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Previous research supports a contribution of early-life immune disturbances in the etiology of autism spectrum disorders (ASD). Biomarker studies of the maternal innate (non-adaptive) immune status related to ASD risk have focused on one of the acute phase proteins (APP), C-reactive protein (CRP), with conflicting results. We evaluated levels of eight different APP in first-trimester maternal serum samples, from 318 mothers to ASD cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. While no overall associations between high levels of APP and ASD were observed, associations varied across diagnostic sub-groups based on co-occurring conditions. Maternal levels of CRP in the lowest compared to the middle tertile were associated with increased risk of ASD without ID or ADHD in offspring (OR = 1.92, 95% CI 1.08–3.42). Further, levels of maternal ferritin in the lowest (OR = 1.78, 95% CI 1.18–2.69) and highest (OR = 1.64, 95% CI 1.11–2.43) tertiles were associated with increased risk of any ASD diagnosis in offspring, with stronger associations still between the lowest (OR = 3.81, 95% CI 1.91–7.58) and highest (OR = 3.36, 95% CI 1.73–6.53) tertiles of ferritin and risk of ASD with ID. The biological interpretation of lower CRP levels among mothers to ASD cases is not clear but might be related to the function of the maternal innate immune system. The finding of aberrant levels of ferritin conferring risk of ASD-phenotypes indicates a plausibly important role of iron during neurodevelopment.

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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.

+46 70 355 57 56 Word count (text only): 3010 Display items: 1 Table, 4 figures, 12 eFigures, 7 eTables References: 55Running Title: Neonatal acute phase proteins and autism spectrum disorders Abstract Background: Immune signaling pathways influence neurodevelopment and are hypothesized to contribute to the etiology of autism spectrum disorders (ASD). We aimed to assess risk of ASD in relation to levels of neonatal acute phase proteins, key components of innate immune function, measured in neonatal dried blood spots.Method: We included 924 ASD cases, 1092 unaffected population-based controls, and 203 unaffected siblings to ASD cases in this case-control study nested within the register-based Stockholm Youth Cohort. Concentrations of nine different acute phase proteins were measured in eluates from neonatal dried blood spots from cases, controls, and siblings using a bead-based multiplex assay.Results: C reactive protein was consistently associated with odds of ASD in case-control comparisons, with higher odds associated with the highest quintile compared to the middle quintile (OR 1.50, 95% CI 1.10 -2.04) in adjusted analyses. In contrast, the lowest quintiles of alpha-2-macroglobulin (3.71, 1.21 -11.33), ferritin (4.20, 1.40 -12.65), and Serum Amyloid P (3.05, 1.16 -8.01) were associated with odds of ASD in the matched sibling comparison. Neonatal acute phase proteins varied with perinatal environmental factors and maternal/fetal phenotypes. Significant interactions in terms of risk for ASD were observed between neonatal acute phase proteins and maternal infection in late pregnancy, maternal anemia, and maternal psychiatric history.Conclusions: Indicators of the neonatal innate immune response are associated with risk for ASD, though the nature of these associations varies considerably with factors in the perinatal environment and the genetic background of the comparison group.We implemented a case-finding procedure covering all pathways to child and adolescent psychiatric care and habilitation services in Stockholm County (20,21). Ascertainment of ASD, ID, and ADHD in the SYC is described in Table S1. The outcome of ASD was stratified by presence of co-occurring ADHD and ID: ASD with ID, ASD with ADHD, and ASD without ID or ADHD (ASD only). Individuals diagnosed with both co-occurring ID and ADHD (n=111) were included in the ASD with ID group. Laboratory analysisNeonatal dried blood spots (NDBS) were collected from the national biobank at Karolinska University Hospital, Solna. Blood spots were originally collected at approximately 3-5 days after birth (mean=4.1 days, SD=1.3). We selected a smaller sample (born 1998-2000) of the NDBS collected for analysis of immune markers. A sample (12.5 %) of those born 1996-1997 was also included. Our final sample consisted of 924 ASD cases and 1092 controls, as well as 203 unaffected siblings to ASD cases ( Figure S1).A 3.2 mm diameter disc was punched from each NDBS, immersed in 200 μL of phosphate buffered saline, and incubated at room temperature on a rotary shaker (600...