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Annemarie Voss,1 Bianca Kollhorst,2 Katharina Platzbecker,1 Ute Amann,1 Ulrike Haug1,3 1Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 2Department of Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 3Faculty of Human and Health Sciences, University of Bremen, Bremen, GermanyCorrespondence: Ulrike Haug, Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany, Tel +49 421 218 56862, Email haug@leibniz-bips.dePurpose: Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany.Patients and Methods: Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation.Results: Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%.Conclusion: This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.Keywords: atrial fibrillation, oral anticoagulants, direct oral anticoagulants, DOACs, risk profiles

Malte Braitmaier,1 Bianca Kollhorst,1 Miriam Heinig,2 Ingo Langner,2 Jonas Czwikla,3 Franziska Heinze,3 Laura Buschmann,4 Heike Minnerup,4 Xabiér García-Albéniz,5,6 Hans-Werner Hense,4 André Karch,4 Hajo Zeeb,7,8 Ulrike Haug,2,8 Vanessa Didelez1,9 1Department of Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 2Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 3SOCIUM Research Center on Inequality and Social Policy, University of Bremen, Bremen, Germany; 4Institute for Epidemiology and Social Medicine, Faculty of Medicine, Westfälische Wilhelms University of Münster, Münster, Germany; 5Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; 6RTI Health Solutions, Barcelona, Spain; 7Department of Prevention and Evaluation, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany; 8Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany; 9Faculty of Mathematics and Computer Science, University of Bremen, Bremen, GermanyCorrespondence: Vanessa Didelez, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Department of Biometry and Data Management, Achterstraße 30, Bremen, 28359, Germany, Tel +49-421-56939, Fax +49-421-56941, Email didelez@leibniz-bips.deBackground: The efficacy of mammography screening in reducing breast cancer mortality has been demonstrated in randomized trials. However, treatment options - and hence prognosis – for advanced tumor stages as well as mammography techniques have considerably improved since completion of these trials. Consequently, the effectiveness of mammography screening under current conditions is unclear and controversial. The German mammography screening program (MSP), an organized population-based screening program, was gradually introduced between 2005 and 2008 and achieved nation-wide coverage in 2009.Objective: We describe in detail a study protocol for investigating the effectiveness of the German MSP in reducing breast cancer mortality in women aged 50 to 69 years based on health claims data. Specifically, the proposed study aims at estimating per-protocol effects of several screening strategies on cumulative breast cancer mortality. The first analysis will be conducted once 10-year follow-up data are available.Methods and Analysis: We will use claims data from five statutory health insurance providers in Germany, covering approximately 37.6 million individuals. To estimate the effectiveness of the MSP, hypothetical target trials will be emulated across time, an approach that has been demonstrated to minimize design-related biases. Specifically, the primary contrast will be in terms of the cumulative breast cancer mortality comparing the screening strategies of “never screen” versus “regular screening as intended by the MSP”.Ethics and Dissemination: In Germany, the utilization of data from health insurances for scientific research is regulated by the Code of Social Law. All involved health insurance providers as well as the responsible authorities approved the use of the health claims data for this study. The Ethics Committee of the University of Bremen determined that studies based on claims data are exempt from institutional review. The findings of the proposed study will be published in peer-reviewed journals.Keywords: emulated target trial, cancer screening, effectiveness, claims data, mammography

Jonas Reinold,1 Malte Braitmaier,2 Oliver Riedel,1 Ulrike Haug1,3 1Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, 28359, Germany; 2Department of Biometry and Data Management, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, 28359, Germany; 3Faculty of Human and Health Sciences, University of Bremen, Bremen, GermanyCorrespondence: Jonas Reinold, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Achterstraße 30, Bremen, 28359, Germany, Tel +49 421 218-56868, Fax +49 421 218-56821, Email reinold@leibniz-bips.dePurpose: In older adults, fractures are associated with mortality, disability, loss of independence and high costs. Knowledge on their predictors can help to identify persons at high risk who may benefit from measures to prevent fractures. We aimed to assess the potential of German claims data to predict fractures in older adults.Patients and Methods: Using the German Pharmacoepidemiological Research Database (short GePaRD; claims data from ~20% of the German population), we included persons aged ≥ 65 years with at least one year of continuous insurance coverage and no fractures prior to January 1, 2017 (baseline). We randomly divided the study population into a training (80%) and a test sample (20%) and used logistic regression and random forest models to predict the risk of fractures within one year after baseline based on different combinations of potential predictors.Results: Among 2,997,872 persons (56% female), the incidence per 10,000 person years of any fracture in women increased from 133 in age group 65– 74 years (men: 71) to 583 in age group 85+ (men: 332). The maximum predictive performance as measured by the area under the curve (AUC) across models was 0.63 in men and 0.60 in women and was achieved by combining information on drugs and morbidities. AUCs were lowest in age group 85+.Conclusion: Our study showed that the performance of models using German claims data to predict the risk of fractures in older adults is moderate. Given that the models used data readily available to health insurance providers in Germany, it may still be worthwhile to explore the cost–benefit ratio of interventions aiming to reduce the risk of fractures based on such prediction models in certain risk groups.Keywords: fracture, older adults, claims data, prediction

It is often reported that participation in the German colorectal cancer (CRC) screening program is low. However, it must be considered that fecal occult blood testing (FOBT) and colonoscopy are offered in parallel and both are also used for diagnostic purposes. We aimed to quantify and characterize the uptake of these colorectal examinations in Germany. Using the claims database German Pharmacoepidemiological Research Database (~20% of the German population), we included persons aged 50 in 2011 in cohort 1 (cohort 2: age 55) and assessed whether they utilized FOBT or colonoscopy for screening or diagnostic purposes until age 59 (cohort 2: age 64). We have stratified the analyses, i.e. by gender and educational level. Among 185 949 50-year olds, 80% of women and 63% of men had ≥1 colorectal examination (i.e. FOBT or colonoscopy) until age 59; 25% of women and 31% of men had ≥1 colonoscopy (among those, 76 and 62% had a screening colonoscopy). In women with lower vs higher education, 79 vs 82% had any colorectal examination; in men, these proportions were 60 vs 67%. Among 156 258 55-year olds, 78% of women and 69% of men had ≥1 colorectal examination until age 64. Our study demonstrates a high utilization of colorectal examinations in Germany. It also illustrates the value of health claims data to monitor CRC screening in Germany due to their longitudinal character and because they include information on screening, on examinations done for diagnostic reasons as well as information suitable to characterize users and nonusers., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: There is a lack of real-world data on the use of targeted cancer drugs requiring molecular tumor diagnostics in the treatment of lung cancer in Germany., Aims: We aimed to characterize the use of such drugs in lung cancer patients based on longitudinal analyses., Methods and Results: Using the GePaRD database (claims data from ~20% of the German population) we identified lung cancer patients diagnosed in 2016 based on a previously developed algorithm and followed them until death, end of continuous insurance, or end of 2019. We determined the proportion of patients treated with at least one of the drugs under study (EGFR, ALK, and BRAF inhibitors). We described these patients regarding demographic characteristics, treatment patterns, and overall survival. We included 7833 incident lung cancer patients. Of these, 392 (5%) were treated with one of the drugs under study, the majority (62%) being female. In 314 out of the 392 patients (80%), the first dispensation was an EGFR inhibitor (afatinib: 54%, erlotinib: 33%), and in 72 patients (18%), it was an ALK inhibitor (crizotinib: 90%). The proportion of patients treated with these drugs was 4.8% in West Germany and 6.2% in East Germany. About half of these patients had chemotherapy before targeted therapy. Median overall survival after the first targeted therapy was 22 months., Conclusion: One twentieth of lung cancer patients diagnosed in 2016 in Germany received at least one EGFR, ALK, or BRAF inhibitor during follow-up. The proportion was higher in East than in West Germany. As the development and availability of new cancer drugs is a dynamic area, regularly updated utilization studies-ideally as cross-country-comparisons-are required., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Objectives: A lower-quality colonoscopy has been shown to be less effective in reducing colorectal cancer (CRC) incidence than a higher-quality colonoscopy, but the comparison with no-screening colonoscopy (noSC) is lacking. We aimed to compare the 13-year risk of developing CRC between persons with I) a higher-quality screening colonoscopy (higherQualSC), II) a lower-quality screening colonoscopy (lowerQualSC), and III) without a screening colonoscopy., Study Design and Setting: A health-care database (∼20% of the German population) was used to emulate a target trial with three arms: higherQualSC vs lowerQualSC vs noSC at baseline. The quality of screening colonoscopy was categorized based on the polyp detection rate of the examining physician (cut-off: 21.8%). We included persons aged 55-69 years at average CRC risk and CRC screening naïve at baseline. We estimated adjusted cumulative CRC incidence over 13 years of follow-up., Results: The higherQualSC arm comprised 142,960 persons, the lowerQualSC arm 62,338 persons, and the noSC arm 124,040 persons. The adjusted 13-year CRC risk was 1.77% in the higherQualSC arm, 2.09% in the lowerQualSC arm, and 2.74% in the noSC arm. Compared to the noSC arm, the adjusted relative risk was 0.76 (95% CI: 0.70-0.84) in the lowerQualSC arm and 0.65 (95% CI: 0.60-0.69) in the higherQualSC arm., Conclusion: Our study shows that a lowerQualSC is also effective in reducing CRC incidence compared to noSC. However, the effect is about one-third less than that of a higherQualSC., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Rapid digitisation of health occurred during the COVID-19 pandemic worldwide. In October 2020, we conducted a survey on digital health technology use in Germany. This study aimed to conduct a second survey to investigate in more detail the internet use in health context and digital technology use for health promotion and disease prevention in Germany., Methods: A cross-sectional, nationwide telephone survey was conducted in November 2022. Anonymous data on internet and digital technology use, digital health literacy, and sociodemographic characteristics were analysed using descriptive statistics and binary logistic regressions., Results: The 1020 participants were aged 18-92 years, 53% were male, 62% completed primary or secondary education, 71% resided in large cities, and 45% reported a country-average net household income. Overall, 61% reported internet use in health context via 1-4 devices. Among those, more than 50% used the internet and apps to obtain general health information and less than 50% used digital technologies for physical activity promotion or cancer prevention. Overall, 34% were confident in using the internet for health decisions and 71% preferred to receive health information non-digitally (e.g. on paper). Internet, app, and digital technology use were associated with higher digital health literacy and income, and residence in larger cities. Digital technologies were used for physical activity promotion by younger and for cancer prevention by older participants., Conclusion: The internet and digital technologies were predominantly used to obtain health information, but less often for health promotion and disease prevention in 2022 in Germany. While health app and digital technology use for physical activity promotion increased, the confidence in using online information for health decisions decreased in 2022 relative to 2020. Factors that promote confidence in online health information and digital technology use for health promotion and disease prevention need to be investigated in future studies., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Germany has a long-standing colorectal cancer (CRC) screening offer. We aimed to quantify and characterize screen-detected colorectal cancers (sdCRCs) in Germany., Methods: We conducted a cross-sectional study based on a healthcare database covering ~20% of the German population; we included CRC patients aged ≥ 55 years diagnosed in 2010-2018. Patients with a screening colonoscopy or a fecal occult blood test followed by colonoscopy within 180 days before diagnosis were classified as sdCRCs and compared to non-sdCRCs regarding age, stage and comorbidities., Results: In 2018, 25% of male and 22% of female CRC patients were screen-detected. Regarding characteristics of all included CRC cases (N = 82,538), sdCRC patients were younger than non-sdCRCs (average difference men / women: 2.6 / 4.4 years). The proportion of advanced CRC among sdCRCs and non-sdCRCs, respectively, was 33 and 42% in women (men: 36 and 45%). Severe comorbidities were more prevalent in non-sdCRCs compared to sdCRCs (e.g. in male / female patients aged 65-74: 35% vs. 27% / 26% vs. 19%). Prevalences of hypertension and obesity were similar in both groups., Interpretation: Our study suggests that about one fourth of CRCs in Germany are screen-detected. Among patients with non-sdCRC, not only advanced stage but also severe comorbidity was more common than in sdCRCs.

Aims: We aimed to describe treatment of lung cancer patients in Germany based on health claims data, focusing particularly on differences by age., Materials and Methods: Using the German Pharmacoepidemiological Research Database (GePaRD, ~ 20% of the German population) we identified lung cancer patients diagnosed in 2015-2018 based on a previously developed algorithm and followed them until death, end of continuous insurance or end of 2020. We described initial treatment patterns after diagnosis and survival, stratified among others by age., Results: We included 42,629 incident lung cancer patients (58% male). Surgery within three months after diagnosis was performed in 36%, 31%, 29% and 18% of patients aged < 50, 50-69, 70-79 and ≥ 80, respectively. Among patients without surgery, systemic therapy was administered in 77%, 72%, 54% and 25% of patients aged < 50, 50-69, 70-79 and ≥ 80, respectively. Monoclonal antibodies were administered in 15-30% of patients across age groups, and 4% to 15% received protein kinase inhibitors. Overall, 21% of patients remained untreated. In the age groups < 50, 50-69, 70-79 and ≥ 80, this proportions was 9%, 12%, 22% and 48%, respectively., Conclusion: In conclusion, our study provides a comprehensive overview of the therapy of lung cancer patients in Germany and quantitatively demonstrates the considerable differences between age groups. In terms of clinical cancer registration, the results are useful to estimate the completeness of data for the different types of treatment., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest., (© 2024. The Author(s).)

Following implementation of a national prevention program against iodine deficiency-related disorders in 1993 in Germany, the prevalence of thyroid disorders declined, but aggregated drug dispensation data suggested a recent increase in thyroid hormone use. We aimed to systematically investigate trends in the use of thyroid diagnostic and treatment measures between 2008 and 2019 in Germany. Using the GePaRD database (claims data from ~ 20% of the German population), we determined the annual age-specific and age-standardized prevalence of the use of thyroid diagnostics (thyroid-stimulating hormone (TSH) measurement, thyroid ultrasound, scintiscan, biopsy) and treatment (medication, surgery, radioiodine therapy) from 2008 to 2019 stratified by sex. Between 2008 and 2019, the age-standardized prevalence of TSH measurement increased by 44% in males (from 165 to 238 per 1,000 persons) and by 31% in females (from 134 to 176 per 1,000). The prevalence of thyroid ultrasound use showed no clear time trend, while there was a decrease in the prevalence of scintiscan use (males/females: decrease by 42/43%) and biopsy (males/females: decrease by 42/34%). The prevalence of levothyroxine use increased by ~ 31% both in males (from 36 to 47 per 1,000) and females (from 134 to 175 per 1,000), while the prevalence of thionamide use, iodine use, thyroidectomy, and radioiodine therapy decreased. Our study suggests a continued decline in the prevalence of clinically significant thyroid disorders between 2008 and 2019. The substantial increase in the prevalence of TSH measurement and levothyroxine use during this time period might indicate overuse of diagnostics and overtreatment, warranting further investigation., (© 2024. The Author(s).)

Background: Previous studies have repeatedly reported alcohol use disorders (AUDs) in patients after bariatric surgery (BS). This research field can benefit from studies combining health claims data with survey data., Methods: Based on a combined retrospective cohort and cross-sectional study, 2151 patients with BS identified in a large health claims database received a questionnaire, by which we assessed the presence of AUDs based on a validated instrument (AUDIT) as well as by ICD-10 codes from the health claims data. We described patients with vs. without AUDs regarding sex, time since surgery, satisfaction with weight loss and health care resource utilization (HCRU)., Results: The majority of patients were female (80.7%) with a median time since surgery of 6 years (Interquartile range: 4-9 years). For the majority of patients, the bariatric intervention was either a RYGB-Bypass (50%) or sleeve gastrectomy (43%). Overall, 3% had at least one AUD diagnosis code in the claims data (men: 5.5%, women: 2.5%). Among men, 43.6% of diagnoses were coded after but not before the surgery (women: 52%). According to AUDIT (completed by 1496 patients), 9.4% of all patients showed at least hazardous/harmful alcohol consumption. Higher scores were associated with sex of the person, longer time since surgery, dissatisfaction with the weight loss and higher HCRU, with contradicting results regarding psychotherapeutic care., Conclusions: The proportion with AUDs in the study population gives rise to concern as alcohol consumption should be restricted after BS. The results suggest the necessity for close monitoring and post-surgical care., (© 2024. The Author(s).)

Most studies on antipsychotic efficacy and safety, including sex differences, focus on young schizophrenia patients. However, with an aging population, the number of older schizophrenia patients is increasing. This group faces challenges due to varying treatment responses and higher risks of adverse reactions, and guidelines often lack specific recommendations due to insufficient trials. Therefore, we investigated how age and sex influence antipsychotic prescribing practices in schizophrenia using the German Pharmacoepidemiological Research Database (GePaRD). We included patients diagnosed with schizophrenia (ICD-10 code F20.X) who had been prescribed at least one antipsychotic on an outpatient basis in at least two consecutive quarters in 2020, analyzing prescription data for 49,681 patients. Key findings include a notable preference for second-generation antipsychotics (SGAs) across all age groups, especially in younger patients, possibly due to their perceived better tolerability and efficacy. Treatment intensity with SGAs (expressed as the defined daily doses of SGAs per patient in 2020) initially increased with age, peaked among 35- to 44-year-olds, and then decreased, with the lowest treatment intensity in patients aged 65 years and older. The prescription patterns of specific SGAs and first-generation antipsychotics varied across age groups, highlighting the complexity of treatment decisions in schizophrenia management. Sex differences in prescription frequency and treatment intensity were also observed. The basic recommendation of the guideline to consider sex and age when prescribing antipsychotics therefore appears to be followed. Whether this prescribing practice is really optimal for older male and female schizophrenia patients, however, still needs to be proven in clinical trials., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: In Germany, the utilization of health insurance data for scientific research is regulated by the Code of Social Law. All involved health insurance providers as well as the German Federal Office for Social Security and the Senator for Health, Women and Consumer Protection in Bremen as their responsible authorities approved the use of GePaRD data for this study. Informed consent for studies based on claims data is required by law unless obtaining consent appears unacceptable and would bias results, which was the case in this study. According to the Ethics Committee of the University of Bremen studies based on GePaRD are exempt from institutional review board review., (© 2024. The Author(s).)

Purpose: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency-funded project (EUPAS39322), defined a set of metadata to describe real-world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct., Methods: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software. Metadata collection was piloted by 15 data access partners (DAPs) from across Europe., Results: A total of 442 metadata variables were defined in six domains: institutions (organizations connected to a data source); data banks (data collections sustained by an organization); data sources (collections of linkable data banks covering a common underlying population); studies; networks (of institutions); and common data models (CDMs). A total of 26 institutions were recorded in the prototype. Each DAP populated the metadata of one data source and its selected data banks. The number of data banks varied by data source; the most common data banks were hospital administrative records and pharmacy dispensation records (10 data sources each). Quantitative metadata were successfully extracted from three data sources conforming to different CDMs and entered into the prototype., Conclusions: A metadata list was finalized, a prototype was successfully populated, and a good practice guide was developed. Setting up and maintaining a metadata catalogue on RWDSs will require substantial effort to support discoverability of data sources and reproducibility of studies in Europe., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Previous studies have identified substantial regional variations in outpatient antibiotic prescribing in Germany, both in the paediatric and adult population. This indicates inappropriate antibiotic prescribing in some regions, which should be avoided to reduce antimicrobial resistance and potential side effects. The reasons for regional variations in outpatient antibiotic prescribing are not yet completely understood; socioeconomic and health care density differences between regions do not fully explain such differences. Here, we apply a behavioural perspective by adapting the Theoretical Domains Framework (TDF) to examine regional factors deemed relevant for outpatient antibiotic prescriptions by paediatricians and general practitioners., Methods: Qualitative study with guideline-based telephone interviews of 40 prescribers (paediatricians and general practitioners) in outpatient settings from regions with high and low rates of antibiotic prescriptions, stratified by urbanity. TDF domains formed the basis of an interview guide to assess region-level resources and barriers to rational antibiotic prescription behaviour. Interviews lasted 30-61 min (M = 45 min). Thematic analysis was used to identify thematic clusters, and relationships between themes were explored through proximity estimation., Results: Both paediatricians and general practitioners in low-prescribing regions reported supporting contextual factors (in particular good collegial networks, good collaboration with laboratories) and social factors (collegial support and low patient demand for antibiotics) as important resources. In high-prescribing regions, poor coordination between in-patient and ambulatory health services, lack of region-level information on antimicrobial resistance, few professional development opportunities, and regional variations in patient expectations were identified as barriers to rational prescribing behaviour., Conclusions: Interventions targeting professional development, better collaboration structures with laboratories and clearer and user-friendly guidelines could potentially support rational antibiotic prescribing behaviour. In addition, better networking and social support among physicians could support lower prescription rates., (© 2024. The Author(s).)

Leflunomide is contraindicated during pregnancy and treatment cessation is recommended two years before pregnancy. We aimed to describe leflunomide use in women of childbearing age in Germany, the occurrence of pregnancies in women using leflunomide and malformations among children possibly exposed in utero. Using the GePaRD database (claims data, ∼20% of the German population), we determined annual age-standardized prevalences of leflunomide use between 2004 and 2019 among females aged 13-49 years. Further, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by the dispensation plus two years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. For exposed live births, a mother-baby linkage was performed and the presence of congenital malformation was assessed. The age-standardized prevalence of leflunomide use ranged between 0.34 and 0.46 per 1000 females during the study period. About one third of the users were ≤40 years. We identified 205 leflunomide-exposed pregnancies ending during the study period. 71% of these pregnancies ended in a live birth (26% preterm) and 10% in an induced abortion. In 86% of the live births (n=125) the mother-baby linkage was successful. Among these 125 children, 13 children (10%) had congenital malformations. In conclusion, we observed a considerable number of pregnancies in women using leflunomide in the two years before or during early pregnancy. This highlights the importance of monitoring the implementation of existing risk minimization measures for leflunomide in Germany., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ulrike Haug reports financial support was provided by Federal Institute for Drugs and Medical Devices. Christina Princk, Bianca Kollhorst and Ulrike Haug are working at an independent, non-profit research institute, the Leibniz-Institute for Prevention Research and Epidemiology - BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. These are exclusively post-approval safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the association between personality characteristics and use of different cancer screenings., Methods: We used data from the German National Cohort (NAKO; mean age was 53.0 years (SD: 9.2 years)) - a population-based cohort study. A total of 132,298 individuals were included in the analyses. As outcome measures, we used (self-reported): stool examination for blood (haemoccult test, early detection of bowel cancer), colonoscopy (screening for colorectal cancer), skin examination for moles (early detection of skin cancer), breast palpation by a doctor (early detection of breast cancer), x-ray examination of the breast ("mammography", early detection of breast cancer), cervical smear test, finger examination of the rectum (early detection of prostate cancer), and blood test for prostate cancer (determination of Prostate-Specific Antigen level). The established Big Five Inventory-SOEP was used to quantify personality factors. It was adjusted for several covariates based on the Andersen model. Unadjusted and adjusted multiple logistic regressions were computed., Results: A higher probability of having a skin examination for moles, for example, was associated with a higher conscientiousness (OR: 1.07, p < 0.001), higher extraversion (OR: 1.03, p < 0.001), higher agreeableness (OR: 1.02, p < 0.001), lower openness to experience (OR: 0.98, p < 0.001) and higher neuroticism (OR: 1.07, p < 0.001) among the total sample. Depending on the outcome used, the associations slightly varied., Conclusions: Particularly higher levels of extraversion, neuroticism and conscientiousness are associated with the use of different cancer screenings. Such knowledge may help to better understand non-participation in cancer screening examinations from a psychological perspective., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Introduction: Comparing antibiotic prescribing between countries can provide important insights into potential needs of improving antibiotic stewardship programs. We aimed to compare outpatient antibiotic prescribing in early life between children born in Denmark and Germany., Methods: Using the Danish nationwide healthcare registries and a German claims database (GePaRD, ~ 20% population coverage), we included children born between 2004 and 2016, and followed them regarding outpatient antibiotic prescriptions until end of enrollment or the end of 2018. We then determined the median time to first antibiotic prescription. Based on all prescriptions in the first 2 years of life, we calculated the rate of antibiotic treatment episodes and for the children's first prescriptions in this period, we determined established quality indicators. All analyses were stratified by birth year and country., Results: In the 2016 birth cohorts, the median time to first antibiotic prescription was ~ 21 months in Denmark and ~ 28 in Germany; the rate of antibiotic treatment episodes per 1000 person-years was 537 in Denmark and 433 in Germany; the percentage of prescribed antibiotics with higher concerns regarding side effects and/or resistance potential was 6.2% in Denmark and 44.2% in Germany. In the 2016 birth cohorts, the age at first antibiotic prescription was 50-59% higher compared to the 2004 birth cohorts; the rate of antibiotic treatment episodes was 43-44% lower., Conclusions: Infants in Denmark received antibiotics markedly earlier and more frequently than in Germany, while quality indicators of antibiotic prescribing were more favorable in Denmark. Although both countries experienced positive changes towards more rational antibiotic prescribing in early life, our findings suggest potential for further improvement. This particularly applies to prescribing antibiotics with a lower potential for side effects and/or resistance in Germany., (© 2024. The Author(s).)

Background: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero., Methods and Findings: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin., Conclusions: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany., Competing Interests: The authors have declared that no competing interests exist. JR, NW, KP, BK, and UH are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. These are post-authorization safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry. The study presented was not funded by the pharmaceutical industry., (Copyright: © 2024 Reinold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: The authors report no conflicts of interest.

Background: Poorer survival in cancer patients with vs. without comorbidity has been reported for various cancer sites. For patients with colorectal cancer (CRC), limited data are available so far., Methods: Patients with CRC diagnosed between 2010 and 2018 were identified in a health claims database covering 20% of the German population. We assessed the prevalence of comorbidities at cancer diagnosis and categorized the patients into the groups: 'none', 'somatic only', 'mental only' or 'both' types of comorbidities. Hazard ratios (HR, with 95% confidence intervals) for five-year overall survival were estimated by Cox proportional hazard models, adjusted for age, sex and stage at diagnosis (advanced vs. non-advanced)., Results: We included 92,991 patients (females: 49.1%, median age: 72 years) with a median follow-up of 30 months. The proportions assigned to the groups 'none', 'somatic only', 'mental only' or 'both' were 24.7%, 65.5%, 1.4% and 8.4%. Overall, 32.8% of the patients died during follow-up. Compared to patients without comorbidities ('none'), the adjusted HR regarding death from any cause was 1.11 (95% CI: 1.07-1.14) in the group 'somatic only', 1.74 (95% CI: 1.58-1.92) in the group 'mental only' and 1.92 (95% CI: 1.84-2.00) in the group 'both'. For patients with 'mental only' comorbidities, the adjusted HR was higher in males than in females (HR = 2.19, 95% CI: 1.88-2.55 vs. HR = 1.55, 95% CI: 1.37-1.75)., Conclusions: Our results suggest that patients with CRC and with mental comorbidities, particularly males, have a markedly lower overall survival compared to those without any or only somatic comorbidities.

Introduction: The coronavirus disease 2019 (COVID-19), caused by infection with SARS-CoV-2, can lead to post-COVID-19 condition, a secondary syndrome of persistent and new post-acute symptoms, but evidence on this syndrome is still scarce., Methods: In a questionnaire survey, residents of the city of Bremen (Germany) with verified SARS-CoV-2 infection were invited to answer questions (online questionnaire or interview) concerning symptoms experienced at the time of infection and at the time of questionnaire completion at least three months later. Main outcome of the analysis was the presence of a post-COVID-19 condition at the time of the interview, defined as the presence of at least two of three leading symptoms: fatigue, breathing difficulties, or cognitive problems., Results: A post-COVID-19 condition was more likely to be reported if respondents had, at the time of infection, suffered from fatigue (OR 1.75; 95% CI: 1.00, 3.06), breathing difficulties (OR 4.02; 95% CI: 2.80, 5.77), cognitive symptoms (OR 2.98; 95% CI: 1.48, 6.02), or head- & bone aches (OR 2.06; 95% CI: 1.25, 3.42). The odds of developing a post-COVID-19 condition increased with the number of symptoms at infection. Females were more likely to report a post-COVID-19 condition (OR 1.54; 95% CI: 1.05, 2.24). Analyzing only non-hospitalized respondents changed results only slightly., Conclusion: Our study adds to growing evidence that even a mild course of COVID-19 poses a risk for developing a post-COVID-19 condition. Females and those with initial symptoms including fatigue, breathing difficulties, and cognitive symptoms seem more likely to also experience post COVID-19 symptoms several months after infection.KEY MESSAGESEven a mild course of COVID-19 poses a risk for developing a post-COVID-19 condition.Females seem more likely to develop a post-COVID-19 condition.Those with initial symptoms including fatigue, breathing difficulties, and cognitive symptoms seem more likely to develop a post-COVID-19 condition.

Background and Objective: Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero., Methods: Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations., Results: The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation)., Conclusions: We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug., (© 2023. The Author(s).)

Objective: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers., Design: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles., Results: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states ( phase I ), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations ( phase II ). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence., Conclusion: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact., Competing Interests: Competing interests: Board membership: TRL, RES, LG, FM, CS, RS, H-MC, ED, AK, HS, GAM, SI. Consultancy: LG, UL, GPY, FM, JM, SG, ED, AK, HS, SI. Expert testimony: FM. Grants or contract research: RSB, TRL, RES, FM, RS, FM, ED, ML, GAM, LC. Lectures/Other education events: LG, FM, H-MC, ED, AK. Patents: GPY, RSB, BC, AK, GAM. Receipt of equipment or supplies: LG, RES, ED, ML, GAM. Stock/Stock options: GPY, UL, JM, SG, ED, AK, GAM. Other professional relationships: GPY, SG., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Program sensitivity is a key quality indicator for mammography screening programs (MSP). Estimating program sensitivity usually requires a linkage of screening and cancer registry data. For the German MSP, such data linkage-based estimates have only been reported for two out of 16 federal states. We aimed to explore the potential of estimating program sensitivity for the German MSP based on information available in health claims data., Methods: We used data from the second-largest statutory health insurance fund in Germany, BARMER (~ 9 million members all over Germany). We included women aged 50 to 69 years with a non-initial screening mammography between 2010 and 2016 and followed them up for two years. We estimated the rate of screen-detected and interval cancers as well as program sensitivity., Results: Per year, we included 212,400 to 303,667 women (mean age: 60-61 years). Overall, 1,992,287 non-initial MSP screening examinations conducted in these women between 2010 and 2016 were considered for the analyses. Age-standardized program sensitivity ranged between 69.9% [95% CI: 67.3-72.0%] and 71.7% [95% CI: 69.5-73.9%] during the study period. Per 1,000 non-initial screening examinations, the rate of screen-detected breast cancer ranged between 4.6 and 5.3, and the rate of interval breast cancer rates ranged between 0.6 and 0.8 for the first and between 1.3 and 1.4 for the second year after screening., Conclusions: Our results were plausible and consistent with quality indicators estimated for the German MSP based on data linkage and thus support the value of German health claims data in this regard. The quality indicators estimated in our study are in line with levels expected according to European Guidelines., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: In Germany, all women aged 50-69 have been invited to biennial mammography screening since 2009. We aimed to assess longitudinal adherence over ten years in women aged 50 in 2009 and characterize the different adherence groups., Methods: Using the German Pharmacoepidemiological Research Database (GePaRD, ~ 20% of the German population), we included women aged 50 in 2009 (baseline) with continuous health insurance coverage and without breast cancer or in-situ-carcinoma. We followed them until age 59 and categorized them according to mammography screening participation into the following groups: never, 1-2, 3-4, 5-6 times. We characterized these groups, inter alia, regarding the use of other preventive measures, non-screening mammography (i.e., mammography outside the organized screening program) and menopausal hormone therapy., Results: Overall, 82,666 women were included. Of these, 27.6% never participated in the screening program, 15.1% participated 1-2 times, 31.7% participated 3-4 times and 25.6% participated regularly (5-6 times). Among regular participants, 91% utilized other preventive measures (e.g., cervical cancer screening, general health checkup) before baseline as compared to 66% among non-participants. Menopausal hormone therapy was least common among non-participants (11% vs. 18% among regular participants). Among non-participants, the proportions using ≥ 1, ≥ 2, and ≥ 3 non-screening mammographies between age 50-59 were 25%, 18%, and 15%, respectively., Conclusions: Using a large cohort based on claims data, this study provides novel insights into longitudinal adherence to the mammography screening program and the use of mammography outside of the program in Germany. Between age 50-59, 57% of eligible women participated at least three times in the German mammography screening program and 28% (~ 3 in 10 women) never participated. Among non-participants, 15% had at least three non-screening mammographies during this period, indicating potential gray screening. Participants more often utilized other preventive measures as compared to non-participants., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Use of endothelin receptor antagonists (ERAs) and riociguat, approved for treatment of pulmonary hypertension (PH), is contraindicated during pregnancy due to reported teratogenicity in animals. We aimed to investigate prescribing of these drugs in girls/women of childbearing age and to explore - as a secondary aim - the occurrence of pregnancies exposed to these drugs. Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from 20% of the German population) we conducted cross-sectional analyses to determine prescribing prevalence of ERAs and riociguat between 2004 and 2019 and to characterize users and prescribing patterns. In a cohort analysis, we assessed the occurrence of pregnancies exposed to these drugs in the critical time window. Overall, we identified 407 women with ≥ 1 dispensation of bosentan between 2004 and 2019; the respective number was 73 for ambrisentan, 182 for macitentan, 31 for sitaxentan, and 63 for riociguat. In nearly all years, more than 50% of the girls/women were ≤ 40 years. Age-standardized prevalence was highest for bosentan (0.04/1000) in 2012 and 2013, followed by macitentan (0.03/1000) in 2018 and 2019. We observed 10 exposed pregnancies: 5 to bosentan, 3 to ambrisentan, and 2 to macitentan. The increased prevalence of macitentan and riociguat from 2014 onwards might reflect changes in PH treatment. Even though PH is a rare disease and pregnancy should be avoided in women with PH, particularly if they use ERAs, we identified pregnancies exposed to ERAs. Multi-database studies will be needed to assess the risk of these drugs on the unborn child., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents., Methods: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice., Results: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance., Conclusion: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.

Background: Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far., Objective: We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with non-valvular atrial fibrillation from 2011 to 2016/17 in two European countries., Methods: We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥ 2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion., Results: Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N = 127,743, the Netherlands: N = 2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany., Conclusions: Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding., (© 2023. The Author(s).)

Studies have shown that the quality of colonoscopy influences the incidence of post-colonoscopy colorectal cancer (PCCRC). However, data from Germany on this association are lacking. We aimed to assess cumulative incidence of PCCRC in persons undergoing colonoscopy in Germany according to the physician's polyp detection rate (PDR). Using the German Pharmacoepidemiological Research Database (GePaRD) with claims data of ~20% of the German population, we included persons with a baseline colonoscopy between 2008 and 2017 and categorized them according to the procedure at baseline (snare polypectomy, forceps polypectomy, no polypectomy). In each subgroup, we distinguished between persons examined by physicians with a PDR in the lowest quartile vs higher quartiles and described cumulative CRC incidence during follow-up. Overall, 822 715 persons examined by 1752 physicians were included. One quarter of the physicians had a PDR ≤21.8% (lowest quartile). In all subgroups, the 5-year cumulative CRC incidence was statistically significantly higher in persons examined by physicians with a PDR ≤21.8% vs >21.8%: It was 69% higher in persons with snare polypectomy (0.88% vs 0.52%), 87% higher in persons with forceps polypectomy (0.58% vs 0.31%), and 48% higher in persons without polypectomy at baseline (0.31% vs 0.21%). In conclusion, we found a substantially increased PCCRC risk in persons examined by physicians with a low PDR in Germany, irrespective of the baseline findings. Our study highlights the importance of a high-quality colonoscopy to maximize the preventive effect of colonoscopy on CRC incidence., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background and Objective: Methotrexate should be withdrawn before pregnancy because of its teratogenic potential. We aimed to describe the use of methotrexate in women of childbearing age in Germany and the occurrence and outcomes of pregnancies exposed to methotrexate., Methods: Using the German Pharmacoepidemiological Research Database (GePaRD, covering ~ 20% of the German population), we determined the age-specific and age-standardized prevalence of methotrexate use for each year between 2004 and 2019 among women aged 13-49 years (cross-sectional analyses). In a cohort analysis, we assessed the number and outcomes of pregnancies exposed to methotrexate in the critical time window. Exposure was defined as a dispensation overlapping with the onset of pregnancy or a dispensation in the first 8 weeks of pregnancy. For children born from exposed pregnancies, the mother's and children's data were linked and the occurrence of malformations was assessed by reviewing all available data of these children., Results: The age-standardized prevalence of methotrexate use per 1000 females increased from 1.5 in 2004 to 2.3 in 2019, i.e., by 52%. Overall, we identified 184 pregnancies exposed to methotrexate. Of these, 53% ended in a live birth (21% preterm) and 11% in an induced abortion. Among 81 live-born children linked to their mothers, five children (6%) had relevant malformations including congenital heart defects and musculoskeletal malformations., Conclusions: In Germany, the use of methotrexate in women of childbearing age has substantially increased since 2004. Despite the known teratogenic effect, there was a considerable number of exposed pregnancies.  Also, malformations likely associated with methotrexate and thus avoidable were observed., (© 2022. The Author(s).)

Introduction: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections., Methods and Analysis: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed., Ethics and Dissemination: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals., Trial Registration Number: EUPAS30280., Competing Interests: Competing interests: MR and PBJ report participation in research funded by LEO Pharma A/S (no personal fees). participation in studies funded by Alcon, Almirall, Astellas, AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Servier, Pfizer, Menarini Pharmaceuticals, and LEO Pharma, all regulator mandated phase IV studies, all with funds paid to the institution (no personal fees). JH has received teaching fees from Atrium. HS reports participation in research funded by LEO Pharma A/S (no personal fees). He has received personal consulting fees from Bristol-Myers-Squibb, Novartis, Roche, Merck and Pfizer outside the submitted work. He has received teaching fees from Atrium. KF and ØK reports participation in research projects funded by Novo Nordisk and LEO Pharma, all regulator mandated phase IV studies, all with funds paid to the institution (no personal fees). ES, EH and RH are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. AE has received research funding from Pfizer, Eli Lilly, Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the Simon Spies Foundation and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from AbbVie, Almirall, Leo Pharma, Zuellig Pharma, Galápagos NV, Sun Pharmaceuticals, Samsung Bioepis, Pfizer, Eli Lilly and Company, Novartis, Union Therapeutics, Galderma, Dermavant, UCB, Mylan, Bristol-Myers Squibb, Horizon Therapeutics and Janssen Pharmaceuticals. UK, Alessandro Cesare Rosa, and Valeria Belleudi are employees of the Department of Epidemiology ASL Roma1, Lazio Regional Health Service in Rome, Italy. Our publicly funded department performs epidemiological research and receives grants from public national and international organisations. In case of financial support from private organisations, an ethical code of conduct is signed to guarantee transparency and independence. KG, DH and JR are employees of the Centre for Pharmacoepidemiology of the Karolinska Institutet in Sweden, which receives grants from regulatory authorities, pharmaceutical companies, and contract research organisations for performance of drug safety and drug utilisation studies. UH, WS and SS are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology-BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are postauthorisation safety studies (PASS) requested by health authorities. GT declares participation to advisory boards on topics not related to this paper and sponsored by the following pharmaceutical companies in the last two years: Eli Lilly; Sanofi; Amgen; Novo Nordisk; Sobi; Gilead; Celgene; Daikii Sankyo. RG is employed by ARS, a public research centre participating in pharmacoepidemiology studies funded by public or private institutions and compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. Lise Skov Ranch is a full time employee of LEO Pharma A/S., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Large health-care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof-of-concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child., Methods: We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA-exposed ones to all pregnancies., Results: Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA-exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7-88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA-exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9-76.0)., Conclusions: Our proof-of-concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Introduction: We aimed to describe cumulative colorectal cancer (CRC) incidence after screening colonoscopy stratified by tumor location, age, and sex as well as CRC detection rate at first repeat colonoscopy., Methods: Using the German Pharmacoepidemiological Research Database, we included persons with screening colonoscopy and assessed cumulative CRC incidence after baseline screening colonoscopy with snare polypectomy (cohort 1) and without polypectomy (cohort 2). We also determined the CRC detection rate at first repeat colonoscopy by time since screening colonoscopy., Results: Overall, 1,095,381 persons were included. The 10-year cumulative CRC incidence was 1.5% in cohort 1 and 0.6% in cohort 2. The proportion of proximal CRC increased with age: In women of cohort 1, 47% of CRCs in the age group 55-64 years were proximal (men: 42%) while in the age group 65-74 years, this proportion was 55% (men: 49%). In cohort 2, similar patterns were observed. In cohort 1, the CRC detection rate at first repeat colonoscopy among persons examined within 6-8 years after screening colonoscopy was more than twice as high compared with those examined within 4-6 years (1.7% vs 0.8%)., Discussion: Among persons followed up after screening colonoscopy, we observed a steadily increasing predominance of proximal CRC, and this shift showed distinct patterns by age and sex. Because our study suggests higher CRC detection rates among persons with a later repeat colonoscopy, the role of delayed surveillance and the benefit of a reminder system should be explored., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objective: To compare the risk of venous thromboembolism (VTE) among young women for nine combined oral contraceptives (COCs), including progestogens with an as yet unclear risk of VTE such as chlormadinone and nomegestrol, using COCs containing levonorgestrel with low ethinylestradiol (<50 μg) as a reference., Design: Case-control study nested in a cohort of new users of COCs., Setting: German claims data., Population: A total of 1166 cases of VTE matched to 11 660 controls nested in a cohort of 677 331 girls and young women aged 10-19 years with one or more COCs dispensed between 2005 and 2017 after a 1-year period without any COCs., Methods: Confounder-adjusted odds ratios (aORs) of VTE associated with current use of the respective COCs were calculated using conditional logistic regression., Main Outcome Measures: Venous thromboembolism (VTE), defined as a diagnosis of pulmonary embolism or deep vein thrombosis., Results: Compared with levonorgestrel with low ethinylestradiol (<50 μg), the risk of VTE was increased two-fold for COCs containing dienogest (aOR 2.23, 95% CI 1.77-2.80), cyproterone (aOR 2.15, 95% CI 1.43-3.25), chlormadinone (aOR 2.06, 95% CI 1.58-2.68), desogestrel (aOR 1.93, 95% CI 1.44-2.61) and drospirenone (aOR 1.89, 95% CI 1.41-2.55), and increased five-fold for gestodene (aOR 5.05, 95% CI 1.23-20.74). For norgestimate and nomegestrol, the point estimates suggest a two-fold increased risk (aOR 1.90, 95% CI 0.62-5.81) and 40% increased risk (aOR 1.41, 95% CI 0.52-3.81), respectively., Conclusions: Our study confirms that levonorgestrel with low ethinylestradiol (<50 μg) is the COC associated with the lowest risk of VTE and suggests that for chlormadinone the risk of VTE is two times higher, and thus in the same range as for desogestrel and drospirenone., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Given the paucity of epidemiological studies on thyroid storm, we aimed to estimate the incidence rate and case fatality of thyroid storm in Germany based on a large claims database. Methods: Using the German Pharmacoepidemiological Research Database (GePaRD) we identified patients with at least one inpatient discharge diagnosis of thyroid storm ( International Statistical Classification of Diseases and Related Health Problems , 10th revision, German modification; ICD-10-GM E05.5) between 2007 and 2017 and calculated age-standardized and age-specific incidence rates in males and females (no age restriction). We defined deaths occurring within 30 days of the diagnosis as thyroid storm-associated and determined case fatality by sex and age group. Point estimates were reported with confidence intervals [CIs]. Results: We identified 1690 patients with an incident diagnosis of thyroid storm. Of these, 72% were females ( n  = 1212). The mean age was 60 years (standard deviation: 18.6 years). The age-standardized incidence rate per 100,000 persons per year was 1.4 [CI 1.2-1.7] in females and 0.7 [CI 0.5-0.9] in males. In females ≤60 and >60 years of age, the incidence rate was 0.9 [CI 0.9-1.0] (males: 0.4 [CI 0.3-0.4]) and 2.7 [CI 2.5-2.9] (males: 1.7 [CI 1.5-1.9]), respectively. The case fatality of thyroid storm was 1.4% [CI 0.6-2.8] in females ≤60 years and 10.9% [CI 8.6-13.7] in females >60 years. In males, the case fatality was 1.0% [CI 0.2-4.0] in those aged ≤60 years and 16.7% [CI 12.6-21.7] in those >60 years. Conclusions: Incidence rates of thyroid storm were markedly higher in females than in males and were three times higher in persons >60 years compared with younger age groups. The case fatality was below 2% in persons aged ≤60 years and markedly higher in older persons (males: 17 times and females: 8 times).

Background: In 2012, the so-called ambulatory medical specialist care (ASV) was implemented in accordance with para. 116b of Book V of the German Social Code (SGB V), enabling physicians in outpatient practices and hospitals to treat patients with rare diseases or complex courses of disease in a uniform framework. The implementation, however, is slow. The Joint Federal Committee (G-BA) has therefore commissioned an evaluation of the ASV with the aim to examine the reasons for this and to provide recommendations for further development., Methods: The health services research study "GOAL-ASV" (Innovation Fund, 01VSF19002) included a multi-perspective design with primary data collection as well as secondary data analyses. Data from the ASV service center and the central association of statutory health insurances and the notification forms of the extended state committees were analyzed. Data from the Robert Koch-Institute, the Federal Joint Committee, the National Association of Statutory Health Insurance Funds and a literature database analysis were used in order to estimate the proportion of insured persons qualifying for ASV. Care was examined by analyzing pseudonymized routine data from the statutory health insurances using selected indicators. Participating and not participating physicians were asked to complete an online survey., Results: Since the start of ASV, 615,531 insured persons have been treated in this form of care. At the time of analysis, 509 teams were operating, with 26,540 physicians treating 102,898 patients by the end of March 2021 in all indications. This comprises less than 9.8 %. of all approx. 1.05 million eligible patients. Especially in the case of rare diseases, a low willingness of participation can be seen. In addition, there was a relevant proportion of multiple uses of physicians within and outside ASV at 31 percent as well as indications of passive participation of doctors. We found significant regional differences in type and scope of the notification procedure as well as the implementation of teams with 13.4 teams per 1 million inhabitants in Schleswig-Holstein and no team in Mecklenburg-Vorpommern. Patient benefits (84 %), interdisciplinary (82 %) and cross-sectoral cooperation (75 %) were cited as motivations for participation. The main barriers reported by the respondents were the complex and laborious notification procedure (60 %), the administrative and documentation effort during participation (50 %), insufficient billing figures (49 %), and a small proportion of patients (32 %) with a consecutively unfavorable assessment of the cost to income ratio due to the current reimbursement system., Discussion: Nearly ten years after its introduction, the ASV has not become established nationwide. The reasons for this probably are the complex notification procedure and the reimburesement system for rare diseases. In the case of rare diseases, the risk of underuse is becoming apparent., Conclusion: Strategies to further develop the ASV should, in particular, simplify the notification procedure and reduce the obstacles during participation. The remuneration system should take more account of the specific care required., (Copyright © 2022. Published by Elsevier GmbH.)

Introduction: Studies providing detailed information on colonoscopy use are important for the interpretation of patterns and trends in colorectal cancer incidence and mortality, but there is a lack of such studies from Germany. To fill this gap, we aimed to describe the 10-year prevalence of colonoscopy use based on German health claims data., Methods: Using the German Pharmacoepidemiological Research Database (short GePaRD; claims data from ~20% of the German population), we determined the 10-year prevalence of colonoscopy use for the year 2017. We determined this prevalence for any colonoscopy, screening (reimbursable from age 55) and diagnostic colonoscopy, stratified by sex, age, educational level and regional factors (e.g. federal state, physicians density in the district of residence)., Results: In men, the 10-year prevalence of colonoscopy use was as follows (not all age groups reported): 30-34 years: 8%, 40-44 years: 12%, 50-54 years: 21%, 55-59 years: 33% (screening: 10%), 60-64 years: 44% (screening: 23%), 70-74 years: 53% (screening: 23%), 80-84 years: 52% (screening: 15%). In women, the prevalences were similar, with differences mostly less than or equal to 3 percentage points. Also, in analyses stratified by educational level or regional factors, prevalences were mostly similar or varied by less than or equal to 4 percentage points., Conclusion: In 2017, about 45-50% of men and women in Germany aged 60-84 years had any colonoscopy in the previous 10 years, and about 11-26% had a screening colonoscopy. Our findings suggest no relevant social or regional disparities in the utilization of colonoscopy in Germany., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Authorizations of fingolimod, teriflunomide and cladribine were accompanied by risk minimization measures concerning their teratogenic potential. Real-world data on their use are scarce. We aimed to assess trends in the use of fingolimod, teriflunomide and cladribine among women of childbearing age, estimate the number of pregnancies occurring under treatment and explore the occurrence of malformations in newborns exposed during early pregnancy in Germany., Methods: Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from ∼20% of the German population), we determined annual age-standardized prevalences of fingolimod, teriflunomide and cladribine use from their authorization until 2019 among women aged 13-49 years (cross-sectional analyses). In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether there was an overlap between the exposure windows assigned to dispensations and the onset of pregnancy or a dispensation in the first eight weeks of pregnancy. For live births, a mother-baby linkage was performed. All available data of children with in-utero exposure and malformation codes in the first year of life were reviewed to verify the occurrence of congenital malformations., Results: For fingolimod, the age-standardized prevalence of use per 1,000 females increased from 0.14 in 2011 to 0.46 in 2019; for teriflunomide, from 0.06 in 2013 to 0.28 in 2019; for cladribine, from 0.01 in 2017 to 0.07 in 2019. The proportion of users aged ≤40 years was 60% for fingolimod, 45% for teriflunomide and 65% for cladribine. We identified 136 pregnancies exposed to fingolimod, 50 to teriflunomide and one to cladribine. For fingolimod and teriflunomide, respectively, 72% and 62% of exposed pregnancies ended in a live birth. Mother-newborn linkage was successful in 64 (fingolimod) and 20 (teriflunomide) live-born children. Among these, there were six with relevant malformations (mainly heart defects) for fingolimod and two for teriflunomide., Conclusion: Use of fingolimod, teriflunomide and cladribine among women of childbearing age has substantially increased in Germany. A high proportion of users was in age groups in which pregnancies typically occur. Despite risk minimization measures, early pregnancy exposure to these drugs was observed., Competing Interests: Declaration of Competing Interest The authors are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology – BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are post-authorization safety studies (PASS) requested by health authorities. The design and conduct of these studies as well as the interpretation and publication are not influenced by the pharmaceutical industry. The study presented was not funded by the pharmaceutical industry and was performed in line with the ENCePP Code of Conduct., (Copyright © 2022. Published by Elsevier B.V.)

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years., (© 2022. The Author(s).)