Danish Health Registries Research Articles

Total hip arthroplasty performed in summer is not associated with increased risk of revision due to prosthetic joint infection: a cohort study on 58 449 patients with osteoarthritis from the Danish Hip Arthroplasty Register.

Aims: Danish surveillance data indicated a higher risk of revision due to prosthetic joint infection (PJI) following total hip arthroplasty (THA) performed during the summer season. We investigated the association between summer and revision risk following primary THA. Methods: This study identified 58 449 patients from the Danish Hip Arthroplasty Register (DHR) with unilateral primary THA due to osteoarthritis from 2010-2018. From Danish Health Registries, we retrieved information on Charlson Comorbidity Index (CCI), immigration, and death and microbiological data on intraoperative biopsies and cohabitation status. Meteorological data were received from the Danish Meteorological Institute. Summer was defined as June-September, and THAs performed during October-May were used as controls. The primary outcome was revision due to PJI: the composite of revision with culture-positive biopsies or reported PJI to the DHR. The secondary outcome was any revision. The cumulative incidences of revision and the corresponding adjusted relative risk (RR) with 95 % confidence intervals (CI) were calculated by season of the primary THA. Results: A total of 1507 patients were revised, and 536 were due to PJI. The cumulative incidence for THAs performed during summer and the rest of the year was 1.1 % (CI 1.0-1.3) and 1.1 % (CI 1.0-1.2) for PJI revision and 2.7 % (CI 2.5-3.0) and 2.5 % (CI 2.4-2.7) for any revision, respectively. The adjusted RR for THAs performed during summer vs. the rest of the year for PJI revision and any revision was 1.1 (CI 0.9-1.3) and 1.1 (CI 1.0-1.2), respectively. Conclusion: We found no association between summer and the risk of PJI revision or any revision in a northern European climate.

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

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

Confounding and Negative Control Methods in Observational Study of SARS-CoV-2 Vaccine Effectiveness: A Nationwide, Population-Based Danish Health Registry Study.

Observational studies of SARS-CoV-2 vaccine effectiveness are prone to confounding, which can be illustrated using negative control methods. Nationwide population-based cohort study including two cohorts of Danish residents 60-90 years of age matched 1:1 on age and sex: A vaccinated and a non-vaccinated cohort, including 61052 SARS-CoV-2 vaccinated individuals between 1 March and 1 July 2021 and 61052 individuals not vaccinated preceding 1 July 2021. From these two cohorts, we constructed negative control cohorts of individuals diagnosed with SARS-CoV-2 infection or acute myocardial infarction, stroke, cancer, low energy fracture, or head-trauma. Outcomes were SARS-CoV-2 infection, negative control outcomes (eg, mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear), and death. We used Cox regression to calculate adjusted incidence and mortality rate ratios (aIRR and aMRR). Risks of SARS-CoV2 infection and all negative control outcomes were elevated in the vaccinated population, ranging from an aIRR of 1.15 (95% CI: 1.09-1.21) for eye examinations to 3.05 (95% CI: 2.24-4.14) for malignant melanoma. Conversely, the risk of death in the SARS-CoV-2 infected cohort and in all negative control cohorts was lower in vaccinated individuals, ranging from an aMRR of 0.23 (95% CI: 0.19-0.26) after SARS-CoV-2 infection to 0.50 (95% CI: 0.37-0.67) after stroke. Our findings indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be subject to substantial confounding. Therefore, randomized trials are essential to establish vaccine efficacy after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.

COPD and Smoking Status - It Does Matter: Characteristics and Prognosis of COPD According to Smoking Status.

Chronic obstructive pulmonary disease is a chronic, often progressive disease, which in most patients is caused by tobacco smoking. Our study focuses on differences in COPD-related outcomes between never smokers, former smokers, and current smokers. A nationwide, population-based cohort study utilizing Danish health registries. Clinical and socioeconomic variables including smoking status, comorbidities, and dyspnea were obtained. Poisson and Cox Regression were used to calculate the impact of these clinical parameters on the risk of moderate and severe exacerbations and mortality during 12 months of follow-up. A total of 49,826 patients ≥40 years of age, with a hospital diagnosis of COPD in 2008-2017, were identified (mean age 69.2 years, 52% females). A total of 2127 (4%) were never smokers, 29,854 (60%) were former smokers and 17,845 (36%) current smokers. Compared to former and current smokers, never smokers reported a lower modified Medical Research Council score and had a milder COPD stage according to the Global Initiative for Chronic Obstructive Lung Disease classification. During follow-up, never smokers had a significantly lower risk of severe exacerbations (hazard ratio 0.87, 95% confidence interval [CI] 0.78-0.97) and a lower rate of death (mortality ratio 0.75, 95% CI 0.70-0.81) compared to patients with a smoking history. Our nationwide study showed that COPD in never smokers is characterized by a lower level of dyspnea, milder lung function impairment, and a lower risk of exacerbations and death. At the same time, we found active smokers to have the highest risk. These findings highlight the need for campaigns to prevent smoking and may help general practitioners as well as other health care professionals to motivate patients with COPD to stop smoking.

Time to pregnancy and life expectancy: a cohort study of 18 796 pregnant couples.

Is fecundity, measured as time to pregnancy (TTP), associated with mortality in parents? Prolonged TTP is associated with increased mortality in both mothers and fathers in a dose-response manner. Several studies have linked both male and female fecundity to mortality. In women, infertility has been linked to several diseases, but studies suggest that the underlying conditions, rather than infertility, increase mortality. A prospective cohort study was carried out on 18 796 pregnant couples, in which the pregnant women attended prophylactic antenatal care between 1973 and 1987 at a primary and tertiary care unit. The couples were followed in Danish mortality registers from their child's birth date until death or until 2018. The follow-up period was up to 47 years, and there was complete follow-up until death, emigration or end of study. At the first antenatal visit, the pregnant women were asked to report the time to the current pregnancy. Inclusion was restricted to the first pregnancy, and TTP was categorised into <12 months, ≥12 months, not planned, and not available. In sub-analyses, TTP ≥12 was further categorized into 12-35, 36-60, and >60 months. Information for parents was linked to several Danish nationwide health registries. Survival analysis was used to estimate the hazard ratios (HRs) with a 95% CI for survival and adjusted for age at the first attempt to become pregnant, year of birth, socioeconomic status, mother's smoking during pregnancy, and mother's BMI. Mothers and fathers with TTP >60 months survived, respectively, 3.5 (95% CI: 2.6-4.3) and 2.7 (95% CI: 1.8-3.7) years shorter than parents with a TTP <12 months. The mortality was higher for fathers (HR: 1.21, 95% CI: 1.09-1.34) and mothers (HR: 1.29, 95% CI: 1.12-1.49) with TTP ≥12 months compared to parents with TTP <12 months. The risk of all-cause mortality during the study period increased in a dose-response manner with the highest adjusted HR of 1.98 (95% CI: 1.62-2.41) for fathers and 2.03 (95% CI: 1.56-2.63) for mothers with TTP >60 months. Prolonged TTP was associated with several different causes of death in both fathers and mothers, indicating that the underlying causes of the relation between fecundity and survival may be multi-factorial. A limitation is that fecundity is measured using a pregnancy-based approach. Thus, the cohort is conditioned on fertility success and excludes sterile couples, unsuccessful attempts and spontaneous abortions. The question used to measure TTP when the pregnant woman was interviewed at her first attended prophylactic antenatal care: 'From the time you wanted a pregnancy until it occurred, how much time passed?' could potentially have led to serious misclassification if the woman did not answer on time starting unprotected intercourse but on the start of wishing to have a child. We found that TTP is a strong marker of survival, contributing to the still-emerging evidence that fecundity in men and women reflects their health and survival potential. The authors acknowledge an unrestricted grant from Ferring. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. M.L.E. is an advisor to Ro, VSeat, Doveras, and Next. N/A.

Cohort Profile: Better Health in Late Life.

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

Coronary artery calcification score and 19 biomarkers on cardiovascular events; a 10-year follow-up DanRisk substudy

Abstract Background SCORE2 is recommended for the estimation of the 10-year risk of cardiovascular disease (CVD), and guideance of medical therapy. However, the prediction is deficient. Coronary artery calcification (CAC) score has been proven to improve the risk assessment in primary prevention of CVD, however, it is also resource-intensive. Biomarkers may be an advantageous alternative. Purpose This study aims to determine and compare the additive value of CAC-score and 19 biomarkers in risk prediction. Methods Classic cardiovascular (CV) risk factors, CAC-score, and a wide range of blood samples (including lipids, calcium-phosphate metabolism, troponin, inflammation, and kidney function), were collected from 1,211 randomly selected middle-aged men and women in this multicentre prospective cohort in 2009-2010. 10-year follow-up data on CV-events (death from CVD, stroke, myocardial infarction, heart failure or coronary artery revascularization) were obtained from the Danish Health Registries. The association between SCORE2, CAC-score, biomarkers, and CV-events was displayed in Kaplan Meier diagrams, assessed using cox proportional hazard rates (HR) and compared using area under the curve (AUC) calculation of receiver operating characteristic (ROC) curves. The net reclassification improvement (NRI) for CAC-score compared to SCORE2 was also calculated. Results 92 participants had CV-events. Events were seen in 29.3% of 41 participants with a very high risk (SCORE2 ≥10%) and 24.2% of 66 participants with CAC-score ≥400. Adjusted for risk factors, CAC-score was significantly associated with events adjusted HR 1.91 (95%CI: 1.10;3.31), 3.61 (95%CI: 1.93;6.76), and 5.2 (95%CI: 2.63;10.29) for CAC-score 1-99, CAC-score 100-399 and CAC-score ≥400, respectively. HR for the highest quartile of C-reactive protein (CRP) was 2.34 (95%CI: 1.15;4.47), while none of the remaining biomarkers improved HR. CAC-score improved AUC of the SCORE2 model (AUC_CAC+SCORE2: 0.72, AUC_SCORE2: 0.67, p&amp;lt;0.01) as seen in Figure 1. A combination of selected biomarkers (total cholesterol, low-density lipoprotein, phosphate, troponin I, CRP, and creatinine) borderline improved AUC (AUC_Biomarkers+SCORE2: 0.71, AUC_SCORE2: 0.67, p=0.06). Inclusion of CAC-score in the SCORE2 model improved the risk prediction. For participants with a CV-event, 73.9% had increased probabilities and 26.1% had decreased probabilities, compared to 42.4% increased and 57.6% decreased probabilities for participants without an event. NRI was 63% (p&amp;lt;0.0001) Conclusion CAC-score remained to improve the prediction of CV-events, while the selected biomarkers did not.ROC of SCORE2 versus CAC-score+SCORE2

Influence of cholesterol levels on NSAID-associated risks after myocardial infarction: a nationwide population-based cohort study

Abstract Introduction Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, fever, and inflammation, but they can increase the risk of recurrent myocardial infarction (MI), ischemic stroke, atrial fibrillation, and death in patients with MI. Consequently, the European Society of Cardiology warns against using NSAIDs in patients with manifest cardiovascular disease and in high-risk individuals, such as those with dyslipidemia. However, no study has investigated whether NSAID-associated cardiovascular risks differ according to patients’ low-density lipoprotein cholesterol (LDL-C) levels. Purpose To examine whether LDL-C levels influence the cardiovascular risk associated with NSAID use after first-time MI. Methods Using Danish health registries, we conducted a population-based cohort study of all adult patients with a first-time MI hospitalization during 2010–2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and high LDL-C group (&amp;lt;3 vs. ≥3 mmol/L). We used multivariate Cox regression to compute adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between NSAID use (modelled in time-varying manner) and a major adverse cardiovascular event (MACE), defined as a composite of recurrent MI, ischemic stroke, and all-cause death. We repeated the analysis by changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L. Results We followed 50,573 patient with a first-time MI for a mean of 3.5 years (66% males, median age of 68 years. During NSAID use, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11–1.32) overall, 1.19 (1.06–1.33) in the low LDL-C group, and 1.23 (1.07–1.41) in the high LDL-group. The HRs in the low and high LDL-C groups were 1.09 (0.88–1.34) vs. 0.94 (0.74–1.19) for recurrent MI, 0.97 (0.66–1.41) vs. 1.27 (0.86–1.87) for ischemic stroke, and 1.22 (1.07–1.39) vs. 1.54 (1.30–1.83) for all-cause death. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. Conclusion In patients with a first-time MI, NSAID use was associated with an increased risk of MACE. The LDL-C level did not influence the association between NSAID use and MACE, but it might influence the association between NSAID use and all-cause death. Thus, healthcare providers should be mindful of the increased cardiovascular risk associated with NSAID use in patients with previous MI, regardless of LDL-C values.

Validation of the DANCAMI, the Charlson Comorbidity Index, and the Elixhauser Comorbidity Index for predicting mortality in patients with infective endocarditis

Abstract Introduction Comorbidity scores are often used to adjusted for confounding by comorbidity burden in population-based research as they increase statistical efficiency in smaller study populations. However, there is currently no comorbidity index available for predicting infective endocarditis prognosis. This gap in the literature hinders the ability to accurately adjust for confounding in studies investigating the prognosis of infective endocarditis, highlighting the need of validating existing comorbidity indices for this purpose. Purpose To validate the discriminatory ability of the Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI), the Charlson Comorbidity Index (CCI), and the Elixhauser Comorbidity Index (ECI) for predicting in-hospital, 1-year, and 10-year all-cause mortality after infective endocarditis. Methods We used nationwide Danish health registries to identify all patients with a first-time inpatient, primary or secondary diagnosis for infective endocarditis between 1995 and 2021 and their comorbidities. When identifying the comorbidities, we used all in and outpatient hospital information in the 10 years before the infective endocarditis diagnosis. Based on the presence of comorbidities, we estimated the DANCAMI, the CCI, and the ECI scores for each patient. Using a logistic regression model, we calculated area under the receiver operating curves (AUCs) for a baseline model including age and sex and for models including the scores from the comorbidity indices plus age and sex for in-hospital, 1-year, and 10-year all-cause mortality. The AUC describes the probability that for a pair of random patients, the model will assign a greater predicted risk to the patient dying. Results Overall, we identified 12,530 patients with infective endocarditis. The median age was 71 years and 35% were females. For the individual analyses, we had complete follow-up on 12,493 patients when predicting in-hospital mortality, 11,587 when predicting 1-year mortality, and 5,880 patients when predicting 10-year mortality. For in-hospital mortality, the AUCs were 0.62 for the baseline model, 0.65 for the DANCAMI, 0.64 for the CCI, and 0.65 for the ECI. For 1-year mortality, the AUCs were 0.66 for the baseline model, 0.71 for the DANCAMI, 0.70 for the CCI, and 0.70 for the ECI. For 10-year mortality, the AUCs were 0.76 for the baseline model, 0.82 for the DANCAMI, 0.81 for the CCI, and 0.81 for the ECI. Conclusions After accounting for sex and age, adding either the DANCAMI, the CCI, or the ECI did not increase the discriminatory ability for predicting in-hospital all-cause mortality after infective endocarditis but did increase the discriminatory ability for predicting 1-year and 10-year all-cause mortality. Consequently, comorbidity scores might be beneficial in reducing confounding by comorbidity burden when predicting 1-year or 10-year infective endocarditis mortality, depending on their association with the exposure of interest.

Myocardial infarction mortality after COVID-19: a nationwide population-based cohort study

Abstract Background Coronavirus disease 2019 (COVID-19) is associated with an increased risk of myocardial infarction (MI). Small studies suggest that MI in patients with recent COVID-19 may have a distinct clinical course and a worse prognosis, compared to MI without recent COVID-19. Whether previous COVID-19 vaccination modifies the clinical course of MI after recent COVID-19 is also unknown. Purpose To compare mortality in people with MI with and without recent COVID-19, and to examine the impact of previous COVID-19 vaccination. Methods Using Danish health registries, we conducted a nationwide population-based cohort study comprising all adults (≥18 years) with a first-time MI between 26 May 2020 and 9 March 2022. We excluded patients with &amp;lt;1 year of residence in Denmark prior to their MI. The exposure was recent COVID-19 defined by a positive SARS-CoV-2 PCR test ≤90 days before MI. We followed the patients for 30 days from the date of their MI admission until death (if any), or emigration, whichever came first. We used Cox proportional-hazards regression to compute hazard ratios (HRs) for death within 30 days after MI. Using propensity-score balancing of confounders with stabilised inverse probability weighting, we adjusted for differences in age, sex, DANCAMI comorbidity burden, use of selected medications, and calendar period between MI patients with and without recent COVID-19. We stratified by COVID-19 vaccination status. Results Of 11,919 included patients with MI, 332 patients had COVID-19 within 90 days before MI. The COVID-19 exposed patients were characterised by a larger proportion of males and COVID-19 vaccinations, lower age, and a longer median time from first COVID-19 vaccination to MI compared to the COVID-19 unexposed patients. 34 of the patients with recent COVID-19 (10.2%) and 702 of the patients without recent COVID-19 (6.1%) died within 30 days after their MI, resulting in a crude HR of 1.71 with a 95% confidence interval (CI) of 1.21–2.42 for the patients with recent COVID-19. After adjusting by stabilised inverse probability weighting, this HR further increased to 2.08 (95% CI: 1.23–3.52). Previous COVID-19 vaccination modified this association with a three-fold increased mortality in unvaccinated MI patients with recent COVID-19, while the mortality HR associated with recent COVID-19 was close to one in patients who were previously COVID-19 vaccinated. Conclusion Patients with recent COVID-19 had increased short-term mortality after MI, but only if unvaccinated.

Elevated remnant cholesterol in atherosclerotic cardiovascular disease in diabetes: a population-based prospective cohort study

Abstract Background Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population; the association in individuals with diabetes is not known. Purpose We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of peripheral artery disease, myocardial infarction, ischemic stroke, and any ASCVD in individuals with diabetes. Methods We studied 4,569 individuals with diabetes and 102,674 individuals without diabetes from the Copenhagen General Population Study (2003-2015). In those with diabetes, during up to 15 years of follow-up, 236 were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischemic stroke, and 498 with any ASCVD in national Danish health registries. Remnant cholesterol was calculated from a standard lipid-profile as total cholesterol minus HDL cholesterol minus LDL cholesterol. Results Individuals with diabetes had higher levels of remnant cholesterol, but lower levels of LDL cholesterol, compared to individuals without diabetes (Figure 1). Statin use could explain the lower levels of LDL cholesterol but did not associate with levels of remnant cholesterol. Multivariable adjusted hazard ratios (95% confidence interval) per doubling of remnant cholesterol and LDL cholesterol were 1.8 (1.2-2.5) and 0.9 (0.6-1.2) for peripheral artery disease, 1.8 (1.3-2.6) and 1.0 (0.7-1.4) for myocardial infarction, 1.6 (1.1-2.3) and 1.1 (0.8-1.6) for ischemic stroke, and 1.7 (1.4-2.2) and 0.9 (0.7-1.1) for any ASCVD, respectively. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischemic stroke, and 1.6-fold for any ASCVD. Elevated remnant cholesterol explained 14% (95% confidence interval: 6-23%) of excess risk of PAD; corresponding numbers were 26% (10-41%) for myocardial infarction, 34% (5-64%) for ischemic stroke, and 24% (12-36%) for any ASCVD (Figure 2). LDL cholesterol was lower in individuals with diabetes than in individuals without diabetes and could therefore not explain excess risk. Conclusions Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes and explained 24% of their excess risk of ASCVD. Clinical trials should determine if remnant cholesterol lowering can prevent ASCVD in individuals with diabetes.

Paternal preconception exposure to non-steroid anti-inflammatory drugs or opioids and adverse birth outcomes: A nationwide registry-based cohort study.

Paternal use of analgesics during the time of conception and adverse birth outcomes are poorly studied. We investigated the association between paternal exposure to non-steroid anti-inflammatory drugs and opioids within 3 months before the date of conception and the risk of adverse birth outcomes (preterm birth, small for gestational age, low Apgar score, and major congenital malformations). We used nationwide data from the Danish health registers. We included information on all singleton live births, and their fathers and mothers from 1997 to 2018. We created two exposed cohorts, children with preconception paternal exposure to (1) non-steroid anti-inflammatory drugs and (2) opioids. The unexposed cohort was children without preconception paternal exposure to non-steroid anti-inflammatory drugs or opioids, and we performed a sub-analysis against paternal use of acetaminophen (paracetamol). We used logistic regression models to estimate the odds ratios of adverse birth outcomes including 95% confidence intervals. We identified 1,260,934 children, 45,667 children with paternal exposure to non-steroid anti-inflammatory drugs, 10,086 children with paternal exposure to opioids, and 1,205,181 unexposed children. The adjusted odds ratio for preterm birth was 1.08 (95% confidence interval, 1.03-1.13) after paternal exposure to non-steroid anti-inflammatory drugs and 1.21 (95% confidence interval, 1.08-1.35) after paternal exposure to opioids. The adjusted odds ratio for small for gestational age was 1.09 (95% confidence interval, 1.03-1.17) after paternal exposure to non-steroid anti-inflammatory drugs, and 1.03 (95% confidence interval, 0.88-1.21) after paternal exposure to opioids. We found null-associations for a low Apgar score and major congenital malformations. Estimates were attenuated when compared against paternal paracetamol exposure. Overall, we found null-associations across the comparisons made. Weak associations were found for paternal exposure to non-steroid anti-inflammatory drugs or opioids and preterm birth and small for gestational age, but not with low Apgar score or major congenital malformation. All associations were attenuated when compared against an active comparator of paternal paracetamol exposure. The effect sizes were small and less likely to be of clinical relevance.

Inflammatory Bowel Disease in Adults and Elderly: The Use of Selected Non-IBD Medication Examined in a Nationwide Cohort Study.

Real-world data on medications used for conditions other than inflammatory bowel disease (IBD) are sparse. We examined how the onset of IBD affects the prescription pattern of selected non-IBD medication and the risk of becoming an incident user. This nationwide cohort study utilized data from Danish health registers. We included incident patients with young adult-onset IBD (18-39 years of age), adult-onset IBD (40-59 years of age), and elderly-onset IBD (60+ years of age), from 1998 to 2018 and followed all for 3 years. We examined redeemed prescriptions before and after the onset of IBD and estimated the risk of becoming a user of non-IBD medications using logistic regression models. We identified 36165 patients, 16 771 (46%) with young adult onset, 10615 (29%) with adult onset, and 8779 (24%) with elderly onset. The onset of IBD increased the use of antidepressants, antipsychotics, sedatives/hypnotics, opioids, nonopioid analgesics, antidiabetics, and proton pump inhibitors, even in patients with no other underlying comorbid diseases. The adjusted odds ratio for using antidepressants 1 year after the onset of IBD in elderly was 1.50 (95% confidence interval [CI], 1.14-1.82), in opioids 1.69 (95% CI, 1.45-1.95), in nonopioid analgesics 2.10 (95% CI, 1.77-2.48), in cardiovascular medication 2.20 (95% CI, 1.86-2.61), and in proton pump inhibitors 1.51 (95% CI, 1.31-1.74) compared with adults. In all 3 age groups, the proportions of patients with redeemed prescriptions for several groups of non-IBD medication were significantly increased after the IBD diagnosis compared with before. The risk of becoming an incident user for several groups of non-IBD medication was increased in elderly patients.

Retinal vein occlusion as an age-dependent marker of incident dementia in a long-term Danish national cohort.

The aim of this study was to investigate retinal vein occlusion (RVO) as an independent marker of incident dementia. In a prospective nationwide cohort study, we identified 2 225 568 individuals through the Danish national health registers. Individuals older than 65 years, without unspecified retinal vascular occlusion or dementia were included from 1998 to 2020 and followed until 2022. We calculated the incidence rate (IR) and performed a Cox regression analysis with a hazard ratio (HR) and 95% confidence interval (CI) for RVO (exposure) as a marker of all-cause dementia adjusted for systemic comorbidity. We identified 19 669 individuals with RVO who had a higher prevalence of systemic comorbidity at inclusion compared to those without RVO (n = 2 185 483). We performed a Cox regression analysis for age-dependent exposure due to non-proportional hazards in the pre-planned analysis. Exposed individuals younger than 75 years had an increased risk of all-cause dementia (adjusted HR 1.09, 95% CI 1.01-1.18), whereas individuals older than 75 years had a decreased risk of all-cause dementia (adjusted HR 0.92, 95% CI 0.86-0.98). Individuals with RVO had an age-dependent risk of dementia, with a 9% increased risk in individuals with RVO younger than 75 years and an 8% decreased risk in individuals older than 75 years at the time of exposure.

Elevated remnant cholesterol and atherosclerotic cardiovascular disease in diabetes: a population-based prospective cohort study

Aims/hypothesisElevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. This association is not well studied in individuals with diabetes, who are often included in clinical trials of remnant cholesterol-lowering therapy. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of ASCVD in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.MethodsWe included 4569 white Danish individuals with diabetes (58% statin users) nested within the Copenhagen General Population Study (2003–2015). The ASCVDs peripheral artery disease, myocardial infarction and ischaemic stroke were extracted from national Danish health registries without losses to follow-up. Remnant cholesterol was calculated from a standard lipid profile.ResultsDuring up to 15 years of follow-up, 236 individuals were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischaemic stroke and 498 with any ASCVD. Multivariable adjusted HR (95% CI) per doubling of remnant cholesterol was 1.6 (1.1, 2.3; p=0.01) for peripheral artery disease, 1.8 (1.2, 2.5; p=0.002) for myocardial infarction, 1.5 (1.0, 2.1; p=0.04) for ischaemic stroke, and 1.6 (1.2, 2.0; p=0.0003) for any ASCVD. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischaemic stroke and 1.6-fold for any ASCVD. Excess risk explained by elevated remnant cholesterol and low-grade inflammation was 14% and 8% for peripheral artery disease, 26% and 16% for myocardial infarction, 34% and 34% for ischaemic stroke, and 24% and 18% for any ASCVD, respectively. LDL-cholesterol did not explain excess risk, as it was not higher in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.Conclusions/interpretationElevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes. Remnant cholesterol and low-grade inflammation explained substantial excess risk of ASCVD conferred by diabetes. Whether remnant cholesterol should be used as a treatment target remains to be determined in randomised controlled trials.Graphical

Preoperative intravenous iron treatment – a cohort study on colorectal cancer recurrence

BackgroundIntravenous (i.v.) iron treatment has been speculated to increase the malignant potential of colorectal malignancies but also to enhance the immune systems potential to fight the invasive tumor. Clinical data however is very limited. We investigate if preoperative i.v. iron treatment is associated with colorectal cancer (CRC) recurrence. MethodsRetrospective cohort study on surgical CRC patients with iron deficiency anemia (1st March 2013 - 31st December 2019). Patients were grouped based on whether they had received preoperative treatment with i.v. iron. Local data was combined with data from the National Danish Health registries to identify recurrences, death, and emigration. Survival analysis, including Kaplan-Meyer curves and multivariate competing risk analysis adjusting for sex, age, ASA-group, tumor stage, surgical radicality, and miss match repair status was performed. ResultsOf 1228 patients, 125 were available for analysis. 89 patients had received preoperative i.v. iron and 36 had not. The two groups were comparable on baseline and surgical characteristics. Median follow-up times were 4.74 in iron treated patients and 5 years in patients not receiving iron treatment. Five-year rate of non-recurrence was 85 % (0.74–0.91) in the i.v. iron treated group vs. 82 % (0.64–0.91) in the control group, non-significant difference. Multivariate survival analysis did not find iron treatment to be associated with recurrence rates (Hazard Ratio 0.88 (95 % ci; 0.31–2.51). ConclusionNo association between preoperative i.v. iron treatment and the five-year cancer recurrence rate in iron deficient anemic CRC patients was found.

Retinal artery occlusion does not act as an independent marker of upcoming dementia: results from a Danish 20-year cohort study

PurposeRetinal artery occlusion (RAO) is a vision threatening disease associated with cerebral vascular dysfunction, which may reflect initial signs of cerebral pathology. Early detection of patients in risk of dementia could allow for preventative treatment. Hence, this study aimed to investigate RAO as an independent biomarker of incident dementia.MethodsThis study was a nationwide, 20-year longitudinal cohort study in Denmark with inclusion from 1998 to 2020 and follow up until the end of 2022. We identified 2 205 159 individuals aged 65 or older through the Danish national health registers and monitored RAO (exposure) and dementia (outcome) status. We calculated incidence rate and performed a Cox regression analysis with hazard ratio (HR) and 95% confidence interval (CI) for RAO as a marker of dementia in a crude, a semi-adjusted (age and sex), and a fully adjusted model (furthermore adjusted for marital status and systemic comorbidity.)ResultsWe identified 8 863 individuals with RAO. Incidence rates were higher among exposed compared to unexposed individuals (12.28 and 8.18 per 1000 person-years at risk, respectively). Individuals with RAO were more likely to be male and older at inclusion, to have hypertension, dyslipidaemia, cardiovascular disease, chronic kidney disease, and diabetes (p < 0.001). RAO was not associated with all-cause dementia in the crude analysis (HR 1.07 CI [1.00-1.17]) or in the fully adjusted analysis (HR 0.98 CI [0.91–1.06].ConclusionAlthough individuals with RAO had a higher incidence of dementia compared to unexposed individuals, these associations were lost when confounders were taken into account.

Cotinine concentrations in maternal serum and amniotic fluid during pregnancy and risk of testicular germ cell cancer in the offspring: A prospective nested case-control study.

Maternal smoking in pregnancy may increase the risk of testicular germ cell cancer (TGCC) in offspring, but current evidence remains inconclusive. We performed a nested case-control study using cotinine measurements in maternal serum and amniotic fluid as a biomarker for tobacco exposure during pregnancy. A total of 654 males with maternal serum (n = 359, ncases/controls = 71/288) and/or amniotic fluid (n = 295, ncases/controls = 66/229) samples were included. Data on TGCC diagnoses and relevant covariates were derived from nationwide Danish health registries. Cotinine was quantified by liquid chromatography tandem mass spectrometry. An adapted cox regression model estimated the risk of TGCC considering active and inactive tobacco use defined according to cotinine concentrations of <, ≥15 ng/ml. Overall, the concentrations of cotinine were comparable in maternal serum and amniotic fluid (medianserum/amniotic fluid : 2.1/2.6 ng/ml). A strong statistically significant correlation was detected in 14 paired samples (Spearman rho: 0.85). Based on maternal serum cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC in offspring (HR 0.88, 95% CI 0.51; 1.52). Similarly, based on amniotic fluid cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC (HR 1.11, 95% CI 0.64; 1.95). However, different risks were observed for seminomas and nonseminomas in both matrices, but none were statistically significant. Our findings did not provide convincing evidence supporting that exposure to tobacco during pregnancy is associated with TGCC.

No Association Between Previous General Infection and Prosthetic Joint Infection After Total Hip Arthroplasty—A National Register-Based Cohort Study on 58,449 Patients Who Have Osteoarthritis

BackgroundProsthetic joint infection (PJI) following total hip arthroplasty (THA) is a complication associated with increased risk of death. There is limited knowledge about the association between infection before THA, and risk of revision due to PJI. We investigated the association between any previous hospital-diagnosed or community-treated infection 0 to 6 months before primary THA and the risk of revision. MethodsWe obtained data on 58,449 patients who were operated with primary unilateral THA between 2010 and 2018 from the Danish Hip Arthroplasty Register. Information on previous infection diagnoses, redeemed antibiotic prescriptions up to 1 year before primary THA, intraoperative biopsies, and cohabitations was retrieved from Danish health registers. All patients had a 1-year follow-up. Primary outcome was revision due to PJI. Secondary outcome was any revision. We calculated the adjusted relative risk with 95% confidence intervals (CI), treating death as competing risk. ResultsAmong 1,507 revisions identified, 536 were due to PJI with a cumulative incidence of 1.0% ([CI] 0.9 to 1.2) and 0.9% ([CI] 0.8 to 1.0) for patients who did and did not have previous infection. For any revision, the cumulative incidence was 3.1% ([CI] 2.9 to 3.4) and 2.4% ([CI] 2.3 to 2.6) for patients who did and did not have previous infection. The adjusted relative risk for PJI revision was 1.1 ([CI] 0.9 to 1.4) and for any revision 1.3 ([CI] 1.1 to 1.4) for patients who did have previous infection compared to those who did not. ConclusionPrevious hospital-diagnosed or community-treated infection 0 to 6 months before primary THA does not increase the risk of PJI revision. It may be associated with increased risk of any revision.

Ophthalmic symptoms, clinical signs and diagnostic delay in infants diagnosed with brain tumours in Denmark between 2007 and 2017.

To investigate ophthalmic onset manifestations and the impact of diagnostic delay on the prognosis in infants (<1 year) diagnosed with a brain tumour. A retrospective population-based nationwide study of infants diagnosed with a brain tumour between 2007 and 2017 in Denmark. Data was retrieved from the Danish Childhood Cancer Registry, the National Danish Health registries, and medical files. Primary outcome measures included symptoms, clinical findings, time to diagnosis and survival. Thirty-seven infants were diagnosed with a brain tumour in Denmark between 2007 and 2017. In total, 19/37 infants (51%, 95% CI: 34-68) had ophthalmic manifestations at any time prior to or at diagnosis; and in 6/37 (16%, 95% CI: 6-32) ophthalmic manifestations were the initial symptom. The most common ophthalmic manifestations were strabismus (n = 7), sunset eyes (n = 6), nystagmus (n = 4), reduced pupillary light reflex (n = 4), and/or decreased vision (n = 4). The median number of symptoms per infant at the time of diagnosis was three (range 0-9). The median diagnostic delay was 26 days (range 0-283, IQR: 6;90). 5-year survival rate was 75% (95% CI: 61-90) and all children with diagnostic delay > 100 days (n = 9, 24%) were still alive at the end of follow-up (median 6.3 years, range 2.2-10.2). We provide an overview of symptoms and clinical signs in a nation-wide series of infants with CNS tumours and demonstrate that ophthalmic manifestations are frequently observed in infants prior to diagnosis, but, often in combination with other clinical signs. The diagnostic delay was substantial for a large part of the infants, but this was not associated with increased mortality.