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.

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.

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.

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.

Mapping Outcomes and Registries Used in Current Danish Pharmacoepidemiological Research.

Purpose: There is an increasing need for national and international pharmacoepidemiological studies based on high-quality real-world data of which the Danish registries are a valuable source. In lack of a complete overview of which data are used to assess real-world drug safety and effectiveness outcomes, we aimed to map the outcomes, data sources, and the reporting of outcome quality in recent pharmacoepidemiological studies. Methods: We conducted a systematic mapping review of pharmacoepidemiological studies based on Danish registries investigating drug safety and/or effectiveness, published in the period 2018-2019, identified in PubMed and Scopus. Extraction included: Anatomical Therapeutic Chemical level 2 code for drug exposures, outcomes, outcome data sources, and quality of outcomes. Results: Of the 210 included studies, 96% used outcomes categorized as Clinical, 4% utilized outcomes categorized as Society-related, 5% used outcomes categorized as Healthcare cost and utilization, and 3% of the studies applied outcomes categorized as Patient-reported in which the percentages are not mutually exclusive. Diagnosis (66%) and Mortality (38%) were the two most utilized subcategories among those categorized as Clinical outcomes. Danish Health Data Authority and Statistics Denmark registries were the most reported outcome data sources (90%). Ninety-six studies (46%) reported one or more quality parameters related to their outcomes of interest with accuracy/validity being the most reported parameter (22%). Conclusion: The Danish registries support a wide range of outcomes. Across therapeutic areas, most studies investigate traditional clinical outcomes of disease and mortality based on data from a small number of available registries. In contrast, clinical and biochemical databases, despite potentially offering outcomes with high responsiveness, and the high-quality social and healthcare cost registries were rarely used as outcome data sources.

Exposure to duloxetine during pregnancy and risk of congenital malformations and stillbirth: A nationwide cohort study in Denmark and Sweden.

BACKGROUND: The prevalence of depression and the exposure to antidepressants are high among women of reproductive age and during pregnancy. Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the United States and Europe in 2004 for the treatment of depression. Fetal safety of duloxetine is not well established. The present study evaluates the association of exposure to duloxetine during pregnancy and the risk of major and minor congenital malformations and the risk of stillbirths. METHODS AND FINDINGS: A population-based observational study was conducted based on data from registers in Sweden and Denmark. All registered births and stillbirths in the medical birth registers between 2004 and 2016 were included. Malformation diagnoses were identified up to 1 year after birth. Logistic regression analyses were used. Potential confounding was addressed through multiple regression, propensity score (PS) matching, and sensitivity analyses. Confounder variables included sociodemographic information (income, education, age, year of birth, and country), comorbidity and comedication, previous psychiatric contacts, and birth-related information (smoking during pregnancy and previous spontaneous abortions and stillbirths). Duloxetine-exposed women were compared with 4 comparators: (1) duloxetine-nonexposed women; (2) selective serotonin reuptake inhibitor (SSRI)-exposed women; (3) venlafaxine-exposed women; and (4) women exposed to duloxetine prior to, but not during, pregnancy. Exposure was defined as redemption of a prescription during the first trimester and throughout pregnancy for the analyses of malformations and stillbirths, respectively. Outcomes were major and minor malformations and stillbirths gathered from the national patient registers. The cohorts consisted of more than 2 million births with 1,512 duloxetine-exposed pregnancies. No increased risk for major malformations, minor malformations, or stillbirth was found across comparison groups in adjusted and PS-matched analyses. Duloxetine-exposed versus duloxetine-nonexposed PS-matched analyses showed odds ratio (OR) 0.98 (95% confidence interval [CI] 0.74 to 1.30, p = 0.909) for major malformations, OR 1.09 (95% CI 0.82 to 1.45, p = 0.570) for minor malformation, and 1.18 (95% CI 0.43 to 3.19, p = 0.749) for stillbirths. For the individual malformation subtypes, some findings were statistically significant but were associated with large statistical uncertainty due to the extremely small number of events. The main limitations for the study were that the indication for duloxetine and a direct measurement of depression severity were not available to include as covariates. CONCLUSIONS: Based on this observational register-based nationwide study with data from Sweden and Denmark, no increased risk of major or minor congenital malformations or stillbirth was associated with exposure to duloxetine during pregnancy.

Duloxetine Exposure During Pregnancy and the Risk of Spontaneous and Elective Abortion: A Danish Nationwide Observational Study.

BACKGROUND: Depression and antidepressant treatment are widespread among women of childbearing age. OBJECTIVE: This study evaluates the association between duloxetine exposure during pregnancy and spontaneous and elective abortions. PATIENTS AND METHODS: The nationwide, observational study based on register data from Denmark included women with a recorded pregnancy in the birth register or an abortion in the patient register between 2004 and 2016. Duloxetine-exposed women were compared with (1) duloxetine non-exposed, (2) selective serotonin reuptake inhibitor (SSRI)-exposed, (3) venlafaxine-exposed, and (4) women discontinuing duloxetine before pregnancy. Exposure status was based on records of redeemed prescriptions. Cox regression with adjustments and propensity score matching was applied. RESULTS: The data from 1,019,957 pregnancies were used, including 1,212 pregnancies exposed to duloxetine. Duloxetine-exposed women had an increased hazard ratio (HR) for spontaneous abortions compared with SSRI-exposed women: propensity score matched HR 1.25 [95% confidence interval (CI), 1.00-1.57]. No increased hazard was observed for duloxetine-exposed women compared with duloxetine non-exposed: 1.08 (95% CI 0.89-1.31); venlafaxine-exposed: 1.08 (95% CI 0.82-1.41); and duloxetine discontinuers: 0.99 (95% CI 0.76-1.30). An increased HR of elective abortions was observed in duloxetine-exposed women compared to duloxetine non-exposed: 1.41 (95% CI 1.25-1.59); SSRI-exposed: 1.32 (95% CI 1.15-1.51); and duloxetine discontinuers: 1.46 (95% CI 1.23-1.75), but not to venlafaxine-exposed women: 1.09 (95% CI 0.93-1.27). CONCLUSION: There was no increased risk of spontaneous or elective abortion associated with exposure to duloxetine. The increase risk observed for women exposed to duloxetine in comparison with SSRI-exposed for spontaneous and in comparison with all groups (except venlafaxine-exposed) for elective abortion suggested confounding.

Treatment patterns in patients with treatment-resistant depression in Danish patients with major depressive disorder.

OBJECTIVE: To describe treatment patterns in patients with treatment-resistant depression (TRD) and major depressive disorder (MDD) stratified by depression severity and year of diagnosis. Patterns of treatment were also compared to country-specific guidelines. METHODS: All adults registered first time with a hospital contact due to MDD from 1996 through 2015 were identified and followed for all dispensed prescriptions of antidepressants, antipsychotics, lithium, initiation of electroconvulsive therapy (ECT), and psychotherapy in Danish registers 12 months before and after their hospital MDD diagnosis. TRD was characterized by two shifts in treatment. RESULTS: We identified 197,615 patients of whom 15% developed TRD. In total, 88% of patients started treatment with antidepressants or ECT. Selective serotonin reuptake inhibitors (SSRIs) were the most frequently used treatment during the study period and more than half (50.7%) of patients changed treatment at least once. Among patients with TRD, serotonin and noradrenaline reuptake inhibitors (SNRIs) were the most frequently used treatment (55.9%), and 37.0% initiated a new treatment the following year. SSRIs and SNRIs were part of most combinations of treatment, regardless of depression severity, year of diagnosis, or presence of TRD. CONCLUSION: 15% of patients met the criteria for TRD. Irrespective of patient characteristics and year of diagnosis, SSRIs and SNRIs are the most used treatments for depression, even after patients met the criteria for TRD. We confirm that guidelines for first treatment were followed for most patients diagnosed with MDD in Denmark, but for patients with TRD, choice of treatment was arbitrary.

Developing and validating COVID-19 adverse outcome risk prediction models from a bi-national European cohort of 5594 patients.

Patients with severe COVID-19 have overwhelmed healthcare systems worldwide. We hypothesized that machine learning (ML) models could be used to predict risks at different stages of management and thereby provide insights into drivers and prognostic markers of disease progression and death. From a cohort of approx. 2.6 million citizens in Denmark, SARS-CoV-2 PCR tests were performed on subjects suspected for COVID-19 disease; 3944 cases had at least one positive test and were subjected to further analysis. SARS-CoV-2 positive cases from the United Kingdom Biobank was used for external validation. The ML models predicted the risk of death (Receiver Operation Characteristics-Area Under the Curve, ROC-AUC) of 0.906 at diagnosis, 0.818, at hospital admission and 0.721 at Intensive Care Unit (ICU) admission. Similar metrics were achieved for predicted risks of hospital and ICU admission and use of mechanical ventilation. Common risk factors, included age, body mass index and hypertension, although the top risk features shifted towards markers of shock and organ dysfunction in ICU patients. The external validation indicated fair predictive performance for mortality prediction, but suboptimal performance for predicting ICU admission. ML may be used to identify drivers of progression to more severe disease and for prognostication patients in patients with COVID-19. We provide access to an online risk calculator based on these findings.

A Collaborative Medication Review Including Deprescribing for Older Patients in an Emergency Department: A Longitudinal Feasibility Study.

Medication review for older patients with polypharmacy in the emergency department (ED) is crucial to prevent inappropriate prescribing. Our objective was to assess the feasibility of a collaborative medication review in older medical patients (≥65 years) using polypharmacy (≥5 long-term medications). A pharmacist performed the medication review using the tools: Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria, a drug-drug interaction database (SFINX), and Renbase® (renal dosing database). A geriatrician received the medication review and decided which recommendations should be implemented. The outcomes were: differences in Medication Appropriateness Index (MAI) and Assessment of Underutilization Index (AOU) scores between admission and 30 days after discharge and the percentage of patients for which the intervention was completed before discharge. Sixty patients were included from the ED, the intervention was completed before discharge for 50 patients (83%), and 39 (61.5% male; median age 80 years) completed the follow-up 30 days after discharge. The median MAI score decreased from 14 (IQR 8-20) at admission to 8 (IQR 2-13) 30 days after discharge (p < 0.001). The number of patients with an AOU score ≥1 was reduced from 36% to 10% (p < 0.001). Thirty days after discharge, 83% of the changes were sustained and for 28 patients (72%), 1≥ medication had been deprescribed. In conclusion, a collaborative medication review and deprescribing intervention is feasible to perform in the ED.

The "RCT augmentation": a novel simulation method to add patient heterogeneity into phase III trials.

BACKGROUND: Phase III randomized controlled trials (RCT) typically exclude certain patient subgroups, thereby potentially jeopardizing estimation of a drug's effects when prescribed to wider populations and under routine care ("effectiveness"). Conversely, enrolling heterogeneous populations in RCTs can increase endpoint variability and compromise detection of a drug's effect. We developed the "RCT augmentation" method to quantitatively support RCT design in the identification of exclusion criteria to relax to address both of these considerations. In the present manuscript, we describe the method and a case study in schizophrenia. METHODS: We applied typical RCT exclusion criteria in a real-world dataset (cohort) of schizophrenia patients to define the "RCT population" subgroup, and assessed the impact of re-including each of the following patient subgroups: (1) illness duration 1-3 years; (2) suicide attempt; (3) alcohol abuse; (4) substance abuse; and (5) private practice management. Predictive models were built using data from different "augmented RCT populations" (i.e., subgroups where patients with one or two of such characteristics were re-included) to estimate the absolute effectiveness of the two most prevalent antipsychotics against real-world results from the entire cohort. Concurrently, the impact on RCT results of relaxing exclusion criteria was evaluated by calculating the comparative efficacy of those two antipsychotics in virtual RCTs drawing on different "augmented RCT populations". RESULTS: Data from the "RCT population", which was defined with typical exclusion criteria, allowed for a prediction of effectiveness with a bias < 2% and mean squared error (MSE) = 5.8-6.8%. Compared to this typical RCT, RCTs using augmented populations provided improved effectiveness predictions (bias < 2%, MSE = 5.3-6.7%), while returning more variable comparative effects. The impact of augmentation depended on the exclusion criterion relaxed. Furthermore, half of the benefit of relaxing each criterion was gained from re-including the first 10-20% of patients with the corresponding real-world characteristic. CONCLUSIONS: Simulating the inclusion of real-world subpopulations into an RCT before running it allows for quantification of the impact of each re-inclusion upon effect detection (statistical power) and generalizability of trial results, thereby explicating this trade-off and enabling a controlled increase in population heterogeneity in the RCT design.

The "Efficacy-Effectiveness Gap": Historical Background and Current Conceptualization.

BACKGROUND: The concept of the "efficacy-effectiveness gap" (EEG) has started to challenge confidence in decisions made for drugs when based on randomized controlled trials alone. Launched by the Innovative Medicines Initiative, the GetReal project aims to improve understanding of how to reconcile evidence to support efficacy and effectiveness and at proposing operational solutions. OBJECTIVES: The objectives of the present narrative review were 1) to understand the historical background in which the concept of the EEG has emerged and 2) to describe the conceptualization of EEG. METHODS: A focused literature review was conducted across the gray literature and articles published in English reporting insights on the EEG concept. The identification of different "paradigms" was performed by simple inductive analysis of the documents' content. RESULTS: The literature on the EEG falls into three major paradigms, in which EEG is related to 1) real-life characteristics of the health care system; 2) the method used to measure the drug's effect; and 3) a complex interaction between the drug's biological effect and contextual factors. CONCLUSIONS: The third paradigm provides an opportunity to look beyond any dichotomy between "standardized" versus "real-life" characteristics of the health care system and study designs. Namely, future research will determine whether the identification of these contextual factors can help to best design randomized controlled trials that provide better estimates of drugs' effectiveness.