In this large cohort of postmenopausal women, we observed no overall associations between multivitamin use and risk of several common cancers or cardiovascular disease. There were also no associations between multivitamin use and total mortality. Risk estimates did not materially change when stratified by class of multivitamins with the exception of a possible lower risk of MI among users of stress-type supplements. Many stress supplements include high doses of folic acid and other B-vitamins; previous studies have supported a protective role for folic acid in relation to cardiovascular disease and its antecedent risk factors (26
). Alternatively, many statistical tests were conducted as part of this investigation, and it is quite possible that this observation for lower MI risk occurred by chance. For long-term use of multivitamins, there was suggestive evidence for increased risk of endometrial, stomach and kidney cancer, but decreased risk for bladder cancer; however, the variation in risk was not dose-dependent. Long term multivitamin use had no association with any cardiovascular event or total mortality. These results suggest that multivitamin use does not confer meaningful benefit or harm in relation to cancer or cardiovascular disease risk in postmenopausal women.
This report is consistent with most previously published results. The Cancer Prevention II Cohort reported no association of baseline multivitamin use with colorectal cancer, but long-term use (10 years) was associated with significantly reduced risk (RR= 0.71, 95% CI 0.57,0.89) (37
). This same cohort reported no association of multivitamin use with stomach cancer or fatal non-Hodgkin’s lymphoma (24
). A pooled analysis of eight cohort studies from North America and Europe found no overall association of multivitamin use with lung cancer risk, but a RR of 1.17 (95% CI 1.04,1.32) when only women were considered (40
). In the Nurses’ Health Study, multivitamins were associated with lower colon cancer incidence, but only when used for 15 years or more (15
). The Nurses’ Health Study also reported a weak, non-significant protective association for breast cancer for 5–9 years of use multivitamins (41
), but an increased risk for fatal non-Hodgkin’s lymphoma with long term (>10 years) use (24
). The Women’s Health Study was a randomized, placebo-controlled trial of vitamin E and aspirin in 39,876 female health professionals (42
). Since the end of the trial in 2004, participants have been followed as a cohort (42
). The investigators recently reported no association of baseline multivitamin use with subsequent breast cancer risk after an average follow-up of 10 years, nor association by duration of use, but a modest suggestion of effect modification of breast cancer risk by alcohol intake (27
). Fewer cohorts have published data on the association with CVD risk. The Nurses’ Health Study reported an inverse association between multivitamins and risk of MI or any CHD death, but the analysis was focused on B-vitamins, including folic acid (36
). Results from other cohorts with CVD outcomes have not demonstrated any appreciable association of these events with multivitamin use (25
NIH’s Office of Dietary Supplements and Office of Medical Applications sponsored a 2006 conference to evaluate the evidence for multivitamin efficacy in relation to chronic disease prevention. An executive summary concluded that there was insufficient evidence to either promote or discourage the use of multivitamins for chronic disease prevention (2
). This declaration is similar to a 2003 report from the U.S. Preventive Services Task Force stating that data were insufficient to either support or oppose dietary supplements, including multivitamins, for prevention of cardiovascular disease and cancer (43
). The American Heart Association’s Nutrition Committee recommends against the use of antioxidant supplements for cardiovascular disease prevention, but their statement refers to single supplements or mixtures of five or fewer ingredients. No specific statement about standard multivitamins has been issued (44
). The American Cancer Society’s “Guidelines on Nutrition and Physical Activity for Cancer Prevention” do not recommend dietary supplements for cancer prevention; they only suggest that subgroups, such as pregnant women, may benefit from multivitamins (46
). The World Cancer Research Fund’s report on nutrition and cancer prevention made no evaluation about multivitamins (47
). In contrast, a report by Fletcher and Fairfield advised all adults to take a daily multivitamin due to concerns about diet quality in Americans (48
An important question is why do millions of Americans use a daily multivitamin for chronic disease prevention when the supporting scientific data are weak? One reason may be the varied health messages received by the public. The position statements from the scientific and medical community that multivitamins are not effective for disease prevention are juxtaposed with messages to “use a multivitamin if dietary intake is inadequate” (48
). These conflicting messages leave the public confused, especially since multivitamins are often regarded as safe, over-the-counter preparations (49
). However, while many multivitamins contain less than 100% of the RDA (or Adequate Intake (AI)) for particular nutrients, consumers will still exceed the tolerable upper intake level (UL) if they use more than one supplement, eat fortified foods, or use multivitamins exceeding 100% of the RDA (50
). The risks associated with exceeding the UL are just beginning to be understood (51
The gold standard approach to resolving whether a heath practice offers benefit or harm to the public is through the conduct of a well-designed randomized controlled trial. Few large scale RCTs have been conducted to test the efficacy of multivitamins. The Linxian, China intervention and the SUVIMAX study in France tested high-dose, limited ingredient antioxidant vitamins (21
). The Physicians’ Health Trial II is a randomized, double-blind placebo controlled trial testing whether a standard multivitamin (Centrum Silver®) will reduce the incidence of cancer, cardiovascular disease, eye disease and cognitive decline among U.S. male physicians aged 50 years and older (54
). Trial results are expected in 2012, but since the study is limited to male physicians many questions will remain about the efficacy of multivitamin use in women. The remaining US-based supplement trials have been either single agents or a mixture of two to three ingredients, also in high doses that would not typically be classified as a standard multivitamin (54
). While RCTs are a considerable investment of resources, they are the only study design for which causal inference can be established. The scientific community might consider whether a randomized controlled trial of multivitamins in women could definitively resolve whether benefit or harm ensues from routine use of multivitamins.
This study has several strengths. WHI is one of the largest studies on postmenopausal women’s health. Detailed data were collected on numerous exposures using standardized protocols. The reliability of many of these measures has been assessed, including those used as covariates in these analyses (58
). Second, WHI procedures to assess dietary supplement use collected more data that other concurrent cohorts; WHI captured detailed data on dose, frequency and duration of supplements. The direct transcription of information from the participants’ supplement bottles did not rely on participants’ recall thereby minimizing misclassification of exposure. Finally, WHI outcomes were physician adjudicated, minimizing misclassification that might result from self-report alone.
There are also limitations. Despite the state-of-the-art methods used in WHI, dietary supplement use is difficult to assess. Manufacturers frequently change formulations and label ingredient information may not reflect content (8
). Moreover, persons who use supplements frequently engage in other preventive health behaviors and disentangling highly correlated exposures is difficult (59
). In this study, we controlled for other health behaviors; however, it is not possible in observational studies to assure that there is no residual confounding. For example, there may be residual confounding from risk factors that were not assessed in WHI, such as workplace or environmental exposures. Further, WHI may be underpowered for rare cancers with few cases. Moreover, the follow-up time may not have been sufficient for cancers that take many years to develop. Finally, WHI only included postmenopausal women; results may not be generalizeable to other populations.
In conclusion, the WHI Clinical Trial and Observational Study cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of cancer or cardiovascular disease in postmenopausal women. Nutritional efforts should remain a principal focus of chronic disease prevention, but without definitive results from a randomized controlled trial, multivitamin supplements will not likely play a major role in such prevention efforts.