Anne-Siri Øyen

Autism Spectrum Disorder, ADHD, Epilepsy, and Cerebral Palsy in Norwegian Children

BACKGROUND: Numerous studies have investigated the prevalence of neurologic and neurodevelopmental disorders individually, but few have examined them collectively, and there is uncertainty as to what extent they overlap. METHODS: The study has determined the proportions of children aged 0 to 11 years with diagnoses of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), epilepsy, and cerebral palsy (CP) in Norway. The data were obtained from the Norwegian Patient Register, which is nationwide and contains diagnoses assigned by Norwegian specialist health services (hospitals and outpatient clinics). The Norwegian Patient Register started collecting individual-level data in 2008, and the follow-up period for the study is years 2008 through 2010. RESULTS: For ASD, ADHD, and epilepsy, the proportions were highest in the oldest children. At age 11 years, the incidence was 0.7% for ASD, 2.9% for ADHD, and 0.9% for epilepsy. The cumulative incidence is likely to be higher because some cases diagnosed before 2008 were probably missed. For CP, the proportions were ∼0.3% for age ≥5 years. There was considerable overlap between diagnoses. For all disorders, boys had a significantly increased risk. In school-age children (aged 6–11 years) the male/female ratio was 4.3 for ASD, 2.9 for ADHD, 1.2 for epilepsy, and 1.3 for CP. CONCLUSIONS: The findings demonstrate the significant burden of disease associated with neurologic and neurodevelopmental disorders in children and that this burden is disproportionately skewed toward boys.

The Autism Birth Cohort: a paradigm for gene–environment–timing research

The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene × environment × timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107 000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a ‘nested case–control’ design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.

Exposure to antiepileptic drugs in utero and child development: A prospective population‐based study

Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development.

Predicting Language Development at Age 18 Months: Data from the Norwegian Mother and Child Cohort Study

Objectives: This study investigated predictors of delayed language development at 18 months of age in a large population cohort of Norwegian toddlers. Methods: Data were analyzed on 42,107 toddlers. Language outcome at age 18 months was measured using a standard parent report instrument, the Ages and Stages Questionnaire, communication scale. Confirmatory factor analysis was conducted on the Ages and Stages Questionnaire items. A theoretically derived set of child, family, and environmental risk factors were used to predict delayed language development at age 18 months using Generalized Estimating Equation. Results: A number of child factors, including being a boy, low birth weight or gestational age, or a multiple birth child were all significantly associated with low scores on the language outcome at age 18 months. Maternal distress/depression and low maternal education, having older siblings, or a non-Norwegian language background also predicted low scores on the language outcome at age 18 months. Overall, estimated variance in language outcome explained by the model was 4% to 7%. Conclusions: A combination of early neurobiological and genetic factors (e.g., male gender, birth weight, and prematurity) and concurrent family variables (e.g., maternal distress/depression) were associated with slower language development at age 18 months. This finding replicated previous research conducted on slightly older language-delayed 2 year olds but also detected the importance of factors related to family resources for the first time in this younger age group. Despite this finding, most of the variability in language performance in this cohort of 18 month olds remained unexplained by the comprehensive set of purported risk factors.

Interpregnancy interval and risk of autistic disorder

Background: A recent California study reported increased risk of autistic disorder in children conceived within a year after the birth of a sibling. Methods: We assessed the association between interpregnancy interval and risk of autistic disorder using nationwide registry data on pairs of singleton full siblings born in Norway. We defined interpregnancy interval as the time from birth of the first-born child to conception of the second-born child in a sibship. The outcome of interest was autistic disorder in the second-born child. Analyses were restricted to sibships in which the second-born child was born in 1990–2004. Odds ratios (ORs) were estimated by fitting ordinary logistic models and logistic generalized additive models. Results: The study sample included 223,476 singleton full-sibling pairs. In sibships with interpregnancy intervals <9 months, 0.25% of the second-born children had autistic disorder, compared with 0.13% in the reference category (≥36 months). For interpregnancy intervals shorter than 9 months, the adjusted OR of autistic disorder in the second-born child was 2.18 (95% confidence interval 1.42–3.26). The risk of autistic disorder in the second-born child was also increased for interpregnancy intervals of 9–11 months in the adjusted analysis (OR = 1.71 [95% CI = 1.07–2.64]). Conclusions: Consistent with a previous report from California, interpregnancy intervals shorter than 1 year were associated with increased risk of autistic disorder in the second-born child. A possible explanation is depletion of micronutrients in mothers with closely spaced pregnancies.

EARLY GROWTH PATTERNS IN CHILDREN WITH AUTISM

Background: Case-control studies have found increased head growth during the first year of life in children with autism spectrum disorder. Length and weight have not been as extensively studied, and there are few studies of population-based samples. Methods: The study was conducted in a sample of 106,082 children from the population-based Norwegian Mother and Child Cohort. The children were born in 1999–2009; by the end of follow-up on 31 December 2012, the age range was 3.6 through 13.1 years (mean 7.4 years). Measures were obtained prospectively until age 12 months for head circumference and 36 months for length and weight. We compared growth trajectories in autism spectrum disorder cases and noncases using Reed first-order models. Results: Subjects included 376 children (310 boys and 66 girls) with specialist-confirmed autism spectrum disorder. In boys with autism spectrum disorder, mean head growth was similar to that of other boys, but variability was greater, and 8.7% had macrocephaly (head circumference >97th cohort percentile) by 12 months of age. Autism spectrum disorder boys also had slightly increased body growth, with mean length 1.1 cm above and mean weight 300 g above the cohort mean for boys at age 12 months. Throughout the first year, the head circumference of girls with autism spectrum disorder was reduced—by 0.3 cm at birth and 0.5 cm at 12 months. Their mean length was similar to that of other girls, but their mean weight was 150–350 g below at all ages from birth to 3 years. The reductions in mean head circumference and weight in girls with autism spectrum disorder appear to be driven by those with intellectual disability, genetic disorders, and epilepsy. Discussion: Growth trajectories in children with autism spectrum disorder diverge from those of other children and the differences are sex specific. Previous findings of increased mean head growth were not replicated.

Differences across counties in the registered prevalence of autism, ADHD, epilepsy and cerebral palsy in Norway.

BACKGROUND In 2012, we published an overview of the prevalence of developmental disorders and neurological diseases in children in Norway, which was unknown at the time. In this article we will compare diagnostics and treatment across counties and institutions. MATERIAL AND METHOD The prevalence across counties of autism spectrum disorders, ADHD, epilepsy and cerebral palsy in children aged 0-12 was estimated with the aid of data from the Norwegian Patient Register for the years 2008-11. RESULTS In the age group 6-12 years, nationwide prevalence amounted to 0.6% for autism spectrum disorders, 2.0% for ADHD, 0.9% for epilepsy and 0.3% for cerebral palsy. In total, 5.0% of all twelve-year-olds were registered with one or more of these diagnoses. The prevalence of autism spectrum disorders and ADHD varied between the counties, from 0.3% to 1.5% for autism spectrum disorders and from 1.1% to 3.5% for ADHD. For epilepsy and cerebral palsy there was little variation between the counties. Diagnostics and treatment of these four conditions are spread over 29 somatic hospitals and 102 units for child and youth psychiatry. INTERPRETATION The variations across counties in the prevalence of autism spectrum disorders and ADHD are most likely due to variations in diagnostic practices. We ask whether it is appropriate to spread the provision of treatment across such a high number of institutions.

Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring

The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy. ABSTRACT Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; P = 0.03) when adjusted for parity and child’s birth year. No association was found between ASD and the presence of IgG antibodies to Toxoplasma gondii, rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. IMPORTANCE The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy.

Clinical Features of Children With Autism Who Passed 18-Month Screening

This is the first study in which researchers examine developmental and temperamental characteristics of boys and girls screening negative for autism at 18 months. OBJECTIVES: We compared sex-stratified developmental and temperamental profiles at 18 months in children screening negative for autism spectrum disorder (ASD) on the Modified Checklist for Autism in Toddlers (M-CHAT) but later receiving diagnoses of ASD (false-negative group) versus those without later ASD diagnoses (true-negative group). METHODS: We included 68 197 screen-negative cases from the Norwegian Mother and Child Cohort Study (49.1% girls). Children were screened by using the 6 critical items of the M-CHAT at 18 months. Groups were compared on domains of the Ages and Stages Questionnaire and the Emotionality Activity Sociability Temperament Survey. RESULTS: Despite passing M-CHAT screening at 18 months, children in the false-negative group exhibited delays in social, communication, and motor skills compared with the true-negative group. Differences were more pronounced in girls. However, with regard to shyness, boys in the false-negative group were rated as more shy than their true-negative counterparts, but girls in the false-negative group were rated as less shy than their counterparts in the true-negative group. CONCLUSIONS: This is the first study to reveal that children who pass M-CHAT screening at 18 months and are later diagnosed with ASD exhibit delays in core social and communication areas as well as fine motor skills at 18 months. Differences appeared to be more pronounced in girls. With these findings, we underscore the need to enhance the understanding of early markers of ASD in boys and girls, as well as factors affecting parental report on early delays and abnormalities, to improve the sensitivity of screening instruments.

Correction for Mahic et al., “Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring”

[This corrects the article DOI: 10.1128/mSphere.00016-17.].