Trends in the Use of Medications for Secondary Ischemic Stroke Prevention in Denmark, 2005-2021.

BACKGROUND AND OBJECTIVES: Understanding trends in the use of medications for secondary stroke prevention is crucial for identifying areas for improvement in stroke care. We examined the use of lipid-lowering, antihypertensive, glucose-lowering, oral anticoagulant, and antiplatelet medications after ischemic stroke hospitalization, from 2005 to 2021. METHODS: Using nationwide registries in Denmark, we identified a cohort of patients discharged from hospital with a first-time or recurrent ischemic stroke (N = 150,744). Stratified by calendar year, we ascertained the 180-day probability of filling a prescription for the abovementioned medications after discharge. We further assessed factors associated with medication use. RESULTS: From 2005 to 2021, lipid-lowering medication use increased from 58.3% to 82.0%; atorvastatin use rose from 2.1% to 64.8% and simvastatin use decreased from 55.7% to 8.6%. Antihypertensive medication use remained stable, at approximately 89%, and various antihypertensive classes were used comparably. Glucose-lowering medication use increased from 71.5% in 2005 to 84.1% in 2021, driven primarily by an increase in metformin use (from 28.0% to 59.5%). Use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors continually increased (from 1.7% to 17.5% and from 0.5% to 17.3%, respectively) between 2015 and 2021. Anticoagulant medication use rose from 45.9% in 2005 to 87.0% in 2021, primarily because of increased use of direct oral anticoagulant medications starting around 2010 and a decline in warfarin use. Antiplatelet use remained consistently high, at approximately 95%. Trends were consistent across subgroups of interest; however, overall medication use was lower in older patients (65 years and older), patients with severe stroke, and patients with neurologic and psychiatric comorbidities. DISCUSSION: Despite increasing trends in the use of 3 of 5 medication classes, the overall use of lipid-lowering, glucose-lowering, and oral anticoagulant medications was somewhat lower than expected according to clinical guidelines, particularly among older patients with more severe stroke and other comorbidities. The relatively low use in these subgroups may signify appropriate clinical decision making in consideration of frequent contraindications and reduced life expectancy or highlight potential areas of improvement for the care of patients with recent ischemic stroke.

Directed acyclic graphs in clinical research.

Directed acyclic graphs (DAGs), or causal diagrams, are graphical representations of causal structures that can be used in medical research to understand and illustrate potential bias, including bias arising from confounding, selection, and misclassification. Further, they provide guidance for researchers about how to address a potential bias.

Mental Health Conditions in Partners and Adult Children of Stroke Survivors.

Importance: Family caregiving after critical illness has been associated with several adverse health outcomes, including various aspects of mental health, but research focusing specifically on family members of stroke survivors is limited. Objectives: To examine the associations of stroke in a partner or parent with the risk of depression, substance use disorders, anxiety disorders, and self-harm or suicide. Design, Setting, and Participants: This nationwide, population-based cohort study used data from Danish nationwide administrative and clinical registries (2004-2021). Participants included partners and adult children of survivors of stroke. Data analysis was performed from March to December 2023. Exposure: Having a partner or parent who survived stroke. Main Outcomes and Measures: The Aalen-Johansen estimator was used to compute propensity score-weighted 3-year absolute risks, risk differences, and risk ratios for depression, substance use disorders, anxiety disorders, and self-harm or suicide among partners or children of survivors of stroke compared with partners or children of survivors of myocardial infarction (MI) and matched individuals from the general population. Results: The study included a total of 1 923 732 individuals: 70 917 partners of stroke survivors (median [IQR] age, 68 [59-76] years; 46 369 women [65%]), 70 664 partners of MI survivors (median [IQR] age, 65 [55-73] years; 51 849 women [73%]), 354 570 partners of individuals from the general population (median [IQR] age, 68 [59-76] years; 231 833 women [65%]), 207 386 adult children of stroke survivors (median [IQR] age, 45 [36-52] years; 99 382 women [48%]), 183 309 adult children of MI survivors (median [IQR] age, 42 [33-49] years; 88 078 women [48%]), and 1 036 886 adult children of individuals from the general population (median [IQR] age, 45 [36-52] years; 496 875 women [48%]). Baseline characteristics were well balanced across cohorts after propensity score weighting. Among partners of stroke survivors, the 3-year absolute risk was 1.0% for depression, 0.7% for substance use disorders, 0.3% for anxiety disorders, and 0.04% for self-harm or suicide. Risk ratio point estimates for the assessed outcomes ranged from 1.14 to 1.42 compared with the general population and from 1.04 to 1.09 compared with partners of MI survivors. The elevated risk of depression in partners of stroke survivors was more pronounced after severe or moderate stroke than after mild stroke. Among adult children of stroke survivors, the 3-year absolute risk was 0.6% for depression, 0.6% for substance use disorders, 0.2% for anxiety disorders, and 0.05% for self-harm or suicide. Both absolute risks and risk ratios for adult children of stroke survivors were smaller than those reported in the partner analyses. Conclusions and Relevance: In this cohort study of partners and adult children of stroke survivors, risks of several mental health conditions and self-harm or suicide were moderately higher compared with the general population and, to a lesser extent, partners and adult children of MI survivors. These findings highlight the potential consequences of stroke among family members, particularly partners, and its findings may possibly serve as a quantitative foundation for the development of future stroke rehabilitation services.

Risk of Depression after Venous Thromboembolism in Patients with Hematological Cancer: A Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) may complicate the clinical course of cancer patients and add to their psychological burden. OBJECTIVES: We aimed to investigate the association between VTE and risk of subsequent depression in patients with hematological cancer. PATIENTS AND METHODS: We conducted a population-based cohort study using Danish national health registries. Between 1995 and 2020, we identified 1,190 patients with hematological cancer and incident VTE diagnosed within 6 months before to 1 year after cancer diagnosis. A comparison cohort of patients with hematological cancer without VTE (n = 5,325) was matched by sex, year of birth, cancer type, and year of cancer diagnosis. Patients were followed until diagnosis of depression, emigration, death, study end (2021), or for a maximum of 3 years. Depression was defined as hospital discharge diagnosis of depression or ≥1 prescription for antidepressants. Absolute risks of depression were computed with cumulative incidence functions, treating death as competing event. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using Cox proportional hazards regression models, adjusting for comorbidities. RESULTS: Depression was observed in 158 hematological cancer patients with and 585 without VTE. The 3-year absolute risks of depression were 13.3% (95% CI: 11.5-15.3%) in the VTE cancer cohort and 11.1% (95% CI: 10.3-12.0%) in the comparison cancer cohort, corresponding to a risk difference of 2.2% (95% CI: -1.8-6.5%). VTE was associated with an increased relative risk of depression (adjusted HR: 1.56, 95% CI: 1.28-1.90). CONCLUSION: VTE was associated with an elevated risk of subsequent depression in patients with hematological cancer.

Overweight or obesity in children born after assisted reproductive technologies in Denmark: A population-based cohort study.

BACKGROUND: The association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility. METHODS AND FINDINGS: This Danish cohort study included 327,301 children born between 2007 and 2012 (51% males, median age at follow-up 7 years). Of these, 13,675 were born after ART, 7,728 were born after ovulation induction with or without intrauterine insemination [OI/IUI], and 305,898 were born after no fertility treatments. Using the International Obesity Task Force (IOTF) standards, we defined overweight (BMI ≥ IOTF-25) and obesity (BMI ≥ IOTF-30). We compared children born after ART versus OI/IUI; intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilization (IVF); and frozen-thawed versus fresh embryo transfer and estimated crude and adjusted prevalences of children with overweight or obesity at age 5 to 8 years, prevalence odds ratios (PORs), and differences in mean BMI z-scores. Adjustment was performed using stabilized inverse probability of treatment weights, including parity, year of conception, parental causes of infertility, age, educational level, comorbidities, maternal country of origin, BMI, and smoking as covariates. The crude prevalence of obesity was 1.9% in children born after ART, 2.0% in those born after OI/IUI, and 2.7% in those born after no fertility treatment. After adjustment, children born after ART and OI/IUI had the same prevalence of being overweight (11%; POR 1.00, 95% confidence interval [CI] 0.91 to 1.11; p = 0.95) or obese (1.9%; POR 1.01, 95% CI 0.79 to 1.29; p = 0.94). Comparison of ICSI with conventional IVF yielded similar pattern (POR 0.95, 95% CI 0.83 to 1.07; p = 0.39 for overweight and POR 1.16, 95% CI 0.84 to 1.61; p = 0.36 for obesity). Obesity was more prevalent after frozen-thawed (2.7%) than fresh embryo transfer (1.8%) (POR 1.54, 95% CI 1.09 to 2.17; p = 0.01). The associations between fertility treatments and BMI were only modestly different in subgroups defined by the cause of infertility. Study limitations include potential residual confounding, restriction to live births, and lack of detailed technical information about the IVF procedures. CONCLUSIONS: We found no association with BMI at age 5 to 8 years when comparing ART versus OI/IUI or when comparing ICSI versus conventional IVF. However, use of frozen-thawed embryo transfer was associated with a 1.5-fold increased risk of obesity compared to fresh embryo transfer. Despite an elevated relative risk, the absolute risk difference was low.

Cohort Profile: Better Health in Late Life.

Purpose: Humans are living longer and may develop multiple chronic diseases in later life. The Better Health in Late Life cohort study aims to improve our understanding of the risks and outcomes of multimorbidity in the Danish population. Methods: A randomly-selected sample of Danish residents who were 50-65 years of age received a questionnaire and an invitation to participate in this study. Respondents completed an online survey between October 2021 and January 2022 which addressed topics that included self-assessed health, mental health, sleep, specific medical conditions, use of painkillers, diet, alcohol consumption, smoking, physical activity, and body composition. This information was linked to the Danish health and social registries (some established in 1943 and onwards) that maintain data on filled prescriptions, hospital records, socioeconomic status, and health care utilization. Results: Responses were received from 115,431 of the 301,244 residents invited to participate (38%). We excluded respondents who answered none of the questions as well as those who provided no information on sex or indicated an age other than 50-65 years. Of the 114,283 eligible respondents, 54.8% were female, 30.3% were overweight, and 16.7% were obese. Most participants reported a weekly alcohol consumption of less than seven units and 13.3% were current smokers; 5.2% had a history of hospitalization for solid cancer, and 3.0%, 2.3%, 2.0%, and 0.9% reported chronic pulmonary disease, diabetes, stroke, and myocardial infarction, respectively. The most frequently filled prescriptions were for medications used to treat the nervous system and cardiovascular diseases (38.1% and 37.4%, respectively).

Comorbidities and mortality among patients with chronic obstructive pulmonary disease.

INTRODUCTION: Comorbidities are common in patients with chronic obstructive pulmonary disease (COPD). Estimates of prevalence, incidence and prognostic impact of comorbidities provide foundational knowledge of COPD epidemiology. We examined the prevalence, incidence and prognostic impact of 21 comorbidities among patients with COPD compared with the Danish general population. METHODS: We conducted a nationwide, population-based cohort study based on longitudinal Danish registry data, covering all Danish hospitals (2010-2021). The cohorts comprised 142 973 patients with a first-time hospital-based diagnosis of COPD and 428 917 age-matched and sex-matched comparators from the general population. During follow-up, we estimated the 5-year risk and risk difference, using competing risk methods when applicable. RESULTS: At time of diagnosis, the comorbidities with the highest prevalence were mood, stress-related or anxiety disorders (25.2% for patients with COPD vs 13.1% for comparators), osteoporosis/hip fractures (17.4% vs 9.9%), diabetes (15.6% vs 10.5%), peripheral arterial disease (13.5% vs 4.9%) and heart failure (13.3% vs 4.0%). During follow-up, the risk of most incident comorbidities was markedly elevated among patients with COPD. The five comorbidities associated with the highest 5-year absolute risk difference with respect to the risk in the general population were mood, stress-related or anxiety disorders (5.7%), osteoporosis/hip fractures (5.6%), heart failure (4.2%), smoking-related cancers (2.8%) and peripheral arterial disease (2.7%). The 5-year mortality risk was 43% vs 17.7%. Among patients with COPD, the 5-year mortality risk markedly increased with the number of comorbidities present. CONCLUSIONS: Our population-based findings underscore the importance of considering comorbidities in the management of COPD.

Mental Health Conditions Among Children and Adolescents With Congenital Heart Disease: A Danish Population-Based Cohort Study.

BACKGROUND: Despite the known mental health burden among children with congenital heart disease (CHD), the literature is constrained by a lack of comparison cohorts and population-based follow-up data. We examined the incidence of mental health conditions among children with CHD, relative to 3 comparison cohorts. METHODS: This population-based cohort study identified all children with CHD (<18 years of age; n=16 473) in Denmark from 1996 to 2017, through linkage of individual-level data across national registries. This allowed for complete follow-up of the population. Comparison cohorts included children from the general population (n=162 204), siblings of children with CHD (n=20 079), and children with non-CHD major congenital anomalies (n=47 799). Mental health conditions were identified using inpatient and outpatient hospital discharge codes, prescription data, and data on use of community-based psychology, psychiatry, and psychotherapy services. We computed cumulative incidence by 18 years of age, incidence rates, and adjusted hazard ratios (aHRs) using Cox regression. aHRs accounted for sex, year of CHD diagnosis, parental mental health, and socioeconomic status. All estimates were stratified by age, sex, and CHD complexity. RESULTS: The cumulative incidence of mental health conditions by 18 years of age in the CHD cohort was 35.1% (95% CI, 34.0%-36.1%), corresponding to aHRs of 1.64 (95% CI, 1.58-1.71), 1.41 (95% CI, 1.30-1.52), and 1.02 (95% CI, 0.98-1.07) compared with the general population, sibling, and major congenital anomaly cohorts, respectively. Mental health incidence rates showed prominent peaks in early childhood and adolescence. Males and children with severe or single-ventricle CHD demonstrated higher incidence rates of mental health conditions relative to females and children with mild or moderate CHD, respectively. Compared with the general population and sibling cohorts, incidence rates and aHRs in the CHD cohort were highest for severe stress reactions, attention deficit/hyperactivity disorder, intellectual disability, and autism spectrum disorder. Compared with children in the major congenital anomaly cohort, the aHRs were close to 1. CONCLUSIONS: More than one-third of children with CHD were diagnosed or treated for a mental health condition by 18 years of age. Mental health conditions began early in life and were most prominent among males and children with severe or single-ventricle heart disease.

Maternal Smoking During Pregnancy and Risk of Appendicitis in the Offspring.

BACKGROUND: Existing evidence on the link between smoking and appendicitis is scarce and ambiguous. We therefore conducted a population-based cohort study in Denmark to investigate whether smoking during pregnancy is associated with an increased risk of appendicitis in offspring. METHODS: We used the Danish Birth Registry to include all singletons born during 1991-2017 and to identify maternal smoking status during pregnancy. We followed the children from birth until date of appendicitis, emigration, death, or administrative end of study (31 December 2018), whichever came first. We calculated crude and adjusted hazard ratios (HRs) of appendicitis with 95% confidence intervals (CIs) comparing children of mothers who smoked during pregnancy to children of nonsmokers. Further, we conducted a bias analysis and sibling analysis. RESULTS: We included 1,659,526 singletons of whom 19% were born to mothers who smoked during pregnancy. After maximum 28 years of follow-up, hazard rates for children of smokers were slightly higher than for children of nonsmokers [adjusted HR: 1.07 (95% CI = 1.04, 1.10)]. Stratification by sex revealed no association for males [adjusted HR: 1.02 (95% CI = 0.99, 1.06)], but a higher HR for females [adjusted HR: 1.13 (95% CI = 1.09, 1.18)]. This association increased with increasing length of follow-up, indicating that the association may be mediated by later-life exposures. The bias analysis indicated that misclassification of maternal smoking could attenuate a true association, while the sibling analysis showed no association. CONCLUSIONS: Maternal smoking during pregnancy and appendicitis in the offspring may be associated.

A Review of Major Danish Biobanks: Advantages and Possibilities of Health Research in Denmark.

Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health - Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications.

Venous thromboembolism and risk of depression: a population-based cohort study.

BACKGROUND: The psychologic consequences of acute venous thromboembolism (VTE) have not been investigated in depth. OBJECTIVES: We aimed to examine the association between VTE and the risk of subsequent depression. METHODS: Using Danish nationwide registries, we established a population-based cohort of 64 596 individuals with incident VTE during 1996 to 2016 and a comparison cohort (n = 322 999) selected randomly from the general population and individually matched by birth year, sex, and calendar year of VTE. The participants were followed up for 3 years, and depression was defined as any hospital diagnosis of depression or ≥1 prescription for antidepressants. Incidence rates were computed as the number of events per 1000 person-years, and hazard ratios with 95% CIs were computed as estimates of the risk conferred by VTE using the comparison cohort as reference. We estimated absolute risks using cumulative incidence functions, treating death as a competing event. RESULTS: Depression was observed in 6225 individuals after VTE and 16 363 members of the comparison cohort (incidence rates of 44.4 and 19.4 per 1000 person-years, respectively). The absolute risk of depression was 10.3% (95% CI, 10.1%-10.6%) in the VTE cohort and 5.6% (95% CI, 5.5%-5.6%) in the comparison cohort, corresponding to 4.7 excess cases of depression per 100 individuals with VTE. VTE was associated with a 2.35-fold (95% CI, 2.28-2.43) increased risk of depression compared with that in the comparison cohort. The association was attenuated after adjustments for socioeconomic status and comorbidities (hazard ratio, 1.91; 95% CI, 1.85-1.97). CONCLUSION: VTE was associated with an increased risk of depression after adjustment for comorbidities.

Cancer Diagnosis and Prognosis After Guillain-Barré Syndrome: A Population-Based Cohort Study.

Introduction: It is unclear whether Guillain-Barré syndrome (GBS) can be a marker of a paraneoplastic syndrome. We examined whether GBS is associated with cancer and whether the prognosis of GBS patients with cancer differs from that of other cancer patients. Materials and Methods: We conducted a population-based cohort study of patients diagnosed with GBS between 1978 and 2017 using Danish registry-data. Main outcome measures were cancer incidence and mortality after cancer diagnosis. We calculated absolute risks of a cancer diagnosis, treating death as competing risk, and standardized incidence ratios (SIRs) as measures of relative risk. We matched each GBS cancer patient with up to 10 cancer patients without a GBS diagnosis and examined the six-month survival after cancer diagnosis using Cox regression analysis. Results: We identified 7897 patients (58% male, median age 57 years) with GBS. During a median follow-up of 9.5 years, the one-year risk of cancer was 2.7% (95% confidence interval (CI), 2.4-3.1). The SIR was increased throughout follow-up, but most noticeably during the first year after diagnosis (SIR: 3.35, 2.92-3.83). SIRs were particularly elevated for hematologic cancers (SIR: 8.67, 6.49-11.34), smoking-related cancers (SIR: 3.57, 2.81-4.47), and cancers of neurological origin (SIR: 8.60, 5.01-13.77). Lung cancer was the main contributor to the overall excess risk, which persisted after 36 months of follow-up (SIR: 1.17, 1.09-1.25). The mortality rate ratio comparing patients diagnosed with any cancer within one year of their GBS diagnosis and matched GBS-free cancer cohort members was 1.56 (95% CI, 1.27-1.90). Conclusion: GBS patients had a three-fold increased risk of cancer diagnosis in the first year of follow-up. The absolute cancer risk was almost 3.0%. A GBS diagnosis was an adverse prognostic marker for survival following cancer diagnosis. Clinicians should consider occult cancer in patients hospitalized with GBS.

In utero exposure to glucocorticoids and risk of anxiety and depression in childhood or adolescence.

Glucocorticoid use is prevalent in pregnant women, but whether in utero exposure impacts mental health in the offspring has not been fully explored. The aim of this study was to investigate if in utero exposure to synthetic glucocorticoids increases the risk of anxiety and depression in childhood or adolescence. The study was conducted as a nationwide cohort study, including negative control exposure analyses and a sibling design to optimize control of confounding. The study population comprised 1,275,909 children born in 1996-2015 in Denmark (median follow-up of 13 years). Exposure was divided into systemic and local glucocorticoid exposure, levels of cumulative dose, generic type and according to trimester of exposure. The comparison cohort was children without exposure born to maternal never-users. Negative control exposures included children without glucocorticoid exposure born to: maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of systemic glucocorticoids, maternal users of systemic glucocorticoids in the postnatal period, and fathers who were prescribed glucocorticoids. The sibling design compared siblings with and without exposure. 9307 (0.7%) children were exposed to systemic glucocorticoids and 116,389 (9.1%) children were exposed to local glucocorticoids. High-dose systemic glucocorticoids (≥500 mg prednisolone equivalents) increased the risk of anxiety compared to the comparison cohort [aIRR 1.79 (95% CI: 1.36-2.37), cumulative risk 16% vs. 7.8% by age 20]. A similar result was found for depression [aIRR 1.45 (95% CI: 0.80-2.63), cumulative risk 3.6% vs. 2.6% by age 20]. The association with anxiety was consistent in the sibling design [aIRR 1.83 (95% CI: 1.03-3.66), exposed siblings (≥ 500 mg) vs. unexposed]. Sex did not modify the associations. Negative control exposure analyses indicated robustness towards confounding from genetics and family environment. No association was found with low doses of systemic exposure or local use. In conclusion, potential adverse mental health effects of in utero exposure to high-dose glucocorticoids merit clinical attention.

The Interaction Between Venous Thromboembolism and Socioeconomic Status on the Risk of Disability Pension.

Background: Venous thromboembolism (VTE) is associated with increased risk of disability pension. How socioeconomic status (SES) impacts the risk of disability pension after a VTE is unknown. The aim of this nationwide population based cohort study to investigate the interaction between SES and incident VTE on the risk of subsequent disability pension. Methods: Using Danish national medical and administrative databases, we established a nationwide cohort of 41,781 individuals aged 25-65 years with incident VTE during 1995-2016 and a comparison cohort (n=208,905) from the general population matched on year of birth, sex, and calendar year of VTE. We computed incidence rates (IRs) as the number of disability pension events per 1000 person-years at risk and measured the interaction between VTE and levels of SES (high, medium, low) on an additive scale by calculating interaction contrasts (difference in IR difference). Results: Among individuals with high SES, the disability pension IR per 1000 person-years was 5.4 (95% CI: 4.8-6.1) in the VTE cohort and 1.6 (95% CI: 1.5-1.7) in the comparison cohort (IR difference 3.8). The corresponding disability pension IR in individuals with low SES was 55.1 (95% CI: 52.1-58.1) in the VTE cohort and 26.1 (95% CI: 25.1-27.1) in the comparison cohort (IR difference 24.0). An interaction contrast of 25.1 indicated that interaction accounted for 45.6% (25.1/55.1) of the disability pension IR in individuals with VTE and low SES. Conclusion: SES and VTE interact to increase the risk of disability pension after VTE beyond their independent effects.

Prenatal Antidepressant Exposure and the Risk of Attention-deficit/Hyperactivity Disorder in Childhood: A Cohort Study With Triangulation.

BACKGROUND: Uncontrolled confounding from maternal depression and genetic and environmental factors is expected in studies investigating the effect of prenatal antidepressant exposure on the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood and may explain inconsistencies in the existing evidence. We aimed to assess this effect using triangulation. METHODS: Using population-based health registries, we conducted a nationwide cohort study of all children born in Denmark between 1997 and 2017 and followed through 2018 for ADHD. We assessed the effect of prenatal antidepressant exposure on the risk of ADHD in childhood by comparing children with and without prenatal antidepressant exposure in terms of adjusted incidence rate ratios (IRRs), adjusted incidence rate differences (IRDs), and adjusted risk differences (RDs) and the associated 95% confidence intervals (CIs). We triangulated results from four different analytic approaches: an overall analysis, a negative control analysis, a sibling analysis, and a former-user analysis. RESULTS: The overall study cohort consisted of 1,253,362 children, among whom 28,910 (2.3%) had prenatal antidepressant exposure. ADHD during follow-up was diagnosed among 1,411 (4.9%) of the exposed and in 37,196 (3.0%) of the unexposed children. Triangulation suggested an IRR of 1.09-1.15; an IRD less than 1 case/1,000 person-years, and an RD of 0.9%-2.2% over an up to 18-year period. CONCLUSIONS: Based on triangulation, we estimated a modest effect of prenatal antidepressant exposure on the risk of ADHD in childhood. However, considering the limitations of our approaches, this observed association may be partially due to residual biases. See video abstract at, http://links.lww.com/EDE/B935.

Cardiovascular events and all-cause mortality in patients with chronic obstructive pulmonary disease using olodaterol and other long-acting beta2-agonists.

PURPOSE: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored. METHODS: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias. RESULTS: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n = 14 239) compared to users of other LABAs (n = 51 167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis. CONCLUSIONS: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

Cancer Risk in Pulmonary Hypertension Patients.

BACKGROUND: Strong evidence indicates that venous thromboembolism is a presenting symptom of cancer. Cancer is a known cause of pulmonary hypertension; however, it remains unknown whether pulmonary hypertension is a marker of occult cancer. We examined the association between a pulmonary hypertension diagnosis and cancer risk in a cohort study using population-based data from the Danish health system. PATIENTS AND METHODS: Using Danish nationwide registries, we identified 6335 patients with a pulmonary hypertension diagnosis and without a previous cancer diagnosis between 1995 and 2017. We computed the age-, sex-, and calendar year-standardized incidence ratio (SIR) as the ratio of observed to expected number of cancers using national incidence rates as the reference. We performed a subgroup analysis among patients with chronic thromboembolic pulmonary hypertension in the period in which a specific ICD-10 code was available (2006-2017). RESULTS: We identified 212 cancers within the first year of follow-up and 796 cancers thereafter. The one-year risk of cancer was 3.3% and the one-year SIR was 1.96 (95% confidence interval [CI]: 1.70-2.23). In the second and subsequent years, the SIR remained elevated (SIR: 1.15 [95% CI: 1.08-1.24]). In patients with chronic thromboembolic pulmonary hypertension, the one-year SIR was 1.41 (95% CI: 0.82-2.25). CONCLUSION: Cancer risk was clearly higher in patients with pulmonary hypertension compared with the general population. The association was particularly strong in the first year of follow-up, but remained elevated thereafter. However, absolute risks were low, limiting the clinical relevance of pursuing early cancer detection in these patients.

Prenatal exposure to glucocorticoids and the prevalence of overweight or obesity in childhood.

OBJECTIVE: Prenatal exposure to excess cortisol can affect postnatal metabolic health by epigenetic mechanisms. We aimed to investigate if prenatal exposure to pharmacological glucocorticoids increases the risk of overweight/obesity in childhood. DESIGN: A nationwide population registry-based cohort study. METHODS: We identified 383 877 children born in Denmark (2007-2012), who underwent routine anthropometric evaluation at 5-8 years of age. Prenatal exposure to glucocorticoids was divided into systemic and topical glucocorticoids, cumulative systemic dose, and use by trimester. The comparison cohort included children without exposure, born to maternal never-users. Negative control exposures were used to investigate confounding from an underlying disease or unmeasured characteristics. Such exposures included children without glucocorticoid exposure born to maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of glucocorticoids, or paternal users of glucocorticoids during the pregnancy of their partner. We estimated sex-stratified adjusted prevalence ratios (aPR) of overweight/obesity at 5-8 years of age, as epigenetic modifications have shown to be sex-specific. RESULTS: In the study, 21 246 (11%) boys and 27 851 (15%) girls were overweight/obese at 5-8 years of age. Overall, neither systemic nor topical glucocorticoids were associated with overweight/obesity. In boys, high-dose systemic glucocorticoids was associated with higher prevalence of overweight/obesity vs the comparison cohort (aPR: 1.41 (95% CI: 1.07-1.86), prevalence: 16% vs 11%). Negative control exposures indicated robustness to confounding. CONCLUSION: Overweight/obesity might be an adverse effect of prenatal exposure to high-dose systemic glucocorticoids in boys. We found no association for neither prenatal exposure to lower doses of systemic nor topical glucocorticoids. These results merit clinical attention.

Socioeconomic status and risk of incident venous thromboembolism.

BACKGROUND: Although venous thromboembolism (VTE) is a leading cause of morbidity and mortality, and socioeconomic status (SES) affects human health and health behavior, few studies have examined the association between SES and VTE. OBJECTIVES: We aimed to investigate the association between SES, assessed individually and in a composite score by levels of education, income, and employment status, and incident VTE. METHODS: We used Danish national registries to identify 51 350 persons aged 25-65 years with incident VTE during 1995-2016. For each case, we used incidence density sampling to select five age-, sex-, and index-year-matched controls from the general Danish population (n = 256 750). SES indicators, including education, income, and employment status, were assessed 1 and 5 years before the VTE. We used conditional logistic regression to compute odds ratios (ORs) with 95% confidence intervals (CIs) for VTE according to individual SES indicators and a composite SES score in analyses adjusted for age, sex, and comorbidities. RESULTS: Compared with low levels, high educational level (OR 0.74; 95% CI 0.71-0.77), high income (OR 0.70; 95% CI 0.68-0.72), and high employment status (OR 0.66; 95% CI 0.64-0.68) were associated with decreased risk of VTE, even after adjusting for comorbidities. A composite SES score was superior to the individual indicators in assessing VTE risk (OR for high vs. low score: 0.61; 95% CI 0.59-0.63). In sensitivity analysis with SES indicators measured 5 years before the VTE, the risk estimates remained essentially the same. CONCLUSION: High levels of both individual SES indicators and a composite SES score were associated with decreased VTE risk.

Risk of a permanent work-related disability pension after incident venous thromboembolism in Denmark: A population-based cohort study.

BACKGROUND: Long-term complications of venous thromboembolism (VTE) hamper physical function and impair quality of life; still, it remains unclear whether VTE is associated with risk of permanent work-related disability. We aimed to assess the association between VTE and the risk of receiving a permanent work-related disability pension and to assess whether this association was explained by comorbidities such as cancer and arterial cardiovascular disease. METHODS AND FINDINGS: A Danish nationwide population-based cohort study consisting of 43,769 individuals aged 25 to 66 years with incident VTE during 1995 to 2016 and 218,845 birth year-, sex-, and calendar year-matched individuals from the general population, among whom 45.9% (N = 120,540) were women, was established using Danish national registries. The cohorts were followed throughout 2016, with permanent work-related disability pension as the outcome. Hazard ratios (HRs) with 95% confidence intervals (CIs) for disability pension were computed and stratified by sex and age groups (25 to 34, 35 to 44, 45 to 54, and 55 to 66 years of age) and adjusted for comorbidities and socioeconomic variables. Permanent work-related disability pensions were granted to 4,415 individuals with VTE and 9,237 comparison cohort members (incidence rates = 17.8 and 6.2 per 1,000 person-years, respectively). VTE was associated with a 3-fold (HR 3.0, 95% CI: 2.8 to 3.1) higher risk of receiving a disability pension. Adjustments for socioeconomic status and comorbidities such as cancer and cardiovascular diseases reduced the estimate (HR 2.3, 95% CI: 2.2 to 2.4). The risk of disability pension receipt was slightly higher in men than in women (HR 2.5, 95% CI: 2.3 to 2.6 versus HR 2.1, 95% CI: 2.0 to 2.3). As this study is based on medical and administrative registers, information on post-VTE care, individual health behavior, and workplace factors linked to disability pension in the general population are lacking. Furthermore, as disability pension schemes vary, our results might not be directly generalizable to other countries or time periods. CONCLUSIONS: In this study, incident VTE was associated with increased risk of subsequent permanent work-related disability, and this association was still observed after accounting for comorbidities such as cancer and cardiovascular diseases. Our results emphasize the social consequences of VTE and may help occupational and healthcare professionals to identify vulnerable individuals at risk of permanent exclusion from the labor market after a VTE event.