Hjördís Ósk Atladóttir

Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders

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.

Autism After Infection, Febrile Episodes, and Antibiotic Use During Pregnancy: An Exploratory Study

OBJECTIVES: Results of animal studies suggest that maternal immune activation during pregnancy causes deficiencies in fetal neurodevelopment. Infectious disease is the most common path to maternal immune activation during pregnancy. The goal of this study was to determine the occurrence of common infections, febrile episodes, and use of antibiotics reported by the mother during pregnancy and the risk for autism spectrum disorder (ASD) and infantile autism in the offspring. METHODS: We used a population-based cohort consisting of 96 736 children aged 8 to 14 years and born from 1997 to 2003 in Denmark. Information on infection, febrile episodes, and use of antibiotics was self-reported through telephone interviews during pregnancy and early postpartum. Diagnoses of ASD and infantile autism were retrieved from the Danish Psychiatric Central Register; 976 children (1%) from the cohort were diagnosed with ASD. RESULTS: Overall, we found little evidence that various types of mild common infectious diseases or febrile episodes during pregnancy were associated with ASD/infantile autism. However, our data suggest that maternal influenza infection was associated with a twofold increased risk of infantile autism, prolonged episodes of fever caused a threefold increased risk of infantile autism, and use of various antibiotics during pregnancy were potential risk factors for ASD/infantile autism. CONCLUSIONS: Our results do not suggest that mild infections, febrile episodes, or use of antibiotics during pregnancy are strong risk factors for ASD/infantile autism. The results may be due to multiple testing; the few positive findings are potential chance findings.

Association of Hospitalization for Infection in Childhood With Diagnosis of Autism Spectrum Disorders: A Danish Cohort Study

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.

Variation in incidence of neurodevelopmental disorders with season of birth.

Background: The etiologies of autism spectrum disorder and many neurodevelopmental disorders are largely unknown. The detection of a seasonal variation of birth of children diagnosed with a certain disorder could suggest etiological factors that follow a seasonal pattern. We examined the seasonal variation of births of children diagnosed with any of 4 common childhood neuropsychiatric disorders: autism spectrum disorder, hyperkinetic disorder, Tourette syndrome, and obsessive-compulsive disorder. Methods: The study cohort consisted of all children born in Denmark from 1990 through 1999 identified in the Danish Medical Birth Register (n = 669,995). Outcome data consisted of both inpatient and outpatient diagnoses reported to the Danish National Psychiatric Registry from 1995 through 2004 using the International Classification of Diseases, 10th edition, diagnostic coding system. Logistic regression combined with spline (a smoothing method) was used to estimate the variation with season of birth for each disorder. Estimates of risk of each disorder with season of birth were adjusted for differences in follow-up time and change in incidence over time. Results: No convincing variations in season of birth were observed for any of the 4 disorders, or for the autism-spectrum-disorder subtypes. Conclusion: Although we cannot rule out the possibility of seasonal variation of birth for a range of childhood neurodevelopmental disorders, we find little evidence that seasonal environmental factors are related to these disorders.

Neonatal levels of cytokines and risk of autism spectrum disorders: An exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank

The aim of the study was to analyze cytokine profiles in neonatal dried blood samples (n-DBSS) retrieved from The Danish Newborn Screening Biobank of children developing Autism Spectrum Disorders (ASD) later in life and controls. Samples of 359 ASD cases and 741 controls were analyzed using Luminex xMAP technology and clinical data were retrieved from nationwide registers. Findings showed that children developing ASD were more likely to have decreased levels of both T helper-1(Th-1)-like cytokines (i.e. IFN-γ) and Th-2like cytokines (i.e. IL-4, IL-10) which may suggest a depressed or hypoactive immune cell activity during neonatal period in ASD.

The prevalence of 30 ICD-10 autoimmune diseases in Denmark

Epidemiologic studies of autoimmune diseases have not considered them in the aggregate. The objective was to estimate the prevalence of 30 autoimmune diseases separately and in aggregate according to ICD-10 classification. The lifetime prevalence of the entire population of 5,506,574 persons alive in Denmark on October 31, 2006, was estimated by linking records of all visitors to hospitals and specialty clinics via National Patient Registers from January 1, 1977 through October 31, 2006. The prevalences vary from 0.06/1,000 for Pemphigus to 8.94/1,000 for Type 1 diabetes. Nearly 4% of the population had one or more autoimmune disease. The general conclusion is that autoimmune diseases as an aggregate are common.

Gestational Age and Autism Spectrum Disorder: Trends in Risk Over Time.

Autism Spectrum Disorder (ASD) is a serious neurodevelopmental disorder. Several previous studies have identified preterm birth as a risk factor for ASD but none has studied whether the association between gestational age and ASD has changed over time. This is a Danish population‐based follow‐up study including live‐born singletons born in Denmark between 1980 and 2009, identified in the Danish Medical Birth Registry, a study population of 1,775,397 children. We used a Cox regression model combined with spline to study the risk for ASD by gestational age across three decades of birth cohorts. We included 19,020 children diagnosed with ASD. Across all birth year cohorts, we found that the risk of being diagnosed with ASD increased with lower gestational age (P‐value: <0.01). Across all gestational weeks, we found a statistically significant higher risk estimates in birth cohort 1980 to 1989, compared to birth cohorts 1990 to 1999 and 2000 to 2009, respectively. No statistically significant difference in risk estimates was observed between birth cohort 1990 to 1999 and 2000 to 2009. The observed time trend in risk of ASD after preterm birth may reflect: (1) a change in the risk profile of persons with ASD due to the broadening of ASD diagnostic criteria over time; or (2) improved neonatal care for low GA infants, which has reduced risk of adverse outcomes like ASD in preterm children. Autism Res 2016, 9: 224–231.

Patterns of Contact with Hospital for Children with an Autism Spectrum Disorder: A Danish Register-Based Study

The aim of this study was to study patterns of contact with hospital for children with autism spectrum disorder (ASD) using Danish population based register data. We included all children born in Denmark from 1994 through 2002. We found that children diagnosed with ASD had an increased rate of contact with hospital, almost regardless of the cause for the hospital contact. Given the overall association between hospital contact for various causes and ASD observed in these data, hospital data should be used cautiously in future studies searching for associations between a specific disease and ASD. If the increased rate of hospital contact overall for children with ASD is not considered, then misleading over interpretations might be made of observed associations between specific diseases and ASD.

A Descriptive Study on the Neonatal Morbidity Profile of Autism Spectrum Disorders, Including a Comparison with Other Neurodevelopmental Disorders

Abstract The aim of this study was to describe the profile of specific neonatal morbidities in children later diagnosed with autism spectrum disorder (ASD), and to compare this profile with the profile of children with hyperkinetic disorder, cerebral palsy, epilepsy or intellectual disability. This is a Danish population based cohort study, including all children born in Denmark from 1994, through 2010, and surviving the first year of life. Children with ASD as a whole have significantly elevated rates of a range of neurologic, respiratory, inflammatory, and metabolic problems in the neonatal period compared to the general population, but there are few if any indicators of a distinctive neonatal morbidity profile in ASD compared to other neurodevelopmental outcomes.

Using Maternally Reported Data to Investigate the Association between Early Childhood Infection and Autism Spectrum Disorder: the Importance of Data Source

BACKGROUND Childhood infections have been found to be associated with autism spectrum disorder (ASD) in previous studies using hospital data or medical records to identify infections. We aimed to replicate these findings using maternal reports of childhood infection. METHODS We used the Danish National Birth Cohort consisting of 92 583 live singletons born from 1997 to 2003 in Denmark. ASD diagnoses were retrieved from the Danish Psychiatric Central Register, and a total of 945 children from the cohort were diagnosed with ASD. Data were analysed using Cox proportional hazards regression. We studied the association between ASD and maternal reports of infectious disease in the child from birth to 19 months. Furthermore, we performed secondary analyses using hospital registers to investigate the association between ASD and hospital contact in general as well as hospital contact for various infections. RESULTS We did not find a general association between maternal reports of infectious illness and ASD. However, hospital contact for all causes was associated with an increased risk for an ASD diagnosis. Danish children with ASD do not appear to have a general pattern of illness from infection in early life, but do have more contact with medical specialists for infections and other indications compared with the general population. CONCLUSION [corrected] Hospital data should be used cautiously when studying the co-morbidity of ASD; if the increased rate of hospital contact overall for children with ASD is not considered, then misleading interpretations might be made of observed associations between specific diseases and ASD.