Neonatal Levels of Acute Phase Proteins and Risk of Autism Spectrum Disorder

Gardner, Renee M.; Lee, Brian K.; Brynge, Martin; Sjöqvist, Hugo; Dalman, Christina; Karlsson, Håkan

doi:10.1016/j.biopsych.2020.09.005

Cited by 25 publications

(25 citation statements)

References 64 publications

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“…22 In general, lower correlations were observed among APPs in maternal serum compared to those observed in neonatal samples. 31 In accordance with previous evidence, 37 we observed a strong correlation between maternal BMI and CRP, with overweight and obesity being associated with elevated levels.…”

Section: Interpretation and Potential Mechanisms Maternal App And Rissupporting

confidence: 93%

“…We retrieved 0.2 ml serum from all available maternal sera samples, for ASD-cases (n=430) and mothers to control individuals (n=549), from those individuals who also had a neonatal dried blood spots (NDBS) as described in detail previously. 31 Samples were obtained at median gestational week 10.6 (interquartile range: 9.3 – 12.5 weeks) representing a period near the end of the first trimester.…”

Section: Methodsmentioning

confidence: 99%

“…43 In our case-cohort study of neonatal APP measured in dried blood spots, we observed a u-shaped association between CRP and odds of ASD. 31 It is not clear how low levels of maternal CRP in first trimester might influence the risk of ASD in offspring. Considering the opsonizing and complement activating functions of CRP, low levels might represent a suboptimal innate immune effector function.…”

Section: Crp and Asdmentioning

confidence: 99%

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Maternal Levels of Acute Phase Proteins in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Brynge

Gardner

Sjöqvist

et al. 2021

Preprint

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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 maternal serum samples drawn in first trimester, from 318 mothers to ASD-cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. Overall, we found no general trend of high levels of maternal APP being associated with increased risk of ASD. In contrast, 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 = 2.15, 95 % CI 1.17-3.93). Further, levels of maternal ferritin in the lowest (OR = 1.82, 95 % CI 1.19-2.78) and highest (OR = 1.74, 95 % CI 1.16-2.60) tertiles were associated with increased risk of any ASD diagnosis in offspring, with stronger associations still between the lowest (OR = 3.58, 95 % CI 1.79-7.17) and highest (OR = 3.20, 95 % CI 1.62-6.29) 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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Section: Interpretation and Potential Mechanisms Maternal App And Rissupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Crp and Asdmentioning

confidence: 99%

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Maternal Levels of Acute Phase Proteins in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Brynge

Gardner

Sjöqvist

et al. 2021

Preprint

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“…It is possible that for some registered infections, mild CNS-involvement may have gone unnoticed or undocumented, as has been reported for uncomplicated measles virus infections 51 . Moreover, low levels of several molecules involved in the innate immune response at birth were recently associated with ASD risk 24 , supporting the notion of an increased vulnerability to infections in ASD that was proposed based on a genetic correlation between hospitalization for infection and ASD 52 . Further studies are needed to investigate if deficits in immunity associated with ASD risk could contribute to more severe outcomes of childhood infections, such as ID, and potentially contribute to the high co-morbidity between these disorders 53 .…”

Section: Discussionmentioning

confidence: 61%

“…A growing literature associates childhood infections with no apparent CNS involvement with schizophrenia risk in adulthood 19-22 , with a significant portion of risk mediated by reduced cognitive abilities 21 . Observations of deficits in innate immunity among neonates who later develop schizophrenia 23 or ASD 24 further highlight the potential contribution of postnatal infections to these outcomes 25-27 . However, only a handful of studies, with equivocal results, have investigated the relationship between childhood infections and the risk of ASD 18, 28-31 .…”

Section: Introductionmentioning

confidence: 99%

Infections in childhood and subsequent diagnosis of autism spectrum disorders and intellectual disability: a register-based cohort study

Karlsson

Sjöqvist

Brynge

et al. 2021

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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 childrens characteristics, family socioeconomic factors, obstetric complications, and parental histories of both 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 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 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 cannot be excluded in the etiology of ASD, particularly ASD with co-occurring ID.

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Maternal antibodies to gliadin and autism spectrum disorders in offspring—A population‐based case–control study in Sweden

et al. 2021

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While individuals diagnosed with autism spectrum disorders (ASD) have higher levels of antibodies directed towards gliadin, a component of wheat gluten, no study has examined anti‐gliadin antibodies (AGA) in etiologically relevant periods before diagnosis. The objective of this study was to investigate if maternal levels of AGA, during pregnancy and at the time of birth, are associated with ASD in offspring. We analyzed AGA in archived neonatal dried blood spots (NDBS) for 921 ASD cases and 1090 controls, and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations with ASD diagnoses as a group and considering common comorbidities (intellectual disability [ID] and attention‐deficit/hyperactivity disorder). We compared 206 cases to their unaffected siblings to examine the potential for confounding by shared familial factors. Odds of ASD tended to be lower among those with the highest levels (≥90th percentile) of AGA compared to those with low levels (<80th percentile; OR 0.78, 95% CI 0.56–1.09, measured in NDBS). This pattern was more apparent for ASD with comorbid ID when measured in NDBS (0.51, 0.30–0.87), with a similar trend in maternal sera (0.55, 0.24–1.29). High levels of AGA were similarly associated with lower odds of ASD in the sibling comparison. In summary, we found little association between maternal antibodies raised against components of gluten and risk of ASD in general. Exposure to high levels of AGA in the pre‐ and perinatal periods may be protective in terms of risk for ASD with ID. Lay Summary There is a debate among both scientists and community members as to whether an immune reaction to gluten exposure could be considered a cause of autism. We examined antibodies that are directed against gliadin, a part of gluten, in samples collected from pregnant mothers and their newborn babies. We did not see any major differences in the antibody level among those children diagnosed with ASD or their mothers compared to children who were not diagnosed with ASD. High levels of the antibodies were in fact associated with a somewhat lower risk of ASD with co‐occurring intellectual disabilities, though we cannot tell from this study why that might be the case.

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Neonatal Levels of Acute Phase Proteins and Risk of Autism Spectrum Disorder

Cited by 25 publications

References 64 publications

Maternal Levels of Acute Phase Proteins in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Maternal Levels of Acute Phase Proteins in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring

Infections in childhood and subsequent diagnosis of autism spectrum disorders and intellectual disability: a register-based cohort study

Maternal antibodies to gliadin and autism spectrum disorders in offspring—A population‐based case–control study in Sweden

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