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Celiac Disease Autoimmunity and Emotional and Behavioral Problems in Childhood

Rama J. Wahab, Sytske A. Beth, Ivonne P.M. Derks, Pauline W. Jansen, Henriëtte A. Moll and Jessica C. Kiefte-de Jong
Pediatrics October 2019, 144 (4) e20183933; DOI: https://doi.org/10.1542/peds.2018-3933
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Abstract

BACKGROUND AND OBJECTIVES: Celiac disease (CeD) is associated with psychopathology in children. It is unknown whether this association is present in children with celiac disease autoimmunity (CDA) identified by screening. We examined the associations between subclinical CDA and emotional and behavioral problems in children without previous CeD diagnosis.

METHODS: In a population-based cohort study of 3715 children (median age: 6 years), blood titers of tissue transglutaminase autoantibodies were analyzed. CDA was defined as a measurement of tissue transglutaminase autoantibodies ≥7 U/mL (n = 51). Children with previous CeD diagnosis or children on a gluten-free diet, were excluded. The Child Behavior Checklist (CBCL) was filled in by parents and was used to assess behavioral and emotional problems of children at a median age of 5.9 years. Multiple linear regression models were applied to evaluate the cross-sectional associations between CDA and CBCL scores. Sensitivity analyses were done in a subgroup of children who were seropositive carrying the HLA antigen risk alleles for CeD.

RESULTS: In basic models, CDA was not associated with emotional and behavioral problems on the CBCL scales. After adjustment for confounders, CDA was significantly associated with anxiety problems (β = .29; 95% confidence interval 0.02 to 0.55; P = .02). After exclusion of children who did not carry the HLA-DQ2 and/or HLA-DQ8 risk alleles (n = 4), CDA was additionally associated with oppositional defiant problems (β = .35; 95% confidence interval 0.02 to 0.69). Associations were not explained by gastrointestinal complaints.

CONCLUSIONS: Our results reveal that CDA, especially combined with the HLA-DQ2 and HLA-DQ8 risk alleles, is associated with anxiety problems and oppositional defiant problems. Further research should be used to establish whether behavioral problems are a reflection of subclinical CeD.

  • Abbreviations:
    CBCL —
    Childhood Behavioral Checklist
    CDA —
    celiac disease autoimmunity
    CeD —
    celiac disease
    CI —
    confidence interval
    DSM —
    Diagnostic and Statistical Manual of Mental Disorders
    SDS —
    standard deviant score
    SNP —
    single-nucleotide polymorphism
    TG2A —
    tissue transglutaminase autoantibody

    • What’s Known on This Subject:

    Diagnosed celiac disease (CeD) has been linked with several emotional and behavioral problems in children, including anxiety, depression, and aggressive behavior. However, whether this association is already present in children with subclinical CeD identified by screening is unknown.

    What This Study Adds:

    Screening-based celiac disease autoimmunity is associated with anxiety and oppositional defiant problems in children with subclinical CeD identified by screening, independent of gastrointestinal complaints.

    Celiac disease (CeD) is a common immune-mediated chronic disease with an estimated prevalence of nearly 1% in the general pediatric population.1 However, ∼80% of patients are not diagnosed and, thus, untreated.2–4 This can partially be explained by the heterogeneous clinical presentation. Complaints can vary from diarrhea and abdominal distention to nonspecific symptoms such as fatigue or anemia.1 Also, extraintestinal manifestations have been reported,1,5 including emotional and behavioral problems in childhood.6–13 The mechanism of psychological symptoms in CeD remains unclear. Because studies have revealed that psychological symptoms may also emerge before CeD diagnosis in adults, psychological symptoms could only be partly a consequence of disease awareness and the gluten-free diet.11,14 Mechanisms underlying psychological symptoms in unknown CeD may be somatic complaints because of unrecognized CeD,15 nutrient malabsorption,16 or alterations in the gut-brain axis.17,18 Although psychological symptoms in early life predispose to psychopathology in later life and contribute to a lower quality of life,19,20 previous studies have revealed that CeD-related psychopathology resolves under treatment with a gluten-free diet.7,21,22 This emphasizes the need for early identification and, thus, treatment of CeD.19,20,23 However, information on the effect of diagnosis and treatment in patients with celiac disease autoimmunity (CDA) identified by screening is scarce.23,24 To our knowledge, only 1 study has been conducted on psychological manifestations in children with subclinical CeD identified by screening, and this study revealed contradictory results.13

    Therefore, we aimed to investigate whether screening-identified CDA was associated with emotional and behavioral problems in children at the age of 6 years.

    Methods

    Study Design and Subjects

    This study was embedded in the Generation R Study, a population-based, prospective cohort study consisting of 9778 pregnant mothers and their offspring in the region of Rotterdam, Netherlands. Children were born between April 2002 and January 2006 and followed from fetal life until adolescence, as described in detail previously.25,26 At 6 years of age, 6690 children visited the research center. Tissue transglutaminase autoantibody (TG2A) titers were available for 4442 children (median age of 6 years [SD 0.55; range 4.93−9.12]). One child per twin pair (n = 59) and children who consulted a doctor because of CeD (n = 10) or were on a gluten-free diet without CeD diagnosis (n = 6) were excluded (Fig 1). Of the remaining 4365 children with TG2A titers available, parents of 3715 children completed the questionnaire about child mental health. Thus, the final sample consisted of 3715 children for analysis. However, the number for analysis for separate Childhood Behavioral Checklist (CBCL) scales was slightly lower because of missing values. Written consent was obtained from parents of all participants. Approval for the study was obtained from the Medical Ethical Committee of Erasmus University Medical Center (Rotterdam, Netherlands).

    FIGURE 1
    FIGURE 1

    Flowchart of the study participants. IgA, immunoglobulin A.

    CDA

    CDA was defined as a single positive measurement of TG2A without the presence of any classic CeD symptoms. TG2A measurement was considered positive at ≥7 U/mL, according to the manufacturer’s instructions (Phadia AB, Uppsala, Sweden). At the children’s visit to the research center at 6 years of age, blood samples were drawn and stored at room temperature before being transported to the regional laboratory for storage at −80°C.25 In 2013, when follow-up of the whole cohort was completed, TG2A titers were analyzed by using a fluorescence enzyme immunoassay (EliA Celikey IgA, Phadia ImmunoCAP 250; Phadia AB) at the Department of Immunology of Erasmus University Medical Center. Intra- and interassay coefficients of variability were <10% and 15% respectively.

    Measurement of TG2A was performed on a screening basis. Children and caregivers were not aware of the measurement of TG2A. If TG2A titers resulted positive in children without a previous diagnosis of CeD, children were referred to the pediatric gastroenterology department for further follow-up.27

    Emotional and Behavioral Problems

    Emotional and behavioral problems were assessed by using the CBCL for children age 1.5 to 5 years (median age of 5.9 years).28 The CBCL is a questionnaire that includes 99 items describing child behaviors that are to be completed by the primary caregiver (89% mothers in the current study). CBCL items can be scored on 2 broadband scales: internalizing and externalizing problems. These scales are used to capture emotional and behavioral problems, respectively. The broadband scales cover more specific syndrome scales. The internalizing composite includes the emotionally reactive, anxious and/or depressed, somatic complaints, and withdrawn syndrome scales. The externalizing composite covers attention problems and aggressive behavior. The CBCL score is also used to evaluate Diagnostic and Statistical Manual of Mental Disorders (DSM)–oriented scales, which are based on criteria of disorders described in the DSM. DSM-oriented scales include the affective, anxiety, pervasive development, attention-deficit/hyperactivity, and oppositional defiant problems scales. These scales help to relate the assessment of emotional and behavioral problems to DSM categories. DSM scales are more clinically oriented but are less scientifically substantiated.28 Emotional and behavioral problems were measured on both the empirical syndrome scales and the DSM scales. The CBCL is a widely used instrument and has been demonstrated to have good reliability and validity.28

    Covariates

    Age and anthropometric data were collected during the children’s visit to the research center. BMI was calculated. We obtained age-adjusted standard deviant scores (SDSs) using Dutch reference growth curves (Growth Analyzer 3.0; Dutch Growth Research Foundation, Rotterdam, Netherlands).29 The HLA antigen risk profile for CeD was defined as the presence of HLA-DQ2.5 (DQA1*05/DQB1*02), HLA-DQ2.2 (DQA1*02/DQB1*02), or HLA-DQ8 (DQA1*0301/DQB1*0302). A genome-wide association scan (Illumia 610K) of child DNA was taken from cord blood samples. Genotyping was done by using EUROarray according to the manufacturer’s instructions (Euroimmun AG, Lübeck, Germany). The tag single-nucleotide polymorphism (SNP) typing method was used to determine if a child carried the HLA-DQ2 (rs2187668, rs2395182, rs4713586, and rs7775228) and/or HLA-DQ8 (rs7454108) allele, as described in detail previously by Monsuur et al30,31 Sex and birth weight were obtained from obstetric records.32 Ethnicity was based on the country where parents were born, according to criteria used in a previous study.33 Data on maternal income and education level were obtained at enrollment through questionnaires. Classification of income and educational level was based on the classification of Statistics Netherlands.34,35 Gastrointestinal complaints over the past 3 months were assessed in children at a median age of 6 years by using parent-reported questionnaires. Obstipation was defined as present if the following symptoms of Rome III were reported in the past year for at least 2 weeks in a row: defecation frequency <3 times a week, predominantly hard feces for the majority of stools, and ≥1 episode of fecal incontinence per week. Mothers were asked if their child had abdominal pain at least once a week (yes or no) and if their child had diarrhea (“very soft/slushy” or “watery” looking feces).36 Maternal antibody titers were measured during the second trimester of pregnancy. Titers were analyzed as previously described.

    Statistical Analysis

    First, to compare the characteristics of CDA and non-CDA groups, independent t tests, Mann–Whitney U tests, and χ2 tests were performed. Second, given the absence of normality, square root transformation was performed on CBCL scores, and CBCL scores were standardized into z scores.

    Associations between child CDA and CBCL scales were evaluated by using linear regression analyses, with CDA (TG2A-negative titers versus TG2A-positive titers) as an independent variable and the continuous CBCL z scores as dependent variables. We created 4 models for regression: a basic model without any adjustment, an adjusted model with adjustment for confounders, and 2 mediation models consisting of the adjusted model with additional adjustment for BMI and a model with additional adjustment for gastrointestinal complaints on top of adjustment for BMI. Potential confounders (sex, HLA antigen risk profile, sociodemographic factors [income, education], ethnicity, maternal TG2A seropositivity, and birth weight) included in the adjusted model were based on associations described in the literature and were included in the model when they attained a >10% change in effect size, as suggested by Mickey and Greenland,37 determined for the CBCL scales separately.

    Because it can be argued that BMI is in the pathway between CeD and emotional and behavioral problems,17,38 an additional model was created for BMI. Likewise, because gastrointestinal complaints may be a collider (ie, common effect of exposure and outcome) instead of a confounder, we additionally adjusted for gastrointestinal problems.

    A sensitivity analysis was performed to evaluate the robustness of our results. In these analyses, children with TG2A titers with positive results and without the HLA antigen risk alleles were excluded.

    To reduce selection bias due to missing data, multiple imputations of covariates (pooled results of 10 imputed data sets) were performed. Covariates with missing values were HLA antigen risk profile, maternal income, maternal educational level, and ethnicity, obstipation, abdominal pain, and stool consistence, as detailed in Supplemental Tables 4 and 5. P < .05 was considered statistically significant. All analyses were performed by using SPSS version 24.0 for Windows (IBM SPSS Statistics, IBM Corporation, Armonk, NY).

    Results

    Subject Characteristics

    Maternal and child characteristics are shown in Table 1. At the age of 6 years, 51 children had CDA (1.4%) (Fig 1). Of children with CDA, 92.2% carried the HLA-DQ2 or HLA-DQ8 allele (Table 1). Female sex, HLA-DQ2 and/or HLA-DQ8 positivity, Western ethnicity, lower BMI, and maternal TG2A titers with positive results were related to CDA (Table 1). Data on the internalizing CBCL composite were available for 3686 children (99.2%), and data on the externalizing CBCL composite were available for 3703 children (99.7%) (Fig 1).

    View this table:
    TABLE 1

    Characteristics According to CDA

    CDA and Emotional and Behavioral Problems

    Median CBCL scores per scale for children with and without CDA are provided in Table 2.

    View this table:
    TABLE 2

    Median CBCL Scores According to CDA

    In basic models, no significant associations were found between CBCL syndrome scales and CDA (Supplemental Table 6). Adjustment for confounders and additional adjustment for BMI only changed the effect estimates slightly. After adjustment for gastrointestinal complaints, association between CDA and aggressive behavior was borderline significant (adjusted β = .32; 95% confidence interval [CI] 0.00 to 0.65; P = .05). In basic models, no significant associations were found between CDA and the DSM-oriented scales. After adjustment for confounders, CDA was associated with a significantly higher CBCL score on the anxiety scale (adjusted β = .29; 95% CI 0.02 to 0.55; P = .02) and a borderline significantly higher score on the oppositional defiant problems scale (confounder adjusted β = .33; 95% CI 0.00 to 0.65; P = .05) (Table 3). Additional adjustment for BMI had no influence on effect size. Additional adjustment for gastrointestinal complaints revealed a stronger association on the anxiety scale (adjusted β = .31; 95% CI 0.04 to 0.57; P = .01) and oppositional defiant problems scale (adjusted β = .35; 95% CI 0.02 to 0.67; P = .02).

    View this table:
    TABLE 3

    Association of CDA With CBCL Scores

    Emotional and Behavioral Problems in HLA-DQ2–Positive and/or HLA-DQ8–Positive Children

    For sensitivity analyses TG2A-positive children who were not carrying HLA-DQ2 and HLA-DQ8 alleles (n = 4) were excluded. In the HLA-DQ2–positive and HLA-DQ8–positive children, CDA was borderline significantly associated with a higher score on the aggressive behavior subscale on the syndrome scale after adjustment for confounders (adjusted β = .32; 95% CI 0.00 to 0.65; P = .05). On the DSM-oriented scales, children with CDA who were carrying the HLA-DQ2 and/or HLA-DQ8 alleles had a higher score on the anxiety scale (adjusted β = .38; 95% CI 0.08 to 0.67) and the oppositional defiant problems scale (adjusted β = .35; 95% CI 0.02 to 0.69; P = .04) after adjustment for confounders. Gastrointestinal complaints could partly explain association with the oppositional defiant problems scale (adjusted β = .34; 95% CI 0.00 to 0.68; P = .05). Additional adjustment for BMI had no influence on effect size.

    Discussion

    This observational, population-based study revealed that subclinical CDA might be associated with anxiety problems in a population-based cohort of 6-year-old children. The association we found was stronger in children with CDA who were carrying the HLA-DQ2 and/or HLA-DQ8 allele. Additional associations were found with oppositional defiant problems and aggressive behavior in the subgroup carrying the HLA-DQ2 and/or HLA-DQ8 allele. However, no associations were found on the empirical broadband scales of internalizing and externalizing problems.

    Previous studies have revealed a positive association between psychopathological manifestations, including anxiety problems, and CeD in children with symptoms who were diagnosed with CeD.6–8,11,39 Our results reveal that anxiety problems might even occur in children with CDA identified by screening who are unaware of any disease or positive serology. As far as we know, only 1 other study has been conducted to evaluate psychological symptoms in children identified by screening who are unaware of their CDA status.13 Comparable to our results, Smith et al13 reported associations between CDA and anxiety, depression, aggressive behavior, and sleep problems in children age 3.5 years. However, associations were not confirmed in follow-up at age 4.5 years.13 The inconsistency of the associations could have been caused by the lack of adjustment for confounders. For example, Smith et al13 did not adjust for ethnicity and sociodemographic factors, which we found to be highly associated with emotional and behavioral problems and CDA.

    The etiology of emotional and behavioral problems in CeD has yet to be established. The question rises whether emotional and behavioral problems are caused through pathologic pathways of CeD or are a secondary psychological effect of the diagnosis and/or gastrointestinal complaints. The current study involves a population that was unaware of its current CDA status, which ruled out an effect of diagnosis or disease awareness. Furthermore, after additional adjustment for gastrointestinal complaints, the association persisted. Therefore, gastrointestinal complaints related to CeD cannot explain the association between CDA and psychological problems. This suggests that underlying pathologic mechanisms might explain the association between psychopathology and CDA in our cohort. Several hypotheses have been proposed in the literature to explain these mechanisms. First, depression and anxiety disorders have been linked to deficiencies of multiple nutrients such as folate and omega-3 polyunsaturated fatty acid.40–45 These nutrients are essential components in the central nervous system and are involved in brain development, neuroprotection, and neurotransmitter transport.44,46 Children suffering from these nutrient deficiencies have a greater risk of developing behavioral problems.46 CeD is associated with deficiencies of these nutrients that are caused by malabsorption due to villous atrophy.16,47,48 Second, recent studies suggest that the intestinal microbiome may play an important role in the pathogenesis of CeD.49 The intestinal microbiome is suggested to be highly associated with the gut-brain axis,50,51 a system between the brain and gastrointestinal tract that links emotional and cognitive centers of the brain with peripheral functioning of the digestive tract.52 Studies have revealed changes of the microbiome in children with autism.53,54 Additionally, in children with anxiety and depression disorders, probiotics seem to have an influence on psychological well-being, suggesting that the microbiome might have a role in these disorders as well.55 Patients with CeD also have alterations in their intestinal microbiome,17 suggesting that the microbiome might be involved in the psychopathology in patients with CeD. We found stronger associations in the group carrying the HLA-DQ2 and/or HLA-DQ8 allele. Given the high sensitivity and specificity of TG2A, children with CDA who are carrying the HLA-DQ2 and/or HLA-DQ8 haplotype are at increased risk of developing CeD. On the contrary, children without the HLA antigen risk alleles have a negligible chance of developing CeD1,56 and, thus, are not likely to have any of the pathology and mechanisms related to CeD. The stronger associations we found when excluding these children support that CeD-related mechanisms could partially explain anxiety symptoms in patients with CeD instead of a secondary psychological effect of the diagnosis or complaints.

    A major strength of our study is the population-based design, including a large cohort of children with data on a wide range of possible confounding variables available.

    However, limitations should be taken into account, too. First, although sensitivity and specificity of TG2A are high (>95%),1 information on additional antibody testing, such as antiendomysium and biopsies of all TG2A-positive children, was not available. This precluded definite diagnoses of CeD. From 26 children (51%), we had consent to obtain information through medical records on biopsies. Of these children, 23 showed Marsh grade II or III villous atrophy and were diagnosed with CeD. The remaining 3 had Marsh grade I with TG2A titers >10 ULN and required follow-up. Further research should be used to evaluate whether children with elevated TG2A levels identified by screening do have CeD or develop CeD over time.27 We determined presence of the HLA-DQ2 and/or HLA-DQ8 alleles to enhance the identification of children at risk for developing CeD. Remarkably, we observed that 4 children with elevated TG2A titers did not carry the HLA-DQ2 and/or HLA-DQ8 alleles, whereas CeD is restricted to those who carry these alleles. Two of these children had TG2A titers with strong positive results (>10 ULN), and the other 2 children had titers of 65 U/mL and 11 U/mL, respectively. Two children were of non-Western ethnicity. The absence of the HLA antigen risk alleles in these children could have been due to the use of a tag SNP approach of HLA antigen typing.30 Although the tag SNP approach has high positive and negative predicted values in a population with CeD diagnosis, a slightly higher rate of false-positives and false-negatives may be expected in the general population.30 Another limitation was the use of a parent report on emotional and behavioral problems in children. An additional clinical observation would give less subjective measurements. However, the CBCL was proven to be reliable in previous studies.28,57 As in any observational study, residual confounding should be taken into account. We were not able to adjust for all potential confounding factors, such as having siblings with CeD or presence of other autoimmune diseases. Also, because the etiology of CeD is largely unknown, the possibility exists of unknown confounders related to CeD and emotional and behavioral problems.

    Our results reveal that anxiety problems might already be present among children who are screened and unaware of their CDA status. Because it is known that psychological symptoms may improve under treatment with a gluten-free diet,7,22 early diagnosis and treatment of CeD could prevent further development or deterioration of psychopathology in these children. However, information on the effect of diagnosis and treatment on patients identified by screening is scarce.23,24 Further research should be done to determine the effect of treatment on anxiety problems in children with CDA to evaluate if children could benefit from early diagnosis of CeD. Furthermore, our results suggest that clinicians should be aware of CeD in children with reported unexplained anxiety, oppositional defiant problems, and aggressive behavior.

    Conclusions

    Our results do not support the hypothesis that subclinical CDA is associated with the broadband internalizing” and externalizing scales of the CBCL scale. However, our results suggest that subclinical CDA might be associated with anxiety and oppositional defiant problems in 6-year-old children. Further research should be done to evaluate whether behavioral problems can be improved by a gluten-free diet in children with CDA identified by screening.

    Acknowledgments

    The Generation R Study is conducted by the Erasmus University Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and Stichting Trombosedienst & Artsenlaboratorium Rijnmond. We acknowledge the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam.

    Footnotes

      • Accepted July 12, 2019.
    • Address correspondence to Jessica C. Kiefte-de Jong, PhD, Department of Public Health and Primary Care, Campus The Hague, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. E-mail: j.c.kiefte{at}lumc.nl

    • COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-1683.

    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: Supported by Erasmus University Medical Center, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development, and NutsOhra. The sponsors had no role in the design of the study, the data collection and analyses, the interpretation of data, the preparation and review of the manuscript, and the decision to submit the manuscript.

    • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

    References

    1. ↵
      1. Husby S,
      2. Koletzko S,
      3. Korponay-Szabó IR, et al
      ; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease [published correction appears in J Pediatr Gastroenterol Nutr. 2012;54(4):572]. J Pediatr Gastroenterol Nutr. 2012;54(1):136–160
      OpenUrlCrossRefPubMed
    2. ↵
      1. Vriezinga SL,
      2. Auricchio R,
      3. Bravi E, et al
      . Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014;371(14):1304–1315
      OpenUrlCrossRefPubMed
      1. Steens RF,
      2. Csizmadia CG,
      3. George EK,
      4. Ninaber MK,
      5. Hira Sing RA,
      6. Mearin ML
      . A national prospective study on childhood celiac disease in the Netherlands 1993-2000: an increasing recognition and a changing clinical picture. J Pediatr. 2005;147(2):239–243
      OpenUrlCrossRefPubMed
    4. ↵
      1. Rubio-Tapia A,
      2. Ludvigsson JF,
      3. Brantner TL,
      4. Murray JA,
      5. Everhart JE
      . The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107(10):1538–1544; quiz 1537, 1545
      OpenUrlCrossRefPubMed
    5. ↵
      1. Lebwohl B,
      2. Ludvigsson JF,
      3. Green PH
      . Celiac disease and non-celiac gluten sensitivity. BMJ. 2015;351:h4347
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Rosenspire A,
      2. Yoo W,
      3. Menard S,
      4. Torres AR
      . Autism spectrum disorders are associated with an elevated autoantibody response to tissue transglutaminase-2. Autism Res. 2011;4(4):242–249
      OpenUrlPubMed
    7. ↵
      1. Niederhofer H,
      2. Pittschieler K
      . A preliminary investigation of ADHD symptoms in persons with celiac disease. J Atten Disord. 2006;10(2):200–204
      OpenUrlCrossRefPubMed
    8. ↵
      1. Pynnönen PA,
      2. Isometsä ET,
      3. Aronen ET,
      4. Verkasalo MA,
      5. Savilahti E,
      6. Aalberg VA
      . Mental disorders in adolescents with celiac disease. Psychosomatics. 2004;45(4):325–335
      OpenUrlCrossRefPubMed
      1. Barcia G,
      2. Posar A,
      3. Santucci M,
      4. Parmeggiani A
      . Autism and coeliac disease. J Autism Dev Disord. 2008;38(2):407–408
      OpenUrlCrossRefPubMed
      1. Zingone F,
      2. Swift GL,
      3. Card TR,
      4. Sanders DS,
      5. Ludvigsson JF,
      6. Bai JC
      . Psychological morbidity of celiac disease: a review of the literature. United European Gastroenterol J. 2015;3(2):136–145
      OpenUrlCrossRefPubMed
    11. ↵
      1. Butwicka A,
      2. Lichtenstein P,
      3. Frisén L,
      4. Almqvist C,
      5. Larsson H,
      6. Ludvigsson JF
      . Celiac disease is associated with childhood psychiatric disorders: a population-based study. J Pediatr. 2017;184:87–93.e1
      OpenUrl
      1. Slim M,
      2. Rico-Villademoros F,
      3. Calandre EP
      . Psychiatric comorbidity in children and adults with gluten-related disorders: a narrative review. Nutrients. 2018;10(7):E875
      OpenUrl
    13. ↵
      1. Smith LB,
      2. Lynch KF,
      3. Kurppa K, et al
      ; TEDDY study group. Psychological manifestations of celiac disease autoimmunity in young children. Pediatrics. 2017;139(3):e20162848
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Ludvigsson JF,
      2. Reutfors J,
      3. Osby U,
      4. Ekbom A,
      5. Montgomery SM
      . Coeliac disease and risk of mood disorders–a general population-based cohort study. J Affect Disord. 2007;99(1–3):117–126
      OpenUrlCrossRefPubMed
    15. ↵
      1. Mattila E,
      2. Kurppa K,
      3. Ukkola A, et al
      . Burden of illness and use of health care services before and after celiac disease diagnosis in children. J Pediatr Gastroenterol Nutr. 2013;57(1):53–56
      OpenUrlCrossRefPubMed
    16. ↵
      1. Hernanz A,
      2. Polanco I
      . Plasma precursor amino acids of central nervous system monoamines in children with coeliac disease. Gut. 1991;32(12):1478–1481
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Lebwohl B,
      2. Sanders DS,
      3. Green PHR
      . Coeliac disease. Lancet. 2018;391(10115):70–81
      OpenUrlCrossRefPubMed
    18. ↵
      1. Nguyen TT,
      2. Kosciolek T,
      3. Eyler LT,
      4. Knight R,
      5. Jeste DV
      . Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. J Psychiatr Res. 2018;99:50–61
      OpenUrl
    19. ↵
      1. Roza SJ,
      2. Hofstra MB,
      3. van der Ende J,
      4. Verhulst FC
      . Stable prediction of mood and anxiety disorders based on behavioral and emotional problems in childhood: a 14-year follow-up during childhood, adolescence, and young adulthood. Am J Psychiatry. 2003;160(12):2116–2121
      OpenUrlCrossRefPubMed
    20. ↵
      1. Petty CR,
      2. Rosenbaum JF,
      3. Hirshfeld-Becker DR, et al
      . The child behavior checklist broad-band scales predict subsequent psychopathology: a 5-year follow-up. J Anxiety Disord. 2008;22(3):532–539
      OpenUrlPubMed
    21. ↵
      1. Lichtwark IT,
      2. Newnham ED,
      3. Robinson SR, et al
      . Cognitive impairment in coeliac disease improves on a gluten-free diet and correlates with histological and serological indices of disease severity. Aliment Pharmacol Ther. 2014;40(2):160–170
      OpenUrlCrossRefPubMed
    22. ↵
      1. Niederhofer H
      . Association of attention-deficit/hyperactivity disorder and celiac disease: a brief report. Prim Care Companion CNS Disord. 2011;13(3):PCC.10br01104
      OpenUrl
    23. ↵
      1. Chou R,
      2. Bougatsos C,
      3. Blazina I,
      4. Mackey K,
      5. Grusing S,
      6. Selph S
      . Screening for celiac disease: evidence report and systematic review for the US preventive services task force. JAMA. 2017;317(12):1258–1268
      OpenUrl
    24. ↵
      1. Mearin ML
      . The prevention of coeliac disease. Best Pract Res Clin Gastroenterol. 2015;29(3):493–501
      OpenUrl
    25. ↵
      1. Kruithof CJ,
      2. Kooijman MN,
      3. van Duijn CM, et al
      . The Generation R Study: biobank update 2015. Eur J Epidemiol. 2014;29(12):911–927
      OpenUrlCrossRefPubMed
    26. ↵
      1. Kooijman MN,
      2. Kruithof CJ,
      3. van Duijn CM, et al
      . The Generation R Study: design and cohort update 2017. Eur J Epidemiol. 2016;31(12):1243–1264
      OpenUrlCrossRefPubMed
    27. ↵
      1. Jansen M,
      2. van Zelm M,
      3. Groeneweg M, et al
      . The identification of celiac disease in asymptomatic children: the Generation R Study. J Gastroenterol. 2018;53(3):377–386
      OpenUrl
    28. ↵
      1. Achenbach TM,
      2. Rescorla LA
      . Manual for the ASEBA Preschool Forms & Profiles. Burlington, VT: University of Vermont, Research Center for Children, Youth, and Families; 2000
    29. ↵
      1. Durmus B,
      2. Kruithof CJ,
      3. Gillman MH, et al
      . Parental smoking during pregnancy, early growth, and risk of obesity in preschool children: the Generation R Study. Am J Clin Nutr. 2011;94(1):164–171
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Monsuur AJ,
      2. de Bakker PI,
      3. Zhernakova A, et al
      . Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms. PLoS One. 2008;3(5):e2270
      OpenUrlCrossRefPubMed
    31. ↵
      1. Jansen MA,
      2. Kiefte-de Jong JC,
      3. Gaillard R, et al
      . Growth trajectories and bone mineral density in anti-tissue transglutaminase antibody-positive children: the Generation R Study. Clin Gastroenterol Hepatol. 2015;13(5):913–920.e5
      OpenUrl
    32. ↵
      1. Jaddoe VW,
      2. van Duijn CM,
      3. Franco OH, et al
      . The Generation R Study: design and cohort update 2012. Eur J Epidemiol. 2012;27(9):739–756
      OpenUrlCrossRefPubMed
    33. ↵
      1. Jansen MAE,
      2. Beth SA,
      3. van den Heuvel D, et al
      . Ethnic differences in coeliac disease autoimmunity in childhood: the Generation R Study. Arch Dis Child. 2017;102(6):529–534
      OpenUrlAbstract/FREE Full Text
    34. ↵
      Statistics Netherlands. Dutch Standard Classification of Education. Voorburg, Netherlands: Statistics Netherlands; 2004
    35. ↵
      Statistics Netherlands. Welfare in the Netherlands: Income, Welfare and Spending of Households and Individuals. The Hague, Netherlands: Statistics Netherlands; 2012
    36. ↵
      1. Rasquin A,
      2. Di Lorenzo C,
      3. Forbes D, et al
      . Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006;130(5):1527–1537
      OpenUrlCrossRefPubMed
    37. ↵
      1. Mickey RM,
      2. Greenland S
      . The impact of confounder selection criteria on effect estimation [published correction appears in Am J Epidemiol. 1989;130(5):1066]. Am J Epidemiol. 1989;129(1):125–137
      OpenUrlCrossRefPubMed
    38. ↵
      1. Camfferman R,
      2. Jansen PW,
      3. Rippe RC, et al
      . The association between overweight and internalizing and externalizing behavior in early childhood. Soc Sci Med. 2016;168:35–42
      OpenUrl
    39. ↵
      1. D’Amico MA,
      2. Holmes J,
      3. Stavropoulos SN, et al
      . Presentation of pediatric celiac disease in the United States: prominent effect of breastfeeding. Clin Pediatr (Phila). 2005;44(3):249–258
      OpenUrlCrossRefPubMed
    40. ↵
      1. Zhao G,
      2. Ford ES,
      3. Li C,
      4. Greenlund KJ,
      5. Croft JB,
      6. Balluz LS
      . Use of folic acid and vitamin supplementation among adults with depression and anxiety: a cross-sectional, population-based survey. Nutr J. 2011;10:102
      OpenUrlPubMed
      1. Morris MS,
      2. Fava M,
      3. Jacques PF,
      4. Selhub J,
      5. Rosenberg IH
      . Depression and folate status in the US Population. Psychother Psychosom. 2003;72(2):80–87
      OpenUrlCrossRefPubMed
      1. Vinot N,
      2. Jouin M,
      3. Lhomme-Duchadeuil A, et al
      . Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate. PLoS One. 2011;6(6):e20491
      OpenUrlCrossRefPubMed
      1. Jacka FN,
      2. Pasco JA,
      3. Williams LJ,
      4. Meyer BJ,
      5. Digger R,
      6. Berk M
      . Dietary intake of fish and PUFA, and clinical depressive and anxiety disorders in women. Br J Nutr. 2013;109(11):2059–2066
      OpenUrlCrossRefPubMed
    44. ↵
      1. Sanchez-Villegas A,
      2. Henríquez P,
      3. Figueiras A,
      4. Ortuño F,
      5. Lahortiga F,
      6. Martínez-González MA
      . Long chain omega-3 fatty acids intake, fish consumption and mental disorders in the SUN cohort study. Eur J Nutr. 2007;46(6):337–346
      OpenUrlCrossRefPubMed
    45. ↵
      1. Anglin RE,
      2. Samaan Z,
      3. Walter SD,
      4. McDonald SD
      . Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013;202:100–107
      OpenUrlAbstract/FREE Full Text
    46. ↵
      1. Prado EL,
      2. Dewey KG
      . Nutrition and brain development in early life. Nutr Rev. 2014;72(4):267–284
      OpenUrlCrossRefPubMed
    47. ↵
      1. Tárnok A,
      2. Marosvölgyi T,
      3. Szabó É,
      4. Györei E,
      5. Decsi T
      . Low n-3 long-chain polyunsaturated fatty acids in newly diagnosed celiac disease in children with preexisting type 1 diabetes mellitus. J Pediatr Gastroenterol Nutr. 2015;60(2):255–258
      OpenUrl
    48. ↵
      1. Leonard MM,
      2. Sapone A,
      3. Catassi C,
      4. Fasano A
      . Celiac disease and nonceliac gluten sensitivity: a review. JAMA. 2017;318(7):647–656
      OpenUrl
    49. ↵
      1. Ou G,
      2. Hedberg M,
      3. Hörstedt P, et al
      . Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am J Gastroenterol. 2009;104(12):3058–3067
      OpenUrlCrossRefPubMed
    50. ↵
      1. Rhee SH,
      2. Pothoulakis C,
      3. Mayer EA
      . Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 2009;6(5):306–314
      OpenUrlCrossRefPubMed
    51. ↵
      1. Petra AI,
      2. Panagiotidou S,
      3. Hatziagelaki E,
      4. Stewart JM,
      5. Conti P,
      6. Theoharides TC
      . Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther. 2015;37(5):984–995
      OpenUrlCrossRefPubMed
    52. ↵
      1. Jenkins TA,
      2. Nguyen JC,
      3. Polglaze KE,
      4. Bertrand PP
      . Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients. 2016;8(1):E56
      OpenUrl
    53. ↵
      1. Adams JB,
      2. Johansen LJ,
      3. Powell LD,
      4. Quig D,
      5. Rubin RA
      . Gastrointestinal flora and gastrointestinal status in children with autism–comparisons to typical children and correlation with autism severity. BMC Gastroenterol. 2011;11:22
      OpenUrlCrossRefPubMed
    54. ↵
      1. De Angelis M,
      2. Piccolo M,
      3. Vannini L, et al
      . Fecal microbiota and metabolome of children with autism and pervasive developmental disorder not otherwise specified. PLoS One. 2013;8(10):e76993
      OpenUrlCrossRefPubMed
    55. ↵
      1. Foster JA,
      2. McVey Neufeld KA
      . Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305–312
      OpenUrlCrossRefPubMed
    56. ↵
      1. Karell K,
      2. Louka AS,
      3. Moodie SJ, et al
      ; European Genetics Cluster on Celiac Disease. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol. 2003;64(4):469–477
      OpenUrlCrossRefPubMed
    57. ↵
      1. Ivanova MY,
      2. Achenbach TM,
      3. Rescorla LA, et al
      . Preschool psychopathology reported by parents in 23 societies: testing the seven-syndrome model of the child behavior checklist for ages 1.5-5. J Am Acad Child Adolesc Psychiatry. 2010;49(12):1215–1224
      OpenUrlPubMed
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    Pediatrics
    Vol. 144, Issue 4
    1 Oct 2019
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    Celiac Disease Autoimmunity and Emotional and Behavioral Problems in Childhood
    Rama J. Wahab, Sytske A. Beth, Ivonne P.M. Derks, Pauline W. Jansen, Henriëtte A. Moll, Jessica C. Kiefte-de Jong
    Pediatrics Oct 2019, 144 (4) e20183933; DOI: 10.1542/peds.2018-3933
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