Psychiatric disorders in patients with a diagnosis of celiac disease during childhood from 1973 to 2016

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Introduction
In celiac disease, an immune-mediated enteropathy is triggered by intake of dietary gluten in genetically susceptible individuals. The prevalence is about 1-2% in the Western populations 1 and 0.3-2.9% in children, 2 with increasing rates in recent years. 3 In Europe, the highest prevalence is seen in Sweden and Finland, and lower rates in Germany. 4 Several studies describe the wide range of extraintestinal manifestations in celiac disease such as fatigue, 5 neurological conditions 6 including headache and neuropathy, 7 but also psychiatric disorders. 8 A study from 2017 showed a 1.4-fold increased risk of developing a future psychiatric disorder in children with celiac disease compared to the general population. 9 However, that study did not specifically evaluate the risk of psychiatric disorder in adulthood. While a few studies have reported an increased prevalence of neuropsychiatric disorders before a celiac disease diagnosis, 10 11 these have generally lacked in power to give 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. Through a computerized search of the ESPRESSO cohort (see Supplementary Table S1 for topography codes equivalent to the duodenum and jejunum; and for relevant SNOMED codes) we identified individuals with villus atrophy (Marsh III, in this study equivalent to celiac disease). An earlier patient chart validation found that 108/114 (95%) of patients with villus atrophy had celiac disease. 12 Since that validation was performed on individuals biopsied up until 2008, we (JFL) rereviewed the free text of 100 randomly selected biopsy reports with villus atrophy originating from 2009-2017. 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, JFL, March 23, 2020).
Since our outcome measure was any psychiatric disorder, we restricted our study to patients diagnosed during the years spanning 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. 13 None of the reference individuals had celiac disease at matching date, and if they developed celiac disease their follow-up was censored at the date of diagnosis.

Secondary reference individuals
In a separate analysis we compared 13,015 individuals with celiac disease with their non-celiac 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 ICD 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 S2). Psychiatric disorder data were obtained through the National Patient Register. For selected psychiatric disorders, this register has a positive predictive value of 85-95%. 14 15 While data on suicide attempt were retrieved from the Patient Register, data on suicide were obtained from the Cause of Death Register. ADHD was defined as having a relevant ADHD medication in the Prescribed Drug Register. 16

Statistics
We began follow-up on the date of celiac disease diagnosis (or corresponding date in the reference group). Follow-up ended with psychiatric diagnosis/suicide, death, emigration or Dec 31 2016, whichever occurred first. Cox proportional hazard model estimated hazard ratios (HRs) and 95% confidence intervals (Cis) for psychiatric disorder. Stratified analyses were performed according to years of follow-up (<1, 1<5, J o u r n a l P r e -p r o o f 5<10, 10<20, ≥20 years), age at celiac disease diagnosis (<2, 2-<6, 6-<, 11-<16, 16-<18) sex, level of parental education (≤9, 10-12 years, ≥13 years) and country of birth (Nordic, other). We repeated the analysis, now restricting the outcome definition to those with a prescription for a psychiatric drug in the Prescription Drug Register (for a list of included drugs see Supplementary Table S3). Since the Prescribed Drug Register started on July 1, 2005, this sensitivity analysis was carried out in celiac patients diagnosed from July 1, 2006 or later. In separate analyses we examined the risk of psychiatric disorders in celiac disease versus 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 17 and osteoporotic fracture, 18 we compared those children who had persistent villus atrophy to those whose villi healed in the subset of subjects who underwent 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 (18 years) during follow-up. 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 due to an underlying intellectual disability (triggering celiac testing and predisposing to a psychiatric disorder), we excluded anyone with a diagnosis of intellectual disability in a sensitivity analysis.
We used SAS v.9.4 and STATA v. 16.0 for all statistical analyses.

Ethics
J o u r n a l P r e -p r o o f Adults with childhood celiac disease had an elevated risk later for mood disorders, ADHD, and autism spectrum disorder (Supplementary Table S7). When repeating the analysis, now including all subjects regardless of whether they had been diagnosed with psychiatric disease prior to celiac disease diagnosis or prior to 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 diagnosis of intellectual disability prior to study entry (n celiac=19,101; n controls=93,612) the positive association with psychiatric disorders remained (HR = 1.18; 95%CI, 1.14-1.23).

Sibling comparisons
We repeated the above analyses using celiac-free siblings as comparators (n=18,024) restricting our cohort to 13,015 children with celiac disease and at least one sibling (Supplementary Table S8 shows participant characteristics). After conditioned on matching set (within family) and further adjustment for age and sex, celiac disease patients were at a 12% increased risk of psychiatric disorder compared to siblings (95%Cl=1.05-1.20). Sibling analyses yielded very similar data to those of our main analyses with general population reference individuals (Supplementary Table S9). Sibling comparisons found a J o u r n a l P r e -p r o o f 13 positive association between celiac disease and mood disorders, anxiety disorders, eating disorders, and autism spectrum disorder (Supplementary Table S10).

Sensitivity analyses
In a sensitivity analyses we defined psychiatric disorder as having a prescription for a psychiatric drug (

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 1973-2016. During follow-up, 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. 19 20 The overall risk for psychiatric disorder was highest in the first year after diagnosis. This may in part be due in part to surveillance bias, but it is also possible that the systemic inflammatory response is mediating this relationship. In addition to these purported mechanisms, the psychosocial stress associated with adapting to the gluten-free diet may be accounting for the early rise in 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 21 may lead to maladaptive eating patterns 22 23 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 due to the gluten-free diet alone, since we also observed an increased risk of psychiatric disorders preceding the diagnosis of celiac disease, possibly related to the systemic inflammatory response described above.

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. 24 Eating disorders 25 have likewise been linked to celiac disease, though autism has not, 11 despite the popular use of a gluten-free diet among children with this condition. 26

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 through 2016. This compares to 10,903 children followed through 2010 in a previous population-based study in Sweden. 9 This expanded sample size and followup allowed us to evaluate additional outcomes including long-term adult-onset psychiatric disease; to our knowledge, ours is the first study to examine the development of psychiatric disorder particularly in adults with celiac disease diagnosed in childhood. The large sample size and long-term follow-up (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 were also able to perform sensitivity analyses including a comparison to siblings and evaluation of mucosal healing. Our access to follow-up biopsy J o u r n a l P r e -p r o o f 16 data allowed us to examine potential mechanisms behind the association with psychiatric disorder; however, we found no link between mucosal healing (at least in the short term) and psychiatric disorders.
This study also has some limitations. The ICD-codes and thus the criteria used for psychiatric diagnoses (Supplementary Table S1) have changed throughout the years, and this might influence the rates of psychiatric diagnosis. As 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 diagnosis is associated with lower adherence to the gluten-free diet. 27 This may be due to the fact that mucosal healing is an imperfect marker of adherence, particularly given the possibility of gradual healing, i.e. persistent villus atrophy that eventually resolves with further time while maintaining the gluten-free diet.

Clinical implications
This study shows that, though small in absolute magnitude, there is an elevated risk of 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.

Conclusion
In conclusion, this nationwide population-based study including more than 19,000 children with celiac disease, found an increased risk of psychiatric disorder. This risk was highest in the first year after celiac

WHAT YOU NEED TO KNOW
Background: Little is known about the association between childhood celiac disease and longterm 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 risks 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.