Autism spectrum heterogeneity: fact or artifact?

The current diagnostic practices are linked to a 20-fold increase in the reported prevalence of ASD over the last 30 years. Fragmenting the autism phenotype into dimensional "autistic traits" results in the alleged recognition of autism-like symptoms in any psychiatric or neurodevelopemental condition and in individuals decreasingly distant from the typical population, and prematurely dismisses the relevance of a diagnostic threshold. Non-specific socio-communicative and repetitive DSM 5 criteria, combined with four quantitative specifiers as well as all their possible combinations, render limitless variety of presentations consistent with the categorical diagnosis of ASD. We propose several remedies to this problem: maintain a line of research on prototypical autism; limit the heterogeneity compatible with a categorical diagnosis to situations with a phenotypic overlap and a validated etiological link with prototypical autism; reintroduce the qualitative properties of autism presentations and of current dimensional specifiers, language, intelligence, comorbidity, and severity in the criteria used to diagnose autism in replacement of quantitative "social" and "repetitive" criteria; use these qualitative features combined with the clinical intuition of experts and machine-learning algorithms to differentiate coherent subgroups in today's autism spectrum; study these subgroups separately, and then compare them; and question the autistic nature of "autistic traits".

Intolerance of uncertainty and anxiety as explanatory frameworks for extreme demand avoidance in children and adolescents.

BACKGROUND: Pathological demand avoidance (PDA) is a proposed subtype of autism spectrum disorder (ASD), characterised by extreme avoidance of demands. Demand avoidant behaviour has been proposed to be driven by an anxious need to be in control, although has never been explicitly studied. Emerging evidence suggests intolerance of uncertainty (IU) and anxiety may explain the behaviours seen in ASD. We propose these concepts may be useful starting points for furthering understanding of PDA. METHODS: In Study 1, quantitative methods examined the relationship between PDA, IU and anxiety using data collected in an online survey (N = 214). The sample included cases with clinically diagnosed PDA (n = 69) and those with no clinical diagnosis but parent-identified features of PDA (n = 151). 'Children with a diagnosis of PDA scored significantly higher on the IUS-P (t(212) = 2.45, p < .05) compared to those without a diagnosis of PDA. PDA diagnosis did not impact on scores on any other measure.' In Study 2, a selection of Study 1 participants (n = 11) were followed up with a telephone interview to gain descriptive data relating to PDA and its association with IU and anxiety. RESULTS: Regression analyses indicate that demand avoidant behaviour can be conceptualised in part as a possible attempt to increase certainty and predictability to alleviate increasing anxiety. Children and young people with PDA employed varying strategies to manage IU depending on the level of demand presented and degree of anxiety generated. These strategies can be represented by different features of the behaviour profile seen in PDA (control behaviour, withdrawal to fantasy, and meltdown). These behavioural features of PDA showed differential relationships with IU and anxiety, although all were predicted by IU, only meltdown demonstrated a mediation effect by anxiety. CONCLUSIONS: This study represents one of the first attempts to conceptualise and understand the behavioural features of the PDA profile in children and young people. It builds upon emerging evidence from the ASD literature that IU is a relevant construct for conceptualising demand avoidant behaviour in children who show PDA behaviour. This has potential clinical implications for the assessment and management of PDA in children and young people.

Relationship of Weight Outcomes, Co-Occurring Conditions, and Severity of Autism Spectrum Disorder in the Study to Explore Early Development.

OBJECTIVE: To assess contributing factors to increased obesity risk, by comparing children with autism spectrum disorder (ASD), developmental delays/disorders, and general population controls in weight status, and to examine associations between weight status and presence of co-occurring medical, behavioral, developmental, or psychiatric conditions across groups and ASD severity among children with ASD. STUDY DESIGN: The Study to Explore Early Development is a multisite cross-sectional study of children, 2-5 years of age, classified as children with ASD (n = 668), children with developmental delays/disorders (n = 914), or general population controls (n = 884). Using an observational cohort design, we compared the 3 groups. Children's heights and weights were measured during a clinical visit. Co-occurring conditions (medical, behavioral, developmental/psychiatric) were derived from medical records, interviews, and questionnaires. ASD severity was measured by the Ohio State University Global Severity Scale for Autism. RESULTS: The odds of overweight/obesity were 1.57 times (95% CI 1.24-2.00) higher in children with ASD than general population controls and 1.38 times (95% CI 1.10-1.72) higher in children with developmental delays/disorders than general population controls. The aORs were elevated for children with ASD after controlling for child co-occurring conditions (ASD vs general population controls: aOR = 1.51; 95% CI 1.14-2.00). Among children with ASD, those with severe ASD symptoms were 1.7 times (95% CI 1.1-2.8) more likely to be classified as overweight/obese compared with children with mild ASD symptoms. CONCLUSIONS: Prevention of excess weight gain in children with ASD, especially those with severe symptoms, and in children with developmental delays/disorders represents an important target for intervention.

Bias from self selection and loss to follow-up in prospective cohort studies.

Self-selection into prospective cohort studies and loss to follow-up can cause biased exposure-outcome association estimates. Previous investigations illustrated that such biases can be small in large prospective cohort studies. The structural approach to selection bias shows that general statements about bias are not possible for studies that investigate multiple exposures and outcomes, and that inverse probability of participation weighting (IPPW) but not adjustment for participation predictors generally reduces bias from self-selection and loss to follow-up. We propose to substantiate assumptions in structural models of selection bias through calculation of genetic correlations coefficients between participation predictors, outcome, and exposure, and to estimate a lower bound for bias due to self-selection and loss to follow-up by comparing effect estimates from IPP weighted and unweighted analyses. This study used data from the Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway. Using the example of risk factors for ADHD, we find that genetic correlations between participation predictors, exposures, and outcome suggest the presence of bias. The comparison of exposure-outcome associations from regressions with and without IPPW revealed meaningful deviations. Assessment of selection bias for entire multi-exposure multi-outcome cohort studies is not possible. Instead, it has to be assessed and controlled on a case-by-case basis.

Diagnostic validity of the MINI-KID disorder classifications in specialized child and adolescent psychiatric outpatient clinics in Sweden.

BACKGROUND: Missing diagnostic information often results poor accuracy of the clinical diagnostic decision process. The Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) is a short standardized diagnostic interview and covers a rather broad range of diagnoses applicable to children and adolescents. MINI-KID disorder classifications have shown test-retest reliability and validity comparable to other standardized diagnostic interviews and is claimed to be a useful tool for diagnostic screening in Child and Adolescent Psychiatric care. The concordance between the Swedish language version of the MINI-KID Interview and LEAD (Longitudinal, Expert, All Data) research diagnoses was studied in secondary child and adolescent psychiatric outpatient care. METHODS: MINI-KID interviews were performed for 101 patients, boys n = 50, girls n = 51, aged 4 to 18 years. The duration of the interview was on average 46 min, the child/adolescent participating together with the parent(s) in most cases. The seven most prevalent diagnoses were included in the analyses. RESULTS: The average overall percent agreement (OPA) between MINI-KID and LEAD was 79.5%, the average percent positive agreement (PPA) 35.4 and the average percent negative agreement (NPA) 92.7. OPA was highest for Obsessive-Compulsive Disorder (OCD) (0.89), Tic disorders (0.88) and Pervasive developmental disorders (0.81). There were similar results in diagnostic agreement comparing the two versions: the standard MINI-KID and MINI-KID for parents. The specific screening questions in MINI-KID resulted in additional preliminary diagnoses compared with the regular initial clinical assessment. CONCLUSIONS: Overall, there was an acceptable agreement between MINI-KID disorder classifications and research diagnoses according to LEAD. The standardized interview MINI-KID could be considered as a tool with the possibility to give valuable information in the diagnostic process in child and adolescent care which is similar to the setting in the present study.

Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders.

BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

Forty years of referrals and outcomes to a UK Child Development Centre (CDC): Has demand plateaued?

AIMS: To explore 40 years of Child Development Centre (CDC) activity and outcomes at Northampton General Hospital 1974-2014. METHODS: The study comprises 3 data sets: a published report from 1974 to 1999, an internal audit from 2001 to 2004, and more recent data collected from 2005 to 2014. The medical notes of all children who were assessed by the CDC in 2014 were reviewed, along with referral data collected by the CDC manager from this year and the preceding 10 years. RESULTS: From January 1, 1974 to December 31, 2014, 3,786 children were assessed. The male to female ratio is 2.8:1 from 2005 to 2014. Referrals for behavioural difficulties increased from 10% (10/100 referrals) in 1999-2004 to 17.8% (18/101 referrals) in 2014. Similarly, referrals for social and communication problems, "interaction" increased two and a half fold from 10% (10/100 referrals) in 1999-2004 to 26.7% (27/101 referrals) in 2014. Between 2004 and 2014, numbers of referrals for "developmental delay" halved (22.2% to 12%). CONCLUSION: We are aware of no other comparable extant UK CDC database. Services should plan for a referral rate of 6.5 per 1,000 preschool children. Between 1974 and 2014, there has clearly been a change in recorded assessment outcomes. From the mid-1980s, this reflects the change to a preschool assessment role and a shift away from purely educational outcome to include medical conditions. Covering 1974-2014, we demonstrate a clear increase in the number of referrals together with an increasing demand for assessments for social interaction and behavioural difficulties. This reflects the increased awareness of these neurodevelopmental difficulties and the changing diagnostic criteria which will now more likely result in an Autistic Spectrum Disorder diagnosis than previously. Together, these two features are most likely to have considerable implications for service development within Child Development Centres (CDCs) and Child Development Teams (CDTs).

Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden.

Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case-control study nested within the total population of Sweden (children aged 4-17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34-1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46-3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD.

Social disadvantage and developmental diagnosis in pre-schoolers.

AIM: To explore the association between social disadvantage and developmental diagnoses in pre-school children. METHODS: Between 2012 and 2015, 845 pre-school children were assessed by the Child Assessment Team at Campbelltown Hospital. A social worker interviewed 469 families and these children were eligible for inclusion in the study. Autism spectrum disorder (ASD) was confirmed in 290 children. Of those without ASD, 72 did not have global developmental delay (GDD) and were excluded from the study. The remaining 107 children with GDD were used as the comparison group. Social risk factors in the two groups were compared using χ 2 tests. Variables with statistical significance were then entered into a logistic regression. RESULTS: After logistic regression, children with ASD were more likely to be male (odds ratio (OR) 3.1, 95% CI 0.195-0.529; P < 0.001) and their parents were more likely to have a clinically significant stress score (OR 1.3, 95% CI 0.334-0.992; P = 0.047). Children with GDD were more likely to live in a disadvantaged suburb (OR 1.7, 95% CI 1.042-2.940; P = 0.034), more likely to have a sole parent (OR 1.8, 95% CI 1.062-3.082; P = 0.029) and much more likely to have had involvement with child protection services (OR 3.9, 95% CI 2.044-7.416; P < 0.001). CONCLUSIONS: Children with GDD without autism were more likely to be disadvantaged and to have had contact with child protection services than children with ASD. This has implications for the assessment, early intervention and support services for children with disabilities and their families.

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions--phenotypically and genetically--although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism.

BACKGROUND: Studies have raised concern about an association between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and an increased risk of autism spectrum disorders in the offspring. METHODS: We conducted a cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009. Using Danish population registries, we linked information on maternal use of SSRIs before and during pregnancy, autism spectrum disorders diagnosed in the offspring, and a range of potential confounders. We used a survival analysis of the time to diagnosis in the offspring with Poisson regression to estimate rate ratios of autism spectrum disorders according to maternal use of SSRIs. RESULTS: During 5,057,282 person-years of follow-up, we identified 3892 cases of autism spectrum disorder (incidence rate, 77.0 per 100,000 person-years). A total of 52 cases during 42,400 person-years of follow-up involved offspring of women who were exposed to SSRIs during their pregnancy (incidence rate, 122.6 per 100,000 person-years). As compared with no use of SSRIs both before and during pregnancy, use during pregnancy was not associated with a significantly increased risk of autism spectrum disorders (fully adjusted rate ratio, 1.20; 95% confidence interval [CI], 0.90 to 1.61). Among women who received SSRIs before pregnancy but not during pregnancy, the corresponding fully adjusted rate ratio was 1.46 (95% CI, 1.17 to 1.81). CONCLUSIONS: We did not detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring. On the basis of the upper boundary of the confidence interval, our study could not rule out a relative risk up to 1.61, and therefore the association warrants further study. (Funded by the Danish Health and Medicines Authority.).

Health resource utilization varies by comorbidities in children with epilepsy.

OBJECTIVES: Comorbidities in adults with epilepsy have been shown to significantly increase health resource utilization (HRU). The current study aimed to determine whether a similar association exists among children with epilepsy in a universal health insurance system. METHODS: Health administrative databases in Ontario, Canada were used to evaluate the frequency of neurologist visits, emergency department (ED) visits, and hospitalizations. We evaluated the association between HRU and comorbidities, including depression, anxiety, learning disability, attention deficit hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD), adjusting for age, sex, residence, and socio-economic status. RESULTS: The frequency of neurology visits was increased by comorbid depression, ASD, and learning disability (adjusted relative risk [aRR]=1.29-2.07; p<.01). The frequency of ED visits was increased by all comorbidities (aRR=1.26-2.83; p<.0001). The frequency of hospitalizations was increased by comorbid depression, anxiety, ASD, and learning disability (aRR=1.77-7.20; p<.0001). Learning disability had the largest impact on HRU. For each additional comorbidity, the frequency of neurology visits, ED visits, and hospitalizations increased by 1.64 to 3.16 times (p<.0001). CONCLUSIONS: Among children with epilepsy, mental health and developmental comorbidities were associated with increased HRU, and different comorbidities influenced different types of HRU. In addition, we highlight the importance of identifying and managing these comorbidities, as they increased the risks of costly HRU such as ED visits and hospitalizations.

Validation of the French Autism Spectrum Quotient scale and its relationships with schizotypy and Eysenckian personality traits.

BACKGROUND: Autism and schizophrenia spectra were long considered distinct entities. Yet, recent studies emphasized overlapping clinical and personality features suggesting common mechanisms and liabilities. Independent notions, however, highlight that the two spectra oppose each other socially (positive schizotypal hyper-mentalism versus autistic hypo-mentalism). METHODS: To clarify these relationships, we used data from 921 French-speaking Swiss undergraduates to firstly validate the French Autism Spectrum Questionnaire (AQ) identifying an optimal factor structure. Secondly, we assessed relationships between this AQ structure and schizotypic personality traits. RESULTS: Results from correlational and principal component analyses replicated both overlapping and opposing relationships. CONCLUSIONS: We conjecture that autistic traits opposing positive schizotypy represent autistic mentalizing deficits. We discuss implications of our findings relative to theories of autism and schizophrenia spectrum relationships.

Psychiatric disorders in Danish children aged 5-7 years: A general population study of prevalence and risk factors from the Copenhagen Child Cohort (CCC 2000).

BACKGROUND: Knowledge about the presentation of psychopathology in preschool age and associated risk factors is fundamental to preventive intervention before schooling. AIMS: To investigate the full spectrum of psychiatric diagnoses in general population children at the period of transition from preschool to school. METHODS: A sample of 1585 children from the Copenhagen Child Cohort, CCC2000 aged 5-7 years was assessed using the Development and Well-Being Assessment (DAWBA) with diagnostic classification by experienced clinicians. Perinatal, sociodemographic and socio-economic data was obtained from Danish national registries. RESULTS: The prevalence of any ICD-10 psychiatric disorder was 5.7% (95%CI: 4.4-7.1). Pervasive developmental disorders (PDD) were found in 1.3% (95%CI: 0.8-1.8) and behavioural and hyperkinetic disorders were found in 1.5% (95%CI: 0.9-2.1) and 1.0% (95%CI: 0.4-1.6), respectively. Emotional disorders were found in 2.9% (95%CI: 1.9-40). More boys were diagnosed with PDD, behavioural disorders and tics. No gender differences were found in hyperactivity disorders (HD) and emotional disorders. Co-morbidity was frequent, in particular between HD and PDD, but also between HD and emotional disorder and behavioural disorder. Teenage mothers, single parents and low household income the first two years after the child's birth were associated with a three-to fourfold increased risk of psychiatric disorder in the child at age 5-7 years. CONCLUSION: The study results point to two "windows of opportunity" for prevention. In the earliest postnatal years, prevention should target families at socio-economic risk; and in the years before schooling, intervention should focus on children with symptoms of PDD, HD, and behavioural disorders.

[A girl with foetal valproate syndrome and autism spectrum disorder]. / Een meisje met foetaal valproaatsyndroom en autismespectrumstoornis.

We study the case of a 12-year-old girl who, following intra-uterine exposure to valproate, was diagnosed with foetal valproate syndrome, characterised at birth by dysmorphic features. The use of valproate during pregnancy (because of epilepsy or bipolar disorder) can cause not only structural defects in the growing foetus, but also problems in cognitive development and in adaptive and emotional/behavioural functioning in later life. We evaluate these domains of development in our discussion and suggest several other drugs, less harmful than valproate, which can be used to treat epilepsy or bipolar disorder during pregnancy.

Particulate matter exposure, prenatal and postnatal windows of susceptibility, and autism spectrum disorders.

BACKGROUND: Recent studies suggest that exposure to traffic-related air pollutants, including particulate matter (PM), is associated with autism spectrum disorder (autism). METHODS: Children with autism were identified by records-based surveillance (n = 645 born in North Carolina in 1994, 1996, 1998, or 2000, and n = 334 born in the San Francisco Bay Area in California in 1996). They were compared with randomly sampled children born in the same counties and years identified from birth records (n = 12,434 in North Carolina and n = 2,232 in California). Exposure to PM less than 10 µm (PM10) at the birth address was assigned to each child by a geostatistical interpolation method using daily concentrations from air pollution regulatory monitors. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for a 10 µg/m increase in PM10 within 3-month periods from preconception through the child's first birthday, adjusting for year, state, maternal education and age, race/ethnicity, and neighborhood-level urbanization and median household income, and including a nonparametric term for week of birth to account for seasonal trends. RESULTS: Temporal patterns in PM10 were pronounced, leading to an inverse correlation between the first- and third-trimester concentrations (r = -0.7). Adjusted ORs were, for the first trimester, 0.86 (95% CI = 0.74-0.99), second trimester, 0.97 (0.83-1.15), and third trimester, 1.36 (1.13-1.63); and, after simultaneously including first- and third-trimester concentrations to account for the inverse correlation, were: first trimester, 1.01 (0.81-1.27) and third trimester, 1.38 (1.03-1.84). CONCLUSIONS: Our study adds to previous work in California showing a relation between traffic-related air pollution and autism, and adds similar findings in an eastern US state, with results consistent with increased susceptibility in the third-trimester.

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.

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.

Does treatment have an impact on incidence and risk factors for autism spectrum disorders in children with infantile spasms?

OBJECTIVE: Infantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. METHODS: Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule-Generic (ADOS-G). RESULTS: Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). SIGNIFICANCE: ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome.

Hypospadias and increased risk for neurodevelopmental disorders.

BACKGROUND: Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. It has been previously unknown whether this common malformation is associated with increased psychiatric morbidity later in life. Studies of individuals with hypospadias also provide an opportunity to examine whether difference in androgen signaling is related to neurodevelopmental disorders. To elucidate the mechanisms behind a possible association, we also studied psychiatric outcomes among brothers of the hypospadias patients. METHODS: Registry study within a national cohort of all 9,262 males with hypospadias and their 4,936 healthy brothers born in Sweden between 1973 and 2009. Patients with hypospadias and their brothers were matched with controls by year of birth and county. The following outcomes were evaluated (1) any psychiatric (2) psychotic, (3) mood, (4) anxiety, (5) eating, and (6) personality disorders, (7) substance misuse, (8) attention-deficit hyperactivity disorder (ADHD), (9) autism spectrum disorders (ASD), (10) intellectual disability, and (11) other behavioral/emotional disorders with onset in childhood. RESULTS: Patients with hypospadias were more likely to be diagnosed with intellectual disability (OR 3.2; 95% CI 2.8-3.8), ASD (1.4; 1.2-1.7), ADHD (1.5; 1.3-1.9), and behavioral/emotional disorders (1.4; 1.2-1.6) compared with the controls. Brothers of patients with hypospadias had an increased risk of ASD (1.6; 1.3-2.1) and other behavioral/emotional disorders with onset in childhood (1.2; 0.9-1.5) in comparison to siblings of healthy individuals. A slightly higher, although not statistically significant, risk was found for intellectual disability (1.3; 1.0-1.9). No relation between other psychiatric diagnosis and hypospadias was found. CONCLUSIONS: This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability.