Pål Surén

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.

Parental Obesity and Risk of Autism Spectrum Disorder

OBJECTIVES: The objective of the study was to investigate the associations among maternal prepregnancy BMI, paternal BMI, and the risk of autism spectrum disorders (ASDs) in children. METHODS: The study sample of 92 909 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study. The age range was 4.0 through 13.1 (mean 7.4) years. Relative risks of ASDs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models. RESULTS: At the end of follow-up on December 31, 2012, 419 children in the study sample had been diagnosed with ASDs: 162 with autistic disorder, 103 with Asperger disorder, and 154 with pervasive developmental disorder not otherwise specified. Maternal obesity (BMI ≥30) was only weakly associated with ASD risk, whereas paternal obesity was associated with an increased risk of autistic disorder and Asperger disorder. The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41 603) in children of fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07–2.82). For Asperger disorder, analyses were limited to children aged ≥7 years (n = 50 116). The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18% (42 of 22 736) in children of normal-weight fathers, and the adjusted OR was 2.01 (95% CI: 1.13–3.57). No associations were found for pervasive developmental disorder not otherwise specified. CONCLUSIONS: Paternal obesity is an independent risk factor for ASDs in children. The associations should be investigated further in genetic and epigenetic studies.

Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985–2004 and followed up to the end of 2004–2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parents age (mothers 40–49 years vs 20–29 years, RR=1.15 (95% confidence interval (CI): 1.06–1.24), P-value<0.001; fathers⩾50 years vs 20–29 years, RR=1.66 (95% CI: 1.49–1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20–29 years, RR=1.18 (95% CI: 1.08–1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

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.

Community‐acquired pneumonia (CAP) in children in Oslo, Norway

Aim: To investigate the epidemiology and clinical characteristics of community acquired pneumonia (CAP) in children before the introduction of the 7‐valent pneumococcal vaccine in the national vaccination programme.

Epidemiology of coeliac disease and comorbidity in Norwegian children.

Objectives: The aim of this study was to describe the occurrence of clinically diagnosed coeliac disease in children ages 0 to 12 years in Norway, including regional variation and coexisting type 1 diabetes mellitus, thyroid disease, and Down syndrome. Methods: The Norwegian Patient Register (NPR) contains individual-level hospital data from 2008 onward. Small-bowel biopsies for establishing the coeliac disease diagnosis are only performed at public hospitals reporting to the NPR. Data on all hospital contacts during 2008–2011 when a diagnosis of coeliac disease was registered were retrieved from the NPR for patients born between 1999 and 2011, allowing estimation of the proportion registered with coeliac disease at ages 0 to 12 years in a cohort study. Results: A total of 3006 individuals (58.2% girls) were recorded as having coeliac disease among 797,360 children, corresponding to a proportion of 3.8/1000 (95% confidence interval [CI] 3.7–3.9/1000) children, 4.5 (CI 4.3–4.7) among girls and 3.1 (CI 2.9–3.3/1000) among boys (P < 0.001). The proportion increased with age up to approximately 6 years and was 5.0/1000 (CI 4.5–5.6) at the age of 12 years, and was slightly higher in the south/west (3.9/1000) as compared to the middle/north (3.5/1000) regions of Norway (P = 0.013). A total of 214 of 3006 (7.1%) patients with coeliac disease were registered with coexisting conditions: type 1 diabetes mellitus (n = 142, 4.7%), Down syndrome (n = 47, 1.6%), or thyroid disease (n = 41, 1.4%). Conclusions: In this first nationwide study of clinically diagnosed coeliac disease in Norwegian children, we found a high occurrence, comparable with that in Sweden. Comorbidity was common, but routine screening of high-risk groups contributed to a limited number of cases.

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.

Maternal Prepregnancy BMI and Risk of Cerebral Palsy in Offspring.

OBJECTIVES: To investigate the association between maternal pre-pregnancy BMI and risk of cerebral palsy (CP) in offspring. METHODS: The study population consisted of 188 788 children in the Mothers and Babies in Norway and Denmark CP study, using data from 2 population-based, prospective birth cohorts: the Norwegian Mother and Child Cohort Study and the Danish National Birth Cohort. Prepregnancy BMI was classified as underweight (BMI <18.5), lower normal weight (BMI 18.5–22.9), upper normal weight (BMI 23.0–24.9), overweight (BMI 25.0–29.9), and obese (BMI ≥30). CP diagnoses were obtained from the national CP registries. Associations between maternal prepregnancy BMI and CP in offspring were investigated by using log-binomial regression models. RESULTS: The 2 cohorts had 390 eligible cases of CP (2.1 per 1000 live-born children). Compared with mothers in the lower normal weight group, mothers in the upper normal group had a 40% excess risk of having a child with CP (relative risk [RR], 1.35; 95% confidence interval [CI], 1.03–1.78). Excess risk was 60% (RR, 1.56; 95% CI, 1.21–2.01) for overweight mothers and 60% (RR, 1.55; 95% CI 1.11–2.18) for obese mothers. The risk of CP increased ∼4% for each unit increase in BMI (RR, 1.04; 95% CI, 1.02–1.06). Estimates changed little with adjustment for mother’s occupational status, age, and smoking habits. CONCLUSIONS: Higher prepregnancy maternal BMI was associated with increased risk of CP in offspring.

Comorbidity and Childhood Epilepsy: A Nationwide Registry Study

BACKGROUND AND OBJECTIVE: Children with epilepsy are at increased risk of other disorders and difficulties, preceding, cooccurring with, or after the diagnosis of epilepsy. Risk estimates vary, few studies are population-based, and few provide comprehensive assessments of comorbidities. We used nationwide registry data to describe frequencies of medical, neurologic, developmental, and psychiatric conditions occurring before and after children are diagnosed with childhood epilepsy. METHODS: Data were obtained from the Norwegian Patient Registry, which is an administrative database recording International Classification of Diseases, 10th Revision diagnoses from all government-funded specialist health services in Norway (outpatient consultations and hospitalizations). We included data from the years 2008 through 2013 for all children born in Norway between 1996 and 2013 (0–17 years of age at the end of follow-up). Children with epilepsy were compared with the general child population, adjusting for sex and age. We also compared children with complicated epilepsies (ie, epilepsies with additional neurologic and/or developmental disorders) to children with uncomplicated epilepsies. RESULTS: The study population included 1 125 161 children. There were 6635 (0.6%) children with epilepsy. Nearly 80% of children with epilepsy had ≥1 comorbid disorder. All types of disorders were more frequent in children with epilepsy, with additional medical disorders recorded in 55%, neurologic disorders in 41%, and developmental/psychiatric disorders in 43%. Children with complicated epilepsies had the highest overall levels of comorbidity, but the risk of medical and psychiatric comorbidities was also substantial among children with uncomplicated epilepsies. CONCLUSIONS: The overall frequency of comorbid disease is high in children with epilepsy, including children with presumably uncomplicated epilepsies.