A study on the prevalence of autism spectrum disorder (ASD) using data from all live births in Denmark between 1980 and 2012 that were identified in the Central Person Register is presented. Persons ...with suspected ASD receive a multidisciplinary evaluation at a psychiatric department and the final diagnosis is reported by a psychiatrist who has obtained mandatory registry-reporting training. It showed that ASD was reported for 31 961 persons among 2 055 928 live births with each birth cohort cumulative incidence curve followed its own trajectory.
IMPORTANCE: The prevalence of autism spectrum disorders (ASDs) has increased markedly in recent decades, which researchers have suggested could be caused in part by nonetiologic factors such as ...changes in diagnosis reporting practices. To our knowledge, no study has quantified the degree to which changes in reporting practices might explain this increase. Danish national health registries have undergone a change in diagnostic criteria in 1994 and the inclusion of outpatient contacts to health registries in 1995. OBJECTIVE: To quantify the effect of changes in reporting practices in Denmark on reported ASD prevalence. DESIGN, SETTING, AND PARTICIPANTS: We used a population-based birth cohort approach that includes information on all individuals with permanent residence in Denmark. We assessed all children born alive from January 1, 1980, through December 31, 1991, in Denmark (n = 677 915). The children were followed up from birth until ASD diagnosis, death, emigration, or the end of follow-up on December 31, 2011, whichever occurred first. The analysis uses a stratified Cox proportional hazards regression model with the changes in reporting practices modeled as time-dependent covariates. EXPOSURES: The change in diagnostic criteria in 1994 and the inclusion of outpatient diagnoses in 1995. MAIN OUTCOMES AND MEASURES: Autism spectrum disorders. RESULTS: For Danish children born during the study period, 33% (95% CI, 0%-70%) of the increase in reported ASD prevalence could be explained by the change in diagnostic criteria alone; 42% (95% CI, 14%-69%), by the inclusion of outpatient contacts alone; and 60% (95% CI, 33%-87%), by the change in diagnostic criteria and the inclusion of outpatient contacts. CONCLUSIONS AND RELEVANCE: Changes in reporting practices can account for most (60%) of the increase in the observed prevalence of ASDs in children born from 1980 through 1991 in Denmark. Hence, the study supports the argument that the apparent increase in ASDs in recent years is in large part attributable to changes in reporting practices.
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.
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.
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.
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.
Despite substantial similarities and overlaps in the pathophysiology of obsessive-compulsive disorders (OCD) and autism spectrum disorders, little is known about the clinical and etiologic cohesion ...of these two disorders. We therefore aimed to determine the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders.
In a prospective study design we explored the effect of a prior diagnosis of OCD in patients and parents on the susceptibility to autism spectrum disorders and vice versa. Analyses were adjusted for sex, age, calendar year, parental age and place at residence at time of birth. As measures of relative risk incidence rate ratios (IRR) and accompanying 95% confidence intervals (CIs) were employed.
The risk of a comorbid diagnosis of OCD in individuals with autism spectrum disorder and aggregation of autism spectrum disorders in offspring of parents with OCD were increased. Individuals first diagnosed with autism spectrum disorders had a 2-fold higher risk of a later diagnosis of OCD (IRR = 2.18, 95% CI = 1.91-2.48), whereas individuals diagnosed with OCD displayed a nearly 4-fold higher risk to be diagnosed with autism spectrum disorders (IRR = 3.91, 95% CI = 3.46-4.40) later in life. The observed associations were somewhat stronger for less severe types of autism spectrum disorders without a comorbid diagnosis of mental disabilities.
The high comorbidity, sequential risk, and shared familial risks between OCD and autism spectrum disorders are suggestive of partially shared etiological mechanisms. The results have implications for current gene-searching efforts and for clinical practice.
Exposure to prenatal infection has been suggested to cause deficiencies in fetal neurodevelopment. In this study we included all children born in Denmark from 1980, through 2005. Diagnoses of autism ...spectrum disorders (ASDs) and maternal infection were obtained through nationwide registers. Data was analyzed using Cox proportional hazards regression. No association was found between any maternal infection and diagnosis of ASDs in the child when looking at the total period of pregnancy: adjusted hazard ratio = 1.14 (CI: 0.96–1.34). However, admission to hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester were found to be associated with diagnosis of ASDs in the offspring, adjusted hazard ratio = 2.98 (CI: 1.29–7.15) and adjusted hazard ratio = 1.42 (CI: 1.08–1.87), respectively. Our results support prior hypotheses concerning early prenatal viral infection increasing the risk of ASDs.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. ...Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations
and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.
IMPORTANCE Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure ...to valproate may increase the risk of autism. OBJECTIVE To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism autistic disorder, Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 95% CI, 1.7-4.9) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 95% CI, 2.7-10.0). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 95% CI, 0.9-3.2), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 95% CI, 1.4-6.0) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
IMPORTANCE: Several mental disorders have consistently been found to be associated with decreased life expectancy, but little is known about whether this is also the case for obsessive-compulsive ...disorder (OCD). OBJECTIVE: To determine whether persons who receive a diagnosis of OCD are at increased risk of death. DESIGN, SETTING, AND PARTICIPANTS: Using data from Danish registers, we conducted a nationwide prospective cohort study with 30 million person-years of follow-up. The data were collected from Danish longitudinal registers. A total of 3 million people born between 1955 and 2006 were followed up from January 1, 2002, through December 31, 2011. During this period, 27 236 people died. The data were analyzed primarily in June 2015. MAIN OUTCOMES AND MEASURES: We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, maternal and paternal age, place of residence at birth, and somatic comorbidities, to compare persons with OCT with persons without OCD. RESULTS: Of 10 155 persons with OCD (5935 women and 4220 men with a mean SD age of 29.1 11.3 years who contributed a total of 54 937 person-years of observation), 110 (1.1%) died during the average follow-up of 9.7 years. The risk of death by natural or unnatural causes was significantly higher among persons with OCD (MRR, 1.68 95% CI, 1.31-2.12 for natural causes; MRR, 2.61 95% CI, 1.91-3.47 for unnatural causes) than among the general population. After the exclusion of persons with comorbid anxiety disorders, depression, or substance use disorders, OCD was still associated with increased mortality risk (MRR, 1.88 95% CI, 1.27-2.67). CONCLUSIONS AND RELEVANCE: The presence of OCD was associated with a significantly increased mortality risk. Comorbid anxiety disorders, depression, or substance use disorders further increased the risk. However, after adjusting for these and somatic comorbidities, we found that the mortality risk remained significantly increased among persons with OCD.
IMPORTANCE: Increased mortality has been reported among persons with autism spectrum disorder (ASD), especially among those who also have the comorbid condition of epilepsy or intellectual ...disability. The effects of psychiatric and neurologic comorbidity on mortality among persons with ASD have not been rigorously examined in large, population-based studies. OBJECTIVE: To investigate the mortality patterns among persons with ASD overall and to assess the associations of comorbid mental, behavioral, and neurologic disorders with mortality among persons with ASD. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study of children born in Denmark during the period from 1980 to 2010 who were alive at 1.5 years of age and followed up through 2013. This population-based sample of children (N = 1 912 904) was identified via linkage between the Danish Civil Registration Service and the Danish Medical Birth Register using a unique 10-digit identifier assigned to all live births and new residents in Denmark. Children were followed up for diagnoses of ASD (International Classification of Diseases, Eighth Revision ICD-8 codes 299.00, 299.01, 299.02, and 299.03 and ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9) and other mental/behavioral disorders (ICD-8 codes 290-315 and ICD-10 codes F00-F99) in the Danish Psychiatric Central Research Register and for diagnoses of neurologic disorders (ICD-8 codes 320-359 and ICD-10 codes G00-G99) in the Danish National Patient Register. Data analysis was performed in December 2014. MAIN OUTCOMES AND MEASURES: Deaths and causes of death among cohort members were identified via the Danish Civil Registration Service and the Danish Cause of Death Register, respectively. Regressions analyses were performed using Cox regression. RESULTS: Of the 1 912 904 persons included in our study, 20 492 (1.1%) had ASD (15 901 77.6% were male). Of the 20 492 persons with ASD, 68 died (0.3%) (57 of 68 83.8% had comorbid mental/behavioral or neurologic disorders). The adjusted hazard ratio (aHR) for overall mortality was 2.0 (95% CI, 1.5-2.8) for ASD. The aHRs for ASD-associated mortality among cohort members who did not have neurologic (2.0 95% CI, 1.4-3.0) or other mental/behavioral disorders (1.7 95% CI, 1.0-3.1) were similar. The co-occurrence of ASD added no additional mortality risk for persons with neurologic (aHR, 0.7 95% CI, 0.4-1.3) or mental/behavioral disorders (aHR, 0.8 95% CI, 0.5-1.2) compared with persons with these disorders and no ASD. CONCLUSIONS AND RELEVANCE: The mortality risk was 2-fold higher through young adulthood for persons with ASD than for persons without ASD, although mortality affected only 0.3% of persons with ASD. The mechanisms underlying ASD-associated mortality may be mediated through or shared with neurologic or mental/behavioral disorders, thereby providing insights into their potential neurobiological links. Health care professionals and family members should recognize the importance of these disorders with regard to the mortality risk for persons with ASD.
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