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David Bergman,1 Hannes Hagström,2– 4 Andrea Johansson Capusan,5,6 Karl Mårild,7,8 Fredrik Nyberg,9 Kristina Sundquist,10 Jonas F Ludvigsson1,11– 13 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden; 3Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; 4Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; 5Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 6Department of Psychiatry in Linköping, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; 7Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden; 8Department of Pediatric Gastroenterology, Queen Silvia Children’s Hospital, Gothenburg, Sweden; 9School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 10Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden; 11Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; 12Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; 13Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USACorrespondence: Jonas F LudvigssonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, SwedenEmail jonasludvigsson@yahoo.comAim: To improve consistency between register studies in Sweden and ensure valid comparisons of possible changes in alcohol-related disorders and diseases (ARDDs) over time, we propose a definition of ARDDs. Based on this definition, we examined Sweden’s incidence rates of ARDDs from 1970 to 2018 in non-primary healthcare settings (inpatient and outpatient).Methods: Swedish Society of Epidemiology members were invited to give feedback on the International Classification of Disease (ICD) codes with a potential link to alcohol use. We then calculated age-standardised and age-specific incidence of ARDDs over time according to the National Patient Register, and the lifetime prevalence of ARDDs diagnosed in adults alive in Sweden on Dec 31, 2018.Results: Sweden’s estimated incidence of ARDDs increased substantially after introducing the new ICD-9 codes in 1987. In the past 10 years (2009– 2018), the incidence of ARDDs has been stable (males: 110/100,000 person-years, females: 49/100,000 person-years). Requiring at least two ICD records for diagnosed ARDDs led to a somewhat lower incidence of ARDDs (males: 71 per 100,000 person-years, females: 29 per 100,000 person-years). In Sweden, the lifetime prevalence of diagnosed ARDDs in adults on Dec 31, 2018, was 1.9% (95% CI=1.9– 1.9).Conclusion: In this nationwide study, we found an incidence of ARDDs of 50– 100/100,000 person-years. In 2018, 1 in 52 adults in Sweden had been diagnosed with ARDDs in the National Patient Register.Keywords: alcohol, alcohol use disorder, alcohol-related disease, alcohol drinking, drug use, ethanol

Abstract Background Psychological stress has previously been associated with several immunological diseases, e.g. inflammatory bowel disease. Through questionnaire data from the ABIS study (All Babies In southeast Sweden) we examined the association between psychological stress in the family and biopsy-proven coeliac disease (CD) in the child. Methods We used serious life event, parenting stress, and parental worries as measures of psychological stress. Data were collected when the child was 1 and 2.5 years old in some 11,000 and 8,800 children, respectively. CD was confirmed through small intestinal biopsy (with villous atrophy), and the diagnosis was validated through patient chart data. Results Serious life event in the family in the child's first 1 or 2.5 years after childbirth was not associated with future CD in the child (Odds Ratio (OR) = 0.45; 95% Confidence Interval (CI) = 0.01-2.65; P = 0.72; and OR = 1.21; 95% CI = 0.43-3.05; P = 0.64, respectively). Neither did we see any association between CD and parenting stress at age 1 year and at 2.5 years (OR = 0.40; 95% CI = 0.01-2.38; P = 0.73 and OR = 0.74; 95% CI = 0.01-4.56; P = 1.00, respectively). Among children exposed to parental worries at 2.5 years, no child had a diagnosis of CD before end of follow-up, compared to 25/8082 (0.3%) among non-exposed children (OR = 0.00; 95% CI = 0.00-2.34; P = 0.64). There was no association between the combined measures of stress and CD. Conclusion This study found no association between psychological stress and later development of CD in Swedish children. However, we cannot rule out that the lack of such an association is due to limited statistical power.

Background: Childhood antibiotic use has been associated with inflammatory bowel disease (IBD), although the potential contribution of infection frequency remains uncertain., Aims: To explore the association between early-life infections, antibiotics and IBD development., Methods: We used population-based data from ABIS (Sweden) and MoBa (Norway) cohorts following children from birth (1997-2009) until 2021. Prospectively collected questionnaires identified infection frequency (any, gastrointestinal and respiratory) and antibiotics (any, penicillin and non-penicillin) until age 3. IBD diagnosis required ≥ 2 records in national health registries. Cohort-specific hazard ratios (aHR), adjusted for parental education, smoking and IBD were estimated and pooled using a random-effects model. Antibiotic analyses were adjusted for infection frequency., Results: There were 103,046 children (11,872 ABIS and 91,174 MoBa), contributing to 1,663,898 person-years of follow-up, during which 395 were diagnosed with IBD. The frequency of any infection at 0 to < 1 and 1 to < 3 years showed a pooled aHR of 1.01 (95% confidence interval [CI] = 0.96-1.07) and 1.00 (95% CI = 0.99-1.01) per additional infection for IBD. Adjusting for infections, any versus no antibiotics in the first year was associated with IBD (pooled aHR = 1.33 [95% CI = 1.01-1.76]). The aHR for additional antibiotic course was 1.17 (95% CI = 0.96-1.44), driven by penicillin (per additional course, aHR = 1.28 [95% CI = 1.02-1.60]). Although antibiotics at 1 to < 3 years did not show an association with IBD or Crohn's disease, non-penicillin antibiotics were associated with ulcerative colitis (per additional course, aHR = 1.95 [95% CI = 1.38-2.75])., Conclusion: Early-life antibiotic use was, a significant risk factor for childhood and early adult-onset IBD, independent of infection frequency., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Diet has been hypothesized as a risk factor for development of inflammatory bowel disease (IBD)., Objective: To explore associations between maternal diet diversity and quality in pregnancy and the offspring's risk of IBD., Methods: We used data from a nationwide cohort study on 85,129 Norwegian children followed from birth (1999-2009) with information on maternal diet in pregnancy from validated food frequency questionnaires. Hazard ratios (aHRs) for IBD, Crohn's disease (CD), and ulcerative colitis (UC) by maternal diet diversity, quality and intake amounts of individual food groups were adjusted for maternal body mass index, parental IBD, and socio-demographic factors. Sensitivity analyses adjusted for the child's early-life diet quality and antibiotic treatment. Dietary exposures were classified into tertiles, comparing low (reference) to medium, and high levels., Results: During a mean follow-up time of 16.1 years (1,367,837 person-years of follow-up), 268 children developed IBD (CD, n=119; UC, n=76; IBD-unclassified, n=73). High compared with low diet diversity in pregnancy was associated with a lower risk of UC in the offspring (aHR 0.46, 95% confidence interval 0.25-0.87), with consistent findings after further adjustment for the child's early-life diet quality and antibiotic treatment. High compared with low diet diversity in pregnancy yielded aHRs of 0.81 for CD (0.51-1.28) and 0.75 for any IBD (0.55-1.02) in the offspring. A high compared with low diet quality in pregnancy or intakes of specific food groups were not associated with the offspring's risk of IBD or its subtypes., Conclusions: Our findings suggest that a higher maternal diet diversity in pregnancy may be associated with a lower risk of UC in the offspring., Competing Interests: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Annie Guo reports financial support was provided by Henning and Johan Throne-Holst’s Foundation. Annie Guo reports was provided by The Swedish Society for Medical Research. Karl reports financial support was provided by The Swedish Society for Medical Research. Karl reports financial support was provided by The Swedish Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: High gluten and low dietary fiber in pregnancy intake is associated with an increased risk of celiac disease (CeD) in the child. Early life higher dietary quality is suggested to reduce the subsequent risk of CeD., Objectives: The aim was to investigate associations of pregnancy dietary quality and diversity with child risk of CeD., Methods: In The Norwegian Mother, Father and Child Cohort Study, 85,122 mother-child pairs had available data from a validated pregnancy food frequency questionnaire. Pregnancy dietary quality and diversity were estimated by a Pregnancy Healthy Eating Index [mean 99.3, standard deviation (SD) 9.9, range 48.8-128.3], and a Diet Diversity Score (mean 7.0, SD 1.0, range 1.6-9.8), respectively. Child CeD was captured by ≥2 diagnostic codes in the Norwegian Patient Registry. Logistic regression was used to estimate associations between pregnancy dietary quality, diversity and child CeD, adjusted for socioeconomic factors, and parents CeD [adjusted odds ratio (aOR), 95% confidence intervals (CI)]. CeD-susceptible human leukocyte antigen haplotypes (DQ2/DQ8) were present in 30,718 (45.5%)., Results: Up to mean age 16.0 (SD 1.8, 12.4-19.8) y, 1363 (1.6%) children were diagnosed with CeD. Lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD in the child (<5th percentile aOR = 0.67, 95% CI: 0.48, 0.93, >95th percentile aOR = 0.71, 95% CI: 0.52, 0.98, respectively, nonlinear squared term P = 0.011). Analyses on genetically susceptible children, adjustments for pregnancy iron supplementation, gluten, and dietary fiber intake, and child early life dietary quality, gluten intake and iron supplementation, supported the finding. Pregnancy dietary diversity was not associated with child CeD (aOR = 1.00, 95% CI: 0.94, 1.07/score)., Conclusions: In this population-based study, lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD diagnosis in the child. In contrast, no such association was observed with maternal dietary diversity., Competing Interests: Conflict of interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We aimed to investigate whether early-life hygiene-related factors influenced the risk of inflammatory bowel disease (IBD) in a Scandinavian population and test the association's consistency across cohorts., Methods: This study followed 117 493 participants in the All Babies in Southeast Sweden study and the Norwegian Mother, Father, and Child Cohort Study. IBD diagnoses were defined by national registers. Comprehensive data on hygiene-related exposures, such as having pets, rural living, daycare attendance, and siblings, were retrieved from questionnaires administered from pregnancy until child's age of 36 months. A multivariable Cox regression model yielded adjusted hazard ratios (aHRs) for IBD accounting for socioeconomic status and perinatal factors. Cohort-specific estimates were pooled using a random-effects model., Results: In over 2 024 299 person-years of follow-up 451 participants developed IBD. In pooled estimates children attending daycare up to 36 months of life vs not attending daycare were less likely to develop Crohn's disease (aHR, 0.60; 95% confidence interval [CI], 0.37- 0.98). Children having 1 or more siblings had a modestly increased risk of IBD (aHR, 1.17; 95% CI, 0.96-1.42; aHR for each sibling, 1.12; 95% CI, 1.01-1.24). The other hygiene factors were not significantly linked to later IBD. In the Norwegian Mother, Father, and Child Cohort Study cohort, bed sharing was associated with an increased risk of IBD, most notably for ulcerative colitis (aHR, 1.67; 95% CI, 1.01-2.78)., Conclusions: In this birth cohort study from 2 high-income Scandinavian countries, some early-life hygiene-related exposures were associated with IBD risk. The generalizability of these results to countries of other socioeconomic level is unknown., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: Ecological observations suggest a negative relationship between childhood socioeconomic status (SES) and inflammatory bowel disease (IBD) risk. Individual-level analyses have been inconsistent and mostly lacked refined assessments of SES. We aimed to comprehensively study the association between early-life SES and later IBD., Methods: This study included 117 493 participants from the Norwegian Mother, Father and Child cohort and Swedish All Babies in Southeast Sweden cohorts. Participants were followed from birth (1997-2009) through 2021. IBD was identified through national patient registers. Questionnaire and register data were used to define parental educational level, employment, and household income level. Cox regression estimated adjusted hazard ratios (aHRs), accounting for other SES exposures and covariates (eg, parental IBD). Cohort-specific estimates were pooled using a random-effects model., Results: During 2 024 299 person-years of follow-up, 451 participants were diagnosed with IBD (All Babies in Southeast Sweden cohort, n = 113 and Norwegian Mother, Father and Child cohort, n = 338). Early-life maternal, but not paternal, educational level was associated with later IBD (low vs high educational level; pooled aHR, 1.81; 95% confidence interval [CI], 1.16-2.82; and pooled aHR, 1.20; 95% CI, 0.80-1.80; respectively). Having a nonworking mother or father was not significantly associated with IBD (pooled aHR, 0.69; 95% CI, 0.47-1.02; pooled aHR, 0.79; 95% CI, 0.45-1.37). High vs low household income level yielded a pooled aHR of 1.33 (95% CI, 0.94-1.89). Overall, results were largely consistent across cohorts., Conclusions: In this prospective Scandinavian cohort study, low maternal educational level was, independent of other SES and covariates, significantly associated with later IBD in her child. Further research is needed to elucidate factors that may mediate this relationship., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Introduction: Despite its increasing prevalence, the economic impact of eosinophilic esophagitis (EoE) is understudied., Methods: We estimated the societal economic burden of EoE by using real-world data from Swedish health registers., Results: Patients with EoE had 45% higher societal cost ($6,290 vs $4,349) compared with the general population, primarily driven by increased healthcare costs ($2,414 vs $1,022), which accounted for 72% of the excess societal cost in EoE., Discussion: EoE is associated with a considerable economic burden to society. With the prevalence of EoE still rising, the economic burden of EoE is expected to continue to grow., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Individuals with inflammatory bowel disease (IBD) are at increased risk of fracture. It is unclear if this risk varies by recent histological activity., Aims: To determine the fracture risk in IBD during periods with and without histological inflammation., Methods: We studied a nationwide cohort of 54,591 individuals diagnosed with IBD in 1990-2016 with longitudinal data on ileo-colorectal biopsies. Fractures were identified by inpatient and hospital-based outpatient diagnoses. We derived Cox regression estimated hazard ratios (HRs) for fracture during 12 months following a histological inflammation (vs. histological remission) record after adjusting for socio-demographics, comorbidities, IBD duration, IBD-related surgery and hospitalization. We adjusted sensitivity analyses for medical IBD treatment including corticosteroids., Results: Mean age of patients was 44.0 (SD = 18.3) and 45.5 (SD = 17.1) years at biopsy with histological inflammation and remission, respectively. For histological inflammation, there were 1.37 (95% CI 1.29-1.46) fractures per 100 years' follow-up versus 1.31 (95% CI 1.19-1.44) for remission (adjusted [a]HR 1.12; 95% CI 1.00-1.26; p = 0.04). HRs were similar with histological inflammation of Crohn's disease (1.11; 95% CI 0.91-1.36) and ulcerative colitis (1.18; 95% CI 1.02-1.36). Estimates were consistent across age groups. An overall small excess risk of any fracture remained after accounting for corticosteroids. A more prominently raised fracture risk was observed in corticosteroid-naïve IBD patients with histological inflammation versus histological remission (aHR 1.41; 95% CI 1.07-1.85). The aHR of hip fracture following histological inflammation was 1.29 (95% CI 0.87-1.92)., Conclusions: Histological inflammation in IBD predicted a small increase in short-term fracture risk. Measures to reduce disease activity may reduce fracture risk in IBD., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Diet diversity in early childhood promotes microbial diversity, influences the developing immune system, and has been linked to a reduced risk of immune-mediated diseases. This study aimed to determine the association between childhood diet diversity and later inflammatory bowel disease (IBD), for which data are limited., Methods: Questionnaire data from the population-based birth cohorts All Babies in Southeast Sweden (ABIS) and the Norwegian Mother, Father, and Child Cohort (MoBa), including participants from Southeast Sweden and Norway, were used to estimate a diet diversity score at ages 1 and 3 years. This score represents the diversity of intakes across 5 food groups comprising 11 subgroups. A higher score signifies higher diet diversity. We used linked health registry data to identify IBD diagnoses up to the year 2021. Cox regression and random-effect models were used to estimate pooled hazard ratios (aHRs) adjusted for sociodemographics, breastfeeding, and early-life antibiotic use., Results: Among 81 272 children with 1 304 325 person-years of follow-up, 307 developed IBD. Diet diversity at ages 1 and 3 years was in pooled analyses not associated with later IBD (per one-unit increase, aHR = 0.96 [95% CI = 0.81-1.14] and aHR = 0.96 [95% CI = 0.83-1.11]). In MoBa, but not ABIS, a higher diet diversity at 1 and 3 years of age was inversely associated with ulcerative colitis (UC) (per one-unit increase, aHR = 0.78 [95% CI = 0.66-0.94] and aHR = 0.78 [95% CI = 0.65-0.95]). Still, pooled aHRs for UC as well as Crohn's disease approximated one., Conclusions: In this prospective study of 2 Scandinavian birth cohorts, no association was observed between early-life diet diversity and the subsequent risk of IBD., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background: The association of infections and antibiotic use in pregnancy and the risk of inflammatory bowel disease (IBD) development in the offspring have been scarcely investigated. We examined infection and antibiotic use in pregnancy and the risk of IBD in offspring., Methods: We followed participants from the All Babies in Southeast Sweden (ABIS) and the Norwegian mother father and child cohort (MoBa) from birth (1997-2009) until 2020-2021. IBD diagnosis was classified as ≥2 records in national registers. Information on infections (any, gastrointestinal, and respiratory), their timing (early or late in pregnancy), and antibiotic use in pregnancy were collected from questionnaires. Cox proportional-hazard regression and meta-analytic methods were used to estimate pooled adjusted hazard ratios (aHRs) for IBD and its subtypes, adjusted for parental IBD, maternal smoking, and education. Sensitivity analyses accounted for exposure to antibiotics and infections 0-12 months of age., Results: We followed 117 493 children for 2 024 299 person-years (follow-up 22.3 years in ABIS and 16.4 years in MoBa), including 451 IBD cases. The aHRs for any infection and respiratory infections in pregnancy and offspring IBD were close to one (aHR = 0.99 [95% CI = 0.73-1.33] and aHR = 1.00 [95% CI = 0.81-1.23], respectively). However, any versus no infection in early pregnancy was associated with IBD development (aHR = 1.26 [95% CI = 1.02-1.55]), particularly Crohn's disease (CD; aHR = 1.40 [95% CI = 1.01-1.93]). Any versus no gastrointestinal infection in late pregnancy was associated with offspring CD (aHR = 1.95 [95% CI = 1.34-2.84]). Antibiotic use in pregnancy was not associated with IBD in the child (aHR = 1.15 [95% CI = 0.93-1.44])., Conclusions: In this binational birth cohort study, the risk of offspring IBD varied by infection type and timing but not with maternal antibiotic use in pregnancy., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Aim: To examine possible geographical and temporal differences in the incidence of childhood-onset inflammatory bowel disease (IBD) in Norway, motivated by previous research indicating relevant environmental factors explaining changing epidemiology., Methods: We analysed data from children born in Norway from 2004 to 2012 (n = 541 036) in a registry-based nationwide study. After validating registry diagnoses against medical records, we defined IBD as ≥2 entries of International Classification of Diseases, 10th revision (ICD-10) codes K50, K51 and K52.3 in the Norwegian Patient registry. We estimated hazard ratios (HR) for IBD across four geographical regions with a south-to-north gradient and the incidence by period of birth., Results: By the end of follow-up on 31 December 2020, 799 IBD diagnoses were identified (Crohn's disease: n = 465; ulcerative colitis, n = 293, IBD: unclassified, n = 41). Compared to children in the southernmost region, there was almost a two-fold HR for IBD in children in the most Northern region (HR = 1.94, 95% Cl = 1.47-2.57; Mid region: HR = 1.68, 95% CI = 1.29-2.19, p trend  <0.001). These estimates remained largely unchanged after adjustment for potential confounding factors. The cohorts born in 2004-2006 and 2010-2012 had comparable cumulative incidences, with a slightly higher incidence for those born in 2007-2009., Conclusion: We observed an increase in the risk of IBD by increasing latitude which may suggest that environmental factors influence the development of IBD, although non-causal explanations cannot be ruled out., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: To examine the association between early-life atopic manifestations and later risk of inflammatory bowel disease (IBD), for which prospective data are scarce., Study Design: The population-based All Babies in Southeast Sweden (ABIS) and Norwegian Mother, Father, and Child (MoBa) cohorts follow children from birth (ABIS 1997-1999; MoBa 2000-2009) to the end of 2021. Based on validated questionnaires, parents prospectively reported information on asthma, food-related allergic symptoms, atopic dermatitis, and allergic rhinitis by age 3. IBD was defined by ≥ 2 diagnostic records in the national health registries. Cox regression estimated hazard ratios adjusted (aHRs) for parental IBD, atopy, education level, smoking habits, and national origin. Cohort-specific estimates were pooled using a random-effects model., Results: We compiled data on 83 311 children (ABIS, n = 9041; MoBa, n = 74 270). In over 1 174 756 person-years of follow-up, 301 participants were diagnosed with IBD. Children with atopic dermatitis at age 3 had an increased risk of IBD (pooled aHR = 1.46 [95% CI = 1.13-1.88]), Crohn's disease (pooled aHR = 1.53 [95%CI = 1.04-2.26]), and ulcerative colitis (pooled aHR = 1.78 [95%CI = 1.15-2.75]). Conversely, any atopic manifestation by age 3 was not associated with IBD (pooled aHR = 1.20 [95%CI = 0.95-1.52]), nor were analyses specifically focused on early-life food-related allergic symptoms, asthma, and allergic rhinitis., Conclusion: While atopic manifestations in early childhood were overall not associated with IBD, children with atopic dermatitis specifically were at increased risk of developing IBD, suggesting shared etiologic traits; these findings might be useful in identifying at-risk individuals for IBD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest. KM: Birgitta och Göran Karlssons Stiftelse: Swedish Society for Medical Research, The Swedish Research Council, and ALF funding. ABIS was supported by Barndiabetesfonden (Swedish Child Diabetes Foundation); Swedish Council for Working Life and Social Research, Grant/Award Numbers: FAS2004-1775, FAS2004–1775; Swedish Research Council, Grant/Award Numbers: K2005-72X-11242-11A and K2008-69X-20826-01-4, K2008-69X-20826-01-4; Östgöta Brandstodsbolag; Medical Research Council of Southeast Sweden (FORSS); JDRF Wallenberg Foundation, Grant/Award Number: K 98-99D-12813-01A; ALF-and LFoU grants from Region Östergötland and Linköping university, Sweden; Joanna Cocozza Foundation. The funders had no role in study design, data collection, analysis, drafting of the manuscript or publication process., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: The aim of this study was to determine the risk of irritable bowel syndrome (IBS) diagnosis in patients with celiac disease (CD) compared with general population comparators., Methods: Using Swedish histopathology and register-based data, we identified 27,262 patients with CD diagnosed in 2002-2017 and 132,922 age- and sex-matched general population comparators. Diagnoses of IBS were obtained from nationwide inpatient and non-primary outpatient records. Cox regression estimated hazard ratios (aHRs) for IBS adjusted for education level and Charlson Comorbidity Index. To reduce potential surveillance bias our analyses considered incident IBS diagnosis ≥1 year after CD diagnosis. Using conditional logistic regression, secondary analyses were calculated to estimate odds ratios (ORs) for IBS diagnosis ≥1 year before CD diagnosis., Results: During an average of 11.1 years of follow-up, 732 celiac patients (2.7%) were diagnosed with IBS vs 1131 matched general population comparators (0.9%). Overall (≥1-year of follow-up), the aHR for IBS was 3.11 (95% confidence interval [CI], 2.83-3.42), with aHR of 2.00 (95% CI, 1.63-2.45) after ≥10 years of follow-up. Compared with siblings (n = 32,010), celiac patients (n = 19,211) had ≥2-fold risk of later IBS (aHR, 2.42; 95% CI, 2.08-2.82). Compared with celiac patients with mucosal healing, those with persistent villus atrophy on follow-up biopsy were less likely to be diagnosed with IBS (aHR, 0.66; 95% CI, 0.46-0.95). CD was also associated with having an earlier IBS diagnosis (OR, 3.62; 95% CI, 3.03-4.34)., Conclusions: In patients with CD, the risk of IBS is increased long before and after diagnosis. Clinicians should be aware of these long-term associations and their implications on patient management., (Copyright © 2024 The Authos. Published by Elsevier Inc. All rights reserved.)

Celiac disease (CeD) is a chronic autoimmune disorder of global relevance, with the potential for acute and long-term complications. However, the economic burden of CeD is rarely considered and largely thought of as limited to the cost of gluten-free food. Fortunately, recent research has shed light on the various societal costs of CeD across the health care continuum. This article summarizes the current evidence on the economic impacts of CeD, which suggest that the societal economic burden of CeD stretches beyond the cost of gluten-free food. This review provides ample evidence of larger but hidden costs related to excess health care use for complications and comorbidities, as well as reduced productivity. Although significant advances are expected in the management of CeD, their effect on the economic burden of CeD remain uncertain. The aim of this review was to inform stakeholders across society and contribute to improved policies to support patients with CeD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the association between early-life smoking exposure and later risk of inflammatory bowel disease [IBD]., Methods: We followed 115663 participants from the Norwegian Mother, Father and Child [MoBa] and All Babies in Southeast Sweden [ABIS] cohorts from birth [1997-2009] through 2021. IBD was identified through national patient registers. Validated questionnaire data defined maternal smoking during pregnancy, maternal environmental tobacco smoke [ETS] exposure during pregnancy, and child ETS exposure by ages 12 and 36 months. Cox regression was used to estimate adjusted hazard ratios [aHRs] for sex, maternal age, education level, parental IBD, and origin. Cohort-specific estimates were pooled using a random-effects model., Results: During 1 987 430 person-years of follow-up, 444 participants developed IBD [ABIS, 112; MoBa, 332]. Any vs no maternal smoking during pregnancy yielded a pooled aHR of 1.30 [95% CI = 0.97-1.74] for offspring IBD. Higher level of maternal smoking during pregnancy (compared with no smoking, average ≥6 cigarettes/day: pooled aHR = 1.60 [95% CI = 1.08-2.38]) was associated with offspring IBD, whereas a lower smoking level was not (average 1-5 cigarettes/day: pooled aHR = 1.09 [95% CI = 0.73-1.64]). Child ETS exposure in the first year of life was associated with later IBD (any vs no ETS, pooled aHR = 1.32 [95% CI = 1.03-1.69]). Estimates observed for child ETS exposure by 36 months were similar but not statistically significant., Conclusions: In this prospective Scandinavian cohort study, children exposed to higher levels of maternal smoking during pregnancy or ETS during the first year of life were at increased risk of later IBD., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background & Aims: Breastfeeding is critical for offspring health and development. Although many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood., Methods: We used prospectively collected data from 3 population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates., Results: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3-22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% confidence interval, 0.94-1.62; Q = 0.16, I 2  = 0.0%) and 1.02 (95% confidence interval, 0.85-1.21; Q = 1.45, I 2 = 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared with 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses., Conclusions: In prospectively collected data from 3 population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity., Methods: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD)., Results: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98])., Conclusions: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Individuals with inflammatory bowel disease (IBD) are at increased risk of serious infections, but whether this risk varies by histologic disease activity is unclear., Methods: This was a national population-based study of 55,626 individuals diagnosed with IBD in 1990 to 2016 with longitudinal data on ileocolorectal biopsy specimens followed up through 2016. Serious infections were defined as having an inpatient infectious disease diagnosis in the Swedish National Patient Register. We used Cox regression to estimate hazard ratios (HRs) for serious infections in the 12 months after documentation of histologic inflammation (vs histologic remission), adjusting for social and demographic factors, chronic comorbidities, prior IBD-related surgery, and hospitalization. We also adjusted for IBD-related medications in sensitivity analyses., Results: With histologic inflammation vs remission, there was 4.62 (95% CI, 4.46-4.78) and 2.53 (95% CI, 2.36-2.70) serious infections per 100 person-years of follow-up, respectively (adjusted HR [aHR], 1.59; 95% CI, 1.48-1.72). Histologic inflammation (vs remission) was associated with an increased risk of serious infections in ulcerative colitis (aHR, 1.68; 95% CI, 1.51-1.87) and Crohn's disease (aHR, 1.59; 95% CI, 1.40-1.80). The aHRs of sepsis and opportunistic infections were 1.66 (95% CI, 1.28-2.15) and 1.71 (95% CI, 1.22-2.41), respectively. Overall, results were consistent across age groups, sex, and education level, and remained largely unchanged after adjustment for IBD-related medications (aHR, 1.47; 95% CI, 1.34-1.61)., Conclusions: Histologic inflammation of IBD was an independent risk factor of serious infections, including sepsis, suggesting that achieving histologic remission may reduce infections in IBD. The study was approved by the Stockholm Ethics Review Board (approval numbers 2014/1287-31/4, 2018/972-32, and 2021-06209-01)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: We assessed whether early-life diet quality and food intake frequencies were associated with subsequent IBD., Design: Prospectively recorded 1-year and 3-year questionnaires in children from the All Babies in Southeast Sweden and The Norwegian Mother, Father and Child Cohort Study were used to assess diet quality using a Healthy Eating Index and intake frequency of food groups. IBD was defined as >2 diagnoses in national patient registers. Cox regression yielded HRs adjusted (aHRs) for child's sex, parental IBD, origin, education level and maternal comorbidities. Cohort-specific results were pooled using a random-effects model., Results: During 1 304 433 person-years of follow-up, we followed 81 280 participants from birth through childhood and adolescence, whereof 307 were diagnosed with IBD. Compared with low diet quality, medium and high diet quality at 1 year of age were associated with a reduced risk of IBD (pooled aHR 0.75 (95% CI=0.58 to 0.98) and 0.75 (95% CI=0.56 to 1.00)). The pooled aHR per increase of category was 0.86 (0.74 to 0.99). Pooled aHR for children 1 year old with high versus low fish intake was 0.70 (95% CI=0.49 to 1.00) for IBD, and showed association with reduced risk of UC (pooled aHR=0.46; 95% CI=0.21, 0.99). Higher vegetable intake at 1 year was associated with a risk reduction in IBD. Intake of sugar-sweetened beverages was associated with an increased risk of IBD. Diet quality at 3 years was not associated with IBD., Conclusion: In this Scandinavian birth cohort, high diet quality and fish intake in early life were associated with a reduced risk of IBD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The objective of the study is to examine the association between the lack of follow-up for celiac disease (CD) during childhood and dietary adherence, disease remission, and health-related quality of life (HRQoL)., Methods: We invited 243 randomly selected children diagnosed with CD in 2013-2018 in Gothenburg, Sweden, and 162 consented to participate (67%). We retrieved information on clinical follow-up and current wellbeing using medical and laboratory records data, as well as validated questionnaires on symptoms of CD, dietary adherence, and HRQoL. We analyzed tissue-transglutaminase antibodies (tTGA) as a measure of disease remission. We defined lack of follow-up as no CD-related physician/dietician-led visit or measurement of tTGA over the past 24 months of study enrollment., Results: The mean age at study enrolment was 12.7 (range 7.8-18.2) years. Out of 162 children with an average disease duration of 5.3 (range 2.3-8.8) years, 23 (14%) lacked follow-up. tTGA had normalized in 94% [95% confidence interval (CI) = 71%-100%] of children without follow-up versus 91% (95% CI: 85%-95%) of children with continued follow-up. Of children without follow-up, 65% (95% CI: 38%-86%) reported a dietary adherence score indicating very good adherence, versus 72% (95% CI: 63%-80%) of those with continued follow-up. Also, lack of follow-up was not significantly associated with growth, symptom scores, or HRQoL., Conclusions: In this regional cohort study of mostly older children and adolescents, lack of follow-up for CD was not significantly linked to dietary adherence, disease remission, or HRQoL. How these results hold in larger, unselected samples with longer follow-up, including transition to adult care, warrants further study., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Objective: Retrospective data have linked adult physical activity (PA) to reduced risk of inflammatory bowel disease (IBD). We aimed to prospectively examine the association of PA and screen time (ST) in childhood with later risk of IBD, for which data are scarce., Methods: Using two population-based birth cohorts (All Babies in Southeast Sweden [ABIS] and Norwegian Mother, Father, and Child Cohort Study [MoBa]), we retrieved parent-reported data on PA and ST degree at ages 3 and 8 years. Data were modelled as binary (high vs. low) and numerical (hours/day) exposures. Inflammatory bowel disease was defined as ≥2 diagnostic records in national health registers. Cox regression estimated hazard ratios adjusted for potential confounding from parental IBD, country of origin, education, and smoking habits (Adjusted hazard ratio (aHR)). Our 8-year analyses included a 2-year lag period to reduce the risk of reverse causation. Cohort-specific estimates were pooled using random-effects model., Result: Among 65,978 participants from ABIS (n = 8810) and MoBa (n = 57,168) with available data, 266 developed IBD. At 3 years, children with high versus low PA had an aHR of 1.12 for IBD (95%CI = 0.87-1.43); high versus low ST showed an aHR of 0.91 (95%CI = 0.71-1.17). Conversely, at 8 years, high versus low ST was associated with increased risk of later IBD (aHR = 1.51; 95%CI = 1.02-2.25), but PA at 8 years, was not linked to IBD (aHR = 1.19; 95%CI = 0.80-1.76). Subtype-specific analyses for Crohn's disease and ulcerative colitis did not differ appreciably., Conclusion: Acknowledging possible confounding variables, children with high versus low ST at 8 years were at increased risk of IBD. In contrast, PA degree was not linked to IBD at any age category., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Birth cohort studies with linked register-based data on inflammatory bowel disease (IBD) provide opportunities to prospectively study early-life determinants of the disease. However, register-based data often lack information on clinical characteristics and rely on diagnostic algorithms. Within the All Babies in Southeast Sweden (ABIS) cohort, we examined the validity of a register-based definition of IBD, its incidence, and clinical and therapeutic characteristics at diagnosis., Methods: We followed 16,223 children from birth (1997-1999) until the end of 2020 for the diagnosis of IBD as defined by a minimum of two diagnostic codes for IBD in the Swedish National Patient Register (NPR). We described the incidence and cumulative incidence of IBD. Through a medical record review of cases diagnosed by the end of 2017, we examined the positive predictive value (PPV) for IBD and described its clinical characteristics and treatment., Results: By 2020, at an average age of 22.2 years, 113 participants (0.74%, 95% confidence interval [CI] = 0.61-0.89) had a register-based diagnosis of IBD, corresponding to an incidence of 31.3 per 100,000 person-years of follow-up; the incidence for Crohn's disease (CD) was 11.1 per 100,000 person-years and 15.8 for ulcerative colitis (UC). Of 77 participants with a register-based definition of IBD by the end of 2017, medical records were identified for 61 participants, of whom 57 had true IBD (PPV = 93%; 95%CI = 0.87-1.00). While oral 5-aminosalicylic acid treatment was equally common in newly diagnosed CD and UC patients, biologics were more often used for newly diagnosed CD. The median faecal calprotectin levels were 1206 mg/kg at diagnosis and 93 mg/kg at the last follow-up (P < 0.001)., Conclusions: In this population-based sample of Swedish children and young adults the cumulative IBD incidence was 0.74. The validity of register-based definition of IBD was high and supports using such data to identify IBD patients in cohort studies., (© 2023. The Author(s).)

During the past 3 years, the coronavirus disease 2019 (COVID-19) pandemic has had a great impact on people all over the world. However, it has become evident that disease manifestations and severity differ across age groups. Most children have a milder disease course than adults but possibly more pronounced gastrointestinal (GI) symptoms. Given the child's developing immune system, the impact of COVID-19 on disease development may differ compared to adults. This study reviews the potential bi-directional relationship between COVID-19 and GI diseases in children, focusing on common pediatric conditions such as functional GI disorders (FGID), celiac disease (CeD), and inflammatory bowel disease (IBD). Children with GI diseases, in general, and CeD and IBD, in particular, do not seem to have an increased risk of severe COVID-19, including risks of hospitalization, critical care need, and death. While infections are considered candidate environmental factors in both CeD and IBD pathogenesis, and specific infectious agents are known triggers for FGID, there is still not sufficient evidence to implicate COVID-19 in the development of either of these diseases. However, given the scarcity of data and the possible latency period between environmental triggers and disease development, future investigations in this field are warranted., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Aim: To examine the clinical follow up of paediatric coeliac disease and the rate of loss of follow up during childhood, for which data are scarce., Methods: In a cohort of coeliac children diagnosed in 2013-2018 in Gothenburg, Sweden, we retrospectively explored the follow-up practice of paediatric coeliac disease until June 2021. We used medical records from hospital-based paediatric gastroenterology and general paediatric outpatient clinics, laboratory records, and questionnaires. Loss of follow up was defined no coeliac disease-related follow up or tissue transglutaminase test over the past 2 years of study enrolment., Results: We included 162 children (58% girls) aged 7.8-18.2 years (average 12.7). Most participants (76%) were followed at general paediatric outpatient clinics rather than hospital-based clinics. After 2.3-8.8 (average 5.3) years since diagnosis, 23 patients (14%; 95% confidence interval, 9%-21%) had been lost to follow up. Patients with loss of follow up were more often boys (61% versus 39%, p = 0.08), with a somewhat longer average disease duration of 5.8 versus 5.2 years (p = 0.11). There were no between-group differences in socio-economic characteristics and patient-reported experience measures of coeliac disease care., Conclusion: One in seven coeliac patients may experience loss of follow up during childhood., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aims: To examine the use of proton pump inhibitors (PPIs) in Scandinavian children with focus on the geographical variation, temporal changes and possible contributing factors to observed changes., Methods: An observational population-based study of children and adolescents (1-17 years) in Norway, Sweden, and Denmark during the period 2007-2020. Information concerning dispensed PPIs was obtained from the national prescription databases of each country and presented as means per 1,000 children for each country and calendar year in four age categories (1-4, 5-9, 10-13 and 14-17 years)., Results: In 2007, the PPI use in children was similar across Scandinavian countries. An increased PPI use was observed in all countries during the study period, with gradually increasing differences between the countries. In general, Norway showed both the largest total increase and the largest increase in each age category compared to Sweden and Denmark. In 2020 Norwegian children showed, on average, a 59% higher PPI use compared to Swedish children and a more than double the overall dispensation rate than Denmark. In Denmark there was a 19% reduction in dispensed PPIs from 2015 to 2020., Conclusion: Despite being countries with similar health care systems and without indications of increased incidence of gastroesophageal reflux disease (GERD), we observed considerable geographical variation and temporal changes of PPI use in children. Although this study did not contain data on the indication for PPI use, these large differences across countries and time may indicate a current overtreatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Closs, Mårild, Nielsen and Størdal.)

Background: Inflammatory bowel disease (IBD) has been linked to adverse pregnancy outcomes, but it is unclear how risks vary by histological activity., Methods: We performed a nationwide study of Swedish women diagnosed with IBD 1990-2016 and a pre-pregnancy (<12 months) colorectal biopsy with vs. without histological inflammation (1223 and 630 births, respectively). We also examined pregnancy outcomes in 2007-2016 of women with vs. without clinically active IBD (i.e., IBD-related hospitalization, surgery, or medication escalation) <12 months before pregnancy (2110 and 4993 births, respectively). Accounting for smoking, socio-demographics, and comorbidities, generalized linear models estimated adjusted risk ratios (aRRs) for preterm birth (<37 gestational weeks) and small-for-gestational age (SGA, <10th percentile weight for age)., Findings: Of infants to women with vs. without histological inflammation, 9.6% (n = 117) and 6.5% (n = 41) were preterm, respectively (aRR = 1.46; 95%CI = 1.03-2.06). Histological inflammation was associated with preterm birth in ulcerative colitis (UC) (aRR = 1.64; 95%CI = 1.07-2.52), especially extensive colitis (aRR = 2.37; 95%CI = 1.12-5.02), but not in Crohn's disease (aRR = 0.99; 95%CI = 0.55-1.78). Of infants to women with vs. without histological inflammation, 116 (9.6%) and 56 (8.9%), respectively, were SGA (aRR = 1.09; 95%CI = 0.81-1.47). Clinically active disease before pregnancy was linked to preterm birth (aRR = 1.42; 95%CI = 1.20-1.69), but not to SGA birth (aRR = 1.13; 95%CI = 0.96-1.32). Finally, of infants to women without clinical activity, histological inflammation was not significantly associated with preterm birth (aRR = 1.20; 95%CI = 0.68-2.13)., Interpretation: Histological and clinical activity in IBD, especially in UC, were risk factors for preterm birth. Further research is needed to determine the importance of pre-pregnancy histological activity in women without clinically-defined disease activity., Funding: The Swedish Society of Medicine., Competing Interests: Dr Ludvigsson has coordinated an unrelated study on behalf of the Swedish Quality Registry for IBD (SWIBREG). That study received funding from the Janssen corporation. Dr Olén has been PI for projects (unrelated to the current paper) at Karolinska Institutet financed by Janssen, Takeda, AbbVie, Ferring, and Pfizer grants. Karolinska Institutet has received fees for lectures (OO) and participation on advisory boards (OO) from Janssen, Ferring, Bristol Myers Squibb, Galapagos, and Takeda. Dr Halfvarson has served as a speaker or advisory board member for AbbVie, Celgene, Celltrion, Dr. Falk Pharma and the Falk Foundation, Ferring, Galapagos, Gilead, Hospira, Janssen, MEDA, Medivir, MSD, Novartis, Olink Proteomics, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, ThermoFisher Scientific, Tillotts Pharma, Vifor Pharma, and UCB. He has also received grant support from Janssen, MSD, and Takeda. Dr Axelrad has received research grants from BioFire Diagnostics; consultancy fees or honorarium from BioFire Diagnostics, Abbvie, Pfizer, and Janssen; and holds U.S. patent 2012/0052124A1. Dr. Bröms has participated in projects at Karolinska Institutet financed by grants from Janssen, Pfizer, and UCB. Lecturer for Takeda. Dr Marsal has served as a speaker, consultant, or advisory board member for AbbVie, Bayer, Bristol-Myers Squibb, Hospira, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, and Union Chimique Belge and has received grant support from AbbVie, Calpro AS, Fresenius Kabi, Pfizer, SVAR Life Science, and Takeda. The other authors report no conflicts of interest., (© 2022 The Author(s).)

Aim: There is weak evidence that proton pump inhibitors (PPIs) alleviate non-specific complaints often attributed to gastroesophageal reflux in infancy and international guidelines do not recommend their use. We studied PPIs dispensed for infants in three Nordic countries., Methods: This was an observational population-based study of infants living in Norway, Sweden and Denmark in 2007-2020. We used nationwide pharmaceutical registers to study dispensed PPIs. The data provided a total of 3.3 million observed years on about 240 000 annual births., Results: The overall use of PPIs in infancy showed a marked increase in all three countries from 2007 to 2020. In 2020, PPI dispensing was 46.4, 23.4 and 18.9 per 1000 per year in infants aged 0-11 months in Denmark, Norway and Sweden. These were increases of 357%, 585% and 556% respectively. Although the rate was highest in Denmark, it had decreased by 42% in the last 3 years of the study., Conclusion: Despite international recommendations against routine PPI prescribing in infancy, dispensed PPIs increased more than fourfold on average in three Nordic countries from 2007 to 2020. The reason for this notable increase could not be established from the data, but the large variations over time, and between the countries, probably indicated unwarranted use., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: Patients with celiac disease (CD) have an increased risk of encapsulated bacterial infections. Less is known about other serious infections in CD, especially in patients diagnosed in the 21st century., Methods: We contacted all 28 pathology departments in Sweden through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort study and identified 20,088 individuals with CD (defined as villous atrophy) diagnosed in 2002-2017. Patients were matched for sex, age, and calendar year to 80,152 general population comparators and followed up until December 31, 2019. Serious infections were defined as having a hospital-based (inpatient and outpatient) diagnosis in the National Patient Register. Cox regression yielded adjusted hazard ratios (aHR) controlling for education, country of birth, and comorbidities., Results: During 173,695 person-years of follow-up, 6,167 individuals with CD (35.5/1,000 person-years) had a serious infection. This was compared with 19,131 infections during 743,260 person-years (25.7/1,000 person-years) in matched comparators, corresponding to an aHR of 1.29 (95% confidence interval [CI] = 1.25-1.33). aHR were similar when restricted to infection requiring hospital admission (1.23; 95% CI = 1.17-1.29). The excess risk of serious infections also persisted beyond the first year after CD diagnosis (aHR = 1.24; 95% CI = 1.20-1.29). Patients with CD were at risk of sepsis (aHR = 1.26; 95% CI = 1.09-1.45) and gastrointestinal infections (1.60; 95% CI = 1.47-1.74). Mucosal healing during CD follow-up did not influence the risk of subsequent serious infections., Discussion: This nationwide study of patients with celiac disease diagnosed in the 21st century revealed a significantly increased risk of serious infections. While absolute risks were modest, vaccinations should be considered during CD follow-up care., (Copyright © 2022 by The American College of Gastroenterology.)

Objectives: To gather the current evidence and to offer recommendations for follow-up and management., Methods: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%., Results: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care., Conclusions: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management., Competing Interests: Mearin received receipt of grants/research supports from Research Grant Eurospital, ThermoFisher and BioHit and served as member of advisory board and consultancy and speaker from ThermoFisher. Agardh received receipt of grants/research supports from Novo Nordisk Foundation and served as member of advisory board from Takeda and ThermoFischer. Antunes received receipt of payment/honorarium for lectures from Danone, Catassi received receipt of payment/honorarium for consultation from Dr Schar Food. Dolinsek received receipt of payment/honorarium for lectures from Medis, Abbot, Merit. Guandalini served as member of advisory board from ExeGIPharma, Imaware. Koletzko received receipt of grants/research supports from Mead-Johnson, Biogaia; served as member of advisory board from Abbvie, Danone, Jannsen, Sanofi, Takeda; receipt of payment/honorarium for lectures from Danone, Mead-Johnson, Nestlé Nutrition, Pfizer, Takeda; receipt of payment/honorarium for consultation from Danone. Korponay-Szabó other support from patent on celiac disease rapid test licensed to Labsystems Oy, Vantaa, Finland. Kurppa received receipt of grants/research supports from Finnish Pediatric Foundation, Päivikki, and Sakari Sohlberg Foundation; served as member of advisory board from Finnish Coeliac Society; receipt of payment/honorarium for lectures from Thermo Fisher; and receipt of payment/honorarium for consultation from Takeda. Rodriguez-Herrera received other support from Patent and detecting gluten peptides in human fluids, March 29, 2019—Universidad de Sevilla. Shamir received receipt of grants/research supports from Helmsley Foundation; served as member of advisory board: Nestle Nutrition Institute, Teva; receipt of payment/honorarium for lectures from Abbott, Nutricia, Nestle Nutrition Institute; receipt of payment/honorarium for consultation from Abbott, Else, Nutricia, Nestle Nutrition Institute and Stock shareholder from NGS. Ciacci received receipt of honoraria or consultation fees from Takeda, GSK, Mediserve, Biogen Celltrion. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: To determine the risk of inflammatory bowel disease (IBD) in patients with celiac disease (CeD) (and vice versa ) compared with general-population comparators., Methods: Using Swedish histopathology and healthcare register data, we identified 48,551 patients with CeD and 83,529 with IBD diagnosed in 1969-2016. Each patient was compared with age- and sex-matched general-population comparators (CeD: n = 240,136; IBD: n = 408,195). Cox regression estimated hazard ratios (HRs) for IBD in patients with CeD and vice versa . Our main analyses were limited to events beyond the first year of follow-up to reduce potential surveillance bias., Results: During follow-up, 784 (1.6%) patients with CeD were diagnosed with IBD compared with 1,015 (0.4%) matched comparators. In patients with CeD, the HR for IBD was 3.91 (95% confidence interval [CI] 3.56-4.31), with largely similar HRs for Crohn's disease (4.36; 3.72-5.11) and ulcerative colitis (3.40; 3.00-3.85). During follow-up, 644 (0.8%) patients with IBD and 597 (0.1%) comparators were diagnosed with CeD. The HR for CeD in patients with IBD was 5.49 (95% CI 4.90-6.16), with the highest risk estimates seen in ulcerative colitis (HR = 6.99; 6.07-8.05), and the HR for Crohn's disease was 3.31 (2.69-4.06). In patients with CeD and IBD, the diagnostic interval was usually &lt;1 year; however, HRs of 3-4 were seen even after 10 years of follow-up. During 20 years of follow-up, 2.5% of patients with CeD developed incident IBD, and 1.3% of patients with IBD developed CeD., Discussion: The bidirectional association between CeD diagnosis and IBD warrants attention in the initial assessment and follow-up of these conditions. Their co-occurrence, independent of temporal sequence, suggests shared etiology., (Copyright © 2022 by The American College of Gastroenterology.)

Objectives: Celiac disease (CD) is a common yet largely underdiagnosed disease. This study aimed to test the feasibility of incorporating a non-targeted CD screening in a pediatric outpatient setting and evaluate its short-term impact on children with serological evidence of disease., Methods: Over five months, 500 children (aged 2-17 years) attending a general pediatric outpatient clinic in Gothenburg, Sweden, were enrolled and surveyed for current symptoms, quality of life, and background characteristics; 481 children were screened for tissue-transglutaminase antibodies (tTGA); repeated tTGA-positivity was defined as CD autoimmunity (CDA). Children with CDA were investigated for CD and for one year monitored for changes in symptoms, and quality of life., Results: Eleven of 481 (2.3%) screened children had CDA. Children with CDA were younger (median 3.8 years) than those without CDA (8.8 years). No other major between-group differences were reported in background characteristics, symptoms, or quality of life. The screening was well-accepted by the families/participants. During 1-year follow-up, 8 of 11 children with CDA were diagnosed with CD. Children with screening-detected CD reported no significant changes in symptoms and quality of life and the dietary adherence rate was good., Conclusions: Non-targeted screening for CD was feasible in a general pediatric outpatient setting. While hampered by small sample size, our results are in line with previous screening studies indicating that symptoms do not differentiate CDA from non-CDA children. Also, among an overall minimal-symptomatic group of children, diagnosing CD and installation of treatment did not significantly change their well-being during 1-year follow-up.

Objectives: To systematically review the literature on the utilization and effectiveness of electronic-health technologies (eHealth), such as smartphone applications, in managing patients with celiac disease (CD)., Methods: PubMed, Scopus, and the Cochrane Library were all searched (until February 2021). Inclusion criteria were full-text English articles reporting original data on the use of eHealth technologies in the follow-up of CD patients, with no age restriction. Exclusion criteria were studies only using non-interactive websites and phone consultation as the primary eHealth method. The results were summarized narratively., Results: Using identified keywords, 926 unique studies were identified. After title and abstract screening by two independent reviewers, 26 studies were reviewed in full text. Finally, eight studies were included in this systematic review, and their quality appraised using standardized forms. Of the eight studies, six were randomized-controlled trials, one mixed-methods study, and one cross-sectional, observational study. Studies were assessed to be of "low" to "moderate" methodological quality. Studied eHealth technologies included web-based interventions, smartphone applications, text messaging, and online consultations. The most consistently reported effects related to improved quality of life (number of studies = 4), knowledge on CD (n = 3), and dietary adherence (n = 2); notably, only one study reported reduced costs of eHealth vs. standard (in-office) care., Conclusions: Although eHealth has the potential to improve the management of CD, so far, the research in the field is scarce and generally of low-moderate methodological quality. Hence, the effectiveness of eHealth in CD management remains uncertain, and more high-quality evidence is required before its utility is known., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background & Aims: Celiac disease (CD) affects around 1% of the population worldwide. Data on work disability in patients with CD remain scarce. We estimated work loss in patients with CD, including its temporal relationship to diagnosis., Methods: Through biopsy reports from Sweden's 28 pathology departments, we identified 16,005 working-aged patients with prevalent CD (villus atrophy) as of January 1, 2015, and 4936 incident patients diagnosed with CD in 2008 to 2015. Each patient was matched to up to 5 general-population comparators. Using nationwide social insurance registers, we retrieved prospectively recorded data on compensation for sick leave and disability leave to assess work loss in patients and comparators., Results: In 2015, patients with prevalent CD had a mean of 42.5 lost work days as compared with 28.6 in comparators (mean difference, 14.7; 95% confidence interval [CI], 13.2-16.2), corresponding to a relative increase of 49%. More than one-half of the work loss (60.1%) in patients with CD was derived from a small subgroup (7%), whereas 75.4% had no work loss. Among incident patients, the annual mean difference between patients and comparators was 8.0 days (range, 5.4-10.6 days) of lost work 5 years before CD diagnosis, which grew to 13.7 days (range, 9.1-18.3 days) 5 years after diagnosis. No difference in work loss was observed between patients with or without mucosal healing at follow-up., Conclusions: Patients with CD lost more work days than comparators before their diagnosis, and this loss increased after diagnosis. Identifying patients with an increased risk of work loss may serve as a target to mitigate work disability, and thereby reduce work loss, in patients with CD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Coeliac disease is an immune-mediated condition characterized by chronic inflammation of the small bowel with villous atrophy driven by gluten ingestion in genetically predisposed individuals. It occurs frequently in both children and adults, affecting 1-4% of the population. The disease is associated with both gastrointestinal and extra-intestinal symptoms related to malabsorption and/or immune activation, and autoantibodies to tissue transglutaminase. Removal of gluten from the diet results in resolution of symptoms and enteropathy in the majority of patients. A good diagnostic work-up is important to avoid unnecessary restrictive diets in children. In this review on pediatric coeliac disease, we address epidemiology including predisposing environmental factors and possible preventive strategies, as well as the clinical presentation, diagnosis and follow-up. What is Known: •Primary prevention of coeliac disease is not possible; however, secondary prevention by targeting high-risk groups is recommended. •The diagnosis is safe without duodenal biopsies if specific conditions are met, also in asymptomatic children. What is New: •HLA-DQ typing is not routinely required for the diagnosis, whereas it can rule out coeliac disease if HLA-DQ2 and HLA-DQ8 are absent. •Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance and quality of life., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Coeliac disease (CD) is one of the most common chronic diseases of childhood. Follow-up of CD aims to ensure dietary adherence and prevent disease complications, but there are few real-world data on how its management in children is conducted. This study aimed to survey the follow-up practice of pediatric CD in Western Sweden. Two web-based surveys were distributed to all 22 pediatric outpatient clinics rendering answers from 48 physicians and 12 dietitians. Overall, clinical practice was similar throughout the region and in line with national and international CD guidelines, including an annual to biannually follow-up frequency and dietary adherence assessment through unstructured interviewing and serology measurements. The study identified possible areas of improvement, such as implementing a formal transition process to adult care and the use of validated questionaries to assess dietary adherence. Additionally, a positive attitude towards electronic-health technologies (eHealth) as part of CD follow-up was identified., Competing Interests: The study was supported by a grant to investigator K.M. from the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement (ALFGBG-771121). The funders had no role in the design and conduct of the study or in the management, analysis, and interpretation of the data. The remaining authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background & Aims: Celiac disease (CD) is associated with increased mortality, in part due to cancer. Most studies investigating this cancer risk involved patients diagnosed before widespread increases in CD diagnosis rates and access to gluten-free food. We performed a population-based study of the risk of cancer in CD., Methods: We identified all patients in Sweden with CD as defined as duodenal/jejunal villus atrophy, using the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. Each patient was matched to ≤5 controls by age, sex, and county. We used stratified Cox proportional hazards model, following patients from diagnosis until first cancer, or by December 31, 2016., Results: Among 47,241 patients with CD, 30,080 (64%) were diagnosed since 2000. After a median follow-up of 11.5 years, the incidence of cancer was 6.5 and 5.7 per 1000 person-years in CD patients and controls, respectively. The overall risk of cancer was increased (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.07-1.15), but it was only significantly elevated in the first year after CD diagnosis (HR, 2.47; 95% CI, 2.22-2.74) and not subsequently (HR, 1.01; 95% CI, 0.97-1.05), although the risks of hematologic, lymphoproliferative, hepatobiliary, and pancreatic cancers persisted. The overall risk was highest in those diagnosed with CD after age 60 years (HR, 1.22; 95% CI, 1.16-1.29) and was not increased in those diagnosed before age 40. The cancer risk was similar among those diagnosed with CD before or after the year 2000., Conclusions: There is an increased risk of cancer in CD even in recent years, but this risk increase is confined to those diagnosed with CD after age 40 and is primarily present within the first year of diagnosis., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: To test whether parechovirus and anellovirus, frequent enteric viruses, were associated with subsequent celiac disease (CD). We hypothesized that children who later developed CD would have increased frequency of parechovirus infections before transglutaminase 2 (TG2) antibody development. Anellovirus testing was exploratory, as a potential marker of immune status., Methods: Matched case-control design nested within a longitudinal birth cohort (the MIDIA study) of children at genetic risk of CD (carrying the human leukocyte antigen genotype DR4-DQ8/DR3-DQ2, recruited throughout Norway during 2001-2007). We retrospectively tested blood samples taken at age 3, 6, 9, and 12 months, and then annually, to determine when TG2 antibodies developed. Of 220 genetically at-risk children tested, 25 were diagnosed with CD (cases; ESPGHAN 2012 criteria) and matched for follow-up time, birthdate, and county of residence with 2 randomly selected children free from CD (controls) from the cohort. Viruses were quantified in monthly stool samples (collected from 3 through 35 months of age) using real-time polymerase chain reaction methods., Results: Parechovirus was detected in 222 of 2,005 stool samples (11.1%) and was more frequent in samples from cases before developing TG2 antibodies (adjusted odds ratio 1.67, 95% confidence interval 1.14-2.45, P = 0.01). The odds ratio was higher when a sample was positive for both parechovirus and enterovirus (adjusted odds ratio 4.73, 95% confidence interval 1.26-17.67, P = 0.02). Anellovirus was detected in 1,540 of 1,829 samples (84.2%), but did not differ significantly between case and control subjects., Discussion: Early-life parechovirus infections were associated with development of CD in genetically at-risk children.

Objectives: To determine the association between childhood growth prior to the development of celiac disease (CD) and CD autoimmunity (CDA) identified by periodic serological screening., Study Design: The Diabetes Autoimmunity Study in the Young cohort includes 1979 genetically at-risk children from Denver, Colorado, with annual growth measurements from age nine months until ten years. Between 1993 and February 2019, 120 children developed CDA defined by persistent positive tissue transglutaminase autoantibodies (TGA); among these, 71 met our criteria for CD based on histopathological findings or high TGA levels. Age- and sex-specific z -scores of weight, body mass index (BMI), and height prior to seroconversion were derived using US reference charts as standards. Joint modeling of serial growth measurements was used to estimate adjusted hazard ratios (aHRs) accounting for celiac-associated human leukocyte antigens, early-life feeding practices, and socio-demographics., Results: In the first 10 years of life, there were no significant associations between the child's current weight, BMI and height and the risk of screening-detected CDA or CD, neither was the weight nor BMI velocity associated with CDA or CD as identified by screening (all aHRs approximated 1). Increased height velocity was associated with later CD, but not CDA, development (aHR per 0.01- z score/year, 1.28; 95% confidence interval [CI] 1.18-1.38 and 1.03; 0.97-1.09, respectively)., Conclusions: In the first 10 years of life, from prospectively collected serial growth measurements, we found no evidence of impaired childhood growth before CD and CDA development as identified through early and periodic screening.

Maternal diet can influence the developing immune system of the offspring. We hypothesized that maternal fibre and gluten intake during pregnancy were associated with the risk of celiac disease in the child. In the Norwegian Mother, Father and Child Cohort Study (MoBa, n = 85,898) higher maternal fibre intake (median 29.5 g/day) was associated with a lower risk of celiac disease in the offspring (adjusted relative risk 0.90, 95% CI 0.83 to 0.98 per 10 g/d increase). Gluten intake during pregnancy (median 13.0 g/d) was associated with a higher risk of childhood CD (adjusted relative risk = 1.21, 95% CI 1.02 to 1.43 per 10 g/d increase). These results were largely unaffected by adjustment for the child's gluten intake at 18 months. In an independent study of 149 mother/child dyads, maternal fibre intake did not predict concentrations of total or sub-types of short-chain fatty acids in repeated infant stool samples, or fecal microbiome diversity in the mother or child. Our results suggest that high fibre and low gluten intake during pregnancy could be protective factors for celiac disease, although the mechanism is unknown.

Objectives: During pregnancy, small quantities of maternal cells are naturally transmitted to the fetus. This transmission, termed maternal microchimerism (MMc), has been implicated in autoimmune diseases but its potential role is unclear. We aimed to investigate if MMc at birth predicted childhood celiac disease (CD) risk, a common immune-mediated enteropathy often presenting in childhood., Methods: We designed a case-control study, nested in the Norwegian Mother, Father and Child Cohort. Participants were HLA class II typed to determine noninherited, nonshared maternal alleles (NIMA). Droplet digital (dd) PCR assays specific for common HLA class II NIMAs (HLA-DQB103:01, 04:02 and 06:02/03) were used to estimate the quantity of maternal DNA, as a marker of maternal cells, in cord blood DNA from 124 children who later developed clinically diagnosed CD (median age at end of study 7.4 years, range 3.6-12.9) and 124 random controls. We tested whether presence of MMc was associated with CD using logistic regression, and compared ranks between cases and controls., Results: MMc, for example, maternal HLA antigens not inherited by the child, was found in 42% of cases and 43% of controls, and not associated with CD (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.58-1.60). The ranks of MMc quantities in cases and controls were also similar (Mann-Whitney U-test, P = 0.71). The subgroup with HLA-DQB1:03*01 as their NIMA had a potential association with MMc, where levels greater than median was associated with CD (OR 3.78, 95% CI 1.28-11.18)., Conclusion: MMc measured in cord blood was not associated with later risk of CD.

Introduction: Celiac disease (CD) affects 1% of the population. Its effect on healthcare cost, however, is barely understood. We estimated healthcare use and cost in CD, including their temporal relationship to diagnosis., Methods: Through biopsy reports from Sweden's 28 pathology departments, we identified 40,951 prevalent patients with CD (villous atrophy) as of January 1, 2015, and 15,086 incident patients with CD diagnosed in 2008-2015, including 2,663 who underwent a follow-up biopsy to document mucosal healing. Each patient was compared with age- and sex-matched general population comparators (n = 187,542). Using nationwide health registers, we retrieved data on all inpatient and nonprimary outpatient care, prescribed diets, and drugs., Results: Compared with comparators, healthcare costs in 2015 were, on average, $1,075 (95% confidence interval, $864-1,278) higher in prevalent patients with CD aged <18 years, $715 ($632-803) in ages 18-64 years, and $1,010 ($799-1,230) in ages ≥65 years. Half of all costs were attributed to 5% of the prevalent patients. Annual healthcare costs were $391 higher 5 years before diagnosis and increased until 1 year after diagnosis; costs then declined but remained 75% higher than those of comparators 5 years postdiagnosis (annual difference = $1,044). Although hospitalizations, nonprimary outpatient visits, and medication use were all more common with CD, excess costs were largely unrelated to the prescription of gluten-free staples and follow-up visits for CD. Mucosal healing in CD did not reduce the healthcare costs., Discussion: The use and costs of health care are increased in CD, not only before, but for years after diagnosis. Mucosal healing does not seem to lower the healthcare costs.

There are few longitudinal data on whether childhood growth and pubertal timing may be impaired by adult-diagnosed celiac disease (CD). Through school health care records and national registers, we retrieved serial growth measurements on 37,672 Swedish boys born in 1945 to 1961, out of whom 72 (0.2%) were clinically diagnosed with CD as adults. Boys with, versus without, adult-diagnosed CD exhibited no appreciable mean differences in body mass index (BMI, kg/m) and height (cm) at ages 8 or 20 to 21 years (childhood BMI, 15.9 [CD] vs 15.7 [comparators]; childhood height, 129.1 [CD] vs 128.6 [comparators]; adult BMI, 21.3 [CD] vs 21.4 [comparators]; adult height, 180.7 [CD] vs 180.4 [comparators]). Neither did we observe any between-group differences in growth development during puberty nor in the timing of pubertal growth spurt (all P values ≥0.30). Conclusively, in this population-based longitudinal study, boys with adult-diagnosed CD had similar growth and pubertal timing as their peers.

Background: The relationship between maternal gluten intake in pregnancy, offspring intake in childhood, and offspring risk of type 1 diabetes has not been examined jointly in any studies. Our aim was to study the relationship between maternal and child intake of gluten and risk of type 1 diabetes in children., Methods and Findings: We included 86,306 children in an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), with recruitment from 1999 to 2008 and with follow-up time to April 15, 2018. We used registration of type 1 diabetes in the Norwegian childhood diabetes registry as the outcome. We used Cox proportional hazard regression to estimate hazard ratios (HRs) for the mother's intake of gluten up to week 22 of pregnancy and offspring gluten intake when the child was 18 months old. The average time followed was 12.3 years (0.70-16.0). A total of 346 children (0.4%) children were diagnosed with type 1 diabetes, resulting in an incidence rate of 32.6/100,000 person-years. Mean gluten intake per day was 13.6 g for mothers and 8.8 g for children. There was no association between the mother's intake of gluten in pregnancy and offspring type 1 diabetes, with an adjusted HR (aHR) of 1.02 (95% confidence interval [CI] 0.73-1.43, p = 0.91) for each 10-g-per-day increment. There was an association between offspring intake of gluten and a higher risk of type 1 diabetes, with an aHR of 1.46 (95% CI 1.06-2.01, p = 0.02) for each 10-g-per-day increment. Among the limitations are the likely imprecision in estimation of gluten intake and that we only had information regarding gluten intake at 2 time points in early life., Conclusions: Our results show that, while the mother's intake of gluten in pregnancy was not associated with type 1 diabetes, a higher intake of gluten by the child at an early age may give a higher risk of type 1 diabetes., Competing Interests: The authors have declared that no competing interests exist.

Background: Maternal microchimerism (MMc), the transmission of small quantities of maternal cells to the fetus, is relatively common and persistent. MMc has been detected with increased frequency in the circulation and pancreas of type 1 diabetes (T1D) patients. We investigated for the first time whether MMc levels at birth predict future T1D risk. We also tested whether cord blood MMc predicted MMc in samples taken at T1D diagnosis., Methods: Participants in the Norwegian Mother and Child Cohort study were human leukocyte antigen (HLA) class II typed to determine non-inherited, non-shared maternal alleles (NIMA). Droplet digital (dd) polymerase chain reaction (PCR) assays specific for common HLA class II NIMA (HLADQB1*03:01, *04:02, and *06:02/03) were developed and validated. MMc was estimated as maternal DNA quantity in the fetal circulation, by NIMA specific ddPCR, measured in cord blood DNA from 71 children who later developed T1D and 126 controls within the cohort., Results: We found detectable quantities of MMc in 34/71 future T1D cases (48%) and 53/126 controls (42%) (adjusted odds ratio [aOR] 1.27, 95% confidence interval (CI) 0.68-2.36), and no significant difference in ranks of MMc quantities between cases and controls (Mann-Whitney P = .46). There was a possible association in the NIMA HLA-DQB1*03:01 subgroup with later T1D (aOR 3.89, 95%CI 1.05-14.4). MMc in cord blood was not significantly associated with MMc at T1D diagnosis., Conclusions: Our findings did not support the hypothesis that the degree of MMc in cord blood predict T1D risk. The potential subgroup association with T1D risk should be replicated in a larger cohort., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To determine the association between the amount of gluten intake in childhood and later celiac disease (CD), for which data are currently scarce., Methods: The prospective Diabetes Autoimmunity Study in the Young cohort includes 1875 at-risk children with annual estimates of gluten intake (grams/d) from age 1 year. From 1993 through January 2017, 161 children, using repeated tissue transglutaminase (tTGA) screening, were identified with CD autoimmunity (CDA) and persistent tTGA positivity; of these children, 85 fulfilled CD criteria of biopsy-verified histopathology or persistently high tTGA levels. Cox regression, modeling gluten intake between ages 1 and 2 years (i.e., in 1-year-olds), and joint modeling of cumulative gluten intake throughout childhood were used to estimate hazard ratios adjusted for confounders (aHR)., Results: Children in the highest third of gluten intake between the ages of 1 and 2 years had a 2-fold greater hazard of CDA (aHR 2.17; 95% confidence interval [CI], 1.22-3.88; P value = 0.01) and CD (aHR 1.96; 95% CI, 0.90-4.24; P value = 0.09) than those in the lowest third. The risk of developing CDA increased by 5% per daily gram increase in gluten intake (aHR 1.05; 95% CI, 1.00-1.09; P value = 0.04) in 1-year-olds. The association between gluten intake in 1-year-olds and later CDA or CD did not differ by the child's human leukocyte antigen genotype. The incidence of CD increased with increased cumulative gluten intake throughout childhood (e.g., aHR 1.15 per SD increase in cumulative gluten intake at age 6; 95% CI, 1.00-1.32; P value = 0.04)., Discussion: Gluten intake in 1-year-olds is associated with the future onset of CDA and CD in children at risk for the disease.