Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders

Abstract

Animal models indicate that maternal infection during pregnancy can result in behavioral abnormalities and neuropathologies in offspring. We examined the association between maternal inpatient diagnosis with infection during pregnancy and risk of ASD in a Swedish nationwide register-based birth cohort born 1984–2007 with follow-up through 2011. In total, the sample consisted of 2,371,403 persons with 24,414 ASD cases. Infection during pregnancy was defined from ICD codes. In the sample, 903 mothers of ASD cases (3.7%) had an inpatient diagnosis of infection during pregnancy. Logistic regression models adjusted for a number of covariates yielded odds ratios indicating approximately a 30% increase in ASD risk associated with any inpatient diagnosis of infection. Timing of infection did not appear to influence risk in the total Swedish population, since elevated risk of ASD was associated with infection in all trimesters. In a subsample analysis, infections were associated with greater risk of ASD with intellectual disability than for ASD without intellectual disability. The present study adds to the growing body of evidence, encompassing both animal and human studies, that supports possible immune-mediated mechanisms underlying the etiology of ASD.

Introduction

Little is known about the etiology of autism spectrum disorders (ASD), but there is suggestive evidence for the role of environmental exposures during critical periods of early neurodevelopment (Newschaffer et al., 2007). Prenatal infection is a plausible risk factor for ASD, given that the teratogenic effect of prenatal infections such as rubella, cytomegalovirus or Toxoplasma gondii on the central nervous system is well established (Johnson, 1994). Numerous animal studies demonstrate that prenatal or early postnatal infections can result in both acute and persistent neurological and behavioral abnormalities in offspring resembling autistic traits or schizophrenia (Asp et al., 2009, Meyer et al., 2007, Patterson, 2011). However, the validity of such animal models for human ASD is uncertain.

The first studies suggesting an association of prenatal infection with ASD focused on viruses with affinity to the CNS based on the hypothesis of a direct neurotoxic effect. Epidemiological studies of small samples suggested that rubella (Chess et al., 1978, Deykin and MacMahon, 1979), measles, mumps, and influenza (Deykin and MacMahon, 1979) were associated with ASD. More recently, epidemiological studies have expanded infectious exposures to a wide range of viruses and also other pathogens including bacteria. The largest study of over 10,000 ASD cases drawn from Danish electronic health registers reported that maternal hospitalization for viral infection in the first trimester and any infection or bacterial infection in the second trimester were associated with increased ASD risk (Atladottir et al., 2010). However, epidemiological findings have not consistently found evidence of increased ASD risk with infection. For example, a California study of 407 ASD cases reported that hospitalization with infection was associated with increased risk (Zerbo et al., 2013), while a Swedish study of 1216 ASD cases found no such evidence (Buchmayer et al., 2009),

In order to build the evidence base concerning prenatal infection and ASD risk, additional epidemiological studies are necessary. Moreover, as different subtypes of ASD may have different environmental components (Frazier et al., 2014), it is important to examine whether prenatal infection differentially influences ASD subtype risk (with or without intellectual disability). Here, we examined whether maternal hospitalization with infection during pregnancy, type of infection, and timing of infection influences risk of ASD in the largest study to-date. In a subsample of the Swedish population with information on ASD co-morbid with or without intellectual disability, we further examined the associations of prenatal infection with these different subtypes of ASD (Szatmari et al., 2007).