Childhood-onset inflammatory bowel disease-health care use, impact on growth and school achievements

The aim of this thesis was to explore the Impact of Inflammatory bowel disease (IBD) on growth and school achievements. We also assessed the Incidence and health care use of patients with very early-onset IBD (VEO-IBD). Furthermore, we examined the validity of register-based definitions of IBD and its subtypes in children.

In study 1, we investigated whether patients with childhood-onset IBD are at an increased risk of poorer final grade point average (GPA) at the end of compulsory school (ninth grade) and not qualifying for high school. We identified 2827 children with IBD in National Patient Register (NPR) between 1990 -2014 and compared their final grades obtained from School Register with matched reference individuals and IBD-free siblings. We adjusted for potential confounders, such as parental psychosocial problems and education. We found a statistically significantly lower GPA (adjusted mean grade difference [AMGD] −4.9, 95% CI −7.1 to −2.6, standardised mean difference [SMD] −0.08, 95% CI −0.11 to −0.04) compared to reference individuals though the difference was minimal. Children with IBD did not have an increased risk of not qualifying for high school compared to their siblings or reference individuals (OR 1.14, 95% CI 0.99 to 1.31). In addition, we found that IBD children with markers of longstanding and severe disease underperformed more commonly compared to reference individuals and IBD-free siblings.

In study 2, we studied the attained final height and growth retardation in patients with childhood-onset IBD compared to matched reference individuals and their IBD-free full biological siblings using information from the National Patient Register and Pass Register.Analyses were adjusted for potential confounders, including birth order, number of siblings, parental height, parental mental health problems, and education. The adjusted analysis demonstrated that patients with IBD attained a statistically significant shorter final height in adult age (adjusted mean height difference (AMHD) -0.9 cm, 95% CI -1.1 to -0.7) compared to reference individuals and IBD-free full siblings (AMHD-0,8 CM, 95% CI -1.0 to-0.6). Differences in adult mean heights were more prominent in patients with IBD onset before puberty (AMHD -1.6 cm, 95% CI -2.0 to-1.2) than in patients with onset during or after puberty (AMHD-0.8 cm, 95% CI -0.9 to-0.6) and in the subsets of patients exposed to bowel surgery (AMHD -1.9 cm, 95% CI -2.4 to-1.4), perianal surgery (AMHD -1.5 cm, 95% CI -2.3 to -0.7), or inpatient treatment for >30 days listing IBD as the primary diagnosis (AMHD -1.4 cm, 95% CI -1.8 to -1.0) during childhood. Patients with IBD had an increased risk of growth retardation compared to general population reference individuals (OR 1.99, 95% CI 1.68 to 2.37).

In study 3, we analysed the positive predictive value (PPV) of the commonly used register-based algorithm (≥2 diagnostic listings) for childhood-onset IBD in the NPR and its subtypes, both for prevalent and incident definitions. We also studied the PPV of childhood-onset IBD diagnosis using Swibreg and combining IBD listings in the NPR and pathology codes from the ESPRESSO cohort.

We found the PPV of a commonly used register-based definition of childhood-onset IBD in the NPR (at least two diagnostic listings of IBD) to be high (PPV=93%) when using the Copenhagen criteria based on medical chart review as the gold standard. The PPV for a definition also using pathology reports suggestive of IBD was even higher (97%) and 100% for patients registered in SWIBREG. Using the revised Porto criteria as the gold standard, the PPV for different IBD subtypes based on ICD codes in the NPR at the start of follow-up (incident definition) was 78% for CD and 74% for UC and somewhat higher at the end of follow-up (prevalent definition: 88% for CD and 71% for UC).

In study 4, we identified 5308 patients with childhood-onset IBD in the NPR and ESPRESSO cohorts from 2006 until 2020 using ICD codes or a combination of ICD codes with pathology codes and further stratified them by age of IBD onset [infantile onset (<2 years), preschool onset (2-<6), very early onset (<6, VEO-IBD), early onset IBD (6-<10) and adolescent onset (10-<18)]. We described the incidence of VEO-IBD patients (<6 years of age) and analysed and compared health care use (medications, hospitalisations, outpatient visits, surgeries) in VEO-IBD patients compared to older groups. We analysed all these outcomes separately in infantile and toddler groups. The incidences of all childhood-onset IBD age groups (including VEO-IBD) were stable. VEOIBD patients were equally exposed to steroids but significantly less exposed to 5ASA, immunomodulators and targeted therapies (mostly driven by the infantile-onset group) than older-onset children. Time to first hospitalization was shorter in the infantile group while yearly rate of hospitalizations after the second year and of outpatient visits after the year of diagnosis was similar across age groups. The number of surgeries were low and there were no significant differences between VEO-IBD and older onset IBD patients.

List of scientific papers

I. Malmborg P, Mouratidou N, Sachs MC, Hammar U, Khalili H, Neovius M, Anders Hjern, MD, Karin E. Smedby, KE, MD, Anders Ekbom, MD, Johan Askling, Jonas F. Ludvigsson, MD, Ola Olén. Effects of Childhood-onset Inflammatory Bowel Disease on School Performance: A Nationwide Population-based Cohort Study Using Swedish Health and Educational Registers. Inflamm Bowel Dis. 2019;25(10):1663-73.
https://doi.org/10.1093/ibd/izz040

II. Mouratidou N, Malmborg P, Sachs MC, Askling J, Ekbom A, Neovius M, Karin E. Smedby, Lars Sävendahl, Jonas F. Ludvigsson , Ola Olén. Adult height in patients with childhoodonset inflammatory bowel disease: a nationwide population-based cohort study. Aliment Pharmacol Ther. 2020;51(8):789-800.
https://doi.org/10.1111/apt.15667

III. Mouratidou N, Malmborg P, Jaras J, Sigurdsson V, Sandstrom O, Fagerberg UL, Gabriella Bröms, Jonas F Ludvigsson , Ola Olén. Identification of Childhood-Onset Inflammatory Bowel Disease in Swedish Healthcare Registers: A Validation Study. Clin Epidemiol. 2022;14:591-600.
https://doi.org/10.2147/CLEP.S358031

IV. Natalia Mouratidou, Petter Malmborg , Gabriella Bröms , Matti Bryder, Mehdi Osooli, *The Swibreg Study Group, Holm Uhlig, Eric I Benchimol, Gilaad G. Kaplan, Dan Turner, Åsa Hallqvist Everhov , Ola Olén. Incidence and healthcare use of patients with very early-onset inflammatory bowel disease in Sweden - a nationwide population-based study 2006-2020. [Submitted]