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Background: Inflammatory bowel disease (IBD) may be life-threatening and often reduces quality of life. We determined trends in life expectancy and health-adjusted life expectancy in people with and without IBD., Methods: We conducted a retrospective cohort study of population-level health administrative, demographic and health survey data available from databases in Ontario. We matched people with a diagnosis of IBD to those without a diagnosis of IBD. We used period life tables that were generated using age- and sex-specific 5-year mortality rates to calculate life expectancy (for 1996, 2000, 2008 and 2011). We incorporated the Health Utility Index (National Population Health Study; Canadian Community Health Survey) to estimate health-adjusted life expectancy (for 1996, 2000 and 2008)., Results: Life expectancy in patients with IBD increased between 1996 and 2011 (females: from 75.5 to 78.4 yr, difference: 2.9 yr [95% confidence interval (CI) 1.3 to 4.5]; males: from 72.2 to 75.5 yr, difference: 3.2 yr [95% CI 2.1 to 4.4]). Between 1996 and 2008, health-adjusted life expectancy decreased among males by 3.9 years (95% CI 1.2 to 6.6). There was no statistically significant change in health-adjusted life expectancy among females with IBD (difference: 2.0 yr, 95% CI -1.6 to 5.7). Life expectancy and health-adjusted life expectancy were lower in people with IBD compared with those without IBD. Differences in life expectancy in people with and without IBD ranged from 6.6 to 8.1 years in females and 5.0 to 6.1 years in males, depending on the year. Differences in health-adjusted life expectancy for people with and without IBD ranged from 9.5 to 13.5 years in females and 2.6 to 6.7 years in males., Interpretation: Whilst life expectancy has increased among people with IBD, a gap in life expectancy between those with and without IBD remains, and the effect of pain on daily functioning contributes substantially to reduced health-adjusted life expectancy, suggesting that improved pain mitigation strategies should be implemented., Competing Interests: Competing interests: None declared., (© 2020 Joule Inc. or its licensors.)

Background: Originally used for screening of inborn errors of metabolism, routine metabolite profiles of newborns have also been associated with prematurity and some childhood diseases. We sought to determine whether metabolites measured during routine newborn screening could identify infants who develop inflammatory bowel disease (IBD) in childhood., Methods: We conducted a population-based matched case-control study using health administrative data from Ontario, Canada. Children born 2006 to 2015 with IBD were identified using a validated algorithm and matched to 5 controls based on birth date, sex, rural/urban household, and mean neighborhood income quintile at birth. Cases and controls were linked deterministically to metabolic profiles from Newborn Screening Ontario. We fit a lasso penalized logistic regression model and used 10-fold cross-validation to obtain internally valid performance measures. Models included metabolites, amino acids, and endocrine markers. Models also included ratios of metabolites, gestational age, birth weight, mode of delivery, age at serum collection, maternal age at delivery, maternal history of IBD, and parity., Results: Three hundred eight cases of IBD, diagnosed at 5.5 ± 2.8 years, were matched to 1540 controls. No individual metabolites were associated with IBD. The c-statistic was 0.50 for the training data. After 10-fold cross-validation the C statistic was 0.50, indicating no significant association between metabolites and IBD diagnosis., Conclusions: Newborn screening serum metabolites could not identify children who will develop IBD in this population-based cohort. Future studies with an expanded panel of metabolites may provide improved prediction of IBD., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Inflammatory bowel disease (IBD) is associated with a high risk of venous thromboembolism (VTE) during hospitalization. It is unclear if this association persists after discharge. We aimed to assess the incidence of postdischarge VTE in IBD patients and to determine if IBD is associated with increased VTE risk., Methods: We performed a population-based cohort study between 2002 and 2016 using Ontario health administrative data sets. Hospitalized (≥72 hours) adults with IBD were stratified into nonsurgical and surgical cohorts and matched on propensity score to non-IBD controls. Time to postdischarge VTE was assessed by Kaplan-Meier methods, and VTE risk was assessed by Cox proportional hazard models., Results: A total of 81,900 IBD discharges (62,848 nonsurgical and 19,052 surgical) were matched to non-IBD controls. The cumulative incidence of VTE at 12 months after discharge was 2.3% for nonsurgical IBD patients and 1.6% for surgical IBD patients. The incidence increased in the nonsurgical IBD cohort by 4% per year (incidence rate ratio, 1.04; 95% CI, 1.02-1.05). In our propensity score-matched analysis, the risk of VTE at 1-month postdischarge was greater in nonsurgical IBD patients (hazard ratio [HR], 1.72; 95% CI, 1.51-1.96) and surgical patients with ulcerative colitis (HR, 1.68; 95% CI, 1.16-2.45) but not surgical patients with Crohn's disease. These trends persisted through 12 months., Conclusions: Nonsurgical IBD patients and surgical patients with ulcerative colitis are 1.7-fold more likely to develop postdischarge VTE than non-IBD patients. These findings support the need for increased vigilance and consideration of thromboprophylaxis in this population., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: The combination of infliximab and azathioprine is more efficacious than either therapy alone for Crohn's disease [CD] and ulcerative colitis [UC]. However, it is uncertain whether these benefits extend to real-world clinical practice and to other combinations of biologics and immunomodulators., Methods: We collected health administrative data from four Canadian provinces representing 78 413 patients with inflammatory bowel disease [IBD] of whom 11 244 were prescribed anti-tumour necrosis factor [anti-TNF] agents. The outcome of interest was the first occurrence of treatment failure: an unplanned IBD-related hospitalization, IBD-related resective surgery, new/recurrent corticosteroid use or anti-TNF switch. Multivariable Cox proportional hazards modelling was used to assess the association between the outcome of interest and receiving combination therapy vs anti-TNF monotherapy. Multivariable regression models were used to assess the impact of choice of immunomodulator or biologic on reaching the composite outcome, and random effects generic inverse variance meta-analysis of deterministically linked data was used to pool the results from the four provinces to obtain aggregate estimates of effect., Results: In comparison with anti-TNF monotherapy, combination therapy was associated with a significant decrease in treatment ineffectiveness for both CD and UC (CD: adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.66-0.90; UC: aHR 0.72, 95% CI 0.62-0.84). Combination therapy was equally effective for adalimumab and infliximab in CD. In UC azathioprine was superior to methotrexate as the immunomodulatory agent (aHR = 1.52 [95% CI 1.02-2.28]) but not CD (aHR = 1.22 [95% CI 0.96-1.54])., Conclusion: In an analysis of a database of real-world patients with IBD, combination therapy decreased the likelihood of treatment failure in both CD and UC., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: High-income nations have the highest rates of inflammatory bowel disease (IBD). The incidence of pediatric-onset IBD is increasing faster than IBD diagnosed in older individuals. Previous epidemiological studies have shown that air pollution might be a risk factor for development of earlier-onset IBD, but results remain mixed., Objectives: The objective of this study was to evaluate the associations between maternal and early-life exposures to nitrogen dioxide (NO 2 ), fine particulate matter (PM 2.5 ), ozone (O 3 ,) and oxidant capacity (O x ) and risk of pediatric-onset IBD diagnosis., Methods: We conducted a retrospective cohort study using linked population-based health administrative data. Singleton livebirths in Ontario, Canada between April 1st, 1991 and March 31st, 2014 were included. We investigated the association between weekly exposures during pregnancy and annual exposures from birth until the age of 18 years, and IBD diagnosed <18 years of age using Cox proportional hazards models. We reported hazard ratios (HR) and 95% confidence intervals (CI) for an associated increase in the interquartile range (IQR) of each pollutant. Models were mutually adjusted for exposures in both prenatal and postnatal periods, as well as for sex, rurality of residence at birth, maternal IBD, and neighborhood income., Results: 2,218,789 newborns were included in this study, of whom 2491 developed IBD during follow-up. Increased associations with pediatric-onset IBD were noted for childhood exposure to O x (HR 1.08, 95% CI 1.01-1.16). IBD development was also associated with O x during the second trimester (HR 1.21, 95% CI 1.03-1.42), but not the overall pregnancy period (HR 1.12, 95% CI 0.79-1.59). There were no associations of IBD with exposure to NO 2 , PM 2.5 , or O 3 ., Discussion: Exposure to O x during childhood was associated with IBD < 18 years. This suggests that air pollution may impact the developing child physiology in such a way that leads to early onset of IBD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Objectives: Biliary atresia (BA) is the most common reason for liver transplant in childhood, and outcomes worsen with older age at hepatoportoenterostomy (HPE). We determined direct health care costs in children with BA, compared to controls in a population-based cohort of children in Ontario, Canada., Methods: We used health administrative data to identify all children diagnosed with BA between 2002 and 2016 (n = 121) and matched controls (n = 602). We determined annual direct healthcare costs, and rates of health services utilization, liver transplantation, death, portal hypertension, cirrhosis, esophageal varices, and major upper gastrointestinal bleeding requiring hospitalization. Multivariable regression models determined the association between age at HPE, risk of liver transplant, and direct costs., Results: Incidence of BA was 6.07 (4.99-7.15) per 100,000 live births. The annual median (interquartile range) direct health care costs were higher in BA cases ($4210; interquartile range $1091-$16,765) compared to controls ($283; $112-$634). Compared to age at HPE <45 days, there was no significant association between direct costs and HPE ≥90 days (rate ratio 1.24, 95% confidence interval [CI] 0.78-1.97) or 45 to 90 days (rate ratio 1.05, 95% CI 0.73-1.50). Age at HPE ≥90 days was significantly associated with risk of undergoing liver transplant compared to age <45 days (hazard ratio 5.27, 95% CI 2.45-11.34). Direct costs were higher in patients with BA who underwent liver transplantation compared to those who did not ($39,476±$84,367 vs $22,579 ± $67,913)., Conclusions: Direct ealth care costs were high in patients with BA, especially in those who underwent liver transplantation. Age at HPE was associated with risk of liver transplantation, but not direct health care costs, utilization, or other risk outcomes.

Background and Aims: Surgical treatment of inflammatory bowel disease (IBD) may impair female fertility. We conducted a systematic review to determine the risk of infertility and pregnancy outcomes in women with IBD who underwent surgery., Methods: We identified studies evaluating the impact of IBD surgery on infertility and pregnancy outcomes. Risk ratios (RR) and 95% confidence intervals (CIs) were pooled when data were presented using contingency tables. Odds ratios (OR) were pooled when raw numbers were not provided. GRADE was used to evaluate the certainty of evidence., Results: Sixteen observational studies were included, comparing women with and without surgery, open and laparoscopic surgery and before and after surgery. All studies were of low quality. The effect of surgery on infertility at 12 months (RR 5.45, 95% CI 0.41 to 72.57) was uncertain. Similarly, the fertility effects of laparoscopic versus open surgery method were unclear (RR 0.70, 95% CI 0.38 to 1.27). The impact of IBD surgery on pregnancy outcomes should be interpreted with caution. Surgery was associated with miscarriage (OR 2.03, 95% CI 1.14 to 3.60), use of assisted reproductive technologies (RR 25.09, 95% CI 1.56 to 403.76) and caesarean section (RR 2.23, 95% CI 1.00 to 4.95), but not with stillbirth (RR 1.96, 95% CI 0.42 to 9.18), preterm birth (RR 1.91, 95% CI 0.67 to 5.48), low birth weight (RR 0.61, 95% CI 0.08 to 4.83) or small for gestational age (RR 2.54, 95% CI 0.80 to 8.01)., Conclusion: The effect of surgical therapy for IBD on rates of female infertility and pregnancy-related outcomes was uncertain due to poor quality of existing literature., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Background: Variation in health care, when not based on patient preference, may result in poorer care. We determined whether variation in health services utilization, gastroenterologist care and outcomes existed among patients with elderly-onset inflammatory bowel disease (IBD)., Methods: Patients with IBD (diagnosed ≥65 years) were identified from population-based health administrative data from Ontario, Canada (1999 to 2014). We assessed variation across multispecialty physician networks in gastroenterologist care and outcomes using multilevel logistic regression. Median odds ratios (MOR) described variation. We evaluated the association between gastroenterologist supply, specialist care and outcomes., Results: In 4806 patients, there was significant variation in having ever seen a gastroenterologist (MOR 3.35, P < 0.0001), having a gastroenterologist as the primary IBD care provider (MOR 4.16, P < 0.0001), 5-year colectomy risk in ulcerative colitis (MOR 1.38, P = 0.01), immunomodulator use (MOR 1.47, P = 0.001), and corticosteroid use (MOR 1.26, P = 0.006). No variation in emergency department visits, hospitalizations or intestinal resection (Crohn's) was noted. Patients in networks with fewer gastroenterologists were less likely to see a gastroenterologist (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.15 to 0.56), have a gastroenterologist as their primary care provider (OR 0.27, 95% CI 0.12 to 0.59), be hospitalized within 5 years (OR 0.82, 95% CI 0.69 to 0.98), and be prescribed biologics within 1 year (OR 0.50, 95% CI 0.28 to 0.89)., Conclusions: Utilization of gastroenterology care in patients with elderly-onset IBD varies greatly. Patients treated by gastroenterologists and in networks with more gastroenterologists have better outcomes. There is a need to ensure all individuals with IBD have equal access to and utilization of specialist care to ensure the best possible outcomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Background: As a chronic noncurable disorder often diagnosed in childhood or adolescence, inflammatory bowel disease (IBD) confers a significant financial lifetime burden. The objective of this systematic review was to determine the disease-associated costs (both direct and indirect) associated with IBD in children and young adults., Methods: We conducted a systematic review of the literature and included any study reporting direct health services-related costs or the indirect economic burden of IBD in persons aged ≤19 years (PROSPERO protocol number CRD2016036128). A technical panel of experts in pediatric gastroenterology and research methodology formulated the review questions, reviewed the search strategies and review methods, and provided input throughout the review process., Results: Nine studies met criteria for inclusion, 6 of which examined direct costs, 1 of which examined both direct and indirect costs, 1 of which assessed indirect costs, and 1 of which assessed out-of-pocket (OOP) costs. Inflammatory bowel disease-associated costs were significantly higher compared with costs in non-IBD populations, with wide variations in cost estimates, which prevented us from conducting a meta-analysis. Costs in Crohn's disease were higher than in ulcerative colitis. Overall, direct costs shifted from inpatient hospitalization as a major source of direct costs to medications, mainly driven by anti-tumor necrosis factor agents, as the leading cause of direct costs. Predictors of high costs included uncontrolled disease, corticosteroid treatment in the previous year, and comorbidity burden., Conclusions: The pediatric literature examining IBD-attributable costs is limited, with widely variable cost estimates. There is a significant knowledge gap in the research surrounding indirect costs and OOP expenses., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The prevalence of inflammatory bowel disease (IBD) is increasing. The total direct costs of IBD have not been assessed on a population-wide level in the era of biologic therapy., Design: We identified all persons with IBD in Manitoba between 2005 and 2015, with each matched to 10 controls on age, sex, and area of residence. We enumerated all hospitalizations, outpatient visits and prescription medications including biologics, and their associated direct costs. Total and per capita annual IBD-attributable costs and health care utilization (HCU) were determined by taking the difference between the costs/HCU accrued by an IBD case and their controls. Generalized linear modeling was used to evaluate trends in direct costs and Poisson regression for trends in HCU., Results: The number of people with IBD in Manitoba increased from 6,323 to 7,603 between 2005 and 2015. The total per capita annual costs attributable to IBD rose from $3,354 in 2005 to $7,801 in 2015, primarily driven by an increase in per capita annual anti-tumor necrosis factor costs, which rose from $181 in 2005 to $5,270 in 2015. There was a significant decline in inpatient costs for CD ($99 ± 25/yr. P < 0.0001), but not for ulcerative colitis ($8 increase ±$18/yr, P = 0.63)., Discussion: The direct health care costs attributable to IBD have more than doubled over the 10 years between 2005 and 2015, driven mostly by increasing expenditures on biological medications. IBD-attributable hospitalization costs have declined modestly over time for persons with CD, although no change was seen for patients with ulcerative colitis.

Objective: Patients with inflammatory bowel disease (IBD) have an elevated risk of mental illness. We determined the incidence and correlates of new-onset mental illness associated with IBD during pregnancy and post partum., Design: This cohort study using population-based health administrative data included all women with a singleton live birth in Ontario, Canada (2002-2014). The incidence of new-onset mental illness from conception to 1-year post partum was compared between 3721 women with and 798 908 without IBD, generating adjusted HRs (aHR). Logistic regression was used to identify correlates of new-onset mental illness in the IBD group., Results: About 22.7% of women with IBD had new-onset mental illness versus 20.4% without, corresponding to incidence rates of 150.2 and 132.8 per 1000 patient-years (aHR 1.12, 95% CI 1.05 to 1.20), or one extra case of new-onset mental illness per 43 pregnant women with IBD. The risk was elevated in the post partum (aHR 1.20, 95% CI 1.09 to 1.31), but not during pregnancy, and for Crohn's disease (aHR 1.12, 95% CI 1.02 to 1.23), but not ulcerative colitis. The risk was specifically elevated for a new-onset mood or anxiety disorder (aHR 1.14, 95% CI 1.04 to 1.26) and alcohol or substance use disorders (aHR 2.73, 95% CI 1.42 to 5.26). Predictors of a mental illness diagnosis were maternal age, delivery year, medical comorbidity, number of prenatal visits, family physician obstetrical care and infant mortality., Conclusion: Women with IBD were at an increased risk of new-onset psychiatric diagnosis in the postpartum period, but not during pregnancy. Providers should look to increase opportunities for prevention, early identification and treatment accordingly., Competing Interests: Competing interests: SNV: receives royalties from UpToDate Inc for authorship of topics focused on depression and antidepressant medication use in pregnancy. LET: received investigator-initiated funding from Janssen Canada and served on advisory boards for AbbVie Canada, Takeda Canada, Merck Canada, Pfizer Canada and Mallinckrodt USA. CHS: serves on advisory boards and as a speaker for Janssen Canada, Abbvie Canada, Shire Canada, Takeda Canada, Ferring Canada and received educational grants from Janssen Canada., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Women with inflammatory bowel disease (IBD) may require surgery, which may result in higher risk of infertility. Restorative proctocolectomy with ileal anal pouch anastomosis (IPAA) may increase infertility, but the degree to which IPAA affects infertility remains unclear, and the impact of other surgical interventions on infertility is unknown., Objectives: Primary objective• To determine the effects of surgical interventions for IBD on female infertility.Secondary objectives• To evaluate the impact of surgical interventions on the need for assisted reproductive technology (ART), time to pregnancy, miscarriage, stillbirth, prematurity, mode of delivery (spontaneous vaginal, instrumental vaginal, or Caesarean section), infant requirement for resuscitation and neonatal intensive care, low and very low birth weight, small for gestational age, antenatal and postpartum hemorrhage, retained placenta, postpartum depression, gestational diabetes, and gestational hypertension/preeclampsia., Search Methods: We searched MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to September 27, 2018, to identify relevant studies. We also searched references of relevant articles, conference abstracts, grey literature, and trials registers., Selection Criteria: We included observational studies that compared women of reproductive age (≥ 12 years of age) who underwent surgery to women with IBD who had a different type of surgery or no surgery (i.e. treated medically). We also included studies comparing women before and after surgery. Any type of IBD-related surgery was permitted. Infertility was defined as an inability to become pregnant following 12 months of unprotected intercourse. Infertility at 6, 18, and 24 months was included as a secondary outcome. We excluded studies that included women without IBD and those comparing women with IBD to women without IBD.., Data Collection and Analysis: Two review authors independently screened studies and extracted data. We used the Newcastle-Ottawa Scale to assess bias and GRADE to assess the overall certainty of evidence. We calculated the pooled risk ratio (RR) and 95% confidence interval (CI) using random-effects models. When individual studies reported odds ratios (ORs) and did not provide raw numbers, we pooled ORs instead., Main Results: We identified 16 observational studies for inclusion. Ten studies were included in meta-analyses, of which nine compared women with and without a previous IBD-related surgery and the other compared women with open and laparoscopic IPAA. Of the ten studies included in meta-analyses, four evaluated infertility, one evaluated ART, and seven reported on pregnancy-related outcomes. Seven studies in which women were compared before and after colectomy and/or IPAA were summarized qualitatively, of which five included a comparison of infertility, three included the use of ART, and three included other pregnancy-related outcomes. One study included a comparison of women with and without IPAA, as well as before and after IPAA, and was therefore included in both the meta-analysis and the qualitative summary. All studies were at high risk of bias for at least two domains.We are very uncertain of the effect of IBD surgery on infertility at 12 months (RR 5.45, 95% CI 0.41 to 72.57; 114 participants; 2 studies) and at 24 months (RR 3.59, 95% CI 1.32 to 9.73; 190 participants; 1 study). Infertility was lower in women who received laparoscopic surgery compared to open restorative proctocolectomy at 12 months (RR 0.70, 95% CI 0.38 to 1.27; 37 participants; 1 study).We are very uncertain of the effect of IBD surgery on pregnancy-related outcomes, including miscarriage (OR 2.03, 95% CI 1.14 to 3.60; 776 pregnancies; 5 studies), use of ART (RR 25.09, 95% CI 1.56 to 403.76; 106 participants; 1 study), delivery via Caesarean section (RR 2.23, 95% CI 1.00 to 4.95; 20 pregnancies; 1 study), stillbirth (RR 1.96, 95% CI 0.42 to 9.18; 246 pregnancies; 3 studies), preterm birth (RR 1.91, 95% CI 0.67 to 5.48; 194 pregnancies; 3 studies), low birth weight (RR 0.61, 95% CI 0.08 to 4.83), and small for gestational age (RR 2.54, 95% CI 0.80 to 8.01; 65 pregnancies; 1 study).Studies comparing infertility before and after IBD-related surgery reported numerically higher rates of infertility at six months (before: 1/5, 20.0%; after: 9/15, 60.0%; 1 study), at 12 months (before: 68/327, 20.8%; after: 239/377, 63.4%; 5 studies), and at 24 months (before: 14/89, 15.7%; after: 115/164, 70.1%; 2 studies); use of ART (before: 5.3% to 42.2%; after: 30.3% to 34.3%; proportions varied across studies due to differences in which women were identified as at risk of using ART); and delivery via Caesarean section (before: 8/73, 11.0%; after: 36/75, 48.0%; 2 studies). In addition, women had a longer time to conception after surgery (two to five months; 2 studies) than before surgery (5 to 16 months; 2 studies). The proportions of women experiencing miscarriage (before: 19/123, 15.4%; after: 21/134, 15.7%; 3 studies) and stillbirth (before: 2/38, 5.3%; after: 3/80: 3.8%; 2 studies) were similar before and after surgery. Fewer women experienced gestational diabetes after surgery (before: 3/37, 8.1%; after: 0/37; 1 study), and the risk of preeclampsia was similar before and after surgery (before: 2/37, 5.4%; after: 0/37; 1 study). We are very uncertain of the effects of IBD-related surgery on these outcomes due to poor quality evidence, including confounding bias due to increased age of women after surgery.We rated evidence for all outcomes and comparisons as very low quality due to the observational nature of the data, inclusion of small studies with imprecise estimates, and high risk of bias among included studies., Authors' Conclusions: The effect of surgical therapy for IBD on female infertility is uncertain. It is also uncertain if there are any differences in infertility among those undergoing open versus laparoscopic procedures. Previous surgery was associated with higher risk of miscarriage, use of ART, Caesarean section delivery, and giving birth to a low birth weight infant, but was not associated with risk of stillbirth, preterm delivery, or delivery of a small for gestational age infant. These findings are based on very low-quality evidence. As a result, definitive conclusions cannot be made, and future well-designed studies are needed to fully understand the impact of surgery on infertility and pregnancy outcomes.

Canada has one of the highest rates of inflammatory bowel disease (IBD) in the world, with 1 in 140 Canadians currently living with the disease. IBD occurs less often among individuals living in rural households. This protective effect is particularly pronounced in young children, and early-life exposure to the rural environment greatly reduces the risk. However, individuals living in rural areas who have IBD have decreased access to specialist gastroenterology care., (Copyright © 2019 Longwoods Publishing.)

Background & Aims: Inflammatory bowel diseases (IBDs) exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. We aimed to determine the past current, and future prevalences of IBD in Canada., Methods: We performed a retrospective cohort study using population-based health administrative data from Alberta (2002-2015), British Columbia (1997-2014), Manitoba (1990-2013), Nova Scotia (1996-2009), Ontario (1999-2014), Quebec (2001-2008), and Saskatchewan (1998-2016). Autoregressive integrated moving average regression was applied, and prevalence, with 95% prediction intervals (PIs), was forecasted to 2030. Average annual percentage change, with 95% confidence intervals, was assessed with log binomial regression., Results: In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716-735) and annual average percent change was estimated at 2.86% (95% confidence interval 2.80%-2.92%). The prevalence in 2030 was forecasted to be 981 per 100,000 (95% PI 963-999): 159 per 100,000 (95% PI 133-185) in children, 1118 per 100,000 (95% PI 1069-1168) in adults, and 1370 per 100,000 (95% PI 1312-1429) in the elderly. In 2018, 267,983 Canadians (95% PI 264,579-271,387) were estimated to be living with IBD, which was forecasted to increase to 402,853 (95% PI 395,466-410,240) by 2030., Conclusion: Forecasting prevalence will allow health policy makers to develop policy that is necessary to address the challenges faced by health systems in providing high-quality and cost-effective care., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Direct health care costs of illness reflect the costs of medically necessary services and treatments paid for by public and private payers, including hospital-based care, outpatient physician consultations, prescription medications, diagnostic testing, complex continuing care, and home care. The costs of caring for persons with inflammatory bowel disease (IBD) have been rising well above inflation over the past fifteen years in Canada, largely due to the introduction and penetration of expensive biologic therapies. Changing paradigms of care toward frequent patient monitoring and achievement of stricter endpoints for disease control have also increased health services utilization and costs among IBD patients. While the frequency and costs of surgeries and hospitalizations have declined slightly in parallel with increased biologic use (due to better overall disease control), the direct medical costs of care for IBD patients are largely dominated by prescription drug costs. Introduction and penetration of biosimilar agents (at a markedly lower price point than the originator drugs) and increasing gastroenterologist involvement in the care of IBD patients may help to balance rising health care costs while improving health outcomes and quality of life for IBD patients. Ultimately, however, the predicted rise in the prevalence of IBD over the next decade, combined with increasing use of expensive biologic therapies, will likely dictate a continued rise in the direct costs of IBD patient care in Canada for years to come. In 2018, direct health care costs of IBD are estimated to be at least $1 billion Canadian dollars (CAD) and possibly higher than $2 billion CAD., Highlights: 1. In Canada, the direct cost of caring for people living with IBD is estimated in 2018 to be close to $1.28 billion (roughly $4731 per person with IBD).2. The costs of caring for people living with IBD are dominated by prescription drugs, followed by hospitalization costs. There has been a shift away from hospitalizations and toward pharmaceuticals as the predominant driver of direct health care costs in IBD patients, due to the introduction and widespread use of expensive biologic therapies.3. The rates of hospitalizations and major abdominal surgeries have been declining in IBD patients in Canada over the past two decades, possibly due to penetration of biologic therapies and advances in patient management paradigms.4. Inflammatory bowel disease patients cared for by gastroenterologists have better outcomes, including lower risks of surgery and hospitalization. Canadians who live in rural and underserviced areas are less likely to receive gastroenterologist care, potentially due to care preferences or poorer access, which may result in poorer long-term outcomes.5. Introduction of biosimilar agents at a lower price point than originator biologic therapies, increased gastroenterologist care of IBD patients, and improvements in IBD care paradigms may balance overall treatment costs while improving health outcomes and quality of life for IBD patients. However, in the long-term, direct costs of care may continue to increase, dictated by a rising IBD prevalence and increasing use of biologic therapies., Key Summary Points: 1. The costs of health care for patients with IBD are more than double those without IBD.2. Prescription drug use accounts for 42% of total direct costs in IBD patients, and costs to treat IBD continue to rise due to increased use of existing biologic therapies and the introduction of several new biologic therapies in recent years.3. In Manitoba, the mean health care utilization and medication costs for persons with IBD in the year before beginning anti-TNF therapy was $10,206 and increased to $44,786 in the first year of therapy.4. Biosimilar agents to anti-TNF drugs are now entering the Canadian marketplace and may result in cost savings in patients using biologic agents to treat their IBD.5. Timely gastroenterologist care has been associated with reduced risks of requiring surgery and emergency care among ambulatory IBD patients and a reduced risk of death among hospitalized patients with ulcerative colitis.6. Inflammatory bowel disease care provided by gastroenterologists has increased over the past two decades. Even then, the average time from symptom onset to IBD diagnosis exceeds six months, and only one-third of IBD patients receive continuing care with a gastroenterologist during the first five years following diagnosis.7. Senior (age ≥65), rural-dwelling, and non-immigrant IBD patients have less frequent gastroenterologist care than other groups.8. About one in five adults with Crohn's disease and one in eight adults with ulcerative colitis are hospitalized in Ontario every year. Hospitalizations are most common during the first year following IBD diagnosis. Children with IBD (age <18) have the highest rates of hospitalizations and hospital re-admissions.9. In Canada, 16% of patients hospitalized for Crohn's disease undergo an intestinal resection, and 11% of patients hospitalized for ulcerative colitis undergo a colectomy during their initial hospitalization. Rates of intestinal resection and colectomy are declining in Canada in persons with Crohn's disease and ulcerative colitis, respectively.10. In Ontario, one-third of adult-onset Crohn's disease patients undergo intestinal resection within ten years of diagnosis. Among Canadian children with Crohn's disease, approximately one in fifteen children will require intestinal surgery within the first year of diagnosis, and up to one-third will require surgery within ten years of diagnosis.11. In Ontario, the ten-year colectomy risk following ulcerative colitis diagnosis is 13.3% among young persons and adults and 18.5% among individuals with senior-onset ulcerative colitis. In children with ulcerative colitis, the risk of colectomy is 4.8% to 6% in the first year following diagnosis and increases to 15% to 17% by ten years., Gaps in Knowledge and Future Directions: 1. Forecasting models are necessary to predict the rising costs attributable to biologics associated with increasing prevalence of IBD, more frequent use of these medications, and the introduction of newer agents.2. Research into ways to minimize the escalating costs associated with increasing use of biologic therapies to treat IBD (and other chronic diseases) is necessary to ensure sustainability of our publicly funded health care system. Biosimilars offer an opportunity to drive down the cost of biologic therapies, and future research should assess the uptake of biosimilars as new biosimilars are introduced into the marketplace.3. Cost-utility models and budget impact analyses that integrate changes in direct costs (i.e., reduced hospitalizations and increased pharmaceutical costs) with indirect cost savings from improved quality of life are necessary to inform policy decisions.4. Research into ways to reduce IBD hospitalizations further through targeted outpatient interventions is equally important for health system sustainability and to improve patient quality of life.5. Research into reasons for reduced gastroenterologist care among rural and underserviced IBD residents would allow targeted interventions to improve specialist care and thereby improve patient health outcomes and quality of life.

Canada has among the highest rates of IBD in the world, and the number of people living with these disorders is growing rapidly. This has placed a high burden on the health care system and on the Canadian economy-a burden that is only expected to grow in the future. It is important to understand IBD and its impact on Canadian society in order to appropriately plan for health care expenditures, reduce the burden on patients and their families, and improve the quality of life for those afflicted with IBD. In Canada, there is a lack of public awareness of the impact of Crohn's disease and ulcerative colitis. Raising awareness is crucial to reducing the social stigma that is common with these diseases and to help individuals maximize their overall quality of life. A better public understanding of IBD can also help to raise and direct funds for research, which could lead to improved treatments and, ultimately, to a cure. This report from Canadian clinicians and researchers to Crohn's and Colitis Canada makes recommendations aimed at the public, policy-makers, scientific funding agencies, charitable foundations and patients regarding future directions for advocacy efforts and areas to emphasize for research spending. The report also identifies gaps in knowledge in the fields of clinical, health systems and epidemiological research.

The indirect cost of illness represents the portion of human capital that is foregone due to lost productivity of patients and their caregivers and out-of-pocket healthcare expenses borne directly by patients. Indirect costs among persons with inflammatory bowel diseases (IBD) may be substantial because disease onset occurs during the teens and 20s for most persons and is lifelong. Thus, most persons with IBD are affected during periods of study or employment. The literature on indirect health-related costs among persons with IBD is limited, particularly with regard to Canadian studies. The greatest burden of indirect costs in this population relates to absenteeism and presenteeism among working individuals and premature retirement. However, costs related to reduced professional development and personal achievement due to illness-as well as caregiver costs-are largely unknown. After being extrapolated from multiple sources, the total indirect health-related cost of IBD in Canada in 2018 is estimated to be $1.29 billion Canadian dollars. Notably, this may be a significant underestimate because costs relating to presenteeism, reduced achievement and caregiver burden could not be estimated and are excluded from this calculation., Highlights: Indirect costs account for a major portion of total healthcare costs among persons with inflammatory bowel disease (IBD) and are higher than indirect costs among persons without IBD.Persons with IBD are more likely to require time off work (absenteeism) and have reduced productivity at work (presenteeism) due to illness as compared with persons without IBD.Premature retirement and long-term disability are major factors contributing to indirect costs among IBD patients.A substantial proportion of individuals with IBD pay out-of-pocket for complementary and alternative medicines.After being extrapolated from multiple sources, the total annual indirect cost of IBD in Canada is estimated to be $1.29 billion CAD in 2018, or $4781 CAD per person with IBD., Key Summary Points: The total indirect economic burden of IBD in Canada is estimated to be $1.29 billion CAD in 2018, or roughly $4781 CAD per person with IBD. This estimate comprises lost wages related to sick days and disability, premature retirement and premature death, and out-of-pocket costs. Losses from presenteeism, reduced professional development and caregiver burden are not included due to insufficient data on the cost impact of these factors.In a meta-analysis of studies between 1994 and 2014, the annual indirect cost of absenteeism for IBD patients ranged from $515.67 USD (USA) to $14,727 USD (Germany) per patient per annum (pooled estimate $7189 USD), after adjusting for purchasing power disparity.A large US survey found that, on average, IBD patients incurred an extra 4.8 days off of work and $783 USD in excess lost wages annually compared with persons without IBD.A study based on US private insurance claims found that ulcerative colitis patients cost an additional $2164 per person per annum relating to disability days and medically related absenteeism.A prospective study from an IBD centre reported weekly indirect health-related costs of $1133 for IBD patients with active disease, $370.13 for IBD patients in remission, and $191.23 for persons without IBD relating to both presenteeism and absenteeism.In a survey of 744 IBD patients from Manitoba, reduced workplace productivity during the previous 14 days was reported in 37% of individuals, including a reduction of one to two days by 18% of patients, thre to nine days by 16% of patients, and on most days by 3% of patients.The estimated average lifetime lost wages due to premature retirement is $1,044,498 CAD per person with Crohn's disease and $994,760 CAD per person with ulcerative colitis. Aggregated over all IBD retirees, this equates to roughly $629 million CAD in permanent lost wages annually due to premature retirement.The lifetime indirect cost associated with premature death among IBD patients is estimated to be $746,070 CAD per decedent, or roughly $33.6 million aggregated across all IBD decedents of working age.In a US study of caregivers of children, the average unadjusted annual work loss was 214 hours for caregivers of Crohn's disease patients and 170 hours for caregivers of children without IBD, translating to an additional $1122 in lost productivity for caregivers of persons with Crohn's disease.Canadian studies have reported complementary and alternative medicines (CAMs) use in 56% to 74% of people with IBD. A US national survey study estimated annual per-person out of pocket costs of $1603 USD for Crohn's disease patients and $1263 USD for ulcerative colitis patients, which were substantially higher than in persons without IBD., Gaps in Knowledge and Future Directions: Canadian-specific data on indirect health-related costs of IBD is sparse across all domains of indirect costs.In particular, the rates of absenteeism, presenteeism and premature retirement among IBD patients living in Canada require further study to gauge more accurately the indirect health-related costs of IBD in Canada.Indirect costs relating to decreased professional development, caregiver burden and out-of-pocket purchases among IBD patients are largely unknown and require further study.Indirect costs incurred by Canadian children with IBD and their families or caregivers are largely unknown.

Canada has among the highest rates of childhood-onset IBD in the world. Over 7000 children and youth under 18 years old are living with IBD in Canada, and 600 to 650 children under 16 years old are diagnosed annually. While the peak age of onset of IBD is highest in the second and third decades of life, over the past two decades incidence has risen most rapidly in children under 5 years old. The treatment of children with IBD presents important challenges including therapeutic choices, risk of adverse events to medications, psychosocial impact on the child and family, increased cost of health care and the implications of the transition from pediatric to adult care. Despite the unique circumstances faced by children and their families, there is a lack of research to help understand the causes of the rising incidence and the best therapies for children with IBD. Scientific evidence-and specifically clinical trials of pharmaceuticals-are too often extrapolated from adult research. Health care providers must strive to understand the unique impact of childhood-onset IBD on patients and families, while researchers must expand work to address the important needs of this growing patient population., Highlights: In 2018, there are over 7000 children and youth under 18 years old living with IBD in Canada, and 600 to 650 young children (under 16 years) diagnosed every year.The number of children in Canada living with IBD is growing rapidly, increasing 50% in the first decade of the 21st century.Inflammatory bowel disease is still rare in children younger than 5 years of age, but it is occurring in such young children more often than in the past.Children with IBD are different from adults. For example, delayed growth, extent of disease and difficulties encountered during adolescence are all unique to the pediatric experience.We must consider the psychosocial well-being of both children and their families, given that caring for a child with IBD can affect the global functioning of families.Treatment approaches in children sometimes differ from those in adults. However, to date, all effective therapies in adults have also been effective in children. There is great need for clinical trials of new therapies in children so that they have equal access to emerging treatments and optimal pediatric dosing can be established., Key Summary Points: Rates of new diagnoses in children under 16 years old were increasing most rapidly in Ontario (increased 5.8% per year) and Quebec (increased 2.8% per year).Nova Scotia has the highest rate of pediatric IBD, with lower rates in Quebec and Ontario. However, even Ontario and Quebec have higher rates of pediatric IBD than most countries in the world.Inflammatory bowel disease is caused by the interaction between genes, environmental risk factors, the microbiome and the immune system. Since children experience shorter exposures and possibly fewer environmental risk factors, the interaction between these risk factors and genes may be stronger with childhood-onset IBD.The microbiome is mostly established in early childhood and is affected by a number of factors such as environment, diet, pregnancy/delivery factors and antibiotic use. Changing the microbiome to a healthier state may prevent the disease and may also be a novel therapeutic target to treat active inflammation in children with IBD.Children with IBD are different from adults. They are more likely to have extensive involvement of their intestines, especially in ulcerative colitis, and are at risk for growth impairment, osteoporosis, and psychosocial difficulties affecting their families.Children with IBD may incur more direct health costs for treatment of their IBD compared with adults. However, this is not universally true for all children because those who are very young at diagnosis (2 to 6 years old) may have milder disease or respond better to medications. This may result in decreased use of the health system, fewer hospitalizations and less risk of surgery than older children and adolescents.The choice of treatments for children with IBD may be different from that of adults. It is important to consider pediatric-specific disease considerations. Delayed growth, deficient bone development, psychosocial well-being of the child and family, disease extent, disease severity and risk of poor outcomes during transition from pediatric to adult health care are all important considerations when choosing the best treatment for children and adolescents.While the medications used are similar in children and adults with IBD, research to assess the effectiveness and safety of these medications in children (especially very young children) is sparse.Children with IBD may be more responsive to treatment than adults because they are more likely to have inflammatory (rather than stricturing) disease. Therefore, treating the inflammation earlier in the course of disease may prevent long-term complications such as strictures, obstruction, need for surgery and need for hospitalization.Some medications used in IBD have unique or more pronounced risks in children compared with adults. For example, chronic prednisone use is associated with growth impairment and stunting in children. Anti-TNF biologics are the only medications proven to improve growth in children with Crohn's disease and should be considered early in the course of disease in patients with severe IBD or those with marked growth impairment at the time of diagnosis.Some medications are used differently, depending on the sex of the patient. For example, azathioprine (with or without biologics) is associated with hepatosplenic T cell lymphoma (and other forms of lymphoma) in adolescent and young adult males more often than females. Methotrexate is associated with birth defects in the growing fetus and therefore should be avoided in adolescent and adult women of child-bearing age who are not using two or more forms of birth control.A small group of children, typically presenting in the first two years of life, have single-gene mutations that cause an IBD-like bowel disease and also immune system dysfunction. These patients may not respond to traditional IBD medications and may require therapies such as bone marrow transplant. Canada is leading research efforts to investigate, diagnose and treat this small group of very vulnerable children.Inflammatory bowel disease (especially when it is active) can affect school attendance, social interactions, concentration and learning. Schools should be aware of the implications of IBD and make allowances for these factors in children with active inflammation and symptoms to optimize their chances of academic and social success., Gaps in Knowledge and Future Research Directions: We have limited knowledge on what causes IBD in children and why rates are rising most rapidly in young children. We must better understand the interaction between genes, the environment, the immune system and the microbiome in order to better prevent and treat the disease.Treatment for infants with IBD-like illnesses and single-gene mutations is limited. Future research should work towards identifying these children and learning how best to treat them.There are few clinical trials for biologics in children, and most exclude very young children. Support for such trials is important to understand whether the treatments work, how they should optimally be given and whether they are safe for young children with IBD.Considering the effectiveness of dietary therapies for children with Crohn's disease (exclusive enteral nutrition), we should work to understand how diet affects intestinal inflammation and the microbiome in order to better use dietary therapies to treat IBD.Health services researchers, health care providers and policy-makers should work together to understand why variation in the access to treatment and medical care of children with IBD exists. We must work together to improve the quality of care provided to these children and ensure they have the highest quality of care.Psychosocial implications of IBD in children and their families are of importance to long-term and overall well-being. Children with a chronic, incurable disease are at risk for mental illness associated with their disease. We should design interventions to improve the psychosocial status, mental health and quality of life of children with IBD and their families.While nonlive immunizations are safe for children with IBD, we must understand how to improve their effectiveness in children who are immunosuppressed. While the peak onset of IBD occurs in the second or third decades of life, the frequency of new diagnoses in younger children is rising rapidly. In Canada, the fastest growing group of newly diagnosed people with IBD are children aged under 5 years (termed 'very early onset [VEO] IBD). These young children have not been included in clinical trials of new medications, resulting in a lack of scientific evidence of safety and effectiveness of treatments in this group, and clinical experience has shown that they do not respond to usual medications used for the majority of children with IBD. Providing children with IBD with high-quality care and social support also poses other challenges to care providers, families and the health system. This section will focus on the unique challenges facing Canadian children with IBD. A complete overview of the objectives, working committees and methodology of creating the report can be found in the supplemental file, Technical Document.

Background: Budesonide is an oral glucocorticoid designed for the treatment of inflammatory bowel disease (IBD) that may reduce systemic adverse events (AEs). This review examined the efficacy and safety of budesonide for the induction and maintenance of clinical remission in Crohn's disease (CD)., Methods: MEDLINE, EMBASE, other electronic databases, reference lists and conference proceedings were searched to November 2017 to identify randomized controlled trials of budesonide. Outcomes were the induction and maintenance of remission at eight weeks and one year, respectively, as well as corticosteroid-related AEs and abnormal adrenocorticotropic hormone (ACTH) tests. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random effects models., Results: Thirteen induction and 10 maintenance trials were included. Budesonide 9 mg/day was more effective than placebo (RR 1.93; 95% CI, 1.37-2.73; GRADE: moderate) but less effective than conventional steroids (RR 0.85; 95% CI, 0.75-0.97; GRADE: moderate) to induce remission. Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54-0.76; GRADE: moderate); budesonide did not increase AEs relative to placebo (RR 0.97; 95% CI, 0.76-1.23; GRADE: moderate). Budesonide 6 mg/day was not different from placebo for maintaining remission (RR 1.13; 95% CI, 0.94-1.35; GRADE: moderate). Both induction (GRADE: low for 3 mg/day, moderate for 9 mg/day) and maintenance budesonide treatment (GRADE: very low for 3 mg/day, low for 6 mg/day) increased the risk of an abnormal ACTH test compared with placebo, but less than conventional steroids (GRADE: very low for both induction and maintenance)., Conclusion: For induction of clinical remission, budesonide was more effective than placebo, but less effective than conventional steroids. Budesonide was not effective for the maintenance of remission. Budesonide was safer than conventional steroids, but the long-term effects on the adrenal axis and bone health remain unknown.

Background: Inflammatory bowel diseases (IBD) and asthma share genetic and environmental risk factors. Consequently, several observational studies have explored an association between IBD and asthma. We systematically reviewed and summarized the literature on the co-occurrence of asthma and IBD., Methods: MEDLINE and EMBASE (to April 2017) were searched to identify observational studies on the association between asthma and IBD. Relative risks (RR) were pooled using random effects models. Heterogeneity was assessed using the I 2 and Cochran Q statistics. Meta-regression based on study design, source of patients (population-based vs. tertiary-care center) and study location was conducted to explain between-study heterogeneity., Results: Eighteen studies were identified (15 Crohn's disease, 15 ulcerative colitis (UC)). Asthma was associated with both Crohn's disease (pooled RR 1.30, 95% confidence interval (CI) 1.16-1.47, I 2  = 88%) and UC (RR 1.34, 95% CI 1.24-1.44, I 2  = 93%). The study design and source of patients and study location explained between-study heterogeneity in Crohn's disease, but not UC., Conclusion: Asthma is associated with both Crohn's disease and UC. Additional research is needed to determine if one disease influences the risk of developing the other or if the frequent co-occurrence of these diseases result from shared genetic, environmental, and microbial risk factors.

Background: Understanding of the prevalence, pathophysiology, and management of fecal incontinence (FI) in inflammatory bowel disease (IBD) patients without an ileal pouch anal anastomosis (IPAA) is suboptimal. We conducted a systematic review and meta-analysis on the prevalence, pathophysiology, and management of primary FI in IBD patients without IPAA., Methods: We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews (1966 through March 2017) for studies on the prevalence, physiology, or management of FI in IBD patients without IPAA. A random effects model was used to calculate pooled prevalence rates and odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was assessed with I2 statistics, Cochran Q statistic, and sensitivity analyses., Results: Seventeen studies were included. Six studies evaluated the prevalence of FI in 4671 IBD patients. There was significant heterogeneity among the studies, but the pooled prevalence of FI among case-control studies was homogeneous at 24% (95% CI 18%-30%, I2 = 50.6%, P = 0.16). FI was more common among IBD patients than non-IBD controls (OR = 7.73; 95% CI 6.26 to 9.84). Therapeutic options were poorly evaluated in uncontrolled studies. Surgery was effective in 70% of patients (7/10), sacral nerve stimulation was effective in 100% of patients (5/5), and 41.6% of patients (5/12) reported subjective improvement in FI with percutaneous tibial nerve stimulation., Conclusions: FI is prevalent in IBD patients without IPAA, and more common than non-IBD controls. Additional controlled studies are warranted to further identify effective therapeutic interventions for FI in IBD. 10.1093/ibd/izx109&#95;video1izx109&#95;Video&#95;15760611117001.

The incidence and prevalence of childhood-onset inflammatory bowel diseases (IBD), including subtypes Crohn's disease and ulcerative colitis, have risen dramatically in recent years, and have emerged globally as important pediatric chronic diseases. Therefore, health care providers are more frequently encountering very young children with IBD, a chronic and incurable condition requiring life-long therapy. These children are living long lives with IBD and therefore knowledge of long-term outcomes is increasingly important to better counsel families and determine the best course of treatment. This review summarizes the current knowledge and literature surrounding long-term outcomes of pediatric IBD, with emphasis on the following areas: need for surgery due to complicated disease behavior, risk of disease remission and recurrence, mental health and psychosocial well-being, educational outcomes, linear growth impairment, cancer risk, and mortality. In addition, we review recent research about predicting negative long-term outcomes in children with IBD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To determine the association between inflammatory bowel disease (IBD) and rural/urban household at the time of diagnosis, or within the first 5 years (y) of life., Methods: Population-based cohorts of residents of four Canadian provinces were created using health administrative data. Rural/urban status was derived from postal codes based on population density and distance to metropolitan areas. Validated algorithms identified all incident IBD cases from administrative data (Alberta: 1999-2008, Manitoba and Ontario: 1999-2010, and Nova Scotia: 2000-2008). We determined sex-standardized incidence (per 100,000 patient-years) and incident rate ratios (IRR) using Poisson regression. A birth cohort was created of children in whom full administrative data were available from birth (Alberta 1996-2010, Manitoba 1988-2010, and Ontario 1991-2010). IRR was calculated for residents who lived continuously in rural/urban households during each of the first 5 years of life., Results: There were 6,662 rural residents and 38,905 urban residents with IBD. Incidence of IBD per 100,000 was 33.16 (95% CI 27.24-39.08) in urban residents, and 30.72 (95% CI 23.81-37.64) in rural residents (IRR 0.90, 95% CI 0.81-0.99). The protective association was strongest in children <10 years (IRR 0.58, 95% CI 0.43-0.73) and 10-17.9 years (IRR 0.72, 95% CI 0.64-0.81). In the birth cohort, comprising 331 rural and 2,302 urban residents, rurality in the first 1-5 years of life was associated with lower risk of IBD (IRR 0.75-0.78)., Conclusions: People living in rural households had lower risk of developing IBD. This association is strongest in young children and adolescents, and in children exposed to the rural environment early in life.

Background & Aims: Asthma and the inflammatory bowel diseases (IBD) each arise through complex interactions between genetic and environmental factors, and share many environmental risk factors. We examined the association between asthma and Crohn's disease or ulcerative colitis., Methods: We performed a population-based case-control study using health administrative data from the province of Alberta, Canada. The odds of a diagnosis of asthma preceding the diagnosis of either Crohn's disease (N = 3087) or ulcerative colitis (N = 2377) were compared with the odds of diagnosis of asthma among persons without IBD (N = 402,800) using logistic regression. Effect measure modification by age at diagnosis of IBD (16 years or less, 17-40 years, or older than 40 years) was tested using a likelihood ratio test., Results: A diagnosis of asthma was associated with increased odds of incident Crohn's disease (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.31-1.60). No effect measure modification was observed for age at diagnosis for Crohn's disease (P = .42). However, we observed effect measure modification by age at diagnosis for ulcerative colitis (P = .0103), with an adjusted OR of 1.49 (95% CI, 1.08-2.07) among individuals diagnosed at an age of 16 years or less (OR) and an adjusted OR of 1.57 (95% CI, 1.31-1.89) among individuals diagnosed at an age older than 40 years. However, there was no association between asthma and ulcerative colitis among individuals diagnosed between ages 17 and 40 (adjusted OR, 1.05; 95% CI, 0.86-1.26)., Conclusions: In a population-based case-control study, we associated asthma with Crohn's disease, and with early and late-onset ulcerative colitis., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: NOD2 and smoking are risk factors for Crohn's disease. We meta-analyzed NOD2-smoking interactions in Crohn's disease (Phase 1), then explored the effect of age at diagnosis on NOD2-smoking interactions (Phase 2)., Methods: Phase 1: MEDLINE and EMBASE were searched for studies (n=18) providing data on NOD2 and smoking in Crohn's disease. NOD2-smoking interactions were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) calculated using random effects models. Phase 2: A case-only study compared the proportion of smokers and carriers of the 1007fs variant across ages at diagnosis (≤16, 17-40, >40years)., Findings: Phase 1: Having ever smoked was less common among carriers of the 1007fs variant of NOD2 (OR 0.74, 95%CI:0.66-0.83). There was no interaction between smoking and the G908R (OR 0.96, 95%CI:0.82-1.13) or the R702W variant (OR 0.89, 95%CI:0.76-1.05). Phase 2: The proportion of patients (n=627) carrying the 1007fs variant decreased with age at diagnosis (≤16years: 15%; 17-40: 12%; >40: 3%; p=0.003). Smoking was more common in older patients (≤16years: 4%; 17-40: 48%; >40: 71%; p<0.001)., Interpretation: The negative NOD2-smoking interaction in Crohn's disease is specific to the 1007fs variant. However, opposing rates of this variant and smoking across age at diagnosis may explain this negative interaction., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Induction treatment of mild-to-moderate Crohn's disease is controversial., Purpose: To compare the induction of remission between different doses of mesalamine, sulfasalazine, corticosteroids, and budesonide for active Crohn's disease., Data Sources: We identified randomized controlled trials from existing Cochrane reviews and an updated literature search in Medline, EMBASE, and CENTRAL to November 2015., Study Selection: We included randomized controlled trials (n = 22) in adult patients with Crohn's disease that compared budesonide, sulfasalazine, mesalamine, or corticosteroids with placebo or each other, for the induction of remission (8-17 wks). Mesalamine (above and below 2.4 g/d) and budesonide (above and below 6 mg/d) were stratified into low and high doses., Data Extraction: Our primary outcome was remission, defined as a Crohn's Disease Activity Index score <150. A Bayesian random-effects network meta-analysis was performed on the proportion in remission., Data Synthesis: Corticosteroids (odds ratio [OR] = 3.64; 95% credible interval [CrI]: 2.16-6.19), high-dose budesonide (OR = 2.99; 95% CrI: 1.83-4.90), and high-dose mesalamine (OR = 1.87; 95% CrI: 1.14-3.15) were superior to placebo. Corticosteroids were similar to high-dose budesonide (OR = 1.21; 95% CrI: 0.79-1.89), but more effective than high-dose mesalamine (OR = 1.95; 95% CrI: 1.14-3.25). Sulfasalazine was not significantly superior to any therapy including placebo., Limitations: Randomized controlled trials that use a strict definition of induction of remission and disease severity at enrollment to assess effectiveness in treating mild-to-moderate Crohn's disease are limited., Conclusions: Corticosteroids and high-dose budesonide were effective treatments for inducing remission in mild-to-moderate Crohn's disease. High-dose mesalamine maybe an option among patients preferring to avoid steroids.

Background: Studies examining the association between smoking and the need for surgery in patients with Crohn's disease and ulcerative colitis have reached inconsistent conclusions. These studies often do not differentiate between patients undergoing early surgery and patients having surgery later in their disease course. Our study examined the association between smoking status and time to first bowel resection in patients with Crohn's disease and ulcerative colitis., Methods: We searched MEDLINE and EMBASE for studies (n = 12) reporting on the association between smoking status (current, former, and never) and surgery in IBD, and incorporated disease duration in the analysis. Hazard ratios (HR) with 95% confidence intervals (CI) were pooled across studies using random effects models., Results: Current smokers with Crohn's disease were at increased risk of intestinal resection compared to never smokers (HR 1.27, 95% CI 1.08 to 1.49); however, there was no difference in the need for surgery when comparing former and never smokers (HR 1.11, 95% CI 0.95 to 1.30). In patients with ulcerative colitis, there was no difference in the need for colectomy when comparing current smokers to never smokers (HR 0.98, 95% CI 0.67 to 1.44). Former smokers with ulcerative colitis were at increased risk of colectomy (HR 1.38, 95% CI 1.04 to 1.83) compared to never smokers., Conclusions: Current smokers with Crohn's disease are at increased risk of surgery, while former smokers with ulcerative colitis have increased risk of colectomy.

Importance: Cigarette smoking increases the risk of surgery in Crohn's disease. However, the effect of smoking on the need for surgery for diverticulitis is unknown., Objective: We evaluated whether smoking was a risk factor for surgery among patients admitted to hospital with acute diverticulitis., Design: We conducted a population-based comparative cohort study of patients admitted to hospital for diverticulitis who were treated with medical versus surgical management., Setting & Participants: We used the population-based Discharge Abstract Database to identify 176 adults admitted emergently with a diagnosis of diverticulitis between 2009 and 2010 in Calgary., Intervention & Main Outcome: We performed a medical chart review to confirm the diagnosis of diverticulitis and to extract clinical data. The primary outcome was a partial colectomy during hospitalization. Logistic regression evaluated the association between smoking and surgery after adjusting for potential confounders, including age, sex, comorbidity, and disease severity., Results: A partial colectomy was performed on 35.6% of patients with diverticulitis and 1.3% died. Among diverticulitis patients, 26.8% were current smokers, 31.5% were ex-smokers, and 41.6% never smoked. Compared to non-smokers, current smokers (adjusted odds ratio [OR] 9.02; 95% confidence interval [CI]: 2.47-32.97) and former smokers (adjusted OR 5.41; 95% CI: 1.54-18.96) had increased odds of surgery., Conclusion and Relevance: Smoking is associated with the need for surgical management of diverticulitis.

Background: Corticosteroids are commonly used for the induction of remission in Crohn's disease. However, traditional corticosteroids can cause significant adverse events. Budesonide is an alternative glucocorticoid with limited systemic bioavailability., Objectives: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in Crohn's disease., Search Methods: The following electronic databases were searched up to June 2014: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedings were manually searched., Selection Criteria: Randomised controlled trials comparing budesonide to a placebo or active comparator were considered for inclusion., Data Collection and Analysis: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. Meta-analysis was performed using RevMan 5.3.5 software. The primary outcome was induction of remission (defined by a Crohn's disease activity index (CDAI) < 150) by week 8 to 16 of treatment. Secondary outcomes included: time to remission, mean change in CDAI, clinical, histological or endoscopic improvement, improvement in quality of life, adverse events and early withdrawal. We calculated the relative risk (RR) and corresponding 95% confidence intervals (CIs) for each dichotomous outcome and the mean difference and corresponding 95% CI for each continuous outcome. Data were analyzed on an intention-to-treat basis. A random-effects model was used for the pooled analyses. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was evaluated using the GRADE criteria., Main Results: Fourteen studies (1805 patients) were included: Nine (779 patients) compared budesonide to conventional corticosteroids, three (535 patients) were placebo-controlled, and two (491 patients) compared budesonide to mesalamine. Ten studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to open label design. One study was judged to be at high risk of bias due to selective reporting. After eight weeks of treatment, 9 mg budesonide was significantly more effective than placebo for induction of clinical remission. Forty-seven per cent (115/246) of budesonide patients achieved remission at 8 weeks compared to 22% (29/133) of placebo patients (RR 1.93, 95% CI 1.37 to 2.73; 3 studies, 379 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (144 events). Budesonide was significantly less effective than conventional steroids for induction of remission at eight weeks. Fifty-two per cent of budesonide patients achieved remission at week 8 compared to 61% of patients who received conventional steroids (RR 0.85, 95% CI 0.75 to 0.97; 8 studies, 750 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to risk of bias. Budesonide was significantly less effective than conventional steroids among patients with severe disease (CDAI > 300) (RR 0.52, 95% CI 0.28 to 0.95). Studies comparing budesonide to mesalamine were not pooled due to heterogeneity (I(2) = 81%). One study (n = 182) found budesonide to be superior to mesalamine for induction of remission at 8 weeks. Sixty-eight per cent (63/93) of budesonide patients were in remission at 8 weeks compared to 42% (37/89) of mesalamine patients (RR 1.63, 95% CI 1.23 to 2.16). The other study found no statistically significant difference in remission rates at eight weeks. Sixty-nine per cent (107/154) of budesonide patients were in remission at 8 weeks compared to 62% (132/242) of mesalamine patients (RR 1.12, 95% CI 0.95 to 1.32). Fewer adverse events occurred in those treated with budesonide compared to conventional steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better than conventional steroids in preserving adrenal function (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78)., Authors' Conclusions: Budesonide is more effective than placebo for induction of remission in Crohn's disease. Although short-term efficacy with budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement, the likelihood of adverse events and adrenal suppression with budesonide is lower. The current evidence does not allow for a firm conclusion on the relative efficacy of budesonide compared to 5-ASA products.

Background: Corticosteroids are effective for induction, but not maintenance of remission in Crohn's disease. Significant concerns exist regarding the risk for adverse events, particularly when corticosteroids are used for long treatment courses. Budesonide is a glucocorticoid with limited systemic bioavailability due to extensive first-pass hepatic metabolism and is effective for induction of remission in Crohn's disease., Objectives: To evaluate the efficacy and safety of oral budesonide for maintenance of remission in Crohn's disease., Search Methods: The following databases were searched from inception to 12 June 2014: PubMed, MEDLINE, EMBASE, CENTRAL, the Cochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedings were manually searched., Selection Criteria: Randomized controlled trials comparing budesonide to a control treatment, or comparing two doses of budesonide, were included. The study population included patients of any age with quiescent Crohn's disease., Data Collection and Analysis: Two independent investigators reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome was maintenance of remission at various reported follow-up times during the study. Secondary outcomes included: time to relapse, mean change in CDAI, clinical, histological, improvement in quality of life, adverse events and study withdrawal. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference (MD) and 95% CI for continuous outcomes. Data were analysed on an intention-to-treat basis. The Chi(2) and I(2) statistics were used to assess heterogeneity. Random-effects models were used to allow for expected clinical and statistical heterogeneity. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria., Main Results: Twelve studies (n = 1273 patients) were included in the review: eight studies compared budesonide to placebo, one compared budesonide to 5-aminosalicylates, one compared budesonide to traditional systemic corticosteroids, one compared budesonide to azathioprine, and one compared two doses of budesonide. Nine studies used a controlled ileal release form of budesonide, while three used a pH-modified release formulation. Nine studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to blinding and one of these studies also had inadequate allocation concealment. Budesonide 6 mg daily was no more effective than placebo for maintenance of remission at 3 months, 6 months or 12 months. At three months 64% of budesonide 6 mg patients remained in remission compared to 52% of placebo patients (RR 1.25, 95% CI 1.00 to 1.58; 6 studies, 540 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to moderate heterogeneity (I(2) = 56%) and sparse data (315 events). At six months 61% of budesonide 6 mg patients remained in remission compared to 52% of placebo patients (RR 1.15, 95% CI 0.95 to 1.39; 5 studies, 420 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (238 events). At 12 months 55% of budesonide 6 mg patients remained in remission compared to 48% of placebo patients (RR 1.13; 95% CI 0.94 to 1.35; 5 studies, 420 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (215 events). Similarly, there was no significant benefit for budesonide 3 mg compared to placebo at 6 and 12 months. There was no statistically significant difference in continued remission at 12 months between budesonide and weaning doses of prednisolone (RR 0.79; 95% CI 0.55 to 1.13; 1 study, 90 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (51 events) and high risk of bias (no blinding). Budesonide 6 mg was better than mesalamine 3 g/day at 12 months (RR 2.51, 95% CI 1.03 to 6.12; 1 study, 57 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (18 events) and high risk of bias (no blinding). There was no statistically significant difference in continued remission at 12 months between budesonide and azathioprine (RR 0.81; 95% CI 0.61 to 1.08; 1 study 77 patients). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to sparse data (55 events) and high risk of bias (single-blind and no allocation concealment). The use of budesonide 6 mg resulted in slight improvements in CDAI scores when assessed at 6 months (MD -24.30, 95% CI -46.31 to -2.29) and 12 months (MD -23.49, 95% CI -46.65 to -0.32) and mean time to relapse of disease (MD 59.93 days, 95% CI 19.02 to 100.84). Mean time to relapse was significantly shorter for patients receiving budesonide than for those receiving azathioprine (MD -58.00, 95% CI -96.68 to -19.32). Adverse events were not more common in patients treated with budesonide compared to placebo (6 mg: RR 1.51, 95% CI 0.90 to 2.52; 3 mg: RR 1.19, 95% CI 0.63 to 2.24). These events were relatively minor and did not result in increased rates of study withdrawal. Commonly reported treatment-related adverse effects included acne, moon facies, hirsutism, mood swings, insomnia, weight gain, striae, and hair loss. Abnormal adrenocorticoid stimulation tests were seen more frequently in patients receiving both 6 mg (RR 2.88, 95% CI 1.72 to 4.82) and 3 mg daily (RR 2.73, 95% CI 1.34 to 5.57) compared to placebo., Authors' Conclusions: These data suggest budesonide is not effective for maintenance of remission in CD, particularly when used beyond three months following induction of remission. Budesonide does have minor benefits in terms of lower CDAI scores and longer time to relapse of disease. However, these benefits are offset by higher treatment-related adverse event rates and more frequent adrenocorticoid suppression in patients receiving budesonide.