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Original Investigation
December 5, 2018

A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents

Author Affiliations
  • 1Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
  • 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  • 3Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
  • 4The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
  • 5The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark
  • 6Centre for Integrated Register-based Research at Aarhus University (CIRRAU), Aarhus, Denmark
  • 7Department of Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway
  • 8Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Psychiatry. Published online December 5, 2018. doi:10.1001/jamapsychiatry.2018.3428
Key Points

Question  Do infections increase the risk of subsequent mental disorders during childhood and adolescence?

Findings  This nationwide register-based cohort study that included 1 098 930 individuals born in Denmark between 1995 and 2012 found that severe infections requiring hospitalizations increased the risk of hospital contacts due to mental disorders by 84% and the risk of psychotropic medication use by 42%. Less severe infection treated with anti-infective agents increased the risks by 40% and 22%, respectively; the risks differed among specific mental disorders.

Meaning  These findings may be explained by consequences of infections on the developing brain and by other confounding factors, such as genetics or socioeconomic factors.

Abstract

Importance  Infections have been associated with increased risks for mental disorders, such as schizophrenia and depression. However, the association between all infections requiring treatment and the wide range of mental disorders is unknown to date.

Objective  To investigate the association between all treated infections since birth and the subsequent risk of development of any treated mental disorder during childhood and adolescence.

Design, Setting, and Participants  Population-based cohort study using Danish nationwide registers. Participants were all individuals born in Denmark between January 1, 1995, and June 30, 2012 (N = 1 098 930). Dates of analysis were November 2017 to February 2018.

Exposures  All treated infections were identified in a time-varying manner from birth until June 30, 2013, including severe infections requiring hospitalizations and less severe infection treated with anti-infective agents in the primary care sector.

Main Outcomes and Measures  This study identified all mental disorders diagnosed in a hospital setting and any redeemed prescription for psychotropic medication. Cox proportional hazards regression was performed reporting hazard rate ratios (HRRs), including 95% CIs, adjusted for age, sex, somatic comorbidity, parental education, and parental mental disorders.

Results  A total of 1 098 930 individuals (51.3% male) were followed up for 9 620 807.7 person-years until a mean (SD) age of 9.76 (4.91) years. Infections requiring hospitalizations were associated with subsequent increased risk of having a diagnosis of any mental disorder (n = 42 462) by an HRR of 1.84 (95% CI, 1.69-1.99) and with increased risk of redeeming a prescription for psychotropic medication (n = 56 847) by an HRR of 1.42 (95% CI, 1.37-1.46). Infection treated with anti-infective agents was associated with increased risk of having a diagnosis of any mental disorder (HRR, 1.40; 95% CI, 1.29-1.51) and with increased risk of redeeming a prescription for psychotropic medication (HRR, 1.22; 95% CI, 1.18-1.26). Antibiotic use was associated with particularly increased risk estimates. The risk of mental disorders after infections increased in a dose-response association and with the temporal proximity of the last infection. In particular, schizophrenia spectrum disorders, obsessive-compulsive disorder, personality and behavior disorders, mental retardation, autistic spectrum disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder and conduct disorder, and tic disorders were associated with the highest risks after infections.

Conclusions and Relevance  Although the results cannot prove causality, these findings provide evidence for the involvement of infections and the immune system in the etiology of a wide range of mental disorders in children and adolescents.

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