review article vitamin c and risk of age-related …vitamin c and risk of age-related cataracts: a...

Int J Clin Exp Med 2018;11(9):8929-8940www.ijcem.com /ISSN:1940-5901/IJCEM0067945

Review ArticleVitamin C and risk of age-related cataracts: a systematic review and meta-analysis

Fugui Liu1*, Jie Xiong5*, Jingmei Hu3*, Zhenfang Ran1, Jing Wang1, Zhanhan Li4, Maosheng Chen1, Yonggang Wang2

1Department of Operating Theatre, Chongqing Aier Eye Hospital, Chongqing, China; 2Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei Province, China; 3Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China; 4Department of Metabolism and Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; 5Dongfeng Stomatological Hospital, Hubei University of Medicine, Shiyan, Hubei, China. *Equal contributors.

Received October 25, 2017; Accepted May 24, 2018; Epub September 15, 2018; Published September 30, 2018

Abstract: We aimed to assess whether vitamin C prevents or slows progression of age-related cataracts. We identi-fied studies by searching EMBASE, PubMed, Cochrane Library and Web of Science up to April 2017. Studies were in-cluded if they assessed relationship between vitamin C and risk of age-related cataract. We evaluated the quality of case-control and cohort studies using Newcastle-Ottawa scoring system, and cross-sectional studies using Agency for Healthcare Research and Quality scoring system. Risk ratios (RRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to measure pooled data. A total of 25 studies (11 cohort studies, 6 case-control studies and 8 cross-sectional studies) were included in this meta-analysis. Overall RR of age-related cataracts comparing the highest and lowest levels of vitamin C intake was 0.8 (95% CI: 0.66 to 0.97) for cohort studies. Subgroup analysis according to types of cataracts showed that vitamin C has a protective effect on nuclear cataracts (RR: 0.51, 95% CI: 0.32 to 0.81). A similar protective effect emerged from case-control studies (OR: 0.61, 95% CI: 0.47 to 0.79). As for serum ascorbate, the pooled data of cross-sectional studies showed that higher serum ascorbate has a protective effect on age-related cataracts (OR: 0.72, 95% CI: 0.63 to 0.83). Higher vitamin C intake and serum ascorbate may bring benefits to prevent age-related cataracts, especially nuclear cataracts. For preven-tion of cataracts, it is recommend older people try to increase vitamin C intake.

Keywords: Vitamin C, age-related cataract, protective effect, systematic review, meta-analysis

Introduction

Age-related cataracts are one of the major causes of blindness in the world, affecting about 20 million people [1]. Other factors associ-ated with age-related cataracts are oxidative stress, smoking, and dietary antioxidant intake [2, 3]. However, there have been conflicting results about the effects of vitamin C intake and serum ascorbate concentration on age-related cataract formation [4-7]. Some studies have found protective effects that vitamin C brings in delaying development of age-related cata-racts [8-10], while other studies have found no clear benefits [11-15]. Therefore, we performed this study of the latest and most convincing evidence to systematically assess relationship between vitamin C and risk of age-related cataracts.

Methods

Literature search and selection criteria

This meta-analysis was conducted following the Cochrane Collaboration and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement [16, 17] (Supple- mentary Data). We identified relevant articles in Embase, PubMed, Web of Science and Coch- rane Library up through April 2017. Randomized controlled trials, cohort studies, case-control studies and cross-sectional studies that esti-mated efficacy of vitamin Cin protecting against age-related cataract were included in this study. The search strategy included the following terms “vitamin C”, “serum ascorbate” and “age-related cataract” The appendix has an example of search strategy (Table S1). We read titles and

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The relationship of vitamin C and risk of age-related cataracts

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abstracts of retrieved records, excluding some clearly irrelevant studies. Full texts of all remain-ing studies were read to decide eligible studies. We searched reference lists of identified stud-ies and reviewed articles to identify any other relevant studies (Supplementary Data).

We included studies if they satisfied the follow-ing criteria: 1) Design: randomized controlled trial, case-control studies, cohort studies and cross-sectional studies; 2) Exposure: vitamin C or serum ascorbate; 3) Outcome: incidence of age-related cataracts or incidence of age-relat-ed cataract extraction; 4) Data: relative risk (RR) or odds ratio (OR), with corresponding 95% confidence interval (CI) (comparing the highest and lowest vitamin C or serum ascorbate lev-els). There was no language limitation.

Data extraction

We extracted data from included studies and placed it into a data-extraction sheet. The fol-lowing data was collected: first author, year of publication, country of origin, sample size, mul-tivariate-adjusted (age, sex, race and baseline smoking status) RR (OR) with corresponding 95% CI, and follow up. For duplicated studies, only the most comprehensive or most recent data was included. When necessary, we con-tacted authors for data which needed clarifica-tion or was not presented in the publication.

Risk of bias and quality of evidence assess-ment

Quality of the randomized controlled trial was evaluated using Cochrane’s Collaboration tool. The quality of cohort and case-control studies was evaluated using Newcastle-Ottawa Scale (NOS) [18]. They were evaluated by examining three items: patient selection, comparability, and outcome/exposure. A study could be aw- arded a maximum of one star for each num-bered item within the selection and exposure categories and a maximum of four stars can be given for comparability of the two groups. The quality of each study was graded as either level 1 (0 to 5) or level 2 (6 to 9). We assessed the quality of cross-sectional studies using an 11-item checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [19]. If the item was answered ‘NO’ or ‘UNCLEAR’, it would be scored ‘0’; if the item was answered ‘YES’, then it was scored ‘1’. Study quality was assessed as follows: high quality = 8-11; mod-

erate quality = 4-7; and low quality = 0-3. Quality of available evidence for outcomes was evaluated based on GRADE methodology for risk of bias, inconsistency, indirectness, impre-cision, and publication bias. It was classified as very low, low, moderate or high. Summary evi-dence tables were constructed by the GRADE system [20, 21] (GRADE version 3.6).

Three authors (FL, JX and JH) independently implemented literature search, data extraction, risk of bias assessment and evidence grade assessment using the same approach. Any dis-crepancies were resolved by discussion and consensus.

Statistical analysis

We calculated summary RR (OR) for incidence of age-related cataracts and age-related cata-ract extraction using random-effects models. We performed subgroup analysis by the type of cataract (posterior subcapsular, cortical and nuclear) in instances where data was available from included studies. We assessed clinical heterogeneity across studies using Q test and I2 statistic [22] (I2>50% was considered signifi-cant heterogeneity). We assessed publication bias using Egger’s test and Begg’s test (P< 0.05 indicated statistical significance for publication bias).

Results

Trial selection and risk of bias assessment

Our initial search identified 413 articles. After removing duplicates and screening titles and abstracts, 56 articles were selected and full-text was reviewed. Finally, 1 randomized con-trolled trial [23], 11 cohort studies [4-7, 11-13, 24-27], 6 case-control studies [8, 28-32], and 8 cross-sectional studies [9, 10, 33-38] were eligible for inclusion in our study (Figure 1). The randomized controlled trial [23] was classified as low risk of bias according to Cochrane’s Col- laboration tool. Median bias risk score of cohort and case-control studies were 8 (range: 7-9), and cross-sectional studies was 6 (range: 5-7). Details of risk of bias was supplied in Figure S1 and Table S2.

Characteristics of included studies

These 26 studies involving 209,280 partici-pants, were published from 1989 to 2016. The



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randomized controlled trial [23] reported vita-min C intake and evaluated incidence of cata-ract and cataract extraction. Among 11 cohort studies [4-7, 11-13, 24-27], all reported vitamin C intake, two studies [11, 24] reported serum ascorbate, nine studies [5-7, 11, 12, 24-27] evaluated incidence of cataract and four studies [4, 13, 25, 26] evaluated incidence of cataracts extraction. Among 6 case-control studies, five studies [8, 29-32] reported vitamin C intake, two studies [28, 31] reported serum ascorbate and five studies [8, 28, 29, 31, 32] evaluated incidence of cataracts. Only one [30] evaluated incidence of cataract extraction. As for 7 cross-sectional studies, all reported serum ascorbate and evaluated incidence of cataracts. Only one [38] reported vitamin C intake. Consider- ing that there was only one randomized con-trolled trial, we did not include it in this meta-analysis. Characteristics of eligible studies are provided in Table 1.

Vitamin C intake and incidence of cataract

11 cohort studies, 5 case-control studies, and 7 cross-sectional studies evaluated the rela-

tionship between vitamin C intake and risk of cataracts. We pooled the data by random-effects meta-analysis to assess whether vitamin C intake prevents formation of age-related cat-aracts. Among cohort studies, the combined multivariate-adjusted RR of age-related cata-racts comparing the highest and lowest vitamin C intake levels was 0.8 (95% CI: 0.66 to 0.97), with significant heterogeneity (I2 = 74.1%, P≤0.001). A similar result emerged from case-control studies (OR: 0.61, 95% CI: 0.47 to 0.79; I2 = 45.4%, P = 0.12). No such protective effect was found in cross-sectional studies (OR: 0.60, 95% CI: 0.31 to 1.13; I2 = 73.8%, P = 0.051) (Figure 2A).

We then performed subgroup analysis based on types of cataracts and whether cataract surgery was performed. Among cohort studies, seven studies reported data of any type of cata-ract, four studies reported data of nuclear cata-racts and cortical cataracts, and two studies reported posterior subcapsular cataracts. Nine studies reported incidence of cataracts and four studies reported the incidence of cata-racts extraction. Subgroup analysis, according

Figure 1. The flow diagram of literature selection process.


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Table 1. Characteristics of all included studies (N = 26)

Author/year Study type Country Sample size

Disease subtypes:Adjusted RR (OR) (95% CI)

Incidence of cataract/ extirpation

Vitame C intake/serum ascorbate

Quality score

Christen et al (2010) [23] RCT America 11545 HR:Any type cataract: 1.02 (0.91, 1.14)Nuclear: 1.01 (0.89, 1.14)Cortical: 1.10 (0.92, 1.31)PSC: 0.94 (0.76, 1.17)Anytype cataract: 0.97 (0.85, 1.12)Nuclear: 0.98 (0.85, 1.13)Cortical: 1.16 (0.94, 1.45)PSC: 0.96 (0.75, 1.21)

Incidence of cataract

Incidence of Cataract extraction

Vitamin C intake Low risk of bias

Chasan et al (1999) [4] Cohort America 73956 RR:Any type cataract: 0.95 (0.76, 1.20)

Incidence of Cataract extraction Vitamin C intake 8

Lyle et al (1999) [5] Cohort America 1354 RR: Nuclear: 0.9 (0.5, 1.5) Incidence of cataract Vitamin C intake 9Jacques et al (2001) [24] Cohort America 603 RR: Nuclear: 0.31 (0.16, 0.58)

Nuclear: 0.54 (0.28, 1.02)Incidence of cataract Vitamin C intake

serum ascorbate8

Taylor et al (2002) [11] Cohort America 548 RR: Cortical: 0.89 (0.55, 1.45)PSC: 0.64 (0.29, 1.42)Cortical: 1.47 (0.86, 2.52)PSC: 0.74 (0.32, 1.68)

Incidence of cataract Vitamin C intake

Serum ascorbate

8

Rodrigues et al (2006) [6] Cohort Spain 177 RR: Any type cataract: 0.08 (0.01, 0.75)

Incidence of cataract Vitamin C intake 8

Yoshida et al (2007) [25] Cohort Japan 35186 RR:Any type cataract: 0.65 (0.42, 0.97)0.59 (0.43, 0.89)Any type cataract: 0.7 (0.44, 1.2)0.64 (0.41, 0.94)



Vitamin C intake 8

Christen et al (2008) [12] Cohort America 35551 RR:Any type cataract: 0.94 (0.81, 1.09)


Tan et al (2008) [26] Cohort Australia 2464 RR: Nuclear: 0.55 (0.36, 0.86)Cortical: 0.94 (0.63, 1.4)PSC: 1.15 (0.6, 2.23)Any type cataract: 1.16 (0.76, 1.78)



Vitamin C intake 8

Rautiainen et al (2010) [13] Cohort Sweden 24593 RR:Any type cataract: 1.25 (1.05, 1.50)


Zheng et al (2013) [27] Cohort Sweden 2963 RR: Any type cataract: 1.36 (1.02, 1.81)


Yonvoa et al (2016) [7] Cohort United Kingdom 324 RR: Nuclear: 0.34 (0.09, 0.53) Incidence of cataract Vitamin C intake 8Mohan et al (1989) [28] Case-control India 1990 OR:

Mixed typecataract: 1.87 (1.29, 2.69)Incidence of cataract Serum ascorbate 7

Robertson et al (1991) [8] Case-control Canada 350 OR:Any type cataract: 0.3 (0.12, 0.75)



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Leske et al (1991) [29] Case-control America 1380 OR: Nuclear: 0.48 (0.24, 0.99)Cortical: 0.8 (0.5, 1.29)PSC: 0.73 (0.31, 1.73)Any type cataract: 0.72 (0.46, 1.22)


Tavani et al (1996) [30] Case-control Italy 913 OR:Any type cataract: 0.8 (0.4, 1.3)


Valero et al (2002) [31] Case-control Spian 677 OR: Nuclear: 0.56 (0.38, 0.82)Cortical: 0.92 (0.6, 1.4)PSC: 0.75 (0.51, 1.05)Any type cataract: 0.7 (0.44, 1.13)Nuclear: 0.32 (0.21, 0.51)Cortical: 0.38 (0.23, 0.64)PSC: 0.36 (0.23, 0.57)Any type cataract: 0.3 (0.18, 0.51)

Incidence of cataract Vitamin C intake

Serum ascorbate

9

Theodoropoulou et al (2014) [32] Case-control Greece 628 OR: Nuclear: 0.55 (0.41, 0.72)Cortical: 0.62 (0.37, 1.04)PSC: 0.3 (0.19, 0.49)Any type cataract : 0.5 (0.39, 0.64)


Vitale et al (1993) [33] Cross-sectional America 660 OR: Nuclear: 1.31 (0.65, 2.6)Cortical: 1.01 (0.45, 2.26)

Incidence of cataract Serum ascorbate 6

Wong et al (1993) [34] Cross-sectional China 685 OR: Any type cataract: 0.8 (0.2, 3.2) Incidence of cataract Serum ascorbate 7Simon et al (1999) [9] Cross-sectional America 4001 OR:

Any type cataract: 0.74 (0.56, 0.97)Incidence of cataract Serum ascorbate 6

Gale et al (2001) [35] Cross-sectional United Kingdom 372 OR: Nuclear: 1.0 (0.5, 1.9)Cortical: 1.1 (0.6, 2.2)PSC: (0.9, 0.4, 2.1)


Ferrigno et al (2005) [36] Cross-sectional America 1020 OR: Nuclear: 0.54 (0.3, 0.97)Cortical: 0.7 (0.37, 1.31)PSC: 0.43 (0.17, 1.07)Any type cataract: 0.7 (0.42, 1.15)


Dherani et al (2008) [10] Cross-sectional India 1112 OR: Nuclear: 0.62 (0.4, 0.96)Cortical: 0.62 (0.4, 0.97)PSC: 0.59 (0.35, 0.99)Any type cataract: 0.64 (0.48, 0.85)


Ravindran et al (2011) [37] Cross-sectional India 5638 OR:Any type cataract: 0.78 (0.62, 0.98)Nuclear: 0.66 (0.54, 0.80)Cortical: 0.70 (0.54, 0.90)PSC: 0.58 (0.45, 0.74)Any type cataract: 0.61 (0.51, 0.74)

Incidence of cataract Vitamin C intakeSerum ascorbate

6

Pastor et al (2013) [38] Cross-sectional Spain 599 OR:Any type cataract: 0.4 (0.21, 0.74)Any type cataract: 0.97 (0.51, 1.84)

Incidence of cataract Vitamin C intakeSerum ascorbate

7

RCT: randomized controlled trials; PSC: posterior subcapsular cataract; HR: hazard ratio; RR: risk ratio; OR: odds ratios.


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Figure 2. A. Forest plot of relationship between vitamin C intake and risk of cataracts (comparing the highest and lowest vitamin C intake levels). B. Subgroup analysis according to types of cata-racts among cohort studies. C. Subgroup analysis according to whether cataract surgery among cohort studies. D. Subgroup analysis according to types of cataracts among case-control studies. E. Subgroup analysis according to whether cataracts surgery among case-control studies. F. Forest plot of relationship between serum ascorbate and risk of cataract, comparing high-est and the lowest serum ascorbate levels. G. Subgroup analysis according to types of cataracts among cross-sectional studies.


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to types of cataracts showed that higher vita-min C intake has protective effects on nuclear cataracts (RR: 0.51, 95% CI: 0.32 to 0.81; I2 = 58.5%, P = 0.065) (Figure 2B). Subgroup analysis, based on whether cataract surgery was performed that higher vitamin C intake has pro-tective effects on incidence of cataracts (RR: 0.74, 95% CI: 0.59 to 0.92; I2 = 70.8%, P≤0.001). There was no evidence of the effect of higher vitamin C intake reducing risk of cataract extraction (RR: 0.95, 95% CI: 0.74 to 1.22; I2 = 68.2%, P = 0.013) (Figure 2C). We also conducted sensitivity analysis to find sources of het-erogeneity. Results showed that heterogeneity was greatly influenced by two studies [13, 27] (Figure S2). After removing these two studies, we pooled the results by random-effects meta-analysis and found that heterogeneity between studies has significantly decreased (I2 = 61.8%, P = 0.002), and pooled results had little differ-ence with the former (RR: 0.72, 95% CI: 0.60 to 0.88) (Figure S3). Among case-control studies, five studies reported data of any type of cata-ract, and three studies reported data of nuclear cataracts, cortical cataracts and posterior sub-capsular cataracts. Only one study reported the mixed type cataract. Four studies reported inci-dence of cataracts and one study reported inci-dence of cataract extraction. Subgroup analy-sis based on types of cataracts showed that higher vitamin C intake has protective effects on any type cataracts (OR: 0.61, 95% CI: 0.47 to 0.79; I2 = 45.4%, P = 0.12) and nuclear cata-racts (OR: 0.55, 95% CI: 0.44 to 0.68; I2 = 0%, P = 0.929) (Figure 2D). Subgroup analysis, based on whether cataract surgery was performed, showed that higher vitamin C intake has protective effects on incidence of cataracts (OR: 0.58, 95% CI: 0.44 to 0.78; I2 = 52.7%, P = 0.096) (Figure 2E). Considering the limited number of cross-sectional studies, we did not perform subgroup analysis for them.

Serum ascorbate and incidence of cataracts

Two cohort studies, two case-control studies, and 8 cross-sectional studies evaluated rela-tionship between serum ascorbate and risk of cataracts. We pooled data by random-effects meta-analysis to assess whether higher serum ascorbate prevents the formation of age-relat-ed cataracts. Pooled results of cross-sectional studies showed that higher serum ascorbate has a protective effect on age-related cataracts (OR: 0.72, 95% CI: 0.63 to 0.83, I2 = 8.1%, P

= 0.367). We did not find this protective effect in cohort studies (RR: 0.86, 95% CI: 0.45 to 1.65, I2 = 65.5%, P = 0.055) or case-control studies (OR: 0.76, 95% CI: 0.13 to 4.54, I2 = 96.8%, P≤0.001) (Figure 2F).

Considering the limited number of cohort and case-sectional studies which reporting serum ascorbate, we performed subgroup analysis according to the type of cataract among cross-sectional studies. Subgroup analysis showed that higher serum ascorbate has a protective effect on all types of cataracts (Figure 2G).

Publication bias and strength of evidence

For vitamin C intake and risk of cataract, signifi-cant publication bias was found among cohort studies (Begg’s, P = 0.092; Egger’s, P = 0.011). We then performed nonparametric trim and fill method and found no more missed trials. Results of the cohort studies were stable and reliable (Figure S4). For the serum ascorbate and risk of cataracts, significant publication bias was found among cross-sectional studies (Begg’s, P = 0.213; Egger’s, P = 0.002) and nonparametric trim and fill method found six more studies. After adding six studies, we found that there was no significant difference between results and the former (Figure S5). Consi- dering the limited number of case-control stud-ies in this study, we did not perform publication bias for these studies. We believed that publi-cation bias was unavoidable. We evaluated the quality of evidences by GRADE system [39] (GRADE version 3.6). Quality of evidence con-cerning vitamin C intake and risk of cataracts was at level B and moderate recommendation for cohort and case-control studies. Level of evidence concerning vitamin C intake and risk of cataracts was at level C and low recommen-dation for cross-sectional studies. The level of evidence concerning serum ascorbate and risk of cataract was at level C and low recommen-dation for cohort and cross-sectional studies. It was, at level D and very low recommendation for case-control studies. Details of evidence are provided in Table 2.

Discussion

Main findings

This meta-analysis systematically reviewed cur-rent available literature and found that 1) High-


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Table 2. GRADE evidence profile of Vitamin C and age-related cataract riskQuality assessment

Relative (95% CI) Quality ImportanceNo of studies Design Risk of bias Inconsistency Indirectness Imprecision Other considerations Vitamin C intake (follow-up 0.5-15 years; assessed with: questionnaire) 111 Observational

studiesNo serious risk of bias

Serious No serious indirectness

No serious imprecision

Reporting bias very strong association increased effect for or ~1

OR 0.8 (0.66 to 0.97) Moderate Critical

Vitamin C intake (assessed with: questionnaire) 52 Observational

studiesSerious No serious

inconsistencyNo serious indirectness



OR 0.61 (0.47 to 0.79) Moderate Critical

23 Observational studies

Serious Serious No serious indirectness



OR 0.6 (0.31 to 1.13) Low Critical

Serum ascorbate (follow-up 13-15 years; assessed with: blood test) 21 Observational


Serious No serious indirectness


Reporting bias strong association increased effect for or ~1


Serum ascorbate (assessed with: blood test) 22 Observational


Very serious No serious indirectness


Reporting bias strong association increased effect for rr ~1

OR 0.76 (0.13 to 4.54) Very low Critical

83 Observational studies

Serious No serious inconsistency

No serious indirectness


Reporting bias strong association increased effect for rr ~1



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er vitamin C intake and serum ascorbate may bring benefits to prevent age-related cataracts. This may be because there is a significant con-centration of ascorbate in the aqueous humor, and it bathes the lens and reduces oxidation products in the lens, thus reduces oxidative stress [40, 41]. There is no evidence of a pre-vention effect for higher vitamin C intake on progression of age-related cataracts (cataract extraction). 2) Subgroup analysis found an obvi-ous prevention effect of higher vitamin C intake for nuclear cataracts. 3) Results of prevention effect of higher vitamin C for cataracts were stable and reliable by subgroup analysis, sensi-tivity analysis, and nonparametric trim and fill method. There was, however, heterogeneity between studies.

Comparison with previous studies

In our study, we found that higher vitamin C intake and serum ascorbate may bring benefits to prevent age-related cataracts. This is consistent with a previous meta-analysis [14], but the differences should be noted. First, compar- ed with previous meta-analysis, we included 7 more studies [4, 7, 28, 32, 34, 35, 38] and ana-lyzed the effect of higher vitamin C intake for progression of age-related cataracts (cataract extraction), getting a more stable result. Seco- nd, we believe that data from different types of researches are not suitable for combination [16]. Thus we pooled data based on types of research and got more reliable results. There are many studies and large samples included in this meta-analysis. We believe the conclu-sion of our study is more reasonable, yet it is not consistent with the randomized controlled trial [23]. In addition, we evaluated the quality of evidences and strength of recommenda-tions. Therefore, our study is the latest and most comprehensive meta-analysis.

Guidance for clinical practice

The quality of evidence of prevention effects of vitamin C intake on age-related cataracts was at level B and moderate recommendation. This result prove that our study stable and reliable by subgroup analysis, sensitivity analysis, and nonparametric trim and fill method. Thus, we recommend that older people increase vitamin C intake for cataract prevention. Given that the evidence of this study is from observational

studies, future randomized controlled trials are needed to validate this effect.

Limitations

This study also has some limitations. 1) There was only one randomized controlled trial, thus, we did not include it in the meta-analysis. Evidence of this study was from observational studies, possibly affecting the quality of evi-dence to some extent. 2) This study was limited by a lack of access to enough data enable dose-effect analysis. Therefore, we can’t clarify the proper dose of vitamin C intake necessary to prevent cataracts.

In conclusion, our study suggests that higher vitamin C intake and serum ascorbate may bring benefits preventing age-related cataracts, especially for nuclear cataracts. Future randomized controlled trials are needed to validate this effect.

Acknowledgements

This study was supported by the Science Re- search Foundation of Aier Eye Hospital Group (AM142D17). The funding source of the study was not part of the design of study, collection of information, analysis of data, nor prepara-tion of this manuscript.

Disclosure of conflict of interest

None.

Address correspondence to: Yonggang Wang, Affili- ated Dongfeng Hospital, Hubei University of Medi- cine, No. 16, Daling Road, Shiyan 442000, Hubei Province, China. Tel: +86 18323463223; E-mail: [email protected]; Maosheng Chen, De- partment of Operating Theatre, Chongqing Aier Eye Hospital, No. 11, New South Road, Guanyin Qiao, Jiangbei District, Chongqing 400020, China. Tel: +86 13527361781; E-mail: [email protected]

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Table S1. The retrieval strategy In the pubmed databaseSearch Query Items found#10 Search (((((((((((age-related cataract [Title/Abstract]) OR Age-related cataracts [Title/Abstract]) OR age related cataract

[Title/Abstract]) OR age related cataracts [Title/Abstract]) OR ge-relted ctrct [Title/Abstract]) OR ge-relted ctrcts [Title/Abstract]) OR senile cataract [Title/Abstract]) OR senile cataracts [Title/Abstract])) OR (“Cataract, posterior polar, 1” [Supplementary Concept] OR “Cataract, Age-Related Cortical, 1” [Supplementary Concept] OR “Cataract, Age-Related Nuclear” [Supplementary Concept]))) AND ((“Ascorbic Acid” [Mesh]) OR (((Serum ascorbate [Title/Abstract]) OR Ascorbic Acid [Title/Abstract]) OR vitamin C [Title/Abstract]))

70

#9 Search (((((((((age-related cataract [Title/Abstract]) OR Age-related cataracts [Title/Abstract]) OR age related cataract [Title/Abstract]) OR age related cataracts [Title/Abstract]) OR ge-relted ctrct [Title/Abstract]) OR ge-relted ctrcts [Title/Abstract]) OR senile cataract [Title/Abstract]) OR senile cataracts [Title/Abstract])) OR (“Cataract, posterior polar, 1” [Supplementary Concept] OR “Cataract, Age-Related Cortical, 1” [Supplementary Concept] OR “Cataract, Age-Related Nuclear” [Supplementary Concept])

2474

#8 Search (“Ascorbic Acid” [Mesh]) OR (((Serum ascorbate [Title/Abstract]) OR Ascorbic Acid [Title/Abstract]) OR vitamin C [Title/Abstract])

57197

#7 Search (((((((age-related cataract [Title/Abstract]) OR Age-related cataracts [Title/Abstract]) OR age related cataract [Title/Abstract]) OR age related cataracts [Title/Abstract]) OR ge-relted ctrct [Title/Abstract]) OR ge-relted ctrcts [Title/Abstract]) OR senile cataract [Title/Abstract]) OR senile cataracts [Title/Abstract]

2469

#6 Search “Cataract, posterior polar, 1” [Supplementary Concept] OR “Cataract, Age-Related Cortical, 1” [Supplementary Concept] OR “Cataract, Age-Related Nuclear” [Supplementary Concept]

7

#3 Search ((Serum ascorbate [Title/Abstract]) OR Ascorbic Acid [Title/Abstract]) OR vitamin C [Title/Abstract] 44402

#2 Search “Ascorbic Acid” [Mesh] 39347

Figure S1. The risk of bias assessment of the randomized controlled trial: each risk of bias item (Green means low risk of bias, Yellow means unclear risk of bias, Red means high risk of bias).


2

Table S2.1. The quality of cohort studies according to Newcas-tle-Ottawa Scale (NOS)Study Selection Comparability Outcome Chasan et al 1999 [4] ★★★ ★★ ★★★

Lyle et al 1999 [5] ★★★★ ★★ ★★★

Jacques et al 2001 [24] ★★★ ★★ ★★★

Taylor et al 2002 [11] ★★★ ★★ ★★★

Rodríguez et al 2006 [6] ★★★★ ★ ★★★

Yoshida et al 2007 [25] ★★★★ ★ ★★★

Christen et al 2008 [12] ★★★★ ★ ★★★

Tan et al 2008 [26] ★★★★ ★ ★★★

Rautiainen et al 2010 [13] ★★★ ★ ★★★

Zheng et al 2013 [27] ★★★ ★ ★★★

Yonova et al 2016 [7] ★★★ ★★ ★★★

Table S2.2. The quality of case-control studies according to Newcastle-Ottawa Scale (NOS)Study Selection Comparability Exposure Mohan et al 1989 [28] ★★★ ★ ★★★

Robertson et al 1991 [8] ★★★ ★★ ★★★

Leske et al 1991 [29] ★★★ ★★ ★★★

Tavani et al 1996 [30] ★★★ ★★ ★★★

Valero et al 2002 [31] ★★★★ ★★ ★★★

Theodoropoulou et al 2014 [32] ★★★ ★★ ★★★

Table S2.3. The quality of cross-sectional studies according to Agency for Healthcare Research and Quality (AHRQ)Study Score Vitale et al 1993 [33] 6 Wong et al 1993 [34] 7 Simon et al 1999 [9] 6 Gale et al 2001 [35] 5 Ferrigno et al 2005 [36] 6 Dherani et al 2008 [10] 6 Ravindran et al 2011 [37] 6 Pastor et al 2013 [38] 7


3

Figure S2. Sensitivity analyses of the relationship between vitamin C intake and risk of cataract among cohort stud-ies.

Figure S3. Forest plot of the relationship between vitamin C intake and risk of cataract among cohort studies (after removing Rautiainen et al and Zheng et al).


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Figure S4. The nonparametric trim and fill method of the relationship between vitamin C intake and risk of cataract among cohort studies.

Figure S5. The nonparametric trim and fill method of the relationship between serum ascorbate and risk of cataract among cross-sectional studies.

review article vitamin c and risk of age-related …vitamin c and risk of age-related cataracts: a...

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