Migration and autism spectrum disorder: population-based study.

BACKGROUND: Migration has been implicated as a risk factor for autism, but evidence is limited and inconsistent. AIMS: To investigate the relationship between parental migration status and risk of autism spectrum disorder, taking into consideration the importance of region of origin, timing of migration and possible discrepancies in associations between autism subtypes. METHOD: Record-linkage study within the total child population of Stockholm County between 2001 and 2007. Individuals with high- and low-functioning autism were defined as having autism spectrum disorder with and without comorbid intellectual disability, and ascertained via health and habilitation service registers. RESULTS: In total, 4952 individuals with autism spectrum disorder were identified, comprising 2855 children with high-functioning autism and 2097 children with low-functioning autism. Children of migrant parents were at increased risk of low-functioning autism (odds ratio (OR) = 1.5, 95% CI 1.3-1.7); this risk was highest when parents migrated from regions with a low human development index, and peaked when migration occurred around pregnancy (OR = 2.3, 95% CI 1.7-3.0). A decreased risk of high-functioning autism was observed in children of migrant parents, regardless of area of origin or timing of migration. Parental age, income or obstetric complications did not fully explain any of these associations. CONCLUSIONS: Environmental factors associated with migration may contribute to the development of autism presenting with comorbid intellectual disability, especially when acting in utero. High- and low-functioning autism may have partly different aetiologies, and should be studied separately.

Anxiety Disorders in Adults with Autism Spectrum Disorder: A Population-Based Study.

Anxiety is common in children with ASD; however, the burden of specific anxiety disorders for adults with ASD is under-researched. Using the Stockholm Youth Cohort, we compared anxiety disorder diagnoses among autistic adults (n = 4049), with or without intellectual disability, and population controls (n = 217,645). We conducted additional sibling analyses. Anxiety disorders were diagnosed in 20.1% of adults with ASD compared with 8.7% of controls (RR = 2.62 [95% CI 2.47-2.79]), with greatest risk for autistic people without intellectual disability. Rates of almost all individual anxiety disorders were raised, notably obsessive-compulsive disorder and phobic anxiety disorders. Anxiety disorders were more common in full siblings and half-siblings of people with ASD. The implications of this are explored.

Advancing paternal age and schizophrenia: the impact of delayed fatherhood.

OBJECTIVE: It is well known that advancing paternal age is associated with an increased risk of schizophrenia in offspring, but the mechanism behind this association remains unknown. This study investigates if delayed fatherhood rather than advancing paternal age per se might explain the increased risk of schizophrenia in offspring associated with advancing paternal age. METHODS: This is a register-based study of the Swedish population looking at people born 1955-1985 who have 1 or 2 siblings (n = 2 589 502). The main analysis investigated whether the association between advancing paternal age and schizophrenia was explained by delayed fatherhood. Possible confounding factors were taken into account. Cox regression was used throughout. RESULTS: In the main analysis the association between advancing paternal age and increased risk of schizophrenia in offspring disappeared after controlling for delayed fatherhood (hazard ratio [HR] = 0.93, 95% CI = 0.72-1.21 comparing 45+ years old fathers to those 25-29), whereas delayed fatherhood showed an association with increased risk of schizophrenia in offspring comparing 35-39 and 40-44 years old fathers to 25-29 year olds (HR = 1.37, 95% CI = 1.18-1.58; HR = 1.81, 95% CI = 1.44-2.28, respectively). The results remained when controlling for possible confounders. CONCLUSIONS: This study suggests that the association between paternal age and schizophrenia is not due to paternal age per se, but rather to an unknown factor associated with both delayed fatherhood and schizophrenia.

Maternal body mass index during early pregnancy, gestational weight gain, and risk of autism spectrum disorders: Results from a Swedish total population and discordant sibling study.

BACKGROUND: Prenatal environmental factors such as maternal adiposity may influence the risk of offspring autism spectrum disorders (ASD), though current evidence is inconsistent. The objective of this study was to assess the relationship of parental BMI and gestational weight gain (GWG) with risk of offspring ASD in a population-based cohort study using family-based study designs. METHODS: The cohort was based in Stockholm County, Sweden, including 333,057 individuals born 1984-2007, of whom 6420 were diagnosed with an ASD. We evaluated maternal body mass index (BMI) at first antenatal visit, GWG and paternal BMI at the time of conscription into the Swedish military as exposures using general estimating equation (GEE) models with logit link. RESULTS: At the population level, maternal overweight/obesity was associated with increased risk of offspring ASD [odds ratio (OR)25 ≤ BMI < 30 1.31, 95% confidence interval = 1.21-1.41; ORBMI ≥ 30 1.94, 1.72-2.17], as was paternal underweight (ORBMI < 18.5, 1.19, 1.06-1.33) and obesity (ORBMI ≥ 30 1.47, 1.12-1.92) in mutually adjusted models. However, in matched sibling analyses, the relationship between elevated maternal BMI and ASD risk was not apparent. GWG had a U-shaped association with offspring ASD at the population level (ORinsufficient 1.22, 1.07-1.40; ORexcessive 1.23, 1.08-1.40). Matched sibling analyses were suggestive of elevated risk with excessive GWG (ORinsufficient 1.12, 0.68-1.84; ORexcessive 1.48, 0.93-2.38). CONCLUSIONS: Whereas population-level results suggested that maternal BMI was associated with ASD, sibling analyses and paternal BMI analyses indicate that maternal BMI may also be a proxy marker for other familial risk factors. Evidence is stronger for a direct link between GWG and ASD risk.

Changes in prevalence of autism spectrum disorders in 2001-2011: findings from the Stockholm youth cohort.

In a record-linkage study in Stockholm, Sweden, the year 2011 prevalence of diagnosed autism spectrum disorders (ASD) was found to be 0.40, 1.74, 2.46, and 1.76% among 0-5, 6-12, 13-17, and 18-27 year olds, respectively. The corresponding proportion of cases with a recorded diagnosis of intellectual disability was 17.4, 22.1, 26.1 and 29.4%. Between 2001 and 2011, ASD prevalence increased almost 3.5 fold among children aged 2-17 years. The increase was mainly accounted for by an eightfold increase of ASD without intellectual disability (from 0.14 to 1.10 %), while the prevalence of ASD with intellectual disability increased only slightly (from 0.28 to 0.34%). The increase in ASD prevalence is likely contributed to by extrinsic factors such as increased awareness and diagnostics.

Parental age and the risk of autism spectrum disorders: findings from a Swedish population-based cohort.

BACKGROUND: The objectives of this study were to examine the independent and dependent associations of maternal and paternal age and risk of offspring autism spectrum disorders (ASD), with and without intellectual disability (ID). METHODS: The sample consisted of 417 303 Swedish children born 1984-2003. ASD case status (N = 4746) was ascertained using national and regional registers. Smoothing splines in generalized additive models were used to estimate associations of parental age with ASD. RESULTS: Whereas advancing parental age increased the risk of child ASD, maternal age effects were non-linear and paternal age effects were linear. Compared with mothers at the median age 29 years, those <29 had similar risk, whereas risk increased after age 30, with an odds ratio (OR) of 1.75 [95% (CI): 1.63-1.89] at ages 40-45. For fathers, compared with the median age of 32 years, the OR for ages 55-59 was 1.39 (1.29-1.50). The risk of ASD was greater for older mothers as compared with older fathers. For example, mothers aged 40-45 (≥97.2th percentile) had an estimated 18.63 (95% CI: 17.25-20.01) ASD cases per 1000 births, whereas fathers aged 55-59 (≥99.7th percentile) had 16.35 (95% CI: 15.11-17.58) ASD cases per 1000 births. In analyses stratified by co-parental age, increased risk due to advancing paternal age was evident only with mothers ≤35 years. In contrast, advancing maternal age increased risk regardless of paternal age. Advancing parental age was more strongly associated with ASD with ID, compared with ASD without ID. CONCLUSIONS: We confirm prior findings that advancing parental age increases risk of ASD, particularly for ASD with ID, in a manner dependent on co-parental age. Although recent attention has emphasized the effects of older fathers on ASD risk, an increase of n years in maternal age has greater implications for ASD risk than a similar increase in paternal age.

Deviance in fetal growth and risk of autism spectrum disorder.

OBJECTIVE: Understanding the relationship between fetal growth and autism spectrum disorder (ASD) is likely to advance the search for genetic and nongenetic causes of ASD. The authors explored the associations between fetal growth, gestational age, and ASD with and without comorbid intellectual disability in a Scandinavian study population. METHOD: The authors conducted a matched nested case-control study within the Stockholm Youth Cohort that included all children ages 0-17 who resided in Stockholm County from 2001 to 2007 (N=589,114). The authors identified 4,283 children with ASD: 1,755 with intellectual disability and 2,528 without, and they selected 36,588 age- and sex-matched comparison subjects. ASD case subjects were ascertained from unique identifiers assigned to all Swedish residents and linkage with official registers covering all pathways of assessment or care of ASD in Stockholm County. The authors calculated z scores of deviance in fetal growth from a reference curve using records from the national Swedish Medical Birth Registry, which included ultrasound dating of gestational age as well as birth weight. Crude and adjusted odds ratios for ASD, ASD with intellectual disability, and ASD without intellectual disability were the main outcome measures. RESULTS: ASD risk increased with fetal growth 1.50 standard deviations below and >2.00 standard deviations above the mean for gestational age; the greatest risk was for fetal growth that was less than 2.00 standard deviations below the mean (adjusted odds ratio=1.70; 95% CI=1.44-2.01) or greater than 2.00 standard deviations above the mean (adjusted odds ratio=1.50; 95% CI=1.27-1.77). The same overall pattern was observed for ASD with and without intellectual disabilities. However, poor fetal growth (i.e., growth below the mean) was more strongly associated with ASD with intellectual disabilities than without. Regardless of fetal growth, preterm birth increased ASD risk. CONCLUSIONS: Deviance in fetal growth at either distributional extreme may be a significant antecedent to the development of ASD through genetic and/or nongenetic mechanisms.

Autism spectrum disorders in the Stockholm Youth Cohort: design, prevalence and validity.

OBJECTIVE: Reports of rising prevalence of autism spectrum disorders (ASD), along with their profound personal and societal burden, emphasize the need of methodologically sound studies to explore their causes and consequences. We here present the design of a large intergenerational resource for ASD research, along with population-based prevalence estimates of ASD and their diagnostic validity. METHOD: The Stockholm Youth Cohort is a record-linkage study comprising all individuals aged 0-17 years, ever resident in Stockholm County in 2001-2007 (N = 589,114). ASD cases (N = 5,100) were identified using a multisource approach, involving registers covering all pathways to ASD diagnosis and care, and categorized according to co-morbid intellectual disability. Prospectively recorded information on potential determinants and consequences of ASD were retrieved from national and regional health and administrative registers. Case ascertainment was validated through case-note review, and cross validation with co-existing cases in a national twin study. RESULTS: The 2007 year prevalence of ASD in all children and young people was 11.5 per 1,000 (95% confidence interval 11.2-11.8), with a co-morbid intellectual disability recorded in 42.6% (41.0-44.2) of cases. We found 96.0% (92.0-98.4) of reviewed case-notes being consistent with a diagnosis of ASD, and confirmed ASD in 85.2% (66.2-95.8) of affected twins. CONCLUSIONS: Findings from this contemporary study accords with recently reported prevalence estimates from Western countries at around 1%, based on valid case ascertainment. The Stockholm Youth Cohort, in light of the availability of extensive information from Sweden's registers, constitutes an important resource for ASD research. On-going work, including collection of biological samples, will enrich the study further.