Increased incidence of childhood mental disorders following exposure to early life infection

Highlights

• Incidence of childhood mental disorder was increased following exposure to infectious diseases in early childhood.

• Crude associations between prenatal infection exposure and childhood mental disorder did not survive in adjusted models.

• Maternal mental disorder and other health conditions during pregnancy were strongly associated with offspring mental disorder in childhood.

Abstract

Early life exposure to infectious diseases confers risk for adult psychiatric disorders but relatively few human population studies have examined associations with childhood mental disorder. Here we examined the effects of exposure to maternal infection during pregnancy, and child infectious diseases in early childhood (birth to age 4 years), in relation to first mental disorder diagnosis (age 5–13 years). The study sample comprised 71,841 children represented in a population cohort of children in New South Wales, Australia, followed from birth to early adolescence via linkage of administrative registers. Childhood exposure to infectious disease was determined during the prenatal period (i.e., maternal infection during gestation), and in early childhood (between birth and age 4 years) using the NSW Ministry of Health Admitted Patients data collection. Days to first diagnosis with a mental disorder was determined from recorded diagnoses between age 5–13 years in the NSW Ministry of Health’s Admitted Patients, Emergency Department and Mental Health Ambulatory data collections. While crude hazard ratios for both prenatal infection and childhood infection exposures indicated significantly earlier diagnosis with mental disorders associated with both of these risk factors, only childhood infection exposure was associated with higher adjusted hazard ratios (aHR) for any diagnoses (aHR = 1.21, 95% CI = 1.11–1.32), externalising disorders (aHR = 1.45, 95% CI 1.18–1.79) and developmental disorders (aHR = 1.82, 95% CI 1.49–2.22) when the effects of maternal and early childhood (age < 5 years) mental disorders were taken into account. Exposure to infectious diseases during early childhood, but not prenatal infection exposure, appears to be associated with earlier diagnosis of mental disorders in childhood.

Introduction

Maternal immune activation models suggest that early life immune challenges associated with exposure to prenatal infection confer risk for the development of various neuropsychiatric disorders in later life on the basis of convergent evidence from epidemiology, genetics, and animal models (Brown and Meyer, 2018). While there may be associated social determinants of such risk factors for mental disorder (e.g., socioeconomic disadvantage), the idea that early immune-system challenge may set off a cascade of pathophysiological processes with a causal role in the development of mental illness is a plausible hypothesis, though mechanisms remain speculative (Hagberg et al., 2012, Schlotz and Phillips, 2009). Much evidence from animal studies suggests that pro-inflammatory processes in response to infection can cause a range of relevant phenotypic behaviours in offspring (Enayati et al., 2012, Meyer et al., 2008, Patterson, 2011, Ronovsky et al., 2016), as well as abnormal gene regulation (Fatemi et al., 2008), neurological developmental disturbances (Dantzer et al., 2008), and abnormal immune function (Walker et al., 2006). A growing number of human population-based register studies have also revealed small to moderate associations between prenatal or early childhood infection exposure and adult diagnoses of psychiatric disorders including schizophrenia (Blomstrom et al., 2013, Brown and Derkits, 2010, Dalman et al., 2008, Khandaker et al., 2012, Nielsen et al., 2013a, Nielsen et al., 2016, Sorensen et al., 2008) and affective disorders (Hamdani et al., 2013, Simanek and Meier, 2015).

While the majority of evidence links early-life infection exposure to adult mental disorders, there are accumulating reports of childhood mental disorders following prenatal or early childhood infection exposure (Brown and Meyer, 2018, Hagberg et al., 2012), including the specific diagnosis of Autism Spectrum Disorder (ASD) (Atladottir et al., 2010a, Atladottir et al., 2010b, Hamadé et al., 2013), attention deficit hyperactivity disorder (ADHD) (Zhou et al., 2015), and depression and anxiety in adolescence (Goodwin, 2011). Other recent studies report associations between childhood infection and both neuropsychological and social development in children (Green et al., 2017, Karachaliou et al., 2016, Kariuki et al., 2016). In the present study, we examined associations between exposures to prenatal and/or early childhood infection and the full spectrum of mental disorders with onset in middle childhood (between the ages of 5–13 years), after controlling for the potential effects of other risk factors known to contribute to the development of mental disorders, such as male sex (Miner and Clarke-Stewart, 2008), low socioeconomic status (Ackerman et al., 2003), maternal smoking during pregnancy and young maternal age (Robinson et al., 2008, Thapar et al., 2003), and maternal mental illness (Rutter et al., 1990). We expected small but significant associations between prenatal and childhood exposures to infection and diagnoses of childhood mental disorders identified in state-based hospital and ambulatory mental health records, in the context of significant contributions from other demographic and familial risk factors.