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Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts.

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Affiliations

  • 1. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, WA 98109-1024, USA.
      Authors
    • Neuhouser ML 1
    (1 author)

ORCIDs linked to this article

Archives of Internal Medicine, 01 Feb 2009, 169(3):294-304
https://doi.org/10.1001/archinternmed.2008.540 PMID: 19204221 PMCID: PMC3868488

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Abstract 

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.

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Arch Intern Med. Author manuscript; available in PMC 2013 Dec 19.
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PMCID: PMC3868488
NIHMSID: NIHMS527577
PMID: 19204221

MULTIVITAMIN USE AND RISK OF CANCER AND CARDIOVASCULAR DISEASE IN THE WOMEN’S HEALTH INITIATIVE COHORTS

Marian L. Neuhouser,1 Sylvia Wassertheil-Smoller,2 Cynthia Thomson,3 Aaron Aragaki,1 Garnet L. Anderson,1 JoAnn Manson,4 Ruth E. Patterson,1,5 Thomas E. Rohan,2 Linda van Horn,6 James M. Shikany,7 Asha Thomas,8 Andrea LaCroix,1 and Ross L. Prentice1
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Abstract

Context

Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease.

Objective

To examine associations between multivitamin use and risk of cancer, cardiovascular disease and mortality in postmenopausal women.

Design, Setting and Participants

161,808 participants from the Women’s Health Initiative Clinical Trials (n=68,132 in three overlapping trials of hormone therapy, dietary modification and calcium-vitamin D) or Observational Study (n=93,676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993–1998; women were followed for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease endpoints were collected through 2005.

Outcome Measures

Cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary and lung; cardiovascular disease (myocardial infarction, stroke, venous thrombosis); and total mortality.

Results

41.5% of participants used multivitamins. After a median of 8.0 years of follow-up in the CT and 7.9 years in the OS, 9,619 cases of breast, colorectal, endometrium, kidney, bladder, stomach lung or ovary cancer; 8,751 CVD events and 9,865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamins with risk of cancer (breast HR=0.98, 95%CI 0.91–1.05; colorectal HR = 0.99, 95% CI 0.88–1.11; endometrial HR = 1.05, 95%CI= 0.90–1.21; lung HR = 1.0, 95% CI=0.88–1.13; ovary HR = 1.07, 95%CI =0.88–1.29); CVD (MI HR= 0.96, 95%CI= 0.89–1.03; stroke HR = 0.99, 95%CI =0.91–1.07; VT HR = 1.05, 95%CI =0.85–1.29); or mortality (HR = 1.02, 95% CI=0.97–1.07).

Conclusion

After a median follow-up of 8.0 and 7.9 years in the CT and OS, respectively, the WHI cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of common cancers, cardiovascular disease or total mortality in postmenopausal women.

Clinical Trial Registration

clinicaltrials.gov identifier: NCT00000611

Keywords: dietary supplements, vitamins, minerals, breast cancer, lung cancer, colon cancer, myocardial infarction, stroke

INTRODUCTION

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 over $20 billion dollars 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 (3,4). These views are often fueled by product health claims, consumer testimonials and an industry that is largely unregulated due to the 1994 Dietary Supplement and Health Education Act (DHSEA) (5,6). Despite the widespread use of supplements and the strong consumer beliefs about benefits, convincing scientific data to support efficacy are lacking (7–9). With the exception of recommending a folic-acid containing supplement to women of childbearing potential (10,11) and advising avoidance of high-dose β-carotene by smokers (12), current data are insufficient to formulate public health recommendations for dietary supplement use for otherwise healthy people (2).

The hypothesis that multivitamins might lower the risk of cardiovascular disease and cancer derives from published evidence supporting a role for specific micronutrients in disease prevention. Data are consistent that diets high in fruits and vegetables are associated with a lower risk of cardiovascular disease and cancer. Moreover, low vs. high serum concentrations of B-vitamins, carotenoids and tocopherols have been associated with increased risk of colorectal cancer and cardiovascular disease (13–20). Since these vitamins, minerals and other small molecule compounds can be effectively packaged into pill form, supplements could ensure adequate micronutrient intake or correct low circulating concentrations, especially among persons with poor diets (21). Multivitamins are a potential vehicle since 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 examining associations between supplement use and disease risk, few have explicitly investigated multivitamins. Limited evidence from case-control and cohort studies suggests that multivitamins are associated with reduced risk of colon and bladder cancer, but increased risk of non-Hodgkin’s lymphoma (24). Other observational studies report no associations of multivitamins with colorectal, gastric, or lung cancers. One study of more than 1 million Americans reported no association of multivitamin use with total mortality, CHD mortality or cancer mortality (25). A cohort of men reported no risk reduction for cardiovascular disease or mortality for men who used multivitamins vs. those not using multivitamins (26). A prospective study of 37,920 women reported no association of multivitamin use with risk of breast cancer (27).

In this report we examined the associations between multivitamin use in the Women’s Health Initiative (WHI) Clinical Trial and Observational Study cohorts with risk of site-specific solid tumors: (invasive breast, kidney, endometrium, ovary, bladder and stomach cancers); (2) cardiovascular disease; and (3) total mortality.

METHODS

Overview of The Women’s Health Initiative

The WHI is a study of postmenopausal women’s health investigating risk factors for cancer, heart disease, and skeletal health (28). WHI was designed as a set of randomized controlled Clinical Trials and an Observational Study. Women were eligible for WHI participation if they were 50–79 years of age at screening, postmenopausal, and likely to live in close geographic proximity to one of 40 WHI Clinical Centers for at least three years. Women were excluded for medical conditions with a predicted survival of three years of less, conditions limiting adherence or retention (i.e., alcohol or drug dependency, dementia), or active participation in any other intervention trial where participants were individually randomized to a control or intervention group (28). The Clinical Trials (CT) (N=68,132) included three overlapping components: the Hormone Therapy (HT) Trials (n=27,347), Dietary Modification (DM) Trial (n=48,835), and Calcium and Vitamin D (CaD) Trial (n=36,282). Eligible women could be randomized into one, two, or all three of the CTs. Trial arm assignment was randomly designated (1:1 for the HT and CaD trials; for the DM, 40% were assigned to the low-fat intervention and 60% to usual diet) (28). Women who were ineligible or unwilling to join the CT were invited to join the Observational Study (OS), as were those who were specifically recruited for the OS (n=93,676). CT women attended baseline and annual clinic visits. OS women attended baseline and year 3 clinic visits and completed all other annual study activities by mail (i.e., medical history and lifestyle-exposure updates). Women were followed for a median of 8.0 years in the CT 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. This report is based on data from 161,808 women from both the Observational Study and the Clinical Trials; two 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 CT, and to the baseline and 3-year visit in the OS. A standardized interviewer-administered four-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 directly transcribed the ingredients for each supplement. Staff also queried 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 0.8–1.0 (29,30).

Multivitamins were grouped into three classifications based on ingredients: (i) ‘multivitamins (alone)’ were preparations with 10 or more vitamins and no minerals where the nutrient levels were at least 100% of US RDA; (ii) ‘multivitamins with minerals’ were preparations with 20–30 vitamins and minerals and nutrient levels ≤ 100% of US RDA; (iii) ‘stress multi-supplements’ 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.

Outcomes Ascertainment

Clinical outcomes of interest in WHI included cardiovascular disease (coronary heart disease, stroke, congestive heart failure, angina, peripheral vascular disease, carotid artery disease and coronary revascularization) cancer (breast, colorectal, endometrial, ovarian, 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 semi-annual (in the CT) 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 (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 endpoints reported and adjudicated through the end of the WHI close-out period of March, 2005. We included eight solid tumor cancers (invasive breast, colorectal, endometrial, stomach, ovary, kidney, lung, and bladder) and three CVD endpoints (myocardial infarction, stroke and venous thrombosis (CT only)).

Other Data

Standard procedures used across the CT and OS were employed 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, current health status, and tobacco and alcohol use. Clinic staff measured blood pressure, height and weight using standardized protocols

Statistical Analyses

Descriptive statistics characterized the study population. Cox proportional hazard models estimated hazard ratios and 95% confidence intervals 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 CT and time of enrollment in the OS (32,33). For a particular event, time accrued while a participant was still at risk for an event until date of diagnosis for cancer or cardiovascular disease, death from any cause, loss to follow-up, or March 31, 2005. Proportional hazards assumptions were assessed by a one-degree of freedom test of the interaction between log-survival time and multivitamin use; evidence of non-proportionality did not exist. Hazard ratios were adjusted for baseline characteristics: age, race/ethnicity, years since menopause (<5, 5–10,10–15,>15), BMI, education, alcohol use, smoking, general health, history of bilateral oophorectomy, geographic region, physical activity, duration of prior postmenopausal estrogen therapy use (none,<5, 5–10,10–15, >15 years), duration of prior postmenopausal estrogen+progesterone use (none,<5, 5–10,10–15, >15 years), fruit and vegetable intake, percent energy from fat, single supplements of vitamin C, E or calcium, any other single supplement, and stratified on age (5 year groups), HT trial randomization assignment/study enrollment [active conjugated equine estrogen + medroxyprogesterone acetate, (hereafter called CEE and MPA), placebo CEE+MPA, active CEE, placebo CEE, not randomized], DM trial randomization (intervention, control, not randomized) or OS enrollment (32,33). Specific to cancer analyses, family history of cancer was an additional covariate; women were excluded if they had a prior history of the particular cancer. For breast cancer analyses, women without a mammogram within two years of baseline were excluded. Specific to CVD analysis, treated diabetes, treated hyperlipidemia, systolic blood pressure, and prior history of the particular cardiovascular disease were additional covariates.

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

All statistical tests were two-sided with a p-value<0.05 considered statistically significant. Analyses were conducted with SAS, version 9.1 (SAS Institute, Inc, Cary, NC).

RESULTS

Table 1 presents demographic, health and lifestyle data according to use of multivitamin supplements in 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 taking ‘multivitamins (alone)’ (3.5%) or ‘stress-multivitamins’ (2.3%). Those who used any multivitamins were more likely to also use single supplements of vitamin E, vitamin C or calcium, compared to women who did not use multivitamins (p< 0.001). Compared to women not using multivitamins, multivitamin users were more likely to be white, living in the western United States, have a lower BMI, be more physically active and have a college degree or higher (all p< 0.001). Women who used multivitamins were more likely to consume alcohol and less likely to smoke than were non-users. Multivitamin users reported slightly higher fruit and vegetable consumption and lower percent energy from fat than non-users at baseline.

Table 1

Characteristics of Multivitamin Supplement Users and Non-Users in the Women’s Health Initiative (CT+OS, n=161806)

Combination (N=1091)Stress Multi-Vitamins. (N=3741)Multi-Vitamin w/minerals (N=56296)Multi-Vitamin (N=5667)None (N=95011)P-Value*
N%N%N%N%N%
Age group at screening, years<0.001
50–5942138.6141437.81689530.0166729.43316034.9
60–6946042.2163143.62608046.3252744.64188744.1
70–7921019.269618.61332123.7147326.01996421.0
Years since menopause<0.001
< 5 yrs15815.157215.9661612.367212.51248914.1
5 – <10 yrs21020.170919.7934217.391917.11622418.3
10 – <15 yrs19218.474520.71079520.099718.61728419.5
>= 15 yrs48346.3156743.62716750.4278351.84242248.0
Ethnicity<0.001
White95387.4309382.74916587.3504889.17527379.2
Black645.91804.832535.83225.71080711.4
Hispanic201.8882.416202.91071.946774.9
American Indian50.570.21940.3100.24990.5
Asian/Pacific Islander353.22977.913642.41132.023832.5
Unknown141.3762.07001.2671.213721.4
Body mass index (BMI), kg/m2 (collapsed categories)<0.001
<25 (normal)45742.4157942.72125138.1231541.33072932.6
25 – <30 (overweight)34832.3122833.21953535.0194934.83260634.6
>=30 (obese)27325.389224.11502026.9134424.03083532.7
Education<0.001
High school or less17516.160516.31117220.0111719.82319224.6
School after high school45141.6143338.62113637.8199935.53588338.1
College degree or higher45842.3167645.12361642.2251244.63514637.3
Alcohol<0.001
Non drinker11010.237210.051699.25079.01149412.2
Past drinker20218.771819.31002017.998617.51822119.3
<1/wk35332.7120932.51867233.4184332.63083032.7
1–7/wk31128.897526.21518327.1155227.52317924.6
>7/wk1049.644612.0690612.375913.41054111.2
Smoking<0.001
Never smoked52749.1180848.92823450.8293152.34793151.2
Past smoker48645.3167545.32420543.5235742.13838641.0
Current smoker605.62175.931735.73145.673797.9
General health<0.001
Excellent20518.873219.7975417.496617.11573016.7
Very Good46342.6160043.12393842.7241842.93721639.5
Good34031.3112630.41803632.2180332.03173633.6
Fair/Poor807.42526.842807.64467.9963610.2
Prior bilateral oophorectomy21420.274420.21137220.6108119.41814519.6<0.001
U.S. region<0.001
Northeast14613.482222.01287222.9176431.12130822.4
South27425.168218.21331223.699317.52665828.1
Midwest20018.353114.21252022.2137524.32093722.0
West47143.2170645.61759231.2153527.12610827.5
Physical activity<0.001
None or <2x/week52049.2172547.72804751.5285253.25384559.9
2–4x/week18817.872120.01043619.2100718.81509816.8
>=4x/week34933.0116732.31596929.3149828.02091723.3
Unopposed Estrogen Duration by Category<0.001
None65259.8233562.43463061.5365164.46283466.1
< 5 Years15814.551613.8742813.272912.91260513.3
5 – < 10 Years1029.32837.642247.54147.363386.7
10 – < 15 Years635.82276.134746.23205.648055.1
15+11610.638010.2654011.65539.884278.9
Estrogen + Progesterone Duration by Category<0.001
None75369.0244965.53972570.6413272.97265676.5
< 5 Years16214.864417.2796314.174813.21173412.4
5 – < 10 Years1059.63569.545698.14217.459586.3
10 – < 15 Years454.11905.127304.82414.331503.3
15+262.41022.713092.31252.215111.6
Vitamin C as SINGLE supplement47443.4144038.52019535.9200435.41857819.6<0.001
Vitamin E as SINGLE supplement51246.9157442.12283040.6220638.92146222.6<0.001
Calcium as single supp (including antacids)34031.2101427.11904433.8213037.62030621.4<0.001
Single Supplement (not Vitamins C, E or Ca)93385.53741100.02652847.1247743.72835329.8<0.001
Treated diabetes (pills or shots)333.01012.719343.41993.549005.2<0.001
History of high cholesterol requiring pills11110.747613.3764314.276514.41254114.20.01
Family history of cancer73069.9237366.13635667.4366067.25958765.8<0.001
Mammogram in last 2 yrs91185.7312486.04734986.3481887.27460881.4<0.001
History of breast cancer454.11223.320093.61983.526492.8<0.001
History of colorectal cancer80.7130.33410.6360.65490.60.31
Family history of myocardial infarction (MI)51850.0178550.52825752.9283252.44678052.20.006
Mean(SD)Mean(SD)Mean(SD)Mean(SD)Mean(SD)P-Value
Age at screening, years62.4(7.2)62.4(7.2)63.7(7.2)64.1(7.3)62.9(7.3)<0.001
Fruit and vegetable servings/day4.4(2.2)4.4(2.2)4.3(2.1)4.3(2.1)3.9(2.1)<0.001
Percent Calories from Fat/day31.0(8.3)31.1(8.6)31.7(8.3)31.5(8.2)33.4(8.3)<0.001
Systolic BP125.5(17.7)126.5(18.1)126.9(17.6)127.6(18.0)127.7(17.8)<0.001
*P values are from t-tests for continuous variables and chi-squared test for categorical variables.

There was no evidence that multivitamin use either increased or decreased risk of cancer (Table 2). Overall, there was no association of any multivitamin use with risk for cancers of the breast, colon/rectum, endometrium, ovary, kidney, bladder, stomach or lung. When we examined risk by the three classes of multivitamins, there was also no apparent association and the null value of 1.0 was included in the 95% confidence intervals of all multivariate-adjusted hazard ratio estimates. We observed a non-significant 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 hazard ratio estimates.

Table 2

Multivariable adjusted1 Relative Risk of Major Cancers by Multivitamin Use in the Women’s Health Initiative (CT+OS)

Category of MultivitaminCancer Site
Invasive Breast2Colorectal3Endometrium4Kidney
N*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)p
Any Multivitamin0.530.840.530.37
No2472(0.44)955(0.13)502(0.07)181(0.02)
Yes1928(0.47)0.98(0.91, 1.05)635(0.12)0.99(0.88, 1.11)410(0.08)1.05(0.90, 1.21)137(0.03)1.13(0.87, 1.46)
Type of Multivitamin0.690.900.780.37
None2472(0.44)955(0.13)502(0.07)181(0.02)
Multi-vitamin171(0.47)1.05(0.89, 1.25)60(0.14)1.05(0.79, 1.41)35(0.08)0.99(0.68, 1.45)10(0.02)0.90(0.44, 1.85)
Multi-vitamin w/minerals1620(0.47)0.97(0.90, 1.04)532(0.12)0.98(0.86,1.11)344(0.08)1.04(0.90, 1.22)120(0.03)1.17(0.90, 1.54)
Stress Multi-vitamins105(0.45)0.94(0.75, 1.17)30(0.10)0.89(0.57, 1.37)26(0.09)1.24(0.80, 1.91)4(0.01)0.51(0.16, 1.64)
Category of MultivitaminCancer Site
Bladder5Stomach6Lung7Ovary8
N*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)p
Any Multivitamin0.130.850.950.50
No236(0.03)61(0.01)795(0.11)315(0.04%)
Yes143(0.03)0.83(0.65, 1.06)40(0.01)0.96(0.60,1.53)545(0.11)1.00(0.88,1.13)264(0.05%)1.07(0.88,1.29)
Type of Multivitamin0.440.680.570.74
None236(0.03)61(0.01)795(0.11)315(0.04%)
Multi-vitamin12(0.03)0.84(0.46, 1.55)1(<0.01)0.33(0.05, 2.40)54(0.12)1.19(0.88, 1.61)23(0.05%)1.06(0.66, 1.72)
Multi-vitamin w/ minerals120(0.03)0.82(0.63, 1.05)36(0.01)1.00(0.61, 1.62)452(0.10)0.97(0.85, 1.11)216(0.05%)1.04(0.85, 1.27)
Stress Multi-vitamins9(0.03)1.05(0.51, 2.17)1(<0.01)0.56(0.07, 4.20)28(0.10)0.88(0.56, 1.37)16(0.05%)1.35(0.79, 2.32)
1All hazard ratios from a proportional hazards model adjusted for age(linear), race/ethnicity, years since menopause (<5,5–10,10–15,>15, linear), BMI (<25,25–30,>30, linear), education(<=high school, some college, college grad), alcohol use (non, past,<1/wk,1–7wk,>7wk), smoking(non, past, current), general health (fair/poor, good, very good, excellent), history of bilateral oophorectomy(yes, no), region(northeast, south, midwest, west), physical activity(none/<2,2–4 episodes,>4 episodes), duration of prior E alone use (none,<5,5–10,10–15,>15years), duration of E+P use(none,<5,5–10,10–15,>15years), fruit and vegetable intake (tertiles, linear) and percent energy from fat (tertiles, linear), use of Vitamin C as a single supplement, use of Vitamin E as a single supplement, use of Calcium as a single supplement, use of any other single supplement, family history of cancer and stratified on age (5yr groups), HT trial randomization assignment/study enrollment (active CEE+MPA, placebo CEE+MPA, active CEE, placebo CEE, not randomized), DM trial randomization (intervention, control, not randomized) or OS enrollment.
2In addition to the adjustments listed in 1, models were adjusted for Gail score (tertiles, linear). Women who did not have a mammogram within two years of baseline and/or prior history of breast cancer were excluded.
3Women with a prior history of colorectal cancer were excluded.
4Women with a prior history of endometrial cancer were excluded.
5Women with a prior history of bladder cancer were excluded.
6Women with a prior history of stomach cancer were excluded.
7Women with a prior history of lung cancer were excluded.
8Women with a prior history of ovarian cancer were excluded.
*Number of cases.
£Annualized percent of cases.

We next examined the association of multivitamin use with risk of cardiovascular disease (MI, stroke, venous thrombosis) (Table 3). The annualized percentages of cardiovascular disease events were non-significantly lower among women using multivitamins compared to those not taking multivitamins and the overall hazard ratios 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; for MI the adjusted-HR was 0.75 (95%CI, 0.56–0.99).

Table 3

Events, Annualized Percentages and Multivariable adjusted1 Relative Risk of Cardiovascular Disease by Multivitamin Use in the Women’s Health Initiative (CT+OS)

Category of MultivitaminCVD Events
M.I.2Stroke3Venous Thrombosis4Total Mortality
N*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)p
Any Multivitamin0.270.750.640.48
No2828(0.39)2173(0.30)354(0.10)5911(0.80)
Yes1765(0.35)0.96(0.89, 1.03)1427(0.28)0.99(0.91, 1.07)204(0.10)1.05(0.85, 1.29)3954(0.77)1.02(0.97, 1.07)
Type of Multivitamin0.100.680.850.69
None2828(0.39)2173(0.30)354(0.10)5911(0.80)
Multi-vitamin176(0.40)1.08(0.91, 1.28)140(0.32)1.10(0.91, 1.33)21(0.12)0.91(0.52, 1.60)372(0.83)1.03(0.92, 1.16)
Multi-vitamin w/minerals1497(0.35)0.96(0.89, 1.03)1201(0.28)0.98(0.90, 1.06)173(0.10)1.07(0.86, 1.32)3335(0.77)1.02(0.97, 1.07)
Stress Multi-vitamins64(0.22)0.75(0.56, 0.99)65(0.22)0.97(0.73, 1.29)6(0.05)0.80(0.33, 1.99)181(0.61)0.94(0.80, 1.10)
1All hazard ratios from a proportional hazards model adjusted for age(linear), race/ethnicity, years since menopause (<5,5–10,10–15,>15, linear), BMI (<25,25–30,>30, linear), education(<=high school, some college, college grad), alcohol use (non, past,<1/wk,1–7wk,>7wk), smoking(non, past, current), general health (fair/poor, good, very good, excellent), history of bilateral oophorectomy(yes, no), region(northeast, south, midwest, west), physical activity(none/<2,2–4 episodes,>4 episodes), duration of prior E alone use (none,<5,5–10,10–15,>15years), duration of E+P use(none,<5,5–10,10–15,>15years), fruit and vegetable intake (tertiles, linear) and percent energy from fat (tertiles, linear), use of Vitamin C as a single supplement, use of Vitamin E as a single supplement, use of Calcium as a single supplement, use of any other single supplement, treated diabetes, treated hyperlipidemia, systolic blood pressure (tertiles, linear), and stratified on age (5yr groups), HT trial randomization assignment/study enrollment (active CEE+MPA, placebo CEE+MPA, active CEE, placebo CEE, not randomized), DM trial randomization (intervention, control, not randomized) or OS enrollment.
2Includes fatal and nonfatal MI. In addition to the adjustments listed in 1, models were adjusted for family history of MI and prior history of MI.
3Includes fatal and nonfatal stroke. In addition to the adjustments listed in 1, models were adjusted for family history of stroke and prior history of stroke.
4CT only, includes DVT and PE; outcomes not adjudicated for OS. In addition to the adjustments listed in 1, models were adjusted for prior history of DVT and prior history of PE.
*Number of cases.
£Annualized percent of cases

To investigate variation in risk by total duration of use, we categorized duration into four groups: (i) less than one year; (ii) 1–5 years; (iii) 6–10 years; and (iv) > 10 years. Of the 1,928 invasive breast cancer cases who used multivitamins, 685 (35.5%) reported multivitamin use for at least 10 years (Table 4). While the annualized percent of breast cancer events was slightly higher among those with at least 10 years of use (0.50), compared to non-users of multivitamins (0.44), the adjusted HR was 1.03 (95%CI 0.94, 1.14). Five to ten years and more than 10 years of multivitamin use were associated with small but statistically non-significant increased risks for endometrial cancer (HR= 1.19, 95%CI, 0.91–1.56 and HR = 1.09, 95%CI, 0.89–1.35, respectively) kidney cancer (HR = 1.32, 95% CI, 0.82–2.13 for 5–10 years of use) and stomach cancer (HR= 1.36, 95%CI 0.73, 2.56 for > 10 years of use).

Table 4

Multivariable adjusted1 Relative Risk of Major Cancers by Multivitamin Duration in the Women’s Health Initiative (CT+OS)

Category of MultivitaminCancer Site
Invasive Breast2Colorectal3Endometrium4Kidney
N*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)p
Duration of Multivitamin0.170.560.360.63
None2472(0.44)955(0.13)502(0.07)181(0.02)
<1 yr283(0.44)0.93(0.81, 1.06)114(0.14)1.09(0.87, 1.36)61(0.07)1.01(0.75, 1.35)24(0.03)1.12(0.68, 1.84)
1 to 5 yrs677(0.46)0.97(0.88, 1.07)218(0.12)0.97(0.82, 1.15)133(0.07)0.97(0.78, 1.19)49(0.03)1.16(0.81, 1.65)
6 to 10 yrs283(0.44)0.93(0.81, 1.07)98(0.13)0.92(0.72, 1.17)66(0.09)1.19(0.91, 1.56)23(0.03)1.32(0.82, 2.13)
>10685(0.50)1.03(0.94, 1.14)205(0.12)0.98(0.83, 1.17)150(0.09)1.09(0.89, 1.35)41(0.02)0.99(0.66, 1.48)
Category of MultivitaminCancer Site
Bladder5Stomach6Lung7Ovary8
N*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)p
Duration of Multivitamin0.280.350.080.06
None236(0.03)61(0.01)795(0.11)315(0.04%)
<1 yr19(0.02)0.62(0.35, 1.09)7(0.01)0.90(0.36, 2.27)94(0.11)1.16(0.91, 1.48)34(0.04%)0.87(0.58, 1.30)
1 to 5 yrs53(0.03)0.91(0.66, 1.27)12(0.01)0.87(0.44, 1.73)188(0.10)1.01(0.84, 1.21)84(0.05%)0.93(0.71, 1.23)
6 to 10 yrs17(0.02)0.51(0.27, 0.93)5(0.01)0.41(0.10, 1.72)86(0.11)1.03(0.80, 1.32)51(0.07%)1.32(0.95, 1.85)
>1054(0.03)0.99(0.72, 1.38)16(0.01)1.36(0.73, 2.56)177(0.10)0.89(0.73, 1.08)95(0.06%)1.20(0.93, 1.56)
1All hazard ratios from a proportional hazards model adjusted for age(linear), race/ethnicity, years since menopause (<5,5–10,10–15,>15, linear), BMI (<25,25–30,>30, linear), education(<=high school, some college, college grad), alcohol use (non, past,<1/wk,1–7wk,>7wk), smoking(non, past, current), general health (fair/poor, good, very good, excellent), history of bilateral oophorectomy(yes, no), region(northeast, south, midwest, west), physical activity(none/<2,2–4 episodes,>4 episodes), duration of prior E alone use (none,<5,5–10,10–15,>15years), duration of E+P use(none,<5,5–10,10–15,>15years), fruit and vegetable intake (tertiles, linear) and percent energy from fat (tertiles, linear), use of Vitamin C as a single supplement, use of Vitamin E as a single supplement, use of Calcium as a single supplement, use of any other single supplement, family history of cancer and stratified on age (5yr groups), HT trial randomization assignment/study enrollment (active CEE+MPA, placebo CEE+MPA, active CEE, placebo CEE, not randomized), DM trial randomization (intervention, control, not randomized) or OS enrollment.
2In addition to the adjustments listed in 1, models were adjusted for Gail score (tertiles, linear). Women who did not have a mammogram within two years of baseline and/or prior history of breast cancer were excluded.
3Women with a prior history of colorectal cancer were excluded.
4Women with a prior history of endometrial cancer were excluded.
5Women with a prior history of bladder cancer were excluded.
6Women with a prior history of stomach cancer were excluded.
7Women with a prior history of lung cancer were excluded.
8Women with a prior history of ovarian cancer were excluded.
*Number of cases.
£Annualized percent of cases

Duration of multivitamin use had no apparent association with cardiovascular disease risk. There was a slightly higher annualized percentage of MI cases for multivitamin non-users than users. However, the adjusted hazard ratios for nearly all outcomes in Table 5 were close to 1.0 and all 95% confidence intervals contained the null value of 1.0. There was no association of duration of multivitamin use with total mortality.

Table 5

Events, Annualized Percentages and Multivariable adjusted1 Relative Risk of Cardiovascular Disease by Multivitamin Use* in the Women’s Health Initiative (CT+OS)

Category of MultivitaminCVD Events
M.I.2Stroke3Venous Thrombosis4Total Mortality
N*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)pN*(%)£HR(CI)p
Duration of Multivitamin0.720.360.810.52
None2828(0.39)2173(0.30)354(0.10)5911(0.80)
<1 yr262(0.32)0.93(0.80, 1.07)221(0.27)0.99(0.84, 1.16)35(0.09)0.95(0.64, 1.40)609(0.73)1.00(0.91, 1.10)
1 to 5 yrs645(0.35)0.97(0.88, 1.07)482(0.26)0.94(0.84, 1.06)74(0.10)1.08(0.81, 1.43)1374(0.75)1.01(0.95, 1.08)
6 to 10 yrs270(0.35)0.97(0.84, 1.11)224(0.29)1.00(0.85, 1.17)32(0.11)1.17(0.77, 1.79)608(0.77)1.01(0.92, 1.11)
>10588(0.35)0.97(0.87, 1.07)500(0.30)1.03(0.92, 1.16)63(0.10)1.03(0.74, 1.43)1363(0.80)1.03(0.97, 1.11)
1All hazard ratios from a proportional hazards model adjusted for age(linear), race/ethnicity, years since menopause (<5,5–10,10–15,>15, linear), BMI (<25,25–30,>30, linear), education(<=high school, some college, college grad), alcohol use (non, past,<1/wk,1–7wk,>7wk), smoking(non, past, current), general health (fair/poor, good, very good, excellent), history of bilateral oophorectomy(yes, no), region(northeast, south, midwest, west), physical activity(none/<2,2–4 episodes,>4 episodes), duration of prior E alone use (none,<5,5–10,10–15,>15years), duration of E+P use(none,<5,5–10,10–15,>15years), fruit and vegetable intake (tertiles, linear) and percent energy from fat (tertiles, linear), use of Vitamin C as a single supplement, use of Vitamin E as a single supplement, use of Calcium as a single supplement, use of any other single supplement, treated diabetes, treated hyperlipidemia, systolic blood pressure (tertiles, linear), and stratified on age (5yr groups), HT trial randomization assignment/study enrollment (active CEE+MPA, placebo CEE+MPA, active CEE, placebo CEE, not randomized), DM trial randomization (intervention, control, not randomized) or OS enrollment.
2Includes fatal and nonfatal MI. In addition to the adjustments listed in 1, models were adjusted for family history of MI and prior history of MI.
3Includes fatal and nonfatal stroke. In addition to the adjustments listed in 1, models were adjusted for family history of stroke and prior history of stroke.
4CT only, includes DVT and PE; outcomes not adjudicated for OS. In addition to the adjustments listed in 1, models were adjusted for prior history of DVT and prior history of PE.
*Number of cases.
£Annualized percent of cases

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 to any use in relation to any of the cancer or CVD outcomes are approximately equal (Table 6).

Table 6

Comparison of Multivariable1 Adjusted Relative Risk between multivitamin users and persistent2 users of multivitamins (CT+OS)

EventHR(95%CI) of multivitamin useHR(95%CI) of persistent use
Invasive breast cancer0.98 (0.91,1.05)1.00 (0.92,1.09)
Colorectal cancer0.99 (0.88,1.11)1.09 (0.88,1.36)
Endometrial cancer1.05 (0.90,1.21)1.11 (0.91,1.34)
Kidney cancer1.13 (0.87,1.46)1.06 (0.76,1.46)
Bladder cancer0.83 (0.65,1.06)0.65 (0.47,0.89)
Stomach cancer0.96 (0.60,1.53)0.85 (0.47,1.54)
Lung cancer1.00 (0.88,1.13)1.11 (0.95,1.31)
Ovary cancer1.07 (0.88, 1.29)0.92 (0.72, 1.18)
MI0.96 (0.89,1.03)0.99 (0.91, 1.09)
Stroke0.99 (0.91,1.07)0.98 (0.88, 1.08)
VTE1.05 (0.85,1.29)1.07 (0.84, 1.37)
Death1.02 (0.97,1.07)0.98 (0.92, 1.04)
1Persistent use models had the same multivariable adjustment as the corresponding multivitamin use model (see Table 2 for details).
2Persistent users are defined as participants who were using any multivitamins at baseline and at their first collection of any multivitamin information during follow-up (Year 1 for the CT and Year 3 for the OS).

The associations of multivitamin use with cancer and cardiovascular disease risk were weakly modified by demographic, health and lifestyle characteristics. Analyses by age suggested older multivitamin users (≥70 years at baseline) had a reduced risk of endometrial cancer (HR=0.73, 95% CI=0.55–0.97, p, interaction <0.01) and multivitamin users who were obese had a reduced risk of invasive breast cancer (HR=0.84, 95%CI= 0.74–0.95, p, interaction <0.01). However, younger women using multivitamins were at a slightly higher risk of death (HR=1.07, 95%CI, 1.01–1.14, p, interaction <0.05). Multivitamin users who were current smokers or consumers of more than one alcohol drink per day had non significant increased risks of mortality and myocardial infarction, respectively (p, interaction <0.05). There was a non-significant increased risk of myocardial infarction and ovarian cancer among women who used multivitamins (p, interaction = 0.04 and 0.05, respectively). Fruit and vegetable intake did not modify the associations of multivitamin use with disease outcomes (data not shown).

DISCUSSION

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 (26,34–36). 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) (37,38). This same cohort reported no association of multivitamin use with stomach cancer or fatal non-Hodgkin’s lymphoma (24,39). 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 (44,45). 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 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 (50,51). The risks associated with exceeding the UL 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 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 (21,53). 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 (54–57). 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 (8,51). 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 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.

Acknowledgments

Funding/Support: The WHI program is funded by the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, United States 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 prior to submission.

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

WHI Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L. Kooperberg, Ruth E. Patterson, Anne McTiernan; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; (Medical Research Labs, Highland Heights, KY) Evan Stein; (University of California at San Francisco, San Francisco, CA) Steven Cummings.

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

Footnotes

Financial Disclosures: None of the authors had financial disclosures to report.

Author Contributions: Dr. Prentice and Mr. Aragaki had full access to all of the data in the study and they take responsibility for the integrity of the data and the accuracy of the data analysis.

Study Concept and Design: Neuhouser, Wassertheil-Smoller, Thomson, Prentice

Acquisition of Data: Wassertheil-Smoller, Thomson, Prentice, Anderson, Manson, Patterson, Rohan, Van Horn, Shikany, LaCroix

Analysis and Interpretation of Data: Neuhouser, Aragaki, Prentice, Wassertheil-Smoller, Thomson, Anderson, Shikany, Rohan, Patterson

Drafting of the Manuscript: Neuhouser, Aragaki, Prentice

Critical Revision of the Manuscript for Important Intellectual Content: Neuhouser, Wassertheil-Smoller, Thomson, Prentice, Aragaki, Anderson, Manson, Patterson, Rohan, Van Horn, Shikany, Thomas, LaCroix

Statistical Analyses: Neuhouser, Aragaki, Prentice

Obtained funding: Prentice, Wassertheil-Smoller, Thomson, Anderson, Manson, Van Horn, LaCroix

Administrative, Technical or Material Support: Prentice, Anderson, Wassertheil-Smoller, LaCroix, Patterson

Study Supervision: Neuhouser, Anderson

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