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Objective To identify modifiable risk factors for miscarriage and to estimate the preventable proportion of miscarriages that could be attributed to these. Design Nationwide observational follow-up study. Setting Denmark. Population Ninety-one thousand four hundred and twenty seven pregnancies included in the Danish National Birth Cohort between 1996 and 2002. Methods Information on potentially modifiable risk factors before and during pregnancy was collected by means of computer-assisted telephone interviews and linkage with Danish registers, ensuring almost complete follow-up of pregnancy outcome. Modifiable risk factors for miscarriage were identified by multiple Cox regression analysis, which provided the background for our estimations of population attributable fractions. In all, 88 373 pregnancies had full information on all covariates and were included in this analysis. Main outcome measures Miscarriage before 22 completed weeks of gestation. Results The potentially modifiable pre-pregnant risk factors associated with increased miscarriage risk were: age of 30 years or more at conception, underweight, and obesity. During pregnancy the modifiable risk factors were: alcohol consumption, lifting of >20 kg daily, and night work. We estimated that 25.2% of the miscarriages might be prevented by reduction of all these risk factors to low risk levels. Modification of risk factors acting before and during pregnancy could lead to prevention of 14.7 and 12.5%, respectively, of the miscarriages. Maternal age at conception and alcohol consumption were the most important risk factors. Conclusions Miscarriage risk is increased by multiple potentially modifiable risk factors and a considerable proportion of miscarriages may be preventable. [ABSTRACT FROM AUTHOR]

Objectives: The risk of suicidal behavior after discharge from psychiatric admission is high. The aim of this study was to examine whether the SAFE intervention, an implementation of a systematic safer discharge procedure, was associated with a reduction in suicidal behavior after discharge., Methods: The SAFE intervention was implemented at Mental Health Center Copenhagen in March 2018 and consisted of three systematic discharge procedures: (1) A face-to-face meeting between patient and outpatient staff prior to discharge, (2) A face-to-face meeting within the first week after discharge, and (3) Involvement of relatives. Risk of suicide attempt at six-month post-discharge among patients discharged from the SAFE intervention was compared with patients discharged from comparison mental health centers using propensity score matching., Results: 7604 discharges took place at the intervention site, which were 1:1 matched with discharges from comparison sites. During the six months of follow-up, a total of 570 suicide attempts and 25 suicides occurred. The rate of suicide attempt was 11,652 per 100,000 person-years at the SAFE site, while it was 10,530 at comparisons sites. No observable difference in suicide attempt 1.10 (95% CI: 0.89-1.35) or death by suicide (OR = 1.27; 95% CI:0.58-2.81) was found between sites at 6-month follow-up., Conclusion: No difference in suicidal behavior between the sites was found in this pragmatic study. High rates of suicidal behavior were found during the 6-months discharge period, which could suggest that a preventive intervention should include support over a longer post-discharge period than the one-week follow-up offered in the SAFE intervention., (© 2023. The Author(s).)

Importance: All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders., Objective: To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality., Design, Setting, and Participants: This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years., Exposures: History of psychiatric illness., Main Outcomes and Measures: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level., Results: A total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P < .001), whereas 8-oxodG was not. All-cause mortality was higher in the psychiatric illness group vs the no psychiatric illness group (hazard ratio [HR], 1.44; 95% CI, 1.27-1.64; P < .001) and increased sequentially with each increasing tertile of 8-oxoGuo excretion in both groups to an almost doubled risk in the psychiatric illness/high 8-oxoGuo group compared to the no psychiatric illness/low 8-oxoGuo reference group (HR, 1.99; 95% CI, 1.58-2.52; P < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex., Conclusions and Relevance: This study establishes systemic oxidative stress-induced damage to RNA as a potential mechanism in the accelerated aging observed in psychiatric disorders and urinary 8-oxoGuo as a potentially useful marker of mortality risk in individuals with psychiatric illness.

Objectives: To investigate how body height and trajectories of height from infancy through childhood and adolescence were associated with spinal pain in pre- and late adolescence., Methods: This prospective study included 43,765 individuals born into The Danish National Birth Cohort (DNBC) from 1996 to 2003. DNBC-data were linked with health and social data identified from Statistics Denmark registers. Spinal pain was self-reported in both the 11-year- and 18-year follow-up of DNBC and classified according to severity. Body height was measured from birth and onwards and further modelled as distinct developmental height trajectories by using latent growth curve modelling. Associations were estimated by using multinomial logistic regression models., Results: Taller body height in childhood and adolescence was associated with approximately 20% increased likelihood of spinal pain in pre- and late adolescence among girls compared to their peers in the normal height group. For boys, taller body height was associated with spinal pain by late adolescence only. Spinal pain in pre-adolescence almost doubled the likelihood of spinal pain in late adolescence regardless of body height at age 18. Height trajectories confirmed the relationship for girls with the tall individuals being most likely to have spinal pain in both pre- and late adolescence., Conclusion: Tall body height during childhood and adolescence predisposes to spinal pain among girls in both pre-and late adolescence, and among boys in late adolescence. Body height is a contributing factor to the pathogenesis of spinal pain in adolescence; however, the mechanisms may be related to growth velocity, but for now uncertain., (© 2023. The Author(s).)

Importance: Few studies have estimated the lifetime incidence of mental health disorders and the association with socioeconomic functioning., Objective: To investigate whether the lifetime incidence of treated mental health disorders is substantially higher than previously reported and estimate associations with long-term socioeconomic difficulties., Design, Setting, and Participants: This nationwide population-based register linkage study includes a randomly selected sample of 1.5 million individuals from the population of Denmark from 1995 to 2018. Data were analyzed from May 2022 to March 2023., Main Outcomes and Measures: Lifetime incidence of any treated mental health disorder in the general population was estimated from birth to age 100 years taking into account the competing risk of all-cause death and associations with socioeconomic functioning. Register measures were (1) from hospitals, a diagnosis of any mental health disorder at an inpatient/outpatient hospital contact; (2) from hospitals and prescription statistics, any mental health disorder/psychotropic prescription, including a hospital-contact diagnosis, or any psychotropic medication prescribed by physicians, including general practitioners or private psychiatrists; and (3) socioeconomic functioning as indicated by highest educational achievement, employment, income, residential status, and marital status., Results: Among a sample of 462 864 individuals with any mental health disorder, the median (IQR) age was 36.6 years (21.0-53.6 years), 233 747 (50.5%) were male, and 229 117 (49.5%) were female. Of these, 112 641 were registered with a hospital-contact mental health disorder diagnosis and 422 080 with a prescription of psychotropic medication. The cumulative incidence of a hospital-contact mental health disorder diagnosis was 29.0% (95% CI, 28.8-29.1), 31.8% (95% CI, 31.6-32.0) for females, and 26.1% (95% CI, 25.9-26.3) for males. When also considering psychotropic prescriptions, the cumulative incidence of any mental health disorder/psychotropic prescription was 82.6% (95% CI, 82.4-82.6), 87.5% (95% CI, 87.4-87.7) for females, and 76.7% (95% CI, 76.5-76.8) for males. Socioeconomic difficulties were associated with mental health disorder/psychotropic prescriptions, including lower income (hazard ratio [HR], 1.55; 95% CI, 1.53-1.56), increased unemployment or disability benefit (HR, 2.50; 95% CI, 2.47-2.53), and a greater likelihood of living alone (HR, 1.78; 95% CI, 1.76-1.80) and being unmarried (HR, 2.02; 95% CI, 2.01-2.04) during long-term follow-up. These rates were confirmed in 4 sensitivity analyses with the lowest being 74.8% (95% CI, 74.7-75.0) (1) by using varying exclusion periods, (2) by excluding prescriptions of anxiolytics and quetiapine that may be used for off-label indications, (3) by defining any mental health disorder/psychotropic prescription as any hospital-contact mental health disorder diagnosis or any psychotropic medication prescribed at least 2 times, and (4) by excluding individuals with somatic diagnoses for which psychotropics may be prescribed off-label., Conclusions and Relevance: This registry study of data from a large representative sample of the Danish population showed that the majority of individuals either received a diagnosis of a mental health disorder or were prescribed psychotropic medication during their lifetime, which was associated with subsequent socioeconomic difficulties. These findings may help change our understanding of normalcy and mental illness, reduce stigmatization, and further prompt rethinking the primary prevention of mental illness and future mental health clinical resources.

An aggravation in mental health during the COVID-19 lockdown has been suggested but the impact on self-injury, suicidality and eating disorders (EDs) are less elucidated. Using linear regression in different data set-ups that is longitudinal (n = 7,579) and repeated cross-sectional data (n = 24,625) from the Danish National Birth Cohort, we compared self-reported self-injury, suicidality and symptoms of EDs from before through different pandemic periods until spring 2021. The longitudinal data indicate a reduction in the proportion of self-injury in men (-3.2% points, 95% confidence interval (CI) = -4.3%; -2.2%, P < 0.001, d.f. = 2) and women (5.7% points, 95% CI = -6.6%; -4.8%, P < 0.001, d.f. = 2) and of suicide ideation in men (-3.0% points, 95% CI = -4.6%; -1.4%, P = 0.002, d.f. = 2) and women (-7.4% points, 95% CI = -8.7%; -6.0%, P < 0.001, d.f. = 2), as well as symptoms of EDs in women (-2.3% points, 95% CI = -3.2%; -1.4%, P < 0.001, d.f. = 2). For suicide attempt, indication of an increase was observed in men only (0.4% points, 95% CI = 0.1%; 0.7%, P = 0.019, d.f. = 2). In the repeated cross-sectional data, we observed no changes in any of the outcomes. Our findings provide no support for the increase in self-injury, suicidality and symptoms of EDs after the lockdowns. Key limitations are differential attrition and varying age in pre- and post-lockdown measures in the longitudinal data., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Preterm birth is one of the most important contributors to neonatal mortality and morbidity. Experiencing stress during pregnancy may increase the risk of adverse birth outcomes, including preterm birth. This association has been observed in previous studies, but differences in measures used limit comparability., Objective: The objective of the study was to investigate the association between two measures of maternal stress during pregnancy, life stress and emotional distress, and gestation duration., Methods: Women recruited in the Danish National Birth Cohort from 1996 to 2002, who provided information on their stress level during pregnancy and expecting a singleton baby, were included in the study. We assessed the associations between the level of life stress and emotional distress in quartiles, both collected at 31 weeks of pregnancy on average, and the rate of giving birth using Cox regression within intervals of the gestational period., Results: A total of 80,991 pregnancies were included. Women reporting moderate or high levels of life stress vs no stress had a higher rate of giving birth earlier within all intervals of gestational age (e.g. high level: 27-33 weeks: hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.04, 1.84; 34-36 weeks: 1.10, 95% CI 0.97, 1.25; 37-38 weeks: 1.21, 95% CI 1.15, 1.28). These associations between life stress and preterm birth were mainly driven by pregnancy worries. For emotional distress, a high level of distress was associated with shorter length of gestation in the preterm (27-33 weeks: 1.38, 95% CI 1.02, 1.86; 34-36 weeks: 1.05, 95% CI 0.91, 1.19) and early term (1.11, 95% CI 1.04, 1.17) intervals., Conclusions: Emotional distress and life stress were shown to be associated with gestational age at birth, with pregnancy-related stress being the single stressor driving the association. This suggests that reverse causality may, at least in parts, explain the earlier findings of stress as a risk factor for preterm birth., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: Pregnancy is considered to influence the disease course in women with multiple sclerosis (MS)., Objective: The aim of this study was to investigate the effect of pregnancy on long-term disability accrual in women with MS., Methods: The Danish Multiple Sclerosis Registry (DMSR) was used to identify women diagnosed with clinically isolated syndrome or relapsing-remitting MS. Cox models with pregnancy as a time-dependent exposure and propensity score (PS) models were used to evaluate time to reach confirmed Expanded Disability Status Scale (EDSS) score of 4 and 6., Results: A total of 425 women became parous and 840 remained nulliparous. When including pregnancy as a time-dependent exposure, a non-significant association with time to reach EDSS 4 (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.61-1.20) and EDSS 6 (HR 0.70, 95% CI 0.40-1.20) was found. Correspondingly, the PS model showed no association with pregnancy on time to reach EDSS 4 (HR 0.85, 95% CI 0.56-1.28)., Conclusion: This study concludes that pregnancy does not affect long-term disability accumulation.

The aim of this study was to examine associations between selected sociodemographic, socioeconomic, and health characteristics and the rates of fatherhood in different age groups. We investigated rates between 2011 and 2015 in a population-based register study including all men born from 1945 to 1995 residing in Denmark in 2011. The study population consisted of 1,867,108 men who fathered 268,612 children during the follow-up. The associations were quantified as incidence rate ratios using Poisson regression. Young men had higher rates of fathering a child if they lived outside the Capital Region, had a relatively high income, were previously diagnosed with cardiovascular disease, psychoactive substance abuse, personality disorders, schizophrenia or behavioural and emotional disorders. Men of advanced age had higher rates of fathering a child when born outside Denmark, living in the Capital Region, were in the lower or upper 10th percentile income group, were self-employed or unemployed or previously diagnosed with depression. Men of advanced age had lower rates of fathering a child if previously diagnosed with somatic diseases, psychoactive substance abuse or mental retardation. The findings highlight the importance of consideration of various sociodemographic, socioeconomic, and health characteristics when studying associations between paternal age and offspring health., (© 2021. The Author(s).)

Objective: Treatment-resistant depression (TRD) has been associated with higher mortality and risk of suicide, but this has mainly been showed in few studies which did not include self-harm. The aim was to investigate the association of TRD with all-cause mortality, suicide and self-harm in a nationwide cohort of patients with major depression and explore any differences in relation to patient characteristics., Methods: First-time hospital contacts for major depression between January 1, 1996 and December 31, 2014 were identified in Danish patient registers (ICD-10: F32 and F33). TRD was defined as two shifts in antidepressant treatment, assessed from one year prior depression diagnosis until one year after. Information on mortality, suicide and self-harm was obtained from Danish registers and associations between TRD and the three prognostic outcomes were analyzed using Cox Proportional Hazard Regression., Results: TRD was not associated with all-cause mortality the first year of follow-up (adjusted HR (aHR) 1.04, 95% confidence interval (CI) [0.98-1.11]), and the HR for mortality was lower the following 1-5 years. However, TRD was associated with higher rates of suicide (0-1 year: aHR 2.20, 95% CI [1.77-2.74]; 1-5 years: aHR 1.70, 95% CI [1.42-2.03]) and self-harming behavior (0-1 year: aHR 1.51, 95% CI [1.36-1.66]; 1-5 years: aHR 1.59, 95% CI [1.48-1.70]). The above risk estimates varied only slightly across sociodemographic and clinical patient characteristics., Conclusions: Patients with TRD have higher rates of suicide and self-harm compared with non-TRD patients, whereas there seems to be no increase overall in all-cause mortality - in fact, there was a lower rate at follow-up after 1 year. We found only a few differences in HRs for mortality or suicidality across patient characteristics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To study a potential positive association (referred to as 'a match') between the need for health service (expressed by a mortality risk score) and observed health service utilisation among healthy Danish under-fives. Further, municipal differences in the match were examined to motivate focused comparisons between the organisation of regional health services., Design: Register-based national cohort study., Participants: The population of 1,246,599 Danish children born 1997-2016 who survived until date of first discharge to the home after birth without a diagnosis of severe chronic disease., Main Outcome Measures: Hazard ratios (HR) for a doubling of the mortality rate were calculated for the following health services: total contacts, inpatient contacts (admission > 1 day), outpatient contacts, general practitioner contacts, specialist contacts, medication use, and vaccinations., Results: The use of total contacts, inpatient contacts (> 1 day) and general practitioner contacts as well as medication matched with the mortality risk score, HRs between 1.027 (1.026 to 1.028) and 1.111 (1.108 to 1.113), whereas outpatient and specialist contacts as well as vaccinations did not, HRs between 0.913 (0.912 to 0.915) and 0.991 (0.991 to 0.991). There were some remarkable differences among the 98 Danish municipalities., Conclusions: We found some match between need and use for total contacts, inpatient contacts (> 1 day), contacts with general practitioner, and medication use although the associations were relatively weak. For outpatient and specialist contacts, the mismatch may be related to services not addressing potentially fatal disease whereas for vaccination there was a small mismatch. Our results indicate local discrepancies in diagnosis, and a low adjusted utilisation of hospital admissions in Aarhus compared to the other three major cities in Denmark suggests that a comparison of the organisation of services could be useful., Competing Interests: The authors have declared that no competing interests exist.

Aims: We examined the extent to which associations between education and cardiovascular disease (CVD) morbidity and mortality are attributable to income and work stress., Methods and Results: We included all employed Danish residents aged 30-59 years in 2000. Cardiovascular disease morbidity analyses included 1 638 270 individuals, free of cardiometabolic disease (CVD or diabetes). Mortality analyses included 41 944 individuals with cardiometabolic disease. We assessed education and income annually from population registers and work stress, defined as job strain, with a job-exposure matrix. Outcomes were ascertained until 2014 from health registers and risk was estimated using Cox regression. During 10 957 399 (men) and 10 776 516 person-years (women), we identified 51 585 and 24 075 incident CVD cases, respectively. For men with low education, risk of CVD was 1.62 [95% confidence interval (CI) 1.58-1.66] before and 1.46 (95% CI 1.42-1.50) after adjustment for income and job strain (25% reduction). In women, estimates were 1.66 (95% CI 1.61-1.72) and 1.53 (95% CI 1.47-1.58) (21% reduction). Of individuals with cardiometabolic disease, 1736 men (362 234 person-years) and 341 women (179 402 person-years) died from CVD. Education predicted CVD mortality in both sexes. Estimates were reduced with 54% (men) and 33% (women) after adjustment for income and job strain., Conclusion: Low education predicted incident CVD in initially healthy individuals and CVD mortality in individuals with prevalent cardiometabolic disease. In men with cardiometabolic disease, income and job strain explained half of the higher CVD mortality in the low education group. In healthy men and in women regardless of cardiometabolic disease, these factors explained 21-33% of the higher CVD morbidity and mortality., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: Neurological disorders have been linked to suicide, but the risk across a broad spectrum of neurological disorders remains to be assessed., Objectives: To examine whether people with neurological disorders die by suicide more often than other people and to assess for temporal associations., Design, Setting, and Participants: Nationwide, retrospective cohort study on all persons 15 years or older living in Denmark, from 1980 through 2016 (N = 7 300 395)., Exposures: Medical contact for head injury, stroke, epilepsy, polyneuropathy, diseases of myoneural junction, Parkinson disease, multiple sclerosis, central nervous system infections, meningitis, encephalitis, amyotrophic lateral sclerosis, Huntington disease, dementia, intellectual disability, and other brain diseases from 1977 through 2016 (n = 1 248 252)., Main Outcomes and Measures: Death by suicide during 1980-2016. Adjusted incidence rate ratio (IRRs) were estimated using Poisson regressions, adjusted for sociodemographics, comorbidity, psychiatric diagnoses, and self-harm., Results: Of the more than 7.3 million individuals observed over 161 935 233 person-years (49.1% males), 35 483 died by suicide (median duration of follow-up, 23.6 years; interquartile range, 10.0-37.0 years; mean age, 51.9 years; SD, 17.9 years). Of those, 77.4% were males, and 14.7% (n = 5141) were diagnosed with a neurological disorder, equivalent to a suicide rate of 44.0 per 100 000 person-years compared with 20.1 per 100 000 person-years among individuals not diagnosed with a neurological disorder. People diagnosed with a neurological disorder had an adjusted IRR of 1.8 (95% CI, 1.7-1.8) compared with those not diagnosed. The excess adjusted IRRs were 4.9 (95% CI, 3.5-6.9) for amyotrophic lateral sclerosis, 4.9 (95% CI, 3.1-7.7) for Huntington disease, 2.2 (95% CI, 1.9-2.6) for multiple sclerosis, 1.7 (95% CI, 1.6-1.7) for head injury, 1.3 (95% CI, 1.2-1.3) for stroke, and 1.7 (95% CI, 1.6-1.8) for epilepsy. The association varied according to time since diagnosis with an adjusted IRR for 1 to 3 months of 3.1 (95% CI, 2.7-3.6) and for 10 or more years, 1.5 (95% CI, 1.4 to 1.6, P < .001). Compared with those who were not diagnosed with a neurological disorder, those with dementia had a lower overall adjusted IRR of 0.8 (95% CI, 0.7-0.9), which was elevated during the first month after diagnosis to 3.0 (95% CI, 1.9-4.6; P < .001). The absolute risk of suicide for people with Huntington disease was 1.6% (95% CI, 1.0%-2.5%)., Conclusions and Relevance: In Denmark from 1980 through 2016, there was a significantly higher rate of suicide among those with a diagnosed neurological disorder than persons not diagnosed with a neurological disorder. However, the absolute risk difference was small.

Background: Knowledge of risk factors of treatment-resistant depression (TRD) contributes to understand the underlying mechanisms and to identify patients at risk. However, there is still a lack of studies on how different risk factors associate with TRD. The objective of this study was to determine the independent association of several socio-demographic and clinical risk factors with TRD., Methods: 194.074 patients with a first-time hospital contact for depression identified in the Danish National Patient Registry (DNPR) from 1996 through 2014 were followed for TRD for 12 months after diagnosis. Socio-demographic and clinical risk factors were identified in nation-wide registries. Data were analyzed using Cox Proportional Hazard Regression and Fine-Gray model for competing mortality risk., Results: Indicators of disease severity (recurrent depression (adjusted HR (aHR) 1.17 (1.14-1.20)), severity of depression (aHR 2.01 (1.95-2.08)), admission to a psychiatric ward (aHR 2.03 (1.96, 2.10)) were strong risk factors. Aged 65-84 (aHR 1.96 (1.83-2.10)), lost labor market affiliation ((aHR 1.12 (1.08, 1.16)), cohabiting (aHR 1.27 (1.23, 1.30)), comorbid anxiety (aHR 1.18 (1.10-1.27)), insomnia (aHR 1.27 (1.06-1.51)), migraine (aHR 1.42 (1.16-1.73)) and use of psychotropic drugs was also associated with higher rates of TRD., Limitations: Information on drug use during hospitalization was not available. Information on rating scales could have provided a more precise assessment of symptom severity and treatment response., Conclusions: Besides indicators of disease severity, other important risk factors associated with TRD are age, lost labor market affiliation, cohabiting with a partner as well as anxiety, insomnia, migraine and the use of psychotropic medications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Estimating associations between somatic and socioeconomic risk factors and post-discharge under-five mortality., Design: Register-based national cohort study using multiple Cox regression., Participants: The population of 1,263,795 Danish children live-born 1997-2016 who survived until date of first discharge to the home after birth was followed from that date until death, emigration, 5 years of age or 31 December 2016., Main Outcome Measures: (A) Mortality hazard ratios (HRs) among all children, (B) mortality HRs among children without severe chronic disease, and (C) mortality HRs among children without severe chronic disease or asthma., Main Results: In the total population (1,947 deaths) severe chronic disease was associated with mortality HR = 15.28 (95% CI: 13.77-16.95). In children without severe chronic-disease (719 deaths) other somatic risk factors were immature birth HR = 3.40 (1.92-6.02), maternal smoking HR = 1.84 (1.55-2.18) and low birth weight HR = 1.74 (1.21-2.51). Socioeconomic risk factors for mortality included: maternal age < 25 years HR = 1.91 (1.38-2.64) compared to > 35 years (similar for 30-35 years and 25-29 years), lowest vs. highest family income tertile HR = 1.76 (1.23-2.51), not living with both parents HR = 1.63 (1.25-2.13), maternal unemployment HR = 1.54 (1.12-2.12), presence of siblings HR = 1.44 (1.20-1.71) and secondary vs. tertiary parental education HR = 1.33 (1.07-1.65) for fathers and HR = 1.23 (1.01-1.52) for mothers. Factors not found to be associated with child mortality in this population included presence of asthma HR = 1.29 (0.83-1.98) and non-Danish ethnicity HR = 0.98 (0.70-1.37)., Conclusions: Childhood death after discharge to the home after birth and before 5 years of age is a very rare event in Denmark. This 'post-discharge' mortality was heavily associated with severe chronic disease. In children without severe chronic disease, immature birth, maternal smoking and certain socioeconomic characteristics were noticeable risk factors. Mortality may possibly be decreased by focusing on vulnerable groups., Competing Interests: The authors have declared that no competing interests exist.

Neurobiological mechanisms can be involved in early programming of pain sensitization. We aimed to investigate the association between early-life pain experience and pre-adolescence spinal pain. We conducted a study of 29,861 pre-adolescents (age 11-14) from the Danish National Birth Cohort. As indicators of early-life pain, we used infantile colic and recurrent otitis media, reported by mothers when their children were 6 and 18 months. Self-reported spinal pain (neck, middle back, and/or low back pain) was obtained in the 11-year follow-up, classified according to severity. Associations between early-life pain and spinal pain in pre-adolescents were estimated using multinomial logistic regression models. To account for sample selection, inverse probability weighting was applied. Children experiencing pain in early life were more likely to report severe spinal pain in pre-adolescence. The association appeared stronger with exposure to two pain exposures (relative risk ratio, 1.31; 95% CI, 1.02-1.68) rather than one (relative risk ratio, 1.14; 95% CI, 1.05-1.24). We observed similar results when using headache and abdominal pain as outcome measures, underpinning a potential neurobiological or psychosocial link in programming of pain sensitization.Conclusion: Experience of early-life pain is seemingly associated with spinal pain in pre-adolescence. The study highlights that early-life painful experiences can influence programming of future pain responses.What is Known:• Spinal pain in pre-adolescents is common, causes marked discomfort and impairment in everyday life, and may be an important predictor of spinal pain later in life.• Neurobiological mechanisms have been suggested as involved in early programming of pain sensitization.What is New:• Pain exposure in early postnatal life in terms of infantile colic and recurrent otitis media is associated with spinal pain in pre-adolescence; thus, experience of such painful conditions in the early postnatal period may seemingly influence programming of future pain sensation.

Background: Systematic reviews have consistently shown that individuals with mental disorders have an increased risk of premature mortality. Traditionally, this evidence has been based on relative risks or crude estimates of reduced life expectancy. The aim of this study was to compile a comprehensive analysis of mortality-related health metrics associated with mental disorders, including sex-specific and age-specific mortality rate ratios (MRRs) and life-years lost (LYLs), a measure that takes into account age of onset of the disorder., Methods: In this population-based cohort study, we included all people younger than 95 years of age who lived in Denmark at some point between Jan 1, 1995, and Dec 31, 2015. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and the date and cause of death was obtained from the Danish Register of Causes of Death. We classified mental disorders into ten groups and causes of death into 11 groups, which were further categorised into natural causes (deaths from diseases and medical conditions) and external causes (suicide, homicide, and accidents). For each specific mental disorder, we estimated MRRs using Poisson regression models, adjusting for sex, age, and calendar time, and excess LYLs (ie, difference in LYLs between people with a mental disorder and the general population) for all-cause mortality and for each specific cause of death., Findings: 7 369 926 people were included in our analysis. We found that mortality rates were higher for people with a diagnosis of a mental disorder than for the general Danish population (28·70 deaths [95% CI 28·57-28·82] vs 12·95 deaths [12·93-12·98] per 1000 person-years). Additionally, all types of disorders were associated with higher mortality rates, with MRRs ranging from 1·92 (95% CI 1·91-1·94) for mood disorders to 3·91 (3·87-3·94) for substance use disorders. All types of mental disorders were associated with shorter life expectancies, with excess LYLs ranging from 5·42 years (95% CI 5·36-5·48) for organic disorders in females to 14·84 years (14·70-14·99) for substance use disorders in males. When we examined specific causes of death, we found that males with any type of mental disorder lost fewer years due to neoplasm-related deaths compared with the general population, although their cancer mortality rates were higher., Interpretation: Mental disorders are associated with premature mortality. We provide a comprehensive analysis of mortality by different types of disorders, presenting both MRRs and premature mortality based on LYLs, displayed by age, sex, and cause of death. By providing accurate estimates of premature mortality, we reveal previously underappreciated features related to competing risks and specific causes of death., Funding: Danish National Research Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To describe the temporal development of mortality and health service utilisation defined as in- and outpatient hospital contacts, contacts with general practitioner and specialists, and prescribed dispensed medication among Danish children 0-5 years of age from 1999 to 2016., Design: Register-based descriptive study., Participants: All children born in Denmark in the period 1994-2016 followed until 5 years of age., Main Outcome Measures: Annual incidence rates of mortality and health service utilisation outcomes, and incidence rate ratios compared to the reference calendar year 1999. The new measure of post-discharge mortality is presented., Results: Post-discharge mortality decreased from 1999 to 2016, IRR2016 = 0.49 (95% CI: 0.36 to 0.66). Total contacts did not change much over time, IRR2016 = 1.02 (1.02 to 1.03), but increased among neonates, IRR2016 = 3.69 (3.63 to 3.75), and decreased among children with chronic disease IRR2016 = 0.94 (0.93 to 0.94). In- and out-patient hospitalisations increased, IRR2016 = 1.26 (1.24-1.27) resp. IRR2016 = 1.62 (1.60-1.63), contacts with medical specialists increased, IRR2016 = 1.43 (1.42 to 1.43), whilst contacts with general practitioner decreased, IRR2016 = 0.91 (0.91 to 0.91). Medication use decreased, IRR2016 = 0.82 (0.82 to 0.82)., Conclusions: Our measure of post-discharge mortality was halved during the study period indicating improved health. Overall health service utilisation did not change much, but the type of utilisation changed, and the development over time differed between subgroups defined by age and chronic disease status. Our findings call for considerations about the benefit of increased specialisation and increased use of health services among 'healthy' children not suffering from chronic disease., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To estimate the association between childhood vaccination and subsequent morbidity and mortality by adjusting for environmental and host factors. Further, to examine the degree of residual confounding in such observational studies., Design: Register-based cohort study including 1 122 929 Danish children., Participants: All children born in Denmark in the period 1999-2016 who survived until 16 months of age without prior migration followed from 16 months until the first of the following: event of interest, migration, 5 years of age or 31 December 2016., Main Outcome Measures: Adjusted HRs (aHRs) and absolute risks were calculated for the three outcomes: mortality, hospitalisation for infection and asthma using register data on deaths, specific hospital contacts and dispensed prescribed medication. The exposure was the combination of the routine vaccines against diphteria-tetanus-pertussis-polio- Haemophilus influenzae type b and measles-mumps-rubella (DTP and MMR in short) administered in early childhood. Hospitalisation due to accidents was analysed as a negative control outcome to examine residual confounding., Results: Children with 3DTP+MMR had a lower hazard of mortality than the reference group with 3DTP, adjusted HR (aHR)=0.45 (95% CI: 0.35 to 0.57), whereas the children with 1 or 2 DTP had higher hazards of dying, aHR=1.55 (95% CI: 1.14 to 2.13) and aHR=1.96 (95% CI: 1.34 to 2.89). The vaccination group 3DTP+MMR was associated with a reduced hazard of asthma aHR=0.94 (95% CI: 0.92 to 0.96). Also, the vaccination group 3DTP+MMR was associated with a reduced hazard of hospitalisation due to accidents, aHR=0.83 (0.80 to 0.85) compared with the reference group with 3 DTP., Conclusions: The results suggested a beneficial impact of MMR on under-five mortality but did not support the hypothesis that DTP is detrimental, since the group of children with fewer DTP vaccinations experienced increased mortality. The results of the study may to some degree be prone to residual confounding since an unexpected association between MMR vaccination and hospitalisation for accidents was observed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Drug repurposing is an increasingly promising idea in many fields of medicine. We systematically used Danish nation-wide population-based registers to investigate whether continued use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, high-dose aspirin, statins, allopurinol, and angiotensin agents decrease the rate of incident mania/bipolar disorder., Methods: A nation-wide population-based longitudinal study using Poisson regression analyses including all persons in Denmark who purchased the exposure medication of interest and a random sample of 30% of the Danish population. The follow-up period comprised a 10 years period from 2005 to 2015. Two different outcome measures were included, (1) a diagnosis of mania/bipolar disorder at a psychiatric hospital contact as inpatient or outpatient and (2) a combined measure of a diagnosis of mania/bipolar disorder or initiation of lithium use., Results: A total of 1,605,365 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015, median age 57 years [quartiles: 43;69], and female proportion of 53.1%. Continued use of low-dose aspirin, statins, and angiotensin agents were associated with decreased rates of incident mania/bipolar disorder on both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident bipolar disorder. There were no statistically significant associations for allopurinol., Conclusions: The study supports the potential of agents acting on inflammation and the stress response system in bipolar disorder and illustrates that population-based registers can be used to systematically identify drugs with repurposing potentials., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Studies have shown differences in the risk of caesarean section (CS) between ethnic minority groups. This could be a marker of unequal health care. The aim of this study was to investigate differences in the risk of CS between immigrants of various origins in Denmark, where all health care is free and easy to access, and Danish-born women. A further aim was to determine the possible influence of known risk factors for CS., Methods: The design was a population-based register study using national Danish registers and included all live- and stillborn singleton deliveries by primiparous women in Denmark from 2004 to 2015. The total study population consisted of 298,086 births, including 25,198 births to women from the 19 largest immigrant groups in Denmark. Multinomial logistic regression analysis was used to estimate relative risk ratios (RRR) of emergency and planned CS, using vaginal delivery (VD) as reference, in immigrant women compared to Danish-born women. A number of known risk factors were included separately., Results: Women from Turkey, the Philippines, Thailand, Somalia, Vietnam, Iran and Afghanistan had a statistically significant elevated risk ratio of emergency CS vs. VD compared to Danish-born women; adjusted RRR's ranging 1.15-2.19. The risk ratio of planned CS vs. VD was lower among the majority of immigrant groups, however higher among women from Poland, Thailand and Iran, when compared to Danish-born women. None of the studied explanatory variables affected the risk ratio of planned CS vs. VD, whereas maternal height contributed with varying strength to the risk ratio of emergency CS vs. VD for all immigrant groups., Conclusion: Substantial variations in CS risks by maternal country of birth were documented. Some of the disparities in emergency CS seem to be explained by maternal height.

This study aims to describe the prevalence of spinal pain among Danish children, explore the differential nature of spinal pain, and investigate socio-demographic factors predisposing spinal pain. A descriptive study of 46,726 11-14-year-olds participating in the Danish National Birth Cohort was conducted. Self-reported spinal pain (neck, middle back, and low back pain) was registered and classified according to severity. Socioeconomic data on children and their parents were identified in Statistics Denmark registers. Associations between socio-demographic factors and aspects of spinal pain were estimated using multinomial logistic regression models. To account for sample selection, inverse probability weighting (IPW) was applied. Almost 10% boys and 14% girls reported severe spinal pain, whereas around 30% of all children reported moderate pain. Effect estimates indicated the risk to increase with increasing age. Further, children without biological full siblings, not living with both of their parents, or children living in less-educated or lower-income families were more likely to experience spinal pain. The study conclusions were essentially unaffected by IPW.Conclusion: A considerable number of children suffer from spinal pain, and it is more common among children in more disadvantaged families. Etiology of spinal pain needs to be explored further with the aim of informing efficient and targeted prevention. What is Known: • Childhood spinal pain may cause marked discomfort and impairment in children's everyday life, and is suggested as important predictor of later-in-life spinal pain. • Methodological heterogeneity in previous studies and complexity of measuring pain make inferences at a broader level inadequate. What is New: • Prevalence of severe spinal pain in 11-14-year-olds was estimated to almost 10% for boys and 14% for girls, and children in more disadvantaged families were more likely to experience spinal pain. • The results seemed unaffected by sample selection.

Background: People with schizophrenia have an increased risk of premature mortality compared to the general population. We aimed to quantify which types of causes of death contributed to the excess mortality, and to examine whether there has been an increase in the excess mortality among persons with schizophrenia in the period 1995 to 2015., Method: We used a cohort design including the entire Danish population. We calculated life years lost of the cohort members compared to a set reference-age at 95 years old. Using a decomposition model we examined differences of cause-specific death among those with schizophrenia and the general population, including calendar trends during the last two decades., Results: In the general population, as well as in persons with schizophrenia, we found improvements in life years lost during the last two decades. Men with schizophrenia lost 13.5 years more than the general population (women; 11.4 years). Compared to the general population, a large improvement in life years lost with respect to suicide and accidents was found in those with schizophrenia, but, this improvement was offset by an increasing number of life years lost in deaths from diseases and medical conditions., Conclusion: Our findings highlight the urgent need for focused treatment of general medical conditions in those with schizophrenia. Without such an investment, it is probable that the life years lost among persons with schizophrenia (compared to the general population) will continue to worsen in future decades., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers., Methods: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants., Results: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression., Conclusion: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Varying definitions of treatment-resistant depression (TRD) across studies make it difficult to estimate the size of the problem and to identify patients at increased risk. The aim of this cohort study was to examine the incidence of TRD, disease-related risk factors, and changes over time using different definitions of TRD., Methods: From 1996 through 2014, all patients with a first-time hospital contact for depression (ICD-10 codes F32 and F33) were identified in Danish National Patient Registries. A total of 211,689 patients were followed for shifts in antidepressant treatment in the Danish Patient and Prescription Registries. TRD was defined at the second shift in treatment during the first 12 months after diagnosis. The associations of year and type of hospital contact, depression subtype, and severity of TRD were analyzed using Cox proportional hazard regression., Results: A total of 14.0% of patients experienced a second shift in antidepressant treatment during the first year after admission. When applying 3 other common TRD definitions, the proportion varied from 13% to 31%. Psychiatric inpatients and patients with recurrent or severe depression had the highest incidence of TRD. The incidence of TRD was also slightly higher in patients diagnosed after 2001. All associations were replicated when data were reanalyzed using the alternative definitions of TRD., Conclusions: About 14% of patients with depression developed TRD during the first year after first hospital contact. The incidence was highest in patients with severe depression and was relatively stable over time. Various definitions of TRD provided different estimates of the frequency of TRD but were all associated with disease severity., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Objective: To assess whether implementing patient-controlled admission (PCA) can reduce coercion and improve other clinical outcomes for psychiatric in-patients., Methods: During 2013-2016, 422 patients in the PCA group were propensity score matched 1:5 with a control group (n = 2110) that received treatment as usual (TAU). Patients were followed up for at least one year using the intention to treat principle utilising nationwide registers. In a paired design, the outcomes of PCA patients during the year after signing a contract were compared with the year before., Results: No reduction in coercion (risk difference = 0.001; 95% CI: -0.038; 0.040) or self-harming behaviour (risk difference = 0.005; 95% CI: -0.008; 0.018) was observed in the PCA group compared with the TAU group. The PCA group had more in-patient bed days (mean difference = 28.4; 95% CI: 21.3; 35.5) and more medication use (P < 0.0001) than the TAU group. Before and after analyses showed reduction in coercion (P = 0.0001) and in-patient bed days (P = 0.0003)., Conclusion: Implementing PCA did not reduce coercion, service use or self-harm behaviour when compared with TAU. Beneficial effects of PCA were observed only in the before and after PCA comparisons. Further research should investigate whether PCA affects other outcomes to better establish its clinical value., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe episodes of mood disorders. Temporary memory loss is a common side-effect, but ongoing discussions exist regarding potential long-term adverse cognitive outcomes. Only a few studies have examined the frequency of dementia in patients after ECT. The aim of this study was to examine the association between ECT and risk of subsequent dementia in patients with a first-time hospital diagnosis of affective disorder., Methods: We did a cohort study of patients aged 10 years and older in Denmark with a first-time hospital contact for an affective disorder from Jan 1, 2005, through Dec 31, 2015, identified in the Danish National Patient Registry with ICD-10 codes F30.0 to F39.9. From the registry we retrieved information on all ECTs registered for patients and followed up patients for incidental dementia (defined by hospital discharge diagnoses or acetylcholinesterase inhibitor use) until Oct 31, 2016. We examined the association between ECT and dementia using Cox regression analyses with multiple adjustments and propensity-score matching on sociodemographic and clinical variables., Findings: Of 168 015 patients included in the study, 5901 (3·5%) patients had at least one ECT. During the median follow-up of 4·9 years (IQR 2·4-7·8) and 872 874 person years, the number of patients who developed dementia was 111 (0·1%) of 99 045 patients aged 10-49 years, 965 (2·7%) of 35 945 aged 50-69 years, and 4128 (12·5%) of 33 025 aged 70-108 years. 217 (3·6%) of the 5901 patients treated with ECT developed dementia, whereas of 162 114 patients not treated with ECT 4987 (3·1%) developed dementia. The corresponding incidences were 70·4 cases per 10 000 person-years (95% CI 61·6-80·5) and 59·2 per 10 000 person-years (57·6-60·8). In patients younger than 50 years and 50-69 years, ECT was not associated with a risk of dementia compared with age-matched patients who were not given ECT (age-adjusted hazard ratio [HR] 1·51, 95% CI 0·67-3·46, p=0·32; and 1·15, 0·91-1·47, p=0·22, respectively). In patients aged 70 years and older, ECT was associated with a decreased rate of dementia (0·68, 95% CI 0·58-0·80; p<0·0001), but in the propensity-score matched sample the HR was attenuated (0·77, 0·59-1·00; p=0·062). 31 754 patients (17·6%) died during follow-up (mortality rate per 1000 person-years 35·7, 95% CI 35·3-36·2) and supplementary analyses suggested that the risk of dementia, taking the competing mortality risk into account, was not significantly associated with ECT (subdistribution HR 0·98, 95% CI 0·76-1·26; p=0·24)., Interpretation: ECT was not associated with risk of incidental dementia in patients with affective disorders after correcting for the potential effect of patient selection or competing mortality. The findings from this study support the continued use of ECT in patients with severe episodes of mood disorders, including those who are elderly., Funding: Danish Council for Independent Research, Danish Medical Research Council, the Velux Foundation, the Jascha Foundation, and the Doctor Sofus Carl Emil Friis and Olga Doris Friis grant., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: People with mental disorders have higher mortality rates than the general population and more detailed estimates of mortality differences are needed to address this public health issue. We aimed to assess whether differences in cause-specific mortality between people with and without mental disorders have changed between 1995 and 2014 by quantifying life-years lost and assessing differences over time., Methods: Using a cohort design, we linked nationwide population data from the Danish Civil Registration System to information about hospital contacts from the Psychiatric Central Research Register and deaths from the Danish Cause of Death register. All linked data sources contained longitudinal information covering all individuals aged 15-94 years living in Denmark between 1995 and 2014. We assessed cause-specific mortality differences using rate ratios and average life-years lost., Findings: Between 1995 and 2014, 6 107 234 individuals (3 026 132 men and 3 081 102 women) aged 15-94 years were living in Denmark. The study population was observed over 89 216 177 person-years (men: 43 914 948; women 45 301 229). Cause-specific mortality rates were higher for people with mental disorders than those without (total mortality rate per 1000 person-years in men 27·1 vs 11·4, respectively, and in women 21·2 vs 11·0). When compared with individuals without mental disorders, men and women with mental disorders had 10·20 and 7·34 excess life-years lost, respectively. The largest cause-specific differences between those with and without mental disorders in terms of excess life-years lost were for respiratory diseases (men: 0·9; women: 1·4) and alcohol misuse (men: 2·8; women: 1·2). Between 1995 and 2014, we noted an increase in excess life-years lost for neoplasms (men: 0·7; women: 0·4), heart diseases (men: 1·2; women: 0·3), and respiratory diseases (men: 0·3; women: 0·2), and a decrease for suicide (men: -0·7; women: -0·5) and accidents (men: -0·9; women: -0·5)., Interpretation: By applying a novel approach, more precise estimates of life-years lost were obtained. The increase in excess mortality due to medical diseases and disorders among people with mental disorders emphasises the need for future interventions to address these aspects as well as the continued high shares of excess mortality due to alcohol misuse, suicide, and accidents., Funding: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We examined incidence of depression after acute coronary syndrome (ACS) and whether the timing of depression onset influenced survival. All first-time hospitalizations for ACS (n = 97,793) identified in the Danish Patient Registry during 2001-2009 and a reference population were followed for depression and mortality via linkage to patient, prescription, and cause-of-death registries until the end of 2012. Incidence of depression (as defined by hospital discharge or antidepressant medication use) and the relationship between depression and mortality were examined using time-to-event models. In total, 19,520 (20.0%) ACS patients experienced depression within 2 years after the event. The adjusted rate ratio for depression in ACS patients compared with the reference population was 1.28 (95% confidence interval (CI): 1.25, 1.30). During 12 years of follow-up, 39,523 (40.4%) ACS patients and 27,931 (28.6%) of the reference population died. ACS patients with recurrent (hazard ratio (HR) = 1.62, 95% CI: 1.57, 1.67) or new-onset (HR = 1.66, 95% CI: 1.60, 1.72) depression had higher mortality rates than patients with no depression. In the reference population, the corresponding relative estimates for recurrent (HR =1.98, 95% CI: 1.92, 2.05) and new-onset (HR = 2.42, 95% CI: 2.31, 2.54) depression were stronger. Depression is common in ACS patients and is associated with increased mortality independently of time of onset, but here the excess mortality associated with depression seemed to be lower in ACS patients than in the reference population., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: A recent alarming finding suggested an increased risk of renal tumors among long-term lithium users. The objectives of the present study were to estimate rates of renal and upper urinary tract tumors (RUT), malignant and benign, among individuals exposed to successive prescriptions for lithium, anticonvulsants, and other psychotropic agents used for bipolar disorder, and among unexposed individuals., Methods: This was a nationwide, population-based longitudinal study including time-specific data from all individuals exposed to lithium (n = 24,272) or anticonvulsants (n = 386,255), all individuals with a diagnosis of bipolar disorder (n = 9,651), and a randomly selected sample of 1,500,000 from the Danish population. The study period was from 1995 to 2012, inclusive. Outcomes were hazard rate ratios (HR) for RUT in three groups: (i) combined malignant and benign, (ii) malignant, and (iii) benign. Analyses were adjusted for the number of prescriptions for lithium/anticonvulsants, antipsychotic agents, antidepressants, and use of all other types of medication; age; gender; employment status; calendar year; and a diagnosis of bipolar disorder., Results: Continued treatment with lithium was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.67-1.18, p (trend) = 0.70; adjusted HR malignant: 0.61-1.34, p (trend) = 0.90; adjusted HR benign: 0.74-1.18, p (trend) = 0.70]. Similarly, continued treatment with anticonvulsants was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.97-1.18, p (trend) = 0.10; adjusted HR malignant: 0.82-1.15, p (trend) = 0.80; adjusted HR benign: 0.94-1.36, p (trend) = 0.20]. The associations were confirmed among the 9,651 patients with a diagnosis of bipolar disorder., Conclusions: Treatment with lithium is not associated with increased rates of RUT., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Lithium is the main mood stabilizing drug for bipolar disorder. However, it is controversial whether long-term maintenance treatment with lithium or other drugs for bipolar disorder causes chronic kidney disease (CKD)., Objective: To compare rates of CKD and in particular rates of end-stage CKD among individuals exposed to successive prescriptions of lithium, anticonvulsants, or other drugs used for bipolar disorder., Design, Setting, and Participants: This is a Danish nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly selected sample of 1.5 million individuals among all persons who were registered in Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10,591), and all patients exposed to either lithium (n = 26,731) or anticonvulsants (n=420,959). Cohort 2 included the subgroup of 10,591 patients diagnosed as having bipolar disorder., Main Outcomes and Measures: Possible CKD, definite CKD, and end-stage CKD (defined as long-term dialysis or renal transplantation)., Results: A total of 14,727 (0.8%), 18,762 (1.0%), and 3407 (0.2%) in cohort 1 and 278 (2.6%), 319 (3.0%), and 62 (0.6%) in cohort 2 were diagnosed as having possible, definite, or end-stage CKD, respectively. Based on the total sample and not considering diagnoses, use of lithium was associated with an increased rate of definite CKD (0 prescriptions: hazard ratio [HR] = 1.09, 95% CI, 0.81-1.45; ≥60 prescriptions: HR = 3.65, 95% CI, 2.64-5.05; P for trend < .001) and possible CKD (0 prescriptions: HR = 1.01, 95% CI, 0.79-1.30; ≥60 prescriptions: HR = 2.88, 95% CI, 2.17-3.81; P for trend < .001), whereas use of anticonvulsants, antipsychotics, or antidepressants was not. Neither use of lithium nor use of any other drug class was associated with increasing rates of end-stage CKD. In patients with bipolar disorder, use of lithium was associated with an increased rate of definite CKD (1-2 prescriptions: HR = 0.89, 95% CI, 0.39-2.06; ≥60 prescriptions: HR = 2.54, 95% CI, 1.81-3.57; P for trend < .001) or possible CKD (1-2 prescriptions: HR = 1.26, 95% CI, 0.65-2.43; ≥60 prescriptions, HR = 2.48, 95% CI, 1.80-3.42; P for trend < .001), as was use of anticonvulsants (definite CKD, 1-2 prescriptions: HR = 1.23, 95% CI, 0.76-1.99; ≥60 prescriptions, HR = 2.30, 95% CI, 1.53-3.44; P for trend < .001; possible CKD, 1-2 prescriptions: HR = 1.11, 95% CI, 0.70-1.76; ≥60 prescriptions: HR = 1.97, 95% CI, 1.34-2.90; P for trend < .001). There was no such association with antipsychotics or antidepressants. Also in patients with bipolar disorder, use of lithium was not significantly associated with an increased rate of end-stage CKD, whereas use of anticonvulsants was (1-2 prescriptions, HR = 0 [95% CI, 0.00-infinity]; 30-39 prescriptions: HR = 3.23, 95% CI, 1.26-8.27; ≥60 prescriptions: HR = 2.06, 95% CI, 0.82-5.16; P for trend = .002)., Conclusions and Relevance: Maintenance treatment with lithium or anticonvulsants as practiced in modern care is associated with an increased rate of CKD. However, use of lithium is not associated with an increased rate of end-stage CKD. The associations between use of medication and CKD may at least partly be attributed to bias.

Background: Patients with low socioeconomic position have higher rates of mortality after diagnosis of acute coronary syndrome (ACS), but little is known about the mechanisms behind this social inequality. The aim of the present study was to examine whether any educational inequality in survival after ACS was influenced by comorbid conditions including depression., Methods: From 2001 to 2009 all first-time ACS patients were identified in the Danish National Patient Registry. This cohort of 83 062 ACS patients and a matched reference population were followed for incident depression and mortality until December 2012 by linkage to person, patients and prescription registries. Educational status was defined at study entry and the impact of potential confounders and mediators (age, gender, cohabitation status, somatic comorbidity and depression) on the relation between education and mortality were identified by drawing a directed acyclic graph and analysed using multiple Cox regression analyses., Findings: During follow-up, 29 583(35.6%) of ACS patients and 19 105(22.9%) of the reference population died. Cox regression analyses showed an increased mortality in the lowest educated compared to those with high education in both ACS patients and the reference population. Adjustment for previous and incident depression or other covariables only attenuated the relations slightly. This pattern of associations was seen for mortality after 30 days, 1 year and during total follow-up., Conclusion: In this study the relative excess mortality rate in lower educated ACS patients was comparable with the excess risk associated with low education in the background population. This educational inequality in survival remained after adjustment for somatic comorbidity and depression.

In epidemiology, the concepts of "biologic" and "statistical" interactions have been the subject of extensive debate. We present a new approach to biologic interaction based on Rothman's original (Am J Epidemiol, 104:587-592, 1976) discussion of sufficient causes. We do this in a probabilistic framework using competing risks and argue that sufficient cause interaction between two factors can be evaluated via the parameters in a particular statistical model, the additive hazard rate model. We present empirical conditions for presence of sufficient cause interaction and an example based on data from a liver cirrhosis trial illustrates the ideas.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assumed to increase bleeding risk, but their actual relation to serious bleeding in patients with atrial fibrillation (AF) who are receiving antithrombotic medication is unknown., Objective: To investigate the risk for serious bleeding and thromboembolism associated with ongoing NSAID and antithrombotic therapy., Design: Observational cohort study., Setting: Nationwide registries., Patients: Danish patients with AF hospitalized between 1997 and 2011., Measurements: Absolute risk for serious bleeding and thromboembolism with ongoing NSAID and antithrombotic therapy, assessed by using Cox models., Results: Of 150 900 patients with AF (median age, 75 years [interquartile range, 65 to 83 years]; 47% female), 53 732 (35.6%) were prescribed an NSAID during a median follow-up of 6.2 years (interquartile range, 2.1 to 14.0 years). There were 17 187 (11.4%) and 19 561 (13.0%) occurrences of serious bleeding and thromboembolism, respectively. At 3 months, the absolute risk for serious bleeding within 14 days of NSAID exposure was 3.5 events per 1000 patients compared with 1.5 events per 1000 patients without NSAID exposure. The risk difference was 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients. Use of NSAIDs was associated with increased absolute risks for serious bleeding and thromboembolism across all antithrombotic regimens and NSAID types. An NSAID dosage above the recommended minimum was associated with a substantially increased hazard ratio for bleeding., Limitation: Observational design and unmeasured confounders., Conclusion: Use of NSAIDs was associated with an independent risk for serious bleeding and thromboembolism in patients with AF. Short-term NSAID exposure was associated with increased bleeding risk. Physicians should exercise caution with NSAIDs in patients with AF., Primary Funding Source: None.

To isolate the effect of education from the influence of potential underlying factors, we investigated the association of education with the risk of cardiovascular disease (CVD) and ischemic heart disease (IHD) using twin data to adjust for familial factors shared within twins, including genetic make-up and childhood environment. The study was based on data from the Danish Twin Registry linked to administrative and heath registers in Statistics Denmark. A total of 11,968 monozygotic and 20,464 dizygotic same sexed twins were followed from 1980 to 2009, including more than 8000 events of CVD. Unpaired and intra-pair analyses were compared. In the unpaired analyses, an inverse educational gradient in CVD- and IHD risk was observed. This association was not replicated in the intra-pair analyses that control for shared familial factors exploiting that twins share their intrauterine- and childhood environment and are matched partly or fully on genetic setup. The attenuation of association of education with CVD and IHD in the intra-pair analyses suggests that shared familial factors account for a substantial part of the observed association of education with CVD and IHD in Denmark., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: No study has investigated when preventive treatment with lithium should be initiated in bipolar disorder., Aims: To compare response rates among patients with bipolar disorder starting treatment with lithium early v. late., Method: Nationwide registers were used to identify all patients with a diagnosis of bipolar disorder in psychiatric hospital settings who were prescribed lithium during the period 1995-2012 in Denmark (n = 4714). Lithium responders were defined as patients who, following a stabilisation lithium start-up period of 6 months, continued lithium monotherapy without being admitted to hospital. Early v. late intervention was defined in two ways: (a) start of lithium following first contact; and (b) start of lithium following a diagnosis of a single manic/mixed episode., Results: Regardless of the definition used, patients who started lithium early had significantly decreased rates of non-response to lithium compared with the rate for patients starting lithium later (adjusted analyses: first v. later contact: P<0.0001; hazard ratio (HR) = 0.87, 95% CI 0.76-0.91; single manic/mixed episode v. bipolar disorder: P<0.0001; HR = 0.75, 95% CI 0.67-0.84)., Conclusions: Starting lithium treatment early following first psychiatric contact or a single manic/mixed episode is associated with increased probability of lithium response., (Royal College of Psychiatrists.)

Introduction: The decline in birth rates is a concern in public health. Fertility is partly determined before birth by the intrauterine environment and prenatal exposure to maternal stress could, through hormonal disturbance, play a role. There has been such evidence from animal studies but not from humans. We aimed to examine the association between prenatal stress due to maternal bereavement following the death of a relative and childbirths in the offspring., Materials and Methods: This population-based cohort study included all subjects born in Denmark after 1968 and in Sweden after 1973 and follow-up started at the age of 12 years. Subjects were categorized as exposed if their mothers lost a close relative during pregnancy or the year before and unexposed otherwise. The main outcomes were age at first child and age-specific mean numbers of childbirths. Data was analyzed using Cox Proportional Hazards models stratified by gender and adjusted for several covariates. Subanalyses were performed considering the type of relative deceased and timing of bereavement., Results: A total of 4,121,596 subjects were followed-up until up to 41 years of age. Of these subjects, 93,635 (2.3%) were exposed and 981,989 (23.8%) had at least one child during follow-up time. Compared to unexposed, the hazard ratio (HR) [95% confidence interval] of having at least one child for exposed males and females were 0.98 [0.96-1.01] and 1.01 [0.98-1.03], respectively. We found a slightly reduced probability of having children in females born to mothers who lost a parent with HR = 0.97 [0.94-0.99] and increased probability in females born to mothers who lost another child (HR = 1.09 [1.04-1.14]), the spouse (HR = 1.29 [1.12-1.48]) or a sibling (HR = 1.13 [1.01-1.27])., Conclusions: Our results suggested no overall association between prenatal exposure to maternal stress and having a child in early adulthood but a longer time of follow-up is necessary in order to reach a firmer conclusion.

Objectives: It has been suggested that the handling of heavy loads during pregnancy is associated with impaired fetal growth. We examined the association between quantity and frequency of maternal occupational lifting and the child's size at birth, measured by weight, length, ponderal index, small-for-gestational-age (SGA), abdominal circumference, head circumference, and placental weight., Methods: We analyzed birth size from the Danish Medical Birth Registry of 66 693 live-born children in the Danish National Birth Cohort according to the mother's self-reported information on occupational lifting from telephone interviews around gestational week 16. Data were collected in the period 1996-2002. We used linear and logistic regression models and adjusted for confounders., Results: In the fully adjusted models, most of the mean differences in birth size measures had values indicating a smaller size of offspring among women with occupational lifting versus women with no lifting, but the differences were very small, and there was a statistically significant trend only for placental weight showing lighter weight with increasing number of kilos lifted per day. In jobs likely to include person-lifting, we found increased odds of SGA among children of women who lifted 501-1000 kilos per day [odds ratio (OR) 1.34, 95% confidence interval (95% CI) 0.98-1.83] and >1000 kilos per day (OR 1.51, 95% CI 0.83-2.76) compared to no lifting. In jobs with no person-lifting, occupational lifting was not associated with SGA., Conclusions: Overall, we observed no strong support for an association between maternal occupational lifting and impaired size at birth. Our data indicated a potential association between lifting and SGA among offspring of women in occupations that are likely to include person-lifting. These results should, however, be interpreted with caution due to limited statistical power, and we suggest that future studies include detailed, individual information on job functions and ergonomic routines of lifting procedures.

Background: New-onset atrial fibrillation (AF) is reported to increase the risk of death in myocardial infarction (MI) patients. However, previous studies have reported conflicting results and no data exist to explain the underlying cause of higher death rates in these patients., Methods and Results: All patients with first acute MI between 1997 and 2009 in Denmark, without prior AF, were identified from Danish nationwide administrative registers. The impact of new-onset AF on all-cause mortality, cardiovascular death, fatal/nonfatal stroke, fatal/nonfatal re-infarction and noncardiovascular death, were analyzed by multiple time-dependent Cox models and additionally in propensity score matched analysis. In 89 703 patients with an average follow-up of 5.0 ± 3.5 years event rates were higher in patients developing AF (n=10 708) versus those staying in sinus-rhythm (n=78 992): all-cause mortality 173.9 versus 69.4 per 1000 person-years, cardiovascular death 137.2 versus 50.0 per 1000 person-years, fatal/nonfatal stroke 19.6/19.9 versus 6.2/5.6 per 1000 person-years, fatal/nonfatal re-infarction 29.0/60.7 versus 14.2/37.9 per 1000 person-years. In time-dependent multiple Cox analyses, new-onset AF remained predictive of increased all-cause mortality (HR: 1.9 [95% CI: 1.8 to 2.0]), cardiovascular death (HR: 2.1 [2.0 to 2.2]), fatal/nonfatal stroke (HR: 2.3 [2.1 to 2.6]/HR: 2.5 [2.2 to 2.7]), fatal/nonfatal re-infarction (HR: 1.7 [1.6 to 1.8]/HR: 1.8 [1.7 to 1.9]), and non- cardiovascular death (HR: 1.4 [1.3 to 1.5]) all P<0.001). Propensity-score matched analyses yielded nearly identical results (all P<0.001)., Conclusions: New-onset AF after first-time MI is associated with increased mortality, which is largely explained by more cardiovascular deaths. Focus on the prognostic impact of post-infarct AF is warranted.

Background: Marriage is associated with lower risk of coronary heart disease, but it is unknown if the association depends on time since break-up with a partner. In this study we included both married and unmarried couples to study if the association between broken partnership (BP) and first time incident myocardial infarction (MI) changes with time since BP., Methods: Register study of the entire Danish population: the population was restricted to those aged 30 to 65 years with follow-up for incident MI between 1985 and 2006 with an annual record on each individual; in total 43 million records. The register data were used to identify MI events. Poisson regression was used to study associations between time since BP and MI adjusted for socio-demographic confounders and hospital admissions. Analyses were stratified by sex., Results: Compared with unexposed (no BP), the incidence rate ratio (IRR) of MI in men with BP in the same year was 0.97 [95% confidence interval (CI) 0.90-1.05], year before BP was 1.25 (95% CI 1.17-1.34), 2-3 years after BP was 1.12 (95% CI 1.06-1.18), 4-8 years after BP was 1.09 (95% CI 1.05-1.14) and 9+ years since BP was 1.09 (95% CI 1.05-1.12). In women, the IRR same year as BP was 1.45 (95% CI 1.26-1.66), the year after BP was 1.30 (95% CI 1.14-1.50), 2-3 years after BP was 1.26 (95% CI 1.13-1.39), 4-8 years after BP was 1.17 (95% CI 1.08-1.26) and 9+ years since BP was 1.24 (95% CI 1.17-1.32)., Conclusions: We found both a short-term elevated risk of first time MI following BP and a weaker long-term elevated risk, in both men and women.

Rationale: Use of antidepressants during pregnancy has been associated with an increased rate of children small for gestational age (SGA), but it is unclear whether this is due to an effect of the underlying depressive disorder., Objectives: This study aimed to investigate the effect of antidepressants on SGA in a nationwide sample and to separate the effect of exposure to antidepressants in utero from the effect of maternal depression., Methods: A register study was conducted on all pregnant women in Denmark from 1996 to 2006 linking nationwide individualized data from the Medical Birth Register, the Psychiatric Central Register, and a prescription database. The rate of SGA (birth weight below the 10 percentile at given gestational week) was investigated for children exposed in utero to antidepressants or to a maternal psychiatric diagnosis of depression compared to children not prenatally exposed to antidepressants or maternal diagnosis., Results: A total of 673,853 pregnancies were included in the study of which 35.737 women had a diagnosis of depression and/or used antidepressants before end of pregnancy. Antidepressant use during pregnancy was weakly associated with SGA (hazard ratios (HR) = 1.19; 95 % confidence interval (CI), 1.11-1.28), whereas a psychiatric diagnosis before or during pregnancy was not (HR = 1.02; 95 % CI, 0.92-1.13). The association for use during pregnancy was found for selective serotonin reuptake inhibitors and newer antidepressants, but not for older antidepressants., Conclusions: The use of antidepressants during pregnancy slightly increases the rate of SGA. The association seems unrelated to the underlying maternal depressive disorder.

Objective: The aim of the present study was to examine the association between occupational lifting and the risk of fetal death according to gestational age., Methods: We used data from the Danish National Birth Cohort (1996-2002). Among 71,500 occupationally active women, 2886 experienced a fetal death. Information on lifting and relevant covariates was collected in interviews around week 16 of pregnancy. The majority of fetal losses (N=2032) happened before the scheduled interview, and exposure data were collected retrospectively from these women. We analyzed early miscarriage (≤12 weeks), late miscarriage (13-21 weeks), and stillbirth (≥22 weeks), using Cox-regression models with gestational age as the underlying time variable., Results: The adjusted early miscarriage risk increased with frequency of daily lifts and total burden lifted per day. For example, the hazard ratio was 1.38 [95% confidence interval (95% CI) 1.10-1.74] for a total weight load per day of 101-200 kg and 2.02 (95% CI 1.23-3.33) for a daily load >1000 kg as compared to non-lifters (P for trend <0.0001). Late miscarriage was associated with total daily weight load (P for trend=0.0073) but not with number of lifts per day. There was no association between occupational lifting and stillbirth., Conclusions: In the present study, the risk of miscarriage increased with the number of lifts and total burden lifted per day at work. There may be a case for advising pregnant women against heavy lifting in particular during early pregnancy.

Background: Assortative mating has been demonstrated in mental disorders but the extent of cohabitation between patients with clinically diagnosed psychiatric disease has been poorly explored. Method We conducted a register-based study of all Danes between 18 and 70 years of age in a 13-year observational period, linking data on individuals' contacts with psychiatric services with data on individuals' cohabitation status. Two different Poisson regression analyses were performed: the first comparing the rates of commencing cohabitation with a psychiatric patient between individuals, depending on whether the individuals themselves had, or did not have, a psychiatric diagnosis; the second comparing the incidence rates of psychiatric diagnoses for individuals cohabitating with psychiatric patients with the similar rates for individuals living with unaffected cohabitants., Results: In total, 159 929 (5.0%) out of 3 204 633 individuals were given a psychiatric diagnosis during the study period. Diagnosed individuals had an overall rate ratio (RR) of commencing cohabitation with a psychiatric patient of 1.95 [95% confidence interval (CI) 1.90-2.00] for women and 1.65 (95% CI 1.61-1.69) for men, when compared with unaffected individuals. The overall RR of receiving a psychiatric diagnosis while cohabitating with a psychiatric patient was 2.40 (95% CI 2.31-2.49) for women and 2.91 (95% CI 2.81-3.01) for men, when compared with those cohabitating with unaffected individuals. Individuals with schizophrenia and men with bipolar disorder had the highest RR of commencing cohabitation with a cohabitant with a similar diagnosis., Conclusions: Cohabitation among individuals with severe psychiatric disorders is increased. This has implications for research and for the clinical management of patients.

Aims: Family history is an established risk factor for myocardial infarction (MI), but it is not clear how this risk changes with number and gender of first-degree relatives with MI. We used the entire Danish population to examine the importance of MI in siblings and parents., Methods and Results: This study is a retrospective nationwide register-based cohort study including registered relatives to all Danish citizens diagnosed with MI in the period 1978-2010. In the entire Danish population we identified siblings to 7552 patients with a first-time MI. The rate ratios (RR) calculated by Poisson models showed an RR of 4.30 (95% confidence interval 3.53-5.23) for siblings of a patient with MI. Children of parents with MI also showed high risk: for children of a maternal case RR 2.40 (2.20-2.60), and of a paternal case RR 1.98 (1.98-2.09), respectively; P value for gender interaction <0.0001. A paternal case with MI at an age <50 years was associated with an RR of 3.30 (2.92-3.72) while a case >50 years was associated with a risk of 1.83 (1.73-1.93). For maternal cases below and above 50 years of age the risks were 3.23 (2.56-4.10) and 2.31 (2.11-2.52), respectively., Conclusion: First-degree relatives of a patient with myocardial infarction themselves have a substantial higher risk of myocardial infarction. The risk is particularly elevated when the MI case is the mother or a sibling, and when the MI case has the infarction before the age of 50 years.

Purpose: To investigate whether normal tension glaucoma (NTG) is associated with increased risk of developing dementia/Alzheimer disease (AD)., Methods: A total of 69 patients with NTG were identified in the case note files in the Glaucoma Clinic, University Hospital of Copenhagen (Rigshospitalet), Denmark from 1980 to 2001. The rate of a subsequent diagnosis of dementia as recorded in nationwide health care registers from 1980 to 2005 was estimated and compared with the rate for the general population [standard mortality rate (SMR) = observed number of cases of dementia/expected number of cases of dementia]., Results: The 69 patients had a median age of 64 years (quartiles 57 and 73) at the time of the diagnosis, and the average follow-up period was 12.7 years. The SMR(dementia) was 0.20 (95% CI 0.01-1.11). No patient developed AD., Conclusion: Normal tension glaucoma was not associated with an increased risk of developing dementia/AD., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

The mechanisms behind social differences in mortality rates have been debated. The authors examined the extent to which shared family background and health in early life could explain the association between educational status and all-cause mortality rates using a sibling design. The study was register-based and included all individuals born in Denmark between 1950 and 1979 who had at least 1 full sibling born in the same time period (n = 1,381,436). All individuals were followed from 28 years of age until death, emigration, or December 2009. The authors used Cox regression analyses to estimate hazard ratios for mortality according to educational level. Conventional cohort and intersibling analyses were carried out and conducted separately for deaths occurring before and after the age of 45 years, respectively. The cohort analyses showed an inverse association between educational status and all-cause mortality that was strongest for males, increased with younger birth cohorts, and tended to be strongest in the analyses of death before 45 years of age. The associations were attenuated slightly in the intersibling analyses and after adjustment for serious health conditions in early life. Hence, health selection and confounding by factors shared by siblings explained only a minor part of the association between educational level and all-cause mortality.

Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out-of-hospital cardiac arrest (OHCA) were identified (2001-2007). Association between treatment with specific antidepressants and OHCA was examined by conditional logistic regression in case-time-control models. We identified 19,110 patients with an OHCA; 2,913 (15.2%) were receiving antidepressant treatment at the time of OHCA, with citalopram being the most frequently used type of antidepressant (50.8%). Tricyclic antidepressants (TCAs; odds ratio (OR) = 1.69, confidence interval (CI): 1.14-2.50) and selective serotonin reuptake inhibitors (SSRIs; OR = 1.21, CI: 1.00-1.47) were both associated with comparable increases in risk of OHCA, whereas no association was found for serotonin-norepinephrine reuptake inhibitors/noradrenergic and specific serotonergic antidepressants (SNRIs/NaSSAs; OR = 1.06, CI: 0.81-1.39). The increased risks were primarily driven by: citalopram (OR = 1.29, CI: 1.02-1.63) and nortriptyline (OR = 5.14, CI: 2.17-12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs.

Background: Patients with alcoholic cirrhosis are at higher risk for hepatocellular carcinoma (HCC). The role of HCC surveillance for these patients is undefined., Objective: To provide population-based estimates of HCC incidence and comparisons of HCC-related mortality and total mortality among patients with alcoholic cirrhosis as a basis for assessing the role of HCC surveillance., Design: Nationwide, registry-based, historical cohort study., Setting: Denmark., Patients: All Danish citizens with a first-time hospital diagnosis of alcoholic cirrhosis from 1993 to 2005., Measurements: Hepatocellular carcinoma incidence and mortality starting 1 year after diagnosis of alcoholic cirrhosis through 2009; ratio of HCC-related mortality to total mortality., Results: Among 8482 patients, 169 developed HCC. A total of 5734 patients died, 151 of whom had developed HCC. Five-year cumulative HCC risk was 1.0% (95% CI, 0.8% to 1.3%), and 5-year cumulative mortality was 43.7% (CI, 42.6% to 44.7%). Only 1.8% of all deaths were HCC-related. In sensitivity analyses that included all possible HCC diagnoses and a subpopulation of patients who were followed by hepatologists, the highest 5-year HCC risk was 1.9% (CI, 0.8% to 3.9%). These patients did not have higher mortality than patients in the nationwide cohort., Limitation: Cirrhosis and HCC diagnoses were made by hospital physicians without uniform clinical criteria, and use of registry data precluded detailed information on clinical care of patients, including HCC surveillance., Conclusion: Danish patients with alcoholic cirrhosis have a low risk for HCC, and HCC contributes little to their high mortality. On the basis of these data, HCC surveillance would be expected to have a minimal effect on mortality and is unlikely to be cost-effective.

Background: Controversies still exist regarding the existence of a 'safe' level of alcohol intake during pregnancy. The aim of this study was to assess the risk of fetal death (spontaneous abortion and stillbirth) according to maternal alcohol consumption in a large Danish pregnancy cohort., Methods: A cohort study carried out within the framework of the Danish National Birth Cohort. A total of the 92 719 participants enrolled in the Danish National Birth Cohort who provided information about lifestyle during first trimester of pregnancy were included in the study. Information about average weekly consumption of alcohol during pregnancy, smoking, coffee drinking, occupational status and reproductive history were obtained by means of computer-assisted telephone interviews. Pregnancy outcomes (spontaneous abortion, stillbirth, live birth and other pregnancy outcome) and gestational age at end of pregnancy were obtained through register linkage with the Civil Registration System and the National Discharge Registry. Data were analysed using Cox regression models, taking the varying gestational age at recruitment and time-dependent co-variables into account., Results: Fifty-five per cent of the participants abstained from alcohol drinking during pregnancy and only 2.2% reported four or more drinks per week. The adjusted hazard ratios for fetal death in first trimester were 1.66 [95% confidence interval (CI) 1.43-1.92] and 2.82 (95% CI 2.27-3.49) for women who reported 2-3½; drinks per week and 4 or more drinks per week, respectively, and 1.57 (95% CI 1.30-1.90) and 1.73 (95% CI 1.24-2.41) for fetal death during pregnancy weeks 13-16. No increased risk was found for fetal death after 16 weeks of pregnancy., Conclusions: Even low amounts of alcohol consumption during early pregnancy increased the risk of spontaneous abortion substantially. The results indicate that the fetus is particularly susceptible to alcohol exposure early in pregnancy.

Physical activity is recommended during pregnancy, although strong evidence on reproductive health is lacking. We present exercise habits and predictors of exercise during pregnancy. From the Danish National Birth Cohort (1996-2002), 88,200 singleton pregnancies were analyzed in logistic regression. About one-third of the women exercised in early/mid pregnancy and slightly less in late pregnancy. Bicycling, swimming, and low-impact activities were most common. Exercising more than three times per week was strongly correlated with older age, being a student or out of work, eating disorders, moderate alcohol consumption, and a healthy diet. Multiparity, a normal or less good self-rated health, smoking, and a less health conscious diet were the strongest predictors of not doing exercise. Women of 25 years or older, with metabolic or psychiatric disorders, or who had received subfecundity treatment were more likely to increase their activity level substantially from early to late pregnancy than comparison groups. In conclusion, exercising during pregnancy correlated with a number of maternal characteristics. The findings may be used to identify pregnant women not likely to exercise, to target activities that may fit their needs, and, for research purposes, to identify adjustment variables or guide sensitivity analyses when data on confounders are lacking., (© 2010 John Wiley & Sons A/S.)