction forms were completed by a primary reviewer and were verified for completeness and accuracy by a second reviewer. Evidence Grading We graded the quantity, quality, and consistency of the evidence on efficacy by adapting an evidence grading scheme recommended by the Grading of Recommendations Assessment, Development and Evaluation Working Group (17). The strength of evidence was classified into 1 of 4 categories: high (further research is very unlikely to change our confidence in the estimates of effects), moderate (further research is likely to greatly affect our confidence in the estimates of effects and may change the estimates), low (further research is very likely to greatly affect confidence in the estimates of effects and is likely to change the estimates), or very low (any estimate of effect is very uncertain). Role of the Funding Source This article is based on research conducted at the Johns Hopkins Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (contract no. 290-02-0018), Rockville, Maryland, in response to a task order requested by the National Institutes of Health Office of M