key: cord-0939091-qimst4c4
authors: Kuenzig, M Ellen; Bitton, Alain; Carroll, Matthew W; Kaplan, Gilaad G; Otley, Anthony R; Singh, Harminder; Nguyen, Geoffrey C; Griffiths, Anne M; Stukel, Therese A; Targownik, Laura E; Jones, Jennifer L; Murthy, Sanjay K; McCurdy, Jeffrey D; Bernstein, Charles N; Lix, Lisa M; Peña-Sánchez, Juan Nicolás; Mack, David R; Jacobson, Kevan; El-Matary, Wael; Dummer, Trevor J B; Fung, Stephen G; Spruin, Sarah; Nugent, Zoann; Tanyingoh, Divine; Cui, Yunsong; Filliter, Christopher; Coward, Stephanie; Siddiq, Shabnaz; Benchimol, Eric I
title: Inflammatory Bowel Disease Increases the Risk of Venous Thromboembolism in Children: A Population-Based Matched Cohort Study
date: 2021-06-27
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjab113
sha: b7171d9e698e401f786bd42816698545581dfc2e
doc_id: 939091
cord_uid: qimst4c4

BACKGROUND AND AIMS: Although venous thromboembolism [VTE] is a well-known complication of inflammatory bowel disease [IBD] in adults, limited data exist on the risk in children. We report the incidence of VTE among children with and without IBD. METHODS: We conducted a matched cohort study within a distributed network of population-based Canadian provincial health administrative databases. Children <16 years diagnosed with IBD were identified using validated algorithms from administrative data in Alberta, Manitoba, Nova Scotia, Ontario and Québec and compared to age- and sex-matched children without IBD. Hospitalizations for VTE within 5 years of IBD diagnosis were identified. Generalized linear mixed-effects models were used to pool province-specific incidence rates and incidence rate ratios [IRR] with 95% confidence intervals [CI]. Hazard ratios [HR] from Cox proportional hazards models were pooled with fixed-effects meta-analysis. RESULTS: The 5-year incidence of VTE among 3593 children with IBD was 31.2 [95% CI 23.7–41.0] per 10 000 person-years [PY] compared to 0.8 [95% CI 0.4–1.7] per 10 000 PY among 16 289 children without IBD [unadjusted IRR 38.84, 95% CI 16.59–90.83; adjusted HR 22.91, 95% CI 11.50–45.63]. VTE was less common in Crohn’s disease than ulcerative colitis [unadjusted IRR 0.47, 95% CI 0.27–0.83; adjusted HR 0.52, 95% CI 0.29–0.94]. The findings were similar for deep vein thrombosis and pulmonary embolism when comparing children with and without IBD. CONCLUSIONS: The risk of VTE is much higher in children with IBD than controls without IBD. While the absolute risk is low, we found a higher incidence rate than previously described in the pediatric literature. Conference Presentation: An abstract based on the data included in this paper was presented at Canadian Digestive Diseases Week [Montréal, Canada] in March 2020.

Inflammatory bowel disease [IBD] is a complex systemic inflammatory condition associated with intestinal and extra-intestinal complications. Among the most devastating extra-intestinal complications of IBD is the development of venous thromboembolism [VTE] . VTE is a well-recognized complication of IBD in adults, particularly in the setting of active inflammation or in the post-operative period. [1] [2] [3] [4] Current clinical practice guidelines on the use of VTE prophylaxis recommend adults with IBD who are hospitalized or have active disease with a previous VTE event receive chemoprophylaxis but recommend against chemoprophylaxis in children with IBD who are hospitalized and have not had a previous VTE event. 5 VTE prophylaxis is also recommended in children with ulcerative colitis [UC] in the post-operative setting or in those with acute severe UC in the presence of other factors known to increase the risk of VTE. 6, 7 The risk of VTE in children with IBD is not well described. The only population-based study of VTE incidence in patients under 20 years of age found a significantly lower rate of VTE in this age group compared to adults, but higher rates than in children and adolescents without IBD. 8 Because VTE events remain rare, the authors concluded that the risks and cost of VTE prophylaxis may not outweigh the benefits in children in the absence of other risk factors. Some clinical practice guidelines on the management of paediatric IBD recommend VTE prophylaxis in children requiring surgery or in patients who are otherwise at an increased risk of VTE, while others make no mention of VTE prophylaxis. 6, 7, [9] [10] [11] Recent updates to these guidelines currently recommend VTE prophylaxis in all hospitalized IBD patients, regardless of age, due to the additional pro-thrombotic risk associated with COVID-19. 12, 13 The mixed recommendations regarding thromboprophylaxis in children with IBD are primarily due to a lack of evidence, low perceived absolute risk and absence of risk-benefit analysis in the literature. Further understanding the absolute and relative rates of VTE in children with IBD may help provide guidance on whether thromboprophylaxis should be considered in selected patients.

Canada has amongst the highest incidence of paediatric IBD in the world. 14 The availability of validated, population-based cohorts of IBD patients derived from health administrative data allows for the evaluation of rare disease complications. We used these cohorts to report rates of VTE events among children with IBD using data from five provinces, comprising 79% of the Canadian population. 15 

This study was approved by the Research Ethics Boards at the Children's Hospital of Eastern Ontario, IWK Health Centre, Montreal Jewish General Hospital, University of Alberta, University of Calgary and University of Manitoba. This study was reviewed for privacy concerns by Alberta Health Services, Manitoba Health's Information Privacy Committee, Health Data Nova Scotia, ICES and the Commission d'Accès a l'Information du Québec.

We used health administrative data from five Canadian provinces: Alberta, Manitoba, Nova Scotia, Ontario and Québec. Each province has universal healthcare coverage. Data include demographic information [age, sex, eligibility for provincial healthcare coverage, location of residence, mean neighbourhood income quintile] and all healthcare encounters [outpatient visits, hospitalizations] for all residents of each province eligible to receive health services [>99% of the population]. Mean neighbourhood income quintile is a validated proxy for individual-level income. 16 Supplementary Table 1 provides a detailed description of the data sources in each province. Data are linked deterministically using a unique encrypted identifier. In Ontario, all databases are maintained by ICES according to an agreement with the Ontario Ministry of Health and Ministry of Long-Term Care. In Manitoba, all administrative health data are maintained by Manitoba Health and the study utilized the population-based cohort of persons with IBD with matched controls in the University of Manitoba IBD Epidemiology Database. In Nova Scotia, the administrative health data were made available through Health Data Nova Scotia. In Alberta, the administrative health data were made available through Alberta Health Services. In Québec, data were made available through the Commission d'Accès du Québec. Databases are available to researchers in an uncleaned and unedited format. 17 

Children <16 years of age diagnosed with IBD were identified from health administrative data using previously validated province-specific algorithms [Supplementary Table 1 ]. [18] [19] [20] [21] Validated classification systems based on International Classification of Diseases [ICD]-9 and ICD-10 codes for Crohn's disease [CD, ICD-9 555, ICD-10 K50] and UC [ICD-9 556, ICD-10 K51] were used to differentiate between children with CD and UC. Children were identified as IBD-type unclassifiable when classification systems could not differentiate between CD and UC; these children were included in the overall analyses but not in any disease-specific analyses. The date of IBD diagnosis was considered to be a child's first healthcare encounter with a diagnostic code for IBD that qualified them as an IBD case. We included cases diagnosed during the following fiscal years: Alberta, 2005-2015; Manitoba, 2004 Manitoba, -2014 Nova Scotia, 2001 Ontario, 2002 Ontario, -2014 Québec, 2006 Québec, -2008 . These dates correspond to the introduction of ICD-10 coding in each province. The start of ICD-10 coding was selected as the beginning of the study due to improved ability to identify VTE events using ICD-10 codes relative to ICD-9 codes.

In all provinces, data were available for at least 3 years prior to the start of the study to facilitate the 3-year lookback period required to distinguish incident from prevalent cases. 18 Thus, all children included in the study were required to be continuously eligible for provincial healthcare coverage for 3 years prior to their IBD diagnosis without a diagnostic code for IBD. Children diagnosed with IBD prior to their third birthday were included in the study if they were continually eligible for provincial healthcare coverage from birth until their date of IBD diagnosis. All children were followed into adulthood, until death, end of eligibility for provincial health care [i.e. migration out of the province in which they were diagnosed] or the end of the study period [Alberta: 2017; Manitoba: 2018; Nova Scotia: 2016; Ontario: 2017; Québec: 2010]. Study end dates varied across provinces due to differing data availability.

We conducted a retrospective matched cohort study. Children with IBD were matched to five children without IBD based on birth date, sex, and duration of eligibility for provincial healthcare coverage in Alberta, Manitoba, Nova Scotia and Ontario; controls in Manitoba were additionally matched based on the first three digits of a child's postal code. Eligible controls were selected at random from all children eligible for universal provincial healthcare coverage in their respective province. Data on children without IBD were not available from Québec. Children without IBD were assigned an index date corresponding to the diagnosis date of their matched child with IBD.

Due to provincial privacy regulations, individual-level data cannot be shared across provincial borders. Therefore, a distributed network analysis was conducted in which the same analytical code was used to run analyses in each province and provincial results were then meta-analysed to produce overall national estimates. 14, 22 Validation of this method has demonstrated that meta-analysis of pooled estimates produces similar results to individual-level data analysis in multi-variable regression models. 23 24 We report the incidence of each outcome within 1 and 5 years of diagnosis in children with IBD and, due to rarity of events, within 5 years of index date in children without IBD. We analysed all types of VTE events as a combined outcome, and DVT and PE events individually. There was an insufficient number of cerebral sinovenous thrombosis events to evaluate these separately from other types of VTE. Only the first relevant thrombotic event was included in each analysis. That is, if a child experienced both a DVT and a PE, these would both be counted in the analyses specific to each subtype of VTE but only the first of these events would contribute to the overall count of VTE events.

Using data from Ontario only, we determined the proportion of children experiencing a VTE event who had an IBD-related surgery [intestinal resection or colectomy; see Supplementary Table 3 for a list of validated IBD surgical codes 25, 26 ] either during the same hospitalization or in the 60 days prior to their VTE hospitalization. This analysis was restricted to Ontario since it was the largest provincial paediatric IBD cohort and the only one with a sufficient number of children developing a VTE during the course of the study to report the number of children with surgery around the time of their VTE.

For each province, age at diagnosis is described using means and standard deviations; sex, type of IBD, living in a rural or urban household at the date of diagnosis [using the Statistics Canada definition], and mean neighbourhood income quintile are described using percentages.

The incidence rates of VTE, DVT and PE were calculated using the total number of events occurring in children with and without IBD divided by the total person-years of follow-up in each group. We report the incidence rates of VTE, DVT and PE for all types of IBD combined, and separately for CD and UC. When there were between one and five children experiencing a given outcome in Manitoba, Nova Scotia and Québec, the exact number of events could not be shared within the study team due to privacy regulations. When this occurred, we assigned a random number between one and five to represent the number of events. This random number of events was then used with the known person-time to calculate province-specific incidence rates. In all other provinces [Alberta and Ontario], the exact number of events could be shared for meta-analysis but not published.

The relative and absolute differences in 5-year incidence rates of VTE and DVT among children with IBD, CD and UC were compared to children without IBD, as well as between children with CD vs UC. They are expressed as events per 10 000 person-years [PY] and compared using incidence rate ratios [IRR] and incidence rate differences [IRD] with 95% confidence intervals [CI] . The 5-year incidence rates of PE were also compared in children with IBD vs their matched controls; analyses stratified by disease sub-type could not be conducted due to the small numbers of PE events.

Generalized linear mixed-effects models [GLMMs] were used to pool province-specific incidence rates. 27 Unconditional fixed-effects GLMMs were used to estimate IRRs. 27 IRDs were pooled using fixed-effects Mantel-Haenszel methods. 28 Heterogeneity across provinces was described using the I 2 statistic; this describes the percentage of variability that results from between-province differences.

In provinces where the number of events was sufficient to ensure model convergence, we estimated the association between IBD and risk of VTE, DVT and PE using [1] multivariable modified Poisson regression for binary outcomes to estimate the relative rate [RR] of VTE events across groups 29 and [2] multivariable Cox proportional hazards models to compare the time-to-VTE using hazard ratios [HR] . Models were adjusted for age at diagnosis/index date, sex, mean neighbourhood income quintile and living in a rural household. The number of provinces included in each pooled analysis varied based on the event [i.e. VTE, DVT or PE] and comparison [i.e. children with vs without IBD or children with CD vs UC]. Fixed effects were used to pool RRs and HRs estimated from provincespecific models; inverse-variance weights were used to weight the contribution of individual provinces to the overall pooled estimate. Statistical analyses were conducted using the GENMOD and PHREG procedures in SAS 9.4 [SAS Institute Inc.]. Meta-analyses were conducted using the meta 30 and metafor 31 packages in R. 32

We conducted two sensitivity analyses. The first sensitivity analysis excluded Québec from the calculation of 1-and 5-year incidence rates of VTE, DVT and PE since data from Québec were not available for children without IBD. The second sensitivity analysis re-calculated incidence rates, IRRs and IRDs using extreme values [i.e. either one or five] when privacy regulations prevented the sharing of the actual number of events. For the comparison of children with and without IBD, we compared IRRs and IRDs assuming: [1] one event in both those with and without IBD, [2] one event in those with IBD and five events in those without IBD, [3] five events in those without IBD and one event in those with IBD, and [4] five events in those with and without IBD.

A total of 3593 children with IBD [CD: 2201; UC: 1131] and 16 284 age-and sex-matched children without IBD were included in the study [ Table 1 ].

The 1-and 5-year incidence rates of VTE among children with IBD were 81. 16 Table 3 ]. The association between IBD and DVT was consistent when adjusting for age, sex, rurality and income [ Table 3 ].

CD and UC were both consistently associated with an increased risk of DVT compared with children without IBD [ Table 3 ]. The 5-year incidence of DVT was lower among children with CD compared to children with UC [IRR 0.46, 95% CI 0.25-0.87; IRD −21.54, 95% CI −40.72 to −2.37 per 10 000 PY]. The magnitude of this association was slightly attenuated and no longer significant when adjusting for age, sex, rurality and income. Table 3 ]. The adjusted association between IBD and risk of PE was attenuated but remained statistically significant. Due to the small number of events, we were not able to separately analyse children with CD and UC or compare between the two types of IBD. 

In this population-based Canadian study, we report substantially higher rates of VTE in children diagnosed with IBD as compared to children without IBD. Within 5 years of diagnosis, the incidence rates of any VTE, DVT or PE among children with IBD were 31.18, 24.42 and 3.05 per 10 000 PY, respectively. These rates were 12-to 45-fold higher than controls. While incidence was elevated in both CD and UC, the risk of VTEs in children with UC was nearly double the risk in children with CD. Only a quarter of VTE events were associated with an IBD-related surgery. In addition, we noted that the majority of VTE events occurred in the first year following diagnosis for patients with both CD and UC, a time when they are more likely to have severe, active disease. These findings confirm that VTE is an important complication of IBD in children.

To our knowledge, this is the first population-based North American study to report the risk of VTE in paediatric IBD. The only other population-based study used Danish health administrative data to demonstrate VTE risk in all ages; while the absolute risk was lower in patients less than 20 years old than in older age groups, the relative risk compared to controls was highest in paediatric patients. 8 Another study was conducted using data from an international prospectively collected safety registry where data were collected using a monthly survey of >150 gastroenterologists from 26 countries. 33 Of note, we found that the incidence of VTEs in Canadian children was approximately three-fold higher than rates reported in Danish children and more than six-fold higher than rates reported in the safety registry. For example, we found that overall VTE risk in our patients was 31.18 per 10 000 PY, while the Danish cohort had rates of 8.9 per 10 000 PY and the safety registry reported rates of 4.86 per 10 000 PY. Similarly, risk of DVT in IBD patients in our study was 24.42 per 10 000 PY, compared to 5.4 per 10 000 PY in Denmark. Risk of PE was similar in Canada and Denmark [3.05 vs 3.4 per 10 000 PY]. The incidence of VTEs in children without IBD was similar in Canada and in the Danish study. 8 Adjusted hazard ratios were therefore much higher in Canada compared to Denmark for IBD [22.9 vs 6.6], CD [20.8 vs 6.0] and UC [19.2 vs 6.4] . We restricted our cohort to incident cases only while the Danish study included both prevalent and incident cases, potentially contributing to the differences between the two studies. The incidence of VTE in the safety registry is probably underreported due to non-response among participating gastroenterologists and recall bias [i.e. physicians only report the most severe VTE events to the registry].

We demonstrated a higher incidence of VTEs in the first year following diagnosis, suggesting a role of bowel and systemic inflammatory burden in the pathophysiology of VTE development. Stabilization of disease activity after the first year may have also accounted for the reduced overall risk of developing VTE beyond 1 year in our cohort. Another population-based study primarily of adult patients from the UK found similar incidence of VTE in their IBD population [2.6 per 1000 PY], with much higher rates during hospitalizations [25.2 per 1000 PY], disease flares [9.0 per 1000 PY] or chronically active disease states [5.4 per 1000 PY], even in the ambulatory setting. 2 It is noteworthy that the incidence of VTE in our study during the first year of diagnosis [81.2 per 10 000 PY or 8.12 per 1000 PY] was very similar to the incidence noted in UK adults in the setting of disease flare [9.0 per 1000 PY], reinforcing the importance of disease activity in the risk of VTEs. Therefore, the absolute risk of VTEs in children with active disease may be similar to rates in adult IBD patients.

Canadian clinical practice guidelines recommend VTE prophylaxis in hospitalized adult IBD patients even when in remission, extrapolating from recommendations for non-IBD hospitalized patients. 5 However, thromboprophylaxis was not recommended in hospitalized children with IBD in the absence of a previous VTE event. This was a weak recommendation, based on low certainty of Abbreviations: AB, Alberta; CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; IRD, incidence rate difference; IRR, incidence rate ratio; NS, Nova Scotia; ON, Ontario; PE, pulmonary embolism; PY, person-years; RR, relative rate; VTE, venous thromboembolism.

Because of the small number of PE events, the modified Poisson models comparing children with and without IBD did not converge and we could not present disease-specific analyses. *Modified Poisson models for binary outcomes adjusted for age, sex, rural/urban household and median neighbourhood income quintile. † Cox proportional hazards models adjusted for age, sex, rural/urban household and median neighbourhood income quintile. evidence according to GRADE criteria. The decision was based primarily on the lower absolute risk of VTE in children compared to adults, as demonstrated from a single population-based study, 8 and the discomfort of subcutaneous injection. 5 More recent European and Canadian paediatric practice guidelines did not address the use of prophylaxis against VTE in paediatric CD. 10, 11 However, European practice guidelines recommended prophylaxis in children with severe UC with one or more risk factors, such as smoking, oral contraceptive use, complete immobilization, central venous catheters, obesity, concurrent infection, known prothrombotic disorder, previous VTE and family history of VTE. 7 Guidelines published during the current COVID-19 pandemic recommend all patients hospitalized for moderate-to-severe IBD receive prophylaxis. 12, 13 Paediatric gastroenterologists, although aware of the increased risk of VTE in children with IBD, are hesitant to provide prophylaxis for their patients based on the current lack of literature [e.g. clinical practice guidelines]. 34 Our data suggest that VTE prophylaxis in children could be clinically appropriate, especially in a context of hospitalization for active inflammation or surgical intervention. Updated clinical practice guidelines may be needed. The strengths of this study include its large sample of paediatric IBD patients, population-based nature and the ability to assess the risk of VTEs longitudinally in an inception cohort. However, as with all studies that use health administrative data, there are limitations. There is always a risk of misclassification bias; however, we used validated algorithms to identify both diagnosis of paediatriconset IBD and VTE. Since the algorithm to identify VTE events was only validated in Canadian hospitalization data from the province of Alberta, 24 it is possible we missed some cases diagnosed in the ambulatory setting. However, it is unlikely that a child with IBD diagnosed with VTE would remain an outpatient. In addition, it is unlikely that children with a VTE would be hospitalized for less than 48 h [and therefore missed by our algorithm], since all children would receive consultation from a haematologist, undergo investigation for an underlying pro-thrombotic condition, be counselled and started on appropriate therapy, and monitored for response to therapy with bloodwork, including thrombosis measures. The algorithm we used to identify VTE events did not include mesenteric thrombosis or thrombotic events related to an indwelling catheter [e.g. PICC line]. The magnitude of the comparison between children with and without IBD may have been biased if the threshold for admitting a child with a DVT differed between those with and without IBD. The codes used to identify VTE had a sensitivity of 75%, which may have additionally resulted in an underestimate of the incidence of VTE in our study. 24 Health administrative data do not contain information on risk factors for VTE. This includes disease phenotype or activity and prescription medication in either the inpatient or the outpatient setting [e.g. corticosteroids, anticoagulants]. In addition, we did not have data on other chronic conditions among children with and without IBD in our study. It has been previously estimated that 2.5% of children in Ontario are living with a chronic condition 35 and we would expect this proportion to be similar among the randomly selected children without IBD included in our study. The follow-up periods were slightly different in each province due to data availability. There were no paediatric clinical practice guidelines that recommend prophylaxis in children with IBD that were published during the time period of this study, so we anticipate that rates of prophylaxis were very low and did not change over the course of the study. Improvements in the treatment of IBD in children have occurred over the study period; however, we were not able to determine if the risk of VTE events has changed over time due to the small number of VTE events. We could not determine whether VTE was associated with treatment or disease severity. We included VTE events that occurred during a hospitalization [i.e. the patient was admitted to hospital prior to their VTE event] and events that occurred outside of the hospital for which patients were later admitted to hospital. Because we had so few VTE events in our study, were not able to differentiate between these two types of VTE. The rarity of VTE outcomes limited our ability to provide adjusted rates for all participating provinces. This decrease may have contributed to adjusted analyses being no longer significant, despite effect estimates similar in magnitude to the unadjusted analysis. In addition, privacy regulations prevented the sharing of data when there were small numbers of events. The data from Québec did not contain a cohort of non-IBD children, and we could therefore only report absolute risks from that province. The rarity of outcome rates prevented our ability to assess cerebral sinovenous thrombosis rates. Previous studies have reported a high proportion of cerebral sinovenous thrombosis among thrombotic events in children with IBD; however, both studies may have been subject to reporting biases with more severe thrombotic events more likely to be published as case series/reports or reported to a safety registry. 33, 36 Finally, we did not have a sufficient number of VTE events to report the incidence of VTE events separately for medical and surgical admissions, among individuals with co-occurring pro-thrombotic conditions, or among those experiencing the VTE event during a hospital admission or in an ambulatory setting requiring subsequent hospitalization.

In summary, we have demonstrated that the risk of VTE was much higher in children with IBD compared to controls. In addition, while the absolute risk was low, it was much higher than the previous Danish population-based study and in the study conducted from a prospectively collected safety registry, and similar to the risk reported in adults with IBD. VTE rates were highest in UC patients, and in the first year following diagnosis. Future research should assess the risks and benefits of thromboprophylaxis in this population, as well as identify patients at greatest risk based on clinical, biological and demographic criteria with the goal of informing clinical practice guidelines on the use of VTE prophylaxis in paediatric IBD. Sandoz Canada, Takeda Canada, Merck Canada, Pfizer Canada, Janssen Canada and Roche Canada. J.D.M. has received consultancy fees and/or honoraria from Abbvie, Janssen, Takeda and Pfizer. C.N.B. has been on the advisory boards of Abbvie Canada, Amgen Canada, Bristol Myers Squibb Canada, Janssen Canada, Pfizer Canada, Sandoz Canada, Takeda Canada and Roche Canada, and consulted to Takeda and Mylan Pharmaceuticals. He has been on the speaker's bureau for Abbvie Canada, Janssen Canada, Takeda Canada and Medtronic Canada. He has received unrestricted educational grants from Abbvie Canada, Janssen Canada, Pfizer Canada and Takeda Canada and has done contract research with Abbvie, Janssen, Pfizer, Celgene, Boeringher Ingelheim and Roche. K.J. has been on Advisory boards of Abbvie Canada, Janssen Canada, Merck Canada and Mylan Pharmaceuticals. He has been on the speaker's bureau of Abbvie Canada and Janssen Canada. He has received investigator-initiated research support from Abbvie Canada and Janssen Canada. W.E.M. has received honoraria for speaking or consultancy from Abbvie and MERCK. E.I.B. has acted as a legal consultant for Hoffman La-Roche Limited and Peabody & Arnold LLP for matters unrelated to a medication used to treat inflammatory bowel disease or venous thromboembolic events. 

The Ontario portion of the dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers [e.g. healthcare organizations and government] prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/ DAS [email: das@ices.on.ca]. The full dataset creation plan and underlying analytical code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.

The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study

Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study

Colectomy is a risk factor for venous thromboembolism in ulcerative colitis

Risk of venous thromboembolism after hospital discharge in patients with inflammatory bowel disease: a population-based study

Consensus statements on the risk, prevention, and treatment of venous thromboembolism in inflammatory bowel disease: Canadian Association of Gastroenterology

Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition

Management of paediatric ulcerative colitis, part 2: acute severe colitis-an evidence-based consensus guideline from the European Crohn's and Colitis Organization and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition

Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study

The medical management of paediatric Crohn's disease: an ECCO-ESPGHAN guideline update

Canadian Association of Gastroenterology Clinical Practice guideline for the medical management of pediatric luminal Crohn's disease

Canadian Association of Gastroenterology Clinical Practice guideline for the medical management of pediatric luminal Crohn's disease

Adaptations to the current ECCO/ ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel

Care of the patient with IBD requiring hospitalisation during the COVID-19 pandemic

Trends in epidemiology of pediatric inflammatory bowel disease in Canada: distributed network analysis of multiple population-based provincial health administrative databases

Population estimates, quarterly. Statistics Canada

Inner City Toronto Time Trends Working Group. Socioeconomic misclassification in Ontario's Health Care Registry

Institute for Clinical Evaluative Sciences

Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data

Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian province: a population-based study

Validation of administrative case ascertainment algorithms for pediatric IBD in Nova Scotia

Development and validation of an administrative case definition for inflammatory bowel diseases

Past and future burden of inflammatory bowel diseases based on modeling of population-based data

Distributed Network Meta-Analysis Estimates Results from Individual-Level Analysis Using Ontario Health Administrative Data on Pediatric Inflammatory Bowel Disease Health Services Use: A Population-Based Cohort Study

The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data

Postoperative complications following colectomy for ulcerative colitis: a validation study

Surgical rates for Crohn's disease are decreasing: a population-based time trend analysis and validation study

Mixed-effects poisson regression models for meta-analysis of follow-up studies with constant or varying durations

Estimation of a common effect parameter from sparse follow-up data

A modified poisson regression approach to prospective studies with binary data

meta: an R package for meta-analysis

Conducting meta-analyses in R with the metafor package

R: a language and environment for statistical computing

The incidence and characteristics of venous thromboembolisms in paediatric-onset inflammatory bowel disease

Pediatric gastroenterologists' approach to venous thromboembolism prophylaxis in pediatric inflammatory bowel disease

Residential movement patterns of families of young children with chronic conditions in Ontario, Canada: a population-based cohort study

Thromboembolism in pediatric inflammatory bowel disease: systematic review

Parts of this material are based on data and information compiled and provided by MOH and CIHI. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

Supplementary data are available at ECCO-JCC online.