Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Venous Thrombotic Events in Hospitalized Children and Adolescents With Inflammatory Bowel Disease
Nylund, Cade M.*; Goudie, Anthony†; Garza, Jose M.‡; Crouch, Gary*; Denson, Lee A.‡
*Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD
†Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock
‡Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Address correspondence and reprint requests to Cade M. Nylund, MD, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814 (e-mail: email@example.com).
Received 18 June, 2012
Accepted 27 November, 2012
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.jpgn.org).
The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Air Force, Department of Defense, or the US government.
The authors report no conflicts of interest.
Background: Adults with inflammatory bowel disease (IBD) have an increased risk of venous thrombotic events (TEs). We sought to evaluate the risk for TE in children and adolescents with IBD using a large population database.
Methods: The triennial Healthcare Cost and Utilization Project Kids’ Inpatient Database was used in a retrospective cohort study of hospitalized children in the United States across 1997, 2000, 2003, 2006, and 2009. Billing codes were used to identify discharges with Crohn disease, ulcerative colitis, pulmonary embolism, deep vein thrombosis, thrombophlebitis, thrombosis of intracranial venous sinus, Budd-Chiari syndrome, and portal vein thrombosis. A logistic regression model was fitted to quantify the increased risk of TE in children with IBD, while adjusting for other risk factors of thrombosis.
Results: The total weighted number of pediatric discharges was 7,448,292, and 68,394 (0.92%) were identified with IBD. The incidence of any TE in a hospitalized child or adolescent with IBD was 117.9/10,000 with a relative risk (95% confidence interval) of 2.36 (2.15–2.58). The adjusted odds ratio for any TE in a patient with IBD without surgery was 1.22 (1.08–1.36). Risk factors for TE among patients with IBD include older age, central venous catheter, parenteral nutrition, and an identified hypercoagulable condition. There is an increasing trend of TE in both the IBD and non-IBD patients.
Conclusions: Hospitalized children and adolescents with IBD are at increased risk for TE. Conservative methods of TE prevention including hydration, mobilization, or pneumatic devices should be considered in hospitalized patients with IBD.
The incidence of inflammatory bowel diseases (IBDs), including Crohn disease and ulcerative colitis, has increased dramatically during the last 4 decades, with approximately 5 million individuals affected in North America and Europe. Twenty percent of patients with IBD are diagnosed in childhood (1). Although IBD primarily affects the bowel, there are many known secondary effects on patients with IBD, including an increased risk of cancer, liver disease, bone disease, and venous thrombotic events (TEs). The overall risk of systemic TE is increased in patients with both Crohn disease and ulcerative colitis (2,3). The increased risk of TE in adult patients with IBD has now been generally accepted (4).
Although the risk of TE is known to be increased in adults with IBD, less is known about the risk of TE in children with IBD. Because the risk of TE is lower in the general pediatric population, it is often assumed that the risk of TE in children with IBD is also lower than the risk in adults with IBD, potentially placing children with IBD at risk of TE by neglecting appropriate TE prophylaxis (5). In a population cohort of Danish children with IBD, Kappelman et al (6) demonstrated that they had a lower incidence of TE compared with adults with IBD. Children, however, were shown to have a higher relative risk of deep venous thrombosis and pulmonary embolism (PE). There have been no systematic evaluations of the risk of TE among hospitalized children with IBD or in the US population. Using a large pediatric national inpatient database, we sought to identify the epidemiology of TE in hospitalized children and adolescents with IBD in the United States, the association of IBD with TE, and risk factors for TE among patients with IBD.
Data was obtained from the triennial Healthcare Cost and Utilization Project Kids’ Inpatient Database (HCUP-KID), sponsored by the Agency for Healthcare Research and Quality. HCUP-KID is the first US nationwide inpatient database devoted to children. The database used for the present study consisted of an aggregated, stratified random sample across 5 time periods: 1997, 2000, 2003, 2006, and 2009. Included were discharge data from 22 to 44 states (depending on the year). In 2009, HCUP-KID represented an estimated 96.1% of all pediatric inpatient visits in the United States. Each record in the database included up to 15 diagnostic codes and up to 15 present procedural codes based on international statistical classification of diseases and related health problems, 9th revision (International Classification of Diseases-9 [ICD-9]). HCUP-KID assigns an individual-level population weight that allows an estimation of national case rates and trends (7).
To select a population most representative of IBD, we limited our analysis to nongravid children and adolescents ages 5 to 20 years. Discharges related to pregnancy were identified by procedure codes (72–74) and were then excluded. The main outcome in the present study is the presence or absence of a diagnosis of a TE on an inpatient discharge record. The database was searched for the ICD-9-CM codes in the following TE diagnostic groups: PE (415.1x), deep vein thrombosis (DVT) (415.3, 453, 453.[2–4], 453.8, 453.9, 453.8[3–9]), thrombophlebitis (453.1, 451.x, 453.6, 453.81), Budd-Chiari syndrome (453.0), portal vein thrombosis (452, 572.1), and intracranial venous sinus thrombosis (325). The main predictors included the diagnoses of IBD (555.x, 556.x), with abdominal surgeries common to IBD evaluated as a confounder. The IBD surgery codes were obtained through sorting by frequency the surgical procedural codes for those with IBD, and identifying the top 50 abdominal surgery procedure codes. For ease in reporting and to control for potential multicollinearity, we combined IBD and surgery combinations to a 4-category variable including no IBD, no surgery; no IBD, surgery; IBD, no surgery; and IBD, surgery. In addition, the following procedures and diagnoses were retained for analysis: placement of central venous catheter (CVC) (38.93, 86.07), parenteral nutrition (PN) (99.15), sickle cell anemia (282.41, 282.42, 282.5, 282.6x), primary hypercoagulable conditions (289.81), tobacco use (305.1x), and cancer (140–239).
Demographic data included race, sex, age, payer type, geographic region, and geographic location (urban vs rural) of the hospital. Not all states report race and ethnicity on their inpatient records. To ensure that all inpatient records were included in the analysis, a 5-category race/ethnicity variable was constructed comprising: white, black, Hispanic, other race/ethnicity, and not reported or missing. Payer type was grouped into private (insurance/health maintenance organization), public (Medicaid/Medicare), and uninsured (no pay, self-pay, and any other). The hospital region was designated per HCUP-KID: Northeast, Midwest, South, or West.
Using population weights, a descriptive summary is presented by IBD status (Crohn disease, ulcerative colitis, and no IBD) for the number and percentage of TE and other demographic characteristics. Comparisons between IBD status groups were conducted using Rao-Scott χ2 tests. Also by IBD status, the absolute (weighted prevalence/10,000 inpatient discharges) and relative risks (no IBD is the referent category) along with 95% confidence intervals of any TE and individual TE events are presented.
For the 4-category main predictor variable, the adjusted odds ratios (ORs) for the likelihood of any TE are obtained using a multivariable logistic regression model with inpatient discharges, with no IBD and no surgery as the reference category. ORs are adjusted for age category, sex, hypercoagulable status, CVC, PN, any cancer, sickle cell anemia, tobacco use, race/ethnicity, payer status, urban/rural status, hospital region, and year of inpatient stay. To determine whether differences exist in the significant associations between covariates and IBD status, we use stratified logistic regression models (IBD and no IBD) to compare adjusted ORs. For logistic regression models, all adjusted ORs are significant if 95% confidence intervals do not include 1.00. Model diagnostics for multicollinearity were assessed using Spearman correlations as well as tolerance and variance inflation factor statistics. To identify trends in the prevalence of TEs (between 1997 and 2009 by IBD status) a Cochrane-Armitage test of trend was performed.
All summary-descriptive results, absolute risks, relative risk, and logistic regression analyses incorporated population weights to produce nationally representative estimates and appropriate standard errors for significance testing. All analyses were conducted using SAS Enterprise Guide 9.3 (SAS Institute, Cary, NC).
The total weighted number of inpatient pediatric discharges were 7,448,292; 61,076 (0.82%) identified with Crohn disease and 7318 (0.10%) identified with ulcerative colitis (Table 1). Of those with IBD, Crohn disease was diagnosed in 89.3%, with the remaining 10.7% diagnosed as having ulcerative colitis. Compared with children discharged from a hospital with no indication of IBD, those listed as having any diagnosis of IBD were disproportionately older, white, residing in the northeast, residing in an urban setting, and had private insurance. Children with ulcerative colitis were disproportionately girls compared with children with no IBD.
The absolute risk of any TE was low among all pediatric patients (Table 2). Children with no IBD had an absolute risk of 50.4/10,000 hospitalizations, whereas those with Crohn disease and ulcerative colitis had comparably elevated absolute risks of 119.8 (relative risk 2.37; 95% CI 2.16–2.61) and 101.7 (relative risk 1.99; 95% CI 1.51–2.64)/10,000 hospitalizations, respectively. The absolute risks for TE among children with Crohn disease with and without surgery were 111.2 and 121.2/10,000 hospitalizations, respectively. The absolute risks for TE among children with ulcerative colitis with and without surgery were 115.5 and 98.2/10,000 hospitalizations, respectively. For children with Crohn disease, the relative risks for all individual TEs were higher than those for children with non-IBD, whereas for children with ulcerative colitis, only the relative risks of DVT, thrombophlebitis, and intracranial venous sinus were higher.
The results of the multivariate logistic regression model adjusting for other risk factors of TE demonstrated an increased risk for patients with IBD without surgery (OR 1.21; 95% CI 1.09–1.36) but did not identify a significant risk in patients with IBD with surgery (OR 0.85; 95% CI 0.67–1.08). Those non-IBD patients with an abdominal surgery also had an increased risk of TE (OR 1.42; 95% CI 1.32–1.54). Many other demographic, procedural, and comorbid variables were also found to be associated with TE (a full listing of ORs can be found in Table 3; absolute risks and unadjusted relative risks can be found in supplemental Table 1, http://links.lww.com/MPG/A188).
Stratified logistic regression was performed to compare associated factors for TE among diagnostic groups of IBD and non-IBD (Table 4). Significant associated factors for TE among IBD and non-IBD patients include older age (supplemental Fig. 1, http://links.lww.com/MPG/A189), hypercoagulable condition, CVC, PN, and geographic region (referent northeast). Tobacco use was found to be a risk factor for TE in non-IBD patients (OR 1.20; 95% CI 1.13–1.27), and protective among patients with IBD (OR 0.38; 95% CI 0.20–0.75). Additional factors that were found to be risk factors in the non-IBD group but not found to be significant risk factors in the IBD group were abdominal surgery, cancer, sickle cell anemia, urban location of hospital, and private insurance.
There was an increasing trend for TE among all non-IBD pediatric patients with an average annual percent increase of 15.01 (P < 0.0001), with an average annual percent increase in non-IBD hospitalizations of 1.80 (Fig. 1). The average annual percent increase of patients hospitalized with a diagnosis for IBD and TE was 34.13 (P < 0.0001), yet there was also an increase in the number of hospitalized patients with IBD overall (13.54 average annual percent increase). These trends were supported by the results of the multivariate logistic regression models, which included year as a covariate. These results showed increasing OR for TE as year increases, 1997–2009 (Tables 3 and 4). In the IBD-stratified multivariate logistic regression results (Table 4), however, the year variable was significant only for 2006, suggesting that the increasing trend seen in TE among patients with IBD may be partially because of changes in other variables controlled for in this model.
In adults, IBD is an acknowledged risk factor for initial and recurrent venous TEs, including DVT and PE (8,9). Consistent with adult studies, in this large US hospital-based database, we found that hospitalized children and adolescents with IBD are at an increased risk for TE. In our multivariable analysis, this risk of TE persists after adjusting for common risk factors for TE. We also report an increased risk for thrombophlebitis, intracranial venous sinus thrombosis, Budd-Chiari syndrome, and portal vein thrombosis in patients with Crohn disease as well as DVT, thrombophlebitis, and intracranial venous sinus thrombosis in patients with ulcerative colitis. There are previous case reports of portal vein, mesenteric venous thromboses, and intracranial venous sinus thrombosis in patients with IBD, although these risks have never been quantified (10). In addition, risk factors among patients with IBD are older age, CVC, PN, and an identified primary hypercoagulable condition. Factors that were protective are tobacco use and Hispanic ethnicity.
The previous epidemiologic reports of TE and the specific subtypes of TE in children with IBD are limited. Kappelman et al (6) used a Danish cohort to study venous TEs in adults and children in the hospital and outpatient settings, and reported that 40 of 5424 children with IBD had a venous TE. They also reported an increased hazard ratio for children ages 0 to 20 years with IBD compared with adults, but did not account for risk factors such as indwelling venous lines and administration of PN. Among hospitalized patients, our reported absolute risk of venous TE in children is approximately 5% the size of that reported in adults (11). Our reported incidence of venous TE in the general pediatric non-IBD group is similar to 2 previous studies using 2 different data sources (12,13).
The increased risk for TE in children and adolescents with IBD may also be related to the mechanism for the increased risk of TE in adult patients with IBD. There are multiple proposed etiologies for this increased risk of TE in patients with IBD, yet no consensus has emerged. Thrombosis in IBD is characterized by both systemic TE events and focal microthrombi in the vasculature of inflamed intestine (14). There is evidence that microvascular thrombosis may play a role in the disease process in ulcerative colitis because treatment with enteral extended colon-release tablets of low-molecular-weight heparin has a beneficial effect in patients with ulcerative colitis (15). The potential etiologies for increased thrombosis in patients with IBD include thrombocytosis/platelet activation (16), hyperhomocysteinemia (17–19), increased fibrinogen (20), impaired fibrinolysis (21,22), autoantibodies (23–25), increase in procoagulation factors (26–28), decreased anticoagulation factors (28–35), and procoagulation mutations (29,36,37). In studies of adult patients with IBD, the extent of disease activity has been shown to correlate with patients’ risks for TE (9,30,38). The risk of TE can be found in the absence of active bowel disease and in patients with ulcerative colitis even after protocolectomy, suggesting that the risk of TE may be independent from disease activity (2,9,39,40).
We identified risk factors for TE and compared them with those with and without IBD. Older age was a risk factor for TE in both IBD and non-IBD groups. The presence of procedure codes for CVC, arterial catheter, and PN were associated factors for the development of TE for both IBD and non-IBD groups. These associations are consistent with previous reports (5). Abdominal surgery was a risk factor for TE in non-IBD patients, but was not found to be a significant risk for TE in the patients with IBD. It is possible that we had insufficient numbers to determine significance. Moreover, although surgery in the non-IBD patient may be therapeutic for the inflammatory process, it places them at risk for TE, whereas patients with IBD with surgery may be more likely to be admitted for scheduled/elective surgeries rather than when acutely ill, or patients with IBD may be more likely to receive TE prophylaxis after surgery. HCUP-KID does not contain medication information, so we were unable to assess whether TE prophylaxis was administered.
We also identified 2 protective factors for TE in patients with IBD, Hispanics (white race as referent), and tobacco exposure. Hispanics had lower risk of TE among all children, which is consistent with adult studies (41). Tobacco was only protective for those patients with IBD and was a risk factor for TE in those without IBD. Tobacco use is a well-established risk for TE in adults (42). The reason for the identified protective effect of tobacco on TE in children with IBD is less clear because smoking is associated with a worse clinical course in patients with Crohn disease, and a more benign clinical course in patients with ulcerative colitis (43).
We identified an increasing trend in TE among non-IBD children. This general trend of TE in pediatrics has been identified and described previously using a different data source, and our study confirms these findings (13). An increasing trend of TE also has been described in adults with IBD (44). In our study, we find that there is a significant increasing trend in the rate of TE among patients with IBD, and we are the first to identify this trend in children with IBD. In our stratified multivariate model for IBD (Table 4), however, this trend is less clear, with only the data from year 2006 showing a significant increase risk for TE. It appears from these results that this increasing trend can be explained by other variables, which are also increasing through the years, such as an increasing percent of patients with IBD on PN. The increasing rate of hospitalization of patients with IBD was described previously (45). Our findings may suggest that not only are the rates of IBD patient admissions increasing but the severity of these patients also may be increasing.
Identifying the increased risk of TE leads us to question what primary thromboprophylactic interventions should be instituted in hospitalized children and adolescents with IBD. Primary pharmacologic thromboprophylaxis may be indicated in select hospitalized pediatric IBD patients. In adults with IBD, TE leads to extensive morbidity and mortality within 2 years of the event (9,40,44,46). Children with thromboembolic disease have increased morbidity and mortality, although this risk has not been quantified within the pediatric IBD population (47). The American College of Chest Physicians’ recommendation for adult patients with IBD who are either acutely ill or confined to bed is to provide thromboprophylaxis with low-molecular-weight heparin (48).
There are several published guidelines for the application of primary prophylaxis of venous thrombosis in children. The evidence-based guidelines from the American College of Chest Physicians for primary pharmacologic thromboprophylaxis in children include complex cardiac patients and children with central venous lines or access devices who are receiving long-term home PN. The recommendations for anticoagulation in children with CVC and long-term home PN are based on published rates for central line-associated TE as high as 35%, with the majority of case series ranging between 1% and 7% (5,49). In our study, we found an incidence of approximately 1% of TE in children with IBD, which suggests that primary pharmacologic thromboprophylaxis could be considered beneficial; however, little is known about treatment risk in the IBD pediatric population.
Jackson and Morgan (50) in the United Kingdom developed a guideline for use of thromboprophylaxis in children undergoing surgery or admitted to the ICU. This algorithm assigns points for associated risk factors, including inflammatory conditions (including IBD) and steroid use. There are no published trials for the efficacy of primary pharmacologic thromboprophylaxis in children, and no safety studies in children with IBD. In a consensus statement on the management of severe ulcerative colitis by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Turner et al (51) comment that there is no specific evidence to support the administration of thromboprophylaxis with heparin in children. There is an increased risk of TE in children and adolescents with IBD; however, the absolute risk remains relatively low compared with adult patients with IBD. We would support the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus guideline that thromboprophylaxis should not be used in every hospitalized child with IBD, with the caveat that the decision to implement pharmacologic thromboprophylaxis could be considered in children and adolescents with IBD, based on stratified risk factors such as previous TE, identified primary hypercoagulable condition, family history of TE, bowel disease activity, the presence of CVC, administration of PN, steroid use, and limited mobility. Initiating pharmacologic thromboprophylaxis is a challenging decision, especially in an ill child with IBD who may have ongoing gastrointestinal bleeding and anemia. We recommend that every hospitalized child with IBD be assessed for potential risk factors for TE. Conservative nonpharmacologic methods of prophylaxis such as adequate hydration, mobilization, and compression stockings or pneumatic devices (age-appropriate) should be considered in all hospitalized children with IBD.
The HCUP-KID provides an excellent national representative sample of pediatric hospitalizations. The large sample size allowed us to conduct a broad evaluation of the associated risk of TE in children with IBD, while controlling for potential confounding factors. Use of HCUP-KID does, however, have several weaknesses. Our definitions of both IBD and TE were based on ICD-9 coding. As in all studies using diagnostic codes, there is concern for paucity of clinical information and the inability to verify the diagnostic details or severity. Misclassification and reporting bias are both potential weaknesses. Because the HCUP-KID database reports hospital discharges, not individual patients, it was not possible to distinguish patients readmitted to the hospital for the same diagnosis. Also, although medications frequently given to patients with IBD may also alter the thrombotic cascade, the HCUP-KID does not contain medication information, and thus we were unable to evaluate these potential confounders in our study.
Our population-based study provides novel data about the increased risks of certain TEs in hospitalized children with IBD. Our study supports previous studies in patients with IBD. To our knowledge this is the first study to describe both the epidemiology of TEs and the risks of those events in the pediatric hospitalized IBD population. Increased awareness of the risks provides a background for both preventing complications and their early detection.
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pediatric inflammatory bowel disease; pediatric thrombosis; venous thrombosis
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