American Journal of Epidemiology
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Vol. 173, No. 8
Advance Access publication:
February 22, 2011
Multivitamin Use and the Risk of Mortality and Cancer Incidence
The Multiethnic Cohort Study
Song-Yi Park*, Suzanne P. Murphy, Lynne R. Wilkens, Brian E. Henderson, and Laurence
* Correspondence to Dr. Song-Yi Park, Epidemiology Program, University of Hawaii Cancer Center, 1236 Lauhala Street, Honolulu,
HI 96813 (e-mail: firstname.lastname@example.org).
Initially submitted August 19, 2010; accepted for publication November 24, 2010.
Although multivitamin/mineral supplements are commonly used in the United States, the efficacy of these
supplements in preventing chronic disease or premature death is unclear. To assess the relation of multivitamin
use with mortality and cancer, the authors prospectively examined these associations among 182,099 participants
enrolled in the Multiethnic Cohort Study between 1993 and 1996 in Hawaii and California. During an average 11
years of follow-up, 28,851 deaths were identified. In Cox proportional hazards models controlling for tobacco use
and other potential confounders, no associations were found between multivitamin use and mortality from all
causes (for users vs. nonusers: hazard ratio ¼ 1.07, 95% confidence interval: 0.96, 1.19 for men; hazard
ratio ¼ 0.96, 95% confidence interval: 0.85, 1.09 for women), cardiovascular diseases, or cancer. The findings
did not vary across subgroups by ethnicity, age, body mass index, preexisting illness, single vitamin/mineral
supplement use, hormone replacement therapy use, and smoking status. There also was no evidence indicating
that multivitamin use was associated with risk of cancer, overall or at major sites, such as lung, colorectum,
prostate, and breast. In conclusion, there was no clear decrease or increase in mortality from all causes, cardio-
vascular disease, or cancer and in morbidity from overall or major cancers among multivitamin supplement users.
cohort studies; mortality; neoplasms; vitamins
Abbreviations: ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases,
Multivitamin/mineral supplements are commonly used in
the United States in part because people expect this type of
supplement to improve their health (1, 2). However, the
efficacy of these supplements to prevent chronic disease or
premature death is not proven (3, 4), and the National
Institutes of Health donot recommend multivitamin/mineral
supplements for this purpose (5). A small number of
clinical trials to date have shown that multivitamin use
was effective in reducing the risk of some chronic disease
including cancer and cardiovascular diseases (4, 6). How-
ever, these trials tested specific combinations of vitamins
with or without minerals rather than commonly used multi-
vitamin products. In addition, subjects were not generally
drawn from healthy populations and/or the sample sizes
were small. The Physicians’ Health Study II, an ongoing
large clinical trial, has the potential to provide more defin-
itive evidence of the effects of a widely used multivitamin
product on the risk of chronic disease, but the findings are
not yet available (2, 7, 8).
Although many observational studies have examined the
associations between dietary supplements and risk of dis-
ease or mortality, only a small number of them investigated
multivitamin use. Recently, a large Women’s Health Initia-
tive cohort study with a median follow-up of 8 years re-
ported no association of multivitamin use with the risk of
incidence of cancer and cardiovascular disease and with
mortality among more than 161,000 postmenopausal
906Am J Epidemiol. 2011;173(8):906–914
To further assess the relation of multivitamin use with
mortality and cancer incidence among both men and
women, we examined these associations for participants in
the Multiethnic Cohort, which was established to study diet
and chronic disease in Hawaii and California. Multivitamin
use is closely related to healthy lifestyle factors, which are
major confounders in observational studies (10). Therefore,
we carefully considered health-related factors for adjust-
ment and/or stratification in the analyses.
MATERIALS AND METHODS
In 1993–1996, the Multiethnic Cohort Study enrolled
more than 215,000 adults aged 45–75years, living in Hawaii
and California, whowere mostly African Americans, Native
Hawaiians, Japanese Americans, Latinos, or Whites (11).
The participants completed a 26-page mailed questionnaire
on diet, medical history, and lifestyle when they entered the
cohort. The study was approved by the review boards of
the University of Hawaii and the University of Southern
California. For the analyses, we excluded participants who
were not in one of the targeted 5 ethnic groups (n ¼ 13,991)
or who reported invalid dietary intakes based on total
energy intake or its components (n ¼ 8,264) (12). We also
excluded those with missing information on multivitamin
use (n ¼ 4,451) or smoking (n ¼ 7,013). Therefore, the
analysis included 182,099 participants (82,405 men and
Assessment of multivitamin use and potential
The baseline questionnaire included questions about the
use of multivitamins (with/without minerals) and 7 single
vitamin/mineral supplements. Subjects were asked to indi-
cate whether they had used any of these supplements at least
weekly during the previous year. Subjects were also asked
about the frequency and duration for each supplement they
had used. In a validation study (13), weighted kappa statis-
tics (j) for agreement between three 1-day recalls of multi-
vitamin supplement use and the questionnaire across 6
categories of frequency of use (never use, 1–3/week, 4–6/
week, 1/day, 2/day, and ?3/day) was 0.65, and the j for
reproducibility of questionnaire responses at 2 time points
was 0.54 for multivitamin supplements.
In a follow-up questionnaire approximately 5 years after
baseline (1999–2003), participants were asked the same
question on multivitamin use but without duration of use.
To examine long-term effects of multivitamin use on mor-
tality, we defined long-term users as those who had taken
multivitamins for 5 or more years at cohort entry and also
currently took them at the time of the follow-up survey. We
then compared them with those who were nonusers at both
time points. This analysis was limited to 144,195 partici-
pants who provided information on multivitamin use for
On the baseline questionnaire, participants also provided
information on sociodemographic factors, dietary intake (a
quantitative food frequency questionnaire), weight/height,
personal behaviors, and history of medical conditions, as
well as, for women, menopausal status and use of hormone
defined as self-reported, physician-diagnosed heart attack or
angina, stroke, diabetes, high blood pressure, and/or cancer.
Preexisting cancer was additionally identified by linking to
the Surveillance, Epidemiology, and End Results tumor
registries covering the states of Hawaii and California.
Ascertainment of outcomes
We linked the cohort to the death certificate files in
Hawaii and California and to the National Death Index
through December 31, 2005. During an average 11 years
of follow-up, we identified 28,851 deaths (15,962 men and
12,889 women). Death from all causes was the primary
endpoint in the analyses. In addition, according to the
International Classification of Diseases, Ninth Revision
(ICD-9) and Tenth Revision (ICD-10), we categorized the
primary cause of death into cardiovascular diseases (ICD-9
codes 390–434, 436–448; ICD-10 codes I00–I78), cancer
(ICD-9 codes 140–208; ICD-10 codes C00–C97), and all
other causes. We also linked the cohort to the Surveillance,
Epidemiology, and End Results cancer registries covering
Hawaii and California through December 31, 2004, in order
to identify incident cases of cancer.
We compared baseline characteristics between multivita-
min users and nonusers separately for men and women. Cox
proportional hazards models, with age as the time metric,
provided estimates of hazard ratios and 95% confidence in-
tervals of mortality or cancer incidence related to multivi-
tamin use. Because smoking is related to dietary supplement
use and the outcomes of mortality and cancer incidence, we
used a comprehensive base model for the relation between
smoking and the outcomes that was based on the model
developed to study tobacco use and lung cancer incidence
in the Multiethnic Cohort (14). The model explicitly in-
cluded 4 indicator variables for race/ethnicity; average num-
ber of cigarettes; average number of cigarettes squared;
indicator variables for former and current smokers; number
of years smoked (time dependent); number of years since
quitting (time dependent); and interactions of race/ethnicity
with the following variables: average number of cigarettes,
average number of cigarettes squared, smoking status, and
number of years smoked.
The models were further adjusted for the following strata
variables: age at cohort entry (<50, 50–54, 55–59, 60–64,
65–69, 70–74, ?75 years), body mass index (<18.5, 18.5–
22.4, 22.5–24.9, 25–29.9, 30–34.9, ?35 kg/m2, and miss-
ing), alcohol consumption (ethanol; 0, 1–<5.2, 5.2–<23,
?23 g/day for men; 0, 1–<3, ?3 g/day for women), educa-
tion (12th grade or less, vocational school/some college,
college graduate or postgraduate, and missing), physical
activity (hours spent in vigorous activity per day; <0.1,
0.1–<0.25, 0.25–<0.80, ?0.80, and missing for men;
<0.1, 0.1–<0.25, ?0.25, and missing for women),
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