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.
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.
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.
To investigate the association between proportionality of fetal and placental growth measured at birth and the risk for congenital cerebral palsy (CP).
We identified all live-born singletons born in ...Denmark between 1995 and 2003 and followed them from 1 year of age until December 31st, 2008. Information on four indices of fetal growth: ponderal index, head circumference/ abdominal circumference ratio, cephalization index and birth weight/ placenta weight ratio was collected. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). All measurements were evaluated as gestational age and sex specific z-scores and in z-score percentile groups, adjusted for potential confounders, and stratified on gestational age groups (<32, 32-36, 37-38, 39, 40, ≥ 41 weeks).
We identified 503,784 singleton births, of which 983 were confirmed cases of CP. Head/ abdominal circumference ratio (aHR:1.12; 95%CI:1.07-1.16) and cephalization index (aHR:1.14; 95%CI:1.11-1.16) were associated with the risk of CP irrespective of gestational age. Birth weight-placental weight ratio was also associated with CP in the entire cohort (aHR:0.90; 95%CI:0.83-0.97). Ponderal index had a u-shaped association with CP, where both children with low and high ponderal index were at higher risk of CP.
CP is associated with disproportions between birth weight, birth length, placental weight and head circumference suggesting pre and perinatal conditions contribute to fetal growth restriction in children with CP.
Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have ...functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3–5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure.
•An epigenetic signature of prenatal exposure to cigarette smoke, originally discovered in other studies of cord blood at birth, is detectable in childhood blood samples at ages 3–5.•Prenatal smoking-associated loci do not show similar patterns or magnitudes of DNA methylation differences for other prenatal exposures.•DNA methylation patterns from 26 CpG sites at 3–5 years of age can accurately classify prenatal exposure to smoking.
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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