Publications by authors named "Vera Ehrenstein"

128 Publications

Long-term risk of epilepsy, cerebral palsy and attention-deficit/hyperactivity disorder in children affected by a threatened abortion in utero.

Int J Epidemiol 2021 Apr 13. Epub 2021 Apr 13.

Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.

Background: The birth of a child affected by a threatened abortion (TAB) in utero is associated with autism spectrum disorder; association with other neurological disorders is unknown.

Methods: This nationwide registry-based cohort study included singletons live-born in Denmark (1979-2010), followed through 2016. The outcomes were epilepsy, cerebral palsy (CP) and attention-deficit/hyperactivity disorder (ADHD). We used Cox regression to compute hazard ratios (HRs), adjusted for birth year, birth order, parental age, morbidity, medication use and maternal socio-economic factors. To remove time-invariant family-shared confounding, we applied sibling analyses.

Results: The study population included 1 864 221 singletons live-born in 1979-2010. Among the TAB-affected children (N = 59 134) vs TAB-unaffected children, at the end of follow-up, the cumulative incidence was 2.2% vs 1.6% for epilepsy, 0.4% vs 0.2% for CP and 5.5% vs 4.2% for ADHD (for children born in 1995-2010). The adjusted HRs were 1.25 [95% confidence interval (CI) 1.16-1.34] for epilepsy, 1.42 (95% CI 1.20-1.68) for CP and 1.21 (95% CI 1.14-1.29) for ADHD. In the sibling design, the adjusted HRs were unity for epilepsy (full siblings: 0.96, 95% CI 0.82-1.12; maternal: 1.04, 95% CI 0.90-1.20; paternal: 1.08, 95% CI 0.93-1.25) and ADHD (full: 1.08, 95% CI 0.92-1.27; maternal: 1.04, 95% CI 0.90-1.20; paternal: 1.08, 95% CI 0.93-1.25). For CP, HRs shifted away from unity among sibling pairs (full: 2.92, 95% CI 1.33-6.39; maternal: 2.03, 95% CI 1.15-3.57; paternal: 3.28, 95% CI 1.36-7.91).

Conclusions: The birth of a child affected by TAB in utero was associated with a greater risk of CP, but not epilepsy or ADHD.
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http://dx.doi.org/10.1093/ije/dyab069DOI Listing
April 2021

Assessment of Educational Attainment and Employment Among Individuals With Autism Spectrum Disorder in Denmark.

JAMA Pediatr 2021 Apr 5. Epub 2021 Apr 5.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Importance: Population-based data on educational and employment outcomes in adulthood among individuals diagnosed with autism spectrum disorder (ASD) in childhood are currently limited.

Objective: To evaluate educational attainment and employment among individuals with and without a diagnosis of ASD before age 12 years in Denmark.

Design, Setting, And Participants: This nationwide cross-sectional prevalence study was conducted using data from Danish registers. Individuals with a diagnosis of ASD recorded before age 12 years were identified among all individuals born in Denmark between January 1, 1989, and December 31, 1991, who were alive at age 25 years. Individuals with ASD were then matched on a 10:1 ratio by age, sex, and region of residence with a comparison population of individuals without a diagnosis of ASD at age 12 years. Data were analyzed from March 2019 to December 2020.

Exposures: Autism spectrum disorder diagnosis and diagnostic subtype recorded before age 12 years.

Main Outcomes And Measures: Adjusted prevalence ratios (aPRs) with 95% CIs for the completion of compulsory primary and lower secondary school (grade 9), upper secondary school (grades 10-12 or vocational), and tertiary school (university) and for employment by age 25 years were estimated using log-binomial regression analysis.

Results: A total of 810 individuals with a diagnosis of ASD before age 12 years were matched with a comparison population of 8100 individuals without ASD. The prevalence of ninth-grade completion was similar among those with and without ASD (785 individuals [96.9%] and 7982 individuals [98.5%], respectively; aPR, 0.98; 95% CI, 0.97-1.00). Compared with those without ASD, persons with ASD had a lower prevalence of completing upper secondary school (6338 individuals [78.2%] vs 286 individuals [35.3%], respectively; aPR, 0.46; 95% CI, 0.42-0.50) and tertiary school (2185 individuals [27.0%] vs 70 individuals [8.6%]; aPR, 0.33; 95% CI, 0.26-0.41) and obtaining employment (4284 individuals [77.7%] vs 177 individuals [27.2%]; aPR, 0.35; 95% CI, 0.31-0.40) at age 25 years. A ninth-grade final examination score was available for 394 individuals (48.6%) with ASD and 7417 individuals (91.6%) without ASD. In an analysis stratified by ASD subtype, individuals diagnosed with childhood autism had lower educational attainment and employment than those diagnosed with Asperger syndrome or pervasive developmental disorder not otherwise specified. A total of 461 individuals (56.9%) with ASD were receiving public assistance or a pension (ie, disability benefits) at age 25 years compared with 1094 individuals (13.5%) without ASD in the comparison population.

Conclusions And Relevance: In this population-based cross-sectional study, a diagnosis of ASD in childhood was not associated with the completion of compulsory primary and lower secondary education (ninth grade). An ASD diagnosis before age 12 years was associated with a lower prevalence of attaining education beyond ninth grade and obtaining employment by age 25 years, indicating a substantially higher risk of reliance on public assistance in young adulthood.
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http://dx.doi.org/10.1001/jamapediatrics.2021.0124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022261PMC
April 2021

Mortality Among Parents of Children With Major Congenital Anomalies.

Pediatrics 2021 May 2;147(5). Epub 2021 Apr 2.

Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada;

Background: A mother whose child has a chronic condition, such as a major congenital anomaly, often experiences poorer long-term health, including earlier mortality. Little is known about the long-term health of fathers of infants with a major congenital anomaly.

Methods: In this population-based prospective cohort study, we used individual-linked Danish registry data. Included were all mothers and fathers with a singleton infant born January 1, 1986, to December 31, 2015. Cox proportional hazards regression was used to generate hazard ratios for all-cause and cause-specific mortality among mothers and fathers whose infant had an anomaly and fathers of unaffected infants, relative to mothers of unaffected infants (referent), adjusted for child's year of birth, parity, parental age at birth, parental comorbidities, and sociodemographic characteristics.

Results: In total, 20 952 of 965 310 mothers (2.2%) and 20 655 of 951 022 fathers (2.2%) had an infant with a major anomaly. Median (interquartile range) of parental follow-up was 17.9 (9.5 to 25.5) years. Relative to mothers of unaffected infants, mothers of affected infants had adjusted hazard ratios (aHRs) of death of 1.20 (95% confidence interval [CI]: 1.09 to 1.32), fathers of unaffected infants had intermediate aHR (1.62, 95% CI: 1.59 to 1.66), and fathers of affected infants had the highest aHR (1.76, 95% CI: 1.64 to 1.88). Heightened mortality was primarily due to cardiovascular and endocrine/metabolic diseases.

Conclusions: Mothers and fathers of infants with a major congenital anomaly experience an increased risk of mortality, often from preventable causes. These findings support including fathers in interventions to support the health of parental caregivers.
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http://dx.doi.org/10.1542/peds.2020-028571DOI Listing
May 2021

Use of bisphosphonates in multiple myeloma patients in Denmark, 2005-2015.

Support Care Cancer 2021 Jan 18. Epub 2021 Jan 18.

Haematology Research Unit, Department of Haematology, Odense University Hospital, Odense, Denmark.

Purpose: To describe use of bisphosphonates in newly diagnosed multiple myeloma patients in Denmark.

Methods: Using data from the Danish National Multiple Myeloma Registry, we conducted a population-based cohort study. Among patients newly diagnosed with multiple myeloma from 2005 to 2015, we examined use of bisphosphonates at first- and at progression/second-line anti-myeloma treatment overall, by patient characteristics, and myeloma complications.

Results: Of 2947 patients starting first-line anti-myeloma treatment, 2207 patients (74.9%) received bisphosphonates. During a median follow-up of 27.6 (quartiles, 10.6-52.5) months, disease progression post-first-line treatment was recorded in 1546 patients, of whom 1065 (68.9%) were treated with bisphosphonates. Altogether, 80.9% of patients with and 37.6% of patients without myeloma bone disease were treated with bisphosphonates at first line and 73.0% and 42.7%, respectively, at progression/second line. Moreover, the proportion of patients treated with bisphosphonates decreased with increasing severity of renal impairment at first and at progression/second-line treatment.

Conclusion: The proportion of patients treated with bisphosphonates as part of first- and second-line anti-myeloma treatment increased with presence of myeloma bone disease and decreased by presence and severity of renal impairment. Overall, 25% of newly diagnosed multiple myeloma patients had no record of bisphosphonate treatment, potentially indicating an unmet need.
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http://dx.doi.org/10.1007/s00520-020-05934-8DOI Listing
January 2021

Outcomes in patients with lung cancer treated with crizotinib and erlotinib in routine clinical practice: A post-authorization safety cohort study conducted in Europe and in the United States.

Pharmacoepidemiol Drug Saf 2021 Jun 24;30(6):758-769. Epub 2021 Jan 24.

Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus N, Denmark.

Purpose: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice.

Methods: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately.

Results: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US.

Conclusions: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases.
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http://dx.doi.org/10.1002/pds.5193DOI Listing
June 2021

Associations Between ADHD Medication Use in Pregnancy and Severe Malformations Based on Prenatal and Postnatal Diagnoses: A Danish Registry-Based Study.

J Clin Psychiatry 2021 Jan 5;82(1). Epub 2021 Jan 5.

Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark.

Objective: Attention-deficit/hyperactivity disorder (ADHD) medications are increasingly used in pregnancy. Studies on the pregnancy safety of these medications that are restricted to live births may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The present study addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations.

Methods: A nationwide registry-based study was conducted of 364,012 singleton pregnancies in Denmark from November 1, 2007, to February 1, 2014. Exposures to ADHD medication were obtained from redeemed prescriptions from the Danish Health Services Prescription Database. Outcome data included prenatally diagnosed malformations from the Danish Fetal Medicine Database and postnatally diagnosed malformations from the Danish National Patient Registry. The primary outcome was major malformations overall, and secondary outcomes were malformations of the central nervous system and cardiac malformations. The comparison group was pregnancies with no redeemed prescriptions for ADHD medication. We defined severe cardiac malformations (SCM) as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, postnatal death, or cardiac surgery within 1 year of birth.

Results: The prevalence of first-trimester exposure to ADHD medication increased during the study period from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of the exposures being to methylphenidate. There were 5.1% malformations overall and 2.1% cardiac malformations among the exposed compared to 4.6% and 1.0%, respectively, among the unexposed. For methylphenidate, the adjusted prevalence ratios (PRs) were 1.04 (95% confidence interval [CI], 0.70-1.55) for malformations overall and 1.65 (95% CI, 0.89-3.05) for any cardiac malformations (number needed to harm [NNH] = 92), with septum defects in 10 out of 12 cases. The PR for ventricular septal defect was 2.74 (95% CI, 1.03-7.28) and for SCM, 2.59 (95% CI, 0.98-6.90).

Conclusions: Exposure to methylphenidate was not associated with an increased risk of malformations overall in data that included information from both prenatal and postnatal diagnoses of major malformations. There was an increased risk of cardiac malformations with NNH of 92 based on 12 cases among the exposed. More data are needed on other types of ADHD medication.
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http://dx.doi.org/10.4088/JCP.20m13458DOI Listing
January 2021

Retraction of COVID-19 Pharmacoepidemiology Research Could Have Been Avoided by Effective Use of Reporting Guidelines.

Clin Epidemiol 2020 21;12:1403-1420. Epub 2020 Dec 21.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Two recent high-profile publications (and subsequent retractions) of pharmacoepidemiology studies reporting the effectiveness and risk of hydroxychloroquine in COVID-19 patients received international media attention. Transparent and complete reporting of these studies could have provided peer reviewers and editors with sufficient information to question the methods used and the validity of results. Since these studies used routinely collected health data, the guidelines for the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) should have been applied to ensure complete reporting of the research.

Methods: We evaluated the two retracted articles for completeness of reporting using the RECORD for Pharmacoepidemiology (RECORD-PE) checklist, which includes the checklists for the STengthening the Reporting of OBservational studies in Epidemiology (STROBE) and RECORD. We compared the proportion of STROBE, RECORD and RECORD-PE items adequately reported using Chi-squared statistics.

Results: In the article published by , 29 of 34 STROBE items (85.3%) were adequately reported, compared with 3.5 of 13 RECORD items (26.9%) and 9.5 of 15 RECORD-PE items (63.3%)(χ = 14.839, P <0.001). Similarly, the article published in reported 24 of 34 STROBE items (70.6%), two of 13 RECORD items (15.4%), and 7.5 of 15 RECORD-PE items (50.0%) (χ = 11.668, P = 0.003). Important aspects of the methods unique to research using routinely collected health data were not reported, including variables used to identify exposure, outcome and confounders, validation of the coding or algorithms, a description of the underlying database population and the accuracy of data linkage methods.

Discussion: While STROBE items were generally adequately reported, RECORD and RECORD-PE items were not. Reporting guidelines should be effectively implemented in order for transparency and completeness of research manuscripts, allowing for adequate evaluation by editors and peer reviewers.
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http://dx.doi.org/10.2147/CLEP.S288677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762449PMC
December 2020

Motor Neuron Disease and Risk of Cancer: A Population-Based Cohort Study in Denmark.

Clin Epidemiol 2020 8;12:1347-1353. Epub 2020 Dec 8.

Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.

Background: Some neurogenerative diseases have been linked to a reduced risk of cancer, but the association between motor neuron disease and cancer risk is not well understood. We hypothesized that cancer risk would be lower among those with motor neuron disease and its most common subtype, amyotrophic lateral sclerosis.

Methods: We conducted a population-based cohort study of motor neuron disease and cancer risk using routinely collected data from population-based registries in Denmark. We examined cancer incidence among patients diagnosed with motor neuron disease between January 1980 and December 2013 followed through 2013. Using Danish national cancer rates for the study period, we computed standardized incidence ratios as a measure of relative risks.

Results: In the cohort of 5053 patients with a motor neuron disease, the overall standardized incidence ratio of any cancer was 1.17 (95% confidence interval [CI], 1.03-1.31); the corresponding standardized incidence ratio for amyotrophic lateral sclerosis was 1.24 (95% CI, 0.96-1.57). The standardized incidence ratios of any cancer in the cohort with motor neuron disease was 1.52 (95% CI, 1.22-1.87) for <1 year of follow-up; 0.87 (95% CI, 0.68-1.09) for years 1-5 of follow-up; and 1.22 (95% CI, 1.01-1.46) for >5 years of follow-up. Beyond one year of follow-up, patients in the motor neuron disease had elevated standardized incidence ratios for lymphoid leukemia, non-Hodgkin lymphoma, and basal cell skin cancer.

Conclusion: Findings fail to support the hypothesis that motor neuron disease or amyotrophic lateral sclerosis is associated with reduced cancer incidence. An elevated risk of cancer during the first year of follow-up may be attributable to heightened surveillance.
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http://dx.doi.org/10.2147/CLEP.S271543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733394PMC
December 2020

Acute pancreatitis: 31-Year trends in incidence and mortality - A Danish population-based cohort study.

Pancreatology 2020 Oct 14;20(7):1332-1339. Epub 2020 Sep 14.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Background: Objectives: Increasing incidence rates and declining mortality rates have made acute pancreatitis a common cause of hospitalization. We aimed to examine 31-year trends in first-time hospitalization for acute pancreatitis, the subsequent short-term and long-term mortality, and the prognostic impacts of age, sex, and comorbidity.

Methods: In this nationwide Danish population-based cohort study of 47,711 incident cases, we computed the annual sex-specific age-standardized incidence rates of acute pancreatitis for 1988-2018. Among patients with incident hospitalization for acute pancreatitis, we computed sex-specific 30-day and 31-365-day mortality rates, stratified them, and performed proportional-hazards regression to estimate mortality rate ratios adjusted for sex, age, and comorbidity, measured by Charlson Comorbidity Index categories.

Results: From 1988 to 2018, the standardized incidence rate of acute pancreatitis per 100,000 person-years increased by 29% for men (28.8-37.0%) and by 148% for women (15.7-38.9%). Among patients with pancreatitis, the 30-day mortality declined from 10.0% in those diagnosed in 1988-1992 to 6.3% for those diagnosed in 2013-2017. The corresponding 31-365 day mortality increased from 5.5% to 6.0%. In comparing periods 1988-1992 and 2013-17, the adjusted 30-day mortality rate ratio was 0.36 (95% confidence interval: 0.32-0.41) and the adjusted 31-365 day mortality rate ratio was 0.64 (95% confidence interval: 0.56-0.74). Comorbidity was a strong predictor of mortality among patients with pancreatitis.

Conclusions: Over the 31 years of observations, annual rates of acute pancreatitis more than doubled among women, converging with those among men. The comorbidity burden was a strong prognostic factor for short and long-term mortality. Treatments for acute pancreatitis should focus on existing comorbidities.
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http://dx.doi.org/10.1016/j.pan.2020.09.011DOI Listing
October 2020

Initiation of anti-osteoporotic drugs in high-risk female patients starting glucocorticoid treatment: a population study in Norway.

Arch Osteoporos 2020 08 5;15(1):121. Epub 2020 Aug 5.

Department of Global Public Health and Primary Care, University of Bergen, Kalfarveien 31, N-5018, Bergen, Norway.

Glucocorticoid use is a risk factor for osteoporosis and fractures. We studied whether women initiating glucocorticoid treatment also started anti-osteoporotic treatment, according to clinical guidelines. Women with versus without previous fracture were twice as likely to start anti-osteoporotic treatment within 1 year after initiating glucocorticoid treatment, but the cumulative incidences were low 9.1% vs. 4.6%, respectively.

Purpose: Use of glucocorticoids (GC) is a risk factor for osteoporosis and fractures, and clinical guidelines suggest that preventive treatment with anti-osteoporotic drugs (AOD) should be considered when starting GC. Women with high risk of osteoporosis comprise those with previous fractures or a known inflammatory rheumatic disease, for whom the indication of AOD is even stronger. The purpose of these analyses was to investigate whether women initiating GC treatment also started AOD, especially those with high risk of osteoporosis.

Methods: We used data from the Norwegian Prescription Database to identify all women 55 years and older initiating GC treatment in Norway during 2010-2016 and to obtain information on use of AOD. Data from the Norwegian Patient Registry were used to obtain information on previous fractures and diagnoses.

Results: Among 105,477 women initiating GC treatment during 2010-2016, 3256 had started AOD and 79,638 had discontinued GC treatment after 1-year follow-up. Cumulative incidence of starting AOD after 1 year was 9.1% (95% CI: 7.9, 10.4) for women with vs. 4.6% (95% CI: 4.4%, 4.8%) for women without a previous fracture. Women with rheumatoid arthritis or another inflammatory rheumatic disease were more likely to start AOD than women with other indications. For the whole cohort, the probability of starting AOD treatment within 1 year after initiating GC increased on average 3% per year (HR = 1.03, CI: 1.01, 1.05) from 2010 to 2016.

Conclusions: Having had a previous fracture or an inflammatory rheumatic disease increased the probability of treatment with AOD. However, the proportions starting AOD were much lower than clinically indicated.
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http://dx.doi.org/10.1007/s11657-020-00783-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406535PMC
August 2020

Combined hormonal contraceptive use in Europe before and after the European Commission mandated changes in product information.

Contracept X 2020 14;2:100018. Epub 2020 Jan 14.

Leiden University Medical Center, Department of Clinical Epidemiology, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.

Objectives: We investigated combined hormonal contraceptives (CHC) prescribing patterns (focusing on combined oral contraceptives; COC) in three countries (Netherlands, Denmark, United Kingdom) in a time period preceding and in a time period following the European Commission's decision to update product information, and we estimated changes in incidence of venous thromboembolism (VTE) between the two periods.

Study Design: We conducted a drug utilization analysis and a cohort study using routinely collected data. We calculated number, proportion and incidence rate of new users, switchers, and stoppers of COC in both time periods. VTE incidence was calculated in new users of COC and in all women aged 18-49 years.

Results: In all countries, the largest proportion (> 75%) of new users used COC containing levonorgestrel, norethisterone, or norgestimate, (i.e., indicated by European Medicines Agency (EMA) as the safest preparations) in both time periods. Switching did not demonstrate a clear pattern towards these types of COC and distribution of stoppers was similar in both time periods. While the proportion of new users initiating COC containing levonorgestrel, norethisterone, or norgestimate increased slightly, this did not translate to a decrease in the overall VTE incidence.

Conclusion: All three countries had the greatest proportion of women initiating a COC containing levonorgestrel, norethisterone, or norgestimate, and this proportion increased in the period after the European Commission decision albeit the increase was small due to the high percentage of use before the decision. This did not translate into a measureable change in the incidence of VTE.

Implications: Both before and after the European Commission's decision, the largest proportion of new users started with combined oral contraceptives containing levonorgestrel, norethisterone, or norgestimate. Earlier studies had already indicated an increased risk of VTE associated with COC containing other progestogens compared with these preparations, so it is possible that physicians were already preferentially prescribing COC containing levonorgestrel, norethisterone, or norgestimate to new users.
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http://dx.doi.org/10.1016/j.conx.2020.100018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286180PMC
January 2020

Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States.

Pharmacoepidemiol Drug Saf 2020 08 14;29(8):854-863. Epub 2020 Jun 14.

NoviSci, Inc., Durham, North Carolina, USA.

Purpose: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications.

Methods: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights.

Results: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = -0.6%, 95% CI: -1.1, -0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations.

Conclusions: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies.
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http://dx.doi.org/10.1002/pds.5037DOI Listing
August 2020

No Evidence of Off-label Use of Olodaterol and Indacaterol in Denmark, France, and the Netherlands: A Drug Utilization Study.

Sci Rep 2020 01 17;10(1):586. Epub 2020 Jan 17.

RTI Health Solutions, Av. Diagonal 605, 9-1, 08028, Barcelona, Spain.

To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.
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http://dx.doi.org/10.1038/s41598-019-57397-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968970PMC
January 2020

The Authors Respond.

Epidemiology 2020 01;31(1):e4-e6

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

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http://dx.doi.org/10.1097/EDE.0000000000001114DOI Listing
January 2020

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

Drugs Real World Outcomes 2019 Sep;6(3):133-140

Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark.

Introduction: A Direct Healthcare Professional Communication (DHPC) sent in Denmark on 11 August 2011 provided information on new pioglitazone labelling and guidance on monitoring treatment effectiveness. We describe pioglitazone use in Denmark after the DHPC, estimate the incidence of heart failure (HF), quantify pioglitazone cessation following a diagnosis of bladder cancer (BC) or uninvestigated macroscopic haematuria, and describe glycated haemoglobin (HbA1c) values.

Methods: This was a cohort study. From Danish population-based registries, cohorts of type 2 diabetes mellitus incident or prevalent users of pioglitazone or insulin in 2011-2015 were created. Patient characteristics, treatment patterns, laboratory results (available for a regional subset of the population), and incidence rates of HF and BC were estimated.

Results: There were 80 pioglitazone and 17,699 insulin incident users, 140 pioglitazone and 13,183 insulin prevalent users. There were no new BC cases among incident pioglitazone users, and < 5 new BC cases among prevalent pioglitazone users. Pioglitazone was rarely the first-line treatment. History of haematuria was documented in < 5 incident and 11 prevalent pioglitazone users. During follow-up, there were < 5 HF cases among 77 incident pioglitazone users and < 5 among 133 prevalent pioglitazone users without a history of HF. Median HbA1c at index date was 7.8% and 8.8% in incident pioglitazone and insulin cohorts, and 7.5% and 7.6% in prevalent pioglitazone and insulin cohorts, respectively. During follow-up of up to 4.4 years, 28.8% incident and 20.7% prevalent pioglitazone users discontinued pioglitazone.

Conclusions: Numbers of pioglitazone users in Denmark were low and decreased over time. Risks of BC or HF were low and risk estimates imprecise.
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http://dx.doi.org/10.1007/s40801-019-0160-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702533PMC
September 2019

The Danish health care system and epidemiological research: from health care contacts to database records.

Clin Epidemiol 2019 12;11:563-591. Epub 2019 Jul 12.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Denmark has a large network of population-based medical databases, which routinely collect high-quality data as a by-product of health care provision. The Danish medical databases include administrative, health, and clinical quality databases. Understanding the full research potential of these data sources requires insight into the underlying health care system. This review describes key elements of the Danish health care system from planning and delivery to record generation. First, it presents the history of the health care system, its overall organization and financing. Second, it details delivery of primary, hospital, psychiatric, and elderly care. Third, the path from a health care contact to a database record is followed. Finally, an overview of the available data sources is presented. This review discusses the data quality of each type of medical database and describes the relative technical ease and cost-effectiveness of exact individual-level linkage among them. It is shown, from an epidemiological point of view, how Denmark's population represents an open dynamic cohort with complete long-term follow-up, censored only at emigration or death. It is concluded that Denmark's constellation of universal health care, long-standing routine registration of most health and life events, and the possibility of exact individual-level data linkage provides unlimited possibilities for epidemiological research.
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http://dx.doi.org/10.2147/CLEP.S179083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634267PMC
July 2019

Risk of amyotrophic lateral sclerosis and other motor neuron disease among men with benign prostatic hyperplasia: a population-based cohort study.

BMJ Open 2019 07 4;9(7):e030015. Epub 2019 Jul 4.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Objectives: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder. Sleep disturbance may interfere with clearance of abnormal proteins that aggregate in neurodegenerative diseases. The objective of this study was to examine the association between benign prostatic hyperplasia (BPH), a common disorder causing nocturia and sleep disturbance, and risk of ALS and other motor neuron disease (MND). We hypothesised that men with BPH, in comparison to men in the general population, would be at increased risk.

Design: This is a nationwide, population-based cohort study.

Setting: This study was conducted among the population of Denmark.

Participants: We used linked Danish medical databases to identify all men with a first-time diagnosis of BPH between 1 January 1980 and 30 November 2013 and no prior diagnosis of MND (BPH cohort, n=223 131) and an age-matched general population comparison cohort of men without BPH or MND (n=1 115 642).

Primary Outcome Measure: The primary outcome is diagnosis of MND after the BPH diagnosis (index) date, with follow-up until MND diagnosis, emigration, death or 30 November 2013.

Results: We used Cox regression to compute adjusted HR, comparing men with and without BPH. After 34 years of follow-up, there were 227 cases of MND in the BPH cohort (incidence rate 0.13/1000 person-years) and 1094 MND cases in the comparison cohort (0.12/1000 person-years; HR 1.05, 95% CI 0.90 to 1.22). Risk did not vary by follow-up time.

Conclusions: BPH is not associated with an increased risk of ALS and other MND. Future studies should examine the relation between other disorders that disrupt sleep and MND risk in men and women.
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http://dx.doi.org/10.1136/bmjopen-2019-030015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615877PMC
July 2019

La déclaration RECORD-PE (Reporting of Studies Conducted Using Observational Routinely Collected Health Data Statement for Pharmacoepdemiology) : directives pour la communication des études realisées à partir de données de santé observationelles collectées en routine en pharmacoépidémiologie.

CMAJ 2019 06;191(25):E689-E708

Faculty of Epidemiology and Population Health (Langan, Wing, Smeeth), London School of Hygiene and Tropical Medicine, Londres, Royaume-Uni ; Département d'épidémiologie clinique (Schmidt, Ehrenstein, Petersen, Sørensen), université d'Aarhus, Aarhus, Danemark ; Institut de recherche de l'Hôpital d'Ottawa (Nicholls, Moher) ; École d'épidémiologie et de santé publique (Nicholls), Université d'Ottawa, Ottawa, Ont. ; Département d'épidémiologie, de bio-statistique et de santé au travail (Filion), Université McGill ; Centre d'épidémiologie clinique (Filion), Institut Lady Davis, Hôpital général juif, Montréal, Qué. ; Division of Pharmacoepidemiology and Clinical Pharmacology (Klungel), Utrecht Institute for Pharmaceutical Sciences, université d'Utrecht, Utrecht, Pays-Bas ; Department of Primary Care and Population Health (Petersen), University College London, Londres, Royaume-Uni ; Arthritis Research UK Centre for Epidemiology (Dixon), Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, Royaume-Uni ; ICES (Guttmann, Benchimol) ; Department of Paediatrics (Guttmann), The Hospital for Sick Children, université de Toronto, Toronto, Ont. ; Population, Policy and Practice Programme (Harron), Great Ormond Street Institute of Child Health, University College London, Londres, Royaume-Uni ; Basel Institute for Clinical Epidemiology and Biostatistics (Hemkens), Department of Clinical Research, University Hospital of Basel, université de Basel, Basel, Suisse ; Division of Pharmacoepidemiology and Pharmacoeconomics (Schneeweiss, Wang), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. ; Julius Global Health (Sturkenboom), University Medical Center Utrecht, Utrecht, Pays-Bas ; Cochrane Suisse (von Elm), Institut de médecine sociale et préventive, Université de Lausanne, Lausanne, Suisse ; Département de pédiatrie et École d'épidémiologie et de santé publique (Benchimol), Université d'Ottawa ; Institut de recherche du Centre hospitalier pour enfants de l'est de l'Ontario (Benchimol), Ottawa, Ont.

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http://dx.doi.org/10.1503/cmaj.190347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592814PMC
June 2019

Vaginal bleeding in early pregnancy and risk of occult cancer.

Int J Gynaecol Obstet 2019 09 13;146(3):387-389. Epub 2019 Jun 13.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Vaginal bleeding in early pregnancy is not associated with a higher cancer risk compared with pregnancies in women from the general population of similar age.
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http://dx.doi.org/10.1002/ijgo.12867DOI Listing
September 2019

Pregnancy, Birth, Neonatal, and Postnatal Neurological Outcomes After Pregnancy With Migraine.

Headache 2019 06 8;59(6):869-879. Epub 2019 May 8.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Background: Prevalence of migraine is high during the reproductive age. Although migraine often improves during pregnancy, the risk of adverse pregnancy, birth, neonatal, and neurological outcomes in mother and offspring remains poorly understood.

Objective: To investigate the associations between maternal migraine and risks of adverse pregnancy outcomes in the mother, and birth, neonatal and postnatal outcomes in the offspring.

Methods: We used Danish population registries to assemble a cohort of pregnancies among women with migraine and an age- and conception year-matched comparison cohort of pregnancies among women without migraine. The study period was 2005-2012. We computed adjusted prevalence ratios (aPRs) for pregnancy and birth outcomes and adjusted risk ratios (aRRs) for neonatal and postnatal outcomes, adjusting for age, preconception medical history, and preconception reproductive history.

Results: We identified 22,841 pregnancies among women with migraine and 228,324 matched pregnancies among women without migraine. Migraine was associated with an increased risk of pregnancy-associated hypertension disorders (aPR: 1.50 [95% confidence interval (CI): 1.39-1.61]) and miscarriage (aPR: 1.10 [95% CI: 1.05-1.15]). Migraine was associated with an increased prevalence of low birth weight (aPR: 1.14 [95% CI: 1.06-1.23]), preterm birth (aPR: 1.21 [95% CI: 1.13-1.30]) and cesarean delivery (aPR: 1.20 [95% CI: 1.15-1.25]), but not of small for gestational age offspring (aPR: 0.94 [95% CI: 0.88-0.99]) and birth defects (aPR: 1.01 [95% CI: 0.93-1.09]). Offspring prenatally exposed to maternal migraine had elevated risks of several outcomes in the neonatal and postnatal period, including intensive care unit admission (aRR: 1.22 [95% CI: 1.03-1.45]), hospitalization (aRR: 1.12 [95% CI: 1.06-1.18]), dispensed prescriptions (aRR: 1.34 [95% CI: 1.24-1.45]), respiratory distress syndrome (aRR: 1.20 [95% CI: 1.02-1.42]), and febrile seizures (aRR: 1.27 [95% CI: 1.03-1.57), but not of death (aRR: 0.67 [95% CI: 0.43-1.04]) and cerebral palsy (aRR: 1.00 [95% CI: 0.51-1.94]).

Conclusions: Women with migraine and their offspring have greater risks of several adverse pregnancy outcomes than women without migraine.
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http://dx.doi.org/10.1111/head.13536DOI Listing
June 2019

Comparison of Risk of Osteoporotic Fracture in Denosumab vs Alendronate Treatment Within 3 Years of Initiation.

JAMA Netw Open 2019 04 5;2(4):e192416. Epub 2019 Apr 5.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Importance: Head-to-head randomized clinical trials showed greater efficacy of denosumab vs alendronate in improving bone mineral density. Although there is an association of changes in bone mineral density with reductions in fracture risk, the magnitude of the association is not well established.

Objective: To compare the risk of hip and any fracture in patients treated with denosumab and alendronate in routine practice settings.

Design, Setting, And Participants: This Danish nationwide, population-based, historical cohort study of a population with universal access to health care used prospectively collected, individually linked data from Danish health registries with complete follow-up. Cohorts consisted of 92 355 individuals 50 years or older who were new users of denosumab (n = 4624) or alendronate (n = 87 731) from May 2010 to December 2017 after at least 1 year without an antiosteoporosis medication dispensing.

Exposures: Initiation of denosumab or alendronate.

Main Outcomes And Measures: The primary outcome was hospitalization for hip fracture, and the secondary outcome was hospitalization for any fracture. Inverse probability of treatment weights and the intention-to-treat approach were used to calculate cumulative incidences and adjusted hazard ratios (aHRs) with 95% CIs.

Results: Of the 92 355 included patients, 75 046 (81.3%) were women, and the mean (SD) age was 71 (10) years. The denosumab cohort had a lower proportion of men than the alendronate cohort (12.7% [589] vs 19.0% [16 700]), while age distributions were similar in the 2 cohorts. Within 3 years of follow-up, initiation of denosumab or alendronate was associated with cumulative incidences of 3.7% and 3.1%, respectively, for hip fracture and 9.0% and 9.0%, respectively, for any fracture. Overall, the aHRs for denosumab vs alendronate were 1.08 (95% CI, 0.92-1.28) for hip fracture and 0.92 (95% CI, 0.83-1.02) for any fracture. The aHR of denosumab vs alendronate for hip fracture was 1.07 (95% CI, 0.85-1.34) among patients with a history of any fracture and 1.05 (95% CI, 0.83-1.32) among patients without history of fracture. The aHR for any fracture for denosumab vs alendronate was 0.84 (95% CI, 0.71-0.98) among patients with a history of any fracture and 0.77 (95% CI, 0.64-0.93) among patients with no history of fracture.

Conclusions And Relevance: Treatment with denosumab and alendronate was associated with similar risks of hip or any fracture over a 3-year period, regardless of fracture history.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481596PMC
April 2019

Classification and characteristics of on-label and off-label apixaban use in Denmark and Sweden.

Pharmacoepidemiol Drug Saf 2019 06 16;28(6):867-878. Epub 2019 Apr 16.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Purpose: To estimate the proportion of apixaban users who received the drug for on-label indications and characterise the patients using apixaban for on-label and off-label indications.

Methods: We report results from two independently conducted studies in Denmark and Sweden, with 19,709 Danish and 17,592 Swedish patients, who received at least one outpatient dispensing of apixaban as identified through nationwide prescription registries. Indications, inferred from inpatient and hospital diagnoses recorded at the initial apixaban dispensing, were classified as on-label, off-label, or unclassified according to the Summary of Product Characteristics. All diagnoses were retrieved using inpatient or outpatient hospital diagnoses at the first outpatient dispensing during the study period.

Results: Men comprised 52% of the users in both Denmark and Sweden. The median age was 76 years (interquartile range [IQR]: 68-83 years) among Danish patients and 74 years (IQR: 67-82 years) among Swedish patients. An on-label indication could be assigned to 82.6% (95% confidence interval [CI]: 82.1%-83.1%) of the Danish patients and 86.4% (95% CI: 85.9%-86.9%) of the Swedish patients. The main on-label indication for apixaban was non-valvular atrial fibrillation (NVAF), which accounted for 76.1% of the indications in Denmark and 69.1% of the indications in Sweden. Off-label indications were assigned to 10.8% (95% CI: 10.3-11.2) of the Danish patients (main indication possible mechanical heart valve) and 7.7% (95% CI: 7.3-8.1) of the Swedish patients (main indication off-label atrial fibrillation).

Conclusion: The majority of apixaban initiators in Denmark and Sweden received apixaban for an on-label indication, primarily for NVAF.
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http://dx.doi.org/10.1002/pds.4778DOI Listing
June 2019

Risk of Upper Gastrointestinal Bleeding and Gastroduodenal Ulcers in Persons With Schizophrenia: A Danish Cohort Study.

Clin Transl Gastroenterol 2019 02;10(2):e00005

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Introduction: There is little evidence about gastrointestinal (GI) disorders in patients with schizophrenia. We examined association of schizophrenia with upper GI bleeding (UGIB) and nonbleeding ulcers and associated risk factors and mortality.

Methods: We used the data linked from population-based registries in Denmark. Among patients with incident schizophrenia in 1980-2011, we computed cumulative incidences and standardized incidence ratios of UGIB, bleeding ulcers, and nonbleeding ulcers compared with the general population; evaluated risk factors for the 3 GI endpoints, including somatic and psychiatric comorbidity; and examined subsequent all-cause mortality.

Results: Among 39,998 patients with schizophrenia, the standardized incidence ratios were 2.92 (95% confidence interval (CI), 2.76-3.08) for UGIB, 2.36 (95% CI, 2.15-2.58) for bleeding ulcers, and 2.00 (95% CI, 1.87-2.15) for nonbleeding ulcers. Risk factors for UGIB and nonbleeding ulcers included age, somatic comorbidity, and medication use. UGIB and nonbleeding ulcers were associated with the subsequent increase in mortality.

Conclusions: Schizophrenia is associated with an increased risk of UGIB and nonbleeding ulcers, whose risk factors in patients with schizophrenia are similar to those in the general population.
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http://dx.doi.org/10.14309/ctg.0000000000000005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407813PMC
February 2019

Patterns of initial migraine treatment in Denmark: A population-based study.

Pharmacoepidemiol Drug Saf 2019 03 31;28(3):322-329. Epub 2019 Jan 31.

Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

Purpose: Population-based data are sparse on utilization of prophylactic versus acute therapies for newly diagnosed migraine. We examined initial migraine treatment patterns and associated patient characteristics in Denmark.

Methods: We used population-based health databases to assemble a nationwide cohort of adult migraine patients in 2005 to 2013. Migraine was defined as a first hospital diagnosis of migraine or a second redeemed outpatient prescription for triptans, ergots, pizotifen, or flunarizine. We classified the initial migraine treatment received after migraine onset as "no treatment," "acute only," "prophylactic only," and "both acute and prophylactic" and described distributions of sex, age, comorbidities, and comedications.

Results: Among 97 431 migraine patients (78% women, median age of 41 y [interquartile range of 32-50 y]), the initial migraine treatments received were "acute only" (88.2%), "prophylactic only" (1.9%), and "both acute and prophylactic" (5.2%) whereas 4.6% had no record of treatment. Initiators of prophylactic treatment-with or without acute treatment-were less likely than initiators of acute treatment to be women (71% and 77% versus 79%), were older (median ages: 45 and 44 y versus 41 y), and had more comorbidities (including hypertension [31% and 24% versus 7%] and diabetes [6% and 5% versus 3%]). Nonpersistence with initial prophylactic treatment was common: within the first year, 35% of initiators stopped therapy fully, 50% stopped and restarted, and 15% switched drugs.

Conclusions: For 88% of patients with incident migraine, the initial migraine treatment was acute treatment only. Use of prophylactic medication as initial treatment was low and correlated with higher age and comorbidity.
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http://dx.doi.org/10.1002/pds.4723DOI Listing
March 2019

Fecundability among Danish women with a history of miscarriage: a prospective cohort study.

BMJ Open 2019 01 21;9(1):e023996. Epub 2019 Jan 21.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.

Objective: To examine the association between history of miscarriage and fecundability (the cycle-specific probability of conception).

Design: Nationwide prospective cohort study using web-based questionnaires.

Setting: Denmark, 2007-2012.

Participants: 977 women attempting to conceive, not using fertility treatment, and with a reproductive history of only miscarriage or only live birth.

Exposure And Outcome Measures: Information on previous pregnancy outcomes, including miscarriage, came from self-report or from relevant registries. Participants were followed for up to 12 months or until they reported a pregnancy, stopped trying to conceive or started fertility treatment, whichever came first. We used Kaplan-Meier methods to estimate cumulative probabilities of conception for women whose reproductive history included only miscarriage or only live birth. Using proportional probabilities regression modelling, we computed fecundability ratios (FR) with 95% CI comparing women with a history of only miscarriage with women with a history of only live birth.

Results: After adjustment for potential confounders, the cumulative probabilities of conception within 12 cycles of follow-up were 85% (95% CI 81% to 89%) for women with a history of 1 miscarriage, 85% (95% CI 73% to 92%) for women with a history of ≥2 miscarriages and 88% (95% CI 87% to 89%) for women whose reproductive history included only live birth. Adjusted FRs were 0.87 (95% CI 0.71 to 1.07) and 0.65 (95% CI 0.36 to 1.17) for women with a history of 1 and ≥2 miscarriages, respectively.

Conclusions: Our results indicate that women with a history of miscarriage may have slightly reduced fecundability compared with women with a history of only live birth. The reduction in fecundability was greater for women with repeated miscarriages, although the estimates were imprecise. Despite a potential delay in conception, women with previous miscarriage may have similar probability of pregnancy by 12 cycles of attempts to women with proven fertility.
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http://dx.doi.org/10.1136/bmjopen-2018-023996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347866PMC
January 2019

Cardiovascular Disease Among Women Who Gave Birth to an Infant With a Major Congenital Anomaly.

JAMA Netw Open 2018 09 7;1(5):e182320. Epub 2018 Sep 7.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Importance: Having a child with a major birth defect can be a life-changing and stressful event that may be associated with higher cardiovascular disease (CVD) risk, yet the long-term burden of CVD for the child's mother is unknown.

Objective: To assess whether mothers of an infant born with a major congenital anomaly are at higher risk of CVD compared with a comparison cohort.

Design, Setting, And Participants: A population-based cohort study using individual-level linked registry data in Denmark included 42 943 women who gave birth to an infant with a major congenital anomaly between January 1, 1979, and December 31, 2013; and follow-up was conducted until 2015. A comparison group, comprising 428 401 randomly selected women, was 10:1 matched to each affected mother by maternal age, parity, and her infant's year of birth. Data analyses were performed between November 1, 2017, and February 28, 2018.

Exposures: Live birth of an infant with a major congenital anomaly.

Main Outcomes And Measures: The primary outcome was a CVD composite outcome of acute myocardial infarction, coronary revascularization, or stroke. Secondary outcomes included individual components of the CVD composite and other cardiovascular outcomes, including unstable angina, congestive heart failure, atrial fibrillation, peripheral artery disease, ischemic heart disease, and aortic aneurysm. Cox proportional hazards regression analyses generated hazard ratios (HRs), adjusted for maternal demographic, socioeconomic, and chronic health indicators.

Results: Median maternal age at baseline was 28.8 years (interquartile range, 25.3-32.5 years). After a median follow-up of 19.5 years (interquartile range, 9.9-27.6 years), 914 women whose infant had a major congenital anomaly experienced a CVD event (1.21 per 1000 person-years; 95% CI, 1.13-1.28 per 1000 person-years) vs 7516 women in the comparison group (0.99 per 1000 person-years; 95% CI, 0.97-1.01 per 1000 person-years), corresponding to an unadjusted HR of 1.23 (95% CI, 1.15-1.32), and an adjusted HR (aHR) of 1.15 (95% CI, 1.07-1.23). Women who gave birth to an infant with multiorgan anomalies had an even higher aHR (1.37; 95% CI, 1.08-1.72). Mothers of infants with a major anomaly also had an increased aHR of the individual components of the composite outcome and the other cardiovascular outcomes.

Conclusions And Relevance: Women whose child had a major congenital anomaly experienced a 15% to 37% higher risk of premature cardiovascular disease. These women may benefit from targeted interventions aimed at improving their cardiovascular health.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.2320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324496PMC
September 2018

Stress Disorders and Dementia in the Danish Population.

Am J Epidemiol 2019 03;188(3):493-499

Department of Clinical Epidemiology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.

There is an association between stress and dementia. However, less is known about dementia among persons with varied stress responses and sex differences in these associations. We used this population-based cohort study to examine dementia among persons with a range of clinician-diagnosed stress disorders, as well as the interaction between stress disorders and sex in predicting dementia, in Denmark from 1995 to 2011. This study included Danes aged 40 years or older with a stress disorder diagnosis (n = 47,047) and a matched comparison cohort (n = 232,141) without a stress disorder diagnosis with data from 1995 through 2011. Diagnoses were culled from national registries. We used Cox proportional hazards regression to estimate associations between stress disorders and dementia. Risk of dementia was higher for persons with stress disorders than for persons without such diagnosis; adjusted hazard ratios ranged from 1.6 to 2.8. There was evidence of an interaction between sex and stress disorders in predicting dementia, with a higher rate of dementia among men with stress disorders except posttraumatic stress disorder, for which women had a higher rate. Results support existing evidence of an association between stress and dementia. This study contributes novel information regarding dementia risk across a range of stress responses, and interactions between stress disorders and sex.
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http://dx.doi.org/10.1093/aje/kwy269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395166PMC
March 2019

Bisphosphonate use and risk of renal cell carcinoma: A population-based case-control study.

Basic Clin Pharmacol Toxicol 2019 May 4;124(5):642-646. Epub 2019 Jan 4.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

The purpose of this study was to evaluate the association between the use of bisphosphonates and the risk of developing renal cell carcinoma (RCC). We conducted a case-control study in Denmark, using data linked from population-based health and administrative registries. We identified all cases of RCC from 1996 to 2013 and sampled population controls in a 10:1 ratio from the underlying population free of RCC, while matching on sex, birth year and calendar time. Bisphosphonate use before RCC diagnosis, excluding the year leading up to the diagnosis, was measured using outpatient prescription dispensations. We used conditional logistic regression to compute crude and adjusted odds ratios (ORs) comparing ever vs. never bisphosphonate use in doses indicated for treatment of osteoporosis, overall and stratified by sex, with the OR estimating the incidence rate ratio. We also examined the effects by cumulative dose and specific agent. There were 2748 RCC cases and 27 480 controls. The adjusted ORs for ever vs never bisphosphonate use were 1.07 (95% confidence interval: 0.94-1.22) overall; 1.15 (1.00-1.32) for women; and 0.78 (0.54-1.12) for men. Smoking could not be directly controlled for in the analysis. We found a weak association between use of oral bisphosphonates and risk of renal cell carcinoma in females. The observed association could be due to confounding by cigarette smoking, and future studies are required to assess this association further.
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http://dx.doi.org/10.1111/bcpt.13180DOI Listing
May 2019

The Role of Comorbidity in Mortality After Hip Fracture: A Nationwide Norwegian Study of 38,126 Women With Hip Fracture Matched to a General-Population Comparison Cohort.

Am J Epidemiol 2019 02;188(2):398-407

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Hip fracture patients often have comorbid conditions. We investigated whether the combination of comorbidity and hip fracture could explain the previously observed excess mortality among hip fracture patients as compared with the general population. Using a population-based matched study design with 38,126 Norwegian women who suffered a hip fracture during the period 2009-2015 and the same number of women in a matched comparison cohort, we matched participants on prefracture comorbidity, age, and education. We estimated relative survival and additive and multiplicative comorbidity-hip fracture interactions. An additive comorbidity-hip fracture interaction of 4 or 9 additional deaths per 100 patients, depending on Charlson Comorbidity Index (CCI) score, was observed 1 year after hip fracture. Among women with a CCI score of ≥3, 15 additional deaths per 100 patients were observed; of these, 9 deaths could be attributed to the interaction and 6 to the hip fracture per se. On the relative scale, we observed increasing heterogeneity in survival by comorbidity over time; survival was reduced by 39% after 6 years among patients with a CCI score of ≥3, while among women with no comorbidity, survival was reduced by 17% (hip fracture vs. no hip fracture). In summary, prefracture comorbidity was associated with short-term absolute excess mortality and long-term relative excess mortality.
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http://dx.doi.org/10.1093/aje/kwy251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357811PMC
February 2019