Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1?075?588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged =50 years were 2.2 times (95% confidence interval: 1.26-3.88: P=0.006) more likely to have autism than offspring of men aged =29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P
BACKGROUND: Endosulfan has been used for over 50 years. Although most analogs have been discontinued, endosulfan has less environmental persistence. Nevertheless, pressure groups are lobbying for a worldwide ban. The reasons are: possible rodent male reproductive toxicity, other endocrine effects and cancer; human epidemiology, and exposure studies; residues appearing in remote areas of the world, e.g., the Arctic. METHODS: The endosulfan toxicology database is described and risks of its use assessed. RESULTS: Endosulfan is an antagonist at the GABA(A) receptor Cl(-) ionophore in mammalian CNS. Rat acute toxicity is moderate, LD(50)=48 (M) or 10 mg/kg/d (F), oral gavage; 130 (M), 70 mg/kg/d (F) dermal; LC(50)=34.5 microg/L (M), 12.6 microg/L (F), inhalation. Critical NOELs for risk assessment: acute oral (gavage)=0.7 mg/kg/d (rabbit developmental); Subchronic oral (diet)=1.2 mg/kg/d (rat reproduction); Chronic oral (diet)=0.6 mg/kg/d. There were no acceptable dermal toxicity studies. The critical acute and subchronic inhalation NOELs=0.001 mg/L, chronic inhalation=0.0001 mg/L (estimated). Toxicity to rat sperm occurred at doses causing neurotoxicity. Endocrine effects, resulting from P450 oxygenase(s) induction, were reversible. Increased cancer, genotoxicity, or histopathology in rodents was not observed in any organ. Possible effects on brain biogenic amine levels were probably secondary. CONCLUSIONS: Epidemiology and rodent studies suggesting autism and male reproductive toxicity are open to other interpretations. Developmental/ reproductive toxicity or endocrine disruption occurs only at doses causing neurotoxicity. Toxicity to the fetus or young animals is not more severe than that shown by adults.
Asperger syndrome has so far been the subject of very little systematic empirical inquiry. This paper reviews those few studies in the literature and some data from a new Swedish study which has reported findings pertinent to estimations of Asperger syndrome prevalence. It is concluded that among children with normal intelligence, rates of 10-26 per 10,000 children are minimum figures. Another 0.4 per 10,000 Swedish teenagers showed the combination of Asperger syndrome and mild mental retardation.
The first aim of this study was to evaluate the association between different subgroups of autism spectrum disorders (ASDs) (childhood autism, Asperger syndrome, and pervasive developmental disorder/pervasive developmental disorder - not otherwise specified [PDD/PDD-NOS]) and congenital anomalies. Second, we assessed the association among intellectually disabled children with ASDs in the subgroups of childhood autism and PDD/PDD-NOS.
Nationwide population-based register data for children with a diagnosis of ASD (n=4449; 3548 males, 901 females) were collected during years 1987-2000 from the Finnish Hospital Discharge Register. Data on congenital anomalies were derived from the National Register of Congenital Malformations. Conditional logistic regression models were used as a statistical method. The association between ASD subgroups and congenital anomalies was stratified by the presence or absence of intellectual disability.
Congenital anomalies occurred more frequently in all subgroups of ASD than in comparison participants (adjusted odds ratio [OR] for major congenital anomalies 1.8, 95% confidence interval [CI] 1.5-2.2, p
Comment In: Dev Med Child Neurol. 2015 Jan;57(1):10-125312764
Nanea, Department of Epidemiology, Institute of Public Health, bNational Centre for Register-Based Research, and eInstitute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark. firstname.lastname@example.org
OBJECTIVES: Recent studies suggest that familial autoimmunity plays a part in the pathogenesis of ASDs. In this study we investigated the association between family history of autoimmune diseases (ADs) and ASDs/infantile autism. We perform confirmatory analyses based on results from previous studies, as well as various explorative analyses. METHODS: The study cohort consisted of all of the children born in Denmark from 1993 through 2004 (689 196 children). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry. Information on ADs in parents and siblings of the cohort members was obtained from the Danish National Hospital Register. The incidence rate ratio of autism was estimated by using log-linear Poisson regression. RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes. CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.
The origins and development of autism spectrum disorder (ASD) remain unresolved. No individual-level study has provided estimates of additive genetic, maternal, and environmental effects in ASD across several countries.
To estimate the additive genetic, maternal, and environmental effects in ASD.
Population-based, multinational cohort study including full birth cohorts of children from Denmark, Finland, Sweden, Israel, and Western Australia born between January 1, 1998, and December 31, 2011, and followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018.
Across 5 countries, models were fitted to estimate variance components describing the total variance in risk for ASD occurrence owing to additive genetics, maternal, and shared and nonshared environmental effects.
The analytic sample included 2?001?631 individuals, of whom 1?027?546 (51.3%) were male. Among the entire sample, 22?156 were diagnosed with ASD. The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel). For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%). Maternal effect was estimated to range from 0.4% to 1.6%. Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD.
Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects. The results suggest possible modest differences in the sources of ASD risk between countries.
CommentIn: JAMA Psychiatry. 2019 Oct 1;76(10):1005-1006 PMID 31314055
OBJECTIVE: To investigate the association between hospitalization for infection in the perinatal/neonatal period or childhood and the diagnosis of autism spectrum disorders (ASDs). DESIGN: A population-based cohort study. SETTING: Denmark. PARTICIPANTS: All children born in Denmark from January 1, 1980, through December 31, 2002, comprising a total of 1 418 152 children. EXPOSURE: Infection requiring hospitalization. MAIN OUTCOME MEASURE: The adjusted hazard ratio (HR) for ASDs among children hospitalized for infection compared with other children. RESULTS: A total of 7379 children were diagnosed as having ASDs. Children admitted to the hospital for any infectious disease displayed an increased rate of ASD diagnoses (HR, 1.38 [95% confidence interval, 1.31-1.45]). This association was found to be similar for infectious diseases of bacterial and viral origin. Furthermore, children admitted to the hospital for noninfectious disease also displayed an increased rate of ASD diagnoses (HR, 1.76 [95% confidence interval, 1.68-1.86]), and admissions for infection increased the rate of mental retardation (2.18 [2.06-2.31]). CONCLUSIONS: The association between hospitalization for infection and ASDs observed in this study does not suggest causality because a general association is observed across different infection groups. Also, the association is not specific for infection or for ASDs. We discuss a number of noncausal explanatory models.
Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited.
We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children.
Among 83,389 mother-child pairs enrolled in the Danish National Birth Cohort during 1996-2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child's sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights.
Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in = 90% of the samples. We did not find consistent evidence of associations between mother's PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise.
In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children.
Cites: Environ Sci Technol. 2011 Oct 1;45(19):8151-921682250
Cites: J Autism Dev Disord. 2010 Feb;40(2):139-4819728067
Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34-1.44) and 2.19 (95% CI 2.15-2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36-1.58) and 2.70 (95% CI 2.59-2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.
The total population of children under 10 years in one Swedish urban area and one rural area was screened for infantile autism (IA) and autistic-like conditions (AC). A total prevalence of 6.6 per 10 000 was found, which is somewhat higher than in previous similar studies of the same region. Infantile autism accounted for two-thirds of the cases. Boys far outnumbered girls, but this was entirely accounted for by the IA group. The preponderance of autistic boys was less pronounced among the severely mentally retarded children. Mental retardation was seen in almost 90% of cases and only one child had an IQ exceeding 100; clinical and laboratory signs of brain dysfunction were also found in a majority of cases. Distribution by social class was no different in either patient group from the general population.