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Original Investigation |

Multivitamin Use and Risk of Cancer and Cardiovascular Disease in the Women's Health Initiative Cohorts FREE

Marian L. Neuhouser, PhD; Sylvia Wassertheil-Smoller, PhD; Cynthia Thomson, PhD, RD; Aaron Aragaki, MS; Garnet L. Anderson, PhD; JoAnn E. Manson, MD, DrPH; Ruth E. Patterson, PhD; Thomas E. Rohan, MD, PhD; Linda van Horn, MD, PhD; James M. Shikany, DrPH; Asha Thomas, PhD; Andrea LaCroix, PhD; Ross L. Prentice, PhD
[+] Author Affiliations

Author Affiliations: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington (Drs Neuhouser, Anderson, Patterson, LaCroix, and Prentice and Mr Aragaki); Department of Epidemiology and Preventive Medicine, Albert Einstein College of Medicine, New York, New York (Drs Wassertheil-Smoller and Rohan); Department of Nutritional Sciences, University of Arizona, Tucson (Dr Thomson); Division of Preventive Medicine, Harvard Medical School, Boston, Massachusetts (Dr Manson); Amylin Pharmaceuticals, Inc, San Diego, California (Dr Patterson); Department of Preventive Medicine, Northwestern University, Chicago, Illinois (Dr van Horn); Division of Preventive Medicine, University of Alabama at Birmingham (Dr Shikany); and Medstar Research Institute, Washington, DC (Dr Thomas).


Arch Intern Med. 2009;169(3):294-304. doi:10.1001/archinternmed.2008.540.
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Background  Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease (CVD). Therefore, we decided to examine associations between multivitamin use and risk of cancer, CVD, and mortality in postmenopausal women.

Methods  The study included 161 808 participants from the Women's Health Initiative clinical trials (N = 68 132 in 3 overlapping trials of hormone therapy, dietary modification, and calcium and vitamin D supplements) or an observational study (N = 93 676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993 and 1998; the women were followed up for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease end points were collected through 2005.We documented cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary, and lung; CVD (myocardial infarction, stroke, and venous thromboembolism); and total mortality.

Results  A total of 41.5% of the participants used multivitamins. After a median of 8.0 years of follow-up in the clinical trial cohort and 7.9 years in the observational study cohort, 9619 cases of breast, colorectal, endometrial, renal, bladder, stomach, lung, or ovarian cancer; 8751 CVD events; and 9865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamin use with risk of cancer (hazard ratio [HR], 0.98, and 95% confidence interval [CI], 0.91-1.05 for breast cancer; HR, 0.99, and 95% CI, 0.88-1.11 for colorectal cancer; HR, 1.05, and 95% CI, 0.90-1.21 for endometrial cancer; HR, 1.0, and 95% CI, 0.88-1.13 for lung cancer; and HR, 1.07, and 95% CI, 0.88-1.29 for ovarian cancer); CVD (HR, 0.96, and 95% CI, 0.89-1.03 for myocardial infarction; HR, 0.99, and 95% CI, 0.91-1.07 for stroke; and HR, 1.05, and 95% CI, 0.85-1.29 for venous thromboembolism); or mortality (HR, 1.02, and 95% CI, 0.97-1.07).

Conclusion  After a median follow-up of 8.0 and 7.9 years in the clinical trial and observational study cohorts, respectively, the Women's Health Initiative study provided convincing evidence that multivitamin use has little or no influence on the risk of common cancers, CVD, or total mortality in postmenopausal women.

Trial Registration  clinicaltrials.gov Identifier: NCT00011193

The use of multivitamins is a common health practice in the United States.1 Despite the availability of a diverse and relatively affordable food supply, 50% of Americans routinely use dietary supplements, annually spending more than $20 billion on these products.2 The motivations for supplement use vary, but common reasons include the belief that these preparations will prevent chronic diseases, such as cancer and cardiovascular disease (CVD).3,4 These views are often fueled by product health claims, consumer testimonials, and an industry that is largely unregulated owing to the 1994 Dietary Supplement and Health Education Act.5,6 Despite the widespread use of supplements and the strong consumer beliefs about benefits, convincing scientific data to support efficacy are lacking.79 With the exception of recommending a folic acid–containing supplement to women of childbearing potential10,11 and advising avoidance the use of high-dose beta carotene supplements by smokers,12 current data are insufficient to formulate public health recommendations for dietary supplement use for otherwise healthy persons.2

The hypothesis that taking multivitamins might lower the risk of CVD and cancer derives from published evidence supporting a role for specific micronutrients in disease prevention. Data are consistent in stating that diets high in fruits and vegetables are associated with a lower risk of CVD and cancer. Moreover, low serum concentrations of B vitamins, carotenoids, and tocopherols have been associated with an increased risk of colorectal cancer and CVD.1320 Because these vitamins, minerals, and other small-molecule compounds can be effectively packaged into pill form, supplement use could ensure adequate micronutrient intake or correct low circulating concentrations, especially among persons with poor diets.21 Multivitamins are a potential vehicle, as they contain the micronutrients identified as essential by the Institute of Medicine.22,23

Multivitamins are the most frequently used dietary supplement. However, of the numerous observational studies that have examined associations between supplement use and disease risk, few have explicitly investigated the use of multivitamins. Limited evidence from case-control and cohort studies suggests that multivitamin use is associated with a reduced risk of colon and bladder cancers but with an increased risk of non-Hodgkin lymphoma.24 Other observational studies have reported no associations of multivitamin use with colorectal, gastric, or lung cancers. One study of more than 1 million Americans reported no association of multivitamin use with total mortality, coronary heart disease mortality, or cancer mortality.25 One study reported no risk reduction for CVD or mortality among a cohort of men who used multivitamins compared with those who did not use multivitamins.26 A prospective study of 37 920 women reported no association of multivitamin use with risk of breast cancer.27

In this study, we examined the associations between multivitamin use in the Women's Health Initiative (WHI) clinical trial (CT) and observational study (OS) cohorts and the risk of site-specific solid tumors (invasive breast, renal, endometrial, ovarian, bladder, and stomach cancers)2; CVD; and total mortality.3

OVERVIEW OF THE WHI

The WHI is a study of postmenopausal women's health and risk factors for cancer, heart disease, and skeletal health.28 It was designed as a set of randomized controlled CTs and an OS. Women were eligible for participation if they were 50 to 79 years of age at screening, postmenopausal, and likely to live in close geographic proximity to 1 of 40 WHI clinical centers for at least 3 years. Women were excluded for medical conditions with a predicted survival of 3 years of less, for conditions limiting adherence or retention (eg, alcohol or drug dependency and dementia), or for active participation in any other intervention trial in which participants were individually randomized to a control or intervention group.28 The CTs (N = 68 132) included 3 overlapping components: the hormone therapy trials (N = 27 347), the dietary modification trial (N = 48 835), and the calcium and vitamin D trial (N = 36 282). Eligible women could be randomized into 1, 2, or all 3 of the CTs. Trial arm assignment was randomly designated (1:1 for the hormone therapy and calcium and vitamin D trials; 40% were assigned to low-fat intervention and 60% to usual diet for the dietary modification trial).28 Women who were ineligible or unwilling to join the CTs were invited to join the OS, as were those who were specifically recruited for the OS (N = 93 676). The CT women attended baseline and annual clinic visits. The OS women attended baseline and 3-year clinic visits and completed all other annual study activities by mail (eg, medical history and lifestyle-exposure updates). The women were followed up for a median of 8.0 years in the CTs and 7.9 years in the OS. All WHI participants provided written informed consent, and institutional review board approval was obtained at each of the 40 WHI clinical centers and at the Clinical Coordinating Center at the Fred Hutchinson Cancer Research Center, Seattle, Washington. This report is based on data from 161 808 women in both the OS and the CTs; 2 women were excluded because of incomplete dietary supplement information.

ASSESSMENT OF DIETARY SUPPLEMENT USE

Dietary supplement data were collected during in-person clinic visits. Women brought supplement bottles to the baseline clinic visit and to annual visits thereafter in the CTs and to the baseline and 3-year visits in the OS. A standardized interviewer-administered 4-page form was used to collect information on multivitamins, other mixtures, and single supplements. For the multivitamins, separate sections were provided on the form to designate multivitamins, multivitamins with minerals, or stress supplements. Staff members directly transcribed the ingredients for each supplement. They also asked participants about frequency (pills per week) and duration (months and years) of use for each supplement.29,30 Only supplements used at least once a week were recorded, but there was no limit on the total number of supplements allowed. A validity study of these procedures demonstrated that correlations of interviewer-transcribed doses with data from photocopied labels ranged from 0.8 to 1.0.29,30

Multivitamins were grouped into 3 classifications based on ingredients: (1) multivitamins (alone) were preparations with 10 or more vitamins and no minerals in which the nutrient levels were at least 100% of US Recommended Dietary Allowance (RDA); (2) multivitamins with minerals were preparations with 20 to 30 vitamins and minerals and nutrient levels of 100% or less of US RDA; and (3) stress multisupplements were preparations with higher doses (often >200% of US RDA) of several B vitamins and often including large doses of vitamin C or selected minerals, such as selenium or zinc. Supplement mixtures with fewer than 10 components, such as B complex or antioxidant mixtures, were not considered multivitamins.

ASCERTAINMENT OF OUTCOMES

Clinical outcomes of interest in the WHI included CVD (coronary heart disease, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease, and coronary revascularization), cancer (breast, colorectal, endometrial, ovarian, and other cancers), osteoporotic fractures (hip and other), and other conditions (diabetes, deep vein thrombosis, pulmonary embolism, and total mortality). Outcomes were initially ascertained by self-report using a semiannual (in the CTs) or annual (in the OS) questionnaire and documented by medical records. Charts with potential cardiovascular, cancer, fracture, and death outcomes were sent to local WHI-physician adjudicators for evaluation and classification. Locally adjudicated cases (all cancers) were then sent to the Coordinating Center for central adjudication of selected outcomes.31 Five major cancers (of the breast, colon, rectum, endometrium, and ovary) were centrally coded by trained tumor registry coders using standardized SEER (Surveillance, Epidemiology, and End Results) guidelines. This report includes end points reported and adjudicated through the end of the WHI closeout period of March 2005. We included 8 solid tumor cancers (invasive breast, colorectal, endometrial, stomach, ovarian, renal, lung, and bladder) and 3 CVD end points (myocardial infarction [MI], stroke, and venous thromboembolism [CTs only]).

OTHER DATA

Standard procedures used across the CTs and the OS were used to collect data on age, race/ethnicity, reproductive/gynecological history, education, physical activity, medical history, family or personal history of cancer or coronary heart disease, diabetes mellitus, current health status, and tobacco and alcohol use. The clinic staff members measured blood pressure, height, and weight using standardized protocols.

STATISTICAL ANALYSES

Descriptive statistics characterized the study population. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for any use of multivitamins as well as the categories of multivitamins, multivitamins with minerals, and stress multivitamins for each of the disease outcomes. The time metric for these models was based on the time of randomization in the CTs and time of enrollment in the OS.32,33 For a particular event, time accrued while the participants were still at risk for an event until the date of diagnosis of cancer or CVD, until death from any cause, until they were unavailable for follow-up, or until March 31, 2005. Proportional hazards assumptions were assessed by a 1-df test of the interaction between log-survival time and multivitamin use; evidence of nonproportionality did not exist. Hazard ratios were adjusted for baseline characteristics: age; race/ethnicity; years since menopause (<5, 5-10, 10-15, and >15 years); body mass index; education; alcohol use; smoking; general health; history of bilateral oophorectomy; geographic region; physical activity; duration of prior postmenopausal estrogen therapy use (0, <5, 5-10, 10-15, and >15 years); duration of prior postmenopausal estrogen plus progesterone use (0, <5, 5-10, 10-15, and >15 years); fruit and vegetable intake; percentage of energy from fat; single supplements of vitamin C, E, or calcium and any other single supplement use and stratified according to age (5-year groups), hormone therapy trial randomization assignment or study enrollment (active conjugated equine estrogen [CEE] plus medroxyprogesterone acetate, placebo CEE and medroxyprogesterone acetate, active CEE, placebo CEE, or not randomized), dietary modification trial randomization (intervention, control, or not randomized), or OS enrollment.32,33 Specific to cancer analyses, a family history of cancer was an additional covariate; women were excluded if they had a history of the particular cancer. For breast cancer analyses, women without a mammogram within 2 years of baseline were excluded. Specific to CVD analysis, treated diabetes, treated hyperlipidemia, systolic blood pressure level, and history of the particular CVD were additional covariates.

Additional analyses tested persistent use of multivitamins (ie, use at baseline and follow-up) in relation to risk of cancer or CVD. The likelihood ratio test estimated multiplicative interaction between baseline characteristics (age, smoking, alcohol use, body mass index, and fruit and vegetable consumption) and multivitamin use in relation to the disease outcomes.

All statistical tests were 2-sided, with a P value of less than .05 considered statistically significant. Analyses were conducted with SAS, version 9.1 (SAS Institute Inc, Cary, North Carolina).

Table 1 presents demographic, health, and lifestyle data according to use of multivitamin supplements in the WHI. Of the 161 806 WHI participants with completed dietary supplement data collection forms, 41.5% reported multivitamin use. The most common category was multivitamins with minerals (35.0%), with fewer participants taking multivitamins (alone) (3.5%) or stress multivitamins (2.3%). Women who used any multivitamins were more likely also to use single supplements of vitamin E, vitamin C, or calcium than women who did not use multivitamins (P < .001). Compared with women who did not use multivitamins, multivitamin users were more likely to be white, living in the western United States, have a lower body mass index, be more physically active, and have a college degree or higher (all P < .001). Women who used multivitamins were more likely to consume alcohol and less likely to smoke than nonusers. Multivitamin users reported slightly higher fruit and vegetable consumption and a lower percentage of energy from fat than nonusers at baseline.

Table Graphic Jump LocationTable 1. Characteristics of 161806 Multivitamin Supplement Users and Nonusers in the Women's Health Initiative

There was no evidence that multivitamin use either increased or decreased the risk of cancer (Table 2). Overall, there was no association of any multivitamin use with the risk of cancers of the breast, colon/rectum, endometrium, ovary, kidney, bladder, stomach, or lung. When we examined risk according to the 3 classes of multivitamins, there was also no apparent association, and the null value of 1.0 was included in the 95% CIs of all multivariate-adjusted HR estimates. We observed a modest inverse association between use of stress-type multivitamins and stomach and kidney cancer and an inverse association of multivitamins without minerals and stomach cancer, but the numbers of cases were far too small to provide stable or meaningful HR estimates.

Table Graphic Jump LocationTable 2. Multivariable Adjusteda Relative Risk of Major Cancers by Multivitamin Use in the Women's Health Initiative (CTs and OS)

Next, we examined the association of multivitamin use with risk of CVD (MI, stroke, and venous thromboembolism) (Table 3). The annualized percentages of CVD events were nonsignificantly lower among women taking multivitamins than among those not taking multivitamins, and the overall HRs ranged from 0.96 (95% CI, 0.89-1.03) to 1.05 (95% CI, 0.85-1.29). Stress multivitamins were the only supplements for which a cardiovascular protective association was suggested; the adjusted HR was 0.75 (95% CI, 0.56-0.99) for MI.

Table Graphic Jump LocationTable 3. Events, Annualized Percentages, and Multivariable Adjusteda Relative Risks of Cardiovascular Disease (CVD) by Multivitamin Use in the Women's Health Initiative (CTs and OS)

To investigate variation in risk by total duration of use, we categorized duration into 4 groups: (1) less than 1 year, (2) 1 through 5 years, (3) 6 through 10 years, and (4) more than 10 years. Of the 1928 women with invasive breast cancer who used multivitamins, 685 (35.5%) reported multivitamin use for at least 10 years (Table 4). While the annualized percentage of breast cancer events was slightly higher among those with at least 10 years of use (0.50) compared with nonusers of multivitamins (0.44), the adjusted HR was 1.03 (95% CI, 0.94-1.14). Five to 10 years and more than 10 years of multivitamin use were associated with small but statistically nonsignificant increased risks for endometrial cancer (HR, 1.19, and 95% CI, 0.91-1.56; and HR, 1.09, and 95% CI, 0.89-1.35, respectively), kidney cancer (HR, 1.32, and 95% CI, 0.82-2.13 for 5-10 years of use), and stomach cancer (HR, 1.36, and 95% CI, 0.73-2.56 for >10 years of use).

Table Graphic Jump LocationTable 4. Multivariable Adjusteda Relative Risk of Major Cancers by Duration of Multivitamin Use in the Women's Health Initiative (CTs and OS)

Duration of multivitamin use had no apparent association with CVD risk. There was a slightly higher annualized percentage of MI cases among multivitamin nonusers than among users. However, the adjusted HRs for nearly all outcomes in Table 5 were close to 1.0, and all 95% CIs contained the null value of 1.0. There was no association of duration of multivitamin use with total mortality.

Table Graphic Jump LocationTable 5. Events, Annualized Percentages, and Multivariable Adjusteda Relative Risks of Cardiovascular Disease (CVD) by Multivitamin Usea in the Women's Health Initiative (CTs and OS)

As with overall multivitamin use (Table 2), there was no association of persistent multivitamin use with risk of cancer or CVD. We see that the influence of persistent multivitamin compared with any multivitamin use in relation to any of the cancer or CVD outcomes is approximately equal (Table 6).

Table Graphic Jump LocationTable 6. Comparison of Multivariablea Adjusted Relative Risks Between Multivitamin Users and Persistentb Users of Multivitamins (CTs and OS)

The associations of multivitamin use with cancer and CVD risk were weakly modified by demographic, health, and lifestyle characteristics. Analyses by age suggested that older multivitamin users (≥70 years at baseline) had a reduced risk of endometrial cancer (HR, 0.73, and 95% CI, 0.55-0.97; interaction P, <.01), and multivitamin users who were obese had a reduced risk of invasive breast cancer (HR, 0.84, and 95% CI, 0.74-0.95; interaction P, <.01). However, younger women using multivitamins were at a slightly higher risk of death (HR, 1.07, and 95% CI, 1.01-1.14; interaction P, <.05). Multivitamin users who were current smokers or consumers of more than 1 alcoholic drink per day had nonsignificant increased risks of mortality and MI, respectively (interaction P, <.05). There was a nonsignificant increased risk of MI and ovarian cancer among women who used multivitamins (interaction P, .04 and .05, respectively). Fruit and vegetable intake did not modify the associations of multivitamin use with disease outcomes (data not shown).

In this large cohort of postmenopausal women, we observed no overall associations between multivitamin use and risk of several common cancers or CVD. 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 CVD and its antecedent risk factors.26,3436 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 an increased risk of endometrial, stomach, and kidney cancer but a decreased risk of bladder cancer; however, the variation in risk was not dose dependent. Long-term multivitamin use had no association with any CVD event or total mortality. These results suggest that multivitamin use does not confer meaningful benefit or harm in relation to cancer or CVD risk in postmenopausal women.

Our findings are 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 (relative risk, 0.71, and 95% CI, 0.57-0.89).37,38 This same cohort reported no association of multivitamin use with stomach cancer or fatal non-Hodgkin lymphoma.24,39 A pooled analysis of 8 cohort studies from North America and Europe found no overall association of multivitamin use with lung cancer risk but a relative risk of 1.17 (95% CI, 1.04-1.32) when only women were considered.40 In the Nurses' Health Study, multivitamin use was associated with lower colon cancer incidence but only when such use lasted for 15 years or more.15 The Nurses' Health Study also reported a weak, nonsignificant protective association for breast cancer with 5 to 9 years of multivitamin use41 but an increased risk for fatal non-Hodgkin 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 up 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 they did report 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 multivitamin use and risk of MI or any coronary heart disease death, but the analysis was focused on the use of 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

The National Institutes of Health'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 US Preventive Services Task Force stating that data were insufficient to either support or oppose the use of dietary supplements, including multivitamins, for the prevention of CVD and cancer.43 The American Heart Association's Nutrition Committee recommends against the use of antioxidant supplements for CVD prevention, but their statement refers to single supplements or mixtures of 5 or fewer ingredients. No specific statement about standard multivitamins has been issued.44,45 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 taking multivitamins.46 The World Cancer Research Fund's report on nutrition and cancer prevention made no evaluation about the use of multivitamins.47 In contrast, a report by Fletcher and Fairfield48 advised all adults to take a daily multivitamin because of concerns about diet quality in Americans.

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 because 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)) for particular nutrients, consumers will still exceed the tolerable upper intake level if they use more than 1 supplement, eat fortified foods, or use multivitamins exceeding 100% of the RDA.50,51 The risks associated with exceeding the upper intake level are just beginning to be understood.51,52

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 randomized controlled trials 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.21,53 The Physicians' Health Study II is a randomized, double-blind, placebo-controlled trial testing whether a standard multivitamin (Centrum Silver) will reduce the incidence of cancer, CVD, eye disease, or cognitive decline among US male physicians aged 50 years and older.54 Trial results are expected in 2012, but because 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 involved either single agents or a mixture of 2 to 3 ingredients, also in high doses, that would not typically be classified as standard multivitamins.5457 While randomized controlled trials 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 the routine use of multivitamins.

This study has several strengths. The WHI is one of the largest studies of 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 than other concurrent cohorts; the 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.8,51 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 ensure that there is no residual confounding. For example, there may be residual confounding from risk factors that were not assessed in the WHI, such as workplace or environmental exposures. Furthermore, the 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, the WHI only included postmenopausal women; the results may not be generalizable to other populations.

In conclusion, the WHI CT and OS cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of cancer or CVD 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.

Corresponding Author: Marian L. Neuhouser, PhD, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M4B402, Seattle, WA 98109-1024 (mneuhous@fhcrc.org).

Accepted for Publication: August 21, 2008.

Author Contributions: Dr Prentice and Mr Aragaki had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Neuhouser, Thomson, Anderson, Manson, Patterson, and Prentice. Acquisition of data: Wassertheil-Smoller, Thomson, Manson, Patterson, van Horn, Thomas, LaCroix, and Prentice. Analysis and interpretation of data: Neuhouser, Wassertheil-Smoller, Aragaki, Manson, Patterson, Rohan, Shikany, Thomas, LaCroix, and Prentice. Drafting of the manuscript: Neuhouser, Thomson, Aragaki, and Prentice. Critical revision of the manuscript for important intellectual content: Neuhouser, Wassertheil-Smoller, Thomson, Aragaki, Anderson, Manson, Patterson, Rohan, van Horn, Shikany, Thomas, LaCroix, and Prentice. Statistical analysis: Wassertheil-Smoller, Aragaki, Anderson, Patterson, and Prentice. Obtained funding: Wassertheil-Smoller, Manson, and Prentice. Administrative, technical, and material support: Neuhouser, Thomson, Manson, Thomas, and Prentice. Study supervision: Neuhouser, Thomson, Anderson, Manson, and Thomas. Intellectual input: van Horn.

Financial Disclosure: None reported.

Funding/Support: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Role of the Sponsor: The National Heart, Lung, and Blood Institute Program Office reviewed the manuscript before submission.

Program Office Staff Members: Elizabeth Nabel, Jacques Rossouw, Shari Ludlam, Linda Pottern, Joan McGowan, Leslie Ford, and Nancy Geller, National Heart, Lung, and Blood Institute, Bethesda, Maryland.

Members of the WHI Clinical Coordinating Center: Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L. Kooperberg, Ruth E. Patterson, and Anne McTiernan, Fred Hutchinson Cancer Research Center; Sally Shumaker, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Evan Stein, Medical Research Labs, Highland Heights, Kentucky; and Steven Cummings, University of California at San Francisco.

Members of the WHI Clinical Centers: Sylvia Wassertheil-Smoller, Albert Einstein College of Medicine, New York, New York; Aleksandar Rajkovic, Baylor College of Medicine, Houston, Texas; JoAnn Manson, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Annlouise R. Assaf, Brown University, Providence, Rhode Island; Lawrence Phillips, Emory University, Atlanta, Georgia; Shirley Beresford, Fred Hutchinson Cancer Research Center; Judith Hsia, George Washington University Medical Center, Washington, DC; Rowan Chlebowski, Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, California; Evelyn Whitlock, Kaiser Permanente Center for Health Research, Portland, Oregon; Bette Caan, Kaiser Permanente Division of Research, Oakland, California; Jane Morley Kotchen, Medical College of Wisconsin, Milwaukee; Barbara V. Howard, MedStar Research Institute–Howard University, Washington, DC; Linda van Horn, Northwestern University, Chicago and Evanston, Illinois; Henry Black, Rush Medical Center, Chicago, Illinois; Marcia L. Stefanick, Stanford Prevention Research Center, Stanford, California; Dorothy Lane, State University of New York at Stony Brook; Rebecca Jackson, The Ohio State University, Columbus; Cora E. Lewis, University of Alabama at Birmingham; Tamsen Bassford, University of Arizona, Tucson and Phoenix; Jean Wactawski-Wende, University at Buffalo, Buffalo, New York; John Robbins, University of California at Davis, Sacramento; F. Allan Hubbell, University of California at Irvine; Howard Judd, University of California at Los Angeles; Robert D. Langer, University of California at San Diego, LaJolla and Chula Vista; Margery Gass, University of Cincinnati, Cincinnati, Ohio; Marian Limacher, University of Florida, Gainesville and Jacksonville; David Curb, University of Hawaii, Honolulu; Robert Wallace, University of Iowa, Iowa City and Davenport; Judith Ockene, University of Massachusetts–Fallon Clinic, Worcester; Norman Lasser, University of Medicine and Dentistry of New Jersey, Newark; Mary Jo O’Sullivan, University of Miami, Miami, Florida; Karen Margolis, University of Minnesota, Minneapolis; Robert Brunner, University of Nevada, Reno; Gerardo Heiss, University of North Carolina, Chapel Hill; Lewis Kuller, University of Pittsburgh, Pittsburgh, Pennsylvania; Karen C. Johnson, University of Tennessee, Memphis; Robert Brzyski, University of Texas Health Science Center, San Antonio; Gloria E. Sarto, University of Wisconsin, Madison; Denise Bonds, Wake Forest University School of Medicine; and Susan Hendrix, Wayne State University School of Medicine–Hutzel Hospital, Detroit, Michigan.

Slesinski  MJSubar  AFKahle  LL Trends in use of vitamin and mineral supplements in the US. J Am Diet Assoc 1995;95 (8) 921- 923
PubMed
NIH State-of-the-Science Panel, National Institutes of Health State-of-the-Science Conference Statement: multivitamin/mineral supplements and chronic disease prevention. Ann Intern Med 2006;145 (5) 364- 371
PubMed
Neuhouser  ML Dietary supplement use by American women: challenges in assessing patterns of use, motives and costs. J Nutr 2003;133 (6) 1992S- 1996S
PubMed
Neuhouser  MLPatterson  RELevy  L Motivations for using vitamin supplements. J Am Diet Assoc 1999;99 (7) 851- 854
PubMed
 Dietary Supplement and Health Education Act of 1994, Pub L No. 103-417, 103rd Cong (1994) 
Hathcock  J Dietary supplements: how they are used and regulated. J Nutr 2001;131 (3s) 1114S- 1117S
PubMed
Nesheim  MC What is the research base for the use of dietary supplements? Public Health Nutr 1999;2 (1) 35- 38
PubMed
Hendrich  SFisher  K What do we need to know about active ingredients in dietary supplements? summary of workshop discussion. J Nutr 2001;131 (4) ((suppl)) 1387S- 1388S
PubMed
Fairfield  KMFletcher  RH Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287 (23) 3116- 3126
PubMed
American Academy of Pediatrics Committee on Genetics, Folic acid for the prevention of neural tube defects. Pediatrics 1999;104 (2, pt 1) 325- 327
PubMed
Bentley  JRFerrini  RLHill  LL American College of Preventive Medicine public policy statement: folic acid fortification of grain products in the U.S. to prevent neural tube defects. Am J Prev Med 1999;16 (3) 264- 267
PubMed
Omenn  GS Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annu Rev Public Health 1998;1973- 99
PubMed
Fuchs  CSWillett  WCColditz  GA  et al.  The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev 2002;11 (3) 227- 234
PubMed
Harnack  LJacobs  DRNicodemus  KLazovich  DAnderson  KFolsom  AR Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. Nutr Cancer 2002;43 (2) 152- 158
PubMed
Giovannucci  EStampfer  MColditz  GA Multivitamin use, folate and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129 (7) 517- 524
PubMed
Wei  EKGiovannucci  ESelhub  JFuchs  CSHankinson  SEMa  J Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women. J Natl Cancer Inst 2005;97 (9) 684- 692
PubMed
Comstock  GWAlberg  AJHuang  HY  et al.  The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Cancer Epidemiol Biomarkers Prev 1997;6 (11) 907- 916
PubMed
Dorgan  JFSowell  ASwanson  CA  et al.  Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control 1998;9 (1) 89- 97
PubMed
Losonczy  KGHarris  TBHavlik  RJ Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64 (2) 190- 196
PubMed
Kneckt  PAromaa  AMaatela  J  et al.  Serum selenium and subsequent risk of cancer among Finnish men and women. J Natl Cancer Inst 1990;82 (10) 864- 868
PubMed
Blot  WJLi  JYTaylor  PR  et al.  Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85 (18) 1483- 1492
PubMed
Institute of Medicine,  Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids.   Washington, DC National Academy Press2000;
Institute of Medicine,  Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc.   Washington, DC National Academy Press2001;
Zhang  SMGiovannucci  ELHunter  DJ  et al.  Vitamin supplement use and the risk of non-Hodgkin's lymphoma among women and men. Am J Epidemiol 2001;153 (11) 1056- 1063
PubMed
Watkins  MLErickson  JDThun  MJMulinare  JHeath  CW Multivitamin use and mortality in a large prospective study. Am J Epidemiol 2000;152 (2) 149- 162
PubMed
Muntwyler  JHennekens  CHManson  JAEBuring  JEGaziano  JM Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med 2002;162 (13) 1472- 1476
PubMed
Ishitani  KLin  JManson  JEBuring  JEZhang  SM A prospective study of multivitamin supplement use and risk of breast cancer. Am J Epidemiol 2008;167 (10) 1197- 1206
PubMed
Women's Health Initiative Study Group, Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19 (1) 61- 109
PubMed
Patterson  RELevy  LTinker  LFKristal  AR Evaluation of a simplified vitamin supplement inventory developed for the Women's Health Initiative. Public Health Nutr 1999;2 (3) 273- 276
PubMed
Patterson  REKristal  ARLevy  LMcLerran  DWhite  E Validity of methods used to assess vitamin and mineral supplement use. Am J Epidemiol 1998;148 (7) 643- 649
PubMed
Curb  JDMcTiernan  AHeckbert  SR  et al.  Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol 2003;13 (9) ((suppl)) S122- S128
PubMed
Prentice  RLLanger  RStefanick  ML  et al.  Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol 2005;162 (5) 404- 414
PubMed
Prentice  RLLanger  RDStefanick  ML  et al.  Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol 2006;163 (7) 589- 599
PubMed
Tucker  KLOlson  BBakun  PDallal  GESelhub  JRosenberg  IH Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. Am J Clin Nutr 2004;79 (5) 805- 811
PubMed
Bostom  AGJacques  PFLiaugaudas  GRogers  GRosenberg  IHSelhub  J Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid–fortified cereal grain flour. Arterioscler Thromb Vasc Biol 2002;22 (3) 488- 491
PubMed
Rimm  EBWillett  WCHu  FB  et al.  Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279 (5) 359- 364
PubMed
Jacobs  EJConnell  CJPatel  AV  et al.  Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United States). Cancer Causes Control 2001;12 (10) 927- 934
PubMed
Jacobs  EJConell  CJChao  A  et al.  Multivitamin use and colorectal cancer incedence in a US cohort: does timing matter? Am J Epidemiol 2003;158 (7) 621- 628
PubMed
Jacobs  EJConnell  CJMcCullough  ML  et al.  Vitamin C, vitamin E, and mutivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiol Biomarkers Prev 2002;11 (1) 35- 41
PubMed
Cho  EHunter  DJSpiegelman  D  et al.  Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: a pooled analysis of 8 prospective studies. Int J Cancer 2006;118 (4) 970- 978
PubMed
Zhang  SHunter  DJForman  M Dietary carotenoids and vitamins A, C and E and risk of breast cancer. J Natl Cancer Inst 1999;91 (6) 547- 556
PubMed
Lee  I-MCook  NRGaziano  JM  et al.  Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005;294 (1) 56- 65
PubMed
Morris  CDCarson  S Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003;139 (1) 56- 70
PubMed
Lichtenstein  AHAppel  LJBrands  M  et al.  Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006;114 (1) 82- 96
PubMed
Kris-Etherton  PMLichtenstein  AHHoward  BVSteinberg  DWitztum  JL Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004;110 (5) 637- 641
PubMed
Kushi  LHByers  TDoyle  C  et al.  American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 2006;56 (5) 254- 281
PubMed
World Cancer Research Fund/American Institute for Cancer Research,  Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective.   Washington, DC American Institute for Cancer Research2007;
Fletcher  RHFairfield  KM Vitamins for chronic disease prevention in adults: clinical applications. JAMA 2002;287 (23) 3127- 3129
PubMed
Blendon  RJDesRoches  CMBenson  JMBrodie  MAltman  DE Americans' views on the use and regulation of dietary supplements. Arch Intern Med 2001;161 (6) 805- 810
PubMed
Neuhouser  MLKristal  ARPatterson  REGoodman  PTThompson  IM Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials. Nutr Cancer 2001;39 (1) 12- 18
PubMed
Yetley  EA Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions. Am J Clin Nutr 2007;85 (1) 269S- 276S
PubMed
Cole  BFBaron  JASandler  RS  et al.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297 (21) 2351- 2359
PubMed
Hercberg  SPreziosi  PBriançon  S  et al.  A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study—design, methods, and participant characteristics. Control Clin Trials 1998;19 (4) 336- 351
PubMed
Christen  WGGaziano  JMHennekens  CH Design of Physicians' Health Study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol 2000;10 (2) 125- 134
PubMed
Baron  JABeach  MMandel  JS  et al.  Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340 (2) 101- 107
PubMed
Omenn  GSGoodman  GEThornquist  MD  et al.  Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334 (18) 1150- 1155
PubMed
Greenberg  ERBaron  JATosteson  TD  et al.  A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 1994;331 (3) 141- 147
PubMed
Langer  RDWhite  ELewis  CEKotchen  JMHendrix  SLTrevisan  M The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 2003;13 ((suppl)) S107- S121
Patterson  RENeuhouser  MLWhite  EHunt  JRKristal  AR Cancer-related behavior of vitamin supplement users. Cancer Epidemiol Biomarkers Prev 1998;7 (1) 79- 81
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Characteristics of 161806 Multivitamin Supplement Users and Nonusers in the Women's Health Initiative
Table Graphic Jump LocationTable 2. Multivariable Adjusteda Relative Risk of Major Cancers by Multivitamin Use in the Women's Health Initiative (CTs and OS)
Table Graphic Jump LocationTable 3. Events, Annualized Percentages, and Multivariable Adjusteda Relative Risks of Cardiovascular Disease (CVD) by Multivitamin Use in the Women's Health Initiative (CTs and OS)
Table Graphic Jump LocationTable 4. Multivariable Adjusteda Relative Risk of Major Cancers by Duration of Multivitamin Use in the Women's Health Initiative (CTs and OS)
Table Graphic Jump LocationTable 5. Events, Annualized Percentages, and Multivariable Adjusteda Relative Risks of Cardiovascular Disease (CVD) by Multivitamin Usea in the Women's Health Initiative (CTs and OS)
Table Graphic Jump LocationTable 6. Comparison of Multivariablea Adjusted Relative Risks Between Multivitamin Users and Persistentb Users of Multivitamins (CTs and OS)

References

Slesinski  MJSubar  AFKahle  LL Trends in use of vitamin and mineral supplements in the US. J Am Diet Assoc 1995;95 (8) 921- 923
PubMed
NIH State-of-the-Science Panel, National Institutes of Health State-of-the-Science Conference Statement: multivitamin/mineral supplements and chronic disease prevention. Ann Intern Med 2006;145 (5) 364- 371
PubMed
Neuhouser  ML Dietary supplement use by American women: challenges in assessing patterns of use, motives and costs. J Nutr 2003;133 (6) 1992S- 1996S
PubMed
Neuhouser  MLPatterson  RELevy  L Motivations for using vitamin supplements. J Am Diet Assoc 1999;99 (7) 851- 854
PubMed
 Dietary Supplement and Health Education Act of 1994, Pub L No. 103-417, 103rd Cong (1994) 
Hathcock  J Dietary supplements: how they are used and regulated. J Nutr 2001;131 (3s) 1114S- 1117S
PubMed
Nesheim  MC What is the research base for the use of dietary supplements? Public Health Nutr 1999;2 (1) 35- 38
PubMed
Hendrich  SFisher  K What do we need to know about active ingredients in dietary supplements? summary of workshop discussion. J Nutr 2001;131 (4) ((suppl)) 1387S- 1388S
PubMed
Fairfield  KMFletcher  RH Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287 (23) 3116- 3126
PubMed
American Academy of Pediatrics Committee on Genetics, Folic acid for the prevention of neural tube defects. Pediatrics 1999;104 (2, pt 1) 325- 327
PubMed
Bentley  JRFerrini  RLHill  LL American College of Preventive Medicine public policy statement: folic acid fortification of grain products in the U.S. to prevent neural tube defects. Am J Prev Med 1999;16 (3) 264- 267
PubMed
Omenn  GS Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annu Rev Public Health 1998;1973- 99
PubMed
Fuchs  CSWillett  WCColditz  GA  et al.  The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev 2002;11 (3) 227- 234
PubMed
Harnack  LJacobs  DRNicodemus  KLazovich  DAnderson  KFolsom  AR Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers. Nutr Cancer 2002;43 (2) 152- 158
PubMed
Giovannucci  EStampfer  MColditz  GA Multivitamin use, folate and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129 (7) 517- 524
PubMed
Wei  EKGiovannucci  ESelhub  JFuchs  CSHankinson  SEMa  J Plasma vitamin B6 and the risk of colorectal cancer and adenoma in women. J Natl Cancer Inst 2005;97 (9) 684- 692
PubMed
Comstock  GWAlberg  AJHuang  HY  et al.  The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Cancer Epidemiol Biomarkers Prev 1997;6 (11) 907- 916
PubMed
Dorgan  JFSowell  ASwanson  CA  et al.  Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control 1998;9 (1) 89- 97
PubMed
Losonczy  KGHarris  TBHavlik  RJ Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64 (2) 190- 196
PubMed
Kneckt  PAromaa  AMaatela  J  et al.  Serum selenium and subsequent risk of cancer among Finnish men and women. J Natl Cancer Inst 1990;82 (10) 864- 868
PubMed
Blot  WJLi  JYTaylor  PR  et al.  Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85 (18) 1483- 1492
PubMed
Institute of Medicine,  Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids.   Washington, DC National Academy Press2000;
Institute of Medicine,  Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc.   Washington, DC National Academy Press2001;
Zhang  SMGiovannucci  ELHunter  DJ  et al.  Vitamin supplement use and the risk of non-Hodgkin's lymphoma among women and men. Am J Epidemiol 2001;153 (11) 1056- 1063
PubMed
Watkins  MLErickson  JDThun  MJMulinare  JHeath  CW Multivitamin use and mortality in a large prospective study. Am J Epidemiol 2000;152 (2) 149- 162
PubMed
Muntwyler  JHennekens  CHManson  JAEBuring  JEGaziano  JM Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med 2002;162 (13) 1472- 1476
PubMed
Ishitani  KLin  JManson  JEBuring  JEZhang  SM A prospective study of multivitamin supplement use and risk of breast cancer. Am J Epidemiol 2008;167 (10) 1197- 1206
PubMed
Women's Health Initiative Study Group, Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19 (1) 61- 109
PubMed
Patterson  RELevy  LTinker  LFKristal  AR Evaluation of a simplified vitamin supplement inventory developed for the Women's Health Initiative. Public Health Nutr 1999;2 (3) 273- 276
PubMed
Patterson  REKristal  ARLevy  LMcLerran  DWhite  E Validity of methods used to assess vitamin and mineral supplement use. Am J Epidemiol 1998;148 (7) 643- 649
PubMed
Curb  JDMcTiernan  AHeckbert  SR  et al.  Outcomes ascertainment and adjudication methods in the Women's Health Initiative. Ann Epidemiol 2003;13 (9) ((suppl)) S122- S128
PubMed
Prentice  RLLanger  RStefanick  ML  et al.  Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol 2005;162 (5) 404- 414
PubMed
Prentice  RLLanger  RDStefanick  ML  et al.  Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. Am J Epidemiol 2006;163 (7) 589- 599
PubMed
Tucker  KLOlson  BBakun  PDallal  GESelhub  JRosenberg  IH Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. Am J Clin Nutr 2004;79 (5) 805- 811
PubMed
Bostom  AGJacques  PFLiaugaudas  GRogers  GRosenberg  IHSelhub  J Total homocysteine lowering treatment among coronary artery disease patients in the era of folic acid–fortified cereal grain flour. Arterioscler Thromb Vasc Biol 2002;22 (3) 488- 491
PubMed
Rimm  EBWillett  WCHu  FB  et al.  Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279 (5) 359- 364
PubMed
Jacobs  EJConnell  CJPatel  AV  et al.  Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United States). Cancer Causes Control 2001;12 (10) 927- 934
PubMed
Jacobs  EJConell  CJChao  A  et al.  Multivitamin use and colorectal cancer incedence in a US cohort: does timing matter? Am J Epidemiol 2003;158 (7) 621- 628
PubMed
Jacobs  EJConnell  CJMcCullough  ML  et al.  Vitamin C, vitamin E, and mutivitamin supplement use and stomach cancer mortality in the Cancer Prevention Study II cohort. Cancer Epidemiol Biomarkers Prev 2002;11 (1) 35- 41
PubMed
Cho  EHunter  DJSpiegelman  D  et al.  Intakes of vitamins A, C and E and folate and multivitamins and lung cancer: a pooled analysis of 8 prospective studies. Int J Cancer 2006;118 (4) 970- 978
PubMed
Zhang  SHunter  DJForman  M Dietary carotenoids and vitamins A, C and E and risk of breast cancer. J Natl Cancer Inst 1999;91 (6) 547- 556
PubMed
Lee  I-MCook  NRGaziano  JM  et al.  Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005;294 (1) 56- 65
PubMed
Morris  CDCarson  S Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003;139 (1) 56- 70
PubMed
Lichtenstein  AHAppel  LJBrands  M  et al.  Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation 2006;114 (1) 82- 96
PubMed
Kris-Etherton  PMLichtenstein  AHHoward  BVSteinberg  DWitztum  JL Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004;110 (5) 637- 641
PubMed
Kushi  LHByers  TDoyle  C  et al.  American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin 2006;56 (5) 254- 281
PubMed
World Cancer Research Fund/American Institute for Cancer Research,  Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective.   Washington, DC American Institute for Cancer Research2007;
Fletcher  RHFairfield  KM Vitamins for chronic disease prevention in adults: clinical applications. JAMA 2002;287 (23) 3127- 3129
PubMed
Blendon  RJDesRoches  CMBenson  JMBrodie  MAltman  DE Americans' views on the use and regulation of dietary supplements. Arch Intern Med 2001;161 (6) 805- 810
PubMed
Neuhouser  MLKristal  ARPatterson  REGoodman  PTThompson  IM Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials. Nutr Cancer 2001;39 (1) 12- 18
PubMed
Yetley  EA Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions. Am J Clin Nutr 2007;85 (1) 269S- 276S
PubMed
Cole  BFBaron  JASandler  RS  et al.  Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297 (21) 2351- 2359
PubMed
Hercberg  SPreziosi  PBriançon  S  et al.  A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study—design, methods, and participant characteristics. Control Clin Trials 1998;19 (4) 336- 351
PubMed
Christen  WGGaziano  JMHennekens  CH Design of Physicians' Health Study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol 2000;10 (2) 125- 134
PubMed
Baron  JABeach  MMandel  JS  et al.  Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340 (2) 101- 107
PubMed
Omenn  GSGoodman  GEThornquist  MD  et al.  Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334 (18) 1150- 1155
PubMed
Greenberg  ERBaron  JATosteson  TD  et al.  A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N Engl J Med 1994;331 (3) 141- 147
PubMed
Langer  RDWhite  ELewis  CEKotchen  JMHendrix  SLTrevisan  M The Women's Health Initiative Observational Study: baseline characteristics of participants and reliability of baseline measures. Ann Epidemiol 2003;13 ((suppl)) S107- S121
Patterson  RENeuhouser  MLWhite  EHunt  JRKristal  AR Cancer-related behavior of vitamin supplement users. Cancer Epidemiol Biomarkers Prev 1998;7 (1) 79- 81
PubMed

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