Multivitamin Use and Mortality in a Large Prospective Study

Margaret L. Watkins1, J. David Erickson1, Michael J. Thun2, Joseph Mulinare1 and Clark W. Heath, Jr.2

1 Centers for Disease Control and Prevention, National Center for Environmental Health, Division of Birth Defects, Child Development, Disability and Health, Birth Defects and Pediatric Genetics Branch, Atlanta, GA.
2 Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.

cardiovascular diseases; cerebrovascular disorders; cohort studies; folic acid; mortality; neoplasms; smoking; vitamins

Abbreviations: CI, confidence interval; CPS-II, Cancer Preventions Study II; ICD-9, International Classification of Diseases, Ninth Revision; NTD, neural tube defect; RR, relative risk.


    INTRODUCTION
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
Heart disease, cancer, and cerebrovascular diseases are the three leading causes of death in the United States, accounting for over 60 percent of age-adjusted mortality (1Go). The role of vitamin supplementation in preventing cardiovascular disease and cancer remains unclear in populations that are not clinically malnourished. Observational studies have found cardiovascular disease outcomes to be inversely associated with supplements of vitamins E (2Go3Go–4Go) and C (5Go). However, randomized trials have found no cardiovascular benefit from supplemental beta carotene (6Go7Go–8Go) and a risk reduction for nonfatal myocardial infarction (not cardiovascular death) from supplemental vitamin E (8Go, 9Go). Numerous observational studies have found lower risks for a variety of cancers associated with consumption of fruits and vegetables (10Go). A recent prospective study in women (11Go) and a case-control study in men and women (12Go) found a reduced risk for colon cancer with long-term multivitamin use. However, randomized trials have found no benefit from supplemental beta-carotene for lung cancer (7Go, 13Go, 14Go). Two of these studies actually suggest increased lung cancer risk in smokers treated with beta carotene (13Go, 14Go).

Natural forms of the B vitamin folate occur in many foods, and the synthetic form, folic acid, is used in vitamin supplements and fortified foods. Folic acid is of great interest not only because of its proven benefit against neural tube defects (NTDs) but also because of its potential to lower plasma homocyst(e)ine levels and thereby, theoretically, to reduce the risk of cardiovascular disease (reviewed in detail elsewhere (15Go, 16Go)). Vitamins B6 (pyridoxine) and B12 (cyanocobalamin) also play key roles in homocyst(e)ine metabolism. Vitamin B12 is involved in the methionine synthase reaction, vitamin B6 is involved in the cystathionine synthase reaction of homocyst(e)ine metabolism, and homocyst(e)ine concentrations are inversely related to folate and vitamin B6 and B12 levels. The proven role of folic acid in decreasing NTD risk has led to the recommendation in the United States that all women of childbearing potential consume 400 µg of folic acid daily (17Go) and to a regulation, effective January 1998, that requires the fortification of cereal grain products with folic acid at a level of 140 µg of folic acid per 100 g of cereal grain product (18Go). In addition, there has been much interest in assessing the role of antioxidant vitamins (vitamins C and E and the carotenoids, found in many vitamin A preparations) in cardiovascular disease and cancer, since antioxidants protect DNA and cell membranes against oxidative damage, a process involved in atherogenesis as well as in the initiation, promotion, and progression of cancer.

There are few data that suggest adverse consequences of increased widespread use of multivitamins, but in light of recommendations for increased use of vitamins containing folic acid for NTD prevention and the possible role for folic acid and other vitamins in preventing vascular disease and cancer, there is a need to assess more closely both the possible benefits and the risks of these products. Previous studies have demonstrated no significant differences in overall mortality risk between multivitamin users and nonusers (4Go, 19Go). However, these studies involved a relatively small number of deaths and, in one case (19Go), involved a time period when the amount of folic acid allowed in nonprescription multivitamins was limited to 0.1 mg and many contained no folic acid (20Go). Because of our interest in folic acid, we focused on multivitamin supplements. Our study examines the relation between the use of multivitamin supplements and mortality from ischemic heart disease, cerebrovascular disease, and selected cancers in a prospective study of over 1 million US adults.


    MATERIALS AND METHODS
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
Study population
Cancer Prevention Study II (CPS-II) is a nationwide, prospective mortality study of nearly 1.2 million US men and women aged 30 years and older that began in 1982. At the request of an American Cancer Society volunteer, each enrollee completed a four-page mailed questionnaire in 1982 that requested information on history of cancer and other diseases, use of medicines and vitamins, use of alcohol and tobacco, diet, as well as other factors potentially affecting mortality. This analysis includes 1,063,023 people (453,962 men; 609,061 women) who, at enrollment, reported usable data on vitamin use. We initially stratified the analyses by presence of diagnosed disease at baseline with the idea that people with a history of heart disease, stroke, or cancer may have different health habits (including vitamin use). In subsequent analyses, we excluded persons with a history of the disease of interest at the time of the baseline interview. All-cause mortality analyses included all people, regardless of presence of preexisting disease at baseline.

Mortality outcomes
The follow-up period was 7 years, extending from 1982 through 1989. Using codes from the International Classification of Diseases, Ninth Revision (ICD-9) (21Go), we classified deaths due to ischemic heart disease (ICD-9 codes 410–414), cerebrovascular disease (stroke) (ICD-9 codes 430–438), and all cancers combined, except nonmelanoma skin cancer (ICD-9 codes 140–195 and 199–209). We examined separately the three most common causes of cancer mortality: lung (ICD-9 code 162), colo-rectal (ICD-9 codes 153–154), and (for men) prostate (ICD-9 code 185) and (for women) breast (ICD-9 code 174), and all other cancers combined. All-cause mortality included persons who died of any cause.

Vitamin supplement information
The 1982 questionnaire included separate questions about the use of multivitamins; vitamins A, C, and E; and 11 other medications. We were particularly interested in multivitamins, with or without other vitamin supplements, because most of these products have contained up to 400 µg of folic acid since 1973 (20Go). Most multivitamin formulations also contained vitamins B6 and B12 in 1982. We classified participants into four groups relative to frequency of vitamin use in the month prior to the survey. Multivitamin users were persons who reported any multivitamin use during the preceding month but did not use vitamin A, C, or E. Vitamin A, C, or E users were persons who reported any use (regardless of frequency) of vitamin A, C, or E, but who did not use multivitamins. Users of a combination of multi-vitamins and vitamin A, C, or E were persons who reported use of both a multivitamin and vitamin A, C, or E. Nonusers were persons who reported no multivitamin or vitamin A, C, or E use by reporting zero for "times in last month." An algorithm based on a person's pattern of answers to the other medication questions was used to recode the response of persons who did not supply the information on frequency. First, if a person with missing information on multivitamin frequency wrote zero on any other medications, then that person's multivitamin use was judged to be unknown and that person was deleted from the analysis. Second, if a person had valid usage information for another medication, that person was assumed to be a nonuser of multivitamins. Frequency-of-use categories were as follows: 29 or fewer times per month, 30 or more times a month, and "occasional" use (described qualitatively by respondents). Duration of use was categorized as 5 or fewer years, more than 5 years, and unquantifiable. For persons who used both a multivitamin and vitamin A, C, or E, the duration of multivitamin use was used to define the duration of use. Because our main interest was in folic acid supplementation, we were principally concerned with the contrast between persons who used multivitamins and those who reported no supplement use. Also informative was the contrast between combination users and those who used vitamin A, C, or E only. The analyses were not intended to be informative for vitamin A, C, or E separately, and we combined the use of these vitamins into a single exposure variable because of their antioxidant properties.

Statistical analyses
We utilized Cox proportional hazards to calculate relative risk estimates for death from any cause, ischemic heart disease, stroke, and cancer. We used separate models for men and women. All models involved matching on baseline age (1-year increments). In addition, adjusted models included numerous potential confounders. To facilitate comparison of mortality risks, we used the same covariates in different models to the extent possible. All models were adjusted for exercise (none, slight, moderate, or heavy); education level (less than high school, high school graduate, vocational/some college, college graduate, and postgraduate); body mass index (weight (kg)/height2 (m)) (<20.7, 20.7–24.6, 24.7–27.7, 27.8–31, and >31 for men; <19.1, 19.1–21.9, 22.0–27.2, 27.3–32.2, and >32.2 for women); quartiles of a summary measure of vegetable intake (frequency per week of consuming carrots; tomatoes; squash/corn; green, leafy vegetables; raw vegetables; and cabbage/broccoli/Brussels sprouts). CPS-II estimated intake of a limited number of food items. We chose to use a measure of vegetable intake as a potential confounder because vegetables contain many of the same micronutrients included in multivitamin and vitamin A, C and E supplements and because of the association between vegetable consumption and cancer and cardiovascular disease. Also included in the adjusted models were dichotomous measures for history of diabetes; hypertension (or taking antihypertensive medication); stroke (except in stroke models); heart disease (or taking heart disease medication, except in heart disease models); smoking status (current, former, never); employment; aspirin use; diuretic use; liquor, wine , beer, or coffee consumption; marital status; race (white/other); and estrogen replacement status (women only). All-cause mortality models also adjusted for history of kidney disease, cirrhosis, and cancer reported at baseline.


    RESULTS
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
Thirty percent of men and 37 percent of women used multivitamin supplements alone or in combination with vitamin A, C, or E in the month preceding the questionnaire (table 1). Fifty-eight percent of the men and 50 percent of the women reported no vitamin use in the month preceding the questionnaire, and 12 percent of the men and 13 percent of the women used vitamin A, C, or E without a multivitamin. Compared with men and women who took no vitamin supplements, users, in general, tended to be more educated, less overweight, and more likely to eat more vegetables and drink wine or liquor.


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TABLE 1. Distribution of potential mortality risk factors by category of vitamin use, Cancer Prevention Study II, 1982–1989

 

    Ischemic heart disease and stroke mortality
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
Men and women in our study who reported taking vitamin supplements at baseline generally had lower rates of death from ischemic heart disease and stroke than did people who did not report vitamin use (table 2). However, adjustment of the relative risk estimates for potential risk factors besides age consistently narrowed the difference between people who did and those who did not use vitamin supplements, suggesting that vitamin use itself accounts for, at most, only part of the survival benefit associated with these products. For cardiovascular diseases, the inverse association was strongest in people who reporting taking multivitamins plus vitamin A, C, or E, intermediate in people who reported A, C and/or E only, and weakest in those who reported taking multivitamins only (table 2). There was no consistent gradient of decreasing risk with more prolonged (table 3) or more frequent (data not shown) use of supplements for either ischemic heart disease or stroke. Persons who reported their use qualitatively as "occasional" (19 percent of the men and 23 percent of the women) had the lowest risk of heart disease mortality (relative risk (RR) = 0.90 for men, RR = 0.92 for women), although neither relative risk was significant.


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TABLE 2. Ischemic heart disease and stroke mortality according to no vitamin use (referent); multivitamin use; vitamin A, C, or E use; or multivitamin and vitamin A, C, or E use, by presence of disease, relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 

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TABLE 3. Ischemic heart disease and stroke mortality by duration of multivitamin use among persons who use a multivitamin alone or a multivitamin and vitamin A, C, or E, multivariate relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 

    Cancer mortality
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
The risk of death from cancer among vitamin users tended to be equivalent to or higher than the risk for people who did not use these products (table 4), although the pattern was not as consistent as was the inverse association between vitamin supplements and cardiovascular mortality (table 2). Multi-vitamins alone or in combination with vitamin A, C, or E were associated more often with slightly increased mortality from all cancers combined and from cancers of the lung (both sexes) and colorectum (men) and other cancers (men) than was use of vitamin A, C, or E without multivitamins. Relative risk estimates were generally higher in men who reported cancer (other than nonmelanoma skin cancer) at baseline than in those who did not, although these analyses could not control for the stage of disease. To assess whether confounding could explain the higher risk of cancer mortality among men who reported cancer at baseline (i.e., higher prevalence of vitamin use among persons with more advanced disease), we performed additional analyses, eliminating deaths in the first 3 years after baseline. For all cancer sites in which there was an elevated risk of death from cancer among multivitamin users, the elevation in relative risk was attenuated and became statistically insignificant by eliminating deaths during the first 3 years after baseline (results not shown). For example, the adjusted relative risk for men with a history of cancer decreased from 1.24 (95 percent confidence interval (CI): 1.14, 1.35), to 1.07 (95 percent CI: 0.93, 1.24) for all cancers, from 1.10 to 1.02 in lung cancer, from 1.46 to 0.85 for colon cancer, and from 1.24 to 1.11 for other cancer. This suggests that the apparent elevation in cancer mortality risk among men with preexisting cancer is probably due to confounding by stage of disease. Additionally, for both men and women with a history of cancer, all-cancer mortality was higher among those taking multivitamins for 5 years or less (e.g., men, RR = 1.61, 95 percent CI: 1.44, 1.79) than for those taking them for longer than 5 years (RR = 0.91, 95 percent CI: 0.79, 1.05), further supporting confounding as the explanation.


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TABLE 4. Cancer mortality according to no vitamin use (referent); multivitamin use; vitamin A, C, or E use; or use of multivitamins and vitamin A, C, or E, by presence of cancer at enrollment, relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 
The risk of death from cancer did not increase consistently with either the duration (table 5) or the frequency of multivitamin use (data not shown). The possible exception was prostate cancer (RR = 1.09 for duration of 5 or fewer years, RR = 1.31 for 5 or more years of use).


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TABLE 5. Cancer mortality by duration of multivitamin use among persons who use a multivitamin alone or a multivitamin and vitamin A, C, or E, multivariate relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 
The association between vitamin supplement use and increased cancer mortality was stronger among men who smoked cigarettes than among never smokers (table 6). No cancer risks were statistically significantly increased among never smokers or former smokers who used multivitamins alone or in combination with other vitamins. This finding was also true in men with a history of cancer (data not shown). Among men who used both multivitamins and vitamin A, C, or E, the risk for all-cancer mortality was increased among current smokers (RR = 1.16, 95 percent CI: 1.06, 1.26), but decreased among never (RR = 0.86, 95 percent CI: 0.74, 0.99) and former (RR = 0.90, 95 percent CI: 0.82, 0.98) smokers. Smokers who used vitamin A, C, or E alone or in combination with multivitamins had a greater risk of fatal prostate cancer than did nonusers (RR = 1.44 and RR = 1.58, respectively). Among the men who had never smoked or who no longer smoked, those who took both multivitamins and vitamin A, C, or E had a lower risk of dying from lung cancer than did those who took no vitamins (RR = 0.79). There was no suggestion of effect modification by smoking in women (table 7).


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TABLE 6. Cancer mortality in men{dagger} aacording to no vitamin use (referent); multivitamin use; vitamin A, C, or E use; or multivitamin and vitamin A, C, or E use, by smoking status, multivariate relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 

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TABLE 7. Cancer mortality in women{dagger} according to no vitamin use (referent); multivitamin use; vitamin A, C, or E use; or multivitamin and vitamin A, C, or E use, by smoking status, relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 

    All-cause mortality
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
Although all-cause death rates were 5 percent higher in men who used multivitamins than in those who did not ( RR = 1.05, 95 percent CI: 1.02, 1.08), this was not true in women nor was it seen with other vitamin supplements (table 8). In both men and women, relative risk estimates were inversely associated with the duration of multivitamin use (table 9), but did not vary by frequency of use (data not shown). Men and women who used both multivitamins and vitamin A, C, or E had lower all-cause death rates, and their risk was inversely associated with duration of use (table 9).


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TABLE 8. All-cause mortality according to no vitamin use (referent); multivitamin use; vitamin A, C, or E use; or multivitamin and vitamin A, C, or E use, by presence of disease, relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 

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TABLE 9. All-cause mortality by duration of multivitamin use among persons who use a multivitamin alone or a multivitamin in combination with vitamin A, C, or E, multivariate relative risks and 95% confidence intervals, Cancer Prevention Study II, 1982–1989

 

    DISCUSSION
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 
Ischemic heart disease and stroke mortality
This large prospective study provides limited support for the hypothesis that multivitamin supplements may reduce death rates from ischemic heart disease in the general population. Men and women who took a multivitamin without other supplements had lower death rates from ischemic heart disease than did those who took no multivitamins. However, the association was attenuated when analyses were adjusted for additional cardiovascular risk factors besides age, and no consistent gradient of decreasing risk was seen with either the frequency or the duration of multivitamin use. The risk was lower among people who reported prevalent heart disease when enrolled in the study than among those who did not and among those who took multivitamins in combination with vitamin A, C, or E. No risk reduction in stroke mortality was seen among persons who used multivitamins alone, but reduction was seen in persons who took multivitamins in combination with vitamin A, C, or E.

Men and women who used both multivitamins and vitamin A, C, or E had lower risks of dying from heart disease and stroke than did nonusers than one might expect from the relative risks for users of either only a multivitamin or only a vitamin A, C, or E supplement. For example, the relative risk for ischemic heart disease was 0.84 for men who used both a multivitamin and vitamin A, C or E, 0.99 for those who used only a multivitamin, and 0.94 for those who used only vitamin A, C, or E. One explanation is that there may be a minimum dose of a single vitamin or combination of supplements necessary for risk reduction. Alternatively, this pattern could reflect residual confounding or chance.

Observational studies support an association between elevated plasma homocyst(e)ine levels and vascular disease (15Go, 16Go). Observational studies (15Go) and a randomized trial (22Go) have demonstrated that folic acid consumption increases plasma folate levels and reduces plasma homocyst(e)ine levels. However, definitive proof that increased folic acid consumption reduces cardiovascular disease risk awaits the results of randomized clinical trials. We did not find strong evidence of lower cardiovascular disease risk associated with consumption of multivitamins containing folic acid.

The lack of association between multivitamin use and lower cardiovascular mortality in our study could reflect misclassification of folic acid exposure. Not all manufacturers increased the folic acid content of multivitamins to 400 µg in 1973, when this was first allowed (20Go), although the majority of popular national brands had done so by 1982 (Watkins M, Centers for Disease Control and Prevention, unpublished data from reviews of Physicians' Desk References, 1973–1982). Measurements of folate in serum collected in 1982 in the Physicians' Health Study were significantly higher among current multivitamin users (6.46 ng/ml) than among nonusers (2.89 ng/ml) (23Go). However, the duration of supplementation with 400 µg of folic acid may have been variable among multivitamin users between 1973 and 1982. Misclassification of exposure may also occur because of changes in multivitamin use between 1982 and the end of follow-up or because of unmeasured differences in dietary folate. Mean daily folate intake from dietary sources in the United States around this time was 281 µg for males and 207 µg for females, with an estimated 88 percent of US adults consuming less than 400 µg a day (24Go). In our study population, it is possible that suboptimal dietary folate intake, along with insufficient duration of adequate supplemental folic acid intake could explain the lack of effect.

Cancer mortality
Increased death rates from cancer were observed only among male multivitamin users who currently smoked when enrolled in the study. This apparent interaction between multivitamin use and smoking has not been reported previously in two observational studies (4Go, 19Go). However, two of four intervention trials using high-dose beta-carotene observed an increase in lung cancer mortality in smokers. A Finnish trial (13Go) found an increase of 18 percent in lung cancer mortality and 8 percent in overall mortality in male smokers who were supplemented with beta-carotene in a daily dose of 20 mg. The Beta-Carotene and Retinol Efficacy Trial (14Go) found an increased risk of lung cancer mortality (RR = 1.46) and overall mortality (RR = 1.17) in smokers and workers exposed to asbestos who took daily high-dose beta-carotene (30 mg) and vitamin A (25,000 IU). In contrast, a large trial in rural China found a significant reduction in cancer mortality among persons who were supplemented daily with a combination of 15 mg beta-carotene, 30 mg alpha-tocopherol, and 50 µg selenium (25Go), and a trial involving US physicians found no effect of beta-carotene (50 mg on alternate days) on cancer, cardiovascular, or overall mortality (7Go). It is unlikely that the use of beta-carotene or vitamin A explains our finding of a risk elevation for lung and other cancers among multivitamin users. Beta-carotene was not a common component of multivitamins during the time of our study, and although the exact amount of vitamin A in multivitamins used by participants in our study is unknown, it is likely to be less than the 25,000 IU used in the Beta-Carotene and Retinol Efficacy Trial Study because multivitamin formulations with more than 10,000 IU were rare in 1982.

To determine whether residual confounding (e.g., heavier smoking among multivitamin users than among nonusers) could explain the increased risks among multivitamin users, we performed additional analyses using 13 exposure levels of smoking (combinations of number of cigarettes smoked per day and years of smoking) and found little residual association between multivitamin use and cancer mortality risks (data not shown). Further, our study found that former smokers (men and women) who took both multivitamins and vitamin A, C, or E had lower lung cancer mortality. It is unknown whether this relation is causal or attributable to other factors, e.g., ex-smokers having better health habits that were unmeasurable in our analyses.

The somewhat higher death rates from cancer among men who reported cancer at baseline who took multivitamins compared with those who did not is difficult to interpret, given our inability to control for stage of disease. However, the attenuation of the elevated risk after deleting deaths during the first 3 years of follow-up suggests that there may be confounding by stage of disease.

It is difficult to reconcile the finding of an increased risk for cancer (9 percent) and overall mortality (5 percent) among men who took multivitamins alone (albeit limited to smokers) with the finding of a reduced risk for overall mortality (5 percent) among men who took multivitamins plus vitamin A, C, or E. One explanation is that the increase in cancer mortality in the latter group is counterbalanced by a decrease in cardiovascular mortality, for which there is a greater number of deaths. One hypothesis for the increased cancer risk among men who take multivitamins alone (but not among combination users) is that the use of vitamin A, C, or E provides enough risk reduction to overcome the observed elevated cancer mortality risk among male multivitamin users. Alternatively, residual confounding could explain this finding; i.e., combination users may differ in other ways that may reduce the risk of mortality.

There was a tendency for lower mortality (heart disease and stroke in men and women and cancer in women) among multivitamin users who described their use qualitatively as "occasional." Their frequency of use may well be similar to that of persons who reported quantifiable multivitamin use of 1–29 times per month, but we did not combine the two groups because we thought they may be different in other ways as well. It may be that persons who describe their use qualitatively as occasional have less disability or few symptoms of chronic disease, and therefore, have less perceived need for regular multivitamin use. The relation between vitamin use and actual or perceived health status is complex (26Go, 27Go), and there is relatively little information about this subject.

Strengths of our study are the prospective design, its large size (which allowed the detection of associations that may have been obscured in smaller studies), and the ability to control for many potential confounders. Our study was subject to limitations. Vitamin use may be associated with other healthy behaviors unmeasured in this study, which could result in residual confounding. Relative to the assessment of exposure, vitamin use was self-reported and may not represent actual use. There were no biological markers to validate vitamin use. However, the prevalence of multivitamin use (alone or in combination with other supplements) in CPS-II (a mostly white, educated population) was similar to the findings reported in a national survey in 1986 (28Go). Data on the specific content of multivitamins and the doses in the single supplements are not available in CPS-II. To the extent that we misclassified vitamin supplement use, our analysis potentially underestimated true causal relations between multivitamin supplementation and mortality from cancer, heart disease, and stroke endpoints, especially with regard to folic acid, given the limited information about its presence in multivitamins taken by study participants.

Because CPS-II collected information on vitamin supplement use only once, in 1982, our measurement of duration of use is imprecise, and we potentially misclassify people who changed their use of multivitamin during the 7-year follow-up. This is an important limitation and may explain why we did not find a reduced risk of colon cancer among women with long duration of multivitamin use, as was found in the Nurses' Health Study (11Go), which had repeat assessments of multivitamin use.

Analyses of the frequency of multivitamin use were relatively uninformative. This is possibly due, at least in part, to the imprecision of the questionnaire and the relative homogeneity of vitamin use frequency (half of the persons who took vitamins at all took them daily), which may have obscured the ability to detect differences across levels of vitamin use frequency.

Only limited dietary data were available for use in this analysis. However, despite its lack of precision, the summary measure of vegetable intake we used was sensitive enough to be significantly associated with outcomes (e.g., for heart disease, the fourth quartiles of the summary measure of vegetable intake in men and women were significantly protective compared with the first quartile (RR = 0.90, 95 percent CI: 0.86, 0.95 in men; RR = 0.84, 95 percent CI: 0.78, 0.91 in women (results not shown)). The effect of supplement use (multivitamins; vitamin A, C, or E; or a combination) on heart disease and stroke mortality in men and women changed minimally across quartiles of vegetable intake in our population (data not shown). Our study involves a relatively homogeneous Western population in which diets are generally nutritionally sufficient. It is possible that a more marked protective effect of vitamins might be seen in a nutritionally deprived population. A study in rural China (29Go) found reduced stroke mortality in persons whose diets were supplemented with a vitamin/mineral combination.

Since the health outcome measured in this study was the underlying cause of mortality, not disease incidence, some outcome misclassification is possible. For example, a person with ischemic heart disease could die from another cause. However, a bias due to differential misclassification by vitamin use seems unlikely. Finally, our findings may not be generalizable to nonwhites and persons of low economic status since they are underrepresented in this study (30Go).

Most of the limitations of our study, especially relative to exposure measurement, would be avoided in randomized clinical trials. The Vitamin Intervention for Stroke Prevention trial in the United States, designed to determine whether a multivitamin with high- or low-dose folic acid, vitamin B6, and vitamin B12 reduces the risk of recurrent cerebral infarction and myocardial infarction (31Go), will be informative, but additional trials involving folic acid have been called for (32Go). The role of antioxidant vitamins in larger doses, particularly vitamin E in cardiovascular disease outcomes, is also the subject of much research. Ongoing clinical trials, such as the Women's Health Study (including the Trial of Vitamin E and Aspirin in Women and the Women's Antioxidant and Cardiovascular Study) and a continuation of the Physicians Health Study, the Heart Outcome Prevention Evaluation Study, and the Heart Protection Study in the United Kingdom will be informative, as well as the Arterial Disease Multifactorial Intervention Trial and the Women's Angiographic Vitamin and Estrogen Trials (33Go, 34Go).

Our findings, particularly the reduced cardiovascular mortality risks among users of both multivitamins and vitamin A, C, or E and the increased cancer mortality risks among men who use multivitamins and smoke, are intriguing and warrant corroboration. Randomized controlled trials are still needed to clarify the relation with folic acid (alone or in combination with other vitamins) and heart disease, stroke, and cancer endpoints. Since our study suggests that there may be an interaction between smoking and supplement use relative to cancer mortality endpoints in men, stratification by smoking status should be done in such studies.


    ACKNOWLEDGMENTS
 
The authors acknowledge Dr. Timothy Byers, who suggested the use of CPS-II for this purpose.


    NOTES
 
Reprint requests to Margaret Watkins, Centers for Disease Control and Prevention, National Center for Environmental Health, Division of Birth Defects, Child Development, Disability, and Health, Mailstop F-45, 4770 Buford Highway, Atlanta, GA 30341–3717.

To determine the relation between multivitamin use and death from heart disease, cerebrovascular disease, and cancer, the authors examined a prospective cohort of 1,063,023 adult Americans in 1982–1989 and compared the mortality of users of multivitamins alone; vitamin A, C, or E alone; and multivitamin and vitamin A, C, or E in combination with that of vitamin nonusers by using multivariate Cox proportional hazard models. Multivitamin users had heart disease and cerebrovascular disease mortality risks similar to those of nonusers, whereas combination users had mortality risks that were 15% lower than those of nonusers. Multivitamin and combination use had minimal effect on cancer mortality overall, although mortality from all cancers combined was increased among male current smokers who used multivitamins alone (relative risk (RR) = 1.13, 95% confidence interval (CI): 1.05, 1.23) or in combination with vitamin A, C, or E (RR = 1.16, 95% CI: 1.06, 1.26), but decreased in male combination users who had never (RR = 0.86, 95% CI: 0.74, 0.99) or had formerly (RR = 0.90, 95% CI: 0.82, 0.98) smoked. No such associations were seen in women. These observational data provide limited support for the hypothesis that multivitamin use in combination with vitamin A, C, or E may reduce heart disease and cardiovascular disease mortality, but add to concerns raised by randomized studies that some vitamin supplements may adversely affect male smokers.


    REFERENCES
 TOP
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 Ischemic heart disease and...
 Cancer mortality
 All-cause mortality
 DISCUSSION
 REFERENCES
 

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Received for publication January 11, 1999. Accepted for publication July 19, 1999.