In utero exposure to ADHD medication and long-term offspring outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Inpatient admissions and mortality of anorexia nervosa patients according to their preceding psychiatric and somatic diagnoses.

OBJECTIVE: Anorexia nervosa (AN) is associated with increased risk of mortality, but little is known about the risk of inpatient admissions and mortality outcomes in individuals with diagnoses of both AN and other psychiatric and somatic conditions. We aimed to investigate the inpatient admissions and mortality among people with AN and other diagnosed conditions using Danish national registers. METHOD: This retrospective cohort study included individuals diagnosed with AN in Denmark, born 1977-2010. We identified other mental and somatic conditions in this population. We used Cox proportional hazards regression to estimate the risk of inpatient admission and mortality, focusing on (i) the number of other diagnosed conditions, and (ii) specific combinations of conditions diagnosed prior to the AN diagnosis. Categories of inpatient admissions considered were due to: (i) AN, (ii) any psychiatric disorder, and (iii) any somatic disorder. Additionally, competing risks survival analysis was used to calculate the cumulative incidence of inpatient admission and all-cause mortality over the follow-up period. RESULTS: The study population included 11,489 individuals. The most common conditions individuals had prior to their AN diagnosis were other eating disorders (34.5%) and anxiety disorders (32.7%). During the follow-up, 3184 (27.7%), 4604 (40.1%), and 6636 (57.8%) individuals were admitted for AN, any psychiatric disorder, and any somatic disorder, respectively; and in total 106 (0.9%) died. The risk of all outcomes was highest among those who had received a higher number of other diagnoses. For most combinations, the risks of admission and mortality were increased. DISCUSSION: Our study presents the prevalence of other conditions in patients with AN in Denmark and elucidates their association with higher rates of inpatient admission and mortality. Our findings highlight the need for comprehensive, multidisciplinary care of patients with AN considering the spectrum of other diagnosed conditions to improve health outcomes.

Association between Mental Disorders and Subsequent Medical Conditions.

BACKGROUND: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions. METHODS: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses. RESULTS: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder. CONCLUSIONS: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

New global indicator for workers' health: mortality rate from diseases attributable to selected occupational risk factors.

Through sustainable development goals 3 and 8 and other policies, countries have committed to protect and promote workers' health by reducing the work-related burden of disease. To monitor progress on these commitments, indicators that capture the work-related burden of disease should be available for monitoring workers' health and sustainable development. The World Health Organization and the International Labour Organization estimate that only 363 283 (19%) of 1 879 890 work-related deaths globally in 2016 were due to injuries, whereas 1 516 607 (81%) deaths were due to diseases. Most monitoring systems focusing on workers' health or sustainable development, such as the global indicator framework for the sustainable development goals, include an indicator on the burden of occupational injuries. Few such systems, however, have an indicator on the burden of work-related diseases. To address this gap, we present a new global indicator: mortality rate from diseases attributable to selected occupational risk factors, by disease, risk factor, sex and age group. We outline the policy rationale of the indicator, describe its data sources and methods of calculation, and report and analyse the official indicator for 183 countries. We also provide examples of the use of the indicator in national workers' health monitoring systems and highlight the indicator's strengths and limitations. We conclude that integrating the new indicator into monitoring systems will provide more comprehensive and accurate surveillance of workers' health, and allow harmonization across global, regional and national monitoring systems. Inequalities in workers' health can be analysed and the evidence base can be improved towards more effective policy and systems on workers' health.

Par le biais des objectifs de développement durable 3 et 8 ainsi que d'autres mesures, plusieurs pays se sont engagés à protéger et promouvoir la santé des travailleurs en réduisant l'impact des maladies liées au travail. Mais pour évaluer leurs progrès en la matière, il convient de mettre en place des indicateurs estimant l'impact des maladies liées au travail afin de placer le développement durable et la santé des travailleurs sous surveillance. D'après l'Organisation mondiale de la Santé et l'Organisation internationale du Travail, seulement 363 283 (19%) des 1 879 890 décès liés au travail dans le monde en 2016 découlaient de blessures, tandis que 1 516 607 (81%) d'entre eux étaient causés par des maladies. La plupart des systèmes de surveillance qui s'intéressent à la santé des travailleurs ou au développement durable, comme le cadre mondial d'indicateurs pour les objectifs de développement durable, comportent un indicateur relatif à l'impact des accidents de travail. Cependant, rares sont ceux qui possèdent un indicateur concernant l'impact des maladies professionnelles. Pour combler cette lacune, nous dévoilons un nouvel indicateur mondial: le taux de mortalité dû aux maladies attribuables à certains facteurs de risque professionnels classé par maladie, facteur de risque, sexe et catégorie d'âge. Nous exposons le motif politique de l'indicateur, décrivons l'origine des données et les méthodes de calcul, et communiquons et analysons l'indicateur officiel pour 183 pays. Nous fournissons également des exemples de la façon dont l'indicateur peut être utilisé dans des systèmes nationaux de surveillance de la santé des travailleurs et soulignons ses forces et faiblesses. Nous concluons en affirmant que l'intégration de ce nouvel indicateur dans les systèmes de surveillance offrira un suivi plus complet et précis de la santé des travailleurs et ouvrira la voie à une harmonisation des systèmes mondiaux, nationaux et régionaux. Il est possible d'analyser les inégalités en matière de santé des travailleurs et d'en améliorer les bases factuelles afin d'établir des politiques et systèmes plus efficaces dans ce domaine.

A través de los objetivos de desarrollo sostenible 3 y 8 y de otras políticas, los países se han comprometido a proteger y promover la salud de los trabajadores reduciendo la carga de morbilidad relacionada con el trabajo. Para supervisar los avances en el cumplimiento de estos compromisos, debería disponerse de indicadores que reflejen la carga de morbilidad relacionada con el trabajo, a fin de controlar la salud de los trabajadores y el desarrollo sostenible. La Organización Mundial de la Salud y la Organización Internacional del Trabajo estiman que solo 363 283 (19%) de las 1 879 890 muertes relacionadas con el trabajo a nivel mundial en 2016 se debieron a lesiones, mientras que 1 516 607 (81%) muertes se debieron a enfermedades. La mayoría de los sistemas de vigilancia centrados en la salud de los trabajadores o el desarrollo sostenible, como el marco de indicadores mundiales para los objetivos de desarrollo sostenible, incluyen un indicador sobre la carga de las lesiones laborales. No obstante, pocos de estos sistemas cuentan con un indicador sobre la carga de las enfermedades relacionadas con el trabajo. Para subsanar esta carencia, presentamos un nuevo indicador mundial: la tasa de mortalidad por enfermedades atribuibles a factores de riesgo laborales seleccionados, por enfermedad, factor de riesgo, sexo y grupo de edad. Describimos la justificación política del indicador, describimos sus fuentes de datos y métodos de cálculo, e informamos y analizamos el indicador oficial para 183 países. También proporcionamos ejemplos del uso del indicador en los sistemas nacionales de vigilancia de la salud de los trabajadores y destacamos las ventajas y las limitaciones del indicador. Concluimos que la integración del nuevo indicador en los sistemas de vigilancia proporcionará una vigilancia más exhaustiva y precisa de la salud de los trabajadores, y permitirá la armonización entre los sistemas de vigilancia mundiales, regionales y nacionales. Se podrán analizar las desigualdades en la salud de los trabajadores y se podrá mejorar la base de evidencias para lograr políticas y sistemas más eficaces en materia de salud de los trabajadores.

Agreement between survey- and register-based measures of depression in Denmark.

BACKGROUND: Register-based studies of major depressive disorder (MDD) do not capture all prevalent cases, as untreated cases and diagnoses made by general practitioners are not recorded in the registers. We examined the prevalence and agreement of survey- and register-based measures of depression, and explored sociodemographic and health-related factors that may have influenced this agreement. METHODS: All 32,407 participants in the 2017 Central Denmark Region How are you? survey were linked to hospital and prescription records. A checklist for depressive symptoms within the last 14 days (Major Depression Inventory; MDI) from the survey was compared with register-based assessment of hospital-diagnosed MDD and/or prescriptions for antidepressants. We estimated agreement between survey-based and register-based measures for depression and used logistic regression models to explore selected associated factors. RESULTS: In total, 5.9% of How are you? survey participants screened positive for current depression on the MDI. Of these, 51.3% (95% confidence interval (CI): 49.0-53.6) filled a prescription for an antidepressant medication during the 10 years prior or 2 years following the administration of the survey, and 14.5% (95% CI: 12.9-16.2) were treated for MDD in a psychiatric hospital-based setting. When using a higher threshold of the MDI indicating more severe current depression, 22.8% (95% CI: 19.6-26.1) of those who screened positive also received an MDD diagnosis and 63.4% (95% CI: 59.7-67.2) were prescribed antidepressants during this 12-year period. Among those with current depression, female sex, older age, chronic diseases, hospital-treated self-harm, and being permanently outside the workforce were associated with having a register-based MDD diagnosis or antidepressant prescription. Among those with a register-based depression record, female sex, younger age, hospital-treated self-harm, stress, and severe loneliness were associated with current depression. CONCLUSION: We found that as few as 15% of individuals with current depression in the general Danish population were captured by the psychiatric hospital register, while 51% of these individuals were identifiable in the prescription register. These findings demonstrate that register-based measures significantly underestimate the true prevalence of depression by identifying only the cases that are most severe.

The health care cost of comorbidity in individuals with mental disorders: A Danish register-based study.

AIM: The aim of the study was to estimate the annual health care cost by number of comorbid mental and somatic disorders in persons with a mental disorder. METHODS: All persons living in Denmark between 2004 and 2017 with a hospital diagnosis of a mental disorder were identified. We investigated the cost of different health care services: psychiatric hospitals, somatic hospitals, primary health care (e.g. general practitioners, psychologists and so on) and subsidised prescriptions. Within those with at least one mental disorder, we examined the costs for people with (a) counts of different types of mental disorders (e.g. exactly 1, exactly 2 and so on up to 8 or more) and (b) counts of different types of somatic disorders (e.g. no somatic disorders, exactly 1, exactly 2 and so on up to 15 or more). The estimates are reported in average cost per case and nationwide annual cost in Euro 2017. RESULTS: In total, 447,209 persons (238,659 females and 208,550 males) were diagnosed with at least one mental disorder in the study period. The average annual health care cost per case and nationwide cost was 4471 Euros and 786 million Euro, respectively, for persons with exactly one mental disorder, and 33,273 Euro and 3.6 million Euro for persons with eight or more mental disorders. The annual health care cost was 4613 Euro per case and 386 million Euro for persons without any somatic disorders, while the cost per case was 16,344 Euro and 0.7 million Euro in nationwide cost for persons with 15 or more disorders. The amount and proportion of the different health care costs varied by type of comorbidity and count of disorders. CONCLUSIONS: The annual health care cost per case was higher with increasing number of comorbid mental and somatic disorders, while the nationwide annual health care cost was lower with increasing number of comorbid disorders for persons with a mental disorder in Denmark.

Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency in Denmark: A population-based propensity score-matched cohort study.

BACKGROUND: Women prescribed antidepressants face the dilemma of whether or not to continue their treatment during pregnancy. Currently, limited evidence is available on the efficacy of continuing versus discontinuing antidepressant treatment during pregnancy to aid their decision. We aimed to estimate whether antidepressant discontinuation before or during pregnancy was associated with an increased risk of psychiatric emergency (ascertained by psychiatric admission or emergency room visit), a proxy measure of severe exacerbation of symptoms/mental health crisis. METHODS AND FINDINGS: We carried out a propensity score-matched cohort study of women who gave birth to live-born singletons between January 1, 1997 and June 30, 2016 in Denmark and who redeemed an antidepressant prescription in the 90 days before the pregnancy, identified by Anatomical Therapeutic Chemical (ATC) code N06A. We constructed 2 matched cohorts, matching each woman who discontinued antidepressants before pregnancy (N = 2,669) or during pregnancy (N = 5,467) to one who continued antidepressants based on propensity scores. Maternal characteristics and variables related to disease severity were used to generate the propensity scores in logistic regression models. We estimated hazard ratios (HRs) of psychiatric emergency in the perinatal period (pregnancy and 6 months postpartum) using stratified Cox regression. Psychiatric emergencies were observed in 76 women who discontinued antidepressants before pregnancy and 91 women who continued. There was no evidence of higher risk of psychiatric emergency among women who discontinued antidepressants before pregnancy (cumulative incidence: 2.9%, 95% confidence interval [CI]: 2.3% to 3.6% for discontinuation versus 3.4%, 95% CI: 2.8% to 4.2% for continuation; HR = 0.84, 95% CI: 0.61 to 1.16, p = 0.298). Overall, 202 women who discontinued antidepressants during pregnancy and 156 who continued had psychiatric emergencies (cumulative incidence: 5.0%, 95% CI: 4.2% to 5.9% versus 3.7%, 95% CI: 3.1% to 4.5%). Antidepressant discontinuation during pregnancy was associated with increased risk of psychiatric emergency (HR = 1.25, 95% CI: 1.00 to 1.55, p = 0.048). Study limitations include lack of information on indications for antidepressant treatment and reasons for discontinuing antidepressants. CONCLUSIONS: In this study, we found that discontinuing antidepressant medication during pregnancy (but not before) is associated with an apparent increased risk of psychiatric emergency compared to continuing treatment throughout pregnancy.

Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study.

BACKGROUND: The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results. METHODS AND FINDINGS: In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality. CONCLUSIONS: In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.

Antidepressant use during pregnancy and risk of adverse neonatal outcomes: A comprehensive investigation of previously identified associations.

OBJECTIVE: Prenatal antidepressant use is widespread. Observational studies have investigated the neonatal effects of prenatal antidepressant exposure with inconclusive results. We aimed to comprehensively investigate the associations between prenatal antidepressant exposure and the most commonly studied adverse neonatal outcomes: preterm birth, birthweight, poor neonatal adaptation, persistent pulmonary hypertension of the neonate (PPHN), neonatal admission and congenital malformations. METHODS: We included 45,590 singletons (born 1997-2015) whose mothers used antidepressants within one year before pregnancy. Children were categorised into two groups: continuation (antidepressant use before and during pregnancy) or discontinuation (antidepressant use before but not during pregnancy). We applied random-effects logistic and linear regressions, adjusting for covariates. RESULTS: After adjusting for confounders, prenatal antidepressant exposure was associated with a 2.3 day (95% CI -2.9; -2.0) decrease in gestational age and a 51 g (95% CI -62g; -41 g) decrease in birthweight. The continuation group was at increased risk for moderate-to-late preterm birth (32-37 weeks) (aOR = 1.43; 95%CI 1.33; 1.55), moderately low birthweight (1500-2499 g) (aOR = 1.28; 95%CI 1.17; 1.41), postnatal adaptation syndrome (aOR = 2.59; 95%CI 1.87; 3.59) and neonatal admission (aOR = 1.52; 95%CI 1.44; 1.60) compared to the discontinuation group. CONCLUSION: Prenatal antidepressant exposure was associated with small decreases in gestational age and birthweight, as well as higher risk for moderate-to-late preterm birth, moderately low birthweight, neonatal admission and postnatal adaptation syndrome. No differences in risk were found for PPHN, or congenital malformations. The causality of the observed associations cannot be established due to the potential for unmeasured residual confounding linked to the underlying disease.

Temporal changes in sex- and age-specific incidence profiles of mental disorders-A nationwide study from 1970 to 2016.

OBJECTIVE: Information on mental disorders over time is critical for documenting changes in population burden, and aiding understanding of potential causal and non-causal factors. The aim of this study was to provide temporal changes in the sex- and age-specific incidence rates (IR) of mental disorders diagnosed in Danish hospitals during five decades and investigate whether such changes may be attributable to changes in administrative reporting practice. METHODS: This population-based cohort study included all people living in Denmark between 1970 and 2016. Mental disorders diagnoses were obtained from the Danish Psychiatric Central Research Register. We estimated the IR of each mental disorder (all persons, and sex- and age-specific IRs) and examined the impact of two administrative changes. RESULTS: Our study included 9 107 157 people, followed for 233.0 million person-years. During follow-up, 9.5% were diagnosed with at least one mental disorder. The IR for any mental disorder was 39.0 per 10,000 person-years. Despite fluctuations, this increased between 1970-84 and 2005-2016, from 28.9 to 63.0 per 10,000 person-years. Increases were most pronounced for younger age groups. Administrative changes did appear to influence incidence rates. CONCLUSION: Mental disorder IRs have increased in Denmark since 1970, with age of diagnosis shifting downwards. Both trends were likely impacted by administrative changes, while the latter is likely to be (partly) attributable to earlier detection and increased reporting of child-onset conditions. Our findings may provide valuable context of the epidemiology of mental disorders across age groups for comparison with other studies and populations.

Towards a framework for systematic reviews of the prevalence of exposure to environmental and occupational risk factors.

Exposure prevalence studies (as here defined) record the prevalence of exposure to environmental and occupational risk factors to human health. Applying systematic review methods to the synthesis of these studies would improve the rigour and transparency of normative products produced based on this evidence (e.g., exposure prevalence estimates). However, a dedicated framework, including standard methods and tools, for systematically reviewing exposure prevalence studies has yet to be created. We describe the need for this framework and progress made towards it through a series of such systematic reviews that the World Health Organization and the International Labour Organization conducted for their WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury (WHO/ILO Joint Estimates).We explain that existing systematic review frameworks for environmental and occupational health cannot be directly applied for the generation of exposure prevalence estimates because they seek to synthesise different types of evidence (e.g., intervention or exposure effects on health) for different purposes (e.g., identify intervention effectiveness or exposure toxicity or carcinogenicity). Concepts unique to exposure prevalence studies (e.g., "expected heterogeneity": the real, non-spurious variability in exposure prevalence due to exposure changes over space and/or time) also require new assessment methods. A framework for systematic reviews of prevalence of environmental and occupational exposures requires adaptation of existing methods (e.g., a standard protocol) and development of new tools or approaches (e.g., for assessing risk of bias and certainty of a body of evidence, including exploration of expected heterogeneity).As part of the series of systematic reviews for the WHO/ILO Joint Estimates, the World Health Organization collaborating with partners has created a preliminary framework for systematic reviews of prevalence studies of exposures to occupational risk factors. This included development of protocol templates, data extraction templates, a risk of bias assessment tool, and an approach for assessing certainty of evidence in these studies. Further attention and efforts are warranted from scientific and policy communities, especially exposure scientists and policy makers, to establish a standard framework for comprehensive and transparent systematic reviews of studies estimating prevalence of exposure to environmental and occupational risk factors, to improve estimates, risk assessments and guidelines.

Comorbidity between eating disorders and psychiatric disorders.

OBJECTIVE: Previous literature has established an increased risk of eating disorders among individuals with other psychiatric disorders and vice versa. However, often studies have focused on eating disorders as a single diagnostic entity and/or investigated selected psychiatric comorbidities. We conducted a comprehensive study, exploring bidirectional associations between different types of eating disorders and broad groups of all other psychiatric disorders, to identify patterns of comorbidity. METHOD: We included all people born in Denmark 1963-2010. We collected information on eating disorders and considered the risk of subsequent psychiatric disorders using Cox-proportional hazards regression. Absolute risks were calculated using competing risks survival analyses. We also considered prior psychiatric disorders and subsequent eating disorders. RESULTS: An increased risk was seen for almost all disorder pairs of diagnoses evaluated. Following an anorexia nervosa (AN) diagnosis, the median hazard ratio for the different subsequent psychiatric disorders was 3.80 (range 2.48-6.15); following an other eating disorder (OED) diagnosis, it was 3.16 (range 2.05-5.14). After different psychiatric disorder diagnoses, the median hazard ratio was 2.66 for later AN (range 1.21-5.31), and 2.51 for later OED (range 1.25-4.10). Absolute risk of eating disorders was also higher among those with other psychiatric disorders than those without. DISCUSSION: In this broad examination, we identified bidirectional increases in risk of comorbidity for those with both eating disorder diagnoses and psychiatric disorder diagnoses. Although our findings indicate different patterns of comorbidity between eating disorders, these variations were generally small.

Maternal antibiotic use during pregnancy and asthma in children: population-based cohort study and sibling design.

Antibiotic use during pregnancy may affect asthma risk in offspring. However, epidemiological studies yielded conflicting findings, with an observed association possibly confounded by shared familial factors. We sought to assess the association between maternal antibiotic use during pregnancy and childhood asthma in the offspring, by accounting for time-stable familial factors.We conducted a population-based cohort study and sibling study using data from Danish nationwide registers, which comprised 407 804 liveborn singletons from 2005 to 2011. Antibiotic use during pregnancy was defined as at least one antibiotic prescription filled by the mother from 1 month prior to pregnancy up until delivery, identified in the National Prescription Registry. First-time asthma in the offspring was determined by hospital treatment or asthma medication treatment after age 5 years. We estimated hazard ratios (HRs) of asthma using Cox regression in the population-based cohort and stratified Cox regression in the sibling cohort.Approximately 36.5% of pregnant women redeemed antibiotic prescriptions. Antibiotic use during pregnancy was associated with childhood asthma in cohort analyses (HR 1.21, 95% CI 1.18-1.24), but not in sibling analyses (HR 0.96, 95% CI 0.90-1.03). In the population-based analyses, higher risks of asthma were seen with longer duration of maternal antibiotic use, a higher number of prescriptions and prescriptions of multiple types of antibiotics. All these associations disappeared in the sibling analyses.The associations observed by previous studies for prenatal exposure to antibiotics and offspring asthma risk are likely to be due to confounding factors shared within families.

Comorbidity between types of eating disorder and general medical conditions.

BACKGROUND: Comorbidity with general medical conditions is common in individuals with eating disorders. Many previous studies do not evaluate types of eating disorder. AIMS: To provide relative and absolute risks of bidirectional associations between (a) anorexia nervosa, bulimia nervosa and eating disorders not otherwise specified and (b) 12 general medical conditions. METHOD: We included all people born in Denmark between 1977 and 2010. We collected information on eating disorders and considered the risk of subsequent medical conditions, using Cox proportional hazards regression. Absolute risks were calculated using competing risks survival analyses. We also considered risks for prior medical conditions and subsequent eating disorders. RESULTS: An increased risk was seen for almost all disorder pairs (69 of 70). Hazard ratios for those with a prior eating disorder receiving a subsequent diagnosis of a medical condition ranged from 0.94 (95% CI 0.57-1.55) to 2.05 (95% CI 1.86-2.27). For those with a prior medical condition, hazard ratios for later eating disorders ranged from 1.35 (95% CI 1.26-1.45) to 1.98 (95% CI 1.71-2.28). Absolute risks for most later disorders were increased for persons with prior disorders, compared with reference groups. CONCLUSIONS: This is the largest and most detailed examination of eating disorder-medical condition comorbidity. The findings indicate that medical condition comorbidity is increased among those with eating disorders and vice versa. Although there was some variation in comorbidity observed across eating disorder types, magnitudes of relative risks did not differ greatly.

A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study.

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.

Parental asthma occurrence, exacerbations and risk of attention-deficit/hyperactivity disorder.

OBJECTIVE: To investigate whether intrauterine exposure to maternal asthma or asthma exacerbations increases the risk of attention-deficit/hyperactivity disorder (ADHD). METHODS: Using Danish register data, this cohort study comprised of 961,202 live singletons born in Denmark during 1997-2012. Children were followed to a maximum of 20.0 years from birth until the first of ADHD-diagnosis/prescription, emigration, death, or 31 December 2016. Cox regression models were used to evaluate the association between maternal or paternal asthma, asthma exacerbations and offspring ADHD. RESULTS: During 11.4 million person-years of follow-up, 27,780 (2.9%) children were identified as having ADHD. ADHD risk was increased among offspring born to asthmatic mothers (hazard ratio (HR) 1.41, 95% CI: 1.36-1.46) or asthmatic fathers (HR 1.13, 95% CI: 1.08-1.18). Antenatal antiasthma medication treatment did not increase offspring ADHD. However, higher risks were observed among offspring of mothers with asthma exacerbations compared with children of asthmatic mothers with no exacerbations: HR 1.12 (95% CI: 1.00-1.25) for pre-pregnancy exacerbations; 1.21 (95% CI: 1.00-1.47) for exacerbations during pregnancy; and 1.25 (95% CI: 1.08-1.44) for exacerbations after delivery. CONCLUSIONS: These results support theories regarding shared genetic and environmental risk factors having a role in the development of ADHD.

Mental and behavioural disorders in the children of mothers diagnosed with cancer: A Danish population-based register study.

OBJECTIVE: Maternal cancer may be associated with offspring mental and behavioural disorders through various biological pathways. When postnatally diagnosed, it may cause stress and changes in care, potentially influencing mental health. Prenatally diagnosed cancer could lead to maternal stress and treatment, or influence foetal neural development. This study investigates associations between prenatally or postnatally diagnosed maternal cancers and mental and behavioural disorders in children. METHODS: The study composed of 2 158 430 children born in Denmark (1978-2012). Children were exposed if their mother received a cancer diagnosis prenatally (2 years prepartum, until birth) or postnatally (birth, until 18 years postpartum). Further analyses considered cancer types and diagnostic delays. Children were followed until 18 years of age or the first of the following: diagnosis of a mental or behavioural disorder, emigration, death, end of follow-up. RESULTS: During follow-up 79 682 (3.7%) children were diagnosed with mental or behavioural disorders. There was an increased risk among offspring exposed to postnatally diagnosed cancers (HR 1.05; 95% CI, 1.00-1.11); for prenatally diagnosed cancers HR was 1.07 (0.87-1.31). The strongest associations for disorder types were for prenatal diagnoses with mood/affective disorders (HR 2.45; 1.02-5.89) and postnatal diagnoses with mood/affective disorders (HR 1.43; 1.14-1.79). CONCLUSIONS: The results indicate a link between maternal cancer occurrence during pregnancy or early postnatal life, and mental and behavioural disorders in offspring. This association could be driven by common factors in the two periods, such as psychological stress or genetic factors. No specific foetal programming was identified.

Antidepressant use during pregnancy and childhood cancer in the offspring.

PURPOSE: Antidepressant use during pregnancy has been increasing in recent years. We evaluated whether in utero exposure to antidepressants increased the risk of childhood cancer. METHODS: This population-based cohort study using national registers in Denmark comprised 915 128 liveborn singletons during 1998-2012. We categorised children into three mutually exclusive exposure groups according to maternal redemption of an antidepressant prescription from 2 years before pregnancy until delivery of the index child: Unexposed (N = 863 033), prior user (use before but not during pregnancy) (N = 30 607), and use during pregnancy (N = 21 488). The children were followed from birth until first diagnosis of cancer, death, emigration, or December 31, 2012, whichever came first. The children were followed maximum 14.9 years and contributed to 6.9 × 106 person-years at risk. We estimated hazard ratios (HRs) of cancer using Cox regression with 95% confidence intervals (CIs). RESULTS: In total, 1298 (0.1%) children were diagnosed with cancer. Antidepressant use during pregnancy was not associated with a significantly increased risk of childhood cancer in general; the HR was 1.03 (95% CI, 0.63-1.68), compared to children born by mothers who discontinued antidepressant use prior to pregnancy. The association between in utero exposure to antidepressants and childhood cancer did not depend on type or duration of antidepressant use. There was no strong evidence indicating a higher risk of leukaemia or nervous system tumours among children exposed to antidepressants in utero. CONCLUSION: Antidepressant use during pregnancy was not significantly associated with childhood cancer in general nor with leukaemia or nervous system tumours in specific.

Exposure to maternal smoking during pregnancy and risk of childhood cancer: a study using the Danish national registers.

PURPOSE: The relation between maternal smoking during pregnancy and childhood cancer in the offspring remains uncertain. This paper uses Danish national registers, which have collected data prospectively on smoking and cancer, to investigate the association. METHODS: Smoking during pregnancy was ascertained from maternal self-reported data in the Danish National Patient Register. Index children were followed up from birth until the first of the following events: cancer diagnosis, death, emigration, day before 15th birthday, or end of follow-up. Smoking during pregnancy was considered as a binary variable (no smoking in pregnancy and smoking in pregnancy) and by amounts smoked (no smoking, cessation during pregnancy, ≤5, 6-10, or ≥11 cigarettes/day). RESULTS: Of the 801,867 children included in the study, 20 % were exposed to maternal smoking during pregnancy. Overall, the hazard ratio (HR) for childhood cancer for the exposed compared to the non-exposed was 0.91 [95 % confidence interval (CI) 0.78, 1.07]. Stratification by number of cigarettes also gave statistically nonsignificant inverse associations. There was a statistically significant increased risk of childhood cancer among children whose mothers reported smoking cessation in pregnancy (HR 1.46; 95 % CI 1.01, 2.10). Regarding specific cancer sites, maternal smoking in pregnancy was positively associated with the risk of eye cancers in childhood. CONCLUSIONS: Our results do not provide evidence for an association between maternal smoking in pregnancy and childhood cancer overall. An increased risk of childhood cancer was seen for children whose mothers reported smoking cessation in pregnancy. Future research could employ biomarkers, such as cotinine, to validate maternal smoking status recorded in registers as, even if collected prospectively, this self-reported variable may be subject to reporting bias.