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Psychiatric Disorders in Patients With a Diagnosis of Celiac Disease During Childhood From 1973 to 2016

  • Benjamin Lebwohl
    Affiliations
    Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York

    Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
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  • Linnea Haggård
    Affiliations
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Louise Emilsson
    Affiliations
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway

    Vårdcentralen Årjäng, Centre for Clinical Research, County Council of Värmland, Värmland, Sweden

    Faculty of Medicine and Health, Örebro, Sweden
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  • Jonas Söderling
    Affiliations
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Bjorn Roelstraete
    Affiliations
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Agnieszka Butwicka
    Affiliations
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Stockholm, Sweden

    Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland
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  • Peter H.R. Green
    Affiliations
    Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York
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  • Jonas F. Ludvigsson
    Correspondence
    Reprint requests Address requests for reprints to: Jonas F. Ludvigsson, MD, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; fax: (49) 19-187915.
    Affiliations
    Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York

    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden
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Open AccessPublished:August 11, 2020DOI:https://doi.org/10.1016/j.cgh.2020.08.018

      Background & Aims

      Few studies have explored the link between childhood celiac disease and long-term psychiatric comorbidities. We performed a population-based cohort study of associations between childhood celiac disease and psychiatric disorders and investigated whether risk persists into adulthood.

      Methods

      We performed a nationwide study in Sweden using data from the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. In this cohort, 19,186 children with a diagnosis of biopsy-verified celiac disease from 1973 through 2016 were identified from Sweden’s 28 pathology departments. Each patient was matched with as many as 5 reference children (controls, n = 94,249). Data on psychiatric disorders were obtained from the patient register. We used Cox proportional modeling to estimate hazard ratios (HRs).

      Results

      During a median follow-up period of 12.3 years, 3174 children (16.5%) with celiac disease received a new diagnosis of a psychiatric disorder, compared with 13,286 controls (14.1%). Corresponding incidence rates were 12.2 per 1000 person-years (95% CI, 11.8–12.7) vs 10.3 per 1000 person-years (95% Cl, 10.2–10.5). Childhood celiac disease was associated with a 19% increase in risk of any psychiatric disorder (95% CI, 1.14–1.23); the increase in risk was observed in all childhood age groups. The highest HRs were seen in the first year after celiac diagnosis (HR, 1.70; 95% CI, 1.41–2.05). The risk increase persisted into adulthood (age, >18 y: HR, 1.11; 95% CI, 1.04–1.17). We found increased risks of mood disorders (HR, 1.20; 95% CI, 1.12–1.28), anxiety disorders (HR, 1.12; 95% CI, 1.06–1.19), eating disorders (HR, 1.34; 95% CI, 1.18–1.51), attention deficit hyperactivity disorder (HR, 1.29; 95% CI, 1.20–1.39), and autism spectrum disorder (HR, 1.47; 95% CI, 1.32–1.64). We found no statistically significant risk increase for psychotic disorders, psychoactive substance misuse, behavioral disorders, personality disorders, suicide attempt, or suicide. Celiac disease also was linked to an increased use of psychiatric drugs (HR, 1.34; 95% CI, 1.24–1.43). A conditional logistic regression found that psychiatric disorders also were more common before a diagnosis of celiac disease (odds ratio, 1.56; 95% CI, 1.39–1.76).

      Conclusions

      Childhood celiac disease is associated with an increased risk of subsequent psychiatric disorders, which persists into adulthood. Mental health surveillance should be integral in the care of celiac disease.

      Keywords

      Abbreviations used in this paper:

      ADHD (attention-deficit hyperactivity disorder), HR (hazard ratio), OR (odds ratio)

       Background

      Little is known about the association between childhood celiac disease and long-term psychiatric comorbidities.

       Findings

      A population-based study in Sweden found that childhood celiac disease is associated with a 19% increase in risk of subsequent psychiatric disorders, which persists into adulthood. Children with celiac disease have an increased risk of mood disorders, anxiety disorders, eating disorders, attention deficit hyperactivity disorder, and autism spectrum disorder.

       Implications for patient care

      Mental health surveillance should be integral in the care of celiac disease.
      In celiac disease, an immune-mediated enteropathy is triggered by intake of dietary gluten in genetically susceptible individuals. The prevalence is approximately 1% to 2% in Western populations
      • Ludvigsson J.F.
      • Leffler D.A.
      • Bai J.C.
      • et al.
      The Oslo definitions for coeliac disease and related terms.
      and 0.3% to 2.9% in children,
      • Ludvigsson J.F.
      • Green P.H.
      Clinical management of coeliac disease.
      with increasing rates in recent years.
      • Lebwohl B.
      • Sanders D.S.
      • Green P.H.R.
      Coeliac disease.
      In Europe, the highest prevalence is seen in Sweden and Finland, and lower rates are seen in Germany.
      • Mustalahti K.
      • Catassi C.
      • Reunanen A.
      • et al.
      for the Coeliac EU Cluster, Project Epidemiology. The prevalence of celiac disease in Europe: results of a centralized, international mass screening project.
      Several studies have described the wide range of extraintestinal manifestations in celiac disease such as fatigue,
      • Siniscalchi M.
      • Iovino P.
      • Tortora R.
      • et al.
      Fatigue in adult coeliac disease.
      neurologic conditions
      • Ludvigsson J.F.
      • Zingone F.
      • Tomson T.
      • et al.
      Increased risk of epilepsy in biopsy-verified celiac disease: a population-based cohort study.
      including headache and neuropathy,
      • Lionetti E.
      • Francavilla R.
      • Pavone P.
      • et al.
      The neurology of coeliac disease in childhood: what is the evidence? A systematic review and meta-analysis.
      but also psychiatric disorders.
      • Ludvigsson J.F.
      • Reutfors J.
      • Osby U.
      • et al.
      Coeliac disease and risk of mood disorders: a general population-based cohort study.
      A study from 2017 showed a 1.4-fold increased risk of developing a future psychiatric disorder in children with celiac disease compared with the general population.
      • Butwicka A.
      • Lichtenstein P.
      • Frisén L.
      • et al.
      Celiac disease is associated with childhood psychiatric disorders: a population-based study.
      However, that study did not specifically evaluate the risk of psychiatric disorder in adulthood. Although a few studies have reported an increased prevalence of neuropsychiatric disorders before a celiac disease diagnosis,
      • Pynnönen P.A.
      • Isometsä E.T.
      • Aronen E.T.
      • et al.
      Mental disorders in adolescents with celiac disease.
      ,
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      • Reichenberg A.
      • Hultman C.M.
      • et al.
      A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders.
      these generally lacked power to provide precise risk estimates.
      The aim of this study was to investigate the connection between a childhood diagnosis of celiac disease and later psychiatric morbidity including suicide, and to assess if any such risk increases persist into adulthood.

      Methods

       Celiac Disease

      The Epidemiology Strengthened by histoPathology Reports in Sweden cohort consists of 6.1 million gastrointestinal biopsy reports from 2.1 million individuals. Biopsy reports were classified according to the Systematized Nomenclature of Medicine Clinical Terms, and originated from 1965 to 2017 from Sweden’s 28 pathology departments. Data collection took place between October 12, 2015, and April 10, 2017.
      Through a computerized search of the Epidemiology Strengthened by histoPathology Reports in Sweden cohort (Supplementary Table 1 lists the topography codes equivalent to the duodenum and jejunum, and relevant Systematized Nomenclature of Medicine codes) we identified individuals with villus atrophy (Marsh III, in this study equivalent to celiac disease). An earlier patient chart validation found that 108 of 114 (95%) patients with villus atrophy had celiac disease.
      • Ludvigsson J.F.
      • Brandt L.
      • Montgomery S.M.
      • et al.
      Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers.
      Because that validation was performed on individuals who underwent a biopsy up until 2008, one of the authors (J.F.L.) re-reviewed the free text of 100 randomly selected biopsy reports with villus atrophy originating from 2009 to 2017. Of these, 98 had sufficient information to be validated, and 97 had celiac disease (positive predictive value, 99.0%; 1 patient had misclassified microscopic colitis; personal communication, March 23, 2020).
      Because our outcome measure was any psychiatric disorder, we restricted our study to patients diagnosed during the years spanning from 1973 (the onset of psychiatric diagnosis availability in the National Patient Register) through 2016, the latest availability of follow-up data.

       Reference Individuals

      For each individual with celiac disease, the government agency Statistics Sweden identified up to 5 reference individuals (n = 94,249) matched for age, sex, county, and calendar year from the Swedish Total Population Register.
      • Ludvigsson J.F.
      • Almqvist C.
      • Bonamy A.K.
      • et al.
      Registers of the Swedish total population and their use in medical research.
      None of the reference individuals had celiac disease at a matching date, and if they developed celiac disease their follow-up evaluation was censored at the date of diagnosis.

       Secondary reference individuals

      In a separate analysis we compared 13,015 individuals with celiac disease with their nonceliac siblings (n = 18,024). Sibling analyses takes shared intrafamilial confounding, including genetic and early environmental factors, into account.

       Outcomes

      Our primary outcome was any psychiatric disorder. Secondary outcomes were psychiatric disorders defined according to International Classification of Diseases codes (suicide attempts, psychotic disorders, mood disorders, anxiety disorders, psychoactive substance misuse, eating disorders, behavioral disorders, attention-deficit hyperactivity disorder [ADHD], autism spectrum disorders, and personality disorders), suicide, and suicide attempt (Supplementary Table 2). Psychiatric disorder data were obtained through the National Patient Register. For selected psychiatric disorders, this register has a positive predictive value of 85% to 95%.
      • Sellgren C.
      • Landén M.
      • Lichtenstein P.
      • et al.
      Validity of bipolar disorder hospital discharge diagnoses: file review and multiple register linkage in Sweden.
      ,
      • Rück Christian
      • Larsson K.J.
      • Lind K.
      • et al.
      Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register.
      Although data on suicide attempts were retrieved from the Patient Register, data on suicides were obtained from the Cause of Death Register. ADHD was defined as having a relevant ADHD medication in the Prescribed Drug Register.
      • Wettermark B.
      • Hammar N.
      • Fored C.M.
      • et al.
      The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months.

       Statistics

      We began follow-up evaluation on the date of celiac disease diagnosis (or corresponding date in the reference group). Follow-up evaluation ended with a psychiatric diagnosis/suicide, death, emigration, or December 31, 2016, whichever occurred first.
      Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% CIs for psychiatric disorders. Stratified analyses were performed according to years of follow-up evaluation (<1, 1 to <5, 5 to <10, 10 to <20, and ≥20 y), age at celiac disease diagnosis (<2, 2 to <6, 6 to <11, 11 to <16, and 16 to <18 y) sex, level of parental education (≤9, 10–12, and ≥13 y), and country of birth (Nordic, other). We repeated the analysis, restricting the outcome definition to patients with a prescription for a psychiatric drug in the Prescription Drug Register (Supplementary Table 3 contains a list of included drugs). Because the Prescribed Drug Register started on July 1, 2005, this sensitivity analysis was performed in celiac patients diagnosed from July 1, 2006, or later. In separate analyses we examined the risk of psychiatric disorders in patients with celiac disease vs siblings. In that study, only celiac individuals with a sibling (n = 13,015) were included. Given that persistent villus atrophy after a celiac disease diagnosis is associated with adverse outcomes including lymphoproliferative disease
      • Lebwohl B.
      • Granath F.
      • Ekbom A.
      • et al.
      Mucosal healing and risk for lymphoproliferative malignancy in celiac disease: a population-based cohort study.
      and osteoporotic fracture,
      • Lebwohl B.
      • Michaëlsson K.
      • Green P.H.
      • et al.
      Persistent mucosal damage and risk of fracture in celiac disease.
      we compared those children who had persistent villus atrophy with those whose villi healed in the subset of subjects who underwent a follow-up biopsy.
      We also explored the risk of psychiatric disorders in adulthood in patients diagnosed with celiac disease in childhood in an analysis restricted to patients who reached the age of adulthood (age, 18 y) during the follow-up evaluation. As a sensitivity analysis, we also evaluated this risk when including all patients, even those with a psychiatric diagnosis preceding the diagnosis of celiac disease or preceding age 18 years. To rule out that any association between celiac disease and psychiatric disorder was not caused by an underlying intellectual disability (triggering celiac testing and predisposing to a psychiatric disorder), we excluded anyone with a diagnosis of an intellectual disability in a sensitivity analysis.
      We used SAS v.9.4 (Cary, NC) and STATA v.16.0 (College Station, TX) for all statistical analyses.

       Ethics

      The current study was approved by the Stockholm Ethics Review Board (2014/1287-31/4) on August 27, 2014. The ethics review board did not require informed consent because this was strictly a register-based study.

      Results

      We identified 19,583 individuals with celiac disease diagnosed in childhood (age, <18 y) during the years spanning from 1973 to 2016. In the primary analysis, 397 were excluded because of a previous history of a psychiatric disorder. The remaining 19,186 patients were matched with 94,249 comparators without any history of a psychiatric disorder (Figure 1).
      Figure thumbnail gr1
      Figure 1Flow chart of identified patients and their matched comparators. ADHD, attention deficit hyperactivity disorder; SNOMED, Systematized Nomenclature of Medicine.

       Baseline Characteristics of the Main Study Cohort

      The mean age at the time of celiac disease diagnosis was 6.6 years (SD, 5.2 y) with almost 30% diagnosed at younger than 2 years of age (Table 1). Follow-up time ranged from 0 to 42 years, with a median follow-up time of 12.2 years in individuals with celiac disease.
      Table 1Baseline Characteristics of Study Cohort
      CharacteristicCeliac disease (n = 19,186)Matched comparators (n = 94,249)
      Girls, n (%)12,076 (62.9)59,358 (63.0)
      Boys, n (%)7110 (37.1)34,891 (37.0)
      Age at celiac disease diagnosis, y
       Mean (SD)6.6 (5.2)6.5 (5.2)
       Median (IQR)5.3 (1.7–10.9)5.2 (1.7–10.7)
       Range, minimum–maximum0.0–18.00.0–18.0
      Categories, n (%)
       <2 y5694 (29.7)27,579 (29.3)
       2 to <6 y4545 (23.7)23,460 (24.9)
       6 to <11 y4244 (22.1)20,944 (22.2)
       11 to <16 y3508 (18.3)17,025 (18.1)
       16 to <18 y1195 (6.2)5241 (5.6)
      Country of birth, n (%)
       Nordic country18,837 (98.2)90,009 (95.5)
       Other348 (1.8)4236 (4.5)
       Missing1 (0.0)4 (0.0)
      Highest attained level of education by parents, n (%)
       ≤9 y659 (3.4)4333 (4.6)
       10–12 y8371 (43.6)40,792 (43.3)
       >12 y10,136 (52.8)48,844 (51.8)
       Missing20 (0.1)280 (0.3)
      Starting year of follow-up evaluation
       1973–19891909 (9.9%)9504 (10.1%)
       1990–19995458 (28.4%)27,113 (28.8%)
       2000–20097643 (39.8%)37,524 (39.8%)
       2010–20164176 (21.8%)20,108 (21.3%)
      Psychiatric diagnoses in family before index date, n (%)
       Parents2260 (11.8)11,449 (12.1)
       Siblings331 (1.7)1725 (1.8)
       Any of parents or siblings2505 (13.1)12,627 (13.4)
      Follow-up period, y
       Mean (SD)13.5 (8.4)13.6 (8.4)
       Median (IQR)12.2 (6.6–20.2)12.3 (6.7–20.3)
       Range, minimum–maximum0.0–42.00.0–44.0
      IQR, interquartile range; SD, standard deviation.
      Celiac disease diagnosed in childhood was associated with a 19% increased risk of any psychiatric disorder (95% CI, 1.14–1.23) (Table 2), with the most increased risk within the first year after a celiac diagnosis (HR, 1.70; 95% CI, 1.41–2.05). Restricting follow-up evaluation until the age of 18 years, celiac disease was linked to a 26% increased risk of any psychiatric disorder (95% CI, 1.20–1.33) (Supplementary Table 4).
      Table 2Risk of Any Psychiatric Disorder Overall and by Subgroup in Patients With Celiac Disease and Matched General Population Comparators
      GroupN (%)Events, n (%)Incidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for highest education level attained by parents.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Overall19,186 (100)94,249 (100)3174 (16.5)13,286 (14.1)12.2 (11.8–12.7)10.3 (10.2–10.5)1.19 (1.14–1.23)
      Follow-up period
       0 to <1 y19,186 (100)94,249 (100)148 (0.8)417 (0.4)7.8 (6.5–9.1)4.5 (4.0–4.9)1.70 (1.41–2.05)
       1 to <5 y18,762 (97.8)92,140 (97.8)629 (3.4)2260 (2.5)9.0 (8.3–9.7)6.6 (6.3–6.9)1.38 (1.26–1.51)
       5 to <10 y15,909 (82.9)78,384 (83.2)791 (5.0)3188 (4.1)11.6 (10.8–12.4)9.5 (9.1–9.8)1.24 (1.15–1.34)
       10 to <15 y11,474 (59.8)56,869 (60.3)690 (6.0)3135 (5.5)14.7 (13.6–15.8)13.5 (13.0–14.0)1.11 (1.02–1.21)
       15 to <20 y7379 (38.5)36,593 (38.8)541 (7.3)2584 (7.1)17.9 (16.4–19.4)17.2 (16.5–17.9)1.02 (0.93–1.12)
       ≥20 y4885 (25.5)24,236 (25.7)375 (7.7)1702 (7.0)14.6 (13.1–16.1)13.3 (12.6–13.9)1.10 (0.98–1.23)
      Sex
       Girls12,076 (62.9)59,358 (63.0)2027 (16.8)8772 (14.8)12.5 (11.9–13.0)11.0 (10.7–11.2)1.14 (1.08–1.20)
       Boys7110 (37.1)34,891 (37.0)1147 (16.1)4514 (12.9)11.8 (11.2–12.5)9.3 (9.1–9.6)1.28 (1.20–1.37)
      Age, y
       <25694 (29.7)27,579 (29.3)1001 (17.6)4408 (16.0)8.9 (8.3–9.4)8.2 (7.9–8.4)1.06 (0.98–1.13)
       2 to <64545 (23.7)23,460 (24.9)578 (12.7)2691 (11.5)10.0 (9.2–10.8)8.9 (8.6–9.3)1.11 (1.01–1.22)
       6 to <114244 (22.1)20,944 (22.2)707 (16.7)2753 (13.1)16.1 (14.9–17.3)12.5 (12.0–13.0)1.32 (1.21–1.44)
       11 to <163508 (18.3)17,025 (18.1)668 (19.0)2655 (15.6)19.9 (18.4–21.4)15.7 (15.1–16.3)1.28 (1.17–1.39)
       16 to <181195 (6.2)5241 (5.6)220 (18.4)779 (14.9)18.9 (16.4–21.5)14.5 (13.5–15.5)1.31 (1.12–1.53)
      Year
       1973–19891909 (9.9)9504 (10.1)405 (21.2)1760 (18.5)7.8 (7.0–8.6)6.8 (6.5–7.1)1.15 (1.03–1.28)
       1990–19995458 (28.4)27,113 (28.8)1140 (20.9)5052 (18.6)10.4 (9.8–11.1)9.4 (9.1–9.6)1.12 (1.05–1.19)
       2000–20097643 (39.8)37,524 (39.8)1303 (17.0)5352 (14.3)15.9 (15.0–16.8)13.3 (12.9–13.6)1.22 (1.14–1.29)
       2010–20164176 (21.8)20,108 (21.3)326 (7.8)1122 (5.6)19.4 (17.3–21.6)13.7 (12.9–14.5)1.43 (1.26–1.62)
      Year, first 5 years of follow-up evaluation
       1973–19891909 (9.9)9504 (10.1)13 (0.7)16 (0.2)1.4 (0.6–2.1)0.3 (0.2–0.5)3.84 (1.81–8.15)
       1990–19995458 (28.4)27,113 (28.8)55 (1.0)160 (0.6)2.0 (1.5–2.6)1.2 (1.0–1.4)1.69 (1.24–2.30)
       2000–20097643 (39.8)37,524 (39.8)408 (5.3)1525 (4.1)11.0 (9.9–12.1)8.4 (8.0–8.8)1.32 (1.19–1.48)
       2010–20111707 (8.9)8300 (8.8)143 (8.4)509 (6.1)17.5 (14.7–20.4)12.7 (11.6–13.9)1.39 (1.15–1.68)
      Country of birth
       Nordic18,837 (98.2)90,009 (95.5)3121 (16.6)12,774 (14.2)12.2 (11.7–12.6)10.3 (10.1–10.5)1.18 (1.14–1.23)
       Other348 (1.8)4236 (4.5)53 (15.2)512 (12.1)17.2 (12.5–21.8)12.6 (11.5–13.7)0.99 (0.45–2.19)
      Level of education, y
       ≤9659 (3.4)4333 (4.6)148 (22.5)779 (18.0)13.2 (11.0–15.3)12.2 (11.3–13.0)0.82 (0.48–1.39)
       10–128371 (43.6)40,792 (43.3)1604 (19.2)6676 (16.4)13.1 (12.4–13.7)11.4 (11.1–11.6)1.17 (1.09–1.25)
       >1210,136 (52.8)48,844 (51.8)1419 (14.0)5817 (11.9)11.3 (10.7–11.9)9.2 (9.0–9.5)1.20 (1.13–1.29)
      Psychiatric diagnoses in family
       Parents or sibling2505 (13.1)12,627 (13.4)582 (23.2)2505 (19.8)24.8 (22.8–26.8)20.6 (19.8–21.5)1.28 (1.08–1.52)
      CI, confidence interval; HR, hazard ratio; PY, person-year.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for highest education level attained by parents.
      The risks of each psychiatric disorder in celiac disease patients vs controls are listed in Table 3. Children with celiac disease were at an increased risk of developing mood disorders, anxiety disorders, eating disorders, ADHD, and autism spectrum disorder.
      Table 3Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators
      GroupEvents, n (%)Time at risk, yIncidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and further adjusted for highest attained education in parents
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Psychotic disorders69 (0.4)349 (0.4)278,6651,359,8920.2 (0.2–0.3)0.3 (0.2–0.3)0.96 (0.74–1.25)
      Mood disorders1 190 (6.2)4 832 (5.1)272,9721,337,3674.4 (4.1–4.6)3.6 (3.5–3.7)1.20 (1.12–1.28)
      Anxiety disorders1 573 (8.2)6 829 (7.2)270,9381,327,3395.8 (5.5–6.1)5.1 (5.0–5.3)1.12 (1.06–1.19)
      Eating disorders331 (1.7)1 187 (1.3)277,0151,354,8291.2 (1.1–1.3)0.9 (0.8–0.9)1.34 (1.18–1.51)
      Psychoactive substance misuse720 (3.8)3 257 (3.5)274,6551,342,4962.6 (2.4–2.8)2.4 (2.3–2.5)1.07 (0.99–1.16)
      Behavioral disorders72 (0.4)366 (0.4)278,6831,359,7520.3 (0.2–0.3)0.3 (0.2–0.3)0.98 (0.76–1.27)
      ADHD904 (4.7)3 453 (3.7)274,7721,345,4383.3 (3.1–3.5)2.6 (2.5–2.7)1.29 (1.20–1.39)
      Suicide attempt304 (1.6)1 442 (1.5)276,8461,352,4321.1 (1.0–1.2)1.1 (1.0–1.1)1.02 (0.90–1.16)
      Suicide14 (0.1)90 (0.1)279,1341,361,9820.1 (0.0–0.1)0.1 (0.1–0.1)0.78 (0.44–1.37)
      Personality disorders167 (0.9)719 (0.8)278,1761,358,1060.6 (0.5–0.7)0.5 (0.5–0.6)1.13 (0.95–1.34)
      Autism spectrum disorder417 (2.2)1 396 (1.5)276,8091,354,4051.5 (1.4–1.7)1.0 (1.0–1.1)1.47 (1.32–1.64)
      Any psychiatric disorder3 174 (16.5)13 286 (14.1)259,6331,284,01112.2 (11.8–12.7)10.3 (10.2–10.5)1.19 (1.14–1.23)
      NOTE. n celiac disease/n comparators = 19,186/94,249.
      ADHD, attention deficit hyperactivity disorder; CI, confidence interval; HR, hazard ratio; PY, person-year.
      a Conditioned on matching set (age, sex, county, and calendar period) and further adjusted for highest attained education in parents

       Follow-Up Evaluation From Age 18 Years

      In analyses of adults (age, ≥18 y) with celiac disease diagnosed in childhood and free of psychiatric disease as of age 18, we matched 11,207 celiac disease patients with 49,252 reference individuals (Supplementary Table 5). The median follow-up time after age 18 was 6.4 years for the celiac disease patients and 6 years for the comparators. The overall risk of any psychiatric disorder was increased in celiac disease patients by 11% (HR, 1.11; 95% CI, 1.04–1.17). Having a family history of psychiatric disorder yielded a 1.25-fold increase (HR, 1.25; 95% CI, 1.08–1.46) (Supplementary Table 6).
      Adults with childhood celiac disease had an increased risk later for mood disorders, ADHD, and autism spectrum disorder (Supplementary Table 7). When repeating the analysis, now including all subjects regardless of whether they had been diagnosed with psychiatric disease before a celiac disease diagnosis or before reaching the age of 18 years, the association of childhood celiac disease and psychiatric disorders in adulthood was strengthened (HR, 1.17; 95% CI, 1.11–1.22). When excluding individuals with a diagnosis of intellectual disability before study entry (celiac patients, 19,101; controls, 93,612), the positive association with psychiatric disorders remained (HR, 1.18; 95% CI, 1.14–1.23).

       Sibling Comparisons

      We repeated the earlier-described analyses using celiac-free siblings as comparators (n = 18,024), restricting our cohort to 13,015 children with celiac disease and at least 1 sibling (Supplementary Table 8 shows participant characteristics). After conditioning on matching set (within family) and further adjustment for age and sex, celiac disease patients were at a 12% increased risk of a psychiatric disorder compared with siblings (95% CI, 1.05–1.20). Sibling analyses yielded very similar data to those of our main analyses with general population reference individuals (Supplementary Table 9). Sibling comparisons found a positive association between celiac disease and mood disorders, anxiety disorders, eating disorders, and autism spectrum disorder (Supplementary Table 10).

       Mucosal Healing and Psychiatric Disorder

      During follow-up evaluation, 2604 children with celiac disease had a follow-up biopsy (mucosal healing: n = 2071, 79.5%; persistent villus atrophy: n = 533, 20.5%) (Supplementary Table 11). We found no association between mucosal healing and a subsequent psychiatric disorder (HR, 1.21; 95% CI, 0.95–1.53) (Supplementary Table 12).

       Sensitivity Analyses

      In sensitivity analyses, we defined a psychiatric disorder as having a prescription for a psychiatric drug (Supplementary Table 3). Because of the construction of the Swedish Prescribed Drug Register, this analysis was restricted to children diagnosed between July 2006 and December 2016 (Supplementary Table 13). Using this definition, the incidence rate for any psychiatric disorder was 26.9 (95% CI, 25.3–28.6) per 1000 person-years in celiac disease and 20.5 (95% CI, 19.8–21.2) in the reference group (Supplementary Table 14). The HR for any psychiatric disorder was 1.34 (95% CI, 1.24–1.43) (Supplementary Table 14).
      The increased risk was significant in all categories of psychiatric drugs: antidepressants (HR, 1.35; 95% CI, 1.25–1.46), anxiolytics, hypnotics and sedatives (HR, 1.32; 95% CI, 1.23–1.42), and antipsychotics (HR, 1.34; 95% CI, 1.23–1.46) (Supplementary Table 15).

       History of Psychiatric Disorder Preceding Celiac Disease

      In children with celiac disease a prior history of a psychiatric disorder (preceding the diagnosis of celiac disease) was more common compared with controls (odds ratio [OR], 1.56; 95% CI, 1.39–1.76) (Table 4). This association was statistically significant for mood disorders (OR, 2.05; 95% CI, 1.54–2.72), anxiety disorders (OR, 1.51; 95% CI, 1.20–1.91), and eating disorders (OR, 3.10; 95% CI, 2.39–4.02).
      Table 4Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators Before Start of Follow-Up Evaluation
      GroupEvents, n (%)Odds ratio
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for highest education attained by parents.
      (95% CI)
      Celiac diseaseComparators
      Any psychiatric disorder397 (2.0%)1301 (1.3%)1.56 (1.39–1.76)
      Psychotic disorders2 (0.0%)12 (0.0%)0.76 (0.15–3.93)
      Mood disorders73 (0.4%)171 (0.2%)2.05 (1.54–2.72)
      Anxiety disorders95 (0.5%)314 (0.3%)1.51 (1.20–1.91)
      Eating disorders95 (0.5%)154 (0.2%)3.10 (2.39–4.02)
      Psychoactive substance misuse16 (0.1%)143 (0.1%)0.52 (0.31–0.87)
      Behavioral disorders13 (0.1%)65 (0.1%)1.01 (0.55–1.85)
      ADHD112 (0.6%)478 (0.5%)1.19 (0.96–1.48)
      Suicide attempt17 (0.1%)75 (0.1%)1.10 (0.64–1.88)
      Personality disorders1 (0.0%)2 (0.0%)2.16 (0.12–37.96)
      Autism spectrum disorder69 (0.4%)269 (0.3%)1.26 (0.96–1.65)
      NOTE. n celiac disease/n comparators = 19,583/97,362.
      ADHD, attention-deficit hyperactivity disorder; CI, confidence interval.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for highest education attained by parents.

      Discussion

      In this nationwide and population-based cohort study, we followed up more than 19,000 individuals with childhood celiac disease diagnosed during the years spanning from 1973 to 2016. During follow-up evaluation, we found a 19% increased risk of any psychiatric disorder. The overall risk increase is consistent with earlier findings correlating psychiatric comorbidity with celiac disease in children, as well as in adults.
      • Smith D.F.
      • Gerdes L.U.
      Meta-analysis on anxiety and depression in adult celiac disease.
      ,
      • Zingone F.
      • Swift G.L.
      • Card T.R.
      • et al.
      Psychological morbidity of celiac disease: a review of the literature.
      The overall risk for psychiatric disorder was highest in the first year after diagnosis. This may be owing in part to surveillance bias, but it also is possible that the systemic inflammatory response is mediating this relationship. In addition to these purported mechanisms, the psychosocial stress associated with adapting to a gluten-free diet may account for the early increase in the risk of psychiatric disorders. Unlike most chronic medical conditions that are managed via pharmaceutical approaches, a diagnosis of celiac disease mandates a major lifestyle change for the patient, with a new requirement to attend to ingredient lists, restaurant menus, and social circumstances, given the intermingling of diet with socializing, and the ubiquity of gluten. This treatment has been rated by patients to be highly burdensome,
      • Shah S.
      • Akbari M.
      • Vanga R.
      • et al.
      Patient perception of treatment burden is high in celiac disease compared with other common conditions.
      and may lead to maladaptive eating patterns
      • Cadenhead J.W.
      • Wolf R.L.
      • Lebwohl B.
      • et al.
      Diminished quality of life among adolescents with coeliac disease using maladaptive eating behaviours to manage a gluten-free diet: a cross-sectional, mixed-methods study.
      and hypervigilance, with attendant diminished quality of life.
      • Wolf R.L.
      • Lebwohl B.
      • Lee A.R.
      • et al.
      Hypervigilance to a gluten-free diet and decreased quality of life in teenagers and adults with celiac disease.
      The stress associated with this burden may contribute to the increased incidence of psychiatric disorders in both the short and long term. However, this risk is unlikely to be owing to the gluten-free diet alone because we also observed an increased risk of psychiatric disorders preceding the diagnosis of celiac disease, possibly related to the systemic inflammatory response described earlier.

       Specific Psychiatric Disorders

      The specific psychiatric disorders found to be increased in this study of childhood-diagnosed celiac disease include mood and anxiety disorders, eating disorders, ADHD, and autism-spectrum disorders. The association between celiac disease and depression and anxiety has been studied extensively, largely in the adult population.
      • Sainsbury K.
      • Marques M.M.
      The relationship between gluten free diet adherence and depressive symptoms in adults with coeliac disease: a systematic review with meta-analysis.
      Eating disorders
      • Mårild K.
      • Størdal K.
      • Bulik C.M.
      • et al.
      Celiac disease and anorexia nervosa: a nationwide study.
      likewise have been linked to celiac disease, although autism has not,
      • Ludvigsson J.F.
      • Reichenberg A.
      • Hultman C.M.
      • et al.
      A nationwide study of the association between celiac disease and the risk of autistic spectrum disorders.
      despite the popular use of a gluten-free diet among children with this condition.
      • Blackett J.W.
      • Shamsunder M.
      • Reilly N.R.
      • et al.
      Characteristics and comorbidities of inpatients without celiac disease on a gluten-free diet.

       Strengths and Limitations

      Through data retrieval from Sweden’s all 28 pathology departments, we were able to identify 19,101 children with celiac disease, with follow-up evaluation through 2016. This compares with 10,903 children followed up through 2010 in a previous population-based study in Sweden.
      • Butwicka A.
      • Lichtenstein P.
      • Frisén L.
      • et al.
      Celiac disease is associated with childhood psychiatric disorders: a population-based study.
      This expanded sample size and follow-up period allowed us to evaluate additional outcomes including long-term, adult-onset, psychiatric disease; this study examined the development of psychiatric disorders, particularly in adults with celiac disease diagnosed in childhood. The large sample size and long-term follow-up period (a total of 259,633 person-years in people with childhood-diagnosed celiac disease) allowed us to detect even minor risk increases for specific psychiatric disorders. We also were able to perform sensitivity analyses including a comparison with siblings and evaluation of mucosal healing. Our access to follow-up biopsy data allowed us to examine potential mechanisms behind the association with psychiatric disorders; however, we found no link between mucosal healing (at least in the short term) and psychiatric disorders.
      This study also had some limitations. The International Classification of Diseases codes and thus the criteria used for psychiatric diagnoses (Supplementary Table 1) have changed throughout the years, and this might influence the rates of psychiatric diagnosis. Because this was an observational study, we cannot rule out that residual confounding contributed to the association between celiac disease and psychiatric disorders.
      The lack of association between mucosal healing and psychiatric risk in our study contrasts with a study of 53 patients that found that deterioration of quality of life after a diagnosis is associated with lower adherence to a gluten-free diet.
      • Nachman F.
      • Planzer de Campo M.
      • Gonzalez A.
      • et al.
      Long-term deterioration of quality of life in adult patients with celiac disease is associated with treatment noncompliance.
      This may be because mucosal healing is an imperfect marker of adherence, particularly given the possibility of gradual healing (ie, persistent villus atrophy that eventually resolves with further time while maintaining the gluten-free diet).

       Clinical Implications

      This study showed that although small in absolute magnitude, there is an increased risk of a psychiatric disorder in individuals diagnosed with celiac disease in childhood with an increased risk in the long term, emphasizing the importance of not just somatic surveillance but also mental health surveillance for timely support and intervention.

      Conclusions

      In conclusion, this nationwide population-based study including more than 19,000 children with celiac disease found an increased risk of psychiatric disorders. This risk was highest in the first year after celiac disease diagnosis but persisted over a long time and into adulthood. Mental health surveillance should be integral in the care of celiac disease.

      Acknowledgments

      This project (2014/1287-31/4) was approved by the Research Ethics Committee in Stockholm, Sweden, on August 27, 2014.
      Other researchers can apply for our data through the different Swedish pathology departments, and through the Swedish National Board of Health and Welfare.
      The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

      CRediT Authorship Contributions

      LH wrote the first draft of the paper. All authors conceived and designed the study. JFL and BL supervised the project. PG and JFL funded the study. JS carried out the statistics. All authors interpreted the data and contributed to the writing of the paper. All authors revised and approved the final version. JFL takes responsibility for the integrity of the data and the accuracy of the data analyses. JFL is the guarantor of the data.

      Supplementary Material

      Supplementary Table 1Definitions of Celiac Disease and Normal Mucosa Using SNOMED Codes
      Disease/conditionTopographic codeSNOMED codes
      Celiac diseaseAll T64, only T65, T65000, and T651D6218, D62180, D62188, D6218X, D6218Y; M58, M5800, M58000, M58001, M58005, M58006, M58007
      Normal mucosaAll T64, only T65, T65000, and T651M00100, M00110
      SNOMED, Systematized Nomenclature of Medicine.
      Supplementary Table 2ICD Codes Used for Outcomes
      ComorbidityICD-8 (1969–1986)ICD-9 (1987-1996)ICD-10 (1997–present)
      Psychotic disorders295, 297–299295, 297, 298F20–F29
      Mood disorders296, 300.4296, 300E, 311F30–F39
      Anxiety disorders300 except 300.4, 307300 except 300.E, 308–309F40–F45, F48
      Eating disorders307B, 307FF50
      Psychoactive substance misuse291, 303, 304291, 303, 304, 305A, 305XF10–F19
      Behavioral disordersF91
      ADHD314F90
      Suicide attempt and completed suicideE950–E959E950–E959X60–X84
      Personality disorders301301F60–F62, F69
      Autism spectrum disorder299AF84
      ADHD, attention-deficit hyperactivity disorder; ICD-8, International Classification of Diseases, 8th revision; ICD-9, International Classification of Diseases, 9th revision; ICD-10, International Classification of Diseases, 10th revision.
      Supplementary Table 3ATC Codes Used for Outcomes
      DrugATC code
      AntidepressantsN06A
      Anxiolytics, hypnotics, and sedativesN05B, N05C
      AntipsychoticsN05A
      ATC, Anatomical Therapeutic Chemical.
      Supplementary Table 4Risk of Any Psychiatric Disorder Overall and by Subgroup in Patients With Celiac Disease and Matched General Population Comparators, With Follow-Up Evaluation Ending at Age 18 Years
      GroupN (%)Events, N (%)Incidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Overall19,186 (100)94,249 (100)1747 (9.1)6861 (7.3)9.9 (9.4–10.4)7.9 (7.7–8.1)1.26 (1.20–1.33)
      Follow-up period, y
       0 to <119,186 (100)94,249 (100)141 (0.7)402 (0.4)7.5 (6.3–8.8)4.4 (3.9–4.8)1.70 (1.40–2.06)
       1 to <518,180 (94.8)89,819 (95.3)492 (2.7)1764 (2.0)7.7 (7.0–8.4)5.6 (5.3–5.8)1.40 (1.26–1.55)
       5 to <1013,656 (71.2)67,406 (71.5)525 (3.8)1994 (3.0)9.7 (8.9–10.5)7.5 (7.1–7.8)1.31 (1.19–1.45)
       10 to <158467 (44.1)41,719 (44.3)456 (5.4)2038 (4.9)14.1 (12.8–15.3)12.7 (12.2–13.3)1.10 (0.99–1.22)
       15 to <204671 (24.3)23,007 (24.4)133 (2.8)663 (2.9)18.1 (15.0–21.2)18.1 (16.8–19.5)0.98 (0.80–1.19)
      Sex
       Girls12,076 (62.9)59,358 (63.0)1094 (9.1)4463 (7.5)9.8 (9.2–10.4)8.1 (7.9–8.4)1.22 (1.14–1.30)
       Boys7110 (37.1)34,891 (37.0)653 (9.2)2398 (6.9)10.0 (9.2–10.8)7.4 (7.1–7.7)1.35 (1.23–1.47)
      Age, y
       <25694 (29.7)27,579 (29.3)526 (9.2)2210 (8.0)6.2 (5.7–6.7)5.5 (5.2–5.7)1.10 (0.99–1.21)
       2 to <64545 (23.7)23,460 (24.9)387 (8.5)1726 (7.4)8.4 (7.5–9.2)7.2 (6.9–7.5)1.16 (1.03–1.30)
       6 to <114244 (22.1)20,944 (22.2)463 (10.9)1677 (8.0)15.2 (13.9–16.6)11.1 (10.6–11.6)1.40 (1.25–1.55)
       11 to <163508 (18.3)17,025 (18.1)324 (9.2)1157 (6.8)22.6 (20.1–25.0)16.3 (15.4–17.3)1.41 (1.24–1.60)
       16 to <181195 (6.2)5 241 (5.6)47 (3.9)91 (1.7)41.6 (29.7–53.4)16.7 (13.3–20.2)2.32 (1.57–3.44)
      Year
       1973–19891909 (9.9)9504 (10.1)93 (4.9)362 (3.8)3.4 (2.7–4.1)2.7 (2.4–2.9)1.29 (1.02–1.63)
       1990–19995458 (28.4)27,113 (28.8)506 (9.3)2130 (7.9)7.0 (6.4–7.6)5.9 (5.7–6.2)1.17 (1.06–1.29)
       2000–20097643 (39.8)37,524 (39.8)872 (11.4)3461 (9.2)14.1 (13.2–15.1)11.4 (11.0–11.7)1.26 (1.17–1.36)
       2010–20164176 (21.8)20,108 (21.3)276 (6.6)908 (4.5)18.4 (16.2–20.6)12.3 (11.5–13.1)1.49 (1.30–1.71)
      Year, first 5 years of follow-up evaluation
       1973–19891909 (9.9)9504 (10.1)8 (0.4)15 (0.2)0.9 (0.3–1.5)0.3 (0.2–0.5)2.89 (1.19–7.02)
       1990–19995458 (28.4)27,113 (28.8)40 (0.7)127 (0.5)1.5 (1.1–2.0)1.0 (0.8–1.2)1.51 (1.06–2.17)
       2000–20097643 (39.8)37,524 (39.8)327 (4.3)1206 (3.2)9.7 (8.7–10.8)7.3 (6.8–7.7)1.37 (1.21–1.55)
       2010–20111707 (8.9)8300 (8.8)115 (6.7)424 (5.1)15.6 (12.8–18.5)11.7 (10.6–12.8)1.36 (1.10–1.68)
      Country of birth
       Nordic18,837 (98.2)90,009 (95.5)1718 (9.1)6643 (7.4)9.8 (9.4–10.3)7.8 (7.6–8.0)1.25 (1.19–1.32)
       Other348 (1.8)4236 (4.5)29 (8.3)218 (5.1)15.6 (9.9–21.2)8.9 (7.8–10.1)1.41 (0.46–4.37)
      Level of education, y
       ≤9659 (3.4)4333 (4.6)66 (10.0)343 (7.9)10.7 (8.1–13.2)9.2 (8.3–10.2)1.23 (0.50–3.01)
       10–128371 (43.6)40,792 (43.3)872 (10.4)3411 (8.4)10.6 (9.9–11.3)8.7 (8.4–9.0)1.24 (1.13–1.36)
       >1210,136 (52.8)48,844 (51.8)808 (8.0)3097 (6.3)9.2 (8.5–9.8)7.0 (6.7–7.2)1.25 (1.15–1.37)
      Psychiatric diagnoses in family
       Parents or sibling2505 (13.1)12,627 (13.4)348 (13.9)1487 (11.8)20.7 (18.5–22.9)17.3 (16.4–18.2)1.36 (1.10–1.67)
      HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      Supplementary Table 5Analysis Limited to Those With Available Follow-Up Evaluation Starting at Age 18 Years: Baseline Characteristics of Study Cohort
      CharacteristicCeliac disease (n = 11,207)Matched comparators (n = 49,252)
      Girls, n (%)6958 (62.1)30,266 (61.5)
      Boys, n (%)4249 (37.9)18,986 (38.5)
      Age, y
       Mean (SD)18.0 (0.0)18.0 (0.0)
       Median (IQR)18.0 (18.0–18.0)18.0 (18.0–18.0)
       Range, minimum–maximum18.0–18.018.0–18.0
      Country of birth, n (%)
       Nordic country11,025 (98.4)47,181 (95.8)
       Other182 (1.6)2070 (4.2)
       Missing(0.0)1 (0.0)
      Highest education level attained by parents, n (%)
       ≤9 y476 (4.2)2524 (5.1)
       10–12 y5365 (47.9)23,098 (46.9)
       >12 y5360 (47.8)23,581 (47.9)
       Missing6 (0.1)49 (0.1)
      Start year of follow-up evaluation
       1973–198983 (0.7)385 (0.8)
       1990–1999782 (7.0)3744 (7.6)
       2000–20094985 (44.5)22,484 (45.7)
       2010–20165357 (47.8)22,639 (46.0)
      Psychiatric diagnoses in family before index date, n (%)
       Parents2063 (18.4)9237 (18.8)
       Siblings962 (8.6)4066 (8.3)
       Any of parents or siblings2712 (24.2)11,997 (24.4)
      Follow-up, y
       Mean (SD)7.4 (5.4)7.7 (5.5)
       Median (IQR)6.4 (3.5–10.2)6.6 (3.6–10.5)
       Range, minimum–maximum0.0–35.40.0–35.7
      IQR, interquartile range.
      Supplementary Table 6Analysis Limited to Those With Available Follow-Up Evaluation Starting at Age 18 Years: Risk of Any Psychiatric Disorder Overall and by Subgroup in Patients With Celiac Disease and Matched General Population Comparators
      GroupN (%)Events, N (%)Incidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Overall11,207 (100%)49 252 (100%)1427 (12.7)5833 (11.8)17.2 (16.3–18.1)15.4 (15.0–15.8)1.11 (1.04–1.17)
      Follow-up period, y
       0 to <111,207 (100%)49,252 (100%)245 (2.2)983 (2.0)22.7 (19.8–25.5)20.6 (19.3–21.9)1.07 (0.93–1.23)
       1 to <510,405 (92.8)45,959 (93.3)680 (6.5)2662 (5.8)19.4 (18.0–20.9)17.0 (16.4–17.7)1.14 (1.04–1.24)
       5 to <107024 (62.7)31,802 (64.6)349 (5.0)1497 (4.7)14.8 (13.2–16.3)13.8 (13.1–14.5)1.09 (0.96–1.23)
       10 to <152870 (25.6)13,460 (27.3)96 (3.3)477 (3.5)10.7 (8.5–12.8)11.1 (10.1–12.1)0.96 (0.76–1.21)
       15 to <201003 (8.9)4895 (9.9)37 (3.7)155 (3.2)11.9 (8.1–15.8)9.9 (8.3–11.5)1.15 (0.79–1.68)
       ≥20355 (3.2)1815 (3.7)20 (5.6)59 (3.3)13.5 (7.6–19.4)7.8 (5.8–9.8)1.77 (1.01–3.09)
      Sex
       Girls6958 (62.1)30,266 (61.5)933 (13.4)3901 (12.9)18.2 (17.0–19.3)17.0 (16.4–17.5)1.06 (0.99–1.15)
       Boys4249 (37.9)18,986 (38.5)494 (11.6)1932 (10.2)15.6 (14.2–17.0)13.0 (12.4–13.6)1.20 (1.08–1.32)
      Year
       1973–198983 (0.7)385 (0.8)19 (22.9)42 (10.9)9.1 (5.0–13.2)4.0 (2.8–5.3)2.18 (1.21–3.91)
       1990–1999782 (7.0)3744 (7.6)160 (20.5)569 (15.2)11.6 (9.8–13.4)8.3 (7.6–9.0)1.39 (1.16–1.66)
       2000–20094985 (44.5)22,484 (45.7)782 (15.7)3415 (15.2)16.6 (15.4–17.7)15.9 (15.4–16.5)1.05 (0.97–1.14)
       2010–20165357 (47.8)22,639 (46.0)466 (8.7)1807 (8.0)23.4 (21.3–25.5)21.2 (20.2–22.1)1.10 (0.99–1.22)
      Year, first 5 years of follow-up evaluation
       1973–198983 (0.7)385 (0.8)4 (4.8)2 (0.5)10.0 (0.2–19.7)1.0 (0.0–2.5)10.03 (1.21–83.26)
       1990–1999782 (7.0)3744 (7.6)42 (5.4)94 (2.5)11.1 (7.7–14.4)5.1 (4.1–6.2)2.07 (1.43–3.00)
       2000–20094985 (44.5)22,484 (45.7)447 (9.0)1868 (8.3)19.0 (17.3–20.8)17.6 (16.8–18.4)1.08 (0.97–1.20)
       2010–20112078 (18.5)8954 (18.2)214 (10.3)843 (9.4)22.1 (19.1–25.0)20.1 (18.7–21.4)1.11 (0.96–1.29)
      Country of birth
       Nordic11,025 (98.4)47,181 (95.8)1403 (12.7)5575 (11.8)17.2 (16.3–18.0)15.3 (14.9–15.7)1.11 (1.04–1.18)
       Other182 (1.6)2070 (4.2)24 (13.2)258 (12.5)19.6 (11.8–27.4)17.4 (15.3–19.5)1.08 (0.30–3.82)
      Level of education, y
       ≤9476 (4.2)2524 (5.1)82 (17.2)405 (16.0)16.2 (12.7–19.7)16.2 (14.6–17.8)0.64 (0.32–1.26)
       10–125365 (47.9)23,098 (46.9)732 (13.6)2978 (12.9)18.0 (16.7–19.3)16.4 (15.8–17.0)1.08 (0.98–1.19)
       >125360 (47.8)23,581 (47.9)611 (11.4)2447 (10.4)16.4 (15.1–17.7)14.2 (13.7–14.8)1.14 (1.02–1.26)
      Psychiatric diagnoses in family
       Parents or sibling2712 (24.2)11,997 (24.4)507 (18.7)1947 (16.2)32.3 (29.5–35.1)26.5 (25.3–27.6)1.25 (1.08–1.46)
      HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      Supplementary Table 7Analysis Limited to Those With Available Follow-Up Evaluation Starting at Age 18 Years: Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators
      GroupEvents, N (%)Time at risk, yIncidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Psychotic disorders44 (0.4)192 (0.4)90,425407,3840.5 (0.3–0.6)0.5 (0.4–0.5)1.06 (0.76–1.48)
      Mood disorders618 (5.5)2334 (4.7)87,660397,2607.0 (6.5–7.6)5.9 (5.6–6.1)1.19 (1.08–1.30)
      Anxiety disorders809 (7.2)3401 (6.9)86,843392,0609.3 (8.7–10.0)8.7 (8.4–9.0)1.06 (0.98–1.14)
      Eating disorders112 (1.0)418 (0.8)90,017406,1671.2 (1.0–1.5)1.0 (0.9–1.1)1.19 (0.96–1.47)
      Psychoactive substance misuse409 (3.6)1660 (3.4)88,470399,9484.6 (4.2–5.1)4.2 (4.0–4.4)1.10 (0.98–1.22)
      Behavioral disorders1 (0.0)18 (0.0)90,703408,4030.0 (0.0–0.0)0.0 (0.0–0.1)0.34 (0.04–2.62)
      ADHD234 (2.1)773 (1.6)89,837405,6592.6 (2.3–2.9)1.9 (1.8–2.0)1.39 (1.19–1.61)
      Suicide attempt135 (1.2)542 (1.1)89,787405,2161.5 (1.2–1.8)1.3 (1.2–1.5)1.15 (0.95–1.39)
      Suicide8 (0.1)55 (0.1)90,708408,4830.1 (0.0–0.1)0.1 (0.1–0.2)0.72 (0.34–1.52)
      Personality disorders108 (1.0)392 (0.8)90,091406,2911.2 (1.0–1.4)1.0 (0.9–1.1)1.23 (0.99–1.52)
      Autism spectrum disorder107 (1.0)282 (0.6)90,284407,3101.2 (1.0–1.4)0.7 (0.6–0.8)1.69 (1.35–2.12)
      Any psychiatric disorder1427 (12.7)5833 (11.8)83,030378,37817.2 (16.3–18.1)15.4 (15.0–15.8)1.11 (1.04–1.17)
      NOTE. n celiac disease/n comparators = 11,207/49,252.
      ADHD, attention-deficit hyperactivity disorder; HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      Supplementary Table 8Comparison of Celiac Disease Patients With Siblings: Baseline Characteristics of Study Cohort
      CharacteristicCeliac disease (n = 13,015)Matched comparators (n = 18,024)
      Girls, n (%)8157 (62.7)8831 (49.0)
      Boys, n (%)4858 (37.3)9193 (51.0)
      Age, y
       Mean (SD)6.9 (4.9)7.8 (4.7)
       Median (IQR)6.0 (2.1–10.8)7.1 (3.9–11.4)
       Range, minimum–maximum0.0–18.00.0–18.0
      Categories, n (%)
       <2 y3086 (23.7)1771 (9.8)
       2 to <6 y3400 (26.1)5769 (32.0)
       6 to <11 y3419 (26.3)5628 (31.2)
       11 to <16 y2518 (19.3)3904 (21.7)
       16 to <18 y592 (4.5)952 (5.3)
      Country of birth, n (%)
       Nordic country12,831 (98.6)17,530 (97.3)
       Other183 (1.4)493 (2.7)
       Missing1 (0.0)1 (0.0)
      Highest level of education attained by parents, n (%)
       ≤9 y404 (3.1)739 (4.1)
       10–12 y5387 (41.4)7515 (41.7)
       >12 y7218 (55.5)9760 (54.2)
       Missing6 (0.0)10 (0.1)
      Starting year of follow-up evaluation
       1973–19891173 (9.0%)1643 (9.1%)
       1990–19993470 (26.7%)4924 (27.3%)
       2000–20095365 (41.2%)7374 (40.9%)
       2010–20163007 (23.1%)4083 (22.7%)
      Follow-up evaluation, y
       Mean (SD)13.1 (8.3)12.8 (8.5)
       Median (IQR)11.8 (6.4–19.1)11.4 (6.0–18.9)
       Range, minimum–maximum0.0–39.00.0–44.0
      IQR, interquartile range.
      Supplementary Table 9Comparison of Celiac Disease Patients With Siblings: Risk of Any Psychiatric Disorder Overall and by Subgroups in Patients With Celiac Disease and Matched Sibling Comparators
      GroupN (%)Events, N (%)Incidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (within family) and adjusted further for age and sex.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Overall13,015 (100)18,024 (100)1994 (15.3)2411 (13.4)11.7 (11.2–12.2)10.4 (10.0–10.8)1.12 (1.05–1.20)
      Follow-up period, y
       0 to <113,015 (100)18,024 (100)94 (0.7)90 (0.5)7.3 (5.8–8.8)5.1 (4.0–6.1)1.48 (1.07–2.05)
       1 to <512,725 (97.8)17,331 (96.2,)415 (3.3)467 (2.7)8.8 (8.0–9.7)7.3 (6.7–8.0)1.26 (1.09–1.46)
       5 to <1010,691 (82.1)14,331 (79.5)531 (5.0)655 (4.6)11.7 (10.7–12.7)10.7 (9.9–11.6)1.09 (0.95–1.24)
       10 to <157591 (58.3)10,194 (56.6)437 (5.8)591 (5.8)14.3 (13.0–15.7)14.4 (13.2–15.6)0.86 (0.74–1.00)
       15 to <204731 (36.4)6376 (35.4)303 (6.4)368 (5.8)15.9 (14.1–17.6)14.3 (12.9–15.8)0.96 (0.79–1.16)
       ≥203027 (23.3)4100 (22.7)214 (7.1)240 (5.9)13.6 (11.7–15.4)10.9 (9.5–12.3)1.07 (0.84–1.37)
      Sex
       Girls8157 (62.7)8831 (49.0)1259 (15.4)1267 (14.3)11.8 (11.2–12.5)11.3 (10.6–11.9)1.11 (0.99–1.24)
       Boys4858 (37.3)9193 (51.0)735 (15.1)1144 (12.4)11.4 (10.6–12.2)9.6 (9.1–10.2)1.27 (1.09–1.47)
      Age, y
       <23086 (23.7)1771 (9.8)517 (16.8)183 (10.3)8.4 (7.7–9.1)8.1 (7.0–9.3)1.06 (0.60–1.86)
       2 to <63400 (26.1)5769 (32.0)386 (11.4)777 (13.5)9.0 (8.1–9.8)9.0 (8.4–9.6)1.02 (0.81–1.30)
       6 to <113419 (26.3)5628 (31.2)537 (15.7)757 (13.5)15.0 (13.7–16.2)10.9 (10.1–11.7)1.15 (0.93–1.41)
       11 to <162518 (19.3)3904 (21.7)456 (18.1)573 (14.7)18.6 (16.9–20.3)13.4 (12.3–14.5)1.10 (0.89–1.36)
       16 to <18592 (4.5)952 (5.3)98 (16.6)121 (12.7)16.8 (13.5–20.2)11.8 (9.7–13.9)2.01 (0.64–6.28)
      Year
       1973–19891173 (9.0)1643 (9.1)235 (20.0)244 (14.9)7.4 (6.4–8.3)5.5 (4.8–6.2)1.27 (1.01–1.60)
       1990–19993470 (26.7)4924 (27.3)677 (19.5)882 (17.9)9.8 (9.1–10.5)9.4 (8.7–10.0)1.01 (0.90–1.14)
       2000–20095365 (41.2)7374 (40.9)878 (16.4)1058 (14.3)15.2 (14.2–16.2)13.9 (13.0–14.7)1.08 (0.98–1.20)
       2010–20163007 (23.1)4083 (22.7)204 (6.8)227 (5.6)16.9 (14.5–19.2)14.2 (12.3–16.0)1.14 (0.92–1.42)
      Year, first 5 years of follow-up evaluation
       1973–19891173 (9.0)1643 (9.1)9 (0.8)2 (0.1)1.5 (0.5–2.6)0.2 (0.0–0.6)12.59 (1.19–132.91)
       1990–19993470 (26.7)4924 (27.3)34 (1.0)26 (0.5)2.0 (1.3–2.6)1.1 (0.7–1.5)3.50 (1.75–6.98)
       2000–20095365 (41.2)7374 (40.9)280 (5.2)326 (4.4)10.8 (9.5–12.0)9.4 (8.4–10.4)1.23 (1.03–1.47)
       2010–20111207 (9.3)1607 (8.9)89 (7.4)117 (7.3)15.3 (12.1–18.5)15.6 (12.7–18.4)0.89 (0.65–1.21)
      Country of birth
       Nordic12,831 (98.6)17,530 (97.3)1972 (15.4)2362 (13.5)11.7 (11.1–12.2)10.4 (10.0–10.8)1.11 (1.04–1.19)
       Other183 (1.4)493 (2.7)22 (12.0)49 (9.9)14.1 (8.2–20.0)10.9 (7.8–13.9)1.36 (0.70–2.63)
      Level of education, y
       ≤9404 (3.1)739 (4.1)85 (21.0)146 (19.8)12.1 (9.5–14.7)12.6 (10.5–14.6)1.08 (0.78–1.50)
       10–125387 (41.4)7515 (41.7)956 (17.7)1203 (16.0)12.4 (11.6–13.1)11.4 (10.7–12.0)1.11 (1.00–1.22)
       >127218 (55.5)9760 (54.2)953 (13.2)1061 (10.9)11.0 (10.3–11.7)9.3 (8.8–9.9)1.13 (1.02–1.25)
      HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (within family) and adjusted further for age and sex.
      Supplementary Table 10Comparison of Celiac Disease Patients to Siblings: Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched Sibling Comparators
      GroupEvents, N (%)Time at risk, yIncidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (within family) and further adjusted for age and sex.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Psychotic disorders42 (0.3)62 (0.3)182,804245,1340.2 (0.2–0.3)0.3 (0.2–0.3)1.24 (0.79–1.95)
      Mood disorders774 (5.9)839 (4.7)179,127240,9674.3 (4.0–4.6)3.5 (3.2–3.7)1.22 (1.09–1.37)
      Anxiety disorders977 (7.5)1 175 (6.5)178,017239,2195.5 (5.1–5.8)4.9 (4.6–5.2)1.12 (1.01–1.23)
      Eating disorders219 (1.7)172 (1.0)181,713244,5571.2 (1.0–1.4)0.7 (0.6–0.8)1.59 (1.24–2.05)
      Psychoactive substance misuse448 (3.4)559 (3.1)180,260242,0142.5 (2.3–2.7)2.3 (2.1–2.5)1.14 (0.99–1.31)
      Behavioral disorders50 (0.4)56 (0.3)182,753245,1760.3 (0.2–0.3)0.2 (0.2–0.3)1.19 (0.79–1.80)
      ADHD545 (4.2)651 (3.6)180,452242,4623.0 (2.8–3.3)2.7 (2.5–2.9)1.12 (0.99–1.28)
      Suicide attempt183 (1.4)212 (1.2)181,654244,1091.0 (0.9–1.2)0.9 (0.8–1.0)1.22 (0.97–1.52)
      Suicide9 (0.1)14 (0.1)183,084245,5180.0 (0.0–0.1)0.1 (0.0–0.1)2.62 (0.76–9.06)
      Personality disorders95 (0.7)139 (0.8)182,522244,7870.5 (0.4–0.6)0.6 (0.5–0.7)0.82 (0.60–1.13)
      Autism spectrum disorder272 (2.1)263 (1.5)181,547244,1731.5 (1.3–1.7)1.1 (0.9–1.2)1.59 (1.31–1.92)
      Any psychiatric disorder1994 (15.3)2411 (13.4)170,810231,13811.7 (11.2–12.2)10.4 (10.0–10.8)1.12 (1.05–1.20)
      NOTE. n celiac disease/n comparators = 13,015 /18,024.
      ADHD, attention-deficit hyperactivity disorder; HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (within family) and further adjusted for age and sex.
      Supplementary Table 11Characteristics of Children With Celiac Disease Who Underwent a Follow-Up Biopsy
      CharacteristicMucosal healing (n = 2071)Persistent villus atrophy (n = 533)
      Girls, n (%)1 280 (61.8)330 (61.9)
      Boys, n (%)791 (38.2)203 (38.1)
      Age, y
       Mean (SD)7.0 (4.8)6.5 (4.8)
       Median (IQR)5.1 (2.9–10.6)4.3 (2.7–9.6)
       Range, minimum–maximum1.0–18.01.1–18.0
      Categories, n (%)
       <2 y82 (4.0)39 (7.3)
       2 to <6 y1 084 (52.3)291 (54.6)
       6 to <11 y415 (20.0)91 (17.1)
       11 to <16 y372 (18.0)77 (14.4)
       16 to <18 y118 (5.7)35 (6.6)
      Country of birth, n (%)
       Nordic country2 044 (98.7)525 (98.5)
       Other27 (1.3)8 (1.5)
      Highest level of education attained by parents, n (%)
       ≤9 y67 (3.2)37 (6.9)
       10–12 y950 (45.9)272 (51.0)
       >12 y1 054 (50.9)223 (41.8)
       Missing01 (0.2)
      Start year of follow-up evaluation
       1973–1989127 (6.1%)72 (13.5%)
       1990–1999729 (35.2%)258 (48.4%)
       2000–2009995 (48.0%)167 (31.3%)
       2010–2016220 (10.6%)36 (6.8%)
      Psychiatric diagnoses in family before index date, n (%)
       Parents188 (9.1)49 (9.2)
       Siblings36 (1.7)14 (2.6)
       Any of parents or siblings217 (10.5)62 (11.6)
      Duration since diagnosis, y
       Mean (SD)1.7 (0.9)1.8 (1.0)
       Median (IQR)1.4 (1.1–2.0)1.4 (1.1–2.1)
       Range, minimum–maximum0.5–5.00.5–5.0
      Follow-up period, y
       Mean (SD)14.4 (7.2)17.3 (7.9)
       Median (IQR)13.6 (9.4–20.0)17.8 (10.9–23.3)
       Range, minimum–maximum0.0–34.00.0–39.0
      IQR, interquartile range.
      Supplementary Table 12Risk of Any Psychiatric Disorder Overall and by Subgroups in Patients With Celiac Disease and Mucosal Healing Vs Persistent VA
      GroupN (%)Events, N (%)Incidence rate (95% CI) per 1000 PYHR
      Adjusted for age, sex, start year of follow-up evaluation, duration since diagnosis, highest education attained by parents, and Nordic country of birth.
      (95% CI)
      Mucosal healingPersistent VAMucosal healingPersistent VAMucosal healingPersistent VA
      Overall2071 (100.0)533 (100.0)375 (18.1)90 (16.9)12.6 (11.3–13.9)9.8 (7.7–11.8)1.21 (0.95–1.53)
      Follow-up period, y
       0 to <12071 (100.0)533 (100.0)19 (0.9)3 (0.6)9.2 (5.1–13.4)5.7 (0.0–12.1)1.15 (0.34–3.90)
       1 to <52045 (98.7)527 (98.9)70 (3.4)10 (1.9)9.0 (6.9–11.1)4.8 (1.8–7.8)1.48 (0.76–2.89)
       5 to <101845 (89.1)500 (93.8)94 (5.1)19 (3.8)11.1 (8.9–13.4)8.2 (4.5–11.9)1.13 (0.68–1.88)
       10 to <151495 (72.2)422 (79.2)104 (7.0)27 (6.4)17.5 (14.2–20.9)14.5 (9.1–20.0)1.14 (0.74–1.75)
       15 to <20886 (42.8)325 (61.0)60 (6.8)23 (7.1)17.4 (13.0–21.8)17.0 (10.1–24.0)1.01 (0.62–1.65)
       ≥20517 (25.0)222 (41.7)28 (5.4)8 (3.6)13.7 (8.7–18.8)7.3 (2.2–12.3)1.89 (0.85–4.19)
      Sex
       Girls1280 (61.8)330 (61.9)220 (17.2)59 (17.9)11.9 (10.4–13.5)10.4 (7.7–13.0)1.02 (0.76–1.37)
       Boys791 (38.2)203 (38.1)155 (19.6)31 (15.3)13.7 (11.6–15.9)8.8 (5.7–11.9)1.53 (1.03–2.27)
      Age, y
       <282 (4.0)39 (7.3)16 (19.5)5 (12.8)9.3 (4.7–13.8)5.5 (0.7–10.3)1.89 (0.65–5.55)
       2 to <61084 (52.3)291 (54.6)176 (16.2)54 (18.6)9.5 (8.1–10.9)9.4 (6.9–11.9)1.02 (0.74–1.39)
       6 to <11415 (20.0)91 (17.1)73 (17.6)14 (15.4)15.1 (11.7–18.6)11.0 (5.2–16.7)1.19 (0.66–2.14)
       11 to <16372 (18.0)77 (14.4)84 (22.6)10 (13.0)23.7 (18.6–28.7)11.0 (4.2–17.7)1.69 (0.86–3.34)
       16 to <18118 (5.7)35 (6.6)26 (22.0)7 (20.0)23.2 (14.3–32.1)18.0 (4.7–31.4)1.39 (0.59–3.28)
      Year
       1973–1989127 (6.1)72 (13.5)26 (20.5)12 (16.7)7.9 (4.9–10.9)6.2 (2.7–9.7)1.32 (0.66–2.66)
       1990–1999729 (35.2)258 (48.4)143 (19.6)48 (18.6)10.0 (8.3–11.6)9.1 (6.5–11.7)1.11 (0.80–1.55)
       2000–2009995 (48.0)167 (31.3)180 (18.1)28 (16.8)16.1 (13.7–18.4)15.1 (9.5–20.7)1.21 (0.81–1.83)
       2010–2016220 (10.6)36 (6.8)26 (11.8)2 (5.6)29.8 (18.3–41.2)13.5 (0.0–32.2)2.28 (0.53–9.68)
      Year, first 5 years of follow-up evaluation
       1973–1989127 (6.1)72 (13.5)0000
       1990–1999729 (35.2)258 (48.4)9 (1.2)4 (1.6)2.5 (0.9–4.1)3.1 (0.1–6.2)0.76 (0.23–2.49)
       2000–2009995 (48.0)167 (31.3)58 (5.8)7 (4.2)12.0 (8.9–15.1)8.6 (2.2–14.9)1.60 (0.72–3.54)
       2010–201191 (4.4)18 (3.4)11 (12.1)2 (11.1)25.8 (10.6–41.1)23.6 (0.0–56.3)0.92 (0.20–4.33)
      Country of birth
       Nordic2044 (98.7)525 (98.5)369 (18.1)90 (17.1)12.5 (11.3–13.8)9.9 (7.8–11.9)1.18 (0.93–1.49)
       Other27 (1.3)8 (1.5)6 (22.2)021.7 (4.3–39.1)0
      Level of education, y
       ≤967 (3.2)37 (6.9)14 (20.9)9 (24.3)13.3 (6.3–20.3)14.6 (5.1–24.2)1.02 (0.42–2.52)
       10–12950 (45.9)272 (51.0)194 (20.4)47 (17.3)13.5 (11.6–15.4)9.3 (6.6–11.9)1.30 (0.94–1.80)
       >121054 (50.9)223 (41.8)167 (15.8)34 (15.2)11.7 (9.9–13.5)9.6 (6.4–12.8)1.13 (0.78–1.64)
      Psychiatric diagnoses in family
       Parents or sibling217 (10.5)62 (11.6)60 (27.6)12 (19.4)25.9 (19.4–32.5)15.7 (6.8–24.6)1.61 (0.85–3.04)
      HR, hazard ratio; PY, patient-years; VA, villous atrophy.
      a Adjusted for age, sex, start year of follow-up evaluation, duration since diagnosis, highest education attained by parents, and Nordic country of birth.
      Supplementary Table 13Outcomes Restricted to Those With a Psychiatric Medication Prescription (July 2006–December 2016): Baseline Characteristics of Study Cohort
      CharacteristicCeliac disease (n = 6815)Matched comparators (n = 32,459)
      Girls, n (%)4361 (64.0)20,827 (64.2)
      Boys, n (%)2454 (36.0)11,632 (35.8)
      Age, y
       Mean (SD)8.8 (4.8)8.6 (4.8)
       Median (IQR)8.6 (4.6–12.9)8.4 (4.4–12.6)
       Range, minimum–maximum0.0–18.00.0–18.0
      Categories, n (%)
       <2 y493 (7.2)2440 (7.5)
       2 to <6 y1851 (27.2)9100 (28.0)
       6 to <11 y2051 (30.1)9896 (30.5)
       11 to <16 y1818 (26.7)8538 (26.3)
       16 to <18 y602 (8.8)2485 (7.7)
      Country of birth, n (%)
       Nordic country6608 (97.0)30,230 (93.1)
       Other207 (3.0)2226 (6.9)
       Missing03 (0.0)
      Highest level of education attained by parents, n (%)
       ≤9 y150 (2.2)1312 (4.0)
       10–12 y2431 (35.7)12,409 (38.2)
       >12 y4224 (62.0)18,624 (57.4)
       Missing10 (0.1%)114 (0.4%)
      Start year of follow-up evaluation
       2006 (July)–20092761 (40.5%)13,282 (40.9%)
       2010–20122327 (34.1%)11,112 (34.2%)
       2013–20161727 (25.3%)8065 (24.8%)
      Psychiatric diagnoses in family before index date, n (%)
       Parents1240 (18.2)6099 (18.8)
       Siblings222 (3.3)1095 (3.4)
       Any of parents or siblings1400 (20.5)6818 (21.0)
      Follow-up period, y
       Mean (SD)5.5 (2.8)5.6 (2.8)
       Median (IQR)5.7 (3.2–7.8)5.8 (3.3–7.9)
       Range, minimum–maximum0.0–10.50.0–10.5
      IQR, interquartile range.
      Supplementary Table 14Outcomes Restricted to Those With a Psychiatric Medication Prescription (July 2006–December 2016): Risk of Any Psychiatric Disorder Including Drug Use Overall and by Subgroups in Patients With Celiac Disease and Matched General Population Comparators
      GroupN (%)Events, N (%)Incidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest attained education by parents.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Overall6815 (100)32,459 (100)1016 (14.9)3757 (11.6)26.9 (25.3–28.6)20.5 (19.8–21.2)1.34 (1.24–1.43)
      Follow-up period, y
       0 to <16815 (100)32,459 (100)150 (2.2)412 (1.3)22.6 (19.0–26.3)13.0 (11.7–14.2)1.73 (1.43–2.09)
       1 to <56424 (94.3)30,817 (94.9)535 (8.3)1903 (6.2)25.5 (23.3–27.7)18.7 (17.9–19.6)1.38 (1.25–1.53)
       5 to <103898 (57.2)19,081 (58.8)326 (8.4)1423 (7.5)32.3 (28.8–35.9)28.7 (27.2–30.2)1.15 (1.01–1.30)
      Sex
       Girls4361 (64.0)20,827 (64.2)663 (15.2)2503 (12.0)27.6 (25.5–29.7)21.3 (20.5–22.2)1.30 (1.19–1.42)
       Boys2454 (36.0)11,632 (35.8)353 (14.4)1254 (10.8)25.8 (23.1–28.5)19.0 (17.9–20.0)1.42 (1.26–1.60)
      Age, y
       <2493 (7.2)2440 (7.5)38 (7.7)128 (5.2)11.4 (7.8–15.0)7.8 (6.5–9.2)1.29 (0.87–1.90)
       2 to <61851 (27.2)9100 (28.0)125 (6.8)513 (5.6)11.5 (9.5–13.5)9.6 (8.8–10.5)1.29 (1.05–1.58)
       6 to <112051 (30.1)9896 (30.5)286 (13.9)953 (9.6)26.8 (23.7–29.9)18.1 (17.0–19.3)1.52 (1.32–1.74)
       11 to <161818 (26.7)8538 (26.3)410 (22.6)1607 (18.8)41.8 (37.7–45.8)33.5 (31.9–35.2)1.28 (1.14–1.43)
       16 to <18602 (8.8)2485 (7.7)157 (26.1)556 (22.4)51.7 (43.6–59.7)42.3 (38.8–45.8)1.26 (1.05–1.52)
      Year
       2006 (July)–20092761 (40.5)13,282 (40.9)582 (21.1)2291 (17.2)26.8 (24.7–29.0)21.7 (20.8–22.5)1.27 (1.15–1.39)
       2010–20122327 (34.1)11,112 (34.2)314 (13.5)1119 (10.1)25.9 (23.0–28.7)19.0 (17.9–20.1)1.37 (1.21–1.56)
       2013–20161727 (25.3)8065 (24.8)120 (6.9)347 (4.3)30.5 (25.0–36.0)18.6 (16.6–20.5)1.66 (1.34–2.05)
      Country of birth
       Nordic6608 (97.0)30,230 (93.1)987 (14.9)3521 (11.6)26.8 (25.2–28.5)20.5 (19.8–21.1)1.32 (1.22–1.42)
       Other207 (3.0)2226 (6.9)29 (14.0)236 (10.6)30.2 (19.2–41.1)20.9 (18.3–23.6)1.80 (0.57–5.70)
      Level of education, y
       ≤9150 (2.2)1312 (4.0)28 (18.7)191 (14.6)39.0 (24.6–53.5)27.7 (23.8–31.6)0.33 (0.03–3.20)
       10–122431 (35.7)12,409 (38.2)449 (18.5)1743 (14.0)33.1 (30.0–36.1)24.4 (23.3–25.6)1.23 (1.08–1.41)
       >124224 (62.0)18,624 (57.4)537 (12.7)1813 (9.7)22.9 (21.0–24.9)17.3 (16.5–18.1)1.30 (1.17–1.45)
      Psychiatric diagnoses in family
       Parents or sibling1400 (20.5)6818 (21.0)292 (20.9)1149 (16.9)42.4 (37.5–47.2)33.0 (31.1–34.9)1.46 (1.18–1.80)
      HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest attained education by parents.
      Supplementary Table 15Outcomes Restricted to Those With a Psychiatric Medication Prescription (July 2006-December 2016): Risk of Psychiatric Disorders in Patients With Celiac Disease and Matched General Population Comparators
      GroupEvents, N (%)Time at risk, yIncidence rate (95% CI) per 1000 PYHR
      Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.
      (95% CI)
      Celiac diseaseComparatorsCeliac diseaseComparatorsCeliac diseaseComparators
      Any psychiatric disorder1016 (14.9)3757 (11.6)37,750183,28726.9 (25.3–28.6)20.5 (19.8–21.2)1.34 (1.24–1.43)
      Antidepressants841 (12.3)3070 (9.5)38,377185,73321.9 (20.4–23.4)16.5 (15.9–17.1)1.35 (1.25–1.46)
      Anxiolytics, hypnotics, and sedatives947 (13.9)3526 (10.9)37,975183,98924.9 (23.3–26.5)19.2 (18.5–19.8)1.32 (1.23–1.42)
      Antipsychotics714 (10.5)2610 (8.0)38,735186,99518.4 (17.1–19.8)14.0 (13.4–14.5)1.34 (1.23–1.46)
      NOTE. n celiac disease/n comparators = 6,815 /32,459.
      HR, hazard ratio; PY, person-years.
      a Conditioned on matching set (age, sex, county, and calendar period) and adjusted further for the highest education attained by parents.

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