ReviewMultivitamin/mineral supplements: Rationale and safety – A systematic review
Introduction
An increasing number of individuals take multivitamin/mineral supplements (MVM) to maintain good health and to be protected from different diseases (e.g., cardiovascular disease [CVD], cancer, and cognitive decline). The US Department of Agriculture/Department of Health and Human Services 2010 Dietary Guidelines for Americans acknowledge that “supplements containing combinations of certain nutrients may be beneficial in reducing the risks of some chronic diseases when used by special populations,” yet also state that excessive use of certain supplements has the potential to be harmful [1]. This might in particular be the case for single supplements in concentrations exceeding the normal recommended dietary allowance (RDA), as recently documented [2], or those with an imbalanced composition. This raises the question whether an adequately (within 100% of RDA) composed MVM is safe.
According to a National Institutes of Health (NIH) State of the Science Panel, an “MVM refers to any supplement containing 3 or more vitamins and minerals but no herbs, hormones, or drugs, with each component at a dose less than the tolerable upper level determined by the Food and Nutrition Board—the maximum daily intake likely to pose no risk for adverse health effects” [3]. In an NIH fact sheet regarding MVM [4], a more differentiated approach defines groups of MVM as follows:
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Many MVM are taken once daily and contain all or most recognized vitamins and minerals at levels close to daily values, RDAs, or adequate intakes. Basic formulations are for broad-spectrum use. Formulations for special populations such as children, pregnant women, and seniors provide the same vitamins and minerals in amounts tailored to those populations' specific needs.
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Other MVMs contain vitamins and minerals at levels substantially higher than the recommended values and may also include other nutritional and herbal ingredients. These are sometimes packaged in multiple-pill packs to be taken each day.
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Specialized MVMs, used, for example, to enhance performance or improve immune function or for weight control, are often composed of vitamins and minerals in combination with herbal or specialty ingredients such as coenzyme Q10, probiotics, and glucosamine. These may also include nutrients at levels substantially above recommended levels.
Using the NIH State of the Science Panel and the Agency for Healthcare Research and Quality definition of a multivitamin as containing 3 or more vitamins and/or minerals [5], the supplements listed in the second and third bullets above are indeed MVM. However, to exclude specific formulations or doses of vitamins or minerals near the tolerable upper intake level (UL), we decided to focus our review only on MVM as defined in the first bullet. This is in accordance with the definitions of MVM per the National Health and Nutrition Examination Survey (NHANES) III [6] (10 vitamins + calcium and iron) and the National Health Interview Survey (10 vitamins+5 minerals) [7].
There is indeed a strong difference regarding safety issues if MVM with concentrations at or below the RDA are compared with MVM having doses near the UL or with one or more components that exceed the RDA. The major risk, if any, of MVM at or below RDA may be an insufficient supply of one or more micronutrients that might not cover the individual need in case of a higher demand or inadequate supply through nutrition. MVM with concentrations above the RDA might exert adverse effects (AEs), particularly with long-term use. We only evaluated the safety aspects in the healthy population for dosages within the RDA, because if an MVM shows a beneficial effect, it could be the result of a compensation for an inadequate intake (below RDA) of one or more micronutrients.
Section snippets
Limitations in setting dietary recommendations
A major problem in understanding the effect of micronutrients is that the body's physiological need is not fully understood across all organs and systems. With few exceptions, micronutrients are needed in the cells and tissues and might undergo a specific metabolism within the cells. Blood is the delivery route for nearly all nutrients to cells and tissues. Therefore, the blood may not reflect real adequacy or inadequacy. Typically, a primary indicator (biomarker or blood concentration)
Micronutrient inadequacy—the micronutrient gap
A micronutrient gap may be defined as an intake below the EAR. What does this mean? Those with a micronutrient intake below the EAR might develop clinical signs and symptoms of deficiency depending on the duration of the gap and individual need. Clinical signs of deficiency are the “endpoint” of a deficiency disease. Before symptoms occur, hidden hunger exists, which means that traditional deficiency symptoms are missing, but health problems may occur in either the short or long term. Depending
Pregnancy
A major group that bears a risk of inadequacy in the short term are pregnant women. Pregnancy and early childhood are vulnerable periods for an inadequate supply of micronutrients. There is increasing knowledge that an inadequate supply of certain micronutrients may exert negative effects on birth weight and time of delivery. An extensive review of micronutrient intakes in women living in resource-poor settings revealed that pregnant and non-pregnant, non-lactating women were at the risk of
Safety
In high-income countries in Europe and the United States, multivitamins are the most commonly used vitamin supplements. In particular, the increasing numbers of healthy elderly are the major consumers of multivitamins to improve or maintain their health. However, concerns are raised that multivitamins might create harmful effects, and their long-term safety is in question.
The European Food Safety Authority [19] assesses the safety of supplement use based on the risk of exceeding an established
Literature search and study selection
To uncover studies reporting safety issues related to MVM, we reviewed different databases (i.e., Medline, Embase, and Cochrane Database of Systematic Reviews), as well as the Internet, different library catalogues, and document servers of the University of Hohenheim. We searched mainly for articles published since 2010. MVM commonly used were within a “physiological” range (i.e., a range that can be achieved via nutrition and that does not exceed the RDA).
To exclude AEs that might be related
Safety and pregnancy
The rationale for MVM supplementation during pregnancy is the co-existence of multiple micronutrient deficiencies in pregnant women, in particular in resource-poor settings [16]. Resources, however, are not only a question of availability but also of education and knowledge.
Trials of MVM in pregnant women for primary prevention are carried out to improve either maternal health or birth outcome. Most trials did not specifically address AEs. Nevertheless, differences in birth outcome can be taken
Safety for healthy adults and elderly
Few clinical trials exist that explicitly address the question of AE as a possible consequence of MVM supplementation (Supplemental Table 1B). In the largest randomized clinical trial with adult male physicians (Physicians' Health Study [PHS] II; mean age 64 y) [33] the authors assessed a number of potential AEs of daily multivitamin use and found no significant effect on gastrointestinal tract symptoms (peptic ulcer, constipation, gastritis, and nausea), fatigue, drowsiness, skin
Historical safety concerns
Concerns are frequently raised that the combination of MVM with food, including fortified foods, might result in AEs and could cause long-term users to exceed ULs. In an analysis of the NHANES data for 16 444 participants, the use of MVM supplements reduced the percentage of the population falling below the EAR but did not result in excess intake [10]. In MVM supplement users ≥4 y of age the prevalence of those exceeding the UL was 1.7% for retinol and 2.5% for folic acid.
In analyses of data
MVM supplements for a healthy population?
MVM supplements are safe but according to the PHS II, without a real benefit. That raises the question: Who should supplement and why? Generally spoken micronutrients can compensate inadequate supply or transient micronutrient gaps. The majority of the participants of PHS II celebrated a healthy life style (few smokers, most with a normal weight, a high vegetable intake, and regular exercise) and a supplement seems not really necessary. However, in cases of sudden disease or periods of
Conclusions
Despite a balanced and overall healthy diet, micronutrient gaps may occur from time to time. Any impact on health depends on the gap's duration and severity. Individual needs differ based on health, lifestyle, genetics, and other factors. The precise individual need is difficult to measure and requires further investigation to improve methods of assessment. Nevertheless, MVM supplement consumption has been shown to reduce dietary intake gaps and to improve measures of nutritional status without
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Editorial support was provided by Peloton Advantage and funded by Pfizer. All authors have read and approved the final manuscript. Dr. Biesalski received an honorarium from Pfizer for the development of this manuscript. Jana Tinz has no conflicts of interest.