The Effect of Multivitamin/Mineral Supplements on Age-Related Cataracts: A Systematic Review and Meta-Analysis

Antioxidant vitamins supplements have been suggested as a strategy to decrease the risk of age-related cataract development. However, the results from observational studies and interventional trials of associations between antioxidant vitamins A, C, and E and cataract development have been inconsistent. We aim to evaluate the effectiveness of multivitamin/mineral supplements for decreasing the risk of age-related cataracts by conducting a systematic review and meta-analysis. In September 2013, we searched multiple databases to identify relevant studies including both cohort studies and randomized controlled trials (RCTs). A random-effects model was used to calculate the pooled relative risks (RR) with a 95% confidence interval (CI). Twelve prospective cohort studies and two RCTs were included. Pooled results from the cohort studies indicated that multivitamin/mineral supplements have a significant beneficial effect in decreasing the risk of nuclear cataracts (RR: 0.73; 95% CI: 0.64–0.82), cortical cataracts (RR: 0.81; 95% CI: 0.68–0.94), and any cataracts (RR: 0.66; 95% CI: 0.39–0.93). In addition, there were no decreases in the risk of posterior capsular cataracts (RR: 0.96; 95% CI: 0.72–1.20) or cataract surgery (RR: 1.00; 95% CI: 0.92–1.08). The two RCTs demonstrated that multivitamin/mineral supplements could decrease the risk of nuclear cataracts. There is sufficient evidence to support the role of dietary multivitamin/mineral supplements for the decreasing the risk of age-related cataracts.


Introduction
Age-related cataracts are the main cause of the loss of useful vision among the elderly population, with an estimated 16 million people affected worldwide [1]. Oxidative stress is widely accepted to be a significant factor in the genesis of age-related cataracts [2,3]. Therefore, antioxidant vitamin supplements have been proposed as a strategy to decrease the risk of age-related cataracts [4,5]. In vitro laboratory studies and animal experiments have shown that antioxidants such as vitamin E, vitamin C, and β-carotene reduce oxidative stress, lipid peroxidation, and free radical damage, which are important intermediate steps in the pathogenesis of age-related cataracts [6,7].
In contrast to taking one or several main antioxidant supplements, the use of multivitamin/mineral supplements is more popular among the general population, as confirmed by many population-based surveys [39][40][41][42]. Many of the observational studies reporting associations between the dietary intake of antioxidants from food and supplements and the risk of cataract development are population-based cohort studies, such as The Blue Mountains Eye Study [10] and The Beaver Dam Eye Study [8,9]. The findings of these studies regarding the association between multivitamin/mineral supplements and the risk of cataract development are possibly pertinent to this public health issue and have not yet been fully utilized in data synthesis.
We completed a systematic review and meta-analysis to provide pooled quantitative estimates of the likely magnitude of the effect of multivitamin/mineral supplements on clinical cataract outcomes. This report forms part of a large systematic review and meta-analysis of the existing literature on the association between antioxidants and the risk of cataract formation in humans.

Data Sources
We developed a search strategy to identify studies that investigated the association between multivitamin/mineral supplements and cataract risk. We searched the electronic databases PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials for literature published until 1 September 2013. For maximum sensitivity, we used free text and Mesh terms including "diet OR intake OR supplement OR food OR nutrient OR antioxidant OR micronutrient OR vitamin OR trace elements OR trace minerals" AND "cataract OR age-related cataract OR lens opacity OR cataract surgery OR clinical cataract events". For those titles and/or abstracts that met these criteria, the full article was retrieved.
The search was conducted to identify all published studies of the relationship between multivitamin/mineral supplements and age-related cataracts. RCTs and prospective cohort studies were all included. The reference lists of the identified relevant studies and previous reviews were manually checked for further relevant studies. No language restrictions were applied.

Study Selection
We selected studies if they met the following inclusion criteria: (1) clinical trials in humans that assessed the preventive effect of multivitamin/mineral combination supplements; (2) studies that reported clinical outcomes that were closely associated with clinical cataract events, including any lens opacity, nuclear opacity, cortical opacity, posterior subcapsular opacity, and cataract surgery; (3) studies that were designed as RCTs or as prospective cohort studies; and (4) studies that reported original data about the risks of clinical cataract events, including odds ratios, risk ratios, relative risks, or hazard ratios and their 95% confidence intervals (CIs) with respect to some form of multivitamin/mineral supplement.
The exclusion criteria were the following: studies in which the outcomes were not clearly defined; and review letters, commentaries, and editorials not containing original data.
When multiple publications of the same study existed, we included only the publication containing the most detailed information regarding both the outcomes and antioxidant vitamin supplements. When the same study generated several different reports, we used the findings of the report that included all the participants or the report with the longest follow-up period.

Data Extraction and Study Quality
Data extraction and evaluation of the studies' quality were completed independently by two reviewers (LQZ and HZ). The data were recorded onto a customized data extraction form described in the Cochrane Handbook for Systematic Reviews of Interventions, which included each study's author, year of publication, location, patient characteristics, sample size, mean age or age range of subjects, sex of subjects, methods of measuring multivitamin/mineral supplements, and covariates used for adjustments in multivariate models.
The quality of cohort studies was assessed using the Newcastle-Ottawa Scale for Quality Assessment (NOS) [43]. The reviewers examined the following points of methodological quality: selection, comparability, and exposure or outcome. The quality of RCTs was assessed using the Cochrane Handbook for Systematic Reviews of Interventions [44]. The reviewers examined the following points of methodological quality: allocation concealment, method of allocation of treatment, masking of outcome assessment, and completeness of follow-up. The scores from these instruments were categorized as high, moderate, or low quality.
The two reviewers resolved any disagreement about study inclusion, quality assessment, selection of outcome parameters, and data extraction through discussion until full agreement was reached.

Data Analysis
For the observational studies, the outcome parameters investigated were the pooled relative risk (RR) with a 95% CI for clinical cataract events, comparing the longest duration of multivitamin/mineral supplementation with the shortest duration or with no multivitamin/mineral supplementation. Measures of association (odds ratios, relative risks, risk ratios, or hazard ratios) and their 95% CIs were abstracted or derived using data reported in the publications.
To pool RR estimates from individual studies, we used an inverse-variance weighted random-effects model. Wherever possible, risk estimates from the most fully adjusted models were used in the estimation of the pooled RR. We presented the more conservative pooled RR estimates generated by the inverse-variance weighted random effects models rather than those generated by the fixed effects models because of the different pre-existing conditions involved in the original trials. Clinical trials were analyzed according to the intention to treat principle.
We used the I 2 index to estimate the heterogeneity existing among the studies. Values of 25%, 50%, and 75% represented low, moderate, and high degrees of heterogeneity, respectively. Pre-specified subgroup analyses were conducted to explore the potential sources of heterogeneity existing among the studies when there were sufficient studies to analyze study design (such as population-based studies), study quality, gender differences, and supplement duration.
Finally, we assessed publication bias using funnel plots and Begg's tests. Funnel plots were produced and checked for asymmetries to ascertain whether a publication bias was present.
The systematic review was performed in accordance with the MOOSE guidelines. The PRISMA statement checklist was used [45]. Statistical analyses were performed using STATA version 12 (STATA Corp., College Station, Brazos, TX, USA); P values less than 0.05 were considered statistically significant.
Among the observational studies, two were from The Beaver Dam Eye Study [8,9], one was from The Blue Mountains Eye Study [10], one was from The Swedish Mammography Cohort [11], one was from The Cohort of Swedish Men [12], one was from The Age-Related Eye Disease Study (AREDS) [13], one was from The Longitudinal Study of Cataract [14], one was from The Physicians' Health Study [15], and four were from The Nurses' Health Study [16][17][18][19]. The two RCTs were from The Clinical Trial of Nutritional Supplements and Age-Related Cataract Study [46] and The Linxian Cataract Study [47].
Among these ten independent prospective cohort studies and RCTs, six were from the United States, two from Sweden, one from Australia, and one from China. Two studies exclusively enrolled men, and two studies exclusively enrolled women. The number of subjects enrolled in the studies ranged from 478 to 50828. The age of the participants was older than 40 years. The follow-up was 4.8-15 years. The first article reporting data was published in 1992.
Further information about the individual studies is presented in Tables 1 and 2.

Multivitamin/Mineral Supplements and the Risk of Nuclear Cataracts
Five prospective cohort studies and two RCTs investigated the association between the use of multivitamin/mineral supplements and the risk of nuclear cataract development. All the cohort studies demonstrated that participants receiving between 4.8 and greater than 10 years of multivitamin/mineral supplements had a significant (20%-43%) reduction in the incidence of nuclear cataracts compared with those not receiving any supplementation [8][9][10]13,14,19]. Three studies showed a significant or nearly significant trend towards a decrease in nuclear cataract risk with increased duration of multivitamin/mineral supplementation (p = 0.04, p = 0.02, and p = 0.08, respectively) [8,10,19].
One RCT performed in the USA showed that participants assigned to approximately 9 years of multivitamin/mineral supplements had a significantly lower (34%) incidence of nuclear cataracts than those given a placebo (RR: 0.66; 95% CI: 0.50, 0.88) [46].

Multivitamin/Mineral Supplements and the Risk of Cortical Cataracts
Four prospective cohort studies and two RCTs investigated the association between the use of multivitamin/mineral supplements and the risk of cortical cataract development. Two population-based cohort studies showed that patients who received multivitamin/mineral supplementation for more than 10 years had a significant (23%-30%) reduction in the incidence of cortical cataracts compared with those not receiving supplementation [9,10]. These studies also showed significant trends towards a decrease in cortical cataract risk with increased duration of multivitamin/mineral supplementation (p = 0.002; p = 0.03, respectively) [8,10]. The other two cohort studies showed no significant beneficial effect of multivitamin/mineral supplements [13,18].
One RCT performed in the USA demonstrated a nearly significant 22% reduction (RR: 0.78; 95% CI: 0.60, 1.02) in the prevalence of cortical cataracts for persons assigned to approximately 9 years of multivitamin/mineral supplementation compared with those assigned to the placebo [46].
Another RCT performed in China demonstrated no significant reduction in the prevalence of cortical cataracts for persons assigned to approximately 5 years of multivitamin/mineral supplements compared with those assigned to the placebo (RR: 1.05; 95% CI: 0.88, 1.26) [47].

Multivitamin/Mineral Supplements and the Risk of Posterior Subcapsular Cataracts
Three prospective cohort studies and two RCTs investigated the association between the use of multivitamin/mineral supplements and the risk of PSC development. All cohort studies demonstrated that multivitamin/mineral supplements did not significantly reduce the incidence of PSC in patients who received between 6.3 and more than 10 years of multivitamin/mineral supplements compared with those receiving no supplementation [8,13,18]. One study showed no significant trend towards a decrease in PSC risk with increased duration of multivitamin/mineral supplementation (p = 0.79) [8].
One RCT performed in the USA demonstrated a significant increase (RR: 2.00; 95% CI: 1.35, 2.498) in the prevalence of PSC for persons assigned to approximately 9 years of multivitamin/mineral supplementation compared with those assigned to the placebo [46].
Another RCT performed in China demonstrated no significant reduction in the prevalence of PSC for persons assigned to approximately 5 years of multivitamin/mineral supplementation compared with those assigned to the placebo [47].

Multivitamin/Mineral Supplements and the Risk of Any Type of Cataract
Three prospective cohort studies and one RCT investigated the association between the use of multivitamin/mineral supplements and the risk of developing any cataract. All cohort studies showed that patients receiving between 5 and more than 10 years of multivitamin/mineral supplements had a significant (16%-60%) reduction in the incidence of any cataract compared with those not receiving supplementation [8,13,15]. Two studies showed significant or nearly significant trends towards a decrease in the risk of any cataract with increased duration of multivitamin/mineral supplements (p = 0.002 and p = 0.06, respectively) [8,15]. One study showed that multivitamin/mineral supplements produced a slightly larger reduction in the incidence of any cataract for patients ≥65 years (OR: 0.4; 95% CI: 0.2, 0.7) than for patients aged 43-64 years (OR: 0.5; 95% CI: 0.3, 0.9) [8].
One RCT performed in the USA demonstrated that participants assigned to approximately 9 years of multivitamin/mineral supplements had a significantly reduced incidence (by 18%) of any cataract compared with those assigned to the placebo (OR: 0.82; 95% CI: 0.68, 0.98) [46].

Multivitamin/Mineral Supplements and the Risk of Requiring Cataract Surgery
Four prospective cohort studies and one RCT investigated the association between the use of multivitamin/mineral supplements and the risk of requiring cataract surgery. All cohort studies showed that patients receiving multivitamin/mineral supplements had no significant reduction in the incidence of cataract surgery compared with those not receiving supplementation [11,12,[15][16][17]. One study showed no significant trend towards a decrease in cataract surgery risk with increased duration of multivitamin/mineral supplements (p = 0.30) [16].
One RCT performed in the USA demonstrated no significant reduction (RR: 0.95; 95% CI: 0.71, 1.28) in the risk of cataract surgery for persons assigned to approximately 9 years of multivitamin/mineral supplements compared with those assigned to the placebo [46].

Discussion
Combining the meta-analysis of the prospective cohort studies and the results of the RCTs, there was a strong inverse association between multivitamin/mineral supplements and age-related cataracts. Additionally, there was a significant trend towards a decrease in cataract risk with increasing duration of multivitamin/mineral supplementation. This beneficial effect was even clearer in older participants.
Nuclear opacities are the most frequent type of cataract and are a well-known biological marker of aging [48]. Multivitamin/mineral supplements have a role in the prevention of nuclear cataracts and may have a role in the prevention of cortical cataracts. The meta-analysis of the selected cohort studies demonstrated that 10 years of multivitamin/mineral supplements had a significantly beneficial effect on cortical cataract prevention. A RCT that included approximately 9 years of follow-up data showed a modest borderline protective association (RR: 0.78; 95% CI: 0.60, 1.02) [46]. The results generated by observational and interventional studies demonstrated that multivitamin/mineral supplements had no or even negative effects on the incidence of PSC. The environmental and genetic factors play greater roles in the risk of PSC development than the oxidative damage caused by aging [49,50]. The results obtained from observational and interventional studies also demonstrated that multivitamin/mineral supplements did not decrease the number of people undergoing surgery for cataract removal. This finding may be explained by not only differences in the levels of severity at which different types of cataract require surgery but also differences in the timing of surgery as decided by the patients and/or surgeons.
The use of dietary supplements is increasingly common in the general population of the United States, Europe, and Asia [39][40][41][42]. In the 1999-2000 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional survey of US health and nutrition, 52% of adults reported taking a dietary supplement within the past month, and 35% reported the regular use of a multivitamin/mineral supplement [39]. Centrum(R) (Wyeth Consumer Healthcare, Madison, NJ, USA) was the most popular multivitamin/mineral supplement, and it contains US Recommended Daily Intake (RDI) levels of many nutrients including 26 vitamins and trace minerals.
Of the included studies, some cohort studies and both RCTs used Centrum(R) as the study supplement [13,46,47], and some cohort studies reported a combination of multivitamins and multiminerals as the study supplement [8,9,11]. Other studies did not definitively indicate whether the multivitamin used in the study included minerals. These cohort studies were population-based, and the use of multivitamin/mineral supplements is common in the general population. Thus, we regarded the included studies as all using multivitamin/mineral supplements as the study supplement, and the current meta-analysis is feasible.

Results in Relation to Other Studies
Over the past two decades, many observational epidemiological studies and RCTs have reported associations between diet and cataract development . These studies largely examined populations in well-nourished areas, such as the United States, Australia, and other developed Western nations. Some large-scale cohort studies with a follow-up period of greater than 10 years revealed that a higher dietary intake of vitamin C, vitamin E, lutein/zeaxanthin, carotenoids, riboflavin, folate, niacin, and/or thiamine from food and supplements was associated with a decreased risk of cataract development [16,18,[19][20][21][22][23][24][25][26]. Some studies also demonstrated that the long-term use of vitamins C, E, B 12 , or folate supplements alone could significantly decrease the risk of cataract development [10,14,19,27].
RCTs with between 4 and 9.7 years of follow-up data did not demonstrate any beneficial effect of antioxidant vitamins on the risk of cataract development [28][29][30][31][32][33][34][35][36][37]. A recent study based on a meta-analysis of these RCTs also found no evidence that supplementation with antioxidant vitamins (β-carotene, vitamin C, or vitamin E) prevents or slows the progression of age-related cataracts [38]. Other well-designed RCTs, such as AREDS2, also showed that daily supplementation with lutein/zeaxanthin for about 4.7 years had no statistically significant overall effect on rates of cataract surgery or vision loss [51].
There is a discrepancy in the findings between cohort studies and RCTs with regards to the association between antioxidant vitamins and age-related cataracts. The short duration (<10 years) of the interventional trials may explain this discrepancy. Age-related cataracts develop over the course of many years, and antioxidant vitamins may lessen the cumulative minor damage from oxidative stress that occurs over a long period of time. Further long-term RCTs are warranted to verify this hypothesis.
However, some cohort studies and RCTs included in the current study showed that <10 years of multivitamin/mineral supplementation had a beneficial effect on decreasing the risk of age-related cataracts. The meta-analysis of these cohort studies and the results of RCTs were consistent. Potential synergistic effects of vitamin and/or mineral combinations might play a role in the prevention of age-related cataracts.
The Clinical Trial of Nutritional Supplements and Age-Related Cataract Study [46], which was included in our analysis, led to research investigating how long-term multivitamin/mineral supplementation in accordance with the US Recommended Daily Intake (RDI) affected the plasma levels of selected nutrients [52]. Participants assigned to Centrum(R) showed a significant increase in the mean/median plasma levels of vitamin E, β-carotene, vitamin B 12 , folate, and riboflavin compared with participants assigned to the placebo. This result was consistent with the finding of a recent meta-analysis of cohort studies, which revealed that blood levels of certain antioxidants were inversely associated with age-related cataracts [53].
Some RCTs investigated mixtures of oral antioxidant micronutrients, such as β-carotene, vitamin C, and vitamin E, but revealed that these main antioxidant combinations had no apparent effect on the risk of the development or progression of age-related lens opacities [32][33][34][35][36][37].
There is a lack of published studies reporting associations between minerals and cataract development. Although a few case-control studies have suggested that lens opacities were associated with lower levels of iron and selenium [54,55], neither cohort studies nor RCTs provided additional supporting evidence. The beneficial effect of minerals could not be excluded.
In our study, the potential underlying mechanism by which vitamin and mineral supplements decrease the risk of age-related cataracts is still uncertain; however, the widespread public use of commercially available pharmacological doses of multivitamin/mineral supplements for the prevention of age-related cataracts has significance for public health.

Strengths and Weaknesses of the Study
The current meta-analysis has several strengths. First, several high quality cohort studies and RCTs were included. Population-based, large-scale studies allowed us to quantitatively assess the association between multivitamin/mineral supplements and the risk of age-related cataracts. Second, the meta-analysis of observational data was consistent with the results of the RCTs. These two strengths made the conclusions more powerful than those from any individual study. Third, we systematically reviewed and assessed the summarized association between multivitamin/mineral supplements with different types of cataract, including any lens opacity, nuclear opacity, cortical opacity, posterior subcapsular opacity, and cataract surgery. These findings provided a comprehensive view of the association between multivitamin/mineral supplements and age-related cataracts based on the current evidence.
Our study has several limitations. First, only two RCTs were included. Prospective cohort studies provided the most consistent and strongest evidence regarding multivitamin/mineral supplements in the prevention of age-related cataracts. However, the RCTs showed little heterogeneity, and the results of a meta-analysis of RCTs are known to be more precise and convincing than the results of a meta-analysis of observational data [56].
Second, different cataract assessments and supplement durations were used in the included studies, and available data on the individual multivitamin/mineral supplement dosage were rather limited. Nevertheless, we used relative risks for the highest versus lowest categories of multivitamin/mineral supplement duration, which could, to some extent, reduce the bias caused by different supplement durations. Furthermore, a time-response analysis in the included studies supports our results.
Third, the designs of observational studies are problematic. Follow-up interviews in cohort studies revealed that recall biases and response errors existed in the detailed information collected from the study population, especially when self-reported diet and supplement questionnaires had been used. Although the analyses of some cohort studies included a number of potential confounding variables, such as smoking, sunlight exposure, and diabetes, the possibility of missing and unknown or unmeasured confounding variables cannot be dismissed.
Finally, with the exception of one RCT conducted in China, all studies were conducted in relatively well-nourished populations in the United States and other developed Western countries. There was a lack of studies performed in poorly nourished populations in developing areas. The results were not comprehensive and are not generalizable to other countries with undernourished populations. Moreover, possible publication bias could occur because we did not include articles not in English. The number of large cohort studies and RCTs in non-English countries or areas is limited.

Conclusions
Commonly used multivitamin/mineral supplements in this systematic review demonstrated a significantly beneficial effect in decreasing the risk of age-related cataract in well-nourished Western populations. These results seem to be clinically relevant in terms of public health, particularly given the increasing elderly population and increasing life expectancy, and are strictly concordant with current guidelines and recommendations from US Recommended Daily Intake levels of nutrients.