American Journal of Epidemiology Advance Access published February 17, 2013

American Journal of Epidemiology

The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of
Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

DOI: 10.1093/aje/kws279

Original Contribution
High-Dose Supplements of Vitamins C and E, Low-Dose Multivitamins,
and the Risk of Age-related Cataract: A Population-based Prospective Cohort
Study of Men

Jinjin Zheng Selin, Susanne Rautiainen, Birgitta Ejdervik Lindblad, Ralf Morgenstern, and
Alicja Wolk*

Initially submitted March 14, 2012; accepted for publication May 22, 2012.

We examined the associations of high-dose supplements of vitamins C and E and low-dose multivitamins with
the risk of age-related cataract among 31,120 Swedish men, aged 4579 years, in a population-based prospective cohort. Dietary supplement use was assessed from a questionnaire at baseline in 1998. During follow-up
(January 1998December 2006), 2,963 incident age-related cataract cases were identified. The multivariableadjusted hazard ratio for men using vitamin C supplements only was 1.21 (95% confidence interval (CI): 1.04,
1.41) in a comparison with that of nonsupplement users. The hazard ratio for long-term vitamin C users (10
years before baseline) was 1.36 (95% CI: 1.02, 1.81). The risk of cataract with vitamin C use was stronger
among older men (>65 years) (hazard ratio = 1.92, 95% CI: 1.41, 2.60) and corticosteroid users (hazard
ratio = 2.11, 95% CI: 1.48, 3.02). The hazard ratio for vitamin E use only was 1.59 (95% CI: 1.12, 2.26). Use of
multivitamins only or multiple supplements in addition to vitamin C or E was not associated with cataract risk.
These results suggest that the use of high-dose (but not low-dose) single vitamin C or E supplements may
increase the risk of age-related cataract. The risk may be even higher among older men, corticosteroid users,
and long-term users.
ascorbic acid; cataract; dietary supplements; oxidative stress; vitamin E

Abbreviations: CI, confidence interval; HR, hazard ratio.

Vitamin C and E supplement use has not shown protective effects in prevention of chronic diseases in large longterm randomized controlled trials (1, 2). On the contrary,
studies have reported potential harmful effects of high-dose
antioxidant supplements, such as increased risk of mortality
(3, 4), heart failure (5), and some cancer types (68).
The etiology of age-related cataract is multifactorial, including oxidative damage of the lens (9). Antioxidants may
protect the lens against oxidative stress (10). However, the
effects of antioxidant supplements on cataract risk in randomized controlled trials (1118) and results from observational studies (1926) have been inconsistent. Interestingly,
in vitro and animal studies show that high doses of vitamins C and E have prooxidative properties and increase

oxidative stress in the lens (2731). Indeed, we have recently

observed in a prospective study of women that the use of
high-dose vitamin C supplements (but not multivitamins
with low-dose vitamin C) was associated with increased risk
of age-related cataract extraction (19).
The use of dietary supplements is widespread in many
countries. It is therefore of public health importance to investigate the association of antioxidant supplements with
risk of cataract, especially if single, high-dose supplements
are associated with cataract risk differently from low-dose
(Recommended Daily Intake) supplements. We examined if
high-dose vitamin C and E supplements and low-dose multivitamins are associated with the risk of age-related cataract in men, as well as whether the associations varied by
1

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* Correspondence to Dr. Alicja Wolk, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden
(e-mail: Alicja.Wolk@ki.se).

2 Selin et al.

reactive oxygen speciesgenerating factors, such as age,

smoking, abdominal obesity, hypertension, and corticosteroid use.
MATERIALS AND METHODS
Study population

Ascertainment of cases and follow-up

Between January 1, 1998, and December 31, 2006, we

identied 2,963 incident cataract cases (dened as men
with cataract diagnosis and/or cataract extraction). Cataract
diagnoses and extractions were ascertained by linkage to
the National Outpatient and Inpatient Registers at the National Board of Health and Welfare and to the Swedish
National Day-Surgery Register (International Classication of Diseases, Tenth Revision, code H25 and operation
codes designated CJC, CJD, CJE, and CJG). To complement the preceding data, we also matched against local cataract extraction registers at both public and private clinics
in the study area. Among the men with both cataract diagnosis and extraction in this study, 83% got the extraction
within 1 year after diagnosis. Cataracts that were considered
to be congenital or secondary to ocular trauma, intraocular
inammation, or previous intraocular surgery were excluded.
On the basis of the Swedish National Cataract Register,
most men had a preoperative visual acuity in the cataractcontaining eye of less than 20/40 Snellen equivalents,
which corresponds to difculties in driving. The mean preoperative visual acuity in the cataract-containing eye was
20/70 Snellen equivalents during the study period, which
corresponds to difculties in reading the newspaper. Approximately one-fourth of the men were legally blind
(visual acuity of 20/200 Snellen equivalents) (36).
The Regional Ethical Board at Karolinska Institutet
(Stockholm, Sweden) approved this study, and completion
of the questionnaire was considered to imply informed
consent to participate in this study.

Assessment of dietary supplement use and diet

The questionnaire from 1997 inquired about dietary supplement use starting with a general question: Do you use
vitamin, mineral, or other supplements? with 3 prespecied responses (no, regular use, and occasional use). This
question was followed by more specic questions with prespecied types of supplements and open answers about frequency and duration of use. Men that reported regular or
occasional use were considered as supplement users. Duration of vitamin C, vitamin E, and multivitamin use was inquired by open-ended questions. Long-term and short-term
users were dened as men that reported use 10 and <10
years before baseline, respectively. The most commonly
used dose of vitamin C and vitamin E as single supplements was estimated to be 1,000 mg and 100 mg, respectively (32, 33), and multivitamins were estimated to
contain 60 mg of vitamin C and 9 mg of vitamin E
(doses close to the Recommended Daily Intake) (32).

Statistical analysis

All men were followed from January 1, 1998, until the

date of cataract diagnosis, cataract extraction, date of death
(through linkage to the Swedish Death Register), or the end
of follow-up (December 31, 2006), whichever came rst.
The men were categorized into nonsupplement users
and 1) users of vitamin C only, vitamin E only, or multivitamins only (including both regular and occasional users),
not using other vitamin or mineral supplements, and 2)
users of multiple supplements in addition to vitamin C or
vitamin E. We estimated hazard ratios with 95% condence
intervals (37) using the Cox proportional hazards model
and the PHREG procedure in SAS, version 9.2, software
(SAS Institute, Inc., Cary, North Carolina). The rst multivariable model was adjusted for age, smoking, abdominal
obesity, educational level, history of hypertension, corticosteroid use, alcohol intake, and fruit and vegetable intake.

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The Cohort of Swedish Men was established in the late

fall of 1997 to study major chronic diseases including agerelated cataract. A questionnaire regarding diet and lifestyle
factors, including questions on dietary supplement use,
diet, age, smoking status, waist circumference, educational
level, medical history (including diagnoses of diabetes and
hypertension), corticosteroid use, and alcohol intake, was
sent out to all men, aged 4579 years, living in central
Sweden (rebro and Vstmanlands counties), and 48,850
(49%) men answered.
In this study, we excluded men with missing or erroneous personal identity number (n = 205), who sent a blank
questionnaire (n = 92), who died before January 1, 1998
(n = 55), and with a previous cancer diagnosis other than
nonmelanoma skin cancer (n = 2,592). We also excluded
men with cataract diagnosis or extraction before baseline
(n = 923), men with cardiovascular disease or diabetes
before baseline to avoid potential changes in dietary habits
and use of dietary supplements (n = 7,929), men with
missing information on supplement use (n = 1,506), and
those using supplements not including vitamin C, vitamin
E, or multivitamins (n = 4,428).
Cancer diagnosis was identied through the Swedish National Cancer Register. History of cardiovascular disease
(myocardial infarction, angina pectoris, heart failure, and
stroke) was obtained through linkage with the National Inpatient and Outpatient Registers at the Swedish National
Board of Health and Welfare. Diabetes history was identied through the National Outpatient Register, National Diabetes Register, and self-reported data.
A total of 31,120 men were included in the analysis.

Intakes of vitamin C and vitamin E from diet were assessed by a 96-item food frequency questionnaire at baseline with questions on how often, on average, during the
past year the men had consumed different food items.
Intakes of vitamins C and E were estimated by multiplying
the frequency of consumption of different food items by
the nutrient composition of those items obtained from the
Swedish National Food Agency (34) and adjusted for
energy intake by using the residual method (35).

Vitamin Supplements and Cataract Risk 3

RESULTS

During an average follow-up of 8.4 years (259,949

person-years), we identied 2,963 cases of age-related cataract (among those 744 men with only diagnosis). The mean
age in the cohort was 58.3 years (standard deviation: 9.2),
the mean waist circumference was 95.4 cm (standard deviation: 10.1), and 24.5% were current smokers. Among the
men, 5.3% reported vitamin C use only; 0.5%, vitamin E
use only; and 11.3%, multivitamin use only.
Baseline characteristics of the study population by
dietary supplement use are described in Table 1. The ageand multivariable-adjusted hazard ratios for dietary supplement use and age-related cataract are presented in Table 2.
In the multivariable analysis, vitamin C supplement use
only was associated with 21% (95% condence interval
(CI): 4, 41) increased risk of cataract compared with non
supplement use. Vitamin E use only was associated with
59% (95% CI: 12, 126) increased risk of cataract. Multivitamin use only was not statistically signicantly associated
with cataract risk. Additional adjustments for health status
and healthy behavior as physical activity did not change
the results. When the rst 4 years of follow-up were excluded, similar results were obtained for users of vitamin C
(hazard ratio (HR) = 1.28, 95% CI: 1.07, 1.53), vitamin E
(HR = 1.62, 95% CI: 1.06, 2.48), and multivitamins
(HR = 0.90, 95% CI: 0.78, 1.04). The hazard ratios corrected
for measurement error in self-reported use of supplements
were 3.0 for vitamin C, 3.2 for vitamin E, and 1.1 for
multivitamins.
The multivariable-adjusted hazard ratios for men who
took multiple supplements (one or more other supplements)
in addition to vitamin C (276 cases) or vitamin E (169
cases) were 1.06 (95% CI: 0.93, 1.20) and 1.02 (95% CI:

Table 1. Baseline Characteristicsa of the Men in the Cohort of Swedish Men, 19982006
Dietary Supplement Use
Variables

No Supplement Use
(n = 22,015)
Mean (SD)

Age, years

57.8 (9.0)

Current smoking

Vitamin E
Onlyb (n = 144)

Vitamin C
Onlyb (n = 1,652)
Mean (SD)

58.6 (9.4)

Mean (SD)

Multivitamins
Onlyb (n = 3,532)
%

62.9 (9.4)

Mean (SD)

58.9 (9.7)

25.8

21.1

19.0

21.5

Abdominal obesity

46.4

45.8

43.0

43.6

Education >12 years

16.9

19.1

13.2

25.7

History of hypertension

17.6

18.6

21.4

16.8

8.2

9.2

12.2

9.2

Corticosteroid use
Alcohol intake, g/day

14.8 (20.7)

13.5 (15.1)

12.5 (12.0)

14.5 (28.8)

Diet
Fruits and vegetables, g/day

375.6 (235.8)

414.9 (246.7)

437.3 (246.3)

426.8 (245.5)

Vitamin C, mg/day

105.2 (52.8)

110.6 (54.6)

113.8 (56.4)

112.9 (55.1)

Vitamin E, mg/day

8.8 (1.5)

9.0 (1.5)

8.9 (1.6)

9.0 (1.5)

Abbreviation: SD, standard deviation.

All variables, except age, were directly standardized to the age distribution of the entire study cohort.
b
No reported use of other vitamin or mineral supplements.
c
Defined as waist circumference 94 cm.
a

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The second model was further adjusted for physical activity

and self-reported health. Missing values for any of the potential confounders were treated as a separate category in
the model. The proportional hazard assumption was tested
by including the product of vitamin C, vitamin E, and multivitamin use and the natural logarithm of time in the
models, and we did not nd evidence of violation of this
assumption. The rst 4 years of follow-up were excluded to
evaluate potential risk of reversed causality. We used the
Cox proportional hazards model to analyze the association
between duration of vitamin C and multivitamin use and
cataract risk. The difference between the observed risk estimates for long-term and short-term use and cataract was
tested with the Wald test. Because of few cases, long-term
vitamin E use was not examined. To evaluate the effect of
misclassication of self-reported supplement use on our
risk estimates, we performed correction analyses, using the
episens command in Stata, version 11, software (StataCorp
LP, College Station, Texas) (38). Assumptions of sensitivity and specicity of 0.7 and 0.9 for vitamin C, 0.8 and
0.99 for vitamin E, and 0.7 and 0.98 for multivitamin use,
respectively, were based on results from our previous validation study of men living in central Sweden (33).
We performed stratied analyses to examine if the risk
between vitamin C use and cataract differed by reactive
oxygen speciesgenerating factors (age, smoking, abdominal obesity, history of hypertension, and corticosteroid
use), as well as dietary intakes of vitamin C and vitamin
E. The attributable proportion of risk due to interaction (in
excess of the additive effects between the 2 exposures of
interest) was calculated with 95% condence interval (39,
40). Multiplicative interaction tests were also performed by
the likelihood test. All P values shown are 2 sided, and we
considered P < 0.05 as statistically signicant.

4 Selin et al.

Table 2. Age- and Multivariable-adjusted Hazard Ratios for Dietary Supplement Use and Risk of Age-related Cataract in the Cohort of
Swedish Men, 19982006
Dietary
Supplement Use

Total No. of
Subjects

No. of
Cases

HR

No supplement use
Vitamin C onlyc

95% CI

HR

95% CI

HR

95% CI

22,015

1,937

184,911

1.00

Referent

1.00

Referent

1.00

Referent

1,652

188

13,660

1.21

1.04, 1.40

1.21

1.04, 1.41

1.21

1.04, 1.41

Vitamin E onlyc
Multivitamins onlyc

Multivariable
Adjusted 2b

Multivariable
Adjusted 1a

Age Adjusted
Person-Years

144

32

1,138

1.68

1.18, 2.39

1.59

1.12, 2.26

1.57

1.10, 2.22

3,532

345

29,311

0.97

0.87, 1.09

0.96

0.86, 1.08

0.96

0.85, 1.07

Abbreviations: CI, confidence interval; HR, hazard ratio.

Adjusted for age (5-year age groups: <50, 5054, 5559, 6064, 6569, 7074, 75), smoking (never, past, current smokers 10 and >10
cigarettes/day), abdominal obesity (waist circumference <94 or 94 cm), educational level (<9, 912, or >12 years), history of hypertension (yes
or no), corticosteroid use (yes or no), alcohol intake (g/day in quartiles), and fruit and vegetable intake (g/day, continuous).
b
Adjusted for the same covariates as multivariable model 1 and additionally for physical activity (metabolic equivalent hours/day, quartiles)
and self-reported health (scale of 15, from good (i.e., 1) to bad (i.e., 5)).
c
No reported use of other vitamin or mineral supplements.
a

reactive oxygen speciesgenerating factors (age, smoking,

abdominal obesity, history of hypertension, and corticosteroid use). We observed a stronger positive association for
vitamin C use among older men ( >65 years) and corticosteroid users (Table 4). The attributable proportion due to
interaction on the additive scale was borderline statistically
signicant for age and statistically signicant for corticosteroid use. However, the multiplicative interaction was not
statistically signicant for age (P = 0.23) or corticosteroid
use (P = 0.17). Interaction between the other reactive
oxygen speciesgenerating factors and vitamin C use was
not statistically signicant on either the additive (all 95%

Table 3. Age- and Multivariable-adjusted Hazard Ratios for Duration of Dietary Supplement Use and Risk of Age-related Cataract in the
Cohort of Swedish Men, 19982006
Duration of Dietary
Supplement Use

Age Adjusted

Total No. of
Subjects

No. of
Cases

Person-Years

22,015

1,937

<10 years before baseline

521

10 years before baseline

Multivariable Adjusteda

HR

95% CI

HR

95% CI

184,911

1.00

Referent

1.00

Referent

56

4,355

1.28

0.98, 1.66

1.26

0.97, 1.65

420

48

3,458

1.34

1.01, 1.79

1.36

1.02, 1.81

<10 years before baseline

71

16

559

N/Ac

N/Ac

10 years before baseline

14

114

N/Ac

N/Ac

<10 years before baseline

1,212

102

10,185

0.99

0.81, 1.21

0.97

0.80, 1.19

10 years before baseline

657

65

5,418

0.94

0.73, 1.20

0.94

0.73, 1.21

No supplement use
Vitamin C onlyb

Vitamin E onlyb

Multivitamins only

Abbreviations: CI, confidence interval; HR, hazard ratio; N/A, not available.
a
Adjusted for age (5-year age groups: <50, 5054, 5559, 6064, 6569, 7074, 75), smoking (never, past, current smokers 10 and >10
cigarettes/day), abdominal obesity (waist circumference <94 or 94 cm), educational level (<9, 912, or >12 years), history of hypertension (yes
or no), corticosteroid use (yes or no), alcohol intake (g/day in quartiles), fruit and vegetable intakes (g/day, continuous), physical activity
(metabolic equivalent hours/day, quartiles), and self-reported health (scale of 15, from good (i.e., 1) to bad (i.e., 5)).
b
No reported use of other vitamin or mineral supplements.
c
Not available because of too few cases.

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0.87, 1.20), respectively, in a comparison with non

supplement users.
Long-term vitamin C use only (10 years before baseline) compared with nonsupplement use was associated
with 36% (95% CI: 2%, 81%) increased risk of cataract
(Table 3). The difference between the observed risk estimates for long-term vitamin C users and short-term users
was not statistically signicant (P = 0.71). Multivitamin use
only 10 or <10 years before baseline was not associated
with cataract risk.
Furthermore, we examined if the association between
vitamin C use and risk of cataract was modied by putative

Vitamin Supplements and Cataract Risk 5

Table 4. Multivariable-adjusted Hazard Ratios for Vitamin C Supplement Use and Risk of Age-related Cataract by Subgroups of Age and
Corticosteroid Usea in the Cohort of Swedish Men, 19982006

Subgroups

Total No. of
Subjects

No Supplement Use (n = 22,015)

No. of
Cases

HR

95% CI

Vitamin C Only (n = 1,652)b

No. of
Cases

HR

95% CI

Attributable
Proportion
due to Interactionc

95% CI

0.19

0.01, 0.40

0.29

0.01, 0.56

Age, years
65

18,311

804

1.00

Referent

63

1.07

0.83, 1.38

>65

5,356

1,133

1.48

1.14, 1.91

125

1.92

1.41, 2.60

16,270

1,283

1.00

Referent

123

1.18

0.98, 1.42

1,942

239

1.33

1.16, 1.53

31

2.11

1.48, 3.02

Corticosteroid
usee
Never
users
Ever users

CIs for interaction including 0) or the multiplicative (all Ps

for interaction > 0.8) scale. There were too few cases to
examine if the association between vitamin E use and cataract risk was stronger with long-term use or among men
with reactive oxygen speciesgenerating factors.
Compared with that for nonsupplement users, the multivariable-adjusted hazard ratio for vitamin C only supplement users with low vitamin C intake from diet (< median,
96.9 mg/day) was 1.30 (95% CI: 1.06, 1.58), and for high
vitamin C intake from diet ( median), the hazard ratio
was 1.12 (95% CI: 0.90, 1.40) (P for interaction = 0.32).
Among vitamin E only supplement users with low vitamin
E intake from diet (< median, 8.8 mg/day), the hazard ratio
for cataract was 1.70 (95% CI: 1.09, 2.65), and for high
vitamin E intake ( median), the hazard ratio was 1.38
(95% CI: 0.78, 2.44) (P for interaction = 0.56). Vitamin C
or vitamin E from diet ( median compared with < median)
was not associated with cataract risk; the hazard ratios were
1.04 (95% CI: 0.95, 1.13) and 1.00 (95% CI: 0.92, 1.08),
respectively.
DISCUSSION

In this large, prospective, population-based cohort of

men, we observed that those who used high-dose vitamin C
or vitamin E supplements (but not low-dose multivitamins)
had a statistically signicant increased risk of age-related
cataract. The positive association between vitamin C use
and risk of cataract was even stronger among those with
higher oxidative stress because of older age and corticosteroid use and among long-term users. The limited number
of vitamin E users only did not allow us to evaluate the
associations for long-term vitamin E use and associations

between vitamin E use and factors associated with increased reactive oxygen species levels.
Our results are in agreement with our previous prospective observations in 24,593 women (2,497 cataracts), where
the use of high-dose vitamin C supplements (but not lowdose multivitamins) was associated with increased risk of
cataract extraction (HR = 1.25, 95% CI: 1.05, 1.50), especially among older women (HR = 1.74, 95% CI: 1.24,
2.46) and corticosteroid users (HR = 1.97, 95% CI: 1.35,
2.88) (19). The present results are partly in line with a recently published randomized controlled trial (8 years duration) that reported for high-dose vitamin C supplements
(500 mg) a nonsignicant increased risk of cataract among
obese (body mass index: 30) and smoking men (11).
However, no effect was reported for high-dose vitamin E
supplements (268 mg) in that study (11). Vitamin C and/or
vitamin E use was associated with nonsignicant increased
risk of cataract in men (26). Other prospective studies of
vitamin C use observed statistically signicant increased
risk of cortical opacities among older women using vitamin
C for >10 years (21) and a nonsignicant increased risk of
cataract extraction among women aged 60 years (20). No
association of cataract risk was reported in some randomized controlled trials testing vitamin E use only (50402 mg
daily or alternate days) (1113, 15) or high-dose vitamin C
and vitamin E use combined with other constituents (1416),
as well as in some observational studies of vitamin C and
vitamin E use (20, 21, 23). In contrast, one randomized controlled trial testing daily high-dose vitamin C (750 mg),
vitamin E (268 mg), and -carotene (15 mg) supplements
combined for 3 years reported a small deceleration of cataract progression (17), and another randomized controlled
trial examining multivitamin/mineral supplements with

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Abbreviations: CI, confidence interval; HR, hazard ratio.

a
A total of 7,453 men (out of 31,120 men) using other supplements than vitamin C only were excluded.
b
No reported use of other vitamin or mineral supplements.
c
The attributable proportion of risk due to interaction (in excess of the additive effects between the 2 exposures) and the corresponding 95%
confidence interval.
d
Adjusted for age (5-year age groups: <50, 5054, 5559, 6064, 6569, 7074, 75), smoking (never, past, current smokers 10 and >10
cigarettes/day), abdominal obesity (waist circumference <94 or 94 cm), educational level (<9, 912, or >12 years), history of hypertension (yes
or no), corticosteroid use (yes or no), alcohol intake (g/day in quartiles), fruit and vegetable intakes (g/day, continuous), physical activity
(metabolic equivalent hours/day, quartiles), and self-reported health (scale of 15, from good (i.e., 1) to bad (i.e., 5)).
e
Of 23,667 men, there were 5,455 men with missing information on corticosteroid use.

6 Selin et al.

recently published large randomized controlled trial examining the effect of vitamin E and selenium supplements
(taken separately or together) on the risk of prostate cancer
(7). The risk was increased in the groups receiving only
vitamin E (HR = 1.17, 95% CI: 1.004, 1.36) or selenium
(HR = 1.09, 95% CI: 0.93, 1.27), but in the group receiving
vitamin E and selenium together, the risk was attenuated
(HR = 1.05, 95% CI: 0.89, 1.22) (7).
The biological mechanisms behind the observed statistically signicant interaction between vitamin C use and corticosteroid use may involve an inammatory mechanism (49).
Corticosteroid use is a known risk factor for cataract (50)
and has also been associated with increased reactive oxygen
species production (51). Furthermore, use of corticosteroids
may indicate an underlying illness associated with increased
oxidative stress and inammation. Oxidative stress associated
with aging may also explain the higher risk estimates for cataract among men aged >65 years using vitamin C.
There are several strengths of this study. First, the large,
population-based, prospective design includes many cases
of cataract. Second, we had information on both cataract
diagnosis and extraction. Third, the validity of the selfreported supplement use data, as assessed by sensitivity
and specicity, was relatively high, which allowed us to
correct for misclassication bias of the exposure.
There are also some limitations of this study. The possibility of outcome misclassication exists because lens
opacities can occur without symptoms. This may lead to
underestimation of the association. Because of the lack of
standardized eye examinations in the cohort, we did not
have information on cataract subtypes or grade of lens
opacity and could therefore not examine whether the association was restricted to a certain subtype. As we did not
have information on the exact doses of supplements used
in this study, we used an estimation of the most commonly
used doses in Sweden (32, 33). One could speculate that
our results may be affected inasmuch as men using supplements may be more health conscious and seek medical
help earlier. However, multivitamin use was not associated
with increased cataract risk. By excluding the rst 4 years
of follow-up, we found that the risk estimates remained
similar, which contradicts the notion that the association is
due to reversed causality. After adjustments for health
status and health behaviorrelated factors, such as fruit and
vegetable intakes, education, and physical activity, similar
results were obtained. Moreover, everyone has the same
access to cataract extractions ( patient charge of <$50/
surgery) in the Swedish health-care system.
In conclusion, the use of high-dose vitamin C or vitamin
E supplements (but not low-dose multivitamins or vitamins
C and E together with other supplements) may be associated
with increased risk of age-related cataract among men. The
risk for cataract with vitamin C use may be even higher
among those with potentially higher oxidative stress and
among long-term users. In the broader context of accumulating evidence from other recent studies also showing potentially harmful effects of high-dose antioxidant supplements,
our results further underscore the need to consider use of
unregulated supplements with caution.

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relatively low doses of vitamin C (180 mg/day) and vitamin

E (40 mg/day) reported decreased risk of nuclear cataracts
only among participants aged 65 years (18). Prospective
studies have also observed decreased risk for nuclear (22,
24) and cortical cataracts among women aged <60 years (21)
and for long-term users (25). Multivitamin use was not associated with cataract risk in some prospective studies (20, 21)
and randomized controlled trials (14, 18), whereas others observed a decreased risk of cataract (23, 25, 26) and some
cataract subtypes (18, 22, 24).
Several factors may contribute to the differences between
our results and those of other studies. First, the outcomes
differed, as some studies investigated the risk of cataract
diagnosis or extraction (1115, 18), while others examined
the change in lens opacication (16, 17). Second, the dose
of supplements used differed. Third, the randomized controlled trials were based on populations with different baseline nutritional status and were ongoing for shorter periods
(36 years), except for 2 studies (89 years) (11, 12).
However, the populations in these 2 studies were based on
physicians and nurses, who are generally more health conscious and well nourished: Only 3%4% among the physicians were current smokers (11), compared with 24% of the
men in this study. In another randomized controlled trial,
malnutrition was common at baseline (18).
Although vitamin C and vitamin E have been proposed,
because of antioxidant properties, to decrease the risk of
cataract (10, 41), in vitro and animal studies using large
doses of vitamin C and vitamin E have shown their prooxidative effects, such as enhancing the toxic effect of hydrogen peroxide in glutathione-depleted lens epithelial cells
(42). High vitamin C concentrations may disturb oxidationreduction homeostasis of the lens and promote cataractogenesis (43), for example, by increasing glycation of lens
proteins (2830) and generating superoxide (31). The
plasma vitamin C concentration is suggested to reach a
plateau by intake of 200 mg of vitamin C/day (44).
However, vitamin C concentrations in the lens are from 50to 60-fold higher than in plasma, and a linear relation
between dietary intake and lens concentrations has been reported (44). This suggests that oversupplementation may
lead to an even higher vitamin C accumulation in the lens
and result in a prooxidative state. High vitamin E concentrations may also disturb oxidation-reduction homeostasis
of the lens, by inducing lipid peroxidation (45) and inhibiting glutathione S-transferase (27). Moreover, vitamin E
supplements containing only -tocopherol may also reduce
other natural forms of vitamin E (46). Studies have shown
2-fold higher vitamin E concentrations in cataract lenses
compared with noncataract lenses (47), and high plasma
vitamin E concentrations have been associated with increased risk of all types of cataracts, but this was not observed for vitamin C (48).
Our observation that the increased risk of cataract was
attenuated and not statistically signicant for users of multiple supplements in addition to vitamin C or vitamin E
could be because the use of other supplements may lessen
the increased risk associated with use of vitamin C or
vitamin E only. These results resemble the results from a

Vitamin Supplements and Cataract Risk 7

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Author afliations: Division of Nutritional Epidemiology,

Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden (Jinjin Zheng Selin, Susanne Rautiainen,
Birgitta Ejdervik Lindblad, and Alicja Wolk); Division of
Biochemical Toxicology, Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden (Ralf Morgenstern);
Division of Preventive Medicine, Brigham and Womens
Hospital and Harvard Medical School, Boston, Massachusetts
(Susanne Rautiainen); Department of Ophthalmology, rebro
University Hospital, rebro, Sweden (Birgitta Ejdervik Lindblad); and School of Health and Medical Sciences, rebro
University, rebro, Sweden (Birgitta Ejdervik Lindblad).
This work was supported by research grants from the
Swedish Council for Working Life and Social Research (Dnr.
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