Project description: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.
Project description:The coronavirus SARS-CoV-2 pandemia is infecting millions of people and some studies relate conditions that might increase the risk of developing a fatal course for the disease, such as diabetes, cardiovascular diseases and obesity. In COVID-19 physiopathology, one of the main inflammation mechanisms is the "cytokine storm", causing a pro-inflammatory state, related to cardiac and pulmonary damage. There is also a less effective role of lymphocyte B and T in the humoral immunity due to the reduction of their proliferative response. The physiopathology of ASD (Autism Spectrum Disorder) involves several modifications at the genetic and at the immune level, such as the increase of inflammatory cytokines and abnormal immune response in several levels. We hypothesize that ASD could be a risk-factor as the other conditions are.
Project description:Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.
Project description:Controversial results of the association between maternal body mass index (BMI) and risk of autism spectrum disorder (ASD) in offspring were reported among several studies. This meta-analysis was conducted to estimate the overall association between maternal BMI and risk of ASD in offspring. PubMed, EMBASE, Web of Science, and the Cochrane Library were searched until January 2016. Cohort and case-control studies addressing the association between maternal BMI and risk of ASD in offspring were included. We used random-effect models to estimate the summary relative risks (RRs), we also performed a dose-response meta-analysis to estimate the trend from the correlated log RR estimates across levels of BMI quantitatively. Totally, 6 cohort studies and 1 case-control study involving 8,403 cases and 509,167 participants were included for analysis. The summary RR (95% confidence interval) for ASD in offspring in relation to maternal underweight, overweight, and obesity vs. normal weight during pre-pregnancy or pregnancy, was 1.07 (0.93, 1.23), 1.28 (1.19, 1.36) and 1.36 (1.03, 1.78), respectively. A linear dose-response relationship was found, with a pooled RR of 1.16 (1.01, 1.33) for each 5?kg/m2. increment in maternal BMI. The present study suggests that excessive maternal BMI is associated with increased ASD risk in offspring.
Project description:Previous studies indicate a role of immune disturbances during early development in the etiology of autism spectrum disorders (ASD). Any potential disturbances during fetal development are best addressed by prospective evaluation of maternal markers of inflammation. Previous studies have investigated maternal cytokines, a group of powerful effectors of the immune system, with inconsistent results. In this study, we aimed to clarify the relationship between maternal cytokines and ASD by evaluating levels of 17 cytokines 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. Overall, we observed no consistent associations between levels of maternal cytokines and ASD. While we observed a number of individual associations, the patterns varied across the diagnostic sub-groups. Levels above the 90th percentile of IL-1β (OR = 2.31, 95% CI 1.16-4.60), IL-7 (OR = 2.28, 95% CI 1.20-4.33), IL-13 (OR = 2.42, 95% CI 1.29-4.55), and MCP-1 (OR = 2.09, 95% CI 1.03-4.24) were associated with increased odds of ASD with co-occurring intellectual disability (ID), whereas GMCSF (OR = 2.06, 95% CI 1.03-4.11) and TNF-α (OR = 2.31, 95% CI 1.18-4.50) were associated with increased odds of ASD with ADHD but none survived correction for multiple comparisons. Also, none of the measured maternal cytokines were associated with ASD without co-occurring ID or ADHD. Implementing a data-driven approach using machine learning (Random Forest's Variable Importance measurement), we found no evidence to suggest that adding these cytokines and other markers of maternal immunity, to register-based maternal factors (e.g., psychiatric history) improves prediction of ASD. In summary, we found no robust evidence of an association between maternal immune markers during early pregnancy and ASD.
Project description:We have previously reported that prenatal progestin exposure induces autism-like behavior in offspring through ERβ (estrogen receptor β) suppression in the brain, indicating that progestin may induce autism spectrum disorders (ASD). In this study, we aim to investigate whether prenatal progestin exposure is associated with ASD. A population-based case-control epidemiology study was conducted in Hainan province of China. The ASD children were first screened with the Autism Behavior Checklist (ABC) questionnaire, and then diagnosed by clinical professionals using the ASD diagnosis criteria found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). Eventually, 235 cases were identified as ASD from 37863 children aged 0-6 years old, and 682 matched control subjects with typically developing children were selected for the analysis of potential impact factors on ASD prevalence using multivariate logistic regression. Our data show that the ASD prevalence rate in Hainan was 0.62% with a boy:girl ratio of 5.4:1. Interestingly, we found that the following factors were strongly associated with ASD prevalence: use of progestin to prevent threatened abortion, use of progestin contraceptives at the time of conception, and prenatal consumption of progestin-contaminated seafood during the first trimester of pregnancy. All the above factors were directly or indirectly involved with prenatal progestin exposure. Additionally, we conducted in vivo experiments in rats to further confirm our findings. Either endogenous (progesterone) or synthetic progestin (norethindrone)-treated seafood zebrafish were used to feed pregnant dams, and the subsequent offspring showed autism-like behavior, which further demonstrated that prenatal progestin exposure may induce ASD. We conclude that prenatal progestin exposure may be associated with ASD development.
Project description:Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.Genetic association between autism spectrum disorder and MIF was investigated in 2 independent sets of families of probands with autism spectrum disorder, from the United States (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for autism spectrum disorder diagnoses. Genotyping was performed for 2 polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were conducted in a subset of Dutch patients from whom plasma was available.There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder-related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms.These results identify MIF as a possible susceptibility gene for autism spectrum disorder. Additional research is warranted on the precise relationship between MIF and the behavioral components of autism spectrum disorder, the mechanism by which MIF contributes to autism spectrum disorder pathogenesis, and the clinical use of MIF genotyping.
Project description:Our goal in this study was to determine whether maternal fat intake before or during pregnancy was associated with risk of autism spectrum disorder (ASD) in the offspring. Our primary analysis included 317 mothers who reported a child with ASD and 17,728 comparison mothers from the Nurses' Health Study II (index births in 1991-2007). Dietary information was collected prospectively through a validated food frequency questionnaire. Binomial regression was used to estimate crude and adjusted risk ratios. Maternal intake of linoleic acid was significantly inversely associated with ASD risk in offspring, corresponding to a 34% reduction in risk in the highest versus lowest quartiles of intake. Mothers in the lowest 5% of ω-3 fatty acid intake had a significant increase in offspring ASD risk as compared with the remaining distribution (risk ratio = 1.53, 95% confidence interval: 1.00, 2.32); this association was also seen in the subgroup of women (86 cases and 5,798 noncases) for whom dietary information during pregnancy was available (risk ratio = 2.42, 95% confidence interval: 1.19, 4.91). Thus, variations in intake of polyunsaturated fats within the range commonly observed among US women could affect fetal brain development and ASD risk. Because the number of women with diet assessed during pregnancy was small, however, these results should be interpreted cautiously.
Project description:The maternal immune system may play a role in offspring neurodevelopment. We examined whether maternal autoimmune disease, asthma, and allergy were associated with child autism spectrum disorder (ASD) and developmental delay without autism (DD) using 560 ASD cases, 391 typically developing controls, and 168 DD cases from the CHildhood Autism Risk from Genetics and the Environment (CHARGE) study. Results from conditional logistic regression demonstrated few significant associations overall. Maternal autoimmune disease was significantly associated with a modest increase in odds of developmental disorders (combined ASD + DD; OR = 1.46, 95% CI 1.01, 2.09) but not of ASD alone. Associations with certain allergens and onset periods were also suggested. These findings suggest maternal autoimmune disease may modestly influence childhood developmental disorders (ASD + DD).