Cataract and age-related macular degeneration (AMD) are leading causes of impaired vision and blindness worldwide,1 often coexisting in elderly patients older than 65 years. Although cataract surgery improves visual acuity (VA) and quality of life (QoL) of patients with AMD,2–5 it remains uncertain whether it affects the risk of AMD development or progression.6–9 Indeed, a recent systematic review (2014) found the current state of evidence inconclusive and encouraged better-designed prospective studies to move toward a more definitive answer on the topic.7 For example, a large population-based study in 2454 Australians who returned for follow-up at 10 years found a 3-fold higher risk of developing late AMD in nonphakic compared with phakic eyes.10 Similar findings in other population-based studies have also been reported.11–14 However, more recent, clinic-based epidemiological studies15,16 have in contrast, not reported an association between cataract surgery and progression to late AMD.7
Another major limitation of current evidence is that existing findings were derived predominantly from white cohorts, which may not be generalizable to Asians, as there are known differences in AMD phenotypes between white and Asian patients.17 That said, only few Asian cross-sectional studies have explored this topic, with inconsistent findings.18–20
Without a clear answer to this question, recent guidelines for recommending cataract surgery to older patients with visual impairment are complicated by possible risks of AMD development.3,21,22 Evidently, more information on longitudinal population-based studies in diverse populations is needed to address this clinical knowledge gap. Against this background, we determined associations between cataract surgery and AMD incidence in a well-characterized multiethnic Asian cohort, followed for an average of 6 years. Based on previous population-based studies in whites, we hypothesized that cataract surgery may be associated with a higher risk of incident AMD, and particularly its late stage.
The Singapore Malay Eye Study (SiMES-1 and -2) and Singapore Indian Eye Study (SINDI-1 and 2) are population-based cohort studies of Malay and Indian adults aged 40–80 years living in Singapore, with baseline examinations conducted between 2004 and 2006, and 2007 and 2009, and follow-up examinations between 2011 and 2013, and 2013 and 2015, respectively. Details of study design and methodology have been described elsewhere.23,24 Briefly, a 10-year age-stratified random sampling in each ethnic group was used to select 4168 Malays and 4497 Indians aged 40 years and older. Response rates of 78.7% and 75.6% led to 3280 Malays and 3400 Indians participating in the study, respectively. After excluding 644 Malay and 486 Indian individuals owing to residential address change, terminal illness or death, 1901 of 2636 (72.1%) eligible Malay individuals and 2200 of 2914 (75.5%) eligible Indian persons attended the follow-up visits. The current study included a total of 3475 participants with no late AMD in at least 1 eye at baseline who returned for the follow-up visit and had complete data including gradable fundus photographs. In addition to showing more early signs of AMD, eligible individuals who were lost to follow-up were significantly older, had poorer socioeconomic status, and were systemically less healthy than controls (Supplementary Table 1).
The study was approved by the SingHealth Institutional Review Board and all study procedures followed the principles of the Declaration of Helsinki. Both baseline and follow-up study procedures were conducted at the Singapore Eye Research Institute (SERI), and all participants gave written informed consent.
Assessment of AMD
Fundus photography was performed using a digital retinal camera (Canon CR-DGi with digital 10D SLR camera backing; Canon, Tokyo, Japan) after pupil dilation. Two-field color photographs were taken for each eye—one centered on the optic disc and the other on the fovea—according to the Early Treatment for Diabetic Retinopathy Study guidelines. Of the 6680 participants from SiMES and SINDI, 6489 (97.1%) had fundus photographs gradable for AMD signs. Participants’ AMD presence and severity was graded at the University of Sydney, Westmead Institute for Medical Research following the modified Wisconsin Age-Related Maculopathy Grading System.25 Early AMD was defined as the presence of either soft indistinct drusen, reticular drusen, or the co-presence of soft, distinct drusen, and retinal epithelium pigmentation abnormalities. Late AMD was defined as the presence of exudative macular degeneration or geographic atrophy or both. Three outcomes were defined for this analysis: incident any AMD, incident early AMD, and incident late AMD.
VA and Ocular Biometry
All participants underwent standardized eye examinations at both baseline and follow-up visits. VA was measured uniocularly using a logarithm of the minimum angle of resolution (LogMAR) number chart (Lighthouse International, New York, USA) at 4 meters.24 Presenting VA was measured with participants wearing their habitual prescription, whereas best-corrected VA was measured with the best possible correction derived from subjective refraction performed by trained optometrists. Axial length was measured in the horizontal and vertical meridian using a noncontact partial coherence laser interferometry machine (IOLMaster version 3.01; Carl Zeiss Meditec AG, Jena, Germany).
Clinical assessment of cataract was performed by study ophthalmologists after pupil dilation under slit lamp examination, and graded following the Lens Opacities Classification System 3 (LOCSIII).26 Cataract surgery was identified as the presence of an intraocular lens implant (pseudophakia) or the absence of the natural crystalline lens (aphakia). The presence of cataract surgery at the baseline assessment indicated that a participant had cataract surgery before enrolment, whereas presence of cataract surgery only at the follow-up assessment indicated that a participant had surgery sometime between the baseline and follow-up visits.
Ocular Comorbidities Assessment
Diabetic retinopathy was graded from retinal photographs using the modified Airlie House Classification System from the Early Treatment for Diabetic Retinopathy Study.27 Glaucoma was diagnosed and classified following the International Society of Geographic and Epidemiologic Ophthalmology Scheme.28
Assessment of Other Covariables
Trained interviewers administered standardized questionnaires to collect data on participants’ sociodemographic characteristics and medical history in English, Malay, or Tamil according to participant preference. Low socioeconomic status was defined as primary and below education, and a monthly income of <SGD2000. Systolic and diastolic blood pressures were measured twice using a digital automatic blood pressure monitor (Dinamap Pro Series DP110X-RW; GE Medical Systems Information Technologies, Inc.). If the difference between each pair of readings was >10 mm Hg and 5 mm Hg, respectively, a third measurement was obtained. The final reading was calculated as the average of the 2 closest readings. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, antihypertensive use, or self-reported history of hypertension. Height was measured using a wall-mounted, adjustable measuring scale, and weight using a calibrated scientific weighing scale. Nonfasting blood samples were collected for assessments of hemoglobin A1C, random glucose, and total, high-density lipoprotein, low-density lipoprotein cholesterol, and triglyceride. Diabetes was defined as random glucose ≥11.1 mmol/L, hemoglobin A1C ≥6.5%, diabetic medication use, or self-reported history of diabetes. Hyperlipidemia was defined as total cholesterol ≥6.2 mmol/L or lipid-lowering medication use. Cardiovascular disease was defined as self-reported history of angina, myocardial infarction, or stroke.
Baseline characteristics of participants were summarized by mean and standard deviation for continuous variables and by counts and percentages for categorical variables. We used a z test with nonparametric standard errors that are robust to intereye correlation when comparing characteristics between eyes with and without AMD. Our primary analysis examined the effect of having any cataract surgery on incident AMD. Modified Poisson regression analysis with generalized estimating equations was performed to determine the associations of cataract surgery with incidence of AMD, adjusting for variables that were clinically important or statistically significant in univariable analyses. We explored the sensitivity of our conclusions to the timing of cataract surgery by repeating the multivariable model analyses after including only eyes that received cataract surgery recorded at baseline and during follow-up. The reference group of comparison consisted of eyes that were phakic from baseline through follow-up. Lastly, we determined whether existing cataract in patients was associated with higher incidence of AMD compared with eyes that were free of cataract at baseline. Eyes that received surgery during follow-up were excluded to ensure that any outcome differences observed were not driven by surgery in eyes with cataract during follow-up. We reported risk ratios with 95% confidence intervals and judged a P value <0.05 as statistically significant. All analyses were performed using the statistical software, Stata 15.0 (StataCorp LP, College Station, TX).
Of the 6680 individuals who participated in SiMES-1 and SINDI-1, 6466 (96.8%) had no or early AMD in at least 1 eye, and data on cataract surgery assessment at baseline. Of these, 4006 (62.0%) attended the follow-up assessment (SiMES-2 and SINDI-2) and a further 3915 (97.7%) had gradable fundus photographs. After excluding 440 (11.2%) individuals with incomplete covariate data, 3475 participants were included in the final analyses (Fig. 1).
The mean age (SD) of the 3475 participants was 55.5 (9.1) years and 1673 (48.1%) were male. These participants contributed a total of 6790 eyes. A total of 238 (3.6%) of 6599 eyes with no AMD at baseline developed incident any AMD, of which 222 (3.4%) were early cases and 16 (0.2%) were late cases. Among 191 eyes with early AMD at baseline, 13 (6.8%) developed late AMD at follow-up. In total, 29 (0.4%) eyes developed incident late AMD; the mean baseline presenting VA was 6/9.5 (0.2 LogMAR) with an average age of 62.5 years; 37.9% underwent cataract surgery. Among eyes that received cataract surgery, <1% of eyes (0.8%, 6/715) with no AMD at baseline developed late AMD, whereas nearly 9% of eyes (9.1%, 5/55) with early AMD at baseline developed late AMD.
Several baseline eye-level characteristics differed between those who developed incident any AMD versus those who did not (Table 1). Eyes with incident AMD had on average a shorter axial length and poorer presenting VA compared with eyes without incident AMD. Participants who developed incident AMD were on average, older, had more systemic comorbidities, including diabetes, hypertension, and cardiovascular disease, and were more likely to be using lipid-lowering medication. A significantly higher proportion of eyes that developed incident late AMD had signs of early AMD [drusen and retinal pigment epithelium (RPE) abnormalities] at baseline in the study eye, and such signs in the fellow eye, compared with eyes that did not develop incident late AMD (Table 2).
A total of 770 of 6790 (11.3%) eyes received cataract surgery, amongst which 325 (42.2%) eyes had surgery before baseline compared with 445 (57.8%) eyes that had surgery during follow-up. Most operated eyes were pseudophakic (99.7%).
After adjusting for age, sex, and ethnicity, presenting VA, early AMD signs in the study eye, and such signs in the fellow eye, any cataract surgery was associated with a 3.5 times higher incidence risk of late AMD [risk ratio (RR): 3.47, 95% confidence interval (CI) 1.40–8.57] (Table 3). The absolute risk of incident late AMD in relation to any cataract surgery was marginal and estimated to be 0.3 (95% CI 0.0 to 0.6) % higher in eyes without, and 1.8 (95% CI −0.3 to 3.9) % higher in eyes with early AMD signs at baseline. Neither the multivariable-adjusted association between any cataract surgery and incident early AMD or any AMD reached statistical significance. In subgroup analyses, surgery recorded at baseline (RR: 4.09, 95% CI 1.18–14.15) and occurring during follow-up (RR: 3.36, 95% CI 1.12–10.08) were both associated with a higher incidence of late AMD. The presence of cataract at baseline was not associated with any of the 3 incident outcomes (Table 4).
In this population-based cohort study of Asian Malay and Indian participants, cataract surgery was associated with a 3.5 times higher incidence risk of late AMD. This association persisted in analyses of the separate effects of cataract surgery that occurred before study enrolment and during the follow-up period until the second visit. Our findings seem to agree with several population-based studies but not clinic-based studies on this topic. Population-based cohort studies with a larger number of individuals with incident late AMD and more regular follow-up checks are needed to confirm our findings. Considering the unequivocal benefits of cataract extraction to vision and QoL improvement, the marginal risk of late AMD in operated eyes may be too small to be of concern clinically, particularly in those not exhibiting any initial signs of AMD. Patients with signs of early AMD, however, should continue to be monitored post-surgery to preempt the progression of AMD to its late stages.
Our finding that incident late AMD was >3 times more likely in those who had cataract surgery compared with those who did not, is similar to other population-based cohort studies with an average follow-up of at least 5 years. For example, in the Blue Mountains Eye Study,10 nonphakic eyes were 3.3 times more likely to develop incident late AMD after 10 years compared with phakic eyes. A number of prominent clinic-based studies, such as the Age-Related Eye Diseases Study (AREDS),15,29 and the Australian Cataract Surgery and AMD Study,16 in contrast, found no association between cataract surgery and incidence of late AMD after 11 and 4 to 5 years of follow-up, respectively.
Qian and Young7 reported in their systematic review that studies with positive findings tended to be population-based,10,12–14 whereas those with negative findings tended to be clinic-based.15,16 Particular differences between study participants may help explain the disparity in results. First, participants in population-based and clinic-based cohorts differ in their ocular health status. For instance, although >40% of the AREDS cohort was at high risk of late AMD at baseline,15 only 20% of our cohort showed early signs of macular pathology. Second, the AREDS cohort was also substantially older (mean age: 68 years) than our cohort (mean age: 56 years), and may be more representative of the demographics of patients recommended for cataract surgery in the clinic, rather than that of the population.
As cataract and AMD share common risk factors, these risk factors or indeed cataract presence itself arguably underlie the associations observed between cataract surgery and AMD. However, a secondary analysis of phakic eyes found that existing cataract was not associated with any of the 3 incident outcomes, suggesting that the associations found were not likely cataract driven in our study. Although retinal photographic grading would have at least identified late stage lesions in our study, early and subtle signs of AMD may have been masked by the presence of severe cataract and identified only after cataract extraction before the follow-up visit, leading to confounding that is not duly accounted for. As a sensitivity analysis, we excluded eyes with nuclear opalescence or posterior subcapsular cataract of grade 4 and above on LOCSIII and still found an OR of a similar magnitude and significance relating cataract surgery to incident late AMD [3.76 (95% CI 1.21–11.71), P = 0.022].
Two mechanisms have been suggested as to how cataract surgery may influence the pathogenesis of AMD. As ultraviolet and visible radiation is known to damage the retinal pigment epithelium in animal models, replacing the eye's natural lens may predispose the retina to damage from shorter light wavelengths.30–33 Inflammation induced by surgery, particularly by extracapsular extraction, can also mediate AMD disease development or progression.34,35
A key strength of our study is its prospective design and large, comprehensively-characterized multiethnic Asian population. Assessment of ophthalmic conditions followed standardized and established protocols. Finally, our sample of 3426 individuals and 6790 eyes included a substantial number of incident cases of any AMD (238 eyes) and early AMD (222 eyes) which allowed adjustment for observed differences in sociodemographic, systemic, and ocular characteristics when examining these 2 outcomes.
Our study has however several limitations, the first among which was a small number of incident late AMD cases. Although the number of covariates that could be adjusted for in the regression models was limited, we were able to include critical and all potentially confounding variables which showed significant differences by late AMD incidence (Table 2), that is, the clinical signs of early AMD (drusen and RPE abnormalities) in study eye, and such signs in the fellow eye, in addition to the basic sociodemographics and presenting VA at baseline.
A second limitation is a lack of information on the exact latency period between surgery and incident AMD. Of particular concern is whether incident AMD could have developed before cataract surgery during follow-up. Patients who develop impaired vision as a result of late AMD may undergo cataract surgery if a coexisting cataract was detected. However, larger associations between surgery that was recorded at baseline and incident late AMD suggested the above scenario could not entirely explain our findings, and that longer average duration since cataract surgery may be further associated with AMD advancement.
A third important limitation is that our study comprises a relatively young cohort (mean age under 60 years), with consequently few cases of operated eyes that developed incident late AMD. A paired-eye analysis, arguably more robust to confounding, was not admissible due to an inadequate number of discordant cases in unilaterally pseudophakic eyes. Last, selection or survival bias may be present due to lost to follow-up, and exclusion of eligible individuals with ungradable retinal photographs.
In summary, in our Asian population of Singaporean Malays and Indians, we found that cataract surgery was associated with late-stage AMD incidence, consistent with the findings of other large population-based cohort studies but disagreeing with those of clinic-based studies of white cohorts. However, given the small absolute risk of late AMD in eyes that undergo cataract surgery, we are of the view that cataract surgery should continue to be recommended for elderly patients, balancing its risks and benefits. Monitoring of patients with early AMD signs for progression to late AMD after cataract surgery should continue, as is currently practised.
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