Undiagnosed type 2 diabetes during pregnancy is associated with increased perinatal mortality: a large population-based cohort study in Ontario, Canada.

AIM: To compare perinatal outcomes in women with undiagnosed diabetes with gestational diabetes alone, pre-existing diabetes and women without diabetes, and to identify risk factors which distinguish them from women with gestational diabetes alone. METHODS: This population-based cohort study included administrative data on all women who gave birth in Ontario, Canada, during 2002-2015. Maternal/neonatal outcomes were compared across groups using logistic regression, adjusting for confounders. A nested case control study compared women with undiagnosed type 2 diabetes with women with gestational diabetes alone to determine risk factors that would help identify these women. RESULTS: Among 995 990 women, 68 163 had gestational diabetes (6.8%) and, of those women with gestational diabetes,1772 had undiagnosed type 2 diabetes (2.6%). Those with undiagnosed type 2 diabetes were more likely to be older, from a lower income area, have parity > 3 and BMI ≥ 30 kg/m2 compared with gestational diabetes alone. Infants had a higher risk of perinatal mortality (OR 2.3 [1.6-3.4]), preterm birth (OR 2.6 [2.3-2.9]), congenital anomalies (OR 2.1 [1.7-2.5]), neonatal intensive care unit admission (OR 3.1 [2.8-3.5]) and neonatal hypoglycaemia (OR 406.0 [357-461]), which were similar to women with pre-existing diabetes. The strongest predictive risk factors included early gestational diabetes diagnosis, previous gestational diabetes and chronic hypertension. CONCLUSIONS: Women diagnosed with gestational diabetes who develop diabetes within 1 year postpartum are at higher risk of adverse pregnancy outcomes, including perinatal mortality. This highlights the need for earlier diagnosis, preferably pre-pregnancy, and more aggressive treatment and surveillance of suspected type 2 diabetes during pregnancy.

Risk of contralateral lower limb amputation and death after initial lower limb amputation - a population-based study.

BACKGROUND: Lower limb amputation (LLA) is a complication of lower limb atherosclerosis, infection and tissue gangrene. Following ipsilateral LLA, the risk of major amputation of the contralateral limb or of death is unknown. The aim of this study was to determine the incidence of a contralateral major LLA, comparing those with a non-malignant/non-traumatic ipsilateral major vs. ipsilateral minor LLA. METHODS: We used pre-existing linked administrative health databases for the study. Data were provided by the Institute for Clinical Evaluation Sciences (ICES), Toronto, Ontario. This is a retrospective population-based cohort study across Ontario, Canada, 2002-2012. Cause-specific Cox regression models were used to obtain hazard ratios. Cumulative incidence functions were used to calculate the risk of contralateral major LLA and the risk of the competing event death. Individuals who did not survive at least 30 days after their first ipsilateral LLA were excluded since they were ineligible to have a contralateral LLA. RESULTS: 5,816 adults underwent an ipsilateral major and 4,143 an ipsilateral minor LLA. The incidences of contralateral major LLA were 4.8 and 2.2 (adjusted HR 2.41, 95% CI 2.04-2.84) after ipsilateral major and minor LLA, respectively. Incidence of death was 18.9 and 11.4 (adjusted HR 1.22, 95% CI 1.13-1.31) following ipsilateral major and minor LLA, respectively. CONCLUSION: There is high incidence of a contralateral major LLA and even higher risk of death following the ipsilateral LLA. Healthcare professionals should develop strategies for contralateral limb preservation in individuals with existing ipsilateral LLA.

Effect of multiparity and ethnicity on the risk of development of diabetes: a large population-based cohort study.

AIMS: To investigate the relationship between increasing parity and diabetes in a large, population-based cohort, and to examine if this relationship is different among high-risk ethnic groups. METHODS: A population-based, retrospective cohort study was performed in 738 440 women aged 18-50 years, who delivered babies in Ontario between 1 April 2002 and 31 March 2011. Diabetes incidence postpartum was calculated for each parity and ethnic group. A multivariable analysis of the effect of parity and ethnicity on the incidence of diabetes was performed using a Cox proportional hazards model, adjusting for confounders. RESULTS: The diabetes incidence rate per 1000 person-years was 3.69 in women with 1 delivery, 4.12 in women with 3 deliveries and 7.62 in women with ≥5 deliveries. Women with ≥3 deliveries had a higher risk of developing diabetes compared with women with 1 delivery [adjusted hazard ratios 1.06 (95% CI 1.01-1.11) for 3 deliveries, 1.33 (95% CI 1.25-1.43) for 4 deliveries and 1.53 (95% CI 1.41-1.66) for ≥5 deliveries). A similar rise in risk could be seen in Chinese and South-Asian women, with the most influence in Chinese women [hazard ratio 4.59 (95% CI 2.36-8.92) for ≥5 deliveries]. CONCLUSIONS: There was a positive and graded relationship between increasing parity and risk of development of diabetes. The influence of parity was seen in all ethnicities. This association may be partly related to increasing weight gain and retention with increasing parity, or deterioration in ß-cell function. This merits further exploration.

Impact of diabetes on healthcare costs in a population-based cohort: a cost analysis.

AIMS: To estimate the healthcare costs attributable to diabetes in Ontario, Canada using a propensity-matched control design and health administrative data from the perspective of a single-payer healthcare system. METHODS: Incident diabetes cases among adults in Ontario were identified from the Ontario Diabetes Database between 2004 and 2012 and matched 1:3 to control subjects without diabetes identified in health administrative databases on the basis of sociodemographics and propensity score. Using a comprehensive source of administrative databases, direct per-person costs (Canadian dollars 2012) were calculated. A cost analysis was performed to calculate the attributable costs of diabetes; i.e. the difference of costs between patients with diabetes and control subjects without diabetes. RESULTS: The study sample included 699 042 incident diabetes cases. The costs attributable to diabetes were greatest in the year after diagnosis [C$3,785 (95% CI 3708, 3862) per person for women and C$3,826 (95% CI 3751, 3901) for men], increasing substantially for older age groups and patients who died during follow-up. After accounting for baseline comorbidities, attributable costs were primarily incurred through inpatient acute hospitalizations, physician visits and prescription medications and assistive devices. CONCLUSIONS: The excess healthcare costs attributable to diabetes are substantial and pose a significant clinical and public health challenge. This burden is an important consideration for decision-makers, particularly given increasing concern over the sustainability of the healthcare system, aging population structure and increasing prevalence of diabetic risk factors, such as obesity.

Early specialist care for diabetes: who benefits most? A propensity score-matched cohort study.

AIMS: To examine whether early endocrinologist care reduces the risk of cardiovascular complications among newly diagnosed patients with diabetes of differing complexity. METHODS: We conducted a population-based propensity score-matched cohort study using provincial health data from Ontario, Canada. Adults (≥ 30 years) diagnosed with diabetes between 1 April 1998 and 31 March 2006 who received endocrinologist care in the first year of diagnosis were matched to a comparison group receiving primary care alone (N = 79 020) based on propensity scores and medical complexity (assigned using information on chronic conditions). Individuals were followed for 3- and 5-year outcomes, including non-fatal acute myocardial infarction or coronary heart disease death (primary endpoint), major cardiovascular events (acute myocardial infarction, stroke) or all-cause death, amputation and end-stage renal disease. RESULTS: Among medically complex patients, early endocrinologist care was associated with a lower 3-year incidence of the primary endpoint (hazard ratio 0.89, 95% CI 0.78-1.01) and major cardiovascular events or all-cause death (hazard ratio 0.91, 95% CI 0.85-0.97). These effects persisted after accounting for a higher incidence of end-stage renal disease on follow-up and were greatest in those with ≥ 3 visits to an endocrinologist (primary endpoint: hazard ratio 0.69, 95% CI 0.56-0.86 and 0.61, 95% CI 0.45-0.82, for unadjusted and end-stage renal disease adjusted analyses, respectively). In contrast, no benefit was observed in the non-medically complex subgroup. Overall effects were similar at 5 years. CONCLUSIONS: Early endocrinologist care is associated with a lower incidence of cardiovascular events and death among newly diagnosed patients with diabetes who have comorbid medical conditions.

Gender differences in the impact of poverty on health: disparities in risk of diabetes-related amputation.

AIMS: To assess the combined impact of socio-economic status and gender on the risk of diabetes-related lower extremity amputation within a universal healthcare system. METHODS: We conducted a population-based cohort study using administrative health databases from Ontario, Canada. Adults with pre-existing or newly diagnosed diabetes (N = 606 494) were included and the incidence of lower extremity amputation was assessed for the period 1 April 2002 to 31 March 2009. Socio-economic status was based on neighbourhood-level income groups, assigned to individuals using the Canadian Census and their postal code of residence. RESULTS: Low socio-economic status was associated with a significantly higher incidence of lower extremity amputation (27.0 vs 19.3 per 10,000 person-years in the lowest (Q1) vs the highest (Q5) socio-economic status quintile. This relationship persisted after adjusting for primary care use, region of residence and comorbidity, and was greater among men (adjusted Q1:Q5 hazard ratio 1.41, 95% CI 1.30-1.54; P < 0.0001 for all male gender-socio-economic status interactions) than women (hazard ratio 1.20, 95% CI 1.06-1.36). Overall, the incidence of lower extremity amputation was higher among men than women (hazard ratio for men vs women: 1.87, 95% CI 1.79-1.96), with the greatest disparity between men in the lowest socio-economic status category and women in the highest (hazard ratio 2.39, 95% CI 2.06-2.77 and hazard ratio 2.30, 95% CI 1.97-2.68, for major and minor amputation, respectively). CONCLUSIONS: Despite universal access to hospital and physician care, we found marked socio-economic status and gender disparities in the risk of lower extremity amputation among patients with diabetes. Men living in low-income neighbourhoods were at greatest risk.

Impact of socio-economic status on breast cancer screening in women with diabetes: a population-based study.

AIMS: There is evidence to suggest that mammography rates are decreased in women with diabetes and in women of lower socio-economic status. Given the strong association between low socio-economic status and diabetes, we explored the extent to which differences in socio-economic status explain lower mammography rates in women with diabetes. METHODS: A population-based retrospective cohort study in Ontario, Canada, of women aged 50 to 69 years with diabetes between 1999 and 2010 age matched 1:2 to women without diabetes. Main outcome measure is the likelihood of at least one screening mammogram in women with diabetes within a 36-month period, starting as of either 1 January 1999, their 50th birthday, or 2 years after diabetes diagnosis--whichever came last. Outcomes were compared with those in women without diabetes during the same period as their matched counterparts, adjusting for socio-economic status based on neighbourhood income and other demographic and clinical variables. RESULTS: Of 504,288 women studied (188,759 with diabetes, 315,529 with no diabetes), 63.8% had a screening mammogram. Women with diabetes were significantly less likely to have a mammogram after adjustment for socio-economic status and other factors (odds ratio 0.79, 95% CI 0.78-0.80). Diabetes was associated with lower mammogram use even in women from the highest socio-economic status quintile (odds ratio 0.79, 95% CI 0.75-0.83). CONCLUSIONS: The presence of diabetes was an independent barrier to breast cancer screening, which was not explained by differences in socio-economic status. Interventions that target patient, provider, and health system factors are needed to improve cancer screening in this population.

Mortality trends in patients with and without diabetes in Ontario, Canada and the UK from 1996 to 2009: a population-based study.

AIMS/HYPOTHESIS: The aim of this study was to determine the contemporary rate ratio of mortality and changes over time in individuals with vs without diabetes. METHODS: Annual age- and sex-adjusted mortality rates were compared for adults (>20 years) with and without diabetes in Ontario, Canada, and the UK from January 1996 to December 2009 using The Health Improvement Network (THIN) and Ontario databases. The total number of individuals evaluated increased from 8,757,772 in 1996 to 12,696,305 in 2009. RESULTS: The excess risk of mortality for individuals with diabetes in both cohorts was significantly lower during later vs earlier years of the follow-up period (1996-2009). In Ontario the diabetes mortality rate ratio decreased from 1.90 (95% CI 1.86, 1.94) in 1996 to 1.51 (1.48, 1.54) in 2009, and in THIN from 2.14 (1.97, 2.32) to 1.65 (1.57, 1.72), respectively. In Ontario and THIN, the mortality rate ratios among diabetic patients in 2009 were 1.67 (1.61, 1.72) and 1.81 (1.68, 1.94) for those aged 65-74 years and 1.11 (1.10, 1.13) and 1.19 (1.14, 1.24) for those aged over 74 years, respectively. Corresponding rate ratios in Ontario and THIN were 2.45 (2.36, 2.54) and 2.64 (2.39, 2.89) for individuals aged 45-64 years, and 4.89 (4.35, 5.45) and 5.18 (3.73, 6.69) for those aged 20-44 years. CONCLUSIONS/INTERPRETATION: The excess risk of mortality in individuals with vs without diabetes has decreased over time in both Canada and the UK. This may be in part due to earlier detection and higher prevalence of early diabetes, as well as to improvements in diabetes care.

The impact of exercise consultation on activity levels and metabolic markers in obese adolescents: a pilot study.

Objective. To assess the impact of exercise consultation on physical activity (PA) levels, anthropometric measures, and metabolic markers in obese adolescents. Methods. Obese adolescents (14-18 years) were randomized to either an exercise consultation (intervention group) or to review "Canada's Physical Activity Guide for Youth" (control group). Outcomes, including accelerometry, anthropometrics, blood pressure, stage of exercise behavior change, fasting glucose, insulin, and lipids, were measured at baseline and 3 months later. Results. Thirty adolescents (mean BMI = 36.1 kg/m(2); SD = 6.9) completed the study. At follow-up, the intervention group had significantly greater PA compared with controls (P < .05). Similarly, the intervention group weighed an average 2.6 kg less than the control group (P < .05), with a mean BMI z-score of 2.15 compared to 2.21 for controls (P = .054). No other differences were noted. Conclusion. Exercise consultation may be a simple approach to increase PA levels, reduce weight, and lower BMI in obese adolescents.

Use of vascular risk-modifying medications for diabetic patients differs between physician specialties.

AIMS: Although heart disease and stroke are the underlying causes of death in most people with diabetes, vascular risk modification targets are frequently not met. This study examined whether vascular risk-modifying medication utilization for diabetic patients differed among physician specialties. METHODS: A population-based study using administrative data from 105 715 people aged >/= 65 years with newly diagnosed diabetes in Ontario between 1994 and 2001. The receipt of antihypertensive and lipid-lowering drugs was compared between patients who had regular care from endocrinologists, internists/geriatricians and family physicians. Hierarchical logistic regression adjusted for patient-level differences, physician-level differences and patient clustering within physicians. RESULTS: Only two-thirds of patients received antihypertensive drugs and about one-quarter received lipid-lowering drugs. Compared with patients of family physicians, the adjusted odds ratios for antihypertensive drug use were 1.27 [95% confidence interval (CI) 1.16, 1.38] for patients of internists/geriatricians and 1.03 (95% CI 0.94, 1.12) for patients of endocrinologists. For lipid-lowering drugs, the odds ratios were 1.20 (95% CI 1.11, 1.30) for patients of internists/geriatricians and 1.58 (95% CI 1.42, 1.76) for patients of endocrinologists. CONCLUSIONS: Despite recommendations to use vascular risk-modifying medication for most older people with diabetes, many patients were not receiving these medications. Medication utilization differed between physician specialties, with family physicians having the lowest rates of use. Notably, although blood pressure control has the greatest evidence of benefit and is cost-saving, endocrinologists did not use antihypertensive drugs more often than family physicians after adjustment for other differences.

Distinct clonal composition of primary and metastatic adrencorticotrophic hormone-producing pituitary carcinoma.

The pathogenetic mechanisms underlying pituitary tumorigenesis are largely unknown. Previous reports have suggested that aggressive pituitary adenomas and/or carcinomas may be associated with genetic alterations that are distinct from those responsible for the more common and less aggressive pituitary adenomas. Here, we describe the clonal composition of a pituitary carcinoma, its recurrence and its metastasis. The samples studied were from a 48-year-old woman who presented with recurrent Cushing's syndrome. During the 8-year course of her disease, she had an ACTH-producing pituitary carcinoma requiring two transsphenoidal procedures and resection of a metastatic cervical lymph node. Her disease remained active despite surgical resection, external beam irradiation and medical treatment with ketoconazole. Ultimately, bilateral adrenalectomy was performed to control the hypercortisolism. Morphological and immunohistochemical studies revealed that the primary and recurrent pituitary tumours and the metastatic lesion were an endocrine tumour with ACTH and growth hormone immunoreactivity. Primary, recurrent and metastatic tumour DNAs were analysed for X-chromosome inactivation and loss of heterozygosity (LOH) at several microsatellite loci on chromosomes 9,10, 11, 13 and 22. All three lesions were monoclonal in composition as suggested by the pattern of X chromosome inactivation of the PGK-1 allele. Moreover, the primary, recurrent and metastatic lesions demonstrated LOH at the microsatellite allelic markers PYGM and D10S217. In contrast, however, the metastatic lesion showed a loss-to-retention pattern at two distinct loci (IFNA and D22S156) compared to the primary and recurrent pituitary tumours. These findings, while consistent with a clonal composition of the primary and metastatic pituitary lesions, show each clone to be distinct. This is the first description of a metastatic pituitary carcinoma with a distinct clonal composition from its primary source.

Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care.

OBJECTIVE: To establish guidelines for the screening and treatment of hyperhomocysteinemia in the investigation and management of coronary artery disease (CAD). OPTIONS: Measurement of plasma total homocysteine (tHcy) levels in the fasting state or 4-6 hours after oral methionine load; vitamin supplementation with folic acid and vitamins B6 and B12; adherence to the recommended daily allowance of dietary sources of folate and vitamins B6 and B12. OUTCOMES: This article reviews the available evidence on the association between plasma tHcy levels and CAD and the effect of lowering tHcy levels through vitamin supplementation or dietary intake. EVIDENCE: MEDLINE was searched for relevant English-language articles published from January 1966 to June 1999; also reviewed were additional articles identified from the bibliographies. BENEFITS, HARMS AND COSTS: Cardiovascular disease is the leading cause of death in Canada. Homocysteine, generated in the metabolism of methionine, may have a role in the development of cardiovascular disease. The prevalence of hyperhomocysteinemia in the general population is between 5% and 10% and may be as high as 30%-40% in the elderly population. If population-based studies are correct, tHcy may be responsible for up to 10% of CAD events and thus may represent an important and potentially modifiable risk factor for cardiovascular disease. Laboratory testing for tHcy is currently restricted to research centres, and costs range from $30 to $50 per person. Newer, less costly techniques have been developed and should become readily available with time. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. RECOMMENDATIONS: Although there is insufficient evidence to recommend the screening or management of hyperhomocysteinemia at present (grade C recommendation), adherence to recommended daily allowance of dietary sources of folate and vitamins B12 and B6 should be encouraged. If elevated tHcy levels are discovered, vitamin deficiency should be ruled out to allow specific treatment and prevention of complications, such as neurological sequelae due to vitamin B12 deficiency. Experts in the field advocate treatment of elevated tHcy levels in high-risk people, such as those with a personal or family history of premature atherosclerosis or a predisposition to develop hyperhomocysteinemia. Definitive guidelines for the management of hyperhomocysteinemia await the completion of randomized trials to establish the effect of vitamin supplementation on CAD events. VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care. SPONSORS: The Canadian Task Force on Preventive Health Care is funded through a partnership between the Provincial and Territorial Ministries of Health and Health Canada.

Clinicopathological variations in cushing's syndrome.

In the majority of cases, Cushing's disease is the result of a small basophilic corticotroph microadenoma with an average size of less than 5 mm. Transsphenoidal microsurgery can cure patients with Cushing's disease; however, selective removal of the lesion requires precise preoperative localization. In this article, we present the pathological findings and clinical outcomes of four patients who underwent inferior petrosal sinus sampling (IPSS) for ACTH, pituitary imaging and subsequent transsphenoidal surgery for the diagnosis and treatment of Cushing's disease. All patients fulfilled accepted biochemical criteria for the diagnosis of ACTH-dependent Cushing's syndrome. Histological examination revealed a basophilic corticotroph adenoma in two patients. In one other patient, only Crooke's hyalinization was found; however, the patient achieved a complete clinical and biochemical remission following a hemihypophysectomy based on IPSS findings. Thus, a microadenoma was assumed or proven in three patients, of whom two were cured by surgery alone. In the third patient, cortisol excess persisted following transsphenoidal surgery because of a coexistent functioning adrenal adenoma. The fourth patient developed recurrent nodular corticotroph hyperplasia following a 17-yr remission. The second transsphenoidal procedure failed to ameliorate cortisol excess, necessitating a subsequent bilateral adrenalectomy. IPSS accurately localized the site of the lesion in all four cases. Although magnetic resonance imaging (MRI) identified a distinct lesion in three cases, two of these represented false positives (a cyst in one case and a prolactinoma in the other), whereas in only one did MRI correctly match the site of the lesion. In each case, conflicting test results and/or difficult management decisions posed a challenge. Thus, successful resolution of disease requires a multidisciplinary approach to validate clinical, biochemical, and radiographic data based on morphologic findings.

Improved diagnostic accuracy of inferior petrosal sinus sampling over imaging for localizing pituitary pathology in patients with Cushing's disease.

The majority of patients with Cushing's disease can be cured by transsphenoidal microsurgery; however, precise localization of the pituitary source of ACTH is not always possible by standard imaging techniques. Bilateral venous sampling from the inferior petrosal sinuses (IPSS) is also useful for diagnosing Cushing's disease, but the interpretation of discordant findings between IPSS and imaging remains problematic. We tested the ability of imaging and IPSS to localize an ACTH-secreting pituitary lesion in comparison to definitive histopathological examination of the pituitary in patients with Cushing's disease (n = 37). Bilateral IPS catheterization was technically feasible in 32 patients and provided evidence of lateralization in 31 patients. Histological examination confirmed a corticotropic adenoma in 28 patients and corticotropic hyperplasia in 2 patients; Crooke's hyaline change was found in 7 patients, among whom 1 subsequently was found to have an ectopic sphenoid corticotropic adenoma, and the remainder had suspected microadenomas that were not identified microscopically. Accurate localization of the pituitary lesion was more frequent when based on IPSS results than on imaging studies (70% vs. 49%, P < 0.06). The 2 tests provided directly discrepant results for 8 patients; among these, IPSS was more likely than imaging to agree with final pathology (63% vs. 13%, P < 0.10). Imaging was entirely normal for another 9 patients, in whom IPSS accurately localized the lesion for the majority (89%; 95% confidence interval: 50-99%). We suggest that IPSS is an effective tool for localizing pituitary pathology and planning surgery for patients with Cushing's disease.

The treatment of unrelated disorders in patients with chronic medical diseases.

BACKGROUND: Patients can have several illnesses concurrently, yet some of these diseases may be neglected if one problem consumes attention. We conducted a population-based analysis in Ontario, Canada - where universal health insurance is provided - to determine whether unrelated disorders are less likely to be treated in patients with chronic diseases. METHODS: We studied the 1,344,145 residents of Ontario in 1995 who were 65 or older and eligible to receive prescription medications free of charge as part of the Ontario Drug Benefit program. Patients with diabetes mellitus were identified by prescriptions for insulin, pulmonary emphysema by prescriptions for ipratropium bromide, and psychotic syndromes by prescriptions for haloperidol. For each chronic disease, we selected an unrelated treatment: estrogen-replacement therapy for patients with diabetes mellitus, lipid-lowering medications for those with pulmonary emphysema, and medical treatment of arthritis for those with psychotic syndromes. RESULTS: The 30,669 patients with diabetes mellitus were less likely to receive estrogen-replacement therapy than the other subjects in the study (2.4 percent vs. 5.9 percent, P<0.001). The disease was associated with a 60 percent reduction in the odds of estrogen treatment (odds ratio, 0.40; 95 percent confidence interval, 0.37 to 0.43). Findings were similar for the 56,779 patients with pulmonary emphysema, who were less likely to receive lipid-lowering medications (odds ratio, 0.69; 95 percent confidence interval, 0.67 to 0.72; P<0.001), and the 17,336 patients with psychotic syndromes, who were less likely to receive medical treatments for arthritis (odds ratio, 0.59; 95 percent confidence interval, 0.57 to 0.62; P<0.001). CONCLUSIONS: In patients 65 or older who have chronic medical diseases and who receive prescription medications free of charge, unrelated disorders are undertreated. Clinicians caring for patients with chronic diseases should remain alert to other disorders and minimize the number of missed opportunities for treating them.