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

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.

Figure.. Risk of Hospitalization for Any Mental Disorder and Risk of Prescription for Any Psychotropic Medication

A and B, Risk is shown for persons born between 1995 and 2012 in Denmark with and without hospitalization for infection who redeemed anti-infective agent prescriptions. HRR indicates hazard rate ratio. The error bars represent 95% CIs. All analyses were adjusted for age, sex, parental educational level, and parental mental disorders.