Carsten Bøcker Pedersen

The Danish Civil Registration System

Introduction: The Danish Civil Registration System (CRS) was established in 1968, and all persons alive and living in Denmark were registered for administrative use. Content: CRS includes individual information on the unique personal identification number, name, gender, date of birth, place of birth, citizenship, identity of parents and continuously updated information on vital status, place of residence and spouses. Validity and coverage: Since 1968, CRS has recorded current and historical information on all persons living in Denmark. Among persons born in Denmark in 1960 or later it contains complete information on maternal identity. For women born in Denmark in April 1935 or later it contains complete information on all their children. CRS contains complete information on immigrations and emigrations from 1969 onwards, permanent residence in a Danish municipality from 1971 onwards, and full address in Denmark from 1977 onwards. Conclusion: CRS in connection with other registers and biobanks will continue to provide the basis for significant knowledge relevant to the aetiological understanding and possible prevention of human diseases.

Effects of family history and place and season of birth on the risk of schizophrenia.

BACKGROUND Although a family history of schizophrenia is the best-established risk factor for schizophrenia, environmental factors such as the place and season of birth may also be important. METHODS Using data from the Civil Registration System in Denmark, we established a population-based cohort of 1.75 million persons whose mothers were Danish women born between 1935 and 1978. We linked this cohort to the Danish Psychiatric Central Register and identified 2669 cases of schizophrenia among cohort members and additional cases among their parents. RESULTS The respective relative risks of schizophrenia for persons with a mother, father, or sibling who had schizophrenia were 9.31 (95 percent confidence interval, 7.24 to 11.96), 7.20 (95 percent confidence interval, 5.10 to 10.16), and 6.99 (95 percent confidence interval, 5.38 to 9.09), as compared with persons with no affected parents or siblings. The risk of schizophrenia was associated with the degree of urbanization of the place of birth (relative risk for the capital vs. rural areas, 2.40; 95 percent confidence interval, 2.13 to 2.70). The risk was also significantly associated with the season of birth; it was highest for births in February and March and lowest for births in August and September. The population attributable risk was 5.5 percent for a history of schizophrenia in a parent or sibling, 34.6 percent for urban place of birth, and 10.5 percent for the season of birth. CONCLUSIONS Although a history of schizophrenia in a parent or sibling is associated with the highest relative risk of having the disease, the place and season of birth account for many more cases on a population basis.

Absolute Risk of Suicide After First Hospital Contact in Mental Disorder

CONTEXT Estimates of lifetime risk of suicide in mental disorders were based on selected samples with incomplete follow-up. OBJECTIVE To estimate, in a national cohort, the absolute risk of suicide within 36 years after the first psychiatric contact. DESIGN Prospective study of incident cases followed up for as long as 36 years. Median follow-up was 18 years. SETTING Individual data drawn from Danish longitudinal registers. PARTICIPANTS A total of 176,347 persons born from January 1, 1955, through December 31, 1991, were followed up from their first contact with secondary mental health services after 15 years of age until death, emigration, disappearance, or the end of 2006. For each participant, 5 matched control individuals were included. MAIN OUTCOME MEASURES Absolute risk of suicide in percentage of individuals up to 36 years after the first contact. RESULTS Among men, the absolute risk of suicide (95% confidence interval [CI]) was highest for bipolar disorder, (7.77%; 6.01%-10.05%), followed by unipolar affective disorder (6.67%; 5.72%-7.78%) and schizophrenia (6.55%; 5.85%-7.34%). Among women, the highest risk was found among women with schizophrenia (4.91%; 95% CI, 4.03%-5.98%), followed by bipolar disorder (4.78%; 3.48%-6.56%). In the nonpsychiatric population, the risk was 0.72% (95% CI, 0.61%-0.86%) for men and 0.26% (0.20%-0.35%) for women. Comorbid substance abuse and comorbid unipolar affective disorder significantly increased the risk. The co-occurrence of deliberate self-harm increased the risk approximately 2-fold. Men with bipolar disorder and deliberate self-harm had the highest risk (17.08%; 95% CI, 11.19%-26.07%). CONCLUSIONS This is the first analysis of the absolute risk of suicide in a total national cohort of individuals followed up from the first psychiatric contact, and it represents, to our knowledge, the hitherto largest sample with the longest and most complete follow-up. Our estimates are lower than those most often cited, but they are still substantial and indicate the continuous need for prevention of suicide among people with mental disorders.

NEONATAL VITAMIN D STATUS AND RISK OF SCHIZOPHRENIA: A POPULATION-BASED CASE-CONTROL STUDY

CONTEXT Clues from the epidemiology of schizophrenia suggest that low levels of developmental vitamin D may be associated with increased risk of schizophrenia. OBJECTIVE To directly examine the association between neonatal vitamin D status and risk of schizophrenia. DESIGN Individually matched case-control study drawn from a population-based cohort. SETTING Danish national health registers and neonatal biobank. PARTICIPANTS A total of 424 individuals with schizophrenia and 424 controls matched for sex and date of birth. MAIN OUTCOME MEASURES The concentration of 25 hydroxyvitamin D(3) (25[OH]D3) was assessed from neonatal dried blood samples using a highly sensitive liquid chromatography tandem mass spectroscopy method. Relative risks were calculated for the matched pairs when examined for quintiles of 25(OH)D3. RESULTS Compared with neonates in the fourth quintile (with 25[OH]D3 concentrations between 40.5 and 50.9 nmol/L), those in each of the lower 3 quintiles had a significantly increased risk of schizophrenia (2-fold elevated risk). Unexpectedly, those in the highest quintile also had a significantly increased risk of schizophrenia. Based on this analysis, the population-attributable fraction associated with neonatal vitamin D status was 44%. The relationship was not explained by a wide range of potential confounding or interacting variables. CONCLUSIONS Both low and high concentrations of neonatal vitamin D are associated with increased risk of schizophrenia, and it is feasible that this exposure could contribute to a sizeable proportion of cases in Denmark. In light of the substantial public health implications of this finding, there is an urgent need to further explore the effect of vitamin D status on brain development and later mental health.

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.

A Comprehensive Nationwide Study of the Incidence Rate and Lifetime Risk for Treated Mental Disorders

IMPORTANCE Understanding the epidemiologic profile of the life course of mental disorders is fundamental for research and planning for health care. Although previous studies have used population surveys, informative and complementary estimates can be derived from population-based registers. OBJECTIVE To derive comprehensive and precise estimates of the incidence rate of and lifetime risk for any mental disorder and a range of specific mental disorders. DESIGN, SETTING, AND PARTICIPANTS We conducted a follow-up study of all Danish residents (5.6 million persons), to whom all treatment is provided by the government health care system without charge to the patient, from January 1, 2000, through December 31, 2012 (total follow-up, 59.5 million person-years). During the study period, 320,543 persons received first lifetime treatment in a psychiatric setting for any mental disorder; 489,006 persons were censored owing to death; and 69,987 persons were censored owing to emigration. Specific categories of mental disorders investigated included organic mental disorders, substance abuse disorders, schizophrenia, mood disorders, anxiety, eating disorders, personality disorders, mental retardation, pervasive developmental disorders, and behavioral and emotional disorders. EXPOSURES Age and sex. MAIN OUTCOMES AND MEASURES Sex- and age-specific incidence rates and cumulative incidences and sex-specific lifetime risks. RESULTS During the course of life, 37.66% of females (95% CI, 37.52%-37.80%) and 32.05% of males (31.91%-32.19%) received their first treatment in a psychiatric setting for any mental disorder. The occurrence of mental disorders varied markedly between diagnostic categories and by sex and age. The sex- and age-specific incidence rates for many mental disorders had a single peak incidence rate during the second and third decades of life. Some disorders had a second peak in the sex- and age-specific incidence rate later in life. CONCLUSIONS AND RELEVANCE This nationwide study provides a first comprehensive assessment of the lifetime risks for treated mental disorders. Approximately one-third of the Danish population received treatment for mental disorders. The distinct signatures of the different mental disorders with respect to sex and age have important implications for service planning and etiologic research.

Meta-Analysis of the Association of Urbanicity With Schizophrenia

The association between urbanicity and risk of schizophrenia is well established. The incidence of schizophrenia has been observed to increase in line with rising levels of urbanicity, as measured in terms of population size or density. This association is expressed as Incidence Rate Ratio (IRR), and the results are usually presented by comparing the most urban with the most rural environment. In this study, we undertook to express the effect of urbanicity on the risk of schizophrenia in a linear form and to perform a meta-analysis of all available evidence. We first employed a simple regression analysis of log (IRR) as given in each study on the urbanicity category, assuming a uniform distribution and a linear association. In order to obtain more accurate estimates, we developed a more sophisticated method that generates individual data points with simulation from the summary data presented in the original studies, and then fits a logistic regression model. The estimates from each study were combined with meta-analysis. Despite the challenges that arise from differences between studies as regards to the number and relative size of urbanicity levels, a linear association was observed between the logarithm of the odds of risk for schizophrenia and urbanicity. The risk for schizophrenia at the most urban environment was estimated to be 2.37 times higher than in the most rural environment. The same effect was found when studies measuring the risk for nonaffective psychosis were included.

Risks and Predictors of Readmission for a Mental Disorder During the Postpartum Period

CONTEXT It has been suggested that the risk of inpatient psychiatric readmissions is elevated during the postpartum period. To our knowledge, no prior study has compared mothers and nonmothers to determine whether the risk of readmission differs between these 2 groups of women. OBJECTIVES To compare mothers and nonmothers to assess whether childbirth increases the risk for psychiatric readmission and to identify predictors of psychiatric readmission during the postpartum period. DESIGN A population-based cohort study merging data from the Danish Civil Registration System and the Danish Psychiatric Central Register. SETTING The population of Denmark. PARTICIPANTS Two partly overlapping study populations included a total of 28 124 women, 10 218 of whom were mothers, who were followed up from January 1, 1973, through June 30, 2005. Main Outcome Measure Readmission rates to psychiatric hospitals during the 12 months after childbirth (first live-born child). RESULTS The period of highest risk of psychiatric readmission in new mothers was 10 to 19 days post partum (relative risk [RR], 2.71; 95% confidence interval [CI], 1.68-4.37), and the period of lowest risk was during pregnancy (0.54; 0.43-0.69). Childbirth was associated with an increased risk of readmission during the first postpartum month, after which risk for readmission was higher among nonmothers (RR, 1.53; 95% CI, 1.31-1.80). A previous diagnosis of bipolar affective disorder was the strongest predictor of readmissions 10 to 19 days post partum (RR, 37.22; 95% CI, 13.58-102.04). In all, 26.9% of mothers with this diagnosis were readmitted within the first postpartum year. CONCLUSIONS Mothers with mental disorders have lower readmission rates compared with women with mental disorders who do not have children. However, the first month after childbirth is associated with increased risk of psychiatric readmission, and women with a history of bipolar affective disorder are at particular risk of postpartum psychiatric readmissions.

CACNA1C (rs1006737) is associated with schizophrenia

molecules are not altered in all neuropsychiatric disorders. Taken together, these findings show that hyperinsulinemia may have a role in the onset of schizophrenia. This has important implications, as elevated insulin levels can have deleterious effects on brain function. In addition, this suggests the possibility that drugs that improve insulin signaling may represent a novel treatment strategy. In this regard, the insulin-related molecules identified here, and potentially other co-secreted insulin-secretory granule proteins, may have utility as biomarkers for patient stratification and for monitoring the responses to existing and novel therapeutic treatment strategies.

Increased Risk of Precocious Puberty in Internationally Adopted Children in Denmark

BACKGROUND. Studies have indicated that internationally adopted children have an increased risk of developing precocious puberty, but no epidemiologic risk estimates have previously been calculated. We aimed to assess the risk of developing precocious puberty in intercountry adoptees, children immigrating with their family, and descendants of immigrants living in Denmark. METHODS. Patients who were registered with the diagnosis of precocious puberty during the period 1993–2001 were identified through the national patient registry. The background population of children born from 1983 to 2001 were identified through the unique Danish Civil Registration System and subsequently categorized as being Danish (N = 1062333), adopted (N = 10997), immigrating with their family (N = 72181), or being descendants of immigrants (N = 128152). The incidence rate ratio of precocious puberty was estimated by log-linear Poisson regression. All rate ratios were adjusted for age and its interaction with gender and calendar year. P values were based on likelihood ratio tests, and 95% confidence intervals were calculated by Walds test. RESULTS. In the study period, 655 children developed precocious puberty during 5627763 person-years at risk. Adopted children were followed during 39978 person-years at risk, during which 45 girls and 6 boys developed precocious puberty. The risk of developing precocious puberty was significantly increased 10 to 20 times in adopted girls compared with girls with Danish background. The risk of developing precocious puberty depended on the country of origin. In children immigrating with their family, the risk of developing precocious puberty was only marginally increased. Older age at adoption significantly increased the risk of precocious puberty in adoptees independent of region of origin. The incidence rate ratio was significantly higher in children adopted after the age of 2. In children immigrating with their family, we found no effect of age at migration. DISCUSSION. In this large, nationwide, register-based study including 655 cases of precocious puberty, we found that intercountry boys and girls were 10 to 20 times more likely to develop precocious puberty compared with the Danish reference group. Older age at adoption significantly increased the risk of precocious puberty. Uncertainty of the exact age is a well-known problem in adopted children, and systematic underestimation of age might bias the result. However, using the worst-case scenario that all children who according to the Danish Civil Registration System were adopted after 2 years of age were in fact 1 year older, we still observed a highly increased risk of precocious puberty associated with adoption and especially with adoption after 2 years of age. Surprisingly, the risk of precocious puberty was not increased in the large group of children adopted from Korea. One case of precocious puberty was identified among Korean children, whereas >20 cases of precocious puberty would have been expected if the risk for a Korean child was at the same level as observed among adopted children from India and South America. In the study population, 99% of Korean children were adopted before 2 years of age, which may contribute to explaining our finding. In Korea, children appointed for adoption are often living in foster care settings from birth to adoption, whereas most other countries are reported to take care of the children in orphanages before adoption. It can only be speculated whether a relation between preadoption living conditions and later risk of precocious puberty exists. Genetic factors play a key role in the timing of puberty, and large variations in age at menarche are observed worldwide. Age at menarche is reported to be in the same age range in South Korea as in well-off populations in other parts of the world, indicating that the different risk of precocious puberty observed between Korean and other adoptees probably cannot be explained by genetic factors alone. The finding that the risk of precocious puberty was significantly increased among adoptees in contrast to what was seen in children immigrating with their families contradicts a direct effect of migration. An increasing number of studies have shown long-term effects of certain prenatal and postnatal growth patterns, including advancement in pubertal maturation after poor intrauterine growth and catch-up growth during childhood. Different growth patterns and dietary habits between adoptees and children immigrating with their families might contribute to explain our findings. It has been hypothesized that stressful psychosocial factors in infancy and childhood may lead to earlier pubertal maturation. In general, adoptees have experienced several traumatic life events, and it may be speculated that these events alter the susceptibility for developing precocious puberty. CONCLUSIONS. Foreign-adopted children originating from regions other than Korea had a 15- to 20-fold increased risk of precocious puberty compared with Danish-born children, whereas adoptees originating from Korea had no increased risk of precocious puberty. In addition, children immigrating with their families had no increased risk of precocious puberty. The effect of country of origin might be explained by genetic factors or by different environmental exposures and living conditions in the different countries. Older age at adoption increased the risk for premature onset of puberty, which may suggest that environmental factors influence the risk of precocious pubertal development in adopted children.