Multivitamin Use, Folate, and Colon Cancer in Women in
the Nurses' Health Study Edward Giovannucci, MD, ScD;
Meir J. Stampfer, MD, DrPH; Graham A. Colditz, MD, DrPH;
David J. Hunter, MBBS, ScD; Charles Fuchs, MD, MPH;
Bernard A. Rosner, PhD; Frank E. Speizer, MD; and Walter
C. Willett, MD, DrPH
1 October 1998 | Volume 129 Issue 7 | Pages 517-524
Background: High intake of folate may reduce risk for colon
cancer, but the dosage and duration relations and the impact
of dietary compared with supplementary sources are not well
understood. Objective: To evaluate the relation between
folate intake and incidence of colon cancer. Design:
Prospective cohort study. Setting: 88 756 women from the
Nurses' Health Study who were free of cancer in 1980 and
provided updated assessments of diet, including multivitamin
supplement use, from 1980 to 1994. Patients: 442 women with
new cases of colon cancer. Measurements: Multivariate
relative risk (RR) and 95% CIs for colon cancer in relation
to energy-adjusted folate intake. Results: Higher energy-
adjusted folate intake in 1980 was related to a lower risk
for colon cancer (RR, 0.69 [95% CI, 0.52 to 0.93] for intake
Quoted message said:400 [micro sign]g/d compared with intake <or=to200 [micro
sign]g/d) after controlling for age; family history of
colorectal cancer; aspirin use; smoking; body mass; physical
activity; and intakes of red meat, alcohol, methionine, and
fiber. When intake of vitamins A, C, D, and E and intake of
calcium were also controlled for, results were similar.
Women who used multivitamins containing folic acid had no
benefit with respect to colon cancer after 4 years of use
(RR, 1.02) and had only nonsignificant risk reductions after
5 to 9 (RR, 0.83) or 10 to 14 years of use (RR, 0.80). After
15 years of use, however, risk was markedly lower (RR, 0.25
[CI, 0.13 to 0.51]), representing 15 instead of 68 new cases
of colon cancer per 10 000 women 55 to 69 years of age.
Folate from dietary sources alone was related to a modest
reduction in risk for colon cancer, and the benefit of long-
term multivitamin use was present across all levels of
dietary intakes. Conclusions: Long-term use of multivitamins
may substantially reduce risk for colon cancer. This effect
may be related to the folic acid contained in multivitamins.
Folate is essential for regenerating methionine, the methyl
donor for DNA methylation, and for producing the purines and
pyrimidines required for DNA synthesis. Inadequate
availability of folate may contribute to aberrations in DNA
methylation and may lead to abnormalities in DNA synthesis
or repair, either of which may influence colon
carcinogenesis. Epidemiologic evidence, including that from
two prospective studies done in men [1,2], suggests that
inadequate intake of folate may increase risk for colon
cancer [3]. Prospective data on women are limited, but one
case-control study found a lower risk for colon cancer among
women who used supplements that contained folic acid [4].
Whether intake from dietary sources higher than that
considered adequate to avoid deficiency confers additional
benefits is unknown. In addition, the temporal relation
between folate status and incidence of colon cancer is
unclear. In this report, we examine the temporal and dosage
relations between intake of folate, both from supplements
and from foods, and risk for colon cancer in women in the
Nurses' Health Study. We pay particular attention to the
problem of possible confounding by multivitamin use.
Methods
Top Methods Results Discussion References
Study Sample The Nurses' Health Study began in 1976 when 121
700 U.S. female registered nurses 30 to 55 years of age
completed a mailed questionnaire on risk factors for cancer
and coronary heart disease [5]. Every 2 years, we update
information and ask women to report newly diagnosed cases of
cancer. In 1980, we used a semiquantitative food-frequency
questionnaire to establish a "dietary cohort." For this
analysis, we excluded women with implausibly high or low
scores for total energy intake; those who left 10 or more
items blank on the food-frequency questionnaire; and those
who reported previous cancer (other than nonmelanoma skin
cancer), ulcerative colitis, or a familial polyposis
syndrome. We also excluded women who provided incomplete
information on aspirin and multivitamin use in 1980. After
exclusions, 88 756 women formed the analytic cohort. Dietary
Assessment The 1980 semiquantitative food-frequency
questionnaire [6,7] included items on 61 foods and beverages
plus vitamin and mineral supplements. Similar but expanded
questionnaires were administered in 1984, 1986, and 1990.
Current multivitamin use was assessed in each biennial
questionnaire from 1980 to 1992. We also asked about the
brands and types of breakfast cereal and multivitamins
typically used, and we asked women who were current
multivitamin users in 1980 to state how many years they had
been taking multivitamin supplements. For each food listed,
a commonly used unit or portion size was specified. Each
woman was asked how often over the past year, on average,
she had consumed that amount of each food; she could choose
from nine possible responses. We computed nutrient intakes
by multiplying the consumption frequency of each unit of
every food by the nutrient content of the specified portions
by using composition values from U.S. Department of
Agriculture sources [8] supplemented with other data,
including data on specific brands and types of multivitamins
and breakfast cereal. In addition to giving information on
diet, participants provided information on age, weight,
height, smoking history, physical activity, aspirin use,
colonoscopy or sigmoidoscopy, and parental history of
colorectal cancer. Identification of Cases of Colon Cancer
When a woman (or next of kin for decedents) reported a
diagnosis of colon or rectal cancer, we asked for permission
to obtain hospital records and pathology reports. The
responses to the follow-up questionnaires accounted for 96%
of potential person-years through the end of the follow-up
period (June 1994). Most deaths were reported by family
members or the postal system in response to the follow-up
questionnaires or were identified through the National Death
Index [9]. A study physician who was blinded to exposure
information reviewed medical records and extracted pertinent
data. We confirmed a total of 655 new cases of colorectal
adenocarcinoma (excluding carcinoma in situ). Of these, 442
were in the colon (218 in the proximal colon [cecum to
splenic flexure] and 224 in the distal colon), 143 were in
the rectum, and 70 were at undetermined sites. Data Analysis
We analyzed total, supplementary, and dietary intake of
folate in relation to risk for colon cancer. Because risk
factors for rectal cancers may differ, we did not consider
them in the major analyses but report results for them
separately. We conducted additional analyses for total colon
cancer, including cases of colorectal cancer for which
subsite information was unavailable (these cases may have
included some cases of rectal cancer), colorectal cancer,
proximal colon cancer, and distal colon cancer. We first
examined total and dietary intake of folate in 1980 in
relation to risk for colon cancer in the period from 1980 to
1994. Then, to examine the potential time lag between folate
intake and risk for colon cancer, we computed the time
elapsed since the start of use of multivitamin supplements
containing folic acid and updated this variable every 2
years on the basis of the brand and type of multivitamins
used and the frequency of multivitamin use reported
biennially from 1980 to 1992. For example, if a woman began
using multivitamin supplements in 1976, she was considered a
user of 4 years in 1980 and a user of 6 years in 1982.
Before 1973, 100 [micro sign]g of folic acid was the maximum
dose allowed in supplements according to U.S. Food and Drug
Administration (FDA) regulations, and many supplement
formulations at that time did not contain folic acid. Thus,
we considered 1973 (when doses of 400 [micro sign]g were
first allowed [10]) to be the earliest possible starting
point. Although our analysis of duration of use did not
require that users report multivitamin consumption on each
questionnaire, multivitamin use tended to be consistent. For
example, 70% of women who had 15 or more years of use
reported multivitamin use on most questionnaires, and 75% of
women using multivitamins in 1980 also took multivitamins in
1992. Our basic model included variables suspected to be
related to risk for colon cancer, including cigarette
smoking before age 30 years; family history of colorectal
cancer; physical activity level; body mass index (kg/m2);
aspirin use; and intakes of red meat (beef, pork, or lamb as
a main dish), alcohol, and fiber. Intakes of folate,
methionine, and other nutrients were adjusted for total
energy intake by using residual analysis [11]. We used all
variables as assessed in 1980 with the exception of age,
which was updated biennially. In additional models, we
considered intake of total and saturated fat; intake of
calcium; intake of vitamins A, C, D, and E; postmenopausal
estrogen use; and history of endoscopic screening. Women
were followed from the month in 1980 in which they
responded, and they accumulated persontime until the month
of diagnosis, the month of death from other causes, or June
1994. We used the Mantel-Haenszel summary estimator to
adjust for age (across 5-year categories). For multivariate
analyses, we used pooled logistic regression, which accounts
for varying time to the outcome event [12] and is
asymptotically equivalent to a Cox regression model with time-
dependent covariates, given short time intervals and a low
probability of outcome [13]. A participant contributed up to
seven observations based on seven 2-year periods from 1980
to 1994; if a woman received a diagnosis of colon cancer or
died of any cause, the subsequent 2-year periods were
censored. Each 2-year set of observations contributed by
each participant was pooled in the logistic regression
analysis. We tested for trends, controlling for multiple
covariates by modeling the specific exposure as a continuous
variable in a logistic model that included the covariates.
All reported P values are two-sided.
Results
Top Methods Results Discussion References
We examined, by level of folate intake in 1980, the
distribution of various factors possibly related to colon
cancer (Table 1). The first three categories of folate
intake reflected primarily dietary sources, whereas
86.3% of women with intake exceeding 400 [micro sign]g/d
used multivitamin supplements. The group with the second-
highest intake, of which 9.1% took supplements, had the
highest frequency of aspirin use, the lowest average body
mass index, the lowest frequency of cigarette use in
young adulthood, and the highest intake of dietary fiber.
Alcohol use decreased with increasing folate intake. In
multivariate models, we adjusted for these factors in
addition to strong predictors of colon cancer (physical
activity, red meat, and methionine) in this population.
Anth