Marianne Giørtz Pedersen

Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events.

CONTEXT Most societies believe that a mothers psychological state can influence her unborn baby. Severe adverse life events during pregnancy have been consistently associated with an elevated risk of low birth weight and prematurity. Such events during the first trimester have also been associated with risk of congenital malformations. OBJECTIVE To assess the effect in offspring of antenatal maternal exposure to an objective measure of stress on risk of adverse neurodevelopment, specifically schizophrenia. We hypothesized that the strongest relationship would be to maternal exposures during the first trimester. DESIGN Population-based study. SETTING Denmark. PARTICIPANTS In a cohort of 1.38 million Danish births from 1973 to 1995, mothers were considered exposed if 1 (or more) of their close relatives died or was diagnosed with cancer, acute myocardial infarction, or stroke syndrome up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of schizophrenia, or June 30, 2005; admissions were identified by linkage to the Central Psychiatric Register. Main Outcome Measure Schizophrenia. RESULTS The risk of schizophrenia and related disorders was raised in offspring whose mothers were exposed to death of a relative during the first trimester (adjusted relative risk, 1.67 [95% confidence interval, 1.02-2.73]). Death of a relative during other trimesters or up to 6 months before pregnancy were not linked with a higher risk of schizophrenia. CONCLUSIONS Our population-based study suggests that severe stress to a mother during the first trimester may alter the risk of schizophrenia in offspring. This finding is consistent with ecological evidence from whole populations exposed to severe stressors and suggests that environment may influence neurodevelopment at the feto-placental-maternal interface.

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.

Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study

BACKGROUND The risk of epilepsy shortly after traumatic brain injury is high, but how long this high risk lasts is unknown. We aimed to assess the risk of epilepsy up to 10 years or longer after traumatic brain injury, taking into account sex, age, severity, and family history. METHODS We identified 1 605 216 people born in Denmark (1977-2002) from the Civil Registration System. We obtained information on traumatic brain injury and epilepsy from the National Hospital Register and estimated relative risks (RR) with Poisson analyses. FINDINGS Risk of epilepsy was increased after a mild brain injury (RR 2.22, 95% CI 2.07-2.38), severe brain injury (7.40, 6.16-8.89), and skull fracture (2.17, 1.73-2.71). The risk was increased more than 10 years after mild brain injury (1.51, 1.24-1.85), severe brain injury (4.29, 2.04-9.00), and skull fracture (2.06, 1.37-3.11). RR increased with age at mild and severe injury and was especially high among people older than 15 years of age with mild (3.51, 2.90-4.26) and severe (12.24, 8.52-17.57) injury. The risk was slightly higher in women (2.49, 2.25-2.76) than in men (2.01, 1.83-2.22). Patients with a family history of epilepsy had a notably high risk of epilepsy after mild (5.75, 4.56-7.27) and severe brain injury (10.09, 4.20-24.26). INTERPRETATION The longlasting high risk of epilepsy after brain injury might provide a window for prevention of post-traumatic epilepsy.

Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study

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.

Autoimmune diseases, bipolar disorder, and non-affective psychosis

OBJECTIVE Clinic-based studies of immune function, as well as comorbidity of autoimmune diseases, bipolar disorder, and schizophrenia, suggest a possible autoimmune etiology. Studies of non-affective psychosis and schizophrenia suggest common etiologies. The objective was to determine the degree to which 30 different autoimmune diseases are antecedent risk factors for bipolar disorder, schizophrenia, and non-affective psychosis. METHODS A cohort of 3.57 million births in Denmark was linked to the Psychiatric Case Register and the National Hospital Register. There were 20,317 cases of schizophrenia, 39,076 cases of non-affective psychosis, and 9,920 cases of bipolar disorder. RESULTS As in prior studies, there was a range of autoimmune diseases which predicted raised risk of schizophrenia in individuals who had a history of autoimmune diseases, and also raised risk in persons whose first-degree relatives had an onset of autoimmune disease prior to onset of schizophrenia in the case. These relationships also existed for the broader category of non-affective psychosis. Only pernicious anemia in the family was associated with raised risk for bipolar disorder (relative risk: 1.7), suggesting a small role for genetic linkage. A history of Guillain-Barré syndrome, Crohns disease, and autoimmune hepatitis in the individual was associated with raised risk of bipolar disorder. CONCLUSIONS The familial relationship of schizophrenia to a range of autoimmune diseases extends to non-affective psychosis, but not to bipolar disorder. The data suggest that autoimmune processes precede onset of schizophrenia, but also non-affective psychosis and bipolar disorder.

Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies?

CONTEXT Studies linking birth weight and mental illness onset are inconclusive. They have primarily focused on the World Health Organization low birth weight threshold (2500 g) and schizophrenia. To our knowledge, low birth weight per se has not been conclusively linked with schizophrenia risk and specificity of the effect to birth weight below the standard threshold or to particular psychiatric diagnoses has not been demonstrated. OBJECTIVES To examine whether (1) low birth weight (<2500 g) is associated with increased risk for adult schizophrenia; (2) risk extends into the normal weight range; and (3) risk is confined to schizophrenia or linked to other adult mental illnesses. DESIGN Population-based cohort study. SETTING Sweden and Denmark. PARTICIPANTS Singleton live births in Sweden (1973-1984) and Denmark (1979-1986) (N = 1.49 million). Births were linked to comprehensive national registers of psychiatric treatment, with follow-up to December 31, 2002 (Sweden), or to June 30, 2005 (Denmark). There were 5445 cases of schizophrenia and 57 455 cases of any adult psychiatric disorder. MAIN OUTCOME MEASURE Crude and adjusted odds ratios for birth weight less than or more than 3500 to 3999 g in consecutive 500-g strata (from 500-1499 g to > or =4500 g) for schizophrenia, any psychiatric diagnoses, and specified psychiatric diagnoses. RESULTS Schizophrenia was associated with birth weight less than 2500 g. The association was not restricted to birth weight less than 2500 g and there was a significant linear trend of increasing odds ratios with decreasing birth weight across the birth weight range. This was mirrored for any psychiatric diagnosis and for each of the categories of psychiatric disorder. CONCLUSIONS Findings suggest there is an association between birth weight and adult mental disorder, but there is no indication this effect is specific to birth weight less than 2500 g or to schizophrenia. Future research should explore common disorder-specific mechanisms that may link birth weight to development of psychiatric disorder in adulthood.

Psychiatric family history and schizophrenia risk in Denmark: which mental disorders are relevant?

BACKGROUND A family history of schizophrenia is the strongest single indicator of individual schizophrenia risk. Bipolar affective disorder and schizo-affective disorders have been documented to occur more frequently in parents and siblings of schizophrenia patients, but the familial occurrence of the broader range of mental illnesses and their role as confounders have not been studied in large population-based samples. METHOD All people born in Denmark between 1955 and 1991 (1.74 million) were followed for the development of schizophrenia (9324 cases) during 28 million person-years at risk. Information of schizophrenia in cohort members and psychiatric history in parents and siblings was established through linkage with the Danish Psychiatric Central Register. Data were analysed using log-linear Poisson regression. RESULTS Schizophrenia was, as expected, strongly associated with schizophrenia and related disorders among first-degree relatives. However, almost any other psychiatric disorder among first-degree relatives increased the individuals risk of schizophrenia. The population attributable risk associated with psychiatric family history in general was 27.1% whereas family histories including schizophrenia only accounted for 6.0%. The general psychiatric family history was a confounder of the association between schizophrenia and urbanization of place of birth. CONCLUSIONS Clinically diagnosed schizophrenia is associated with a much broader range of mental disorders in first-degree relatives than previously reported. This may suggest risk haplotypes shared across many disorders and/or shared environmental factors clustering in families. Failure to take the broad range of psychiatric family history into account may bias results of all risk-factor studies of schizophrenia.

Incidence and prevalence of epilepsy in Denmark

PURPOSE To estimate the occurrence of epilepsy in Denmark between 1977 and 2002, taking gender, age, and secular trends into consideration. METHODS We used the Danish Civil Registration System to identify all persons born in Denmark and the Danish National Hospital Register to identify persons registered with epilepsy between 1977 and 2002. RESULTS Between 1977 and 2002 the average incidence of epilepsy was 68.8 new epilepsy patients per 100,000 person-years at risk. However, the incidence changed with calendar time and increased steeply from 1990 to 1995, probably due to changes in diagnostic system and inclusion of outpatients. From 1995 to 2002 the incidence rate was reasonable constant with an average of 83.3 new cases per 100,000 person-years at risk, except for patients over 60 years of age where we observed an increase in incidence with calendar time. The age-specific incidence rates declined from a high level in children to a low level between 20 and 40 years of age, and thereafter a gradual increase was seen. The incidence rate was slightly higher in men than in women except for the age range 10-20 years. About 2% of the population was diagnosed with epilepsy at some point during the first 25 years of life. The overall 5-year prevalence proportion of epilepsy was 0.6% with a slight variation with age and gender between 0.4 and 0.8% of the population. CONCLUSION The occurrence of epilepsy is age and gender specific. The estimated incidence rate of epilepsy furthermore increased over time for persons older than 60 years of age.

Reduced infant birthweight consequent upon maternal exposure to severe life events.

Objective: To investigate the association between maternal exposure to severe life events and fetal growth (birthweight and small for gestational age). Stress has been associated with adverse pregnancy outcome. Methods: Mothers of 1.38 million singleton live births in Denmark between January 1, 1979 and December 31, 2002 were linked to information on their spouses, parents, siblings, and older children. Exposure was defined as death or serious illness in a relative during pregnancy or in the 6 months before conception. Linear regression was used to examine the effect of exposure on birthweight. Log-linear binomial regression was used to assess the effect of exposure on small for gestational age. Results: Death of a relative during pregnancy or in the 6 months before conception reduced birthweight by 27 g (adjusted estimate −27 g, 95% Confidence Interval (CI) = −33, −22). There was a significant association between maternal exposure to death of a relative and risk of a baby weighing below the 10th percentile (adjusted relative risk (RR) = 1.17, 95% CI = 1.13, 1.22) and 5th percentile (adjusted RR = 1.22, 95% CI = 1.15, 1.29). Conclusions: Mothers exposed to severe life events before conception or during pregnancy have babies with significantly lower birthweight. If this association is causal, the potential mechanisms of stress-related effects on birthweight include changes in lifestyle due to the exposure and stress-related dysregulation of the hypothalamic-pituitary-adrenal axis during pregnancy. IUGR = intrauterine growth restriction; CVA = cerebrovascular accident; AMI = acute myocardial infarction; SGA = small for gestational age; VSGA = very small for gestational age; GHQ = general health questionnaire; SES = socioeconomic status.

Rates of preterm birth following antenatal maternal exposure to severe life events: a population-based cohort study

BACKGROUND Preterm birth and other pregnancy complications have been linked to maternal stress during pregnancy. We investigated the association between maternal exposure to severe life events and risk of preterm birth. METHODS Mothers of all singleton live births (n = 1.35 million births) in Denmark between 1 January 1979 and 31 December 2002 were linked to data on their children, parents, siblings and partners. We defined exposure as death or serious illness in close relatives in the first or second trimesters or in the 6 months before conception. Log-linear binomial regression was used to estimate the effect of exposure on preterm birth, very preterm birth and extremely preterm birth. RESULTS There were 58 626 (4.34%) preterm births (<37 weeks), 11 732 (0.87%) very preterm births and 3288 (0.24%) extremely preterm births in the study cohort. Severe life events in close relatives in the 6 months before conception increased the risk of preterm birth by 16% (relative risk, RR = 1.16, [95% CI: 1.08-1.23]). Severe life events in older children in the 6 months before conception increased the risk of preterm birth by 23% (RR = 1.23, [95% CI: 1.02-1.49]) and the risk of very preterm birth by 59% (RR = 1.59, [95% CI: 1.08-2.35]). CONCLUSIONS Our population-based cohort study suggests that maternal exposure to severe life events, particularly in the 6 months before pregnancy, may increase the risk of preterm and very preterm birth.