Epidemiology Publications // 2013-2014
Ungaro R, Bernstein CN, Gearry R, Hviid A, Kolho KL, Kronman M, Shaw S, Van Kruiningen H, Colombel JF. Antibiotics associated with increased risk of new onset Crohn's disease but not ulcerative colitis: A meta-analysis. American Journal of Gastroenterology 2014; 109: 1728-1738.
The objective of this study was to perform a meta-analysis investigating antibiotic exposure as a risk factor for developing IBD. A literature search using Medline, Embase, and Cochrane databases was performed to identify studies providing data on the association between antibiotic use and newly diagnosed IBD. Included studies reported Crohn's disease, ulcerative colitis (UC), or a composite of both (IBD) as the primary outcome and evaluated antibiotic exposure before being diagnosed with IBD. A total of 11 observational studies (8 case-control and 3 cohort) including 7,208 patients diagnosed with IBD were analyzed. The pooled increased likelihood for IBD patients to be exposed to any antibiotic was an increase of 57%. Antibiotic exposure was significantly associated with Crohn’s disease but was not significant for UC. Exposure to antibiotics most markedly increased the risk of CD in children by nearly threefold. All antibiotics were associated with IBD, with the exception of penicillin. Exposure to metronidazole was associated with a 5-fold risk for IBD and fluoroquinolones were associated with nearly a 2-fold risk for developing IBD.
Targownik LE, Nugent Z, Singh H, Bugden S, Bernstein CN. The prevalence and predictors of opioid use in inflammatory bowel disease: a population based analysis. American Journal of Gastroenterology 2014; 109: 1613-1620.
Opioids are commonly used in the treatment of pain and associated symptoms of IBD. The continuous use of opioids has been associated with adverse outcomes, including death. The prevalence and the risk factors for opioid use in IBD are poorly characterized. We used the population based University of Manitoba IBD Epidemiology Database to identify all persons in Manitoba with IBD who were prescribed opioids both prior to and following diagnosis. We determined the point prevalence of any opioid use, as well as the risk of becoming a heavy opioid user (defined as continuous use for at least 30 days at a dose exceeding 50mg morphine/day or equivalent: Within 10 years of diagnosis, 5% of persons with IBD had become heavy opioid users. Moderate use of opioids prior to diagnosis was strongly predictive of future heavy use. Persons with IBD were significantly more likely to become heavy opioid users than their matched controls. Heavy opioid use was three times as likely to be associated with mortality. We concluded that IBD is an independent risk factor for becoming a heavy opioid user, and heavy opioid use is associated with excess mortality in IBD patients. Clinicians should recognize risk factors for future heavy opioid use among their patients with IBD.
Marrie RA, Garland A, Peschken CA, Hitchon CA, Chen H, Fransoo R, Bernstein CN. Increased incidence of critical illness among patients with inflammatory bowel disease: A population-based study. Clinical Gastroenterology and Hepatology 2014; 12: 2063-2070.
Little is known about intensive care unit (ICU) admission in IBD. We aimed to determine the incidence of, and mortality after ICU admission in IBD as compared to the general population, and the characteristics of critical illness (Critical illness refers to illness that leads to ICU admission) in the IBD population. We identified all persons with IBD in the province of Manitoba using a validated administrative definition of IBD for the period 1984 to 2010. Cases were considered newly diagnosed with IBD if their first health system contact for IBD was in 1989 or later. We identified a population-based control group, matched by age, sex and geography (postal code). Case and control cohorts were linked to the Manitoba ICU database containing clinical data from 93% of provincial high intensity adult ICUs. Incidence of ICU admission, reasons for ICU admission, and mortality after ICU admission were compared between groups. There were 8224 prevalent and 4580 incident cases of IBD. The risk for ICU admission was nearly twofold higher for IBD versus controls. From 2000-2010, the age and sex-standardized annual incidence of ICU admission among the prevalent IBD cohort was 0.55-1.12% (1 out of every 100 to 200 persons with IBD may get admitted to an ICU per year). Compared to controls admitted to ICUs, one year after ICU admission, mortality was increased by 32% in IBD. We concluded that in IBD there is an increased risk for ICU admission and increased mortality at one year post-ICU admission. This underscores the potential severity of IBD.
Targownik LE, Singh H, Nugent Z, Bernstein CN. Prevalence of and outcomes associated with corticosteroid prescription in inflammatory bowel disease. Inflammatory Bowel Diseases 2014; 20: 622-630.
Corticosteroids are widely utilized in the management of inflammatory bowel disease (IBD), and are associated with significant side effects. The real world effectiveness of newer drug therapies at reducing corticosteroid use has yet to be reported. The overall burden of corticosteroid use and its effects are also poorly characterized. We used the population-based University of Manitoba IBD Epidemiology Database to evaluate the overall prevalence of corticosteroid exposure, time free of corticosteroid use, and heavy corticosteroid use over the course of disease. Heavy corticosteroid use was defined as more than 3000mg of prednisone or equivalent in a 365 day period. The proportion of persons with IBD who were prescribed corticosteroids within 1, 5 and 10 years of disease was 35.2%, 52.0%, and 62.8%, respectively. Persons with ulcerative colitis, males, and those diagnosed before age 25 were more likely to use corticosteroids and have higher cumulative corticosteroid exposure. Heavy corticosteroid use in the first year following IBD diagnosis was associated with nearly 3 times increased risk of resective surgery. Cumulative corticosteroid exposure did not decrease among those diagnosed with IBD in more recent years, in spite of increasing use of immunomodulator agents. We concluded that the majority of IBD patients will be exposed to corticosteroids over the course of disease, mostly in the first year. Heavy corticosteroid use in the first year of IBD is a strong predictor of subsequent surgery. Cumulative exposure to corticosteroids use is not decreasing despite increasing uptake of immunomodulators (azathioprine, 6-mercatopurine or methotrexate).
Shaw S, Nugent Z, Targownik LE, Singh H, Bernstein CN. Spring season of birth and Crohn’s disease. Clinical Gastroenterology and Hepatology 2014; 12:277-282.
Similar to many complex diseases, seasonal variation in the incidence of IBD has been demonstrated. Persons born in different seasons may potentially have variable rates of exposures to various potential causative factors, such as sunlight, antibiotics and prevalent infections. This study sought to explore the relationship between season of birth, early childhood antibiotic exposure, and development of childhood IBD. We used the population-based University of Manitoba Inflammatory Bowel Disease Epidemiology Database. Seasons of birth for 11,145 IBD cases and 108,633 controls were compared. Antibiotic data in the first year of life for cases and controls were drawn from the Manitoba Drug Program Information Network, a comprehensive database of all prescription drugs for all Manitobans dating back to 1995. Approximately 27.0% of cases were born between April and June, compared to 25.6% of controls. While this difference seems small it was statistically significant, meaning that it was not likely to happen by chance. Stratification by sex (male vs. female) and type of IBD (ulcerative colitis vs. Crohn’s disease) revealed that only males with Crohn’s disease were more likely to be diagnosed in spring. Antibiotic use for both cases and controls showed a significantly higher amount of antibiotic prescriptions for those born between April and June at 6 months of age and older. In summary, this study found male subjects diagnosed with Crohn’s disease were more likely to have been born between April and June. This raises questions as to whether the important risk for male babies is something in the environment during spring at time of birth or alternatively perhaps when male babies are 6 months of age this is more likely to occur during winter time where there may be an increased risk for flu like illnesses.
El-Matary W, Bernstein CN, Moroz S. Inflammatory bowel disease in children of Manitoba: 30 years' experience of a tertiary center. Journal of Pediatric Gastroenterology and Nutrition 2014; 59: 763-66.
The aim of this study was to describe the incidence and prevalence of IBD in children less than17 years of age in the years from 1978 to 2007. From January 1, 1978, to December 31, 2007, the sex- and age-adjusted annual incidence and prevalence of pediatric IBD per 100,000 population were calculated based on the pediatric IBD database of the only pediatric tertiary center in the province. The annual health statistics records for the Province of Manitoba were used to calculate population estimates for the participants. To ensure validity of data, the University of Manitoba IBD Epidemiology Database was analyzed for patients less than 17 years of age from 1989 to 2000. The sex- and age-adjusted incidence of pediatric Crohn disease increased from 1.2/100,000 in 1978 to 4.68/100,000 in 2007 (P < 0.001). For ulcerative colitis, the incidence has increased from 0.47/100,000 in 1978 to 1.64/100,000 in 2007 (P < 0.001). During the same time period, the prevalence of Crohn disease has increased from 3.1 to 18.9/100,000 (P < 0.001) and from 0.7 to 12.7/100,000 for ulcerative colitis (P < 0.001). During the last 5 years of the study the average annual incidence of IBD in urban patients was 8.69/100,000 as compared with 4.75/100,000 for rural patients (P < 0.001). We concluded that the incidence and prevalence of pediatric IBD are increasing. The majority of patients were residents of urban Manitoba, confirming the important role of environmental factors as causative in IBD.
Targownik LE, Bernstein CN, Nugent Z, Kanos J, Leslie WD. Inflammatory bowel disease and the risk of fracture after controlling for FRAX. Journal of Bone and Mineral Research 2013; 28: 1007-1013.
Subjects with IBD are at increased risk for hip and other major osteoporotic fractures. However, previous analyses have not fully accounted for differences in bone mineral density (BMD) and other clinical factors that affect the risk of fracture. The World Health Organization Fracture Risk Assessment tool (FRAX) can be used to predict the 10-year fracture risk from BMD and clinical risk factors. A population based database containing clinical information on all IBD subjects in the province of Manitoba, Canada, was linked with the Manitoba Bone Mineral Density Database, which contains results of all dual X-ray absorptiometry (DXA) scans in the province. FRAX probabilities were calculated for all subjects age at least age 50 undergoing baseline DXA testing. Subjects were followed for occurrence of major osteoporotic fractures (hip, clinical spine, wrist, humerus). After controlling for FRAX fracture probability computed with BMD, IBD was not associated with a significantly increased risk for major osteoporotic fractures but was associated with a twofold increased risk for hip fracture. The 10 year incidence of hip fracture following DXA among high risk subjects (hip fracture probability ≥3%) was significantly greater for IBD subjects than non-IBD subjects (12.1% vs. 7.1%, p=0.02). Therefore, FRAX will underestimate hip fracture risk in the presence of IBD.
Targownik LE, Bernstein CN, Nugent Z, Leslie WD. Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis. Clinical Gastroenterology and Hepatology 2013; 11: 278-285.
A high prevalence of osteoporosis has been reported in IBD. It is unclear whether IBD is itself a risk factor for low bone mineral density (BMD) or whether low BMD in IBD is related to other associated factors. Subjects with IBD were identified within the Manitoba BMD Database, containing results of BMD testing on all Manitobans since 1997. BMD was assessed at each of lumbar spine (L1-L4 mean), total hip, femoral neck, and trochanter. 45714 subjects underwent BMD testing (1230 with IBD). IBD was associated with a statistically significant, but small effect on T-score (a measure of change in BMD from the mean in healthy young adults), with no increased risk of osteoporosis at any measurement site. Crohn’s disease was associated with an increased risk of osteoporosis at the lumbar spine and trochanter, but ulcerative colitis was not associated with an increased risk of osteoporosis or lower T-score. No IBD-specific variables were associated with increased risk of osteoporosis or lower T-score. We concluded that IBD overall has only a marginal effect on BMD, though effects are more pronounced for Crohn’s disease versus ulcerative colitis. The risk of osteoporosis in IBD is related to other known osteoporosis risk factors.
Shaw S, Blanchard JF, Bernstein CN. Association between early childhood otitis media and pediatric inflammatory bowel disease: an exploratory population-based analysis. Journal of Pediatrics 2013; 162: 510-514.
The most common disease for which antibiotics are used in childhood is otitis media. Since our study exploring antibiotic use in early childhood and risk for IBD had a small sample size (because we could only access antibiotic use back to 1995) we aimed to determine if a diagnosis of otitis media in the first five years of childhood was associated with development of pediatric IBD. Otitis media was a proxy for antibiotic use since it is almost always treated with antibiotics and we could assess for otitis media diagnoses in cases and controls dating back to 1984. We assessed the population-based University of Manitoba IBD Database in Manitoba, Canada. A total of 294 pediatric IBD cases diagnosed between 1989 and 2008 were matched to 2,377 controls, based on age, sex and geographic region (Total N=2,671). Otitis media diagnoses were based on physician claims. IBD status was determined from a validated administrative database definition. By age of 5, 89% of IBD cases had at least one diagnosis of otitis media, compared to 82% of controls. Compared to cases and controls with no otitis media diagnoses, individuals with an otitis media diagnosis by the age of 5 were three times more likely of being an IBD case. This association was detected in stratified models examining Crohn’s disease and ulcerative colitis separately. We concluded that compared to controls, subjects diagnosed with IBD were more likely to have had at least one early childhood episode of otitis media prior to their diagnosis. We suspect otitis media serves as a proxy of antibiotic use.
Lix LM, Sajobi TT, Sawatzky R, Jiu J, Mayo NE, Huang Y, Graff LA, Walker JR, Ediger J, Clara I, Sexton K, Carr R, Bernstein CN. Relative importance measures for re-prioritization response shift. Quality of Life Research 2013; 22: 695-703.
Response shift, a change in the meaning of an individual’s self-evaluation of a target construct, such as health-related quality of life (HRQOL), can affect the interpretation of change in measures of the construct collected over time. This study proposes new statistical methods to test for re-prioritization response shift, in which the relative importance of HRQOL domains changes over time. The methods use descriptive discriminant analysis or logistic regression models and bootstrap inference to test for change in relative importance weights (Method 1) or ranks (Method 2) for discriminating between patient groups at two occasions. The methods are demonstrated using data from the Manitoba IBD Cohort Study (n = 388). Re-prioritization of domains from the IBD Questionnaire (IBDQ) and SF-36 was investigated for groups with active and inactive disease symptoms.We found that the IBDQ bowel symptoms and SF-36 bodily pain domains had the highest ranks for group discrimination. Using Method 1, there was evidence of re-prioritization response shift in the IBDQ social functioning domain and the SF-36 bodily pain and social functioning domains. Method 2 did not detect change for any of the domains. We concluded that compared to IBD patients without active disease symptoms, those with active symptoms were likely to change the meaning of their self-evaluations of pain and social interactions. Further research is needed to compare these new response shift detection methods under a variety of data analytic conditions before recommendations about the optimal method can be made.