Childhood infections and autism spectrum disorders and/or intellectual disability: a register-based cohort study

Abstract

Objective: To explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID), and their co-occurrence.

Methods: The association between specialized care for any infection, defined by ICD-codes, and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987-2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders children's characteristics, family socioeconomic factors, obstetric complications, and parental histories of treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with the exclusion of congenital causes of ASD/ID and documented risk for infections were also performed.

Results: Crude estimates indicated that infections during childhood were associated with later ASD and ID with the largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population, and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later "ASD without ID" (HR 1.24, 95%CI 1.15-1.33), "ASD with ID" (1.57, 1.35-1.82), and "ID without ASD" (2.01, 1.76-2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID.

Conclusions: Infections during childhood may contribute to a later diagnosis of ID and ASD.

Keywords: Autism spectrum disorders; Childhood; Infection; Intellectual disability; Risk.

Fig. 1

Description of outcomes and exposures in the study population. Individuals diagnosed with ASD and/or ID identified in the final study population (n=556,732) as of December 31, 2016 (A). Age at first diagnosis of ASD/ID for the mutually exclusive diagnostic groups (B). Incidence of CNS (C) and non-CNS infections (D) according to age among children unaffected by ASD/ID and among those diagnosed with “ASD without ID,” “ASD with ID,” “ID without ASD.” Note the different scales of the y-axes in C and D. Incidence of one or more infections according to age among children unaffected by ASD/ID and those diagnosed with “ASD without ID” (E), “ASD with ID” (F), and “ID without ASD” (G), throughout childhood and stratified by age at diagnosis of ASD/ID

Fig. 2

Infections during childhood and later diagnosis of ASD or ID. Associations between specialized care for infections during childhood and later, non-mutually exclusive, diagnosis of ASD and ID. Associations between exposure at different age intervals and diagnoses at different age intervals are also shown. Comparison between unrelated individuals in the general population are shown (A–H) and comparisons between full biological siblings (I–P). Hazard ratios presented here are from fully adjusted models. Population-based estimates (A–H) are adjusted for sex, parity, maternal body mass index, pre-eclampsia, parental age, education, income, region of origin, histories of psychiatric illness and infections, season of birth, gestational age at birth, size for gestational age, cesarean section, Apgar score. Estimates from the sibling analyses (I–P) are adjusted for sex, parity, gestational age at birth, and cesarean section

Fig. 3

Infections during childhood and mutually exclusive diagnoses. Associations between specialized care for infections during childhood and later diagnosis of “ASD without ID,” “ASD with ID,” or “ID without ASD.” Associations between exposure at different age intervals and diagnoses at different age intervals are also shown. Comparisons between unrelated individuals in the general population (A–L) and between full biological siblings (M–X) are shown. Hazard ratios presented here are from fully adjusted models. Population-based estimates (A–L) are adjusted for sex, parity, maternal body mass index, pre-eclampsia, parental age, education, income, region of origin, histories of psychiatric illness and infections, season of birth, gestational age at birth, size for gestational age, cesarean section, Apgar score. Estimates from the sibling analyses (M–X) are adjusted for sex, parity, gestational age at birth, and cesarean section

Fig. 4

CNS/non-CNS infections and mutually exclusive diagnostic groups. Associations between specialized care for CNS infections (left) or non-CNS infections (right) during childhood and later diagnosis of “ASD without ID” (A, B), “ASD with ID” (C, D), or “ID without ASD” (E, F). Associations between exposure at different age intervals and later diagnoses are also shown. Hazard ratios are adjusted for sex, parity, maternal body mass index, pre-eclampsia, parental age, education, income, region of origin, histories of psychiatric illness and infections, season of birth, gestational age at birth, size for gestational age, cesarean section, and Apgar score