The Global, Regional, and National Burden of Inflammatory Bowel Disease among Children and Adolescents from 1990 to 2021 and Trend Projections up to 2036

Abstract

Background/Aims

Early-onset inflammatory bowel disease (EO-IBD) poses a global health challenge with its distinct clinical manifestations and complex progression.

Methods

In this study, IBD cases occurring before age 20 were defined as EO-IBD. Data were extracted from the Global Burden of Disease 2021 database. Temporal trends were assessed using Joinpoint regression analysis, and future epidemiological trends were projected using the Bayesian age-period-cohort (BAPC) model. Health disparities across various sociodemographic index (SDI) regions were quantified using the slope index of inequality and concentration index.

Results

From 1990 to 2021, the global number of EO-IBD cases increased, while the incidence rates showed minimal change. Mortality and disability-adjusted life years (DALYs) rates briefly increased before a rapid decline after 1992. In 2021, males had higher mortality and DALYs rates due to EO-IBD than females. The highest mortality and DALYs rates were observed in the <5 years and 15 to 19 years age groups. Geographically, high SDI regions had the highest incidence, prevalence, and DALYs rates, while low SDI regions had the highest mortality rates. BAPC projections indicate that by 2036, the age-standardized incidence rate and prevalence rate will increase, whereas the age-standardized mortality rate and DALYs rates will continue to decline.

Conclusions

The incidence of EO-IBD is projected to exhibit an increasing trend in the future. Although the global mortality and DALYs rates of EO-IBD have decreased, significant disparities persist across age groups and regions. Targeted prevention and control strategies are needed to address the needs of high-risk populations and regions.

INTRODUCTION

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, represents a spectrum of chronic, idiopathic intestinal inflammatory disorders.^1,2 The multifactorial pathogenesis of IBD, involving intricate interactions between genetic susceptibility, environmental triggers, immune dysregulation, and gut microbial alterations, remains incompletely elucidated.² The emergence of IBD in children and adolescents as a distinct clinical entity has garnered increasing attention within the global public health domain, characterized by its unique phenotypic manifestations and complex disease progression.³ Notably, pediatric IBD demonstrates a more aggressive disease course compared to adult-onset disease,⁴ with heightened risks of growth impairment, extraintestinal complications, and diagnostic delays, compounded by therapeutic limitations. While historically predominant in high-income nations,⁵ epidemiological patterns suggest an evolving geographic distribution of IBD, with rising incidence observed in developing regions, potentially attributable to urbanization, dietary Westernization, and environmental modifications. This shifting epidemiological landscape, particularly among pediatric populations, underscores the necessity for comprehensive disease burden assessments. Current research efforts remain predominantly focused on adult populations, with insufficient attention to longitudinal trends, sex disparities, and geographic variations specific to early-onset IBD (EO-IBD). Furthermore, the interplay between sociodemographic determinants, particularly the sociodemographic index (SDI), and EO-IBD burden remains poorly characterized.

To address these critical knowledge gaps, this study leverages comprehensive data from the Global Burden of Disease (GBD) Study (1990 to 2021) to conduct a systematic analysis of incidence, prevalence, mortality, and disability-adjusted life years (DALYs) associated with EO-IBD. Our multidimensional approach examines spatiotemporal distribution patterns, evaluates demographic and socioeconomic determinants, and projects age-standardized rate trajectories through 2036. These findings aim to inform the development of targeted, evidence-based strategies for global EO-IBD prevention and management, ultimately contributing to optimized healthcare resource allocation and improved patient outcomes.

MATERIALS AND METHODS

1. Data source

This study employs a rigorous analytical approach utilizing data extracted from the GBD 2021 database, which underwent comprehensive secondary analysis. All data processing and statistical analyses were conducted using R software (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria). The complete dataset is publicly accessible through the Institute for Health Metrics and Evaluation website (https://www.healthdata.org/). The GBD 2021 database represents a comprehensive epidemiological repository, encompassing 459 health metrics and risk factors across 204 countries and territories from 1990 to 2021. The dataset provides detailed stratification by age, sex, geographical region, and national boundaries, including critical metrics such as incidence, prevalence, mortality, and DALYs.

To ensure robust estimation of disease burden metrics, all results are presented with corresponding 95% uncertainty intervals (UIs),⁶ calculated through advanced statistical modeling techniques. These include spatiotemporal Gaussian process regression, Bayesian regularization, and trimmed meta-regression methodologies.⁷ The GBD project maintains exceptional methodological rigor, having undergone extensive peer review by a consortium of over 12,000 researchers across 160 countries and territories, establishing its findings as authoritative references in global health research. As this study exclusively utilizes de-identified, publicly available data, it is exempt from institutional ethics review requirements.

For disease classification, IBD cases were identified according to the International Classification of Diseases (ICD) system, incorporating both ICD-10 (K50-K52, K52.8-K52.9) and ICD-9 (555-556.9, 558-558.9, 569.5) coding schemes.⁸ This study focuses on the global burden of EO-IBD, defined as IBD diagnosed before 20 years of age and encompassing both pediatric-onset and adolescent-onset disease. This definition criterion facilitates a more comprehensive assessment of IBD epidemiological characteristics spanning adolescence through early adulthood, while simultaneously providing evidence-based references for transitional care management between pediatric and adult healthcare services.

2. SDI regions and GBD regional classification

The GBD 2021 study employs a comprehensive geographical classification system, stratifying global populations based on sociodemographic development levels. Countries and territories are categorized into five distinct groups according to SDI quintiles: high SDI, high-middle SDI, middle SDI, low-middle SDI, and low SDI regions. The SDI, a composite metric integrating three fundamental development indicators (per capita income, educational attainment, and fertility rate), provides a robust measure of regional sociodemographic development. It is noteworthy that SDI values demonstrate temporal variability, reflecting dynamic socioeconomic changes. Detailed SDI metrics are accessible through the Global Health Data Exchange repository (https://ghdx.healthdata.org/record/global-burden-disease-study-2021-gbd-2021-socio-demographic-index-sdi-1950%E2%80%932021).

Furthermore, the study implements a refined geographical framework, dividing the global population into 21 mutually exclusive GBD regions: Andean Latin America, Australasia, Caribbean, Central Asia, Central Europe, Central Latin America, Central Sub-Saharan Africa, East Asia, Eastern Europe, Eastern Sub-Saharan Africa, High-income Asia Pacific, High-income North America, North Africa and Middle East, Oceania, South Asia, Southeast Asia, Southern Latin America, Southern Sub-Saharan Africa, Tropical Latin America, Western Europe, and Western Sub-Saharan Africa.⁹

3. Joinpoint regression analysis

The Joinpoint regression methodology, initially developed by Kim et al.¹⁰ in 1998, represents a sophisticated analytical approach for characterizing temporal trends in disease epidemiology. This method employs a segmented regression framework that identifies significant inflection points (joinpoints) in disease distribution patterns over time, thereby partitioning the study period into distinct temporal intervals. Each interval undergoes independent trend analysis and optimization, enabling detailed examination of disease-specific temporal variations.

For our analysis, we implemented Joinpoint Regression Program (version 5.1.0.0) to systematically evaluate epidemiological patterns. The analytical framework incorporates two key metrics: annual percentage change (APC) and average annual percentage change (AAPC).¹¹ The APC quantifies the trend magnitude within each identified temporal segment, while the AAPC provides a weighted average of APC values across all segments, offering a comprehensive measure of the overall temporal trend. Statistical significance of identified trends was assessed at α=0.05, with 95% confidence intervals (CIs) calculated for all trend estimates.¹⁰ The methodology's strength lies in its ability to objectively identify critical time points of epidemiological transition without a priori assumptions about trend patterns.

4. Health inequality analysis

Health disparities across sociodemographic strata were quantitatively assessed using two complementary metrics: the slope index of inequality (SII) and the concentration index.¹² The SII, derived from linear regression analysis, measures absolute health inequality by quantifying the gradient of health outcomes across the SDI spectrum. Negative SII values indicate disproportionate disease burden concentration in lower SDI regions, while positive values suggest higher burden in more developed regions. The concentration index, ranging from –1 to 1, provides a measure of relative inequality in disease distribution. Values approaching –1 indicate complete concentration of disease burden among disadvantaged populations, while values near 1 suggest concentration among advantaged groups. A concentration index of zero represents perfect equality in disease distribution across the sociodemographic spectrum.¹³

5. BAPC model

The Bayesian age-period-cohort (BAPC) model was employed to disentangle and quantify the independent contributions of age, period, and cohort effects on disease burden trends.¹⁴ The model's hierarchical structure allows for simultaneous estimation of age-specific effects, temporal trends, and generational influences while accounting for potential interactions between these dimensions. In this study, the BAPC model was implemented to project future trends (2022 to 2036) of four key epidemiological metrics: age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) for EO-IBD.

In this study, age-standardized rate is calculated using the formula:

$$ASR=\frac{{\displaystyle {\sum }_{i=1}^N{a}_i{W}_i}}{{\displaystyle {\sum }_{i=1}^N{W}_i}}$$

In the equation, a_i is the specific age rate for the ith age group, w_i represents the population in the same age group from the GBD standard population (or the weight) and N is the number of age groups. Age standardization is performed with 5-year interval age stratification. Standard population age group weights are derived from the global standard population structure defined in the GBD 2021.¹⁵

6. Ethics approval and consent to participate

This study employed data exclusively from the GBD 2021 database, a publicly accessible resource, and utilized information derived entirely from secondary sources, rendering ethical approval or institutional review board review unnecessary.

RESULTS

1. Global burden of EO-IBD

From 1990 to 2021, the global number of EO-IBD cases increased, while the incidence and prevalence rates showed minimal change. Specifically, the number of incident cases rose from 12,305 (95% UI, 10,068 to 15,002) to 14,008 (95% UI, 11,074 to 17,723), marking a 13.84% increase (Fig. 1A). However, the incidence rates changed from 0.54 (95% UI, 0.45 to 0.66) per 100,000 in 1990 to 0.53 (95% UI, 0.42 to 0.67) per 100,000 in 2021 (Fig. 1E), with an AAPC of –0.09% (95% credible interval, –0.34% to 0.15%). Similarly, the number of prevalent cases increased from 51,551 (95% UI, 42,138 to 62,632) in 1990 to 56,995 (95% UI, 44,945 to 72,086) in 2021, marking a 10.56% increase (Fig. 1B). The prevalence rate changed from 2.28 (95% UI, 1.87 to 2.77) per 100,000 in 1990 to 2.16 (95% UI, 1.71 to 2.73) per 100,000 in 2021 (Fig. 1F), with an AAPC of –0.21% (95% CI, –0.43% to 0.01%).

Fig. 1.

Epidemiological trends of early-onset inflammatory bowel disease (EO-IBD). Trends from 1990 to 2021 in the incidence (A), prevalence (B), mortality (C), and disability-adjusted life years (DALYs) (D) rates of EO-IBD. Changes in the incidence (E), prevalence (F), mortality (G), and DALYs (H) rates of EO-IBD from 1990 to 2021 revealed by Joinpoint analysis. Forecasts of age-standardized rates for the incidence (I), prevalence (J), mortality (K), and DALYs (L) rates of EO-IBD, over the next 15 years using the Bayesian age-period-cohort model. Left side of vertical dotted line: observed rates (1990–2021); right side of vertical dotted line: predicted rates (2022–2036); shaded area: 95% credible interval.

From 1990 to 2021, global EO-IBD mortality and DALYs initially showed a slight increase before exhibiting a significant decline, with the inflection point occurring in 1992. By 2021, both measures had declined significantly, being markedly lower than in 1990. Specifically, the number of deaths increased slightly from 1,360 (95% UI, 884 to 1,986) in 1990 to 1,395 (95% UI, 928 to 1,987) in 1992, before declining to 658 (95% UI, 496 to 781) by 2021 (Fig. 1C), marking a 51.62% decrease. The mortality rates increased slightly from 1990 to 1992, then declined rapidly, reaching 0.02 (95% UI, 0.02 to 0.03) per 100,000 by 2021 (Fig. 1G), with an AAPC of –2.85% (95% CI, –3.17% to –2.53%). DALYs showed a slight increase from 121,429 (95% UI, 80,287 to 175,048) in 1990 to 124,506 (95% UI, 83,836 to 175,004) in 1992, before declining to 61,352 (95% UI, 48,238 to 73,253) by 2021 (Fig. 1D), marking a 49.48% decrease. The DALYs rates increased from 5.38 (95% UI, 3.55 to 7.75) per 100,000 in 1990 to 5.44 (95% UI, 3.66 to 7.64) per 100,000 in 1992, before declining to 2.33 (95% UI, 1.83 to 2.78) per 100,000 by 2021 (Fig. 1H), with an AAPC of –2.71% (95% CI, –2.99% to –2.43%).

2. BAPC model projections

The BAPC model projected that global ASIR of EO-IBD will increase from 2021 to 2036. By 2036, the ASIR is expected to reach 0.55 per 100,000, a 7.62% increase from 2021 (Fig. 1I), while the ASPR is expected to reach 2.12 per 100,000, a 2.74% increase from 2021 (Fig. 1J). In contrast, ASMR and ASDR are projected to decline, with the ASMR expected to reach 0.01 per 100,000 by 2036, a 57.41% decrease from 2021 (Fig. 1K), and the ASDR expected to reach 0.88 per 100,000, a 61.88% decrease from 2021 (Fig. 1L).

3. EO-IBD burden by age and sex

Age-stratified analysis showed that incidence and prevalence increased with advancing age (Fig. 2A and B). In contrast, mortality and DALYs were highest in the <5 years and 15–19 years age groups (Fig. 2C and D). From 1990 to 2021, mortality and DALYs rates declined across all age groups, with the fastest decline observed in the <5 years group (AAPC, –4.94% [95% CI, –5.31% to –4.57%] and –4.95% [95% CI, –5.32% to –4.57%], respectively), while the 15–19 years group showed minimal decline (Supplementary Fig. 1A and B). Notably, in 2021, the <5 years group accounted for a small proportion of EO-IBD incidence and prevalence but contributed disproportionately to mortality and DALYs (Fig. 2E-H). Additionally, EO-IBD cases accounted for 3.73% (14,008/375,140) of incident cases, 1.49% (56,995/3,830,119) of prevalent cases, 1.55% (658/42,423) of deaths, and 4.06% (61,352/1,510,784) of DALYs among all IBD patients in 2021 (Supplementary Fig. 2).

Fig. 2.

Age- and sex-specific epidemiology of early-onset inflammatory bowel disease (EO-IBD). The incidence (A), prevalence (B), mortality (C), and disability-adjusted life years (DALYs) rates (D) of age-specific EO-IBD by sex in 2021. Age-specific incidence (E), prevalence (F), mortality (G), and DALYs (H) rates of EO-IBD in 2021. The trend of incidence (I), prevalence (J), mortality (K), and DALYs (L) rates of EO-IBD from 1990 to 2021 in subgroup of sexes. SDI, sociodemographic index.

Sex-based analysis revealed minimal differences in incidence and prevalence between males and females (Supplementary Tables 1 and 2, Fig. 2I and J). However, the AAPCs for mortality and DALYs rates was –2.40% (95% CI, –2.60% to –2.19%) and –2.32% (95% CI, –2.61% to –2.02%) for males, respectively, compared to –3.44% (95% CI, –3.82% to –3.06%) and –3.20% (95% CI, –3.44% to –2.95%) for females, indicating a slower decline in males (Supplementary Tables 3 and 4). By 2004, the burden of EO-IBD in males began to exceed that in females, and this disparity continued to widen over time (Fig. 2K and L).

4. EO-IBD burden by region

From 1990 to 2021, Mortality and DALYs rates generally declined across all SDI regions, with the most rapid declines observed in high-middle SDI regions (AAPC, –5.21% [95% CI, –5.57% to –4.85%] for mortality and –4.66% [95% CI, –5.08% to –4.24%] for DALYs) (Supplementary Fig. 1C and D). In 2021, high SDI regions exhibited the highest incidence (2.01 [95% UI, 1.60 to 2.55] per 100,000), prevalence (7.86 [95% UI, 6.28 to 9.90] per 100,000) and DALYs rates (2.92 [95% UI, 2.45 to 3.50] per 100,000), whereas low SDI regions recorded the highest mortality rate (0.03 [95% UI, 0.02 to 0.04] per 100,000). Conversely, low SDI regions had the lowest incidence rate (0.29 [95% UI, 0.23 to 0.37] per 100,000) and prevalence rate (1.20 [95% UI, 0.93 to 1.53] per 100,000), while high-middle SDI regions reported the lowest mortality (0.02 [95% UI, 0.01 to 0.02] per 100,000) and DALYs rates (1.80 [95% UI, 1.48 to 2.21] per 100,000) (Supplementary Tables 1-4).

Health inequality analysis revealed a positive correlation between incidence rates and SDI in 2021 (Supplementary Fig. 3A and B). These findings are consistent with the results presented in Fig. 3. Notably, the SII for incidence rate is 0.83, and the Concentration Index is 11% (Supplementary Fig. 3A and B). However, a U-shaped relationship was observed between SDI and DALYs rates in 2021, with the highest burden occurring in regions at both extremes of the SDI spectrum (Supplementary Fig. 4). Notably, from 1990 to 2021, the SII for DALYs rates changed from 0.4 to –1.06, and the concentration index changed from –14% to –23% (Supplementary Fig. 3C and D), indicating increased health inequality between high- and low-income countries and a growing burden of EO-IBD in low-income countries.

Fig. 3.

The incidence rate across 204 countries and territories in 2021, and their correlation with the sociodemographic indexes. Figure was generated using R4.4.1 software.

Across GBD regions, mortality and DALYs rates declined in most regions, with the largest declines observed in East Asia. In 2021, Australasia had the highest incidence rate (2.85 [95% UI, 2.26 to 3.64] per 100,000), while Western Europe had the highest prevalence rate (10.92 [95% UI, 8.8 to 13.8] per 100,000) (Supplementary Tables 1 and 2). In contrast, Central Latin America had the lowest incidence (0.12 [95% UI, 0.09 to 0.16] per 100,000) and prevalence rates (0.59 [95% UI, 0.44 to 0.78] per 100,000) (Supplementary Tables 1 and 2). Central Asia had the highest mortality (0.07 [95% UI, 0.06 to 0.09] per 100,000) and DALYs rates (6.06 [95% UI, 4.95 to 7.53] per 100,000), while Oceania had the lowest mortality (0 [95% UI, 0 to 0]) and DALYs rates (0.34 [95% UI, 0.24 to 0.51] per 100,000) (Supplementary Tables 3 and 4).

5. EO-IBD burden by country

In 2021, among 204 countries and territories, San Marino (5.84 [95% UI, 4.63 to 7.55] per 100,000), Canada (5.45 [95% UI, 4.32 to 6.98] per 100,000), and the Netherlands (5.31 [95% UI, 4.26 to 6.81] per 100,000) had the highest incidence rates (Fig. 3, Fig 4A). San Marino (23.25 [95% UI, 18.31 to 30.03] per 100,000), the Netherlands (21.03 [95% UI, 16.76 to 26.82] per 100,000), and Canada (20.93 [95% UI, 16.25 to 26.66] per 100,000) had the highest prevalence rates (Fig. 4B, Supplementary Fig. 5). Tajikistan (0.12 [95% UI, 0.07 to 0.22] per 100,000), Gambia (0.10 [95% UI, 0.05 to 0.17] per 100,000), and Turkmenistan (0.08 [95% UI, 0.05 to 0.12] per 100,000) had the highest mortality rates (Fig. 4C, Supplementary Fig. 6). Tajikistan (10.66 [95% UI, 5.79 to 19.03] per 100,000), Gambia (7.30 [95% UI, 3.75 to 12.81] per 100,000), and Turkmenistan (6.95 [95% UI, 4.72 to 10.11] per 100,000) had the highest DALYs rates (Fig. 4D, Supplementary Fig. 4).

Fig. 4.

Incidence (A), prevalence (B), mortality (C), and disability-adjusted life years (DALYs) (D) rates of early-onset inflammatory bowel disease in 204 countries and territories in 2021. Figure was generated using R4.4.1 software.

Among 204 countries and territories, Italy had the smallest AAPC for incidence (–2.28%; 95% CI, –2.40% to –2.16%), indicating the fastest decline, while Libya had the largest AAPC for incidence (2.28%; 95% CI, 2.17% to 2.39%) and prevalence rates (2.05%; 95% CI, 2.00% to 2.10%), indicating the fastest increase (Fig. 5A and B). Latvia had the smallest AAPC for mortality rate (–8.43%; 95% CI, –10.18% to –6.66%), indicating the fastest decline, while Niue had the largest AAPC for mortality rate (6.31%; 95% CI, 3.89% to 8.80%), indicating the fastest increase (Fig. 5C). China had the smallest AAPC for DALYs rates (–6.56%; 95% CI, –7.42% to –5.70%), indicating the fastest decline, while Niue had the largest AAPC for DALYs rates (6.00%; 95% CI, 3.54% to 8.51%), indicating the fastest increase (Fig. 5D).

Fig. 5.

Average annual percentage changes (AAPCs) of early-onset inflammatory bowel disease from 1990 to 2021 in 204 countries and territories. (A) AAPC of incidence rates. (B) AAPC of prevalence rates. (C) AAPC of mortality rates. (D) AAPC of disability-adjusted life years (DALYs) rates. Figure was generated using R4.4.1 software.

DISCUSSION

This study presents the first systematic evaluation of the global burden of EO-IBD from 1990 to 2021 using the GBD 2021 database, elucidating its spatiotemporal evolution and dynamic associations with sex, age, and SDI. Furthermore, we projected trends in ASIR, ASPR, ASMR, and ASDR up to 2036, providing critical evidence for optimizing global prevention and control strategies for EO-IBD.

Based on the GBD 2021 database and BAPC modeling projections, the global incidence of EO-IBD is anticipated to demonstrate a sustained upward trajectory, consistent with the systematic review evidence presented by Kuenzig et al.¹⁶ The observed changes may be associated with multiple factors, including shifts in environmental risk factors (such as dietary Westernization in regions previously exhibiting low incidence rates) and advancements in the diagnostic capacity for EO-IBD (e.g., improvements in gastrointestinal endoscopy and radiological imaging techniques).^16-18

Notably, the management of EO-IBD was partially impacted during the coronavirus disease 2019 (COVID-19) pandemic. Due to constraints in diagnostic testing and referral pathways, delays occurred in both IBD diagnosis and disease progression assessment, resulting in a decline in newly confirmed IBD cases.^19,20 This phenomenon may have contributed to a transient reduction in IBD incidence and prevalence, potentially leading to an underestimation of projected prevalence rates in the BAPC model for the period between 2022 and 2036.

However, the mortality and DALYs of EO-IBD has shown a declining trend, consistent with findings from Chen et al.²¹ using the GBD 2019 database. This favorable epidemiological transition likely reflects the synergistic effects of multiple contributing factors. The therapeutic revolution brought about by biologic agents has fundamentally transformed disease management paradigms, with targeted modulation of specific inflammatory pathways (e.g., tumor necrosis factor α inhibition, interleukin [IL]-12/23 blockade) leading to substantial reductions in disease relapse rates, disability progression, and mortality.^22,23 Nevertheless, the ongoing development and advancement of novel immunomodulators may further reduce mortality rates in IBD patients. Therefore, we cannot exclude the possibility that the actual decline in mortality during 2022 to 2036 may exceed the predicted rate in the BAPC model. Concurrently, the global promotion of health education and preventive measures for EO-IBD has enhanced public awareness and recognition of the disease, encouraging the adoption of healthier lifestyles and thereby reducing its global mortality and DALYs.^24,25 Furthermore, socioeconomic advancements and healthcare system reforms have improved access to evidence-based interventions, facilitating early diagnosis and optimized disease management, which collectively contribute to improved long-term outcomes. Nevertheless, DALYs alone are inadequate to fully represent the disease burden of EO-IBD, as this metric does not sufficiently account for critical dimensions such as psychosocial adaptation, growth and developmental impairments, and educational disruptions in pediatric and adolescent patients. Notably, studies indicate a rising prevalence of anxiety, depression, and other mental health disorders among children and adolescents,^26,27 which may further compound the overall disease burden in EO-IBD.^28-30

Our analysis reveals substantial heterogeneity in disease burden patterns across the sociodemographic spectrum. High SDI regions demonstrate persistently elevated incidence and prevalence rates potentially linked to a Westernized dietary pattern characterized by excessive consumption of fats, sugars, and processed foods, alongside insufficient dietary fiber intake. Emerging evidence indicates that such dietary habits may disrupt gut microbiota composition and functionality, impair intestinal barrier integrity, and provoke dysregulated immune responses, collectively contributing to an increased risk of EO-IBD.³¹ Nevertheless, the reduction in mortality and DALYs rates in these regions has been less pronounced, with both metrics exceeding those of other SDI strata by 2021. This trend may be explained by the substantial existing patient burden in high SDI regions and the limitations of national healthcare policies. Conversely, high-middle SDI regions have demonstrated remarkable progress in disease control, achieving substantial reductions in DALYs rates through strategic healthcare investments and implementation of standardized care pathways.^32,33 This success likely reflects improved access to primary care services and the establishment of integrated, hierarchical healthcare delivery systems. Health inequality metrics reveal a complex dual-dimensional pattern: while incidence demonstrate positive correlations with SDI, DALYs rates show inverse relationships. These findings, consistent with Zhou et al.’s observations,³⁴ underscore the multifaceted nature of healthcare disparities. High SDI regions benefit from advanced diagnostic infrastructure and therapeutic resources, facilitating early intervention and optimized disease management. In contrast, low SDI settings face substantial barriers to care, including diagnostic delays, limited access to advanced therapies, and inadequate long-term disease monitoring, resulting in disproportionately higher mortality and disability burdens.³⁵ These patterns align with Bernstein et al.’s cohort findings,³⁶ which established significant associations between socioeconomic disadvantage and adverse IBD outcomes.

Sex-based epidemiological differences indicate that since 2004, the burden of EO-IBD has been higher in males than in females, with this disparity widening over time. Several potential factors may contribute to this observed sex disparity in disease burden. Studies have shown that the R30Q DLG5 variant is associated with a reduced risk of Crohn’s disease in females, yet this protective effect is not observed in males.^37-39 Additionally, there is a significant sex-based disparity in treatment response—females are 3.5 times more likely to achieve long-term remission with infliximab therapy compared to males (odds ratio, 3.46; 95% confidence interval, 1.41 to 8.46).⁴⁰ Furthermore, multiple studies indicate that male sex itself is an independent risk factor for disease complications,^41,42 particularly the need for surgical intervention. Male patients generally require more IBD-related surgeries than females, regardless of whether they have Crohn’s disease or ulcerative colitis.^43,44 In addition, environmental exposures and disparities in healthcare access may also contribute to these sex-based differences. Unfortunately, most studies adjust for sex without providing sex-stratified risks related to environmental factors, particularly early-life exposures (e.g., antibiotic use, breastfeeding).⁴² Therefore, future public health policies and clinical practices should pay greater attention to male EO-IBD patients. Targeted interventions, such as enhanced health education, lifestyle improvements, and increased adherence to medical services, could further reduce the disease burden.

Geospatial analysis reveals distinct epidemiological patterns across development spectrums. High-income nations, including San Marino, Canada, and the Netherlands, demonstrate consistently elevated incidence and prevalence rates, potentially attributable to advanced diagnostic infrastructure, environmental determinants (e.g., urbanization, pollution), and lifestyle factors associated with Westernization.^2,3,45 Conversely, low- and middle-income countries, exemplified by Tajikistan and Gambia, bear disproportionate mortality and DALYs burdens, reflecting systemic challenges in healthcare access and early intervention capabilities.⁴⁶ Notable success stories emerge from China, showcasing divergent yet effective disease control strategies. China's substantial DALYs reduction demonstrates the effectiveness of primary healthcare reforms and population-level interventions.³³ Regional analysis reveals polarized disease burden patterns: Australasia's incidence fluctuations may reflect climate-mediated microbiome alterations,^47,48 while East Asia's mortality reductions highlight the efficacy of precision public health approaches.³³ Western Europe's persistent high prevalence may represent the enduring legacy of dietary transitions, antibiotic overuse during industrialization and long-term accrual of incident cases.^49,50 Central Asia's elevated mortality rates expose critical healthcare resource allocation deficiencies, while the accelerating disease burden in small developing nations like Niue underscores urgent needs for pediatric gastroenterology capacity building and nutritional intervention programs.

Age-stratified analysis reveals distinct epidemiological patterns across developmental stages. The progressive increase in incident case with advancing age likely reflects the natural history of EO-IBD progression. However, the disease burden demonstrates a bimodal distribution, with peak mortality and DALYs observed in the <5 years and 15–19 years age groups. This age-specific burden distribution suggests distinct pathophysiological mechanisms operating during critical developmental windows. In early childhood (<5 years), genetic factors interact with perinatal factors to jointly influence immune development patterns, thereby leading to disease onset. During the perinatal period, the vertical transmission of the maternal microbiota and the establishment of the early-life microbiota play key roles in disease occurrence.⁵¹ Additionally, studies have shown that mutations in critical genes such as the IL-10 signaling pathway (IL-10/IL-10RA/B), XIAP, and NADPH oxidase are relatively common in very EO-IBD (VEO-IBD; defined as disease onset before 6 years of age) patients, with those having IL-10 signaling defects often presenting symptoms before 3 months of age.^52-54 However, it is regrettable that the current GBD 2021 database does not allow for analysis of IBD in the <6-year age group. Consequently, our study was limited to investigating the epidemiological characteristics of IBD in children under 5 years of age. This finding provides a compelling explanation for the incidence of IBD in children under 5 years of age and highlights the significance of genetic screening for precise diagnosis and treatment in this population. Moreover, these cases are often characterized by a severe refractory phenotype, including extensive gastrointestinal involvement, perianal complications, and systemic manifestations.^55,56 The high incidence of surgical complications and poor response to conventional treatments in this subgroup are important factors contributing to increased mortality and DALYs. Conversely, the adolescent peak (15 to 19 years) potentially mediated by pubertal hormonal influences and sex-specific behavioral factors.⁵⁷ While this group exhibits high incidence and prevalence rates, the overall burden trajectory shows encouraging declines across all age strata, with the most substantial improvements observed in the <5 years group. This favorable trend likely reflects global advancements in neonatal and pediatric care, including earlier diagnostic capabilities, optimized nutritional support, and targeted therapeutic strategies.

However, this study has several limitations that should be acknowledged. Firstly, the aggregate nature of our analysis precludes subtype-specific stratification (e.g., ulcerative colitis vs Crohn's disease), potentially obscuring subtype-specific epidemiological patterns. Furthermore, inherent limitations in data quality and completeness from low SDI regions (particularly low-income countries in Africa and Southeast Asia) within the GBD 2021 database may account for observed discrepancies between GBD-derived IBD estimates and population-based studies particularly regarding incidence rates and prevalence trends.⁵⁸ Finally, the BAPC model has several limitations, including stringent data requirements, challenges in handling complex relationships and outliers, considerable predictive uncertainty, and limited capacity for causal inference and forecasting in rapidly evolving epidemiological contexts. It must be acknowledged that COVID-19 may have influenced the predictive accuracy of the BAPC model in this study.

In conclusion, the incidence of EO-IBD is projected to exhibit an increasing trend in the future. Despite substantial global progress in EO-IBD management, persistent health inequalities across development spectrums remain a critical challenge. Our findings reveal a paradoxical burden distribution: high-income nations demonstrate elevated incidence and prevalence rates, potentially linked to a Westernized dietary pattern, while low-income countries bear disproportionate mortality and DALYs burdens, underscoring systemic healthcare disparities. The remarkable progress in early childhood disease control, particularly in the <5 years age group, highlights the effectiveness of early intervention strategies and pediatric healthcare advancements. Moving forward, global efforts should focus on optimizing healthcare resource distribution, enhancing diagnostic and treatment capacities in low-income countries, and advancing basic research and clinical innovation to achieve more equitable and effective EO-IBD prevention and control strategies, ultimately improving patient outcomes and quality of life.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl250261.