See corresponding editorial on page 987.

Carotenoids, vitamin A, vitamin C, vitamin E, and folate and risk of

self-reported hearing loss in women1,2
Sharon G Curhan,3,11* Konstantina M Stankovic,8–10 Roland D Eavey,5 Molin Wang,3,6,7 Meir J Stampfer,3,7

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and Gary C Curhan3,4,7,11
3
Channing Division of Network Medicine and 4Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 5Vanderbilt Bill
Wilkerson Center for Otolaryngology and Communication Sciences, Vanderbilt University School of Medicine, Nashville, TN; and Departments of
6
Biostatistics and 7Epidemiology, Harvard School of Public Health, Boston, MA, 8Eaton-Peabody Laboratories and Department of Otolaryngology, Massa-
chusetts Eye and Ear Infirmary, Boston, MA; 9Department of Otology and Laryngology, Harvard Medical School, Boston, MA; 10Program in Speech and
Hearing Bioscience and Technology, Division of Health Science and Technology, Harvard and Massachusetts Institute of Technology, Boston, MA; 11Harvard
Medical School, Boston MA

ABSTRACT
Background: Higher intake of certain vitamins may protect against
cochlear damage from vascular compromise and oxidative stress,
thereby reducing risk of acquired hearing loss, but data are limited.
Objective: We prospectively examined the relation between carot-
enoids, vitamin A, vitamin C, vitamin E, and folate intake and risk
of self-reported hearing loss in women.
Design: This prospective cohort study followed 65,521 women in the
Nurses’ Health Study II from 1991 to 2009. Baseline and updated
information obtained from validated biennial questionnaires was used
in Cox proportional hazards regression models to examine independent
associations between nutrient intake and self-reported hearing loss.
Results: After 1,084,598 person-years of follow-up, 12,789 cases
of incident hearing loss were reported. After multivariable ad-
justment, we observed modest but statistically significant in-
verse associations between higher intake of b-carotene and
b-cryptoxanthin and risk of hearing loss. In comparison with
women in the lowest quintile of intake, the multivariable-adjusted
RR of hearing loss among women in the highest quintile was
0.88 (95% CI: 0.81, 0.94; P-trend , 0.001) for b-carotene and
0.90 (95% CI: 0.84, 0.96; P-trend , 0.001) for b-cryptoxanthin.
In comparison with women with folate intake 200–399 mg/d,
very low folate intake (,200 mg/d) was associated with higher
risk (RR: 1.19; 95% CI: 1.01, 1.41), and higher intake tended to
be associated with lower risk (P-trend = 0.04). No significant
associations were observed for intakes of other carotenoids or vitamin
A. Higher vitamin C intake was associated with higher risk; in com-
parison with women with intake ,75 mg/d, the RR among women
with vitamin C intake $1000 mg/d (mainly supplemental) was 1.22
(95% CI: 1.06, 1.42; P-trend = 0.02). There was no significant trend
between intake of vitamin E intake and risk.
Conclusion: Higher intakes of b-carotene, b-cryptoxanthin, and
folate, whether total or from diet, are associated with lower risk of
hearing loss, whereas higher vitamin C intake is associated with higher
risk. Am J Clin Nutr 2015;102:1167–75.
Keywords: aging, carotenoids, epidemiology, hearing loss, vitamins
INTRODUCTION
Hearing impairment is a highly prevalent sensory deficit, af-
fecting approximately 48 million individuals in the United States
in at least one ear (1). Approximately 360 million (5.3%) in-
dividuals worldwide have hearing impairment that is disabling by
WHO criteria (2). The risk of acquired hearing loss increases
considerably with age (3), and the prevalence is expected to grow
along with the aging population; therefore, identifying modifiable
risk factors could lead to preventive interventions.
Vascular compromise and oxidative stress contribute to the
development of acquired hearing loss (4–6). Therefore, it has
been proposed that higher intake of foods or nutrients that can
provide vascular or antioxidative benefits (e.g., carotenoids,
vitamin A, vitamin C, vitamin E, and folate) may be protec-
tive. A recent metabolomic and network analysis of pharma-
cotherapies for sensorineural hearing loss identified the retinoic
acid pathway as a promising target for the development of
prevention and treatment strategies (7). In animal models,
b-carotene and vitamins A, C, and E have been protective
against hearing loss (4, 8, 9), but cross-sectional studies in
humans have produced conflicting results (10–12), and pro-
spective data are limited (10, 13). In an Australian study of
older individuals, no prospective associations were observed
between dietary intake of b-carotene, vitamin A, vitamin C, or
vitamin E and 5-y incidence of audiometrically assessed hear-
ing loss, but case numbers were limited, and follow-up was
relatively short in duration (10). In an 18-y prospective US
study among 26,000 older men, we observed no associations
1
Supported by grants DC010811 and UM1 CA176726 from the NIH and
the Vanderbilt University School of Medicine.
2
Supplemental Tables 1–9 are available from the “Online Supporting Ma-
terial” link in the online posting of the article and from the same link in the
online table of contents at http://ajcn.nutrition.org.
*To whom correspondence should be addressed. E-mail: scurhan@
partners.org.
Received February 13, 2015. Accepted for publication August 4, 2015.
First published online September 9, 2015; doi: 10.3945/ajcn.115.109314.

Am J Clin Nutr 2015;102:1167–75. Printed in USA. Ó 2015 American Society for Nutrition 1167
1168 CURHAN ET AL.
between intakes of b-carotene, vitamin A, vitamin C, or vitamin
E and risk of self-reported hearing loss, but higher folate intake
was inversely associated with risk in men aged $60 y (13).
Cross-sectional associations between low intake and low plasma
red blood cell concentrations of folate and higher prevalence of
hearing loss have been observed (14, 15). A randomized clinical
trial in the Netherlands showed that daily oral folic acid sup-
plementation was inversely associated with hearing decline over
3 y (16). However, the trial was performed in a subset of in-
dividuals with very high plasma homocysteine concentrations
and in a country without folate fortification of the food supply.
Thus, the generalizability of these results is uncertain. Because
the relation between vitamin intake and risk of hearing loss re-
mains unclear, we prospectively examined the associations be-
tween intake of carotenoids, vitamin A, vitamin C, and vitamin E
and folate and risk of hearing loss in the Nurses’ Health Study II,
a cohort study of 65,521 women with repeated dietary assess-
ments and long-term follow-up from 1991 to 2009.
METHODS
Study population
The Conservation of Hearing Study examines risk factors for
hearing loss among participants in the Nurses’ Health Study II,
an ongoing cohort study of 116,430 female registered nurses in
the United States aged 25–42 y at cohort inception in 1989.
Participants have been followed by biennial mailed question-
naires that elicit updated information on diet, lifestyle, incident
disease, and various health outcomes; the follow-up rate over
22 y exceeds 90% of eligible person-time. Beginning in 1991,
detailed information on diet and nutrient intake from foods
and supplements has been obtained every 4 y; thus, 1991 served
as our study baseline. The 2009 questionnaire asked women
whether they have a hearing problem and, if so, at what age
a change in hearing was first noticed. Of the 90,488 women who
answered that 2009 questionnaire, 12,160 were excluded be-
cause they had not answered the 1991 baseline diet question-
naire. Women who reported a hearing problem that began before
1991 (n = 2584), reported a hearing problem but did not report
a date of onset (n = 173), did not answer the hearing questions
(n = 9191), or reported a history of cancer other than non-
melanoma skin cancer (because of possible exposure to ototoxic
chemotherapeutic agents; n = 859) were also excluded, leaving
65,521 women included in the analysis. The 1991 baseline
characteristics of participants who did and did not answer the
2009 questionnaire did not differ appreciably (data not shown).
The study protocol was approved by the Institutional Review
Board of the Partners Health Care System.
Ascertainment of dietary intake
Intake of carotenoids; vitamins A, C, and E; and folate was
assessed in 1991, 1995, 1999, 2003, and 2007 with a detailed val-
idated semiquantitative food-frequency questionnaire (SFFQ)12
that included .130 items. For each food, a commonly used
12
Abbreviations used: BMHS, Blue Mountains Hearing Study; HPFS,
Health Professionals Follow-Up Study; PTA, pure-tone audiometry; SFFQ,
semiquantitative food-frequency questionnaire.
unit or portion size was specified, and participants were asked
how often, on average, they had consumed each type of food or
beverage during the previous year. Nine possible response op-
tions were provided that ranged from “never or less than one
per month” to “6 or more times per day.” Intakes of the nu-
trients of interest were calculated by multiplying the portion
size of a single serving of each food by its reported frequency of
intake, multiplying the total amount consumed by the nutrient
content of the food, and then summing the nutrient contribu-
tions of all food items, using USDA food composition data
(17–19). Vitamin supplement use was assessed by collecting
information on use of multiple vitamins (specific brand and
usual number of tablets taken per week) and on use of specific
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supplements, including vitamin A, b-carotene, vitamin E, vi-
tamin C, and folic acid (dose of tablet and the usual number of
tablets taken per week). Vitamin A intake was assessed as both
retinol (preformed vitamin A from animal sources, supplements,
and fortified foods) and total vitamin A (retinol activity equiva-
lents, described in the section on statistical analysis). All com-
puted nutrient intakes were adjusted for total energy intake.
Energy adjustment reduces variation introduced by questionnaire
responses that underreport or overreport intake and improves
the accuracy of nutrient measurements (20).
Nutrient intakes for the individual carotenoids were computed
by using the USDA’s carotenoid database. Lutein and zeaxanthin
intakes are presented together because the analytic procedures
did not permit the individual quantification of these carotenoids
in foods. The carotenoid content of tomato-based food products
was updated with values from the USDA. In our data, the foods
providing the greatest contribution to the total absolute nutrient
intake of the specific carotenoids were carrots for a-carotene;
carrots, spinach, and tomato products for b-carotene; tomato
products for lycopene; oranges, orange juice, and peaches for
b-cryptoxanthin; and spinach, broccoli, and peas for lutein/
zeaxanthin. Foods providing the greatest contribution to vitamin
A intake were romaine lettuce and carrots; to retinol intake,
milk; to vitamin C intake, orange juice; to vitamin E intake, cold
cereal and olive oil; and to folate intake, cold cereal.
The validity and reproducibility of the SFFQ has been de-
scribed previously (21, 22). In validation studies of the SFFQ
compared with detailed 1-wk diet records, the correlation co-
efficients were 0.79 for total vitamin A from food only, 0.59 for
retinol from food only (20), 0.49 for total vitamin A (including
contributions from food and supplements), 0.75 for total vitamin
C, and 0.77 for total folate (21). The correlation between the
questionnaire and measured serum folate was 0.63 (23). For
dietary information that was collected before 1998, data on the
folate content of foods reflect values before mandatory fortifi-
cation of the food supply.
Ascertainment of outcome
On the 2009 questionnaire, participants were asked, “Do you
have a hearing problem?” (response options: no, mild, moderate,
severe) and, if so, “At what age did you first notice a change
in your hearing?” (,30, 30–39, 40–44, 45–49, 50–54, 55–59,
60+ y). The primary outcome, self-reported hearing loss, was
determined based on the response to this question, and a case
was defined as a hearing problem first noticed after 1991. Al-
though hearing loss can be subtle in onset, incident cases were
 CAROTENOID AND VITAMIN INTAKE AND HEARING LOSS
defined as hearing loss at the age it was first noticed by the
participant. We did not have information on severity of hearing
loss at time of onset, and thus we could not perform prospective
analyses that considered severity of hearing loss as the outcome.
Hearing loss measured by pure-tone audiometry (PTA) is con-
sidered the gold standard for hearing loss evaluation; however,
questionnaires have been used in large populations to assess
hearing loss and have been found to be reasonably reliable in
previous studies (24, 25).
In addition, a recent study in NHANES that examined the
accuracy of subjective assessment of hearing (self-report based
on a single question that asked respondents to report their level of
hearing without the use of hearing aids as excellent, good, a little
trouble, a lot of trouble, or deaf) compared with objective as-
sessment of hearing impairment, defined as PTA (0.5,1,2,4 kHz)
.25 dB in the better-hearing ear, found that 77.4% of women
aged 50–59 y classified their hearing status correctly (26). The
wording used on our questionnaire has not been validated
against other surveys and may not be sensitive to mild or slight
hearing loss, which could lead to misclassification of the out-
come and bias the results toward the null.
Our participants were asked whether they had a hearing
problem. Although not all hearing problems may be hearing loss
per se, hearing loss is highly prevalent. Although we were not
able to separate out hearing problems such as difficulty un-
derstanding speech in noise or hyperacusis, hearing loss is the
most prevalent hearing problem, and the finding in our study
population of 19.5% of the women reporting a hearing problem is
consistent with data from NHANES 1999–2004 that show the
prevalence of bilateral hearing loss, defined as PTA (0.5,1,2,4 kHz)
$25 dB in both ears, was 7.5%; unilateral hearing loss, defined
as PTA (0.5,1,2,4 kHz) $25 dB in 1 ear only, was 12%; and high-
frequency hearing loss, defined as PTA (3,4,6 kHz) $25 dB in
either ear, was 34% in white women aged 50–59 y (3). We
herein use the term hearing loss based on the assumption that
hearing loss describes the hearing problem reported by most
participants.
Ascertainment of covariates
Potential confounders of the relation between carotenoid and
vitamin intake and the risk of hearing loss that were considered
covariates in multivariable analyses included age (3); race (3);
socioeconomic status (3); smoking (27); BMI (in kg/m2) (28);
waist circumference (28); physical activity (28); intake of al-
cohol (27), vitamin B-12, magnesium (29), potassium (30), and
long-chain omega-3 PUFAs (31); history of hypertension (32);
history of diabetes (33); acetaminophen use (34); ibuprofen use
(34); and tinnitus (35). Covariate information was obtained from
the biennial questionnaires or the SFFQs and updated through-
out the analysis whenever new information became available.
Statistical analysis
Person-time of follow-up was calculated from the date of
return of the 1991 SFFQ until the date of self-reported hearing
loss or end of follow-up in 2009. Participants who reported
cancers other than nonmelanoma skin cancer were excluded
at baseline or when cancer was reported during follow-up. Date
of reported hearing loss was considered the midpoint of the
1169
category for reported age of first noticing a change in hearing.
During follow-up, participants with missing dietary data were
skipped for the associated time period.
Total intakes of carotenoids, retinol, total vitamin A, and
vitamin E were categorized into quintiles based on the distri-
bution of the entire analytic cohort. Total vitamin A was mea-
sured in retinol activity equivalents, a measure of vitamin A
activity based on the capacity to convert provitamin carot-
enoids containing at least one unsubstituted ionone ring to
retinaldehyde (1 mg retinol activity equivalents = 1 mg retinol =
12 mg b-carotene = 24 mg other vitamin A precursor carot-
enoids) (36). We chose to use prespecified cutoffs to categorize
both vitamin C and folate intake—from less than the US Rec-
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ommended Dietary Allowance of 75 mg/d (referent) up to
$1000 mg/d for vitamin C and ,200 mg/d up to $1000 mg/d
for folate—because of the very skewed distribution of the
intakes of these vitamins, to examine commonly used high
doses, and to be consistent with previous literature (37, 38). For
b-carotene; vitamins A, C, and E; and folate, we also analyzed
the association between hearing loss and intake from foods and
supplements separately. In our final multivariable models, the
nutrient covariates that were not confounders but were highly
correlated with the exposures of interest (magnesium, potas-
sium, trans fat, and vitamin B-12) were removed from the mul-
tivariable model to reduce the influence of collinearity.
In addition to analyzing the association for each specific ca-
rotenoid, we also analyzed total carotenoid intake by summing
the intake of the specific carotenoids to create a total carotenoid
intake variable. We also calculated a total carotenoid score by
summing the quintile score for each carotenoid (scores ranged
from 5 to 25) to reflect the difference in intake amounts across the
specific carotenoids (39).
Descriptive analyses for baseline characteristics in 1991 were
examined for the entire cohort and by categories of nutrient intake.
We used Cox proportional hazards regression models with age and
questionnaire period as the time scale to estimate RRs and 95%
CIs by using the lowest category of intake of each nutrient as the
referent group for the carotenoids and vitamins A, C, and E. For
folate, relatively few women had intake ,200 mg/d; therefore, we
used intake 200–399 mg/d as the referent category. We used the
Anderson-Gill (40) data structure, with a new data record created
for each biennial questionnaire cycle in which the participant was
at risk with covariates set to represent the value from the latest
returned questionnaire to handle time-varying covariates effi-
ciently. For all RRs, we calculated 95% CIs.
All analyses were prospective, using information on dietary
intake that was collected before the date when a change in hearing
was first noticed. The temporal relation between these micro-
nutrients and risk of hearing loss is unknown; therefore, dietary
intake was examined in 3 ways: baseline intake (1991 SFFQ),
most recently reported intake before the change in hearing, and
cumulative average intake. Cumulative average intake was cal-
culated by assigning the 1991 intake to the 1991–1995 follow-up
period; the average of the 1991 and 1995 intake to the 1995–
1999 follow-up period; the average of the 1991, 1995, and 1999
intake to the 1999–2003 follow-up period; and so forth. We
present the result for the cumulative average models because
this method captures long-term dietary intake and reduces
measurement error due to within-person variation over time,
minimizing misclassification (41).
1170 CURHAN ET AL.

Tests for linear trend for the exposures of interest were per-
formed by assigning the median value of each category to all
participants in that group. We conducted analyses stratified by
age ,50 and $50 y, smoking status (never, past, frequency of
current smoking), and amount of magnesium intake to examine
potential interactions between antioxidant vitamin intake because
these factors may increase oxidative stress or have been impli-
cated as modifying factors (42). In addition, the relation between
folate intake and incident hearing loss was analyzed stratified
by amount of alcohol intake, categorized as low (0–5 g/d),
medium (5.1–19.9 g/d), and high ($20 g/d). All P values are
2-tailed. Statistical tests were performed with SAS statistical
software, version 9.3 (SAS Institute Inc.).
vitamin C or E supplements, and had higher intakes of other
vitamins and minerals.
After 1,084,598 person-years of follow-up, 12,789 cases of
hearing loss were reported to have occurred. Higher intakes of
carotenoids, specifically of b-carotene and b-cryptoxanthin, were
statistically significantly associated with a lower risk of hearing
loss (Table 2). For example, in comparison with women in the
lowest quintile of b-carotene intake, the multivariable-adjusted
RR of hearing loss in women in the highest quintile was 0.88
(95% CI: 0.81, 0.94; P-trend , 0.001). In comparison with
women in the lowest quintile of b-cryptoxanthin intake, the
multivariable-adjusted RR of hearing loss in women in the
highest quintile was 0.90 (95% CI: 0.84, 0.96; P-trend , 0.001).

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A higher total carotenoid score was also significantly associ-
ated with lower risk (RR: 0.84; 95% CI: 0.79, 0.90; P-trend ,
RESULTS
0.001). No significant associations were observed for intakes
Baseline characteristics are presented in Table 1. The mean 6 of a-carotene, lycopene, or lutein/zeaxanthin.
SD age of the cohort at baseline was 36.3 6 4.6 y, the partici- A higher intake of vitamin C was associated with a higher risk
pants were predominantly white women, and the mean 6 SD of hearing loss (Table 3). In comparison with women whose
BMI was 24.5 6 5.2. Two-thirds of the women had never been intake of vitamin C was ,75 mg/d, the multivariable-adjusted
smokers, 44% took multivitamins, 20.1% took a vitamin C RR of hearing loss in women was 1.13 (95% CI: 1.02, 1.26)
supplement, and 6.7% took supplemental vitamin E. Baseline for vitamin C intake 75–249 mg/d, 1.18 (95% CI: 1.05, 1.32)
characteristics according to category of specific nutrients are for intake 250–499 mg/d, 1.19 (95% CI: 1.06, 1.35) for intake
presented in Supplemental Tables 1–5. Overall, women with 500–999 mg/d, and 1.22 (95% CI: 1.06, 1.42; P-trend = 0.02)
higher intake of carotenoids; vitamins A, C, and E; and folate for intake $1000 mg/d. More than half of the women in the
tended to be more physically active, were less likely to be higher intake categories of total vitamin C took vitamin C sup-
current smokers, were more likely to take multivitamins and plements. Although the difference in the point estimates in the
age-adjusted and multivariable-adjusted models indicates the
TABLE 1 presence of negative confounding, no individual covariate pre-
Age-standardized baseline characteristics of the study population, Nurses’ dominantly influenced the results. A higher intake of vitamin E
Health Study II (1991) (n = 65,521)1 was modestly associated with higher risk; however, there was
Characteristic Value no significant trend between intake of vitamin E and risk of
hearing loss (P-trend = 0.27). In comparison with women in the
Age, y 36.3 6 4.62 lowest quintile of vitamin E intake, the multivariable-adjusted
BMI, kg/m2 24.5 6 5.2 RR of hearing loss in women was 1.09 (95% CI: 1.02, 1.17) in
Waist circumference (1993), cm 77.9 6 12.5
the fourth quintile of vitamin E intake and 1.08 (95% CI: 1.00,
Physical activity, METs 12.6 (5.2–26.5)3
Smoking status, % 1.16) in the fifth quintile. No significant associations were ob-
Never 66.6 served between intakes of retinol or total vitamin A and risk of
Past 22.3 hearing loss.
Current 10.9 A higher intake of folate tended to be associated with a lower
History of hypertension, % 6.0 risk of hearing loss (P-trend = 0.04). In comparison with women
History of diabetes, % 0.8 whose intake of folate was 200–399 mg/d, the multivariable-
History of tinnitus, % 8.7 adjusted RR of hearing loss in women with lower folate intake
White race, % 95.1
(,200 mg/d) was 1.19 (95% CI: 1.01, 1.41). In comparison with
Ibuprofen use,4 % 9.2
Acetaminophen use,4 % 7.4 women whose intake of folate was 200–399 mg/d, higher folate
Alcohol intake, g/d 0.9 (0.0–3.5) intake ($600 mg/d) was marginally associated with lower risk;
Vitamin B-12 intake,5 mg/d 7.0 (5.0–11.0) the multivariable-adjusted RR of hearing loss in women was
Potassium intake,5 mg/d 2941 (532) 0.90 (95% CI: 0.84, 0.96) with folate intake 600–799 mg/d, 0.92
Magnesium intake,5 mg/d 316 (74) (95% CI: 0.84, 1.00) with folate intake 800–999 mg/d, and 0.88
Long-chain v-3 PUFA intake,5 g/d 0.2 (0.2) (95% CI: 0.78, 1.00) with folate intake $1000 mg/d.
Multivitamin use, % 44.0 The relations between vitamin intake and hearing loss did not
Vitamin C supplement use, % 20.1
vary by age, smoking status, or amount of magnesium intake
Vitamin E supplement use, % 6.7
(P-interaction $ 0.09 for age; P-interaction $ 0.3 for smoking;
1
Values are standardized to the age and distribution of the study pop- P-interaction $ 0.2 for magnesium intake). In addition, strati-
ulation. Values of polytomous variables may not sum to 100% because of fying by amount of alcohol intake did not influence the rela-
rounding. METs, metabolic equivalent tasks from recreational and leisure-
tion between folate intake and hearing loss (P-interaction = 0.3).
time activities.
2
Mean 6 SD (all such values). We had limited power to examine this relation in women with
3
Median; IQR in parentheses (not age standardized) (all such values). higher alcohol intake ($20 g/d). When dietary intake was also
4
Two days per week or more. examined by using baseline intake (1991 SFFQ) or simple up-
5
Nutrient intakes are adjusted for total energy intake. dating (most recently reported intake before the change in
 CAROTENOID AND VITAMIN INTAKE AND HEARING LOSS 1171
TABLE 2
Age- and multivariable-adjusted relative risks (95% CIs) for hearing loss according to specific carotenoid intake in the Nurses’ Health Study II, 1991–2009
(n = 65,521)1
Quintile of carotenoid intake
P-linear
Carotenoid 1 2 3 4 5 trend2

a-Carotene
Median intake, mg/d 155 379 573 829 1470
Cases, n 2462 2706 2559 2659 2403
Age-adjusted RR (95% CI) 1.00 (referent) 0.99 (0.94, 1.05) 0.92 (0.87, 0.97) 0.93 (0.88, 0.98) 0.86 (0.81, 0.91) ,0.001
Multivariable-adjusted RR (95% CI) 1.00 (referent) 1.03 (0.97, 1.09) 0.99 (0.93, 1.06) 1.03 (0.96, 1.11) 1.01 (0.93, 1.10) 0.84
b-Carotene3
Median intake, mg/d 1478 2469 3373 4541 7028
Cases, n 2480 2678 2600 2656 2375

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Age-adjusted RR (95% CI) 1.00 (referent) 0.95 (0.90, 1.00) 0.89 (0.84, 0.94) 0.88 (0.83, 0.93) 0.79 (0.75, 0.84) ,0.001
Multivariable-adjusted RR (95% CI) 1.00 (referent) 0.97 (0.91, 1.03) 0.94 (0.88, 1.00) 0.95 (0.89, 1.01) 0.88 (0.81, 0.94) ,0.001
b-Cryptoxanthin3
Median intake, mg/d 46 79 115 164 256
Cases, n 2585 2777 2646 2498 2283
Age-adjusted RR 1.00 (referent) 0.99 (0.94, 1.05) 0.93 (0.88, 0.98) 0.87 (0.82, 0.92) 0.81 (0.76, 0.85) ,0.001
Multivariable-adjusted RR (95% CI) 1.00 (referent) 1.02 (0.96, 1.08) 0.96 (0.91, 1.02) 0.94 (0.88, 1.00) 0.90 (0.84, 0.96) ,0.001
Lycopene
Median intake, mg/d 3293 4741 6070 8144 12,487
Cases, n 2442 2521 2650 2723 2453
Age-adjusted RR (95% CI) 1.00 (referent) 0.98 (0.92, 1.04) 0.98 (0.92, 1.04) 1.01 (0.95, 1.07) 0.96 (0.91, 1.02) 0.30
Multivariable-adjusted RR (95% CI) 1.00 (referent) 0.98 (0.92, 1.04) 1.01 (0.95, 1.07) 1.04 (0.98, 1.11) 0.99 (0.93, 1.05) 0.65
Lutein + zeaxanthin
Median intake, mg/d 952 1618 2290 3116 4863
Cases, n 2516 2703 2612 2655 2303
Age-adjusted RR (95% CI) 1.00 (referent) 0.97 (0.91, 1.02) 0.91 (0.87, 0.97) 0.90 (0.85, 0.95) 0.79 (0.75, 0.84) ,0.001
Multivariable-adjusted RR (95% CI) 1.00 (referent) 1.02 (0.96, 1.09) 1.01 (0.94, 1.09) 1.02 (0.95, 1.11) 0.95 (0.87, 1.04) 0.19
Total carotenoid score4
Median score 7 12 15 18 23
Cases, n 2675 2696 2751 2224 2443
Age-adjusted RR (95% CI) 1.00 (referent) 0.96 (0.91, 1.01) 0.91 (0.86, 0.95) 0.89 (0.84, 0.94) 0.78 (0.74, 0.83) ,0.001
Multivariable-adjusted RR (95% CI) 1.00 (referent) 0.97 (0.92, 1.03) 0.94 (0.89, 1.00) 0.94 (0.88, 1.00) 0.84 (0.79, 0.90) ,0.001
1
Cumulative average intake of energy-adjusted nutrients. Cox proportional hazards regression was used to estimate RRs (95% CIs). Multivariable models
were adjusted for age, race, socioeconomic status, BMI, waist circumference, physical activity, alcohol intake, long-chain v-3 fatty acid intake, smoking,
hypertension, diabetes, tinnitus, ibuprofen use, acetaminophen use, retinol intake, vitamin C intake, vitamin E intake, and intake of the other carotenoids,
unless otherwise indicated.
2
P-linear trend was calculated by using the Wald test statistic.
3
The multivariable model was adjusted for all of the above except for intakes of retinol, a-carotene, lycopene, and lutein/zeaxanthin.
4
The total carotenoid score was derived from summing the quintile scores for total b-carotene intake and dietary intakes of a-carotene, b-cryptoxanthin,
lycopene, and lutein/zeaxanthin.

hearing), the results did not materially differ. In sensitivity DISCUSSION

analyses, we excluded women who reported tinnitus $2 d/wk,
but the results were not appreciably changed (results not shown).
We examined the relations between food-only derived sources
of b-carotene, vitamin C, vitamin E, and folate and risk of
hearing loss (Supplemental Tables 6–9). We observed that for
b-carotene, whether from diet or total, the association was the
same. Very few women attained the higher amounts of vitamin
C intake from diet only, and thus we were not able to explore
the relation between high dietary vitamin C intake and risk of
hearing loss. We did not observe a significant trend between
either dietary vitamin E or total vitamin E intake and risk of
hearing loss. For women with very low dietary intake of folate
(,200 mg/d), taking a folate supplement may help reduce the
observed higher risk. For women with intake .200–399 mg/d,
higher total intake is associated with a lower risk, but it is
unclear whether higher dietary intake alone is associated with
lower risk.
In this large prospective study of vitamin intake and risk of
hearing loss in 65,521 US women, higher intakes of b-carotene
and b-cryptoxanthin were independently associated with lower
risk of hearing loss, whereas higher vitamin C intake (from
supplements) was associated with higher risk. Higher folate
intake tended to be associated with lower risk. No significant
associations were observed between intake of vitamin A, other
carotenoids, or vitamin E and risk of hearing loss in these
women.
Acquired hearing loss in adults is multifactorial and results
from the cumulative influence of a number of intrinsic and
extrinsic factors over the course of a lifetime. Factors that
contribute to hearing loss include insufficient cochlear blood
supply that leads to hypoxia and ischemic damage, oxidative
stress, mitochondrial dysfunction and cell injury, and peripheral
and central auditory neurodegeneration (43). There are several
potential mechanisms by which carotenoids and vitamins may
1172 CURHAN ET AL.
TABLE 3
Age- and multivariable-adjusted RRs (95% CIs) for hearing loss according to category or quintile of specific vitamin intake in the Nurses’ Health Study II,
1991–2009 (n = 65,521)1
Quintile or category of intake
P-linear
Nutrient 1 2 3 4 5 — trend2

Total vitamin A3
Median intake, mg/d 562 844 1171 1900 2956
Cases, n 2440 2697 2654 2553 2445
Age-adjusted RR (95% CI) 1.00 (referent) 1.00 (0.94, 1.05) 0.96 (0.91, 1.02) 0.94 (0.89, 0.99) 0.94 (0.88, 0.99) 0.007
Multivariable-adjusted 1.00 (referent) 1.02 (0.96, 1.09) 0.98 (0.92, 1.06) 0.98 (0.90, 1.06) 0.97 (0.89, 1.06) 0.85
RR (95% CI)
Retinol Q1 Q2 Q3 Q4 Q5 —
Median intake, IU/d

Downloaded from https://academic.oup.com/ajcn/article-abstract/102/5/1167/4564382 by guest on 02 April 2020

Cases, n 2384 2651 2718 2604 2432
Age-adjusted RR (95% CI) 1.00 (referent) 1.03 (0.98, 1.09) 1.01 (0.96, 1.07) 0.97 (0.92, 1.03) 0.99 (0.94, 1.05) 0.37
Multivariable-adjusted 1.00 (referent) 1.02 (0.96, 1.08) 1.01 (0.95, 1.07) 0.97 (0.91, 1.04) 1.01 (0.94, 1.09) 0.66
RR (95% CI)
Vitamin C,4 mg/d ,75 75–249 250–499 500–999 $1000 —
Cases, n 467 6891 2442 1388 453
Age-adjusted RR (95% CI) 1.00 (referent) 0.98 (0.89, 1.07) 0.98 (0.88, 1.08) 0.97 (0.88, 1.08) 0.98 (0.86, 1.11) 0.93
Multivariable-adjusted 1.00 (referent) 1.13 (1.02, 1.26) 1.18 (1.05, 1.32) 1.19 (1.06, 1.35) 1.22 (1.06, 1.42) 0.02
RR (95% CI)
Vitamin E4 Q1 Q2 Q3 Q4 Q5 —
Median intake, mg/d 6.6 8.0 9.7 14.5 26.3
Cases, n 2024 2110 2239 2630 2638
Age-adjusted RR (95% CI) 1.00 (referent) 0.98 (0.92, 1.03) 0.98 (0.92, 1.04) 1.02 (0.96, 1.08) 1.00 (0.94, 1.05) 0.85
Multivariable-adjusted 1.00 (referent) 1.00 (0.94, 1.07) 1.04 (0.97, 1.12) 1.09 (1.02, 1.17) 1.08 (1.00, 1.16) 0.27
RR (95% CI)
Folate,4 mg/d ,200 200–399 400–599 600–799 800–999 $1000
Cases, n 682 6514 2458 1622 750 763
Age-adjusted RR (95% CI) 1.13 (0.98, 1.30) 1.00 (referent) 0.98 (0.94, 1.02) 0.91 (0.87, 0.96) 0.90 (0.84, 0.97) 0.87 (0.78, 0.97) ,0.001
Multivariable-adjusted 1.19 (1.01, 1.41) 1.00 (referent) 0.96 (0.91, 1.01) 0.90 (0.84, 0.96) 0.92 (0.84, 1.00) 0.88 (0.78, 1.00) 0.04
RR (95% CI)
1
Cumulative average intake of energy-adjusted nutrients. Cox proportional hazards regression was used to estimate RRs (95% CIs). Multivariable models
were adjusted for age, race, socioeconomic status, BMI, waist circumference, physical activity, alcohol intake, long-chain v-3 fatty acid intake, smoking,
hypertension, diabetes, tinnitus, ibuprofen use, acetaminophen use, retinol intake, vitamin C intake, vitamin E intake, and intake of the specific carotenoids,
unless otherwise indicated. Q, quintile.
2
P-linear trend was calculated by using the Wald test statistic.
3
The multivariable model was adjusted for intake of vitamin C, vitamin E, and folate.
4
Multivariable model was adjusted for all of the above except for intakes of retinol, a-carotene, lycopene, and lutein/zeaxanthin.

influence auditory function, including providing protection
against oxidative damage and mediating vascular and membrane
function (4, 44, 45). Some animal evidence suggests that anti-
oxidant nutrients may attenuate cell damage after exposure to
noise or ototoxins (46, 47); however, results have been in-
consistent, and their role in age-related hearing loss is unclear
(48, 49). Although results from animal studies of antioxidant
treatment are promising, data in humans are limited and not
conclusive (50, 51).
Carotenoids may reduce oxidative stress and DNA damage by
scavenging free radicals. b-Carotene is efficient at quenching
singlet oxygen and inhibits oxidative modification of LDL
cholesterol. Both b-carotene and b-cryptoxanthin may increase
intracellular glutathione concentrations, modulate cytokines,
and alter lipid metabolism (52). Our finding of an inverse
association between higher b-carotene intake and hearing
loss is consistent with those from some human cross-sectional
studies (42, 53); however, it differs from findings from 2 pre-
vious longitudinal studies, one in older US men, the Health
Professionals Follow-Up Study (HPFS) (n = 26,273), and one
in older Australian adults, the Blue Mountains Hearing Study
(BMHS) (n = 798), in which no prospective associations were
observed (10, 13). Possibly, the larger size and longer follow-up
in our study afforded better ability to detect an association.
However, differences in the study populations and the use of self-
report in our study compared with hearing threshold measure-
ments in the BMHS to assess the outcome may account for the
differing results. To our knowledge, no other prospective study has
examined the independent association between intake of
b-cryptoxanthin and risk of hearing loss in women.
Vitamins A, C, and E have been shown to be scavengers of
singlet oxygen, reduce peroxyl radicals, and inhibit lipid perox-
idation (54–56). Although some cross-sectional studies observed
an association between higher vitamin A intake and better
hearing thresholds (10, 53), others have reported worse auditory
function or no association (11, 12). We found no prospective
association between vitamin A intake and risk of incident hearing
loss, consistent with previous prospective studies (10, 13).
Vitamin C can have antioxidant activity and may influence
vascular remodeling, endothelial function (57), and athero-
sclerosis (58). In some cross-sectional studies, individuals
with higher intake of vitamin C tended to have better hearing
 CAROTENOID AND VITAMIN INTAKE AND HEARING LOSS
thresholds than those with lower intake (10, 12, 42) but not all
(11). No prospective association between vitamin C intake and
risk was observed in the BMHS (10) or the HPFS (13). Our
finding of higher risk observed with higher intake of vitamin C
in women was unexpected. Higher intake of vitamin C is as-
sociated with lower plasma concentrations of uric acid (38),
itself a potent intrinsic oxidant and antioxidant. Although hy-
peruricemia may be associated with cochlear dysfunction (59),
the relation between low plasma uric acid and hearing loss is
unclear. Uric acid production may be elevated in human peri-
lymph in conditions of oxidative stress (60) and perhaps may
play a role in mediating oxidative damage. This relation merits
further exploration.
In addition to acting as a scavenger of free radicals, vitamin E
may play a role in lipid peroxidation, inhibition of foam cell
formation, and platelet function (61). An association between
higher vitamin E intake and better prevalent hearing thresholds
was observed in some cross-sectional studies (10, 12, 42) but not
in another (11). Prospective findings from both the HPFS and
BMHS suggested that higher vitamin E intake was not longitu-
dinally associated with the risk of incident hearing loss (10, 13).
Folate may favorably influence cochlear blood flow through
its beneficial effects on endothelial function (62). In our study,
higher folate intake tended to be inversely associated with risk
of hearing loss. This is consistent with our prospective findings
from the HPFS (13). This is also consistent with findings from
a randomized controlled trial in the Netherlands that found that
daily oral folic acid supplementation slowed a 3-y decline in
hearing thresholds (16).
In the United States, dietary supplements are commonly taken
with the hope they will prevent chronic diseases, including
cardiovascular disease and cancer. However, trials examining
the effects of dietary supplementation with vitamins A, C, and
E or folate on the primary prevention of cardiovascular disease,
cancer, and mortality found no effect in healthy populations
(63). In addition, findings from a recent large cohort study did
not support the use of supplemental intake of vitamin A, C, or
E to increase longevity (64). We explored the relations be-
tween dietary and total intake for those nutrients most com-
monly consumed as individual supplements or in multivitamins.
For b-carotene, vitamin E, and folate, we did not observe any
material differences in the results for diet or total intake. For
women with very low dietary intake of folate (,200 mg/d),
supplemental folate intake may help lower the elevated risk.
Because it is difficult to achieve the highest amounts of vitamin
C intake without supplements, we did not have enough women
who derived these higher amounts from diet alone, so we were
unable to draw conclusions.
It has been suggested that the relation between antioxidant
nutrient intake and hearing loss may be modified by the
amount of magnesium intake. In a cross-sectional study,
higher intakes of b-carotene, vitamin C, and magnesium were
associated with better prevalent pure-tone thresholds, and
higher intakes of b-carotene or vitamin C combined with high
magnesium compared with low intakes of both nutrients were
associated with better prevalent high frequency pure-tone
thresholds (42). Examined prospectively, we found that the
association between intake of any of the vitamins and risk of
incident hearing loss did not vary by amount of magnesium
intake.
1173
Our study has limitations. Dietary information was self-
reported, and thus nondifferential misclassification of our
exposures may have resulted in an underestimation of the as-
sociations of interest. Although this could possibly explain null
findings for some of the antioxidant nutrients examined, we
averaged multiple dietary assessments, which helps reduce ran-
dom measurement error (20). We have previously detected im-
portant diet and hearing loss relations for other self-reported
nutrients in this cohort (31). Although the correlations for some
of the nutrients may be moderate, these measures can still be used
to detect significant associations. Nevertheless, misclassification
is a possibility. Notably, the correlation coefficients we report
from the validation study do not take into account the improve-
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ment in accuracy when cumulative averaging is used, as we did
in this study. With cumulative average updated dietary data, we
were able to enhance the precision of dietary assessments and
account for changes in nutrient intakes over time and reduce
misclassification of intake. The lack of an association observed
for certain nutrients examined in this study might reflect non-
differential measurement error of intake, which results in bias
toward the null. Assessment of hearing loss was based on self-
report. Hearing decline is often subtle in onset, and thus there is
imprecision in the assessment of date of onset. Standard PTA
is the gold-standard measure for evaluation of hearing loss;
however, assessment of hearing loss based on self-report has
been found to be reasonably reliable (24, 65). Assessment of
hearing loss was based on participant report in 2009 regarding
date of onset, yet all information on exposures and covariates
was collected before the reported date of hearing loss onset;
therefore, the relations were examined prospectively. We did
not have information on hearing loss severity at the time of
onset, and thus severity of hearing loss could not be considered.
Participants reported whether they had a hearing problem yet
may have had auditory problems other than hearing loss per se.
Hearing loss is highly prevalent (3), and we used the term
hearing loss based on the assumption that this describes the
hearing problem reported by most participants. This is an ob-
servational study, and therefore residual confounding could have
influenced the results; nevertheless, we carefully adjusted for
many potentially confounding variables in our analyses. After
fortification of the US food supply in 1998, total folate intake
,200 mg/d became relatively uncommon, and thus we were
limited in our ability to explore the relation between very low
intake and risk of hearing loss. Our study was limited to pre-
dominantly non-Hispanic white women, and thus further re-
search in additional populations is warranted.
These findings from a large prospective study of carotenoid
and vitamin intake and risk of hearing loss among US women
suggest that higher intake of b-carotene, b-cryptoxanthin, and
folate, whether total or from diet, and avoidance of vitamin C
supplements could play a role in the prevention of acquired
hearing loss.
The authors’ responsibilities were as follows—SGC, KMS, RDE, MW,
MJS, and GCC: contributed to the study concept and design and critically
revised the manuscript for important intellectual content; SGC, RDE, MW,
MJS, and GCC: contributed to the analysis, acquisition, or interpretation of
the data; SGC: drafted the manuscript; MW and GCC: provided statistical
expertise; GCC: provided study supervision and had primary responsibility
for the final content; and all authors: read and approved the final manuscript.
None of the authors reported a conflict of interest.
1174 CURHAN ET AL.
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