Adverse Pregnancy Outcomes and Subsequent First-Time Use of Psychiatric Treatment Among Fathers in Denmark.

Importance: Becoming a first-time parent is a major life-changing event and can be challenging regardless of the pregnancy outcome. However, little is known how different adverse pregnancy outcomes affect the father's risk of psychiatric treatment post partum. Objective: To examine the associations of adverse pregnancy outcomes with first-time psychiatric treatment in first-time fathers. Design, Setting, and Participants: This nationwide cohort study covered January 1, 2008, to December 31, 2017, with a 1-year follow-up completed December 31, 2018. Data were gathered from Danish, nationwide registers. Participants included first-time fathers with no history of psychiatric treatment. Data were analyzed from August 1, 2022, to February 20, 2024. Exposures: Adverse pregnancy outcomes including induced abortion, spontaneous abortion, stillbirth, small for gestational age (SGA) and not preterm, preterm with or without SGA, minor congenital malformation, major congenital malformation, and congenital malformation combined with SGA or preterm compared with a full-term healthy offspring. Main Outcomes and Measures: Prescription of psychotropic drugs, nonpharmacological psychiatric treatment, or having a psychiatric hospital contact up to 1 year after the end of the pregnancy. Results: Of the 192 455 fathers included (median age, 30.0 [IQR, 27.0-34.0] years), 31.1% experienced an adverse pregnancy outcome. Most of the fathers in the study had a vocational educational level (37.1%). Fathers experiencing a stillbirth had a significantly increased risk of initiating nonpharmacological psychiatric treatment (adjusted hazard ratio [AHR], 23.10 [95% CI, 18.30-29.20]) and treatment with hypnotics (AHR, 9.08 [95% CI, 5.52-14.90]). Moreover, fathers experiencing an early induced abortion (≤12 wk) had an increased risk of initiating treatment with hypnotics (AHR, 1.74 [95% CI, 1.33-2.29]) and anxiolytics (AHR, 1.79 [95% CI, 1.18-2.73]). Additionally, late induced abortion (>12 wk) (AHR, 4.46 [95% CI, 3.13-6.38]) and major congenital malformation (AHR, 1.36 [95% CI, 1.05-1.74]) were associated with increased risk of nonpharmacological treatment. In contrast, fathers having an offspring being born preterm, SGA, or with a minor congenital malformation did not have a significantly increased risk of any of the outcomes. Conclusions and Relevance: The findings of this Danish cohort study suggest that first-time fathers who experience stillbirths or induced abortions or having an offspring with major congenital malformation had an increased risk of initiating pharmacological or nonpharmacological psychiatric treatment. These findings further suggest a need for increased awareness around the psychological state of fathers following the experience of adverse pregnancy outcomes.

Identifying people living with cystic fibrosis in the Danish National Patient Registry: A validation study.

BACKGROUND: The Danish National Patient Registry (DNPR) serves as a valuable resource for scientific research. However, to ensure accurate results in cystic fibrosis (CF) studies that rely on DNPR data, a robust case-identification algorithm is essential. This study aimed to develop and validate algorithms for the reliable identification of CF patients in the DNPR. METHODS: Using the Danish Cystic Fibrosis Registry (DCFR) as a reference, accuracy measures including sensitivity and positive predictive value (PPV) for case-finding algorithms deployed in the DNPR were calculated. Algorithms were based on minimum number of hospital contacts with CF as the main diagnosis and minimum number of days between first and last contact. RESULTS: An algorithm requiring a minimum of one hospital contact with CF as the main diagnosis yielded a sensitivity of 96.1 % (95 % CI: 94.2 %; 97.4 %) and a PPV of 84.9 % (82.0 %; 87.4 %). The highest-performing algorithm required minimum 2 hospital visits and a minimum of 182 days between the first and the last contact and yielded a sensitivity of 95.9 % (95 % CI: 94.1 %; 97.2 %), PPV of 91.0 % (95 % CI: 88.6 %; 93.0 %) and a cohort entry delay of 3.2 months at the 75th percentile (95th percentile: 38.7 months). CONCLUSIONS: The DNPR captures individuals with CF with high sensitivity and is a valuable resource for CF-research. PPV was improved at a minimal cost of sensitivity by increasing requirements of minimum number of hospital contacts and days between first and last contact. Cohort entry delay increased with number of required hospital contacts.

Increasing Medication Use and Polypharmacy in Type 2 Diabetes: The Danish Experience From 2000 to 2020.

OBJECTIVE: Type 2 diabetes often coexists with other conditions that are amenable to pharmacological treatment. We hypothesized that polypharmacy among individuals with type 2 diabetes has increased since 2000. RESEARCH DESIGN AND METHODS: Using Danish national registries, we established a cohort of all Danish individuals (aged ≥18 years) with type 2 diabetes between 2000 and 2020. We analyzed their medication use and prevalence of varying degrees of polypharmacy (≥5 or ≥10 medications), stratifying by age, sex, number of chronic diseases, and socioeconomic status. RESULTS: The cohort grew from 84,917 patients in 2000 to 307,011 in 2020, totaling 461,849 unique patients. The number of daily medications used per patient increased from (mean ± SD) 3.7 ± 2.8 (in 2000) to 5.3 ± 3.2 (in 2020). The lifetime risk of polypharmacy was substantial, with 89% (n = 409,062 of 461,849) being exposed to ≥5 medications at some point and 47% (n = 217,467of 461,849) to ≥10 medications. The increases were driven by an expanding group of medications, with analgesics, antihypertensives, proton pump inhibitors, and statins having the largest net increase. Advanced age, male sex, lower socioeconomic status, and Danish ethnicity positively correlated with polypharmacy but could not explain the overall increase in polypharmacy. CONCLUSIONS: Medication use and polypharmacy have increased among patients with type 2 diabetes. Although the implications and appropriateness of this increased medication use are uncertain, the results stress the increasing need for health care personnel to understand the potential risks associated with polypharmacy, including medication interactions, adverse effects, and over- and underprescribing.

Temporal trends and regional variability in BRAF and KRAS genetic testing in Denmark (2010-2022): Implications for precision medicine.

OBJECTIVE: This study aims to evaluate the developments in the testing of Kirsten Rat Sarcoma viral oncogene homolog (KRAS) and v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations across different cancer types and regions in Denmark from 2010 to 2022. STUDY DESIGN AND SETTING: Using comprehensive data from the Danish health registries, we linked molecular test results from the Danish Pathology Registry with cancer diagnoses from the Danish National Patient Registry between 2010 and 2022. We assessed the frequency and distribution of KRAS and BRAF mutations across all cancer types, years of testing, and the five Danish regions. RESULTS: The study included records of KRAS testing for 30 671 patients and BRAF testing for 30 860 patients. Most KRAS testing was performed in colorectal (78%) and lung cancer (18%), and BRAF testing in malignant melanoma (13%), colorectal cancer (67%), and lung cancer (12%). Testing rates and documentation mutational subtypes increased over time. Reporting of wildtype results varied between lung and colorectal cancer, with underreporting in lung cancer. Regional variations in testing and reporting were observed. CONCLUSION: Our study highlights substantial progress in KRAS and BRAF testing in Denmark from 2010 to 2022, evidenced by increased and more specific reporting of mutational test results, thereby improving the precision of cancer diagnosis and treatment. However, persistent regional variations and limited testing for cancer types beyond melanoma, colorectal, and lung cancer highlight the necessity for a nationwide assessment of the optimal testing approach.

Education, employment, and income among people living with cystic fibrosis across three decades - A matched cohort study using Danish health registries.

BACKGROUND: Past and ongoing advancements in cystic fibrosis (CF) care warrant long-term analysis of the societal impact of the condition. This study aims to evaluate changes in key socioeconomic factors across three decades among people living with CF (pwCF), compared with both the general population and an early-onset chronic disease population. METHODS: This nationwide, registry-based, matched cohort study included all pwCF ≥ 18 years in Denmark in the years 1990, 2000, 2010, and 2018. Each person living with CF was matched to five individuals in the general population and five individuals living with type 1 diabetes or juvenile arthritis based on age, sex, and municipality. RESULTS: The Danish adult CF population increased nearly fourfold from 88 in 1990 to 331 in 2018, and mean age increased by ten years. The educational level of pwCF was similar to the two comparator cohorts, while pwCF were less often in employment and more often permanently outside the labor force. Personal and household income levels of the CF cohort were higher than those of the comparator cohorts. CONCLUSIONS: The disadvantage in employment for pwCF remained, but, over time, the societal profiles of the one-year CF cohorts increasingly converged with those of the comparator cohorts, indicative of improved clinical management, extended life expectancy, and the supportive role of the Danish welfare system in reducing health inequalities. Further research should be done to evaluate the effects of the newly introduced modulator therapies on employment, considering the broader societal impact and impact on quality of life.

Association Between First-time Neurologic Events and Metronidazole Treatment: A Case-time Control Study.

PURPOSE: Metronidazole, a widely used antimicrobial medication, has been linked to neurologic adverse drug reactions. This study investigates the association between metronidazole use and first-time neurologic events. METHODS: We conducted a case-time-control study using data from the Danish National Patient Register and the National Prescription Register in years 2013 to 2021. Patients with a first-time diagnosis of encephalopathy, cerebellar dysfunction, or peripheral neuropathy were included. Conditional logistic regression analyses were performed to estimate the risk of neurologic events associated with metronidazole use. FINDINGS: Out of 476,066 first-time metronidazole prescriptions, the 100-day cumulative incidence of peripheral neuropathy was 0.016%, and 0.002% for cerebellar dysfunction or encephalopathy. In the case-time control study, we identified 17,667 persons with a first-time neurologic event and were included for the analysis. The estimated odds ratio for the combined neurologic events was 0.98 (95% CI, 0.59-1.64, P = 0.95) with no statistically significant association across different subgroups and time windows. IMPLICATIONS: Our findings suggest that metronidazole-induced neurologic events may be rarer than previously described, and we did not find any consistent or statistically significant association between metronidazole exposure. Nonetheless, clinicians should remain vigilant to potential neurologic risks in patients receiving metronidazole, to ensure its safe and effective use.

Monitoring and treatment of hypercholesterolemia after an atherosclerotic cardiovascular disease event in Denmark from 2015 to 2020.

BACKGROUND AND AIMS: Lowering the blood concentration of low-density lipoprotein cholesterol (LDL-C), is a cornerstone in preventing atherosclerotic cardiovascular disease (ASCVD). Current European guidelines recommends LDL-C < 1.4 mmol/L for secondary prevention in high-risk patients. The aim of this study is to investigate monitoring and treatment of hypercholesterolemia one year after a ASCVD event. METHODS: Danish patients with hypercholesterolemia and an incident ASCVD event from 2015 to 2020 were included in this nationwide cohort study. Patients' LDL-C measurements and lipid-lowering treatment were followed for one year after ASCVD event, or until death or migration. Imputation was used to estimate absolute LDL-values when patients were unmeasured. RESULTS: A total of 139,043 patients were included in the study with a mean follow-up time of 10.4 months. During the one-year period, 120,020 (86%) patients had their LDL-C measured at least once, 83,723 (60%) patients were measured at least twice. During the period one to six months after ASCVD event 25,999 (19%) achieved an LDL-C < 1.4 mmol/L, 93,349 (67%) failed to achieve an LDL-C < 1.4 mmol/L, and 196,950 (14%) had died or migrated. Missing LDL-C values were estimated via imputation. At the end of month twelve, 60,583 (44%) patients were in statin monotherapy, 2926 (2%) were treated with other lipid-lowering treatment, 42,869 (31%) were in no treatment, and 32,665 (23%) had died or migrated. CONCLUSIONS: Many Danish patients are not appropriately followed-up with LDL-C measurements, and a substantial number of patients are not in lipid-lowering treatment one year after an ASCVD event.

The impact of type 2 diabetes and glycaemic control on mortality and clinical outcomes in hospitalized patients with COVID-19 in the capital region of Denmark.

AIM: To explore the impact of type 2 diabetes (T2D), glycaemic control and use of glucose-lowering medication on clinical outcomes in hospitalized patients with COVID-19. MATERIALS AND METHODS: For all patients admitted to a hospital in the Capital Region of Denmark (1 March 2020 to 1 December 2021) with confirmed COVID-19, we extracted data on mortality, admission to intensive care unit (ICU), demographics, comorbidities, medication use and laboratory tests from the electronic health record system. We compared patients with T2D to patients without diabetes using Cox proportional hazards models adjusted for available confounding variables. Outcomes were 30-day mortality and admission to an ICU. For patients with T2D, we also analysed the association of baseline haemoglobin A1c (HbA1c) levels and use of specific glucose-lowering medications with the outcomes. RESULTS: In total, 4430 patients were analysed, 1236 with T2D and 2194 without diabetes. The overall 30-day mortality was 19% (n = 850) and 10% (n = 421) were admitted to an ICU. Crude analyses showed that patients with T2D both had increased mortality [hazard ratio (HR) 1.37; 95% CI 1.19-1.58] and increased risk of ICU admission (HR 1.28; 95% CI 1.04-1.57). When adjusted for available confounders, this discrepancy was attenuated for both mortality (adjusted HR 1.13; 95% CI 0.95-1.33) and risk of ICU admission (adjusted HR 1.01; 95% CI 0.79-1.29). Neither baseline haemoglobin A1c nor specific glucose-lowering medication use were significantly associated with the outcomes. CONCLUSION: Among those hospitalized for COVID-19, patients with T2D did not have a higher risk of death and ICU admission, when adjusting for confounders.

Age disparities in glucose-lowering treatment for Danish people with type 2 diabetes: a cross-sectional study between 2019 and 2020.

BACKGROUND: The pharmacotherapeutic guidelines for type 2 diabetes have changed considerably during the past decades. SGLT2 inhibitors and GLP-1 receptor agonists have emerged as first-line agents by preventing cardiovascular events within a few years of treatment. In contrast, sulphonylureas and insulin have been deprioritised due to less beneficial effects and the risk of hypoglycaemia-particularly in older people who are frail. We hypothesised that medications with a high risk of hypoglycaemia were used more often in older people compared with younger people. METHODS: In a nationwide cohort of people with type 2 diabetes in Denmark from 2019 to 2020, we described the use of specific glucose-lowering medications in relation to age and glycated haemoglobin A1C (HbA1c) by descriptive statistics and regression models adjusted for sex, socioeconomic factors, renal function, and several comorbidities. FINDINGS: Among 290 890 people with type 2 diabetes, glucose-lowering medication usage peaked at age 70 years. Increasing age was associated with relatively less use of metformin, GLP-1 receptor agonists, and SGLT2 inhibitors and more use of basal insulin, DDP-4 inhibitors, and sulphonylureas. When comparing 80-year-olds with 60-year-olds at similar HbA1c levels of 6·5% (48 mmol/mol), 80-year-olds used 8% (95% CI 7-10%) fewer glucose-lowering medications, were 55% less likely to receive GLP-1 receptor agonists or SGLT2 inhibitors (relative ratio 0·45, 95% CI 0·42-0·48), and 65% more likely to receive sulphonylureas (1·65, 1·54-1·76). Among 23 032 individuals aged 80 years or older with HbA1c levels of less than 6·5% (<48 mmol/mol), 2291 (10%) used sulphonylureas or insulin. INTERPRETATION: In Danish people with type 2 diabetes, the likelihood of using glucose-lowering medications with a high risk of hypoglycaemia (eg, sulphonylureas and basal insulin) increased with age, whereas the likelihood of using GLP-1 receptor agonists and SGLT2 inhibitors decreased. Some people aged 80 years or older with an HbA1c level of less than 6·5% (48 mmol/mol) were potentially overtreated with sulphonylureas or insulin. These findings emphasise the importance of frequently re-evaluating glucose-lowering treatments. FUNDING: None. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Effect of single versus multiple prophylactic antibiotic doses on prosthetic joint infections following primary total hip arthroplasty in patients with osteoarthritis at public and private hospitals in Denmark: protocol for a nationwide cross-over, cluster randomised, non-inferiority trial [The Pro-Hip-Quality Trial].

INTRODUCTION: A feared complication after total hip arthroplasty (THA) is prosthetic joint infection (PJI), associated with high morbidity and mortality. Prophylactic antibiotics can reduce the risk of PJI. However, there is no consensus on the dosages and current recommendations are based on a low evidence level. The objective is to compare the effect of a single versus multiple doses of prophylactic antibiotics administered within 24 hours on PJI. METHODS AND ANALYSIS: The study is designed as a cross-over, cluster randomised, non-inferiority trial. All clinical centres use both antibiotic practices (1 year of each intervention). All Danish orthopaedic surgery departments will be involved: Based on quality databases, 2-year cohorts of approximately 20 000 primary THAs conducted at 39 public and private hospitals, will be included. INCLUSION CRITERIA: age ≥18 years, all indications for THA except patients operated due to acute or sequelae from proximal femoral or pelvic fractures or bone tumour or metastasis. The primary outcome is PJI within 90 days after primary THA. Secondary outcomes include (1) serious adverse events, (2) potential PJI, (3) length of hospitalisation stay, (4) cardiovascular events, (5) hospital-treated infections, (6) community-based antibiotic use, (7) opioid use and (8) use of acetaminophen and non-steroidal anti-inflammatory drugs. All outcome measures will be extracted from national databases. Analyses will be based on the intention-to-treat population. Non-inferiority will be shown if the upper limit of the two-sided 95% CI for the OR is less than 1.32 for the single dose as compared with multiple doses. The results will establish best practice on antibiotic prophylaxis dosages in the future. ETHICS AND DISSEMINATION: This study has been approved by Committees on Health Research Ethics for The Capital Region of Denmark (21069108) and The Danish Medicines Agency (2021091723). All results will be presented in peer-reviewed medical journals and international conferences. TRIAL REGISTRATION NUMBER: NCT05530551.

KRAS G12C mutated advanced non-small cell lung cancer (NSCLC): Characteristics, treatment patterns and overall survival from a Danish nationwide observational register study.

OBJECTIVES: We aimed to characterize the advanced NSCLC population in terms of KRAS G12C prevalence, patient characteristics, and survival outcomes after the introduction of immunotherapies. MATERIALS AND METHODS: We identified adult patients diagnosed with advanced NSCLC between January 1, 2018 and June 30, 2021 using the Danish health registries. Patients were grouped by mutational status (any KRAS mutation, KRAS G12C, and KRAS/EGFR/ALK wildtype [Triple WT]). We analyzed KRAS G12C prevalence, patient and tumor characteristics, treatment history, time-to-next-treatment (TTNT), and overall survival (OS). RESULTS: We identified 7,440 patients of whom 40% (n = 2,969) were KRAS tested prior to the first line of therapy (LOT1). Among the KRAS tested, 11% (n = 328) harbored KRAS G12C. More KRAS G12C patients were women (67%), smokers (86%), had a high (≥50%) level of PD-L1 expression (54%), and more frequently received anti-PD-L1 treatment than any other group. From the date of the mutational test result, OS (7.1-7.3 months) was similar between the groups. OS from LOT1 (14.0 months) and LOT2 (10.8 months), and TTNT from LOT1 (6.9 months) and LOT2 (6.3 months) was numerically longer for the KRAS G12C mutated group compared to any other group. However, from LOT1 and LOT2, the OS and TTNT were comparable when stratifying the groups by PD-L1 expression level. Regardless of the mutational group, OS was markedly longer for patients with high PD-L1 expression. CONCLUSION: In patients diagnosed with advanced NSCLC after the implementation of anti-PD-1/L1 therapies, the survival in KRAS G12C mutated patients is comparable to patients with any KRAS mutation, Triple WT, and all NSCLC patients.

Duloxetine Exposure During Pregnancy and the Risk of Offspring Being Born Small for Gestational Age or Prematurely: A Nationwide Danish and Swedish Safety Study.

BACKGROUND: Depression or depressive symptoms are common among pregnant women. The use of antidepressants during pregnancy has grown steadily. The risk of offspring being born small for gestational age or prematurely when exposed to duloxetine during pregnancy is not established. OBJECTIVE: We aimed to investigate the association between duloxetine exposure during pregnancy and offspring being born small for gestational age or prematurely. METHODS: We conducted an observational study including live births in Sweden and Denmark (2004-2016). Duloxetine exposure during early (0-140 days) or late (141 to delivery) pregnancy compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, venlafaxine-exposed, and duloxetine discontinuers. RESULTS: In total, 2,083,467 pregnancies were identified, where 1589 and 450 were duloxetine exposed in early and late pregnancy, respectively. For small for gestational age, no increased risk was seen for duloxetine across comparators. In the early and late exposure windows, propensity score-matched odds ratios for small for gestational age ranged between 0.64 (95% confidence interval 0.44-0.95) and 1.48 (95% confidence interval 0.85-2.57). For preterm birth, the findings differed across comparators and exposure-time windows, but trended towards an increased risk for duloxetine-exposed when compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, and duloxetine discontinuers in both early exposure and late exposure. The odds ratios ranged between 1.17 and 2.04, of which some did not reach statistical significance. No clear association was observed when compared with venlafaxine exposed, 0.91 (95% confidence interval 0.73-1.14) for early exposure and 1.26 (95% confidence interval 0.86-1.86) for late exposure. Most preterm births (79.2%) occurred in weeks 33-36 of gestation. CONCLUSIONS: Duloxetine exposure during pregnancy is unlikely to increase the risk of small for gestational age. Although not consequently statistically significant across comparisons, a trend towards an increased risk of preterm birth was observed for duloxetine exposed. Therefore, an increased risk of preterm birth cannot be excluded, especially for women exposed to duloxetine throughout pregnancy.

Discontinuation of antipsychotics in individuals with first-episode schizophrenia and its association to functional outcomes, hospitalization and death: a register-based nationwide follow-up study.

BACKGROUND: Discontinuation of antipsychotic medication may be linked to high risk of relapse, hospitalization and mortality. This study investigated the use and discontinuation of antipsychotics in individuals with first-episode schizophrenia in relation to cohabitation, living with children, employment, hospital admission and death. METHODS: Danish registers were used to establish a nationwide cohort of individuals ⩾18 years with schizophrenia included at the time of diagnosis in1995-2013. Exposure was antipsychotic medication calculated using defined daily dose and redeemed prescriptions year 2-5. Outcomes year 5-6 were analysed using binary logistic, negative binomial and Cox proportional hazard regression. RESULTS: Among 21 351, 9.3% took antipsychotics continuously year 2-5, 38.6% took no antipsychotics, 3.4% sustained discontinuation and 48.7% discontinued and resumed treatment. At follow-up year 6, living with children or employment was significantly higher in individuals with sustained discontinuation (OR 1.98, 95% CI 1.53-2.56 and OR 2.60, 95% CI 1.91-3.54), non-sustained discontinuation (OR 1.25, 95% CI 1.05-1.48 and 2.04, 95% CI 1.64-2.53) and no antipsychotics (OR 2.00, 95% CI 1.69-2.38 and 5.64, 95% CI 4.56-6.97) compared to continuous users. Individuals with non-sustained discontinuation had more psychiatric hospital admissions (IRR 1.27, 95% CI 1.10-1.47) and longer admissions (IRR 1.68, 95% CI 1.30-2.16) year 5-6 compared to continuous users. Mortality during year 5-6 did not differ between groups. CONCLUSION: Most individuals with first-episode schizophrenia discontinued or took no antipsychotics the first years after diagnosis and had better functional outcomes. Non-sustained discontinuers had more, and longer admissions compared to continuous users. However, associations found could be either cause or effect.

Healthcare resource utilization in patients with treatment-resistant depression-A Danish national registry study.

OBJECTIVES: To investigate healthcare resource utilization (HRU) and associated costs by depression severity and year of diagnosis among patients with treatment-resistant depression (TRD) in Denmark. METHODS: Including all adult patients with a first-time hospital contact for major depressive disorder (MDD) in 1996-2015, TRD patients were defined at the second shift in depression treatment (antidepressant medicine or electroconvulsive therapy) and matched 1:2 with non-TRD patients. The risk of utilization and amount of HRU and associated costs including medicine expenses 12 months after the TRD-defining date were reported, comparing TRD patients with non-TRD MDD patients. RESULTS: Identifying 25,321 TRD-patients matched with 50,638 non-TRD patients, the risk of psychiatric hospitalization following TRD diagnosis was 138.4% (95%-confidence interval: 128.3-149.0) higher for TRD patients than for non-TRD MDD patients. The number of hospital bed days and emergency department (ED) visits were also higher among TRD patients, with no significant difference for somatic HRU. Among patients who incurred healthcare costs, the associated HRU costs for TRD patients were 101.9% (97.5-106.4) higher overall, and 55.2% (50.9-59.6) higher for psychiatric services than those of non-TRD patients. The relative differences in costs for TRD-patients vs non-TRD patients were greater for patients with mild depression and tended to increase over the study period (1996-2015), particularly for acute hospitalizations and ED visits. LIMITATIONS: TRD was defined by prescription patterns besides ECT treatments. CONCLUSION: TRD was associated with increased psychiatric-related HRU. Particularly the difference in acute hospitalizations and ED visits between TRD and non-TRD patients increased over the study period.

Psoriasis and adverse pregnancy outcomes: A nationwide case-control study in 491,274 women in Denmark.

Background: The chronic systemic inflammation associated with psoriasis supposedly creates an undesirable milieu for a pregnancy, resulting in an increased risk of adverse pregnancy outcomes (APOs). Objective: To investigate the association between psoriasis and APOs as well as how the association differs according to psoriasis severity (mild and moderate-to-severe). Methods: This nationwide register-based case-control study collected data from 1973 to 2017. Cases were APOs (spontaneous abortion, ectopic pregnancy [EP], intrauterine fetal death, and stillbirth). Singleton live births were controls. Adjusted logistic regression models were used for statistical analyses. Results: In total, 42,041 (8.56%) APOs and 449,233 (91.44%) controls were included. EP was the only APO that was found to be statistically associated with psoriasis (odds ratio, 1.34; 95% CI, 1.06-1.68). Odds ratio for EP was the highest for women with moderate-to-severe psoriasis (odds ratio, 2.77; 95% CI, 1.13-6.76). The absolute risk of EP was 2.48% higher for women with moderate-to-severe psoriasis compared with women without psoriasis (3.98% vs 1.50%). Limitations: No access to clinical data confirming psoriasis severity. Conclusion: The present study found a significant association between EP and psoriasis (absolute risk of 3.98%). As EP is the leading cause of maternal morbidity and mortality in the first trimester of pregnancy, our findings call for particular care for women of reproductive age with psoriasis.

Short-term mortality following tramadol poisonings in Denmark.

Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess the 30-day mortality following morphine, oxycodone, and mixed poisonings compared to tramadol poisonings; and (3) assess the development in tramadol poisonings during a 12-year period. Poisonings were identified from 2006 to 2017. A Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) along with 95% confidence intervals (CIs) for 30-day mortality following morphine, oxycodone or mixed poisonings compared to tramadol poisonings. We identified 7718 opioid poisonings among 6365 patients. The patients with a tramadol poisoning were younger and had less comorbidities than the patients with a morphine, oxycodone or mixed poisoning. Within 30 days, a total of 205 patients died. The 30-day mortality risk was higher following morphine (aHR 3.2, 95% CI 2.0-5.1), oxycodone (aHR 2.1, 95% CI 1.2-3.6) and mixed poisonings (aHR 1.6, 95% CI 1.0-2.7) compared to tramadol poisonings. The annual number of tramadol poisonings increased from 233 in 2006 to 501 in 2013 and declined to 348 in 2017. In conclusion, despite a lower mortality risk compared to other opioid poisonings, physicians should consider the poisoning and abuse risks when prescribing tramadol.

Clozapine- and non-clozapine-associated neutropenia in patients with schizophrenia: a retrospective cohort study.

Introduction: The antipsychotic drug clozapine remains underutilized partly because of the risk of life-threatening adverse effects, such as neutropenia. Therefore, an extensive hematological monitoring program was set up to detect neutropenia. Methods: In this retrospective cohort study, we used registry-based data from the Capital Region of Denmark to investigate incidence rates of neutropenia among patients with a diagnosis of schizophrenia or other psychotic disorders and treated with clozapine for the first time. In a within-subject design, we compared rates of neutropenia in time periods where patients were exposed to clozapine versus time periods, where they were not exposed to clozapine. We also investigated whether the lengths of clozapine-associated neutropenia (CAN) were related to discontinuation of clozapine treatment. Results: Data from 520 clozapine users were included. The incidence rate of CAN was 3.2 cases per 100 person-years (95% confidence interval [CI]: 2.1-4.8) throughout the entire study. There was no significant difference in incidence rates of neutropenia during clozapine exposure and non-clozapine exposure, with an incidence rate ratio of 0.7 (95% CI: 0.4-1.3). One episode of severe neutropenia was detected. Episodes of CAN with only one sub-threshold neutrophil count were not associated with higher clozapine discontinuation (26%) than CAN episodes of more than one sub-threshold neutrophil count (28%). Conclusion: In the present study, we could not confirm that clozapine treatment was associated with neutropenia.

Intracranial Hemorrhage Following Anticoagulant Treatment in Denmark: Spontaneous Adverse Drug Reaction Reports Versus Real-World Data.

INTRODUCTION: In Denmark, physicians are legally obliged to report serious adverse drug reactions (ADRs), such as intracranial hemorrhage (ICH) following anticoagulant (AC) treatment, to the Danish Medicines Agency. We were therefore puzzled to discover a high number of reports concerning ICHs following treatment with the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin. This was surprising, as all DOACs have been found to be associated with a lower risk of ICH compared with warfarin in phase III randomized controlled trials. OBJECTIVES: The primary aim of the study was to estimate the level of underreporting of ICH as an ADR following treatment with warfarin, dabigatran, rivaroxaban, and apixaban. METHODS: This observational study covered a 5-year period (2014-2018). Using nationwide registries held by the Danish Health Data Authority, the number of users, exposure time in person-years, and related ICH events for each of the study drugs were estimated. Data on ADR-ICH reports were extracted from the interactive ADR overviews held by the Danish Medicines Agency. RESULTS: From 2014 to 2018, 97.0% of the identified warfarin-related ICH events were not reported as ADRs. For the DOACs, the level of underreporting ranged from 88.8 to 90.8%. CONCLUSION: We found a heavy and differentiated level of underreporting of ICH as an ADR following treatment with the four study drugs.

Prophylactic anticoagulation with low molecular weight heparin in COVID-19: cohort studies in Denmark and Sweden.

OBJECTIVES: To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19. METHODS: Using healthcare records from the Capital Region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis. RESULTS: We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N = 432) and the pooled risk ratio was 0.91 (CI 0.60-1.38) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (0.76-1.66), while we observed no increased risk of bleeding 0.63 (0.13-2.94). The relative risk of venous thromboembolism was 0.80 (0.43-1.47). CONCLUSION: We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH.

Exposure to Tramadol During Early Pregnancy and Risk of Spontaneous Abortion or Major Congenital Malformations.

OBJECTIVE: To investigate whether exposure to tramadol during early pregnancy is associated with an increased risk of spontaneous abortion or major congenital malformations. METHODS: The study is a nationwide cohort study including all registered pregnancies in Denmark between January 1, 1997, and December 31, 2016. The Danish National Prescription Register was used to identify maternal exposure to tramadol. Pregnancies with maternal exposure to tramadol were matched with pregnancies without maternal exposure to tramadol in a ratio of up to 1:4 using propensity scoring. The primary outcomes were spontaneous abortion and major congenital malformations. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) of spontaneous abortion, and log binominal models were used to estimate the relative risk ratios (RRs) of major congenital malformations. RESULTS: A total of 36,467 (tramadol exposure n=7,310) and 18,907 (tramadol exposure n=3,796) pregnancies were included in the analyses of spontaneous abortion and major congenital malformations, respectively. Spontaneous abortion occurred in 893 (12.2%) pregnancies with maternal exposure to tramadol and in 3,471 (11.9%) pregnancies without maternal exposure to tramadol (HR 1.06, 95% CI 0.99-1.14). A major congenital malformation occurred in the offspring of 151 (4.0%) pregnancies with maternal exposure to tramadol, compared with 579 (3.8%) in pregnancies without maternal exposure to tramadol (RR 1.04, 95% CI 0.87-1.24). CONCLUSION: Exposure to tramadol during early pregnancy does not appear to be associated with an increased risk of spontaneous abortion or major congenital malformations.