Antipsychotic use during pregnancy and risk of specific neurodevelopmental disorders and learning difficulties in children: a multinational cohort study.

Background: Antipsychotics are commonly prescribed to treat a range of psychiatric conditions in women of reproductive age and during pregnancy, including schizophrenia, bipolar disorder, anxiety, depression, autism spectrum disorder, and insomnia. This study aimed to evaluate whether children exposed to antipsychotic medication prenatally are at increased risk of specific neurodevelopmental disorders and learning difficulties. Methods: Our population-based cohort study used nationwide register data (1 January 2000-31 December 2020) on pregnant women diagnosed with a psychiatric disorder and their live-born singletons from Denmark, Finland, Iceland, Norway, and Sweden. Cox proportional hazard regression yielded propensity score-weighted hazard ratios (aHRs) and 95% confidence intervals (CIs) for risk of intellectual-, speech or language-, learning-developmental disorders, and a composite outcome of the listed disorders. We defined poor performance as scoring within the lowest quartile on national school tests in mathematics and language arts. We estimated propensity score-weighted risk ratios (aRRs) using Poisson regression. We analysed data from Denmark separately and pooled results using random effects meta-analysis. Findings: Among 213,302 children (median follow-up: 6.7 years), 11 626 (5.5%) were exposed to antipsychotics prenatally. Adjusted risk estimates did not suggest an increased risk of neurodevelopmental disorders: aHR of 1.06 (95% CI 0.94-1.20) for the composite outcome, or for poor academic performance: aRR of 1.04 (95% CI 0.91-1.18) in mathematics, and of 1.00 (95% CI 0.87-1.15) in language arts. Results were generally consistent across individual medications, trimesters of exposure, sibling- and sensitivity analyses. Interpretation: The findings of this large multinational cohort study suggest there is little to no increased risk of child neurodevelopmental disorders or learning difficulties after prenatal exposure to antipsychotics. Our findings can assist clinicians and women managing mental illness during pregnancy. Funding: This study was funded by the NordForsk Nordic Program on Health and Welfare (Nordic Pregnancy Drug Safety Studies, project No. 83539), by the Research Council of Norway (International Pregnancy Drug Safety Studies, project No. 273366) and by the Research Council of Norway through its Centres of Excellence funding scheme (project No. 262700), and UNSW Scientia Programme Awards (PS46019, PS46019-A).

Comorbidity, Criminality, and Costs of Patients Treated for Gambling Disorder in Denmark.

Gambling disorder is associated with increased mental comorbidity, unhealthy lifestyle, criminality, and costs-of-illness, but the available evidence is mainly based on self-reported survey data. We examined the registry-recorded mental and somatic comorbidities, medication use, criminality, and costs-of-illness associated with gambling disorder. We identified individuals diagnosed with or treated for gambling disorder in hospitals or specialized treatment centers during 2013-2017 and matched them by age and sex to general population comparisons. Using individual-level healthcare and socioeconomic registries, we characterized their history of mental and somatic comorbidities, medication use, and criminality. We estimated their cost-of-illness of welfare services (direct) and lowered productivity (indirect) using the human capital approach. We identified 1381 individuals with gambling disorder, primarily young (median age: 34 years) men (87%). Individuals with gambling disorder more frequently than their comparisons had previous hospital-recorded comorbidity [e.g., myocardial infarction (0.8% vs. 0.5%)], medication use [e.g., respiratory system drugs (35.6% vs. 28.6%)], and hospital-recorded or pharmacologically treated mental comorbidity [e.g., depression (39.8% vs. 14.9%)]. Also, sentenced criminality was much more common in individuals with gambling disorder (7.0%) than in comparisons (1.1%). The estimated attributable direct costs were €4.0 M corresponding to €2.9 K per person with gambling disorder, and attributable indirect costs were €17.6 M, corresponding to €13.2 K per person with gambling disorder in 2018. In conclusion, individuals diagnosed with or treated for gambling disorder have a high burden of mental and somatic comorbidities as well as criminality compared with the general population. This needs attention to minimize the societal and personal costs of gambling disorder.

Preconception use of antibiotics and fecundability: a Danish prospective cohort study.

OBJECTIVE: To assess the association between preconception antibiotic use and fecundability, the per menstrual cycle probability of conception. DESIGN: SnartForaeldre.dk, a Danish prospective cohort study of women trying to conceive (2007-2020). SETTING: Not applicable. SUBJECT(S): 9462 female participants, median age 29 years at enrollment. EXPOSURE: Antibiotic use was defined by filled prescriptions retrieved from the Danish National Prescription Registry, using Anatomical Therapeutic Chemical codes, and modeled as time-varying (menstrual cycle-varying) exposure. MAIN OUTCOME MEASURE(S): Pregnancy status was reported on female follow-up questionnaires every 8 weeks for up to 12 months or until conception. Fecundability ratios (FR) and 95% confidence intervals (CI) were computed using proportional probabilities regression models, with adjustment for age, partner age, education, smoking, folic acid supplementation, body mass index, parity, cycle regularity, timing of intercourse, and sexually transmitted infections. RESULT(S): During all cycles of observation, the percentage of participants filing at least 1 antibiotic prescription was 11.9%; 8.6% had a prescription for penicillins, 2.1% for sulfonamides, and 1.8% for macrolides. Based on life-table methods, 86.5% of participants conceived within 12 cycles of follow-up. Recent preconception antibiotic use was associated with reduced fecundability (≥1 prescription vs. none: adjusted FR = 0.86; 95% CI, 0.76-0.99). For participants using penicillins, sulfonamides, or macrolides, the adjusted FRs were 0.97 (95% CI, 0.83-1.12), 0.68 (95% CI, 0.47-0.98), and 0.59 (95% CI, 0.37-0.93), respectively. CONCLUSION(S): Preconception use of antibiotics, specifically sulfonamides and macrolides, was associated with decreased fecundability compared with no use. The observed associations may be explained plausibly by confounding by indication, as we lacked data on indications for the prescribed antibiotics. Consequently, we cannot separate the effect of the medication from the effect of the underlying infection.

Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations.

OBJECTIVE: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. METHODS: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. RESULTS: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. INTERPRETATION: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US.

Importance: Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. Objective: To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. Design, Setting, and Participants: This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. Exposures: One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Main Outcomes and Measures: Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. Results: A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. Conclusions and Relevance: In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study.

BACKGROUND: Antipsychotics are increasingly used among women of childbearing age and during pregnancy. OBJECTIVE: To determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders. Design Population-based cohort study, including a sibling analysis. Setting Nationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016). Participants 4 324 086 children were eligible for inclusion to the study cohort. Intervention Antipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use. Main outcome measures Non-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors. FINDINGS: Among 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD. DISCUSSION: Our findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics. CLINICAL IMPLICATIONS: Results regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.

Pretreatment Hemoglobin Adds Prognostic Information To The NCCN-IPI In Patients With Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Containing Chemotherapy.

BACKGROUND: Hemoglobin (Hgb) concentration at diagnosis is associated with outcome in cancer. In a recently reported simplified 3-factor prognostic score in Hodgkin lymphoma, Hgb, along with age and clinical stage, outperformed the classical International Prognostic Score with seven parameters. METHODS: In the present study, we investigated if pretherapeutic Hgb concentration added prognostic information to the NCCN-IPI in diffuse large B-cell lymphoma. We included patients from the Danish Lymphoma Registry (LYFO; N = 3499) and from the Molecular Epidemiology Resource (MER; N = 1225), Mayo Clinic and University of Iowa. Four sex-specific Hgb groups were defined: below transfusion threshold, from transfusion threshold to below lower limit of normal, from lower limit of normal to the population mean, and above the mean. We used multivariable Cox regression to estimate the hazard rate ratios (HR) and 95% CIs for overall survival (OS) and event-free survival (EFS), adjusting for sex, NCCN-IPI, comorbidity, and rituximab treatment. RESULTS: Approximately half of the patients had Hgb levels below the lower limit of normal. Compared to patients with Hgb levels above the mean, an inferior OS was directly correlated with lower pretreatment Hgb within the predefined groups (HR=1.23, HR=1.51, and HR=2.05, respectively). These findings were validated in the MER. CONCLUSION: Based on multivariable analysis, lower pretreatment Hgb, even within the normal range but below the mean, added prognostic information to established indices such as the NCCN-IPI and the Charlson comorbidity index.

Post-authorisation Safety Study of Pioglitazone Use and Safety Endpoints of Interest in Denmark After Direct Healthcare Professional Communication.

INTRODUCTION: A Direct Healthcare Professional Communication (DHPC) sent in Denmark on 11 August 2011 provided information on new pioglitazone labelling and guidance on monitoring treatment effectiveness. We describe pioglitazone use in Denmark after the DHPC, estimate the incidence of heart failure (HF), quantify pioglitazone cessation following a diagnosis of bladder cancer (BC) or uninvestigated macroscopic haematuria, and describe glycated haemoglobin (HbA1c) values. METHODS: This was a cohort study. From Danish population-based registries, cohorts of type 2 diabetes mellitus incident or prevalent users of pioglitazone or insulin in 2011-2015 were created. Patient characteristics, treatment patterns, laboratory results (available for a regional subset of the population), and incidence rates of HF and BC were estimated. RESULTS: There were 80 pioglitazone and 17,699 insulin incident users, 140 pioglitazone and 13,183 insulin prevalent users. There were no new BC cases among incident pioglitazone users, and < 5 new BC cases among prevalent pioglitazone users. Pioglitazone was rarely the first-line treatment. History of haematuria was documented in < 5 incident and 11 prevalent pioglitazone users. During follow-up, there were < 5 HF cases among 77 incident pioglitazone users and < 5 among 133 prevalent pioglitazone users without a history of HF. Median HbA1c at index date was 7.8% and 8.8% in incident pioglitazone and insulin cohorts, and 7.5% and 7.6% in prevalent pioglitazone and insulin cohorts, respectively. During follow-up of up to 4.4 years, 28.8% incident and 20.7% prevalent pioglitazone users discontinued pioglitazone. CONCLUSIONS: Numbers of pioglitazone users in Denmark were low and decreased over time. Risks of BC or HF were low and risk estimates imprecise.

Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study.

PURPOSE: Phthalate exposure is ubiquitous and especially high among users of drug products formulated with phthalates. Some phthalates mimic estradiol and may promote breast cancer. Existing epidemiologic studies on this topic are small, mostly not prospective, and have given inconsistent results. We estimated associations between longitudinal phthalate exposures and breast cancer risk in a Danish nationwide cohort, using redeemed prescriptions for phthalate-containing drug products to measure exposure. METHODS: We ascertained the phthalate content of drugs marketed in Denmark using an internal Danish Medicines Agency ingredient database. We enrolled a Danish nationwide cohort of 1.12 million women at risk for a first cancer diagnosis on January 1, 2005. By combining drug ingredient data with the Danish National Prescription registry, we characterized annual, cumulative phthalate exposure through redeemed prescriptions. We then fit multivariable Cox regression models to estimate associations between phthalate exposures and incident invasive breast carcinoma according to tumor estrogen receptor status. RESULTS: Over 9.99 million woman-years of follow-up, most phthalate exposures were not associated with breast cancer incidence. High-level dibutyl phthalate exposure (≥ 10,000 cumulative mg) was associated with an approximately two-fold increase in the rate of estrogen receptor-positive breast cancer (hazard ratio, 1.9; 95% CI, 1.1 to 3.5), consistent with in vitro evidence for an estrogenic effect of this compound. Lower levels of dibutyl phthalate exposure were not associated with breast cancer incidence. CONCLUSION: Our results suggest that women should avoid high-level exposure to dibutyl phthalate, such as through long-term treatment with pharmaceuticals formulated with dibutyl phthalate.

Depth of neutrophil nadir after first cycle of R-CHOP predicts outcome in diffuse large B-cell lymphoma - a nationwide population-based cohort study.

We investigated if survival was predicted by nadir neutrophil counts after the first cycle of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Neutrophil counts (109/L) were categorized in four grades in the nadir time frame. Prognostic indices and comorbidity levels were calculated and used to adjust the Cox regression model. Kaplan-Meier and Cox regression methods were used to estimate and compare survival. We identified 965 patients. Grade 4 neutropenia was present in 432 (45%). Grade 0 patients had a 5-year overall survival of 67%, grade 1-2: 78%, grade 3: 64%, and grade 4: 57%. Compared with grade 0 adjusted hazard ratios (HR) for death were: 0.77 (95% CI 0.49-1.21) for grade 1-2, 1.18 (95% CI 0.82-1.71) for grade 3, and 1.33 (95% CI 1.02-1.73) for grade 4. Grade 4 neutropenia after the 1st cycle of chemotherapy predicted inferior outcome compared with grade 0 and 1-2. Grade 1-2 neutropenia seemed to have superior outcome.

Increased mortality among patients with rheumatoid arthritis and COPD: A population-based study.

OBJECTIVES: Only few studies have addressed the prognostic impact of chronic obstructive pulmonary disease (COPD) among patients with rheumatoid arthritis (RA), although both diseases are frequent and smoking is a shared risk factor. The objectives of the present study were to investigate the burden of COPD among RA patients and the subsequent mortality. METHODS: We included patients who had a first-time diagnosis of RA in the Danish National Patient Registry between 2004 and 2016. RA patients with COPD were identified and matched with RA patients without COPD for year of birth, gender, and age at RA diagnosis. Mortality risks were assessed using Kaplan-Meier mortality curves. Adjusted hazard rate ratios (aHRRs) for death were estimated using Cox regression models. RESULTS: The study population included 31,333 individuals with RA. 3254 of those (10.4%) had a diagnosis of COPD and were matched to 9706 RA patients without COPD. The mortality risks in RA patients with COPD and RA patients without COPD were 4.5% and 1.5% within 2-6 months (aHRR = 3.0, CI 2.3-3.9), and 59.3% and 39.8% within 0.5-10 years (aHRR = 2.1, CI 1.9-2.1). CONCLUSION: Mortality was significantly increased among RA patients with COPD. The relative mortality risk remained significantly increased throughout the course of follow up.

Use of risk-adjusted CUSUM charts to monitor 30-day mortality in Danish hospitals.

BACKGROUND: Monitoring hospital outcomes and clinical processes as a measure of clinical performance is an integral part of modern health care. The risk-adjusted cumulative sum (CUSUM) chart is a frequently used sequential analysis technique that can be implemented to monitor a wide range of different types of outcomes. OBJECTIVE: The aim of this study was to describe how risk-adjusted CUSUM charts based on population-based nationwide medical registers were used to monitor 30-day mortality in Danish hospitals and to give an example on how alarms of increased hospital mortality from the charts can guide further in-depth analyses. MATERIALS AND METHODS: We used routinely collected administrative data from the Danish National Patient Registry and the Danish Civil Registration System to create risk-adjusted CUSUM charts. We monitored 30-day mortality after hospital admission with one of 77 selected diagnoses in 24 hospital units in Denmark in 2015. The charts were set to detect a 50% increase in 30-day mortality, and control limits were determined by simulations. RESULTS: Among 1,085,576 hospital admissions, 441,352 admissions had one of the 77 selected diagnoses as their primary diagnosis and were included in the risk-adjusted CUSUM charts. The charts yielded a total of eight alarms of increased mortality. The median of the hospitals' estimated average time to detect a 50% increase in 30-day mortality was 50 days (interquartile interval, 43;54). In the selected example of an alarm, descriptive analyses indicated performance problems with 30-day mortality following hip fracture surgery and diagnosis of chronic obstructive pulmonary disease. CONCLUSION: The presented implementation of risk-adjusted CUSUM charts can detect significant increases in 30-day mortality within 2 months, on average, in most Danish hospitals. Together with descriptive analyses, it was possible to use an alarm from a risk-adjusted CUSUM chart to identify potential performance problems.

A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality.

OBJECTIVES: To compare mortality risks in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and patients with RA without ILD. DESIGN: Matched cohort study. SETTING: The study was conducted in Denmark, using nationwide, prospectively collected data. PARTICIPANTS: Among patients with RA diagnosed between 2004 and 2016, 679 patients with RA-ILD were matched for birth year, gender and age at RA diagnosis with 11 722 patients with RA but without ILD. MAIN OUTCOME MEASURES: Mortality risks were assessed using Kaplan-Meier mortality curves, and hazard rate ratios (HRRs) for death were estimated using Cox proportional hazards regression models. RESULTS: The number of prevalent RA patients more than doubled from 15 352 to 35 362 individuals during the study period. RA-ILD was seen in 2.2% of incident RA patients. 34.0% of RA-ILD cases were diagnosed within 1 year prior to and 1 year after the RA diagnosis. One-year mortality was 13.9% (95% CI, 11.4% to 16.7%) in RA-ILD and 3.8% (95% CI, 3.5% to 4.2%) in non-ILD RA, 5-year mortality was 39.0% (34.4% to 43.5%) and 18.2% (17.3% to 19.1%) and 10-year mortality was 60.1% (52.9% to 66.5%) and 34.5% (32.8% to 36.1%), respectively. The HRRs for death were 2 to 10 times increased for RA-ILD compared with non-ILD RA, irrespective of follow-up period. Stratified analysis showed that the HRR for death was highest in the first months after the diagnosis of RA-ILD was made, especially in patients diagnosed with RA before diagnosis of ILD. HRR was higher in males and in patients without comorbidity as assessed by the Charlson Comorbidity Index. CONCLUSIONS: ILD is a serious complication in RA, with a significantly increased mortality compared with a large matched cohort of RA comparisons without ILD.

30-year nationwide trends in incidence of atrial fibrillation in Denmark and associated 5-year risk of heart failure, stroke, and death.

BACKGROUND: Long-term nationwide trends in atrial fibrillation (AF) incidence and 5-year outcomes are rare. METHODS: We conducted a population-based cohort study using the Danish National Patient Registry covering all Danish hospitals. We computed standardized incidence rates during 1983-2012. We used Cox regression to estimate hazard ratios (HRs) of heart failure, stroke, and death within 5years, comparing 5-year calendar periods with the earliest period (1983-1987) as reference. RESULTS: We identified 312,420 patients with first-time hospital-diagnosed AF. The incidence rate per 100,000person-years increased from 98 in 1983 to 307 in 2012. The mean annual increase during the 30-year study period was 4%, with a 6% increase annually until 2000 and a 1.4% increase annually thereafter. The incidence trends were most pronounced among men and persons above 70years. Among high-risk subgroups, AF incidence was consistently highest in patients with valvular heart disease or heart failure. The rate of heart failure following AF declined by 50% over the entire study period (HR: 0.49, 95% confidence interval (CI): 0.48-0.51) and the mortality rate declined by 40% (HR: 0.62, 95% CI: 0.61-0.63). Within the last two decades, the rate for ischemic stroke declined by 20% (HR 0.81, 95% CI: 0.78-0.84), but increased almost as much for haemorrhagic stroke (HR: 1.14, 95% CI: 1.01-1.29). CONCLUSIONS: The long-term risk of heart failure, ischemic stroke, and death following onset of AF has decreased remarkably over the last three decades. Still, the threefold increased incidence of hospital-diagnosed AF during the same period is a major public health concern.

Prescribing pattern of antipsychotic drugs during the years 1996-2010: a population-based database study in Europe with a focus on torsadogenic drugs.

INTRODUCTION: Antipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs. AIM: The aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010. METHODS: A cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year. RESULTS: A total of 559 276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients. CONCLUSIONS: Substantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.

Thirty-year trends in heart failure hospitalization and mortality rates and the prognostic impact of co-morbidity: a Danish nationwide cohort study.

AIMS: We examined 30-year nationwide trends in heart failure hospitalization and mortality rates, and the prognostic impact of co-morbidity. METHODS AND RESULTS: We conducted a population-based cohort study of 317 161 patients with first-time inpatient hospitalizations for heart failure during 1983-2012. We computed the standardized hospitalization rate and 5-year mortality risk. Co-morbidity levels and calendar periods of diagnosis were compared by means of mortality rate ratios (MRRs) based on Cox regression. The standardized hospitalization rate (per 100 000 persons) decreased between 1983 and 2012 by 25% for women (from 192 to 144) and by 14% for men (from 217 to 186). The decrease reflected an average annual 1% increase until 2000 and a 3.5% decline thereafter. Between 1983-1987 and 2008-2012, 1-year mortality declined from 45% to 33% and 1- to 5-year mortality from 59% to 43%. The decline occurred independently of patients' co-morbidity levels. Comparing 2008-2012 with 1983-1987, the 5-year age-, sex-, and co-morbidity-adjusted MRR was 0.57 [95% confidence interval (CI) 0.56-0.58]. Using low co-morbidity as reference, the adjusted 5-year MRR in 2003-2007 was increased by 43% for moderate, 66% for severe, and 2.2-fold for very severe co-morbidity. The magnitude of co-morbidity-associated mortality increased over time and was highest in the youngest patients. CONCLUSIONS: Hospitalization rates for heart failure have declined markedly since 2000 in Denmark. One- and five-year mortality declined >40% over the last three decades. The decline in mortality occurred for patients with all levels of co-morbidity, but co-morbidity burden was a strong prognostic factor.

Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients.

OBJECTIVE: We aimed to investigate the impact of hyponatremia severity on mortality risk and assess any evidence of a dose-response relation, utilizing prospectively collected data from population-based registries. DESIGN: Cohort study of 279 ,508 first-time acute admissions to Departments of Internal Medicine in the North and Central Denmark Regions from 2006 to 2011. METHODS: We used the Kaplan-Meier method (1 - survival function) to compute 30-day and 1-year mortality in patients with normonatremia and categories of increasing hyponatremia severity. Relative risks (RRs) with 95% CIs, adjusted for age, gender and previous morbidities, and stratified by clinical subgroups were estimated by the pseudo-value approach. The probability of death was estimated treating serum sodium as a continuous variable. RESULTS: The prevalence of admission hyponatremia was 15% (41,803 patients). Thirty-day mortality was 3.6% in normonatremic patients compared to 7.3, 10.0, 10.4 and 9.6% in patients with serum sodium levels of 130-134.9, 125-129.9, 120-124.9 and <120 mmol/l, resulting in adjusted RRs of 1.4 (95% CI: 1.3-1.4), 1.7 (95% CI: 1.6-1.8), 1.7 (95% CI: 1.4-1.9) and 1.3 (95% CI: 1.1-1.5) respectively. Mortality risk was increased across virtually all clinical subgroups, and remained increased by 30-40% 1 year after admission. The probability of death increased when serum sodium decreased from 139 to 132  mmol/l. No clear increase in mortality was observed for lower concentrations. CONCLUSIONS: Hyponatremia is highly prevalent among patients admitted to Departments of Internal Medicine and is associated with increased 30-day and 1-year mortality risk, regardless of underlying disease. This risk seems independent of hyponatremia severity.

Trends in paediatric macrolide use in five European countries-a population-based study.

PURPOSE: The study aims to analyse overall as well as subgroup-specific outpatient paediatric macrolide use in five European countries, including time trends of macrolide prescription rates, and to provide potential targets for future interventions aiming to promote judicious macrolide use. METHODS: Macrolide prescription rates per 1000 person years to paediatric outpatients (≤18 years) were calculated using healthcare databases from Denmark, Germany, Italy, The Netherlands and the UK. Poisson regression analysis was used to estimate the influence of increasing calendar year on total macrolide and subgroup-specific prescription rates based on monthly data, adjusted for seasonal variations. Time periods for which data were available varied between 4 (Italy 2007-10, Germany 2005-8) and 10 years (UK 2000-9). RESULTS: Paediatric macrolide use in 2008 varied between 199 (Italy) and 47 (Netherlands) prescriptions per 1000 person years. Prescription rates of short-acting macrolides declined significantly in all countries but the UK. The use of intermediate-acting macrolides significantly rose with increasing calendar year in Denmark (rate ratio (RR) = 1.12) and the UK (RR = 1.06), but decreased in Germany (RR = 0.84) and The Netherlands (RR = 0.97). Prescription rates of long-acting agents increased in Denmark (RR = 1.05), The Netherlands (RR = 1.05) and the UK (RR = 1.11) (all trends p < 0.05). The greatest seasonal variations of macrolide use between summer and winter months were observed in Italy and Germany. CONCLUSIONS: The observed trend toward increased prescribing of intermediate- and/or long-acting agents might further increase resistance pressure on bacterial pathogens due to their prolonged plasma half-life and broader antibacterial activity. Marked seasonality of prescription rates in the high-utilising countries, Italy and Germany, suggests frequent prescription of macrolides to treat respiratory infections which may be of viral origin.

Systemic antibiotic prescribing to paediatric outpatients in 5 European countries: a population-based cohort study.

BACKGROUND: To describe the utilisation of antibiotics in children and adolescents across 5 European countries based on the same drug utilisation measures and age groups. Special attention was given to age-group-specific distributions of antibiotic subgroups, since comparison in this regard between countries is lacking so far. METHODS: Outpatient paediatric prescriptions of systemic antibiotics during the years 2005-2008 were analysed using health care databases from the UK, the Netherlands, Denmark, Italy and Germany. Annual antibiotic prescription rates per 1,000 person years were estimated for each database and stratified by age (≤4, 5-9, 10-14, 15-18 years). Age-group-specific distributions of antibiotic subgroups were calculated for 2008. RESULTS: With 957 prescriptions per 1000 person years, the highest annual prescription rate in the year 2008 was found in the Italian region Emilia Romagna followed by Germany (561), the UK (555), Denmark (481) and the Netherlands (294). Seasonal peaks during winter months were most pronounced in countries with high utilisation. Age-group-specific use varied substantially between countries with regard to total prescribing and distributions of antibiotic subgroups. However, prescription rates were highest among children in the age group ≤4 years in all countries, predominantly due to high use of broad spectrum penicillins. CONCLUSIONS: Strong increases of antibiotic prescriptions in winter months in high utilising countries most likely result from frequent antibiotic treatment of mostly viral infections. This and strong variations of overall and age-group-specific distributions of antibiotic subgroups across countries, suggests that antibiotics are inappropriately used to a large extent.

Validity of the International Classification of Diseases, 10th revision discharge diagnosis codes for hyponatraemia in the Danish National Registry of Patients.

OBJECTIVE: To examine the validity of the International Classification of Diseases, 10th revision (ICD-10) codes for hyponatraemia in the nationwide population-based Danish National Registry of Patients (DNRP) among inpatients of all ages. DESIGN: Population-based validation study. SETTING: All somatic hospitals in the North and Central Denmark Regions from 2006 through 2011. PARTICIPANTS: Patients of all ages admitted to hospital (n=819 701 individual patients) during the study period. The patient could be included in the study more than once, and our study did not restrict to patients with serum sodium measurements (total of n=2 186 642 hospitalisations). MAIN OUTCOME MEASURE: We validated ICD-10 discharge diagnoses of hyponatraemia recorded in the DNRP, using serum sodium measurements obtained from the laboratory information systems (LABKA) research database as the gold standard. One sodium value <135 mmol/L measured at any time during hospitalisation confirmed the diagnosis. We estimated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ICD-10 codes for hyponatraemia overall and for cut-off points for increasing hyponatraemia severity. RESULT: An ICD-10 code for hyponatraemia was recorded in the DNRP in 5850 of the 2 186 642 hospitalisations identified. According to laboratory measurements, however, hyponatraemia was present in 306 418 (14%) hospitalisations. Sensitivity of hyponatraemia diagnoses was 1.8% (95% CI 1.7% to 1.8%). For sodium values <115 mmol/L, sensitivity was 34.3% (95% CI 32.6% to 35.9%). The overall PPV was 92.5% (95% CI 91.8% to 93.1%) and decreased with increasing hyponatraemia severity. Specificity and NPV were high for all cut-off points (≥99.8% and ≥86.2%, respectively). Patients with hyponatraemia without a corresponding ICD-10 discharge diagnosis were younger and had higher Charlson Comorbidity Index scores than patients with hyponatraemia with a hyponatraemia code in the DNRP. CONCLUSIONS: ICD-10 codes for hyponatraemia in the DNRP have high specificity but very low sensitivity. Laboratory test results, not discharge diagnoses, should be used to ascertain hyponatraemia.