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Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study
Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study Nathalie Auger, Tina Tang, Jessica Healy-Profit´os, Gilles Paradis PII: DOI: Reference:
S1056-8727(17)30231-3 doi: 10.1016/j.jdiacomp.2017.08.003 JDC 7079
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
17 February 2017 9 May 2017 4 August 2017
Please cite this article as: Auger, N., Tang, T., Healy-Profit´os, J. & Paradis, G., Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.08.003
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ACCEPTED MANUSCRIPT Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study
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Nathalie Auger MD MSc FRCPC,a-c,* Tina Tang MD,d Jessica Healy-Profitós MSc,a,b Gilles
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c
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University of Montreal Hospital Research Centre, Montreal, Quebec, Canada Institut national de santé publique du Québec, Montreal, Quebec, Canada
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a
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Paradis MD MSc FRCPC FACPM FAHA FCAHSb,c
Department of Epidemiology, Biostatistics and Occupational Health, McGill University,
Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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d
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Montreal, Quebec, Canada
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Running Title: Gestational diabetes and cataract
*
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Correspondence: Dr. Nathalie Auger, 190 Cremazie Blvd E, Montreal, Quebec H2P 1E2,
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Canada, Tel: 514-864-1600 ext. 3717, Fax: +1.514.864.1616, Email: [email protected]
Counts: Abstract 200, Manuscript 3076, Tables 4, Figures 1, Supplemental Tables 1, References 31
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ACCEPTED MANUSCRIPT STRUCTURED ABSTRACT Aims: We assessed the long-term risk of cataract following a pregnancy complicated by
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gestational diabetes.
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Methods: We carried out a longitudinal cohort study of 1,108,541 women who delivered infants between 1989-2013 in Quebec, Canada, with follow-up extending up to 25 years later. The cohort
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included 71,862 women with gestational diabetes and 5,247 with cataracts. We used Cox
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regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of gestational diabetes with subsequent risk of cataract, adjusted for age, parity,
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socioeconomic status, time period, comorbidity, and type 2 diabetes. Results: Women with gestational diabetes had an elevated incidence of cataract (22.6 per 1,000)
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compared with no gestational diabetes (15.1 per 1,000), with 1.15 times the risk (95% CI 1.04-
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1.28). Women with gestational diabetes who subsequently developed type 2 diabetes had a higher risk of cataract compared with no gestational and type 2 diabetes (HR 3.62, 95% CI 3.01-4.35),
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but women with gestational diabetes who did not develop type 2 diabetes continued to be at risk
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(HR 1.12, 95% CI 1.00-1.25).
Conclusions: Gestational diabetes may be an independent risk factor for cataract later in life, although risks are greatest for women who subsequently develop type 2 diabetes. Keywords: Cataract; Diabetes, gestational; Diabetes mellitus, type 2; Longitudinal studies; Ophthalmology; Pregnancy
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ACCEPTED MANUSCRIPT 1. INTRODUCTION Diabetes is associated with the development of cataracts [1], a leading cause of visual impairment
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worldwide [2]. While the relationship between type 2 diabetes and cataract is well established [1],
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less is known on how gestational diabetes is linked with the risk of cataract in the years following pregnancy. Gestational diabetes is common, occurring in about 6-7% of pregnancies [3]. Women
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with gestational diabetes have an increased risk of developing type 2 diabetes subsequent to
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pregnancy [4]. The biologic pathways linking gestational diabetes with the formation of cataracts may resemble those for type 2 diabetes. Cataracts in type 2 diabetes are formed after long term
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exposure to elevated sugar levels which cause osmotic stress in the lens of the eye, a pathway common to many forms of diabetes [1]. Few studies however have addressed the possibility that
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gestational diabetes is an independent risk factor for cataract development.
Gestational diabetes has the potential to impact cataract formation both during and after
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pregnancy. During pregnancy, high levels of sugars converted to sorbitol in the eye can disrupt
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the lens integrity early on even if exposure is short lived and ends at delivery [1]. Certain reports suggest that cataracts can form rapidly in patients with type 1 diabetes after only brief exposures to hyperglycemia [5–7]. In addition, gestational diabetes may be a marker for subclinical metabolic dysfunction [8], and a predisposition to systemic disease [9]. A number of studies suggest that gestational diabetes is an independent risk factor for long term cardiovascular morbidity, beyond risks associated with type 2 diabetes [9]. As well, patients with cardiovascular disease are known to have a high prevalence of cataracts [10]. Thus, gestational diabetes has the potential for both acute and chronic effects on cataract formation. Our objective was to evaluate gestational diabetes as a possible risk factor for cataract development past pregnancy, independent of risks associated with type 2 diabetes. 3
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2. SUBJECTS, MATERIALS AND METHODS
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2.1. Study design and population
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We designed a longitudinal cohort study of 1,108,541 women who were pregnant and delivered infants in any hospital in the province of Quebec (Canada) between 1989 and 2013. We followed
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the women over time for subsequent inpatient cataract extractions up to 25 years after pregnancy,
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with follow-up ending March 31, 2014. We extracted the data from discharge abstracts in the Maintenance and Use of Data for the Study of Hospital Clientele registry, a file containing all
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hospitalizations in the province [11]. Each discharge abstract has up to 26 diagnoses and 15 procedures for each hospitalization. Hospitalization data in Quebec are validated by the Ministry
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of Health and regularly used for research [11]. The cohort comprised the majority of parous
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women in the province because nearly all women in Quebec give birth in hospitals [12]. We
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diseased women.
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avoided Berkson’s selection bias by including all women regardless of health status and not only
We excluded women with preexisting diabetes who were not at risk of developing gestational diabetes, as well as women with a prior medical history of cataract. Furthermore, as screening for gestational diabetes is commonly performed between the 24th and 28th weeks of pregnancy, we excluded women who never reached 28 weeks of gestation. After exclusions, the final sample comprised 1,084,799 women with data on the main exposure (gestational diabetes) and outcome (cataract extraction).
2.2. Gestational diabetes
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ACCEPTED MANUSCRIPT We assessed if gestational diabetes was present at the first or in any subsequent pregnancies. We identified women with gestational diabetes using the 9th and 10th revisions of the International
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Classification of Diseases (ICD 648.8, O24.8). During the study, gestational diabetes was
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screened with a 50g oral glucose challenge between the 24th and 28th weeks of gestation, followed by a confirmatory 100g oral glucose tolerance test [3]. Starting in 1998, a confirmatory 75g oral
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glucose tolerance test was implemented [3].
We further determined if the severity of gestational diabetes was an important predictor of
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cataract development and subsequent extraction. To assess severity, we determined if macrosomia was present in the neonate. We defined macrosomia as a birth weight of 4000g or
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more, and severe macrosomia as 4500g or more, following evidence in the literature [13].
2.3. Cataract
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The outcome was cataract surgery, reflecting cataracts that progressed to an advanced stage.
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Indications for cataract surgery involve poor visual acuity and effect on daily function [14]. We used procedure codes from the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures (27.2-27.9) and Canadian Classification of Health Interventions (1.CL.53-1.CL.55, 1.CL.59-1.CL.89) to identify women who had inpatient procedures for cataract extraction after pregnancy. We maximized the ascertainment of cataracts through ICD diagnostic codes (366, H25, H26, H28.0-H28.2). In Quebec, the majority of cataract extractions are performed in hospitals [15], though some may occur in ambulatory settings [16].
2.4. Late onset diabetes
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ACCEPTED MANUSCRIPT We accounted for pregnant women who subsequently developed late onset or type 2 diabetes mellitus, a potential mediator of the association between gestational diabetes and cataract. We
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used ICD diagnostic codes (249, 250, E10-E14) to identify women who were hospitalized with a
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diagnosis of diabetes any time after the index pregnancy, and considered this variable time-fixed
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as we did not know the exact time of onset.
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2.5. Covariates
In addition to type 2 diabetes, we considered several covariates that could confound the
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association between gestational diabetes and subsequent onset of cataracts. We evaluated a composite indicator of comorbidity (hypertension, dyslipidemia, obesity, smoking, or asthma)
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recorded at delivery or during later hospitalizations. These comorbidities have all been associated
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with an increased risk of cataract [17, 18]. We considered baseline age (<20, 20-24, 25-29, 30-34, 35-39, ≥40 years) and year (1989-1996, 1997-2004, 2005-2013) at cohort inception, total parity
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(1, 2, ≥3 births), and socioeconomic status (poorest fifth of population, no, unknown) as
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additional confounders.
2.6. Data analysis
We calculated the cumulative incidence of cataract surgery after 25 years of follow-up per 1,000 women with and without gestational diabetes, as well as the annual incidence rate per 10,000 person-years. In primary analyses, we used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the risk of cataract in women with gestational diabetes compared with no gestational diabetes. We censored women who died (competing risk) or did not undergo cataract surgery by the last day of follow-up, March 31, 2014. We adjusted the models initially for comorbidity, age, year, parity, and socioeconomic status, and subsequently 6
ACCEPTED MANUSCRIPT for type 2 diabetes. We assessed the proportional hazards assumption using log(-log survival) plots. Cox regression models the time between gestational diabetes and cataract surgery directly,
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and is ideal for exposures that involve glycemic fluctuation and osmotic imbalance that can
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potentiate the development of cataract [19].
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We considered gestational diabetes as both a time-fixed and time-varying exposure. In the time-
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fixed analysis, we hypothesized that gestational diabetes reflected an underlying pathology present from the start of the study, even if gestational diabetes was only documented during a
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later pregnancy. In the time-varying analysis, we hypothesized that the increased risk of cataract began at the first pregnancy complicated by gestational diabetes, not before [20]. However, we
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restricted the time-varying analysis to a subsample comprised of all women with gestational
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diabetes and a random unmatched selection of three unexposed for every exposed woman, to
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ensure that models converged.
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In secondary analyses, we explored the additive effect of type 2 diabetes on the risk of cataract surgery. To do so, we used Cox regression models to examine the association of joint exposure to gestational diabetes and subsequent type 2 diabetes. Here, we assigned women to a four category exposure variable (gestational and type 2 diabetes, gestational diabetes only, type 2 diabetes only, no gestational or type 2 diabetes). We adjusted these models for comorbidity, age, year, parity, and socioeconomic status.
We examined the robustness of the results in four sets of sensitivity analyses. First, we ensured that the results were valid by excluding cataracts in which trauma or medications were implicated (ICD 366.2, 366.45, H26.1, H26.3). Second, we restricted the analysis to women who entered the 7
ACCEPTED MANUSCRIPT cohort in the first decade of the study (1989-1998), as cataract is heavily age-dependent and women entering later in the study had less follow-up time. Third, we adjusted for age as a
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continuous variable in splines with knots at the 5th, 50th and 95th percentiles [21], in the event that
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adjustment for age in 6 categories was insufficient to control for confounding. Fourth, we tested an alternate infant birth weight cut-off of 4250g for severe macrosomia, in the event that 4500g
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was too strict a threshold.
We performed the analyses using SAS v9.3 software (SAS Institute, Cary, NC), and set statistical
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significance to P=0·05 using two-sided hypothesis tests. The institutional review board of the
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include identifying information.
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University of Montreal Hospital Centre waived the need for ethical approval as the data did not
3. RESULTS
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There were 1,084,799 women in this study, including 71,862 (6.6%) with gestational diabetes
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and 13,943 (1.3%) with type 2 diabetes after pregnancy. Among women with gestational diabetes, 1,923 delivered infants with birth weights of 4500g or more (2.7%), and 7,819 with birth weights between 4000 and 4499g (10.9%). During the 15,668,423 person-years of follow-up, 5,247 (0.5%) women underwent cataract extraction (Table 1). The incidence of cataracts was higher in women with than without gestational diabetes (5.4 vs. 3.3 per 10,000 person-years). Women who developed cataracts were older at first pregnancy, had lower parity, and more comorbidity and type 2 diabetes. Median age at pregnancy and at cataract surgery differed little between women with and without gestational diabetes (Table S1).
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ACCEPTED MANUSCRIPT Women with gestational diabetes had a higher cumulative incidence of cataract surgery after 25 years of follow-up than women without gestational diabetes (22.6 vs. 15.1 per 1,000) (Table 2).
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The cumulative incidence of cataract surgery was high regardless of the infant birth weight.
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However, women with gestational diabetes who later developed type 2 diabetes had an even higher cumulative incidence (76.0 per 1,000) compared with women with no gestational or type 2
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diabetes (14.3 per 1,000). Thus, the incidence of cataract surgery was more strongly correlated
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with the subsequent development of type 2 diabetes than with macrosomia during pregnancy.
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When we examined each year post delivery, women with gestational diabetes whose infants weighed 4500g or more nonetheless underwent cataract extraction earlier than women with
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gestational diabetes whose infants had normal weights (Figure 1). Compared with women who
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were never diabetic, the incidence of cataracts for women with type 2 diabetes began diverging after only eight years of follow-up, regardless of gestational diabetes. However, women with both
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gestational and type 2 diabetes developed cataracts earlier than women with only type 2 diabetes
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once 20 years had elapsed.
Women with gestational diabetes had a greater risk of cataract extraction compared with no gestational diabetes (Table 3). This was the case regardless of the severity of gestational diabetes, as risks were similar for all infant birth weights. Adjustment for comorbidity, age, year, parity, and socioeconomic status attenuated the associations somewhat, but adjustment for type 2 diabetes attenuated the HRs further. In the fully adjusted models, women with gestational diabetes had a significantly greater risk of cataract extraction relative to no gestational diabetes (time-fixed HR 1.15, 95% CI 1.04-1.28; time-varying HR 1.14, 95% CI 1.01-1.29). Associations changed little when gestational diabetes was treated as time-varying. 9
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In analyses of joint effects, women with both gestational and type 2 diabetes had the highest risk
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of cataract (Table 4). The combination of gestational and type 2 diabetes was associated with
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around four times the risk of cataract extraction compared with no diabetes (time-fixed HR 3.62, 95% CI 3.01-4.35; time-varying HR 3.81, CI 3.10-4.68). Women with only gestational diabetes
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had a weaker risk of cataract extraction (time-fixed HR 1.12, 95% CI 1.00-1.25; time-varying HR
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only gestational diabetes also had elevated risk.
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1.15, CI 1.01-1.31). Thus, there was a large additive effect of type 2 diabetes, but women with
In sensitivity analyses, excluding 67 women with cataracts attributed to trauma or drugs had no
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impact on the magnitude of the associations. Exclusion of women who entered after the first
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decade of the study and adjustment for age as a continuous variable did not significantly change the results. Similarly, testing an alternate cut-off of 4250g for infant macrosomia did not impact
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the trends.
4. DISCUSSION
4. 1. Main Findings
In this population-based cohort study, we found that women with gestational diabetes had a higher risk of requiring cataract surgery after pregnancy compared with no gestational diabetes. Risk of cataract extraction was elevated regardless of the infant birth weight, a potential measure of the severity of gestational diabetes. Women with gestational diabetes who subsequently developed type 2 diabetes were most at risk, but women with gestational diabetes who never developed type 2 diabetes continued to have an elevated risk. Gestational diabetes is growing in incidence around the world [22], and cataract is the most important cause of visual impairment, 10
ACCEPTED MANUSCRIPT responsible for 51% of blindness worldwide [2]. Pregnancy-related risk factors receive little attention, despite a greater prevalence of cataract among women [23]. Our study provides
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evidence that gestational diabetes may be an independent risk factor for cataract, and may be a
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4.2. Interpretation
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venue for prevention at early reproductive ages.
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To our knowledge, this is the first study of the association between gestational diabetes and cataract. Epidemiological studies have mainly focused on risk factors for cataract such as age
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[17], smoking [24], hypertension [17, 18], dyslipidemia [17, 18], and type 2 diabetes [1]. The pathophysiology of how gestational diabetes contributes to cataract formation has yet to be
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investigated; more is known on the mechanism linking type 2 diabetes with cataract. In type 2
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diabetes, high levels of sugars in the blood are converted to sorbitol in the eye, creating an osmotic force that draws fluid into the lens, disturbing its integrity [1]. In addition, osmotic stress
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is associated with production of free radicals and impaired antioxidation, accelerating the process
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of cataract formation [1]. Gestational diabetes may follow a similar mechanism, though the extent to which it is mediated by type 2 diabetes is unclear. Gestational diabetes is a well-known risk factor for type 2 diabetes [4], and we found that women with both gestational and type 2 diabetes had the highest risk of cataract extraction. There was nonetheless an independent effect of gestational diabetes even controlling for type 2 diabetes, suggesting that the pathway between gestational diabetes and cataract is not entirely explained by type 2 diabetes. Low grade type 2 diabetes that is undetected or that never results in hospitalization may also contribute.
Studies of the association between gestational diabetes and ocular pathologies are rare, though a few have addressed retinal disorders. Case reports have documented early signs of proliferative 11
ACCEPTED MANUSCRIPT retinopathy in women with gestational diabetes [25, 26]. However, some research suggests that women with gestational diabetes have normal retinal exams during antenatal screening [27]. A
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larger body of research suggests that gestational diabetes may be a risk factor for cardiovascular
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disease [9]. Patients with cardiovascular disease also have a high prevalence of cataracts [10], suggesting that gestational diabetes may be part of a systemic process predisposing women to
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chronic disease later in life, including cataracts and cardiovascular disease.
We found no compelling evidence that the severity of gestational diabetes altered the risk of
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cataract extraction. However, we measured severity by presence of fetal macrosomia [13], as we did not have data on blood sugar levels, a clinical measure of severity [28]. Women with higher
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glucose levels or poorly controlled diabetes may be monitored more closely and induced early to
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avoid excessive macrosomia or stillbirth [28]. This may explain why women with gestational diabetes had a higher incidence of cataract extraction regardless of infant birth weight. Similarly,
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the associations strengthened little when gestational diabetes was measured as a time-varying,
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suggesting that the risk of cataract reflects a predisposing phenotype present prior to clinical gestational diabetes. Age is unlikely to explain the associations as we carefully adjusted for this confounder, and survival analysis models the time between pregnancy and cataract surgery directly.
4.3. Strengths and Limitations This was a large population-based study, but a number of limitations are present. We relied on administrative hospital data, as we could not audit charts. There may be coding errors, although hospital data are rigorously validated in Quebec [11]. Screening protocols for gestational diabetes have changed over time [3], which can introduce errors of inclusion in the main exposure. In 12
ACCEPTED MANUSCRIPT addition, preexisting diabetes may be misclassified as gestational, especially if patients were unaware of glucose intolerance prior to pregnancy. We did not have glycemic measures and
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could not assess the degree of dysglycemia. We used fetal macrosomia as an indicator of severity
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of gestational diabetes, but this method may not be optimal. Late onset diabetes may be under ascertained in women who were never rehospitalized, but we do not expect the proportion
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rehospitalized to differ depending on gestational diabetes. Better ascertainment of exposure in
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women with cataracts may have resulted in a stronger association with type 2 diabetes, although prevalence of type 2 diabetes in our data was close to women in the same age group in Quebec
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[29].
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We could not determine if women received treatment for cataracts outside the province, although
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we have no reason to suspect this varied with gestational diabetes. We did not have data on specific types of cataract (nuclear, subcapsular, or cortical) and could not determine if
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associations with gestational diabetes differed. Studies indicate that type 2 diabetes is more
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strongly related to cortical and subcapsular cataracts [1]. We adjusted for many confounding variables, but did not have information on sun exposure, ethnicity, or drug use [18, 30]. Our study is representative of all residents in a large Canadian province; further research may be required to generalize to other populations.
4.4. Conclusion In this population-based study of more than one million women with follow-up over two decades, gestational diabetes was associated with an increased risk of cataract surgery later in life. Type 2 diabetes accounted for part of the association, but women with gestational diabetes who never developed type 2 diabetes still had an elevated risk. The results of this study suggest that women 13
ACCEPTED MANUSCRIPT with gestational diabetes may benefit from enhanced vigilance for cataract prevention. More study is needed to determine if organizations such as the American Academy of Ophthalmology
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should recommend ocular screening for women with gestational diabetes [31]. Further research is
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comprehensive care of women with gestational diabetes.
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merited to better understand the underlying biological mechanisms and improve the
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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS The study was funded by the Canadian Institutes of Health Research (grant number MOP-
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130452) and the Fonds de recherche du Québec-Santé (career award 25128). The sponsors were
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not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. NA and JHP conceived and
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designed the study. JHP analysed the data under guidance of NA. TT and GP helped interpret the
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results. NA, TT, and JHP drafted the manuscript and GP reviewed it critically for intellectual
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content. All authors approved the final version submitted.
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22. Hunt KJ, Schuller KL (2007) The increasing prevalence of diabetes in pregnancy. Obstet
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Francisco, CA
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ACCEPTED MANUSCRIPT Table 1 Incidence of cataracts according to characteristics of women
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Incidence per 10,000 person-years (95% confidence interval)
444 17 50 377 4,803
5.4 (4.9, 5.9) 7.0 (4.3, 11.3) 5.3 (4.0, 7.0) 5.4 (4.8, 5.9) 3.3 (3.2, 3.4)
390 4,857
14.6 (13.2, 16.1) 3.2 (3.1, 3.2)
1,299 3,948
6.6 (6.2, 6.9) 2.9 (2.8, 3.0)
86 488 1482 1,765 1,099 327
0.9 (0.7, 1.1) 1.4 (1.3, 1.5) 2.5 (2.4, 2.6) 4.6 (4.4, 4.9) 8.9 (8.4, 9.4) 16.7 (15.0, 18.7)
2,995 1,758 494
4.6 (4.4, 4.8) 2.7 (2.6, 2.8) 1.8 (1.7, 2.0)
946 3,520
3.3 (3.1, 3.5) 3.2 (3.1, 3.3)
4,446 635 166 5,247
4.3 (4.2, 4.4) 1.7 (1.6, 1.9) 1.0 (0.9, 1.2) 3.3 (3.3, 3.4)
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Gestational diabetes mellitus Yes, any infant birth weight 822,914 Yes, birth weight ≥4500g 29,026 Yes, birth weight 4000-4499g 111,663 Yes, birth weight <4000g 827,679 No 14,700,056 Late onset or type 2 diabetes Yes 267,752 No 15,400,670 Comorbiditya Yes 1,976,790 No 13,691,633 Age at baseline, years <20 937,338 20-24 3,552,857 25-29 5,937,978 30-34 3,810,711 35-39 1,234,179 ≥40 195,359 Total parity 1 6,500,507 2 6,496,677 ≥3 2,671,239 Socioeconomic status Disadvantaged 2,844,289 No 11,114,129 Year at baseline 1989-1996 10,402,683 1997-2004 3,678,964 2005-2013 1,586,776 Total 15,668,423 a Hypertension, dyslipidemia, obesity, smoking, asthma
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No. person-years
No. women with cataracts
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ACCEPTED MANUSCRIPT Table 2 Cumulative incidence of cataract for women with and without gestational diabetes
71,862 1,923 7,819 62,120 1,012,937
444 17 50 377 4,803
22.6 (19.0, 26.6) 22.5 (12.1, 38.2) 20.0 (13.9, 27.9) 23.0 (18.9, 27.7) 15.1 (14.3, 15.9)
124 320 223 4,580
76.0 (61.6, 92.3) 17.5 (14.0, 21.7) 73.9 (50.2, 103.4) 14.3 (13.6, 15.1)
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3,188 68,674 5,775 1,007,162
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No. women with cataract
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Gestational diabetes Yes, any infant birth weight Yes, birth weight ≥4500g Yes, birth weight 4000-4499g Yes, birth weight <4000g No Late onset or type 2 diabetes Gestational and type 2 diabetes Gestational diabetes only Type 2 diabetes only No diabetes
Cumulative incidence at 25 years per 1,000 women (95% confidence interval)
No. women
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ACCEPTED MANUSCRIPT Table 3 Association between gestational diabetes and subsequent risk of cataract
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Hazard ratio (95% confidence interval) Unadjusted Partially adjusteda Adjustedb
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Time-fixed analysis Gestational diabetes Yes 1.55 (1.41, 1.71) 1.32 (1.20, 1.46) 1.15 (1.04, 1.28) No Referent Referent Referent Gestational diabetes and infant birth weight Yes, ≥4500g 1.84 (1.14, 2.96) 1.76 (1.09, 2.84) 1.37 (0.85, 2.20) Yes, 4000-4499g 1.47 (1.11, 1.94) 1.33 (1.01, 1.76) 1.11 (0.84, 1.47) Yes, <4000g 1.55 (1.40, 1.72) 1.30 (1.17, 1.45) 1.15 (1.03, 1.28) No Referent Referent Referent Time-varying analysis Gestational diabetes Yes 1.61 (1.46, 1.78) 1.33 (1.19, 1.50) 1.14 (1.01, 1.29) No Referent Referent Referent Gestational diabetes and infant birth weight Yes, ≥4500g 2.03 (1.26, 3.29) 1.81 (1.12, 2.93) 1.36 (0.84, 2.22) Yes, 4000-4499g 1.59 (1.19, 2.12) 1.35 (1.01, 1.80) 1.11 (0.83, 1.48) Yes, <4000g 1.67 (1.48, 1.88) 1.31 (1.16, 1.49) 1.14 (1.01, 1.30) No Referent Referent Referent a Adjusted for comorbidity (hypertension, dyslipidemia, obesity, smoking, asthma), age, year, parity, and socioeconomic status Adjusted for comorbidity, age, year, parity, socioeconomic status, and type 2 diabetes
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ACCEPTED MANUSCRIPT Table 4 Influence of type 2 diabetes on the association between gestational diabetes and subsequent risk of cataract
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Hazard ratio (95% confidence interval) Unadjusted Adjusteda
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Time-fixed analysis Gestational and type 2 diabetes 6.15 (5.14, 7.35) 3.62 (3.01, 4.35) Gestational diabetes only 1.25 (1.12, 1.40) 1.12 (1.00, 1.25) Type 2 diabetes only 4.82 (4.22, 5.52) 2.81 (2.44, 3.24) No diabetes Referent Referent Time-varying analysis Gestational and type 2 diabetes 6.40 (5.31, 7.72) 3.81 (3.10, 4.68) Gestational diabetes only 1.31 (1.15, 1.49) 1.15 (1.01, 1.31) Type 2 diabetes only 6.14 (4.73, 7.98) 3.67 (2.78, 4.83) No diabetes Referent Referent a Adjusted for comorbidity (hypertension, dyslipidemia, obesity, smoking, asthma), age, year,
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parity, and socioeconomic status
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ACCEPTED MANUSCRIPT Figure 1 Gestational diabetes and cumulative incidence of cataract according to number of years
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after delivery
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Legend: Panel A = Gestational diabetes according to infant birth weight; Panel B = Gestational
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diabetes and later onset of type 2 diabetes
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ACCEPTED MANUSCRIPT Table S1 Gestational diabetes and age at pregnancy and at cataract extraction
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3,837 (5.3) 13,527 (18.8) 24,152 (33.6) 19,487 (27.1) 8,750 (12.2) 2,109 (2.9)
26 (2.0) 38 (6.3) 45 (24.3) 50 (35.1) 53.5 (23.9) 56 (8.3)
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60,144 (5.9) 227,284 (22.4) 380,615 (37.6) 247,806 (24.5) 83,009 (8.2) 14,079 (1.4)
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31 (1.6) 38 (9.6) 44 (28.6) 49 (33.5) 54 (20.7) 58 (6.0)
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At cataract extraction
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Gestational diabetes Median age, years Age group, N (%) <20 20-24 25-29 30-34 35-39 ≥40 No gestational diabetes Median age, years Age group, N (%) <20 20-24 25-29 30-34 35-39 ≥40
At pregnancy
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ACCEPTED MANUSCRIPT HIGHLIGHTS
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Type 2 diabetes is associated with cataract, but the risk for women with gestational diabetes has
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not been studied.
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We show that gestational diabetes may be an independent risk factor for cataract, even among
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women who never develop type 2 diabetes.
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Women with gestational diabetes may merit closer follow-up after pregnancy for prevention and
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treatment of cataracts.
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ACCEPTED MANUSCRIPT
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S1056-8727(17)30231-3 doi: 10.1016/j.jdiacomp.2017.08.003 JDC 7079
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
17 February 2017 9 May 2017 4 August 2017
Please cite this article as: Auger, N., Tang, T., Healy-Profit´os, J. & Paradis, G., Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study, Journal of Diabetes and Its Complications (2017), doi: 10.1016/j.jdiacomp.2017.08.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Gestational diabetes and the long-term risk of cataract surgery: A longitudinal cohort study
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Nathalie Auger MD MSc FRCPC,a-c,* Tina Tang MD,d Jessica Healy-Profitós MSc,a,b Gilles
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c
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University of Montreal Hospital Research Centre, Montreal, Quebec, Canada Institut national de santé publique du Québec, Montreal, Quebec, Canada
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a
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Paradis MD MSc FRCPC FACPM FAHA FCAHSb,c
Department of Epidemiology, Biostatistics and Occupational Health, McGill University,
Faculty of Medicine, McGill University, Montreal, Quebec, Canada
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d
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Montreal, Quebec, Canada
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Running Title: Gestational diabetes and cataract
*
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Correspondence: Dr. Nathalie Auger, 190 Cremazie Blvd E, Montreal, Quebec H2P 1E2,
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Canada, Tel: 514-864-1600 ext. 3717, Fax: +1.514.864.1616, Email: [email protected]
Counts: Abstract 200, Manuscript 3076, Tables 4, Figures 1, Supplemental Tables 1, References 31
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ACCEPTED MANUSCRIPT STRUCTURED ABSTRACT Aims: We assessed the long-term risk of cataract following a pregnancy complicated by
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gestational diabetes.
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Methods: We carried out a longitudinal cohort study of 1,108,541 women who delivered infants between 1989-2013 in Quebec, Canada, with follow-up extending up to 25 years later. The cohort
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included 71,862 women with gestational diabetes and 5,247 with cataracts. We used Cox
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regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of gestational diabetes with subsequent risk of cataract, adjusted for age, parity,
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socioeconomic status, time period, comorbidity, and type 2 diabetes. Results: Women with gestational diabetes had an elevated incidence of cataract (22.6 per 1,000)
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compared with no gestational diabetes (15.1 per 1,000), with 1.15 times the risk (95% CI 1.04-
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1.28). Women with gestational diabetes who subsequently developed type 2 diabetes had a higher risk of cataract compared with no gestational and type 2 diabetes (HR 3.62, 95% CI 3.01-4.35),
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but women with gestational diabetes who did not develop type 2 diabetes continued to be at risk
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(HR 1.12, 95% CI 1.00-1.25).
Conclusions: Gestational diabetes may be an independent risk factor for cataract later in life, although risks are greatest for women who subsequently develop type 2 diabetes. Keywords: Cataract; Diabetes, gestational; Diabetes mellitus, type 2; Longitudinal studies; Ophthalmology; Pregnancy
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ACCEPTED MANUSCRIPT 1. INTRODUCTION Diabetes is associated with the development of cataracts [1], a leading cause of visual impairment
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worldwide [2]. While the relationship between type 2 diabetes and cataract is well established [1],
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less is known on how gestational diabetes is linked with the risk of cataract in the years following pregnancy. Gestational diabetes is common, occurring in about 6-7% of pregnancies [3]. Women
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with gestational diabetes have an increased risk of developing type 2 diabetes subsequent to
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pregnancy [4]. The biologic pathways linking gestational diabetes with the formation of cataracts may resemble those for type 2 diabetes. Cataracts in type 2 diabetes are formed after long term
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exposure to elevated sugar levels which cause osmotic stress in the lens of the eye, a pathway common to many forms of diabetes [1]. Few studies however have addressed the possibility that
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gestational diabetes is an independent risk factor for cataract development.
Gestational diabetes has the potential to impact cataract formation both during and after
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pregnancy. During pregnancy, high levels of sugars converted to sorbitol in the eye can disrupt
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the lens integrity early on even if exposure is short lived and ends at delivery [1]. Certain reports suggest that cataracts can form rapidly in patients with type 1 diabetes after only brief exposures to hyperglycemia [5–7]. In addition, gestational diabetes may be a marker for subclinical metabolic dysfunction [8], and a predisposition to systemic disease [9]. A number of studies suggest that gestational diabetes is an independent risk factor for long term cardiovascular morbidity, beyond risks associated with type 2 diabetes [9]. As well, patients with cardiovascular disease are known to have a high prevalence of cataracts [10]. Thus, gestational diabetes has the potential for both acute and chronic effects on cataract formation. Our objective was to evaluate gestational diabetes as a possible risk factor for cataract development past pregnancy, independent of risks associated with type 2 diabetes. 3
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2. SUBJECTS, MATERIALS AND METHODS
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2.1. Study design and population
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We designed a longitudinal cohort study of 1,108,541 women who were pregnant and delivered infants in any hospital in the province of Quebec (Canada) between 1989 and 2013. We followed
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the women over time for subsequent inpatient cataract extractions up to 25 years after pregnancy,
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with follow-up ending March 31, 2014. We extracted the data from discharge abstracts in the Maintenance and Use of Data for the Study of Hospital Clientele registry, a file containing all
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hospitalizations in the province [11]. Each discharge abstract has up to 26 diagnoses and 15 procedures for each hospitalization. Hospitalization data in Quebec are validated by the Ministry
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of Health and regularly used for research [11]. The cohort comprised the majority of parous
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women in the province because nearly all women in Quebec give birth in hospitals [12]. We
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diseased women.
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avoided Berkson’s selection bias by including all women regardless of health status and not only
We excluded women with preexisting diabetes who were not at risk of developing gestational diabetes, as well as women with a prior medical history of cataract. Furthermore, as screening for gestational diabetes is commonly performed between the 24th and 28th weeks of pregnancy, we excluded women who never reached 28 weeks of gestation. After exclusions, the final sample comprised 1,084,799 women with data on the main exposure (gestational diabetes) and outcome (cataract extraction).
2.2. Gestational diabetes
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ACCEPTED MANUSCRIPT We assessed if gestational diabetes was present at the first or in any subsequent pregnancies. We identified women with gestational diabetes using the 9th and 10th revisions of the International
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Classification of Diseases (ICD 648.8, O24.8). During the study, gestational diabetes was
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screened with a 50g oral glucose challenge between the 24th and 28th weeks of gestation, followed by a confirmatory 100g oral glucose tolerance test [3]. Starting in 1998, a confirmatory 75g oral
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glucose tolerance test was implemented [3].
We further determined if the severity of gestational diabetes was an important predictor of
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cataract development and subsequent extraction. To assess severity, we determined if macrosomia was present in the neonate. We defined macrosomia as a birth weight of 4000g or
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more, and severe macrosomia as 4500g or more, following evidence in the literature [13].
2.3. Cataract
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The outcome was cataract surgery, reflecting cataracts that progressed to an advanced stage.
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Indications for cataract surgery involve poor visual acuity and effect on daily function [14]. We used procedure codes from the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures (27.2-27.9) and Canadian Classification of Health Interventions (1.CL.53-1.CL.55, 1.CL.59-1.CL.89) to identify women who had inpatient procedures for cataract extraction after pregnancy. We maximized the ascertainment of cataracts through ICD diagnostic codes (366, H25, H26, H28.0-H28.2). In Quebec, the majority of cataract extractions are performed in hospitals [15], though some may occur in ambulatory settings [16].
2.4. Late onset diabetes
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ACCEPTED MANUSCRIPT We accounted for pregnant women who subsequently developed late onset or type 2 diabetes mellitus, a potential mediator of the association between gestational diabetes and cataract. We
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used ICD diagnostic codes (249, 250, E10-E14) to identify women who were hospitalized with a
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diagnosis of diabetes any time after the index pregnancy, and considered this variable time-fixed
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2.5. Covariates
In addition to type 2 diabetes, we considered several covariates that could confound the
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association between gestational diabetes and subsequent onset of cataracts. We evaluated a composite indicator of comorbidity (hypertension, dyslipidemia, obesity, smoking, or asthma)
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recorded at delivery or during later hospitalizations. These comorbidities have all been associated
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with an increased risk of cataract [17, 18]. We considered baseline age (<20, 20-24, 25-29, 30-34, 35-39, ≥40 years) and year (1989-1996, 1997-2004, 2005-2013) at cohort inception, total parity
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(1, 2, ≥3 births), and socioeconomic status (poorest fifth of population, no, unknown) as
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additional confounders.
2.6. Data analysis
We calculated the cumulative incidence of cataract surgery after 25 years of follow-up per 1,000 women with and without gestational diabetes, as well as the annual incidence rate per 10,000 person-years. In primary analyses, we used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the risk of cataract in women with gestational diabetes compared with no gestational diabetes. We censored women who died (competing risk) or did not undergo cataract surgery by the last day of follow-up, March 31, 2014. We adjusted the models initially for comorbidity, age, year, parity, and socioeconomic status, and subsequently 6
ACCEPTED MANUSCRIPT for type 2 diabetes. We assessed the proportional hazards assumption using log(-log survival) plots. Cox regression models the time between gestational diabetes and cataract surgery directly,
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and is ideal for exposures that involve glycemic fluctuation and osmotic imbalance that can
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potentiate the development of cataract [19].
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We considered gestational diabetes as both a time-fixed and time-varying exposure. In the time-
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fixed analysis, we hypothesized that gestational diabetes reflected an underlying pathology present from the start of the study, even if gestational diabetes was only documented during a
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later pregnancy. In the time-varying analysis, we hypothesized that the increased risk of cataract began at the first pregnancy complicated by gestational diabetes, not before [20]. However, we
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restricted the time-varying analysis to a subsample comprised of all women with gestational
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diabetes and a random unmatched selection of three unexposed for every exposed woman, to
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ensure that models converged.
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In secondary analyses, we explored the additive effect of type 2 diabetes on the risk of cataract surgery. To do so, we used Cox regression models to examine the association of joint exposure to gestational diabetes and subsequent type 2 diabetes. Here, we assigned women to a four category exposure variable (gestational and type 2 diabetes, gestational diabetes only, type 2 diabetes only, no gestational or type 2 diabetes). We adjusted these models for comorbidity, age, year, parity, and socioeconomic status.
We examined the robustness of the results in four sets of sensitivity analyses. First, we ensured that the results were valid by excluding cataracts in which trauma or medications were implicated (ICD 366.2, 366.45, H26.1, H26.3). Second, we restricted the analysis to women who entered the 7
ACCEPTED MANUSCRIPT cohort in the first decade of the study (1989-1998), as cataract is heavily age-dependent and women entering later in the study had less follow-up time. Third, we adjusted for age as a
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continuous variable in splines with knots at the 5th, 50th and 95th percentiles [21], in the event that
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adjustment for age in 6 categories was insufficient to control for confounding. Fourth, we tested an alternate infant birth weight cut-off of 4250g for severe macrosomia, in the event that 4500g
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was too strict a threshold.
We performed the analyses using SAS v9.3 software (SAS Institute, Cary, NC), and set statistical
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significance to P=0·05 using two-sided hypothesis tests. The institutional review board of the
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include identifying information.
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University of Montreal Hospital Centre waived the need for ethical approval as the data did not
3. RESULTS
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There were 1,084,799 women in this study, including 71,862 (6.6%) with gestational diabetes
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and 13,943 (1.3%) with type 2 diabetes after pregnancy. Among women with gestational diabetes, 1,923 delivered infants with birth weights of 4500g or more (2.7%), and 7,819 with birth weights between 4000 and 4499g (10.9%). During the 15,668,423 person-years of follow-up, 5,247 (0.5%) women underwent cataract extraction (Table 1). The incidence of cataracts was higher in women with than without gestational diabetes (5.4 vs. 3.3 per 10,000 person-years). Women who developed cataracts were older at first pregnancy, had lower parity, and more comorbidity and type 2 diabetes. Median age at pregnancy and at cataract surgery differed little between women with and without gestational diabetes (Table S1).
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ACCEPTED MANUSCRIPT Women with gestational diabetes had a higher cumulative incidence of cataract surgery after 25 years of follow-up than women without gestational diabetes (22.6 vs. 15.1 per 1,000) (Table 2).
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The cumulative incidence of cataract surgery was high regardless of the infant birth weight.
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However, women with gestational diabetes who later developed type 2 diabetes had an even higher cumulative incidence (76.0 per 1,000) compared with women with no gestational or type 2
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diabetes (14.3 per 1,000). Thus, the incidence of cataract surgery was more strongly correlated
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with the subsequent development of type 2 diabetes than with macrosomia during pregnancy.
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When we examined each year post delivery, women with gestational diabetes whose infants weighed 4500g or more nonetheless underwent cataract extraction earlier than women with
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gestational diabetes whose infants had normal weights (Figure 1). Compared with women who
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were never diabetic, the incidence of cataracts for women with type 2 diabetes began diverging after only eight years of follow-up, regardless of gestational diabetes. However, women with both
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gestational and type 2 diabetes developed cataracts earlier than women with only type 2 diabetes
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once 20 years had elapsed.
Women with gestational diabetes had a greater risk of cataract extraction compared with no gestational diabetes (Table 3). This was the case regardless of the severity of gestational diabetes, as risks were similar for all infant birth weights. Adjustment for comorbidity, age, year, parity, and socioeconomic status attenuated the associations somewhat, but adjustment for type 2 diabetes attenuated the HRs further. In the fully adjusted models, women with gestational diabetes had a significantly greater risk of cataract extraction relative to no gestational diabetes (time-fixed HR 1.15, 95% CI 1.04-1.28; time-varying HR 1.14, 95% CI 1.01-1.29). Associations changed little when gestational diabetes was treated as time-varying. 9
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In analyses of joint effects, women with both gestational and type 2 diabetes had the highest risk
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of cataract (Table 4). The combination of gestational and type 2 diabetes was associated with
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around four times the risk of cataract extraction compared with no diabetes (time-fixed HR 3.62, 95% CI 3.01-4.35; time-varying HR 3.81, CI 3.10-4.68). Women with only gestational diabetes
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had a weaker risk of cataract extraction (time-fixed HR 1.12, 95% CI 1.00-1.25; time-varying HR
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only gestational diabetes also had elevated risk.
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1.15, CI 1.01-1.31). Thus, there was a large additive effect of type 2 diabetes, but women with
In sensitivity analyses, excluding 67 women with cataracts attributed to trauma or drugs had no
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impact on the magnitude of the associations. Exclusion of women who entered after the first
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decade of the study and adjustment for age as a continuous variable did not significantly change the results. Similarly, testing an alternate cut-off of 4250g for infant macrosomia did not impact
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the trends.
4. DISCUSSION
4. 1. Main Findings
In this population-based cohort study, we found that women with gestational diabetes had a higher risk of requiring cataract surgery after pregnancy compared with no gestational diabetes. Risk of cataract extraction was elevated regardless of the infant birth weight, a potential measure of the severity of gestational diabetes. Women with gestational diabetes who subsequently developed type 2 diabetes were most at risk, but women with gestational diabetes who never developed type 2 diabetes continued to have an elevated risk. Gestational diabetes is growing in incidence around the world [22], and cataract is the most important cause of visual impairment, 10
ACCEPTED MANUSCRIPT responsible for 51% of blindness worldwide [2]. Pregnancy-related risk factors receive little attention, despite a greater prevalence of cataract among women [23]. Our study provides
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evidence that gestational diabetes may be an independent risk factor for cataract, and may be a
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4.2. Interpretation
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venue for prevention at early reproductive ages.
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To our knowledge, this is the first study of the association between gestational diabetes and cataract. Epidemiological studies have mainly focused on risk factors for cataract such as age
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[17], smoking [24], hypertension [17, 18], dyslipidemia [17, 18], and type 2 diabetes [1]. The pathophysiology of how gestational diabetes contributes to cataract formation has yet to be
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investigated; more is known on the mechanism linking type 2 diabetes with cataract. In type 2
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diabetes, high levels of sugars in the blood are converted to sorbitol in the eye, creating an osmotic force that draws fluid into the lens, disturbing its integrity [1]. In addition, osmotic stress
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is associated with production of free radicals and impaired antioxidation, accelerating the process
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of cataract formation [1]. Gestational diabetes may follow a similar mechanism, though the extent to which it is mediated by type 2 diabetes is unclear. Gestational diabetes is a well-known risk factor for type 2 diabetes [4], and we found that women with both gestational and type 2 diabetes had the highest risk of cataract extraction. There was nonetheless an independent effect of gestational diabetes even controlling for type 2 diabetes, suggesting that the pathway between gestational diabetes and cataract is not entirely explained by type 2 diabetes. Low grade type 2 diabetes that is undetected or that never results in hospitalization may also contribute.
Studies of the association between gestational diabetes and ocular pathologies are rare, though a few have addressed retinal disorders. Case reports have documented early signs of proliferative 11
ACCEPTED MANUSCRIPT retinopathy in women with gestational diabetes [25, 26]. However, some research suggests that women with gestational diabetes have normal retinal exams during antenatal screening [27]. A
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larger body of research suggests that gestational diabetes may be a risk factor for cardiovascular
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disease [9]. Patients with cardiovascular disease also have a high prevalence of cataracts [10], suggesting that gestational diabetes may be part of a systemic process predisposing women to
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chronic disease later in life, including cataracts and cardiovascular disease.
We found no compelling evidence that the severity of gestational diabetes altered the risk of
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cataract extraction. However, we measured severity by presence of fetal macrosomia [13], as we did not have data on blood sugar levels, a clinical measure of severity [28]. Women with higher
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glucose levels or poorly controlled diabetes may be monitored more closely and induced early to
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avoid excessive macrosomia or stillbirth [28]. This may explain why women with gestational diabetes had a higher incidence of cataract extraction regardless of infant birth weight. Similarly,
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the associations strengthened little when gestational diabetes was measured as a time-varying,
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suggesting that the risk of cataract reflects a predisposing phenotype present prior to clinical gestational diabetes. Age is unlikely to explain the associations as we carefully adjusted for this confounder, and survival analysis models the time between pregnancy and cataract surgery directly.
4.3. Strengths and Limitations This was a large population-based study, but a number of limitations are present. We relied on administrative hospital data, as we could not audit charts. There may be coding errors, although hospital data are rigorously validated in Quebec [11]. Screening protocols for gestational diabetes have changed over time [3], which can introduce errors of inclusion in the main exposure. In 12
ACCEPTED MANUSCRIPT addition, preexisting diabetes may be misclassified as gestational, especially if patients were unaware of glucose intolerance prior to pregnancy. We did not have glycemic measures and
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could not assess the degree of dysglycemia. We used fetal macrosomia as an indicator of severity
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of gestational diabetes, but this method may not be optimal. Late onset diabetes may be under ascertained in women who were never rehospitalized, but we do not expect the proportion
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rehospitalized to differ depending on gestational diabetes. Better ascertainment of exposure in
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women with cataracts may have resulted in a stronger association with type 2 diabetes, although prevalence of type 2 diabetes in our data was close to women in the same age group in Quebec
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[29].
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We could not determine if women received treatment for cataracts outside the province, although
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we have no reason to suspect this varied with gestational diabetes. We did not have data on specific types of cataract (nuclear, subcapsular, or cortical) and could not determine if
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associations with gestational diabetes differed. Studies indicate that type 2 diabetes is more
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strongly related to cortical and subcapsular cataracts [1]. We adjusted for many confounding variables, but did not have information on sun exposure, ethnicity, or drug use [18, 30]. Our study is representative of all residents in a large Canadian province; further research may be required to generalize to other populations.
4.4. Conclusion In this population-based study of more than one million women with follow-up over two decades, gestational diabetes was associated with an increased risk of cataract surgery later in life. Type 2 diabetes accounted for part of the association, but women with gestational diabetes who never developed type 2 diabetes still had an elevated risk. The results of this study suggest that women 13
ACCEPTED MANUSCRIPT with gestational diabetes may benefit from enhanced vigilance for cataract prevention. More study is needed to determine if organizations such as the American Academy of Ophthalmology
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should recommend ocular screening for women with gestational diabetes [31]. Further research is
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comprehensive care of women with gestational diabetes.
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merited to better understand the underlying biological mechanisms and improve the
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ACCEPTED MANUSCRIPT ACKNOWLEDGEMENTS The study was funded by the Canadian Institutes of Health Research (grant number MOP-
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130452) and the Fonds de recherche du Québec-Santé (career award 25128). The sponsors were
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not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. NA and JHP conceived and
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designed the study. JHP analysed the data under guidance of NA. TT and GP helped interpret the
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results. NA, TT, and JHP drafted the manuscript and GP reviewed it critically for intellectual
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content. All authors approved the final version submitted.
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Kessous R, Shoham-Vardi I, Pariente G, et al (2013) An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. Heart 99:1118–1121
10. Shinohara T, White H, Mulhern ML, Maisel H (2007) Cataract: window for systemic disorders. Med Hypotheses 69:669–677 11. Ministère de la Santé et des Services sociaux (2016) Cadre normatif du système Med-Écho. (Maintenance et exploitation des données pour l’étude de la clientèle hospitalière). 1–259
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ACCEPTED MANUSCRIPT 12. Auger N, Le TUN, Park AL, Luo Z-C (2011) Association between maternal comorbidity and preterm birth by severity and clinical subtype: retrospective cohort study. BMC
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13. Esakoff TF, Cheng YW, Sparks TN, Caughey AB (2009) The association between birthweight 4000 g or greater and perinatal outcomes in patients with and without
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gestational diabetes mellitus. Am J Obstet Gynecol 200: 672.e1-e4
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14. Kessel L, Andresen J, Erngaard D, et al (2016) Indication for cataract surgery. Do we have evidence of who will benefit from surgery? A systematic review and meta-analysis. Acta
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15. Ministère de la Santé et des Services sociaux (2017) Accès aux services spécialisés.
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http://wpp01.msss.gouv.qc.ca/appl/g74web/default.asp. Accessed 16 Jan 2017
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16. Ministère de la Santé et des Services sociaux (2016) Liste des centres médicaux spécialisés ayant reçu un permis en date du 5 janvier 2016.
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http://www.msss.gouv.qc.ca/sujets/organisation/cms/index.php?cms-ayant-un-permis.
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Accessed 16 Jan 2017
17. Lindblad BE, Håkansson N, Philipson B, Wolk A (2008) Metabolic syndrome components in relation to risk of cataract extraction: a prospective cohort study of women. Ophthalmology 115:1687–1692 18. West SK, Valmadrid CT (1995) Epidemiology of risk factors for age-related cataract. Surv Ophthalmol 39:323–334 19. Allison PD (2010) Survival analysis using SAS: A practical guide, second edition. SAS Institute, Cary, NC 20. Schwartz N, Green MS, Yefet E, Nachum Z (2016) Modifiable risk factors for gestational diabetes recurrence. Endocrine 54:714–722 17
ACCEPTED MANUSCRIPT 21. Howe CJ, Cole SR, Westreich DJ, et al (2011) Splines for trend analysis and continuous confounder control. Epidemiology 22:874–875
Gynecol Clin North Am 34:173–199, vii
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22. Hunt KJ, Schuller KL (2007) The increasing prevalence of diabetes in pregnancy. Obstet
23. Prokofyeva E, Wegener A, Zrenner E (2013) Cataract prevalence and prevention in Europe:
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a literature review. Acta Ophthalmol 91:395–405
Study. Arch Ophthalmol 115:1296–1303
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24. Cumming RG, Mitchell P (1997) Alcohol, smoking, and cataracts: the Blue Mountains Eye
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25. Hagay ZJ, Schachter M, Pollack A, Levy R (1994) Development of proliferative retinopathy
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in a gestational diabetes patient following rapid metabolic control. Eur J Obstet Gynecol
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26. Hari Kumar KVS, Ahmad FMH, Sood S, Mansingh S (2016) Visual evoked potential to assess retinopathy in gestational diabetes mellitus. Can J Diabetes 40:131–134
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27. Macfarlane DP, O’Sullivan EP, Dorman S, et al (2013) The utility of retinal screening in
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gestational diabetes. Diabet Med 30:1009–1010 28. Cheng YW, Esakoff TF, Block-Kurbisch I, et al (2006) Screening or diagnostic: markedly elevated glucose loading test and perinatal outcomes. J Matern Fetal Neonatal Med 19:729– 734 29. Émond V, Institut national de santé publique du Québec (2003) Prévalence du diabète au Québec et dans ses régions premières estimations d’après les fichiers administratifs. Institut national de santé publique du Québec, Montréal 30. West SK, Duncan DD, Muñoz B, et al (1998) Sunlight exposure and risk of lens opacities in a population-based study: the Salisbury Eye Evaluation project. JAMA 280:714–718
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ACCEPTED MANUSCRIPT 31. American Academy of Ophthalmology Retina/Vitreous Panel (2016) Preferred practice pattern guidelines. Diabetic retinopathy. American Academy of Ophthalmology, San
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ACCEPTED MANUSCRIPT Table 1 Incidence of cataracts according to characteristics of women
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Incidence per 10,000 person-years (95% confidence interval)
444 17 50 377 4,803
5.4 (4.9, 5.9) 7.0 (4.3, 11.3) 5.3 (4.0, 7.0) 5.4 (4.8, 5.9) 3.3 (3.2, 3.4)
390 4,857
14.6 (13.2, 16.1) 3.2 (3.1, 3.2)
1,299 3,948
6.6 (6.2, 6.9) 2.9 (2.8, 3.0)
86 488 1482 1,765 1,099 327
0.9 (0.7, 1.1) 1.4 (1.3, 1.5) 2.5 (2.4, 2.6) 4.6 (4.4, 4.9) 8.9 (8.4, 9.4) 16.7 (15.0, 18.7)
2,995 1,758 494
4.6 (4.4, 4.8) 2.7 (2.6, 2.8) 1.8 (1.7, 2.0)
946 3,520
3.3 (3.1, 3.5) 3.2 (3.1, 3.3)
4,446 635 166 5,247
4.3 (4.2, 4.4) 1.7 (1.6, 1.9) 1.0 (0.9, 1.2) 3.3 (3.3, 3.4)
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Gestational diabetes mellitus Yes, any infant birth weight 822,914 Yes, birth weight ≥4500g 29,026 Yes, birth weight 4000-4499g 111,663 Yes, birth weight <4000g 827,679 No 14,700,056 Late onset or type 2 diabetes Yes 267,752 No 15,400,670 Comorbiditya Yes 1,976,790 No 13,691,633 Age at baseline, years <20 937,338 20-24 3,552,857 25-29 5,937,978 30-34 3,810,711 35-39 1,234,179 ≥40 195,359 Total parity 1 6,500,507 2 6,496,677 ≥3 2,671,239 Socioeconomic status Disadvantaged 2,844,289 No 11,114,129 Year at baseline 1989-1996 10,402,683 1997-2004 3,678,964 2005-2013 1,586,776 Total 15,668,423 a Hypertension, dyslipidemia, obesity, smoking, asthma
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No. women with cataracts
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ACCEPTED MANUSCRIPT Table 2 Cumulative incidence of cataract for women with and without gestational diabetes
71,862 1,923 7,819 62,120 1,012,937
444 17 50 377 4,803
22.6 (19.0, 26.6) 22.5 (12.1, 38.2) 20.0 (13.9, 27.9) 23.0 (18.9, 27.7) 15.1 (14.3, 15.9)
124 320 223 4,580
76.0 (61.6, 92.3) 17.5 (14.0, 21.7) 73.9 (50.2, 103.4) 14.3 (13.6, 15.1)
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No. women with cataract
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Gestational diabetes Yes, any infant birth weight Yes, birth weight ≥4500g Yes, birth weight 4000-4499g Yes, birth weight <4000g No Late onset or type 2 diabetes Gestational and type 2 diabetes Gestational diabetes only Type 2 diabetes only No diabetes
Cumulative incidence at 25 years per 1,000 women (95% confidence interval)
No. women
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ACCEPTED MANUSCRIPT Table 3 Association between gestational diabetes and subsequent risk of cataract
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Hazard ratio (95% confidence interval) Unadjusted Partially adjusteda Adjustedb
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Time-fixed analysis Gestational diabetes Yes 1.55 (1.41, 1.71) 1.32 (1.20, 1.46) 1.15 (1.04, 1.28) No Referent Referent Referent Gestational diabetes and infant birth weight Yes, ≥4500g 1.84 (1.14, 2.96) 1.76 (1.09, 2.84) 1.37 (0.85, 2.20) Yes, 4000-4499g 1.47 (1.11, 1.94) 1.33 (1.01, 1.76) 1.11 (0.84, 1.47) Yes, <4000g 1.55 (1.40, 1.72) 1.30 (1.17, 1.45) 1.15 (1.03, 1.28) No Referent Referent Referent Time-varying analysis Gestational diabetes Yes 1.61 (1.46, 1.78) 1.33 (1.19, 1.50) 1.14 (1.01, 1.29) No Referent Referent Referent Gestational diabetes and infant birth weight Yes, ≥4500g 2.03 (1.26, 3.29) 1.81 (1.12, 2.93) 1.36 (0.84, 2.22) Yes, 4000-4499g 1.59 (1.19, 2.12) 1.35 (1.01, 1.80) 1.11 (0.83, 1.48) Yes, <4000g 1.67 (1.48, 1.88) 1.31 (1.16, 1.49) 1.14 (1.01, 1.30) No Referent Referent Referent a Adjusted for comorbidity (hypertension, dyslipidemia, obesity, smoking, asthma), age, year, parity, and socioeconomic status Adjusted for comorbidity, age, year, parity, socioeconomic status, and type 2 diabetes
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ACCEPTED MANUSCRIPT Table 4 Influence of type 2 diabetes on the association between gestational diabetes and subsequent risk of cataract
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Time-fixed analysis Gestational and type 2 diabetes 6.15 (5.14, 7.35) 3.62 (3.01, 4.35) Gestational diabetes only 1.25 (1.12, 1.40) 1.12 (1.00, 1.25) Type 2 diabetes only 4.82 (4.22, 5.52) 2.81 (2.44, 3.24) No diabetes Referent Referent Time-varying analysis Gestational and type 2 diabetes 6.40 (5.31, 7.72) 3.81 (3.10, 4.68) Gestational diabetes only 1.31 (1.15, 1.49) 1.15 (1.01, 1.31) Type 2 diabetes only 6.14 (4.73, 7.98) 3.67 (2.78, 4.83) No diabetes Referent Referent a Adjusted for comorbidity (hypertension, dyslipidemia, obesity, smoking, asthma), age, year,
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ACCEPTED MANUSCRIPT Figure 1 Gestational diabetes and cumulative incidence of cataract according to number of years
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Legend: Panel A = Gestational diabetes according to infant birth weight; Panel B = Gestational
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diabetes and later onset of type 2 diabetes
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ACCEPTED MANUSCRIPT Table S1 Gestational diabetes and age at pregnancy and at cataract extraction
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3,837 (5.3) 13,527 (18.8) 24,152 (33.6) 19,487 (27.1) 8,750 (12.2) 2,109 (2.9)
26 (2.0) 38 (6.3) 45 (24.3) 50 (35.1) 53.5 (23.9) 56 (8.3)
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60,144 (5.9) 227,284 (22.4) 380,615 (37.6) 247,806 (24.5) 83,009 (8.2) 14,079 (1.4)
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31 (1.6) 38 (9.6) 44 (28.6) 49 (33.5) 54 (20.7) 58 (6.0)
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At cataract extraction
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Gestational diabetes Median age, years Age group, N (%) <20 20-24 25-29 30-34 35-39 ≥40 No gestational diabetes Median age, years Age group, N (%) <20 20-24 25-29 30-34 35-39 ≥40
At pregnancy
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ACCEPTED MANUSCRIPT HIGHLIGHTS
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Type 2 diabetes is associated with cataract, but the risk for women with gestational diabetes has
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not been studied.
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We show that gestational diabetes may be an independent risk factor for cataract, even among
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women who never develop type 2 diabetes.
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Women with gestational diabetes may merit closer follow-up after pregnancy for prevention and
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treatment of cataracts.
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