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Keywords:

  • inflammatory bowel disease;
  • children;
  • epidemiology;
  • surgery;
  • immunomodulatory therapy;
  • growth

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Background:

The aim was to evaluate the incidence, treatment, surgery rate, and anthropometry at diagnosis of children with inflammatory bowel disease (IBD).

Methods:

Patients diagnosed between January 1, 2007 to December 31, 2009 in Eastern Denmark, Funen, and Aarhus were included from a background population of 668,056 children <15 years of age. For evaluation of incidence, treatment, and surgery rate, a subcohort from Eastern Denmark was extracted for comparison with a previously published population-based cohort from the same geographical area (1998–2006).

Results:

In all, 130 children with IBD: 65 with Crohn's disease (CD), 62 with ulcerative colitis (UC), and three with IBD unclassified (IBDU) were included. The mean incidence rates per 106 in 2007–2009 were: IBD: 6.4 (95% confidence interval [CI]: 5.4–7.7), CD: 3.2 (2.5–4.1), UC: 3.1 (2.4–4.0) and IBDU: 0.2 (0.05–0.5). Comparing the two cohorts from Eastern Denmark we found higher incidence rates for IBD (5.0 and 7.2 in 1998–2000 and 2007–2009, respectively, P = 0.02) and CD (2.3 versus 3.3, P = 0.04). Furthermore, we found a significant decrease in surgery rates (15.8/100 person-years versus 4.2, P = 0.02) and an increase in the rate of initiating immunomodulators (IM) within the first year (29.0/100 person-years versus 69.2, P < 0.001). IM use was associated with a trend towards a decreased surgery risk (relative risk [RR] 0.38; 0.15–1.0). Children with CD had poor nutritional status at diagnosis compared with the general pediatric population.

Conclusions:

Over the past 12 years we found an increase in the incidence of IBD in children, an increasing use of IM, and decreasing 1-year surgery rates. CD patients had poor nutritional status. (Inflamm Bowel Dis 2011;)

Inflammatory bowel disease (IBD) comprises three disorders: Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBDU, formerly designated indeterminate colitis). The etiology of IBD is unknown, but is thought to originate from a complex interaction between genetic disposition and environmental factors including the gut bacterial flora.1 Changes in incidence rates, nutritional status, and the interrelations between medical treatment and surgery are important issues in pediatric IBD.

Several studies over the past decades have reported increasing incidences of IBD and especially CD, whereas the incidence of UC seems to remain stable.2–5

Some pediatric IBD patients are growth-retarded with poor nutritional status at diagnosis.6, 7 However, most studies of growth and nutrition in children with IBD originate from referral centers, where the most severe cases are treated and, therefore, may not represent the true prevalence of growth retardation.6, 7 Very few population-based studies exist, and those that do are retrospective in design8, 9 or include only a small number of patients.4

In the recent years the issue of using “top-down” (early introduction of immunomodulatory therapy) treatment compared to the traditional “step-up” regime (where immunomodulatory therapy is introduced when other treatment modalities fail) in order to possibly change disease course has been debated.10 Whether a change of treatment strategy towards top-down has occurred in pediatric IBD and if this has had an impact on disease course is currently unknown.

The aim of this prospective population-based study was to: 1) evaluate the change in incidence of IBD in children over the period 1998–2009; 2) evaluate the impact of initial treatment regimes on 1-year surgery rates in a recent comparable cohort covering the period 1998–2009; and 3) characterize growth/nutrition parameters and predictors for growth retardation/malnutrition at diagnosis.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

The patients in this study were from two population-based cohorts of children with IBD <15 years of age: 1) A prospective cohort included in the period January 1, 2007 to December 31, 2009 (main prospective cohort); 2) A retrospective cohort included in the period January 1, 1998 to December 31, 2006 (comparative retrospective cohort).

Main Prospective Cohort

The children from the main prospective cohort were from Eastern Denmark, Funen, and Aarhus County (Fig. 1). They were derived from a background population of 668,056 children <15 years of age (January 2009), which comprised 62% of all children <15 years of age in Denmark. The 10 pediatric departments in the areas treating pediatric IBD participated in the study. To ensure that all pediatric patients were included, letters were sent to all adult gastroenterology departments in the catchment area twice in the 3-year study period and 100% responded (17/17). None had diagnosed and/or treated IBD patients <15 years of age during the study period. Very few, if any, children are diagnosed by private practicing gastroenterologists in Denmark, as the healthcare system is free to all inhabitants and because children considered having IBD by general practitioners are referred to a pediatric department for treatment.

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Figure 1. Map of the geographical area for the Danish prospective population-based pediatric IBD study in the period January 1, 2007 to December 31, 2009 covering Eastern Denmark, Funen, Aarhus, and Aarhus County.

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Comparative Retrospective Cohort

Patients from the comparative cohort were from Eastern Denmark, as previously described.11 In summary, all pediatric IBD patients below 15 years of age in Eastern Denmark were included from a background population of 430,913 children <15 years of age (43% of all children <15 years in Denmark). In Eastern Denmark collaboration between all pediatric departments regarding the treatment of pediatric IBD was established in 1997, with the department at Hvidovre University Hospital acting as the principal referral department for pediatric IBD. All pediatric IBD patients in the area are prospectively registered using the diagnostic codes from the World Health Organization (WHO) International Classification of Diseases, v. 10 (ICD-10), in the electronic register of the pediatric departments in the area and in the National Patient Registry (NPR) using the Civil Registration Number (CPR-number). The CPR-number is a unique number given to every person at birth. The use of NPR with regard to IBD has previously been validated.12 To ensure all patients were included we extracted data from the NPR and all pediatric departments in the area using ICD-10 codes DK500–519. All patients in the area were identified by their CPR-number and all medical files on patients registered were reviewed. All pediatric IBD patents at Hvidovre Hospital have been prospectively registered in the Danish Crohn Colitis Database (DCCD) (www.dccd-ibd.dk) since its initiation in 2001. Therefore, DCCD was also checked to ensure all patients were included. The retrospective cohort included 235 IBD patients (117 CD, 108 UC, and 10 IBDU) <15 years of age with similar disease localization and age distribution as in the main prospective cohort (data not shown).

Diagnostic Criteria

Patients in both the main prospective cohort and in the comparative retrospective cohort were diagnosed using the internationally accepted Copenhagen Diagnostic Criteria.13, 14

Data Collection

Main Prospective Cohort

Data on gender, area of residence, onset of symptoms, date of diagnosis, disease localization, IBD in first-degree relatives (mother, farther, and siblings), extraintestinal manifestations (EIM), height (cm) and weight (kg) at diagnosis, change of diagnosis, change in extent of disease, investigational procedures (radiology, endoscopy, capsule endoscopy, magnetic resonance imaging [MRI], etc.), surgical procedures (date and type), medical treatment (type (as described below) and date of initiation and stopping) were registered prospectively from diagnosis until December 31, 2009. Standing height was measured using a stadiometer and weight was measured with an electronic scale.

Comparative Retrospective Cohort

From the retrospective cohort from Eastern Denmark data on diagnosis, medical treatment (type (as described below) and date of initiation and stopping) and surgical procedures were used.

Incidence Rates

The incidence rates of IBD, CD, UC, and IBDU were calculated as the annual number of new cases per 100,000 children below 15 years of age. In order to investigate trends in incidence rates over time, we combined the follow-up period for the comparative retrospective cohort and the subset of patients from the main prospective cohort originating from Eastern Denmark into a single cohort covering Eastern Denmark over the past 12 years (1998–2009). The follow-up period for the combined cohort was divided into four 3-year periods and mean incidence rates were calculated.

Disease Localization

In both the main prospective cohort and the comparative retrospective cohort the Montreal Classification15 was used to classify disease localization in UC and CD and disease behavior in CD. Patients with intraabdominal abscesses and fistulas were considered as having penetrating disease (B3). Only CD patients who underwent resective surgery for stenosis of the gastrointestinal tract were classified as B2 (stricturing disease).

Medical Treatment

In both cohorts medication included: 5-aminosalicylic acid (5-ASA) (oral and/or topical), corticosteroids (CS) (oral, intravenous, or topical), immunomodulators (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]), biological treatment (anti-tumor necrosis factor [TNF]: infliximab or adalimumab), and enteral nutritional therapy (NT).

Change in Surgery and Use of Immunomodulatory Therapy (IM) over Time

In order to compare changes in surgery rates and use of IM therapy (AZA/6MP, MTX, and anti-TNF) over time, we combined the follow-up period of the comparative retrospective cohort and the subset of patients diagnosed in Eastern Denmark from the main prospective cohort (as described in the incidence section above). In this combined cohort, we looked at the risk of surgery (bowel resections only) and the rate of IM use within the first year after diagnosis.

Growth and Nutritional Status

In the main prospective cohort height, weight, and body mass index (BMI) standard deviation scores (SDS) (z-scores) for age at diagnosis were calculated. Similar data from a healthy Danish pediatric population were used for comparison.16 SDS for height less than −2 SDS was considered growth retardation and SDS for BMI and weight below −2 SDS as malnutrition as previously defined.8 We assessed the impact of the following predictors on growth parameters: time from onset to diagnosis, disease localization, IBD in first-degree relatives, EIM (marker for inflammation17), gender, and diagnosis. Furthermore, we assessed if growth abnormalities at diagnosis affected the risk of later surgery. Bone age and IGF-1 were only measured in some of the patients and therefore not included in the analyses of growth.

Statistical Analysis

Data normally distributed are shown as mean and standard deviation (SD), data not normally distributed are shown as median and interquartile range (IQR). To identify factors associated with growth and nutrition parameters (standard deviation score [SDS] of height, weight, and BMI) univariate and multivariate linear regression was used. In the multivariate analysis all variables thought to influence SDS for weight, height, and BMI at diagnosis were included: EIM, gender, IBD in first-degree relatives, time from onset to diagnosis, age at diagnosis, and disease localization at diagnosis. Due to the small number of surgical events in both UC and CD in the main prospective cohort, Cox regression could not be used to assess the impact of growth/nutritional factors on the risk of surgery. Therefore, only numbers are reported and Student's t-test comparing growth/nutritional parameters between surgical and nonsurgical patients were used. Poisson regression analysis was used to investigate trends in incidence rates and 1-year surgery rates by combining the comparative retrospective cohort and the subset of patients from Eastern Denmark in the main prospective cohort. To assess the impact of IM therapy on the rate of surgery within the first year in the combined cohort, a variable (treatment) was coded 1 if the patient had started IM within the first year and 0 if not treated. The follow-up time within the first year was divided into IM-treated and not IM-treated periods using the above-mentioned variables and Poisson regression was used to evaluate the effect of IM treatment on the 1-year rate of surgery. Significance level was set at P < 0.05. All statistical analysis were performed using SAS 9.2 (SAS institute, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patients

In the main prospective cohort a total of 130 patients <15 years of age with IBD were diagnosed in the period 2007–2009, of which 65 (50.0%) had CD, 62 (48.7%) UC, and three (2.3%) IBDU. Age distribution at diagnosis is shown in Figure 2. Demographics, length of follow-up and clinical data are shown in Table 1. Medical treatment is shown in Table 2.

Table 1a. Demographics at Diagnosis in a Population-based Cohort of Pediatric IBD Patients from Denmark (2007–2009)
 CD (n=65)UC (n=62)IBDU (n=3)P-value (CD vs. UC)
Gender (boys:girls)40:2532:301:20.36
Age at diagnosis, median years (IQR)13.2 (11.8-14.2)12.4 (10.6-14.3)11.8 (10.8-13.7)0.23
Follow-up time, median days (IQR)595 (350-1072)511 (191-1053)469 (188-860)0.15
Table 1b. Disease Localization and Behavior at Diagnosis in Pediatric CD Patients in a Population-based Cohort from Denmark (2007–2009)
Disease LocalizationN (%)
  1. L1: Terminal Ileum, L2: Colon, L3: Terminal Ileum and colon, L4: upper gastrointestinal tract proximal to the terminal ileum. B1: inflammatory, B2: stricturing and B3: penetrating.

L111 (16.9)
L219 (29.2)
L318 (27.7)
L42 (3.1)
L1+L46 (9.2)
L2+L44 (6.2)
L3+L45 (7.7)
Perianal fistula/abscess7 (10.8)
B163 (96.9)
B21 (1.5)
B31 (1.5)
Table 1c. Disease Localization at Diagnosis in Pediatric UC Patients in a Population-based Cohort from Denmark (2007–2009)
Disease LocalizationN (%)
  1. E1: proctitis, E2: left-sided distal to the splenic flexure and E3: Extensive colitis proximal to the splenic flexure.

E15 (8.1)
E217 (27.4)
E340 (64.5)
Table 2. Medical Treatment in the Population-based Cohort of Pediatric IBD Patients from Denmark (2007–2009)
 CD (n=65)UC (n=62)IBDU (n=3)
5-ASASystemic13 (20.0%)54 (87.1%)1 (33.3%)
Systemic steroidsBudesonide13 (20.0%)1 (1.6%)1 (33.3%)
Prednisolone47 (72.3%)52 (83.9%)3 (100%)
5-ASA/steroidsTopical4 (6.2%)30 (48.4%)3 (100%)
Immunomodulators:AZA/6-MP40 (61.5%)21 (33.9%)3 (100%)
MTX2 (3.1%)0 (0 %)0 (0%)
Biological treatment:Total16 (24.6%)11 (17.7%)2 (66.7%)
Induction only2 (3.1%)5 (8.1%)1 (33.3%)
Maintenance12 (18.5%)5 (8.1%)1 (33.3%)
On demand2 (3.1%)1 (1.6%)0 (0%)
Enteral nutritionTotal24 (36.9%)1 (33.3%)
Exclusive EN17 (26.2%)1 (33.3 %)
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Figure 2. Age distribution at diagnosis in a pediatric population-based IBD cohort from Denmark (2007–2009).

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Change of Diagnosis

Four patients changed diagnosis, two UC patients changed to CD, one IBDU patient to CD, and one IBDU to UC. The median time to change of diagnosis was 240 days (range: 55–666 days).

Time from Onset to Diagnosis

CD patients had a significantly longer time from onset to diagnosis than UC patients; 6.6 months versus 2.5 months, respectively, P < 0.001.

Family History and EIM

Twelve CD patients (18.5%) reported occurrence of IBD in first-degree relatives compared to 11 of the UC patients (17.7%) and one of the IBDU patients (4.2%) (P = 0.66). A total of six UC patients (8.1%) had EIM (one patient had both skin and joint disease); three patients had joint involvement, two had erythema nodosum, two had liver disease. In CD; all three patients (4.6%) with EIM had involvement of the joints.

Incidence Rates

The mean annual incidence rates (per 100,000 inhabitants aged <15 years) in the main prospective cohort in the years 2007–2009 for IBD, CD, UC, and IBDU in the period were 6.4 (95% confidence interval [CI]: 5.4–7.7), 3.2 (2.5–4.1), 3.1 (2.4–4.0), 0.2 (0.05–0.5), respectively. The mean incidence rates over the past 12 years in Eastern Denmark (combining the patients from the comparative retrospective cohort and the patients from Eastern Denmark in the main prospective cohort) are shown in Figure 3. A significant increase in the incidence of IBD was found in the period 1998–2009 in Eastern Denmark (trend test, P = 0.02). This increase was due to a significant increase in the incidence of CD (trend test, P = 0.04) and a nonsignificant increase in the incidence of UC (trend test, P = 0.08). Adjusting for gender in the analysis on incidence rates did not affect our results (data not shown). However, in CD the incidence rates were significantly higher in males than females over the past 12 years, as shown in Figure 4 (P = 0.02). In UC or in the entire IBD cohort no gender difference was found. No difference in incidence rates over the 12-year period was shown after stratifying the patients into three 5-year age groups (0–4 years, 5–9 years, and 10–14 years) (data not shown).

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Figure 3. Incidence rates (per 100,000 children <15 years of age) over time in a pediatric population-based IBD cohort from Eastern Denmark in the period 1998–2009.

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Figure 4. Incidence rates (per 100,000 children <15 years of age) over time stratified by gender in a pediatric population-based cohort of CD patients from Eastern Denmark in the period 1998–2009.

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Surgery Rates

A total of nine surgical events were recorded in the follow-up period of the main prospective cohort of 130 patients; four having CD and five UC, resulting in a 1-year cumulative risk of surgery of 2.2% and 2.4% in CD and UC, respectively. When combining the subset of patients from Eastern Denmark in the main prospective cohort and the patients from the comparative retrospective cohort we found a significant decrease in the 1-year surgery rate for IBD over the period 1998–2009 (Fig. 5). When stratifying by diagnosis, the decrease was shown in CD (trend test P = 0.03) but not in UC (trend test, P = 0.15). Furthermore, a significant increase in the 1-year rate of IM treatment over time was shown in the same period (Fig. 5). In the same combined cohort the use of IM was associated with decreased risk of surgery within the first year after diagnosis in the entire IBD cohort; relative risk (RR) = 0.4 (95% CI: 0.14–1.0), P = 0.05.

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Figure 5. One-year surgery rates and the rate of IM treatment per 100 person years over time in a pediatric population-based IBD cohort from Denmark (2007–2009). IM(a) = use of AZA/6MP, MTX, anti-TNF.

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Growth and Nutritional Parameters

In the main prospective cohort a total of six CD patients (9.5%) had a weight SDS below −2, five (8.1%) had a height SDS below −2, and 12 (19.4%) had a BMI SDS below −2. In UC no patients had weight or height SDS below −2, but seven (11.5%) had a BMI SDS below −2. In CD patients we found a significant deviation from the reference general population in mean weight SDS (−0.47, P < 0.001) and mean BMI SDS (−0.87, P < 0.001) at diagnosis, but not for mean height SDS (−0.03, P = 0.82). UC patients were significantly higher than the reference population (mean height SDS = 0.27, P = 0.04), but did not differ with respect to median weight (−0.1, P = 0.44) or mean BMI (−0.2, P = 0.2). Figure 6 shows boxplots comparing SDS for weight, height, and BMI in CD and UC patients. We found a significantly lower median SDS for weight and mean BMI in CD versus UC (P = 0.01 and P = 0.004, respectively). However, no difference in mean SDS for height was shown P = 0.18).

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Figure 6. Boxplots showing SDS for weight, height, and BMI in pediatric CD and UC patients in a population-based cohort from Eastern Denmark, Funen, and Aarhus in the period 2007–2009.

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Results from uni- and multivariate linear regression analysis are shown in Tables 3 and 4. IBD in first-degree relatives were associated with a higher SDS for weight and BMI in CD patients (P = 0.04 and P = 0.02). However, in the multivariate analysis this association was no longer significant. In UC, male gender was associated with a higher SDS for weight (P = 0.02) in the univariate analysis, but this association was not significant in the multivariate analysis. Comparing SDS for BMI, weight, and height at diagnosis for the surgical and nonsurgical patients, the surgical patients had a significantly lower SDS for BMI in both CD (−2.3 and −0.8, respectively; (P = 0.02) and UC (−1.2 and −0.1), respectively; P = 0.049). No differences were shown in SDS for height and weight.

Table 3a. Univariate and Multivariate Linear Regression Analysis Results for SDS for Height in the Population-based Cohort of Pediatric CD Patients from Denmark (2007–2009)
 Univariate AnalysisMultivariate Analysisa
VariableRegression CoefficientStandard ErrorP-valueRegression CoefficientStandard ErrorP-value
  • a

    In the multivariate analysis the following variables were included in the model: extraintestinal manifestations (EIM), gender, IBD in 1st degree relatives, age at diagnosis, time from onset to diagnosis, disease localization.

Age at diagnosis0.020.050.70.040.060.5
Gender (ref = female)0.30.30.40.20.30.4
IBD in 1st degree relatives (ref = no)0.30.40.40.30.40.5
Time from onset to diagnosis0.0030.020.80.0040.020.8
EIM (ref = no)0.80.60.61.00.80.2
Disease localization      
 L1−0.20.40.6−0.10.40.8
 L2−0.10.40.9−0.010.41
 L30.20.40.70.20.40.6
L4 (ref)      
Table 3b. Univariate and Multivariate Linear Regression Analysis Results for SDS for Weight in the Population-based Cohort of Pediatric CD Patients from Denmark (2007–2009)
 Univariate AnalysisMultivariate Analysisa
VariableRegression CoefficientStandard ErrorP-valueRegression CoefficientStandard ErrorP-value
  • a

    In the multivariate analysis the following variables were included in the model: extraintestinal manifestations (EIM), gender, IBD in 1st degree relatives, age at diagnosis, time from onset to diagnosis, disease localization.

Age at diagnosis0.070.050.20.090.060.1
Gender (ref = female)−0.020.30.9−0.10.30.7
IBD in 1st degree relatives (ref = no)0.70.30.030.50.40.2
Time from onset to diagnosis0.010.010.50.010.020.4
EIM (ref = no)0.70.60.31.40.80.08
Disease localization      
 L1−0.40.40.4−0.20.40.6
 L2−0.50.40.2−0.40.40.3
 L3−0.20.40.5−0.20.40.6
L4 (ref)      
Table 3c. Univariate and Multivariate Linear Regression Analysis Results on SDS for BMI in the Population-based Cohort of Pediatric CD Patients from Denmark (2007–2009)
 Univariate AnalysisMultivariate Analysisa
VariableRegression CoefficientStandard ErrorP-valueRegression CoefficientStandard ErrorP-value
  • a

    In the multivariate analysis the following variables were included in the model: extraintestinal manifestations (EIM), gender, IBD in 1st degree relatives, age at diagnosis, time from onset to diagnosis, disease localization.

Age at diagnosis0.10.060.10.10.070.1
Gender (ref = female)−0.30.30.4−0.40.30.2
IBD in 1st degree relatives (ref = no)1.020.40.010.70.40.1
Time from onset to diagnosis0.020.020.20.030.020.2
EIM (ref = no)0.30.80.71.30.90.1
Disease localization      
 L1−0.20.50.7−0.10.50.8
 L2−0.80.50.1−0.60.50.2
 L3−0.30.50.5−0.30.50.6
L4 (ref)      
Table 4a. Univariate and Multivariate Linear Regression Analysis Results on SDS for Height in the Population-based Cohort of Pediatric UC Patients from Denmark (2007–2009)
 Univariate AnalysisMultivariate Analysisa
VariableRegression CoefficientStandard ErrorP-valueRegression CoefficientStandard ErrorP-value
  • a

    In the multivariate analysis the following variables were included in the model: extraintestinal manifestations (EIM), gender, IBD in 1st degree relatives, age at diagnosis, time from onset to diagnosis, disease localization.

Age at diagnosis0.060.050.20.050.050.3
Gender (ref = female)0.30.30.30.20.30.4
IBD in 1st degree relatives (ref = no)0.10.30.70.30.30.4
Time from onset to diagnosis0.010.020.60.0070.020.6
EIM (ref = no)0.80.40.080.70.50.1
Disease localization      
 E10.40.30.10.30.30.3
 E2 + E3 (ref)      
Table 4b. Univariate and Multivariate Linear Regression Analysis Results on SDS for Weight in the Population-based Cohort of Pediatric UC Patients from Denmark (2007–2009)
 Univariate AnalysisMultivariate Analysisa
VariableRegression CoefficientStandard ErrorP-valueRegression CoefficientStandard ErrorP-value
  • a

    In the multivariate analysis the following variables were included in the model: extraintestinal manifestations (EIM), gender, IBD in 1st degree relatives, age at diagnosis, time from onset to diagnosis, disease localization.

Age at diagnosis−0.030.050.6−0.040.050.5
Gender (ref = female)0.60.30.020.50.30.09
IBD in 1st degree relatives (ref = no)−0.10.40.7−0.090.40.8
Time from onset to diagnosis0.020.020.20.020.020.4
EIM (ref = no)0.60.50.20.40.50.3
Disease localization      
 E10.40.30.20.40.30.2
 E2 + E3 (ref)      
Table 4c. Univariate and Multivariate Linear Regression Analysis Results on SDS for BMI in the Population-based Cohort of Pediatric UC Patients from Denmark (2007–2009)
 Univariate AnalysisMultivariate Analysisa
VariableRegression CoefficientStandard ErrorP-valueRegression CoefficientStandard ErrorP-value
  • a

    In the multivariate analysis the following variables were included in the model: extraintestinal manifestations (EIM), gender, IBD in 1st degree relatives, age at diagnosis, time from onset to diagnosis, disease localization.

Age at diagnosis−0.10.060.08−0.10.050.1
Gender (ref = female)0.60.30.060.40.30.2
IBD in 1st degree relatives (ref = no)−0.20.40.5−0.20.40.5
Time from onset to diagnosis0.020.020.20.020.020.3
EIM (ref = no)0.20.50.60.080.50.9
Disease localization      
 E10.030.30.90.20.30.6
 E2 + E3 (ref)      

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The strengths of our study are the prospective design and population-based nature. Our study thereby reflects the full population of children with IBD, encompassing the whole spectrum of disease severity, in contrast to studies from tertiary referral centers. Furthermore, our study covers a very recent time period when IM therapy has been widely available and fully implemented in the treatment regimes. Lastly, the use of the population-based comparative cohort results in a relatively long and recent time period available for analyses. The population-based nature of the study is nevertheless a limitation due to the relatively small number of patients, which could induce type II errors in some analyses.

We found rising incidence rates of IBD and CD over the past 12 years, decreasing surgery rates within the first year after diagnosis, increasing rate of treatment with IM within the first year, and a trend towards a decreased risk of surgery within the first year if treated with IM. SDS for BMI and weight were lower for IBD patients compared to the general pediatric background population. No associations between clinical variables and SDS for growth and nutrition were found.

Several studies have shown increasing incidence rates of children with IBD2, 3, 5, 18 and especially CD2, 3, 5 over the past decades. The results have been summarized in a recent review study.19 Our study supports a continuous increase in the incidence of IBD in children, and especially CD, in recent time. Our study also suggests that the incidence of UC might be increasing, where previous studies have shown stable or decreasing incidences of UC over time.2, 20 A study from the Canada21 showed that the increasing incidence of IBD from 1981–2008 seemed to have occurred in the younger age groups 0–9 years. This could not be replicated in our study, as no difference in incidence rates across age groups were found.

The 1-year cumulative risk of surgery in our cohort 2007–2009 was 2.2% and 2.4% in CD and UC, respectively. Our 1-year surgery rates are lower than figures reported from other population-based pediatric studies, where 1-year risks of 7%22 in CD and 8% in UC23 were found. The lower risk in our cohort could be related to the more recent time period from which our patients were recruited. The use of IM was higher in our cohort, where 57% and 33% of CD and UC patients, respectively, were started on IM within the first year after diagnosis, as compared to 61%22 and 25%23 after a median follow-up time of more than 6.5 years. IM treatment has been associated with a decreased risk of surgery in adult24 and pediatric CD and UC patients22, 23 and longer corticosteroid-free remission periods in CD patients.25 We found an increase in the cumulative rate of IM use within the first year after diagnosis and a decrease in the 1-year cumulative risk of surgery in IBD over a 12-year period. This could indicate that IM has an effect on the initial disease course. This tendency towards earlier/increased use of IM has been shown in other population-based studies where the 5-year cumulative probability of IM prescription increased from 32% in 1988–1994 to 68% in 1995–2002 in CD patients22 and similar increases were found in UC patients where 11% and 34% started AZA/6MP in 1988–1994 and 1995–2002, respectively.23 Whether surgery is merely postponed should be addressed in future prospective population-based studies with longer follow-up.

Studies have shown that many pediatric IBD patients are growth retarded at diagnosis,6, 26 but few population-based studies exist.8, 9 Our results confirm the findings from an earlier study from Eastern Denmark in the period 1998–2000 where CD patients were found to be more growth-retarded and malnourished than UC patients at diagnosis.9 Only 9.5%, 8.1%, and 19.4% of the CD patients had weight, height, and BMI SDS lower than −2, respectively, which contrasts with a recently published population-based study on growth and nutrition in CD patients from the French EPIMAD registry8 where the corresponding figures were 27%, 9.5%, and 32%. This discrepancy could be related to the differences in the proportion of patients with structuring and penetrating disease, which was higher in the French cohort (23% versus 1.5% and 3.1% versus 1.5%, respectively).

In conclusion, in this prospective population-based study of Danish children with IBD we showed an increasing incidence rate of IBD, increasing rate of IM use within the first year after diagnosis, and decreasing 1-year surgery rates over a 12-year period, indicating an effect of IM therapy on disease course in pediatric IBD. To fully evaluate if IM (AZA/6MP/MTX/anti-TNF) has indeed changed disease course or merely postponed surgery, long-term follow-up in this and in larger population-based cohorts should be carried out.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Karsten Hjelt, Birgitte Weile, Lars Folmer Hansen, Bente Utoft Andreasen, Charlotte Siggaard, Lars Nickelsen, Dorte Hansen Precht, and Pia Karlsland Aakeson for invaluable help at including patients in this study. We thank statistician Steen Ladelund for support in analyzing the data. We thank Lawrence Weaver for reviewing the English language of the article.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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