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2.
JAMA Psychiatry ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31116379

RESUMO

Importance: Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. Objectives: To estimate the single-nucleotide polymorphism-based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. Design, Setting, Participants: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. Main Outcomes and Measures: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. Results: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604; P = 5.39 × 10-11; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P = .002; t = -3.33) and the hippocampus (P = .001; t = -3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. Conclusions and Relevance: This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.

3.
Philos Trans R Soc Lond B Biol Sci ; 374(1770): 20180120, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30966880

RESUMO

There is great interest in the role epigenetic variation induced by non-genetic exposures may play in the context of health and disease. In particular, DNA methylation has previously been shown to be highly dynamic during the earliest stages of development and is influenced by in utero exposures such as maternal smoking and medication. In this study we sought to identify the specific DNA methylation differences in blood associated with prenatal and birth factors, including birth weight, gestational age and maternal smoking. We quantified neonatal methylomic variation in 1263 infants using DNA isolated from a unique collection of archived blood spots taken shortly after birth (mean = 6.08 days; s.d. = 3.24 days). An epigenome-wide association study (EWAS) of gestational age and birth weight identified 4299 and 18 differentially methylated positions (DMPs) respectively, at an experiment-wide significance threshold of p < 1 × 10-7. Our EWAS of maternal smoking during pregnancy identified 110 DMPs in neonatal blood, replicating previously reported genomic loci, including AHRR. Finally, we tested the hypothesis that DNA methylation mediates the relationship between maternal smoking and lower birth weight, finding evidence that methylomic variation at three DMPs may link exposure to outcome. These findings complement an expanding literature on the epigenomic consequences of prenatal exposures and obstetric factors, confirming a link between the maternal environment and gene regulation in neonates. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

4.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
5.
Brain Behav Immun ; 79: 152-158, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30685531

RESUMO

BACKGROUND: Common infectious pathogens have been associated with psychiatric disorders, self-violence and risk-taking behavior. METHODS: This case-control study reviews register data on 81,912 individuals from the Danish Blood Donor Study to identify individuals who have a psychiatric diagnosis (N = 2591), have attempted or committed suicide (N = 655), or have had traffic accidents (N = 2724). For all cases, controls were frequency matched by age and sex, resulting in 11,546 participants. Plasma samples were analyzed for immunoglobulin G (IgG) antibodies against Toxoplasma gondii and cytomegalovirus (CMV). RESULTS: T. gondii was detected in 25·9% of the population and was associated with schizophrenia (odds ratio [OR], 1·47; 95% confidence interval [CI], 1·03-2·09). Accounting for temporality, with pathogen exposure preceding outcome, the association was even stronger (IRR, 2·78; 95% CI, 1·27-6·09). A very weak association between traffic accident and toxoplasmosis (OR, 1·11; 95% CI, 1·00-1·23, p = 0.054) was found. CMV was detected in 60·8% of the studied population and was associated with any psychiatric disorder (OR, 1·17; 95% CI, 1·06-1·29), but also with a smaller group of neurotic, stress-related, and somatoform disorders (OR, 1·27; 95% CI, 1·12-1·44), and with attempting or committing suicide (OR, 1·31; 95% CI, 1·10-1·56). Accounting for temporality, any psychiatric disorder (IRR, 1·37; 95% CI, 1·08-1·74) and mood disorders (IRR, 1·43; 95% CI, 1·01-2·04) were associated with exposure to CMV. No association between traffic accident and CMV (OR, 1·06; 95% CI, 0·97-1·17) was found. CONCLUSIONS: This large-scale serological study is the first study to examine temporality of pathogen exposure and to provide evidence of a causal relationship between T. gondii and schizophrenia, and between CMV and any psychiatric disorder.

6.
Nat Genet ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478444

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

7.
Pharmacoepidemiol Drug Saf ; 27(10): 1131-1138, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29664233

RESUMO

PURPOSE: It is not possible to fully assess intention of self-harm and suicidal events using information from administrative databases. We conducted a validation study of intention of suicide attempts/self-harm contacts identified by a commonly applied Danish register-based algorithm (DK-algorithm) based on hospital discharge diagnosis and emergency room contacts. METHODS: Of all 101 530 people identified with an incident suicide attempt/self-harm contact at Danish hospitals between 1995 and 2012 using the DK-algorithm, we selected a random sample of 475 people. We validated the DK-algorithm against medical records applying the definitions and terminology of the Columbia Classification Algorithm of Suicide Assessment of suicidal events, nonsuicidal events, and indeterminate or potentially suicidal events. We calculated positive predictive values (PPVs) of the DK-algorithm to identify suicidal events overall, by gender, age groups, and calendar time. RESULTS: We retrieved medical records for 357 (75%) people. The PPV of the DK-algorithm to identify suicidal events was 51.5% (95% CI: 46.4-56.7) overall, 42.7% (95% CI: 35.2-50.5) in males, and 58.5% (95% CI: 51.6-65.1) in females. The PPV varied further across age groups and calendar time. After excluding cases identified via the DK-algorithm by unspecific codes of intoxications and injury, the PPV improved slightly (56.8% [95% CI: 50.0-63.4]). CONCLUSIONS: The DK-algorithm can reliably identify self-harm with suicidal intention in 52% of the identified cases of suicide attempts/self-harm. The PPVs could be used for quantitative bias analysis and implemented as weights in future studies to estimate the proportion of suicidal events among cases identified via the DK-algorithm.

8.
Genome Med ; 10(1): 19, 2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29587883

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. METHODS: We quantified neonatal methylomic variation in 1263 infants-of whom ~ 50% went on to subsequently develop ASD-using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. RESULTS: We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of - 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. CONCLUSIONS: This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.


Assuntos
Transtorno do Espectro Autista/genética , Metilação de DNA/genética , Herança Multifatorial/genética , Parto , Transtorno do Espectro Autista/sangue , Estudos de Coortes , Teste em Amostras de Sangue Seco , Epigênese Genética , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Tabaco/efeitos adversos
9.
Nat Genet ; 50(3): 381-389, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483656

RESUMO

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

10.
Biol Psychiatry ; 83(12): 1044-1053, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29325848

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. METHODS: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). RESULTS: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15). CONCLUSIONS: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

11.
J Neurol Neurosurg Psychiatry ; 88(9): 718-721, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28572274

RESUMO

BACKGROUND, METHODS AND OBJECTIVES: Maternal autoantibodies to neuronal proteins may be one cause of neurodevelopmental disorders. This exploratory study used the Danish archived midgestational sera and their nationwide registers to search for antibodies to the N-methyl-D-aspartate receptor (NMDAR) and contactin-associated protein-like 2 (CASPR2) in maternal sera, and to relate them to subsequent psychiatric diagnoses in the woman or her child. RESULTS: In a sample of 192 women, there was no association between antibody status and subsequent psychosis in the mothers. However, NMDAR antibodies (n=4) or CASPR2 antibodies (n=1) were identified in 5/11 (45.5%) women whose children were given a diagnosis of mild or unspecified mental retardation or disorders of psychological and motor development (collectively abbreviated as mental retardation and/or disorders of psychological development (MR/DPD)) compared with 9/176 (5.1%) of the remaining mother (p<0.001). These findings were followed up in a specifically selected cohort, in which CASPR2 antibodies were detected in 7/171 (4.1%) mothers of MR/DPD progeny, compared with only 1/171 (0.6%) control mother (p=0.067). The combined sample showed a significantly higher frequency of CASPR2 antibodies in mothers of MD/DPD children (p=0.01). These autoantibodies were not increased in mothers of children with autistic spectrum disorder. CONCLUSIONS: These findings complement the known roles of CASPR2 in brain development, and warrant further epidemiological and experimental studies to clarify the role of CASPR2 and possibly other antibodies in neurodevelopmental disorders.


Assuntos
Autoanticorpos/imunologia , Deficiência Intelectual/diagnóstico , Proteínas de Membrana/imunologia , Mães/psicologia , Proteínas do Tecido Nervoso/imunologia , Encéfalo/imunologia , Dinamarca , Feminino , Humanos , Recém-Nascido , Gravidez , Receptores de N-Metil-D-Aspartato
12.
Lancet ; 385(9983): 2190-6, 2015 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-25726514

RESUMO

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common mental disorder associated with factors that are likely to increase mortality, such as oppositional defiant disorder or conduct disorder, criminality, accidents, and substance misuse. However, whether ADHD itself is associated with increased mortality remains unknown. We aimed to assess ADHD-related mortality in a large cohort of Danish individuals. METHODS: By use of the Danish national registers, we followed up 1·92 million individuals, including 32,061 with ADHD, from their first birthday through to 2013. We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, family history of psychiatric disorders, maternal and paternal age, and parental educational and employment status, by Poisson regression, to compare individuals with and without ADHD. FINDINGS: During follow-up (24·9 million person-years), 5580 cohort members died. The mortality rate per 10,000 person-years was 5·85 among individuals with ADHD compared with 2·21 in those without (corresponding to a fully adjusted MRR of 2·07, 95% CI 1·70-2·50; p<0·0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1·86 (95% CI 0·93-3·27), and it was 1·58 (1·21-2·03) for those aged 6-17 years, and 4·25 (3·05-5·78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1·50, 1·11-1·98), and was higher in girls and women (2·85, 1·56-4·71) than in boys and men (1·27, 0·89-1·76). INTERPRETATION: ADHD was associated with significantly increased mortality rates. People diagnosed with ADHD in adulthood had a higher MRR than did those diagnosed in childhood and adolescence. Comorbid oppositional defiant disorder, conduct disorder, and substance use disorder increased the MRR even further. However, when adjusted for these comorbidities, ADHD remained associated with excess mortality, with higher MRRs in girls and women with ADHD than in boys and men with ADHD. The excess mortality in ADHD was mainly driven by deaths from unnatural causes, especially accidents. FUNDING: This study was supported by a grant from the Lundbeck Foundation.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/mortalidade , Causas de Morte/tendências , Acidentes/estatística & dados numéricos , Adolescente , Adulto , Idade de Início , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Transtorno da Conduta/epidemiologia , Estudos Transversais , Dinamarca/epidemiologia , Feminino , Humanos , Lactente , Masculino , Distribuição de Poisson , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto Jovem
13.
Schizophr Bull ; 39(6): 1337-42, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23236080

RESUMO

The association between low birth weight and schizophrenia has been suggested by many studies. Small for gestational age (SGA) is a measure used as a proxy for intrauterine growth restriction. We aim to examine if children who are born SGA are at increased risk of developing schizophrenia and whether an association may be explained by factors shared among siblings. We linked 3 population-based registers: the Danish National Medical Birth Register, the Danish Psychiatric Central Register, and the Danish Civil Registration register to identify all persons born between 1978 and 2000. A nested case-control study and a case-sibling study design were used. There were 4650 cases of schizophrenia. Incidence rate ratios (IRRs) were estimated using conditional logistic regression. SGA was defined as the lowest 10th birth weight percentile for a given sex and gestational age. SGA was associated with an IRR of 1.23 (95% CI: 1.11-1.37) for schizophrenia in the case-control study. An IRR of 1.28 (95% CI: 0.97-1.68) was found in the case-sibling study. There is a modest association between SGA and schizophrenia. Our results indicate that this association is due to an independent effect of factors associated with low birth weight for gestational age per se, rather than other factors shared by siblings.


Assuntos
Retardo do Crescimento Fetal/epidemiologia , Recém-Nascido Pequeno para a Idade Gestacional , Sistema de Registros , Esquizofrenia/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Estudos de Coortes , Comorbidade , Dinamarca/epidemiologia , Feminino , Desenvolvimento Fetal/fisiologia , Idade Gestacional , Humanos , Incidência , Masculino , Risco , Irmãos , Adulto Jovem
14.
Am J Psychiatry ; 168(8): 814-21, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21536690

RESUMO

OBJECTIVE: Several studies based on clinical samples have found an association between Toxoplasma gondii infection and schizophrenia, and a case-control study among U.S. military personnel with specimens available from both before and after diagnosis found a positive association between T. gondii immunoglobulin G (IgG) antibody level and schizophrenia. These findings have never been replicated in a prospective cohort study. The purpose of this study was to determine whether mothers infected with T. gondii have an elevated risk of schizophrenia or related disorders and whether the risk depends on IgG antibody level. METHOD: In a register-based prospective cohort study of 45,609 women born in Denmark, the level of T. gondii-specific IgG antibodies was measured in connection with childbirth between 1992 and 1995. Women were followed up from the date of delivery until 2008. RESULTS: A significant positive association between T. gondii IgG antibody level and schizophrenia spectrum disorders was found. Mothers with the highest IgG level had a relative risk of 1.73 (95% confidence interval [CI]=1.12-2.62) compared with mothers with the lowest IgG level. For schizophrenia, the relative risk was 1.68 (95% CI=0.77-3.46). When the mothers were classified according to IgG level, only those with the highest IgG levels had a significantly higher risk of schizophrenia spectrum disorders. CONCLUSIONS: Women with high levels of T. gondii-specific IgG antibodies have a significantly elevated risk of developing schizophrenia spectrum disorders.


Assuntos
Complicações Parasitárias na Gravidez/diagnóstico , Complicações Parasitárias na Gravidez/psicologia , Esquizofrenia/diagnóstico , Toxoplasma , Toxoplasmose/diagnóstico , Toxoplasmose/psicologia , Adulto , Estudos de Coortes , Estudos Transversais , Dinamarca , Feminino , Seguimentos , Humanos , Imunoglobulina G/sangue , Recém-Nascido , Masculino , Triagem Neonatal , Gravidez , Complicações Parasitárias na Gravidez/epidemiologia , Complicações Parasitárias na Gravidez/imunologia , Estudos Prospectivos , Risco , Esquizofrenia/epidemiologia , Esquizofrenia/imunologia , Toxoplasma/imunologia , Toxoplasmose/epidemiologia , Toxoplasmose/imunologia , Toxoplasmose Congênita/diagnóstico , Toxoplasmose Congênita/epidemiologia , Toxoplasmose Congênita/imunologia , Toxoplasmose Congênita/psicologia , Adulto Jovem
15.
Lancet ; 372(9637): 457-63, 2008 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-18692714

RESUMO

BACKGROUND: No studies have had sufficient size to estimate mortality in children with febrile seizures. We studied mortality after febrile seizures in a large population-based cohort of children in Denmark with up to 28 years of follow-up. METHODS: We identified 1 675 643 children born in Denmark between Jan 1, 1977, and Dec 31, 2004, by linking information from nationwide registers for civil service, health, and cause of death. Children were followed up from 3 months of age, until death, emigration, or Aug 31, 2005. We estimated overall and cause-specific mortality after first febrile seizures with survival analyses. Furthermore, we undertook a case-control study nested within the cohort and retrieved information from medical records about febrile seizure and neurological abnormalities for children who died (N=8172) and individually-matched controls (N=40 860). FINDINGS: We identified 8172 children who died, including 232 deaths in 55 215 children with a history of febrile seizures. The mortality rate ratio was 80% higher during the first year (adjusted mortality rate ratio 1.80 [95% CI 1.31-2.40]) and 90% higher during the second year (1.89 [1.27-2.70]) after the first febrile seizure; thereafter it was close to that noted for the general population. 132 of 100 000 children (95% CI 102-163) died within 2 years of a febrile seizure compared with 67 (57-76) deaths per 100 000 children without a history of this disorder. In the nested case-control study, children with simple (15 min or recurrence within 24 h) febrile seizures (1.99 [1.24-3.21]). This finding was partly explained by pre-existing neurological abnormalities and subsequent epilepsy. INTERPRETATION: Long-term mortality is not increased in children with febrile seizures, but there seems to be a small excess mortality during the 2 years after complex febrile seizures. Parents should be reassured that death after febrile seizures is very rare, even in high-risk children.


Assuntos
Vigilância da População/métodos , Convulsões Febris/mortalidade , Adolescente , Adulto , Distribuição por Idade , Índice de Apgar , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Incidência , Lactente , Masculino , Registros Médicos , Sistema de Registros , Convulsões Febris/classificação , Convulsões Febris/epidemiologia , Índice de Gravidade de Doença
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