Intrauterine device-related uterine perforation incidence and risk (APEX-IUD): a large multisite cohort study.

BACKGROUND: Reports of perforation risk related to intrauterine devices (IUDs) inserted immediately post partum and among non-post-partum individuals are scarce, and previous studies with only 12-month follow-ups underestimate the risk. Breastfeeding at IUD insertion and insertion within 36 weeks post partum have been associated with increased risk of uterine perforation. The aim of these analyses was to compare the incidence and risks of IUD-related uterine perforations by non-post-partum and post-partum intervals at IUD insertion, and among post-partum individuals, to assess the impact of breastfeeding on these outcomes. METHODS: We did a multisite cohort study in the USA, using electronic health records (EHR). Study sites were three health-care systems and a site that used data from a health-care information exchange. The study population included individuals who were aged 50 years or younger and had an IUD insertion between Jan 1, 2001, and April 30, 2018. Individuals were excluded if they had not been in the health-care system for at least 12 months before IUD insertion. The primary outcome for this analysis was any IUD-related uterine perforation diagnosis for the first IUD insertion in this time period. Both complete and partial IUD-related perforations were identified. Chart abstraction was done to validate EHR-based algorithms or confirm perforations. The crude rate and cumulative incidence of uterine perforation were evaluated by non-post-partum and post-partum intervals at IUD insertion in the full cohort, and by breastfeeding status in a subcohort of post-partum individuals. Cox models estimated crude and adjusted hazard ratios (aHRs). FINDINGS: Data from 326 658 individuals in the full cohort and 94 817 individuals in the post-partum subcohort were analysed. In the full cohort, we identified 1008 uterine perforations (51·2% complete), with the 5-year cumulative incidence being the lowest in the non-post-partum group (0·29%, 95% CI 0·26-0·34). The aHR for the post-partum interval relative to non-post partum ranged from 2·73 (95% CI 1·33-5·63; 0 to 3 days post partum) to 6·71 (4·80-9·38; 4 days to ≤6 weeks post partum). The post-partum subcohort of individuals with breastfeeding information had 673 uterine perforations (62% complete), with a 5-year cumulative incidence of 1·37% (95% CI 1·24-1·52) and an increased risk with breastfeeding (aHR 1·37, 95% CI 1·12-1·66). INTERPRETATION: Although the risk for uterine perforation with IUD insertion 4 days to 6 weeks or less post partum is nearly seven times that of insertion non-post partum, perforation remains an incredibly rare event for all clinical time points. Despite a slight increased risk of perforation with breastfeeding at IUD insertion, the benefits of breastfeeding and effective contraception generally outweigh risks and should have little clinical impact. Therefore, IUD insertion timing should be based on individual desire for IUD contraception and patient convenience to assure an IUD insertion can occur. Careful follow-up of individuals at higher risk of uterine perforation is warranted. FUNDING: Bayer AG.

Association between menorrhagia and risk of intrauterine device-related uterine perforation and device expulsion: results from the Association of Uterine Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices are effective instruments for contraception, and 1 levonorgestrel-releasing device is also indicated for the treatment of heavy menstrual bleeding (menorrhagia). OBJECTIVE: To compare the incidence of intrauterine device expulsion and uterine perforation in women with and without a diagnosis of menorrhagia within the first 12 months before device insertion STUDY DESIGN: This was a retrospective cohort study conducted in 3 integrated healthcare systems (Kaiser Permanente Northern California, Southern California, and Washington) and a healthcare information exchange (Regenstrief Institute) in the United States using electronic health records. Nonpostpartum women aged ≤50 years with intrauterine device (eg, levonorgestrel or copper) insertions from 2001 to 2018 and without a delivery in the previous 12 months were studied in this analysis. Recent menorrhagia diagnosis (ie, recorded ≤12 months before insertion) was ascertained from the International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. The study outcomes, viz, device expulsion and device-related uterine perforation (complete or partial), were ascertained from electronic medical records and validated in the data sources. The cumulative incidence and crude incidence rates with 95% confidence intervals were estimated. Cox proportional hazards models estimated the crude and adjusted hazard ratios using propensity score overlap weighting (13-16 variables) and 95% confidence intervals. RESULTS: Among 228,834 nonpostpartum women, the mean age was 33.1 years, 44.4% of them were White, and 31,600 (13.8%) had a recent menorrhagia diagnosis. Most women had a levonorgestrel-releasing device (96.4% of those with and 78.2% of those without a menorrhagia diagnosis). Women with a menorrhagia diagnosis were likely to be older, obese, and have dysmenorrhea or fibroids. Women with a menorrhagia diagnosis had a higher intrauterine device-expulsion rate (40.01 vs 10.92 per 1000 person-years) than those without, especially evident in the first few months after insertion. Women with a menorrhagia diagnosis had a higher cumulative incidence (95% confidence interval) of expulsion (7.00% [6.70-7.32] at 1 year and 12.03% [11.52-12.55] at 5 years) vs those without (1.77% [1.70-1.84] at 1 year and 3.69% [3.56-3.83] at 5 years). The risk of expulsion was increased for women with a menorrhagia diagnosis vs for those without (adjusted hazard ratio, 2.84 [95% confidence interval, 2.66-3.03]). The perforation rate was low overall (<1/1000 person-years) but higher in women with a diagnosis of menorrhagia vs in those without (0.98 vs 0.63 per 1000 person-years). The cumulative incidence (95% confidence interval) of uterine perforation was slightly higher for women with a menorrhagia diagnosis (0.09% [0.06-0.14] at 1 year and 0.39% [0.29-0.53] at 5 years) than those without it (0.07% [0.06-0.08] at 1 year and 0.28% [0.24-0.33] at 5 years). The risk of perforation was slightly increased in women with a menorrhagia diagnosis vs in those without (adjusted hazard ratio, 1.53; 95% confidence interval, 1.10-2.13). CONCLUSION: The risk of expulsion is significantly higher in women with a recent diagnosis of menorrhagia. Patient education and counseling regarding the potential expulsion risk is recommended at insertion. The absolute risk of perforation for women with a recent diagnosis of menorrhagia is very low. The increased expulsion and perforation rates observed are likely because of causal factors of menorrhagia.

Association between intrauterine device type and risk of perforation and device expulsion: results from the Association of Perforation and Expulsion of Intrauterine Device study.

BACKGROUND: Intrauterine devices, including levonorgestrel-releasing and copper devices, are highly effective long-acting reversible contraceptives. The potential risks associated with intrauterine devices are low and include uterine perforation and device expulsion. OBJECTIVE: This study aimed to evaluate the risk of perforation and expulsion associated with levonorgestrel-releasing devices vs copper devices in clinical practice in the United States. STUDY DESIGN: The Association of Perforation and Expulsion of Intrauterine Device study was a retrospective cohort study of women aged ≤50 years with an intrauterine device insertion during 2001 to 2018 and information on intrauterine device type and patient and medical characteristics. Of note, 4 research sites with access to electronic health records contributed data for the study: 3 Kaiser Permanente-integrated healthcare systems (Northern California, Southern California, and Washington) and 1 healthcare system using data from a healthcare information exchange in Indiana (Regenstrief Institute). Perforation was classified as any extension of the device into or through the myometrium. Expulsion was classified as complete (not visible in the uterus or abdomen or patient reported) or partial (any portion in the cervix or malpositioned). We estimated the crude incidence rates and crude cumulative incidence by intrauterine device type. The risks of perforation and expulsion associated with levonorgestrel-releasing intrauterine devices vs copper intrauterine devices were estimated using Cox proportional-hazards regression with propensity score overlap weighting to adjust for confounders. RESULTS: Among 322,898 women included in this analysis, the incidence rates of perforation per 1000 person-years were 1.64 (95% confidence interval, 1.53-1.76) for levonorgestrel-releasing intrauterine devices and 1.27 (95% confidence interval, 1.08-1.48) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 0.22% (95% confidence interval, 0.20-0.24) and 0.63% (95% confidence interval, 0.57-0.68) for levonorgestrel-releasing intrauterine devices and 0.16% (95% confidence interval, 0.13-0.20) and 0.55% (95% confidence interval, 0.44-0.68) for copper intrauterine devices, respectively. The incidence rates of expulsion per 1000 person-years were 13.95 (95% confidence interval, 13.63-14.28) for levonorgestrel-releasing intrauterine devices and 14.08 (95% confidence interval, 13.44-14.75) for copper intrauterine devices; 1-year and 5-year crude cumulative incidence was 2.30% (95% confidence interval, 2.24-2.36) and 4.52% (95% confidence interval, 4.40-4.65) for levonorgestrel-releasing intrauterine devices and 2.30% (95% confidence interval, 2.18-2.44) and 4.82 (95% confidence interval, 4.56-5.10) for copper intrauterine devices, respectively. Comparing levonorgestrel-releasing intrauterine devices with copper intrauterine devices, the adjusted hazard ratios were 1.49 (95% confidence intervals, 1.25-1.78) for perforation and 0.69 (95% confidence intervals, 0.65-0.73) for expulsion. CONCLUSION: After adjusting for potential confounders, levonorgestrel-releasing intrauterine devices were associated with an increased risk of uterine perforation and a decreased risk of expulsion relative to copper intrauterine devices. Given that the absolute numbers of these events are low in both groups, these differences may not be clinically meaningful.

Time Trends and Treatment Pathways in Prescribing Individual Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: An Observational Study of More than Three Million Patients from Europe and the United States.

Background: Data directly comparing trends in the use of different oral anticoagulants (OACs) among patients with atrial fibrillation (AF) from different countries are limited. We addressed this using a large-scale network cohort study in the United States (US), Belgium, France, Germany, and the United Kingdom (UK). Methods: We used nine databases (claims or electronic health records) that had been converted into the Observational Medical Outcomes Partnership Common Data Model with analysis performed using open-source analytical tools. We identified adults with AF and a first OAC prescription, either vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC), from 2010 to 2017. We described time trends in use, continuation, and switching. Results: In 2010, 87.5%-99.8% of patients started on a VKA. By 2017, the majority started on a DOAC: 87.0% (US), 88.3% (Belgium), 93.1% (France), 88.4% (Germany), and 86.1%-86.7% (UK). In the UK, DOACs became the most common starting OAC in 2015, 2-3 years later than elsewhere. Apixaban was the most common starting OAC by 2017, 50.2%-57.8% (US), 31.4% (Belgium), 45.9% (France), 39.5% (Germany), and 49.8%-50.5% (UK), followed by rivaroxaban, 24.8%-32.5% (US), 25.7% (Belgium), 38.4% (France), 24.9% (Germany), and 30.2%-31.2% (UK). Long-term treatment was less common in the US than in Europe, especially the UK. A minority of patients switched from their index OAC in the short and long term. Conclusions: From 2010 to 2017, VKA use had significantly declined and DOAC use had significantly increased in the US and Europe. Apixaban was the most prescribed OAC in 2017, followed by rivaroxaban.

Design of the Association of Uterine Perforation and Expulsion of Intrauterine Device study: a multisite retrospective cohort study.

BACKGROUND: Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006-2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration-mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device-related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion. OBJECTIVE: We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up. STUDY DESIGN: APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights. RESULTS: The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74-177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m2, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record. CONCLUSION: Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.

Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - part I: which parameters from human studies are most relevant for toxicological assessments?

The 2018 European Food Safety Authority/European Chemicals Agency Guidance on the Identification of Endocrine Disruptors lacks clarity on how the presence or absence of substance-induced maternal thyroid hormone imbalance, or the potential for subsequent deleterious consequences in child neurodevelopment, should be established by toxicological assessments. To address these uncertainties, this narrative review evaluates human evidence on how altered maternal thyroid function may be associated with child neurodevelopmental outcomes; and seeks to identify parameters in human studies that appear most relevant for toxicological assessments. Serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) are most frequently measured when assessing thyroid function in pregnant women, whereas a broad spectrum of neurodevelopmental parameters is used to evaluate child neurodevelopment. The human data confirms an association between altered maternal serum fT4 and/or TSH and increased risk for child neurodevelopmental impairment. Quantitative boundaries of effects indicative of increased risks need to be established. Moreover, it is unknown if altered serum levels of total T4, free or total triiodothyronine, or parameters unrelated to serum thyroid hormones might be more relevant indicators of such effects. None of the human studies established a link between substance-mediated liver enzyme induction and increased serum thyroid hormone clearance, let alone further to child neurodevelopmental impairment. This review identifies research needs to contribute to the development of toxicity testing strategies, to reliably predict whether substances have the potential to impair child neurodevelopment via maternal thyroid hormone imbalance.

Feasibility study to identify women of childbearing age at risk of pregnancy not using any contraception in The Health Improvement Network (THIN) database.

BACKGROUND: Worldwide the rate of unplanned pregnancies is more than 40%. Identifying women at risk of pregnancy can help prevent negative outcomes and also reduce healthcare costs of potential complications. It can also allow the investigation of the natural history of pregnancy outcomes, such as ectopic pregnancies or miscarriages. The use of medical records databases has been a crucial development in the field of pharmacoepidemiology - e.g. The Health Improvement Network (THIN) database is a validated database representative of the UK population. This project aimed to test the feasibility of identifying a population of women of childbearing age who are at risk of pregnancy not using any contraception in THIN database. METHODS: First a cohort of women of childbearing age (15-45yo) was identified. By applying a computer-based algorithm, containing codes for contraception methods or other suggestion of contraception, the risk of pregnancy was then ascertained. Next, two validation steps were implemented: 1) Revision of medical records/free text and 2) Questionnaires were sent to primary care practitioners (PCP) of women whose medical records had been reviewed. Positive predicted values (PPV) were calculated. RESULTS: A total of 266,433 women were identified in THIN. For the first validation step, 123 records were reviewed, with a PPV of 99.2% (95%CI: 95.5-99.9). For the questionnaires step, the PPV was of 82.3% (95%CI: 70-91.1). Information on sexual behaviour and attitudes towards conception was not captured by THIN. CONCLUSION: This study shows that by applying a comprehensive computer-based algorithm, THIN can be used to identify women at risk of pregnancy.

A review of studies evaluating the effectiveness of risk minimisation measures in Europe using the European Union electronic Register of Post-Authorization Studies.

PURPOSE: An important element of risk management is the planning and implementation of risk minimisation measures (RMMs) and the evaluation of their effectiveness by process or outcome indicators. The aim of this review is to summarize the characteristics of risk minimisation (RM) effectiveness studies in Europe and provide an overview of RMMs and their effectiveness. METHODS: This was a qualitative review of RM effectiveness studies in the European Union electronic Register of Post-Authorization Studies (EU PAS Register); data extracted included study design, population, sample size, data sources, drug information, RMMs, study period, indicators, and their reported effectiveness. RESULTS: Of the 872 records in the EU PAS Register, 19 studies evaluating the effectiveness of RMMs were included. Eleven were cross-sectional surveys and 8 used secondary data sources. Eighty-nine percent (17/19) evaluated additional RMMs (used when routine RMMs are considered insufficient), and 36% (7/19) evaluated changes in routine RMMs (applicable to all medicinal products). A total of 42 effectiveness indicators were identified: 18 process and 24 outcomes. Half of the indicators (21/42) were successful; 2% (1/42) indicators were partially successful; 17% (7/42) indicators were inconclusive. Effectiveness of the remaining 31% (13/42) indicators could not be determined owing to limited information. The United Kingdom was the most frequent country for the conduct of RM effectiveness studies. CONCLUSIONS: Most of the included studies evaluated additional RMMs. Half of the effectiveness indicators (process and/or outcome) were reported as successful. This review provides evidence to support the development of future guidance on the effectiveness of RM in Europe.

Thrombotic risk minimization for Diane-35 and generics.

BACKGROUND: This study aimed to evaluate the effect of risk minimization measures on cyproterone acetate/ethinylestradiol (CPA/EE) use in the Netherlands. Potential indications of use and concomitant pharmacy dispensing of other hormonal contraceptives (HC) were assessed among new users in 2011, 2012, and 2014. METHODS: In this retrospective drug utilization study, new CPA/EE users were identified by pharmacy dispensings in the PHARMO Database Network in 2011, 2012, and 2014. Recent dispensing of drugs to treat acne and concomitant dispensing of other HC were also assessed. General practitioner records were linked to identify diagnoses of acne, other hyperandrogenic conditions, menstrual problems, or consultations for contraceptive management in the preceding year. RESULTS: The number of new CPA/EE users identified per year was 7876 in 2011 and 7562 in 2012 (3.7 new users per 1000 women in both years) and 1401 in 2014 (0.7 per 1000 women). The proportions of users with acne diagnosis or treatment were 55% in 2011, 52% in 2012, and 47% in 2014. Concomitant use of other HC was observed for 3% of new CPA/EE users in 2011, and 2% in 2012 and 2014 (median duration 78 days). Another 25% were potential concomitant users (median duration 60 days). CONCLUSION: This descriptive analysis showed similar proportions of CPA/EE users examined with acne or other hyperandrogenic conditions, or with recent acne treatment, or concomitant dispensing of other HC in the Netherlands before and after the referral procedure. The key observation was a strong overall reduction of CPA/EE use in the Netherlands.

Literature review of visual representation of the results of benefit-risk assessments of medicinal products.

BACKGROUND: The PROTECT Benefit-Risk group is dedicated to research in methods for continuous benefit-risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. METHODS: A comprehensive review was performed to identify visuals used for medical risk and benefit-risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. RESULTS: Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit-risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. CONCLUSION: We have arrived at recommendations for the use of visual displays for benefit-risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience-visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit-risk analysis information.

Clinical Characterization of Patients Diagnosed with Prostate Cancer and Undergoing Conservative Management: A PIONEER Analysis Based on Big Data.

BACKGROUND: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics. OBJECTIVE: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data. DESIGN, SETTING, AND PARTICIPANTS: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data. RESULTS AND LIMITATIONS: The most common comorbidities were hypertension (35-73%), obesity (9.2-54%), and type 2 diabetes (11-28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12-25%) and emergency department visits (10-14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent. CONCLUSIONS: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data. PATIENT SUMMARY: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis.

How Well do Polygenic Risk Scores Identify Men at High Risk for Prostate Cancer? Systematic Review and Meta-Analysis.

OBJECTIVES: Genome-wide association studies have revealed over 200 genetic susceptibility loci for prostate cancer (PCa). By combining them, polygenic risk scores (PRS) can be generated to predict risk of PCa. We summarize the published evidence and conduct meta-analyses of PRS as a predictor of PCa risk in Caucasian men. PATIENTS AND METHODS: Data were extracted from 59 studies, with 16 studies including 17 separate analyses used in the main meta-analysis with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases. Random effects meta-analysis was used to obtain pooled estimates of area under the receiver-operating characteristic curve (AUC). Meta-regression was used to assess the impact of number of single-nucleotide polymorphisms (SNPs) incorporated in PRS on AUC. Heterogeneity is expressed as I2 scores. Publication bias was evaluated using funnel plots and Egger tests. RESULTS: The ability of PRS to identify men with PCa was modest (pooled AUC 0.63, 95% CI 0.62-0.64) with moderate consistency (I2 64%). Combining PRS with clinical variables increased the pooled AUC to 0.74 (0.68-0.81). Meta-regression showed only negligible increase in AUC for adding incremental SNPs. Despite moderate heterogeneity, publication bias was not evident. CONCLUSION: Typically, PRS accuracy is comparable to PSA or family history with a pooled AUC value 0.63 indicating mediocre performance for PRS alone.

Unanswered questions in prostate cancer - findings of an international multi-stakeholder consensus by the PIONEER consortium.

PIONEER is a European network of excellence for big data in prostate cancer consisting of 37 private and public stakeholders from 9 countries across Europe. Many progresses have been done in prostate cancer management, but unanswered questions in the field still exist, and big data could help to answer these questions. The PIONEER consortium conducted a two-round modified Delphi survey aiming at building consensus between two stakeholder groups - health-care professionals and patients with prostate cancer - about the most important questions in the field of prostate cancer to be answered using big data. Respondents were asked to consider what would be the effect of answering the proposed questions on improving diagnosis and treatment outcomes for patients with prostate cancer and to score these questions on a scale of 1 (not important) to 9 (critically important). The mean percentage of participants who scored each of the proposed questions as critically important was calculated across the two stakeholder groups and used to rank the questions and identify the highest scoring questions in the critically important category. The identification of questions in prostate cancer that are important to various stakeholders will help the PIONEER consortium to provide answers to these questions to improve the clinical care of patients with prostate cancer.

Ectopic pregnancy prevention: Further evidence of benefits of prescription contraceptives.

OBJECTIVE: To estimate the incidence of ectopic pregnancy (EP) associated with prescription contraceptive use. STUDY DESIGN: We performed a retrospective cohort study of women aged 15 to 44 years at Kaiser Permanente Northern and Southern California during 2010 to 2019. We identified EPs and prescription contraceptive use from diagnosis, procedural, and medication codes, and natural language processing of clinical notes from electronic health records. Contraceptive use categories included combined hormonal contraceptives, intrauterine devices, depot-medroxyprogesterone acetate (DMPA), progestin-only pills (POPs), implants, no method after recent discontinuation of a prescription contraceptive in the last 12 months, and no method after discontinuation of a prescription contraceptive more than 12 months ago or no use of prescription contraceptives during the study period. Contraceptive use was updated as women started, stopped, or changed methods. An EP was attributed to a contraceptive method if it occurred 14 days after starting and up to 42 days after stopping a method. Age-adjusted EP incidence and 95% confidence intervals (CI) were estimated per 10,000 woman-years overall and by contraceptive category. RESULTS: There were 11,436 EPs among 3,204,118 women with 11,909,842 woman-years of follow-up for an overall EP incidence of 9.5 per 10,000 woman-years (95%CI 9.3-9.6). The majority of EPs (9662; 84.5%) occurred during no prescription contraceptive use. EP incidence was lowest during DMPA (1.8 per 10,000 woman-years [95%CI 1.2-2.5]) or implant (2.0 per 10,000 woman-years [95%CI 1.2-3.3]) use, and higher during POP use at 15.2 (95%CI 12.2-19.6); however, incidence was highest after recent discontinuation of a prescription contraceptive (20.6 per 10,000 woman-years [95%CI 19.7-21.4]). CONCLUSIONS: EP incidence is lower with prescription contraceptive use than with nonuse. IMPLICATIONS: All prescription contraceptives, including POPs are protective of EP.

Disparities in the Incidence of Ectopic Pregnancy in a Large Health Care System in California, 2010-2019.

IntroductionEctopic pregnancy leads to reproductive health morbidity, including greater risk of another ectopic pregnancy, infertility, and, in rare cases, mortality. Information on trends in the incidence of ectopic pregnancy in the last decade is limited. MethodsA population-based cross-sectional study of women aged 15-44 years enrolled at Kaiser Permanente Northern and Southern California 2010-2019 was conducted. Electronic health records were used to identify ectopic pregnancies. The crude ectopic pregnancy incidence per 1000 pregnancies (live births, induced abortions, and ectopic pregnancies) and 95% confidence interval (CI) was estimated per study year, overall, and stratified by age group. The age-adjusted incidence and 95% CI was estimated per study year, overall, and stratified by race/ethnicity. Temporal trend was assessed using Poisson regression. ResultsThere were 15,537 ectopic pregnancies among 979,027 pregnancies. The overall age-adjusted ectopic pregnancy incidence was 15.8 per 1000 pregnancies, 95% CI: 15.6, 16.1. The annual incidence increased from 15.2, 95% CI: 14.4, 16.1, in 2010 to 16.4, 95% CI: 15.6, 17.2, in 2019 (p < 0.001). The overall incidence was highest among women aged 40-44 years (24.2, 95% CI: 22.7, 25.6) and non-Hispanic Black women (21.9, 95% CI: 21.0, 22.8); compared to 30-34-year-old (16.2, 95% CI: 15.7, 16.6) and non-Hispanic White (14.6, 95% CI: 14.1, 15.0) women, respectively. DiscussionThe increase in ectopic pregnancy incidence during the studied period was largely driven by increasing incidence in younger women. However, disparities in the incidence by age and race/ethnicity persisted. ConclusionEctopic pregnancy remains a significant source of reproductive health morbidity, especially for older ( >40 years) and non-Hispanic Black women.

Secondary Treatment for Men with Localized Prostate Cancer: A Pooled Analysis of PRIAS and ERSPC-Rotterdam Data within the PIONEER Data Platform.

INTRODUCTION: Treatment choice for localized prostate cancer is complicated, as each treatment option comes with various pros and cons. It is well established that active surveillance (AS), may be ended with a change to curative treatment at the time of disease progression, but it is less clear whether secondary treatment after initial curative treatment is required. As part of the PIONEER project, we quantified the probabilities of treatment change. METHODS: A cohort study based on PRIAS and ERSPC-Rotterdam data was conducted. Patients were followed up for 10 years or until the 31st of December 2017. The primary outcome was the incidence of treatment change following initial treatment (i.e., a change to curative treatment following AS or secondary treatment after initial RP/RT). RESULTS: Over a period of 1 to 5 years after initial treatment, the cumulative incidence of treatment change ranged from 3.8% to 42.8% for AS, from 7.6% to 12.1% for radical prostatectomy (RP) and from no change to 5.3% for radiation therapy (RT). While the possibility of treatment change in AS is known, the numbers within a five-year period were substantial. For RP and RT, the rate of change to secondary treatment was lower, but still non-neglectable, with 5 (10)-year incidences up to 12% (20%) and 5% (16%), respectively. CONCLUSION: This is one of the first studies comparing the incidence of guideline-recommended treatment changes in men receiving different primary treatments (i.e., AS, RT, or RP) for localized prostate cancer (PCa).

Association of the Timing of Postpartum Intrauterine Device Insertion and Breastfeeding With Risks of Intrauterine Device Expulsion.

IMPORTANCE: Intrauterine device (IUD) expulsion increases the risk of unintended pregnancy; how timing of postpartum IUD insertion and breastfeeding are associated with risk of expulsion is relevant to the benefit-risk profile. OBJECTIVE: To evaluate the association of postpartum timing of IUD insertion and breastfeeding status with incidence and risk of IUD expulsion. DESIGN, SETTING, AND PARTICIPANTS: The Association of Perforation and Expulsion of Intrauterine Devices (APEX-IUD) cohort study included women aged 50 years or younger with an IUD insertion between 2001 and 2018. The breastfeeding analysis focused on a subcohort of women at 52 or fewer weeks post partum with known breastfeeding status. The study was conducted using data from electronic health records (EHRs) at 4 research sites with access to EHR: 3 Kaiser Permanente sites (Northern California, Southern California, Washington) and the Regenstrief Institute (Indiana). Data analysis was conducted from June to November 2019. EXPOSURES: Timing of IUD insertion post partum was categorized into discrete time periods: 0 to 3 days, 4 days to 6 or fewer weeks, more than 6 weeks to 14 or fewer weeks, more than 14 weeks to 52 or fewer weeks, and non-post partum (>52 weeks or no evidence of delivery). Breastfeeding status at the time of insertion was determined from clinical records, diagnostic codes, or questionnaires from well-baby visits. MAIN OUTCOMES AND MEASURES: Incidence rates and adjusted hazard ratios (aHRs) were estimated using propensity scores to adjust for confounding. RESULTS: The full cohort included 326 658 women (mean [SD] age, 32.0 [8.3] years; 38 911 [11.9%] Asian or Pacific Islander; 696 [0.2%] Hispanic Black; 56 180 [17.2%] Hispanic other; 42 501 [13.0%] Hispanic White; 28 323 [8.7%] non-Hispanic Black; 137 102 [42.0%] non-Hispanic White), and the subcohort included 94 817 women. Most IUDs were levonorgestrel-releasing (259 234 [79.4%]). There were 8943 expulsions. The 5-year cumulative incidence of IUD expulsion was highest for insertions 0 to 3 days post partum (10.73%; 95% CI, 9.12%-12.61%) and lowest for insertions more than 6 weeks to 14 or fewer weeks post partum (3.18%; 95% CI, 2.95%-3.42%). Adjusted HRs using women with non-post partum IUD insertion as the referent were 5.34 (95% CI, 4.47-6.39) for those with postpartum insertion at 0 to 3 days; 1.22 (95% CI, 1.05-1.41) for those with postpartum insertion at 4 days to 6 or fewer weeks; 1.06 (95% CI, 0.95-1.18) for those with postpartum insertion at more than 6 to 14 or fewer weeks; and 1.43 (95% CI, 1.29-1.60) for those with postpartum insertion at more than 14 to 52 or fewer weeks. In the subcohort, 5-year cumulative incidence was 3.49% (95% CI, 3.25%-3.73%) for breastfeeding women and 4.57% (95% CI, 4.22%-4.95%) for nonbreastfeeding women; the adjusted HR for breastfeeding vs not breastfeeding was 0.71 (95% CI, 0.64-0.78). CONCLUSIONS AND RELEVANCE: In this study of real-world data, IUD expulsion was rare but more common with immediate postpartum insertion. Breastfeeding was associated with lower expulsion risk.

Updating and Integrating Core Outcome Sets for Localised, Locally Advanced, Metastatic, and Nonmetastatic Castration-resistant Prostate Cancer: An Update from the PIONEER Consortium.

CONTEXT: Harmonisation of outcome reporting and definitions for clinical trials and routine patient records can enable health care systems to provide more efficient outcome-driven and patient-centred interventions. We report on the work of the PIONEER Consortium in this context for prostate cancer (PCa). OBJECTIVE: To update and integrate existing core outcome sets (COS) for PCa for the different stages of the disease, assess their applicability, and develop standardised definitions of prioritised outcomes. EVIDENCE ACQUISITION: We followed a four-stage process involving: (1) systematic reviews; (2) qualitative interviews; (3) expert group meetings to agree standardised terminologies; and (4) recommendations for the most appropriate definitions of clinician-reported outcomes. EVIDENCE SYNTHESIS: Following four systematic reviews, a multinational interview study, and expert group consensus meetings, we defined the most clinically suitable definitions for (1) COS for localised and locally advanced PCa and (2) COS for metastatic and nonmetastatic castration-resistant PCa. No new outcomes were identified in our COS for localised and locally advanced PCa. For our COS for metastatic and nonmetastatic castration-resistant PCa, nine new core outcomes were identified. CONCLUSIONS: These are the first COS for PCa for which the definitions of prioritised outcomes have been surveyed in a systematic, transparent, and replicable way. This is also the first time that outcome definitions across all prostate cancer COS have been agreed on by a multidisciplinary expert group and recommended for use in research and clinical practice. To limit heterogeneity across research, these COS should be recommended for future effectiveness trials, systematic reviews, guidelines and clinical practice of localised and metastatic PCa. PATIENT SUMMARY: Patient outcomes after treatment for prostate cancer (PCa) are difficult to compare because of variability. To allow better use of data from patients with PCa, the PIONEER Consortium has standardised and recommended outcomes (and their definitions) that should be collected as a minimum in all future studies.

Diagnostic and prognostic factors in patients with prostate cancer: a systematic review.

OBJECTIVES: As part of the PIONEER Consortium objectives, we have explored which diagnostic and prognostic factors (DPFs) are available in relation to our previously defined clinician and patient-reported outcomes for prostate cancer (PCa). DESIGN: We performed a systematic review to identify validated and non-validated studies. DATA SOURCES: MEDLINE, Embase and the Cochrane Library were searched on 21 January 2020. ELIGIBILITY CRITERIA: Only quantitative studies were included. Single studies with fewer than 50 participants, published before 2014 and looking at outcomes which are not prioritised in the PIONEER core outcome set were excluded. DATA EXTRACTION AND SYNTHESIS: After initial screening, we extracted data following the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of prognostic factor studies (CHARMS-PF) criteria and discussed the identified factors with a multidisciplinary expert group. The quality of the included papers was scored for applicability and risk of bias using validated tools such as PROBAST, Quality in Prognostic Studies and Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: The search identified 6604 studies, from which 489 DPFs were included. Sixty-four of those were internally or externally validated. However, only three studies on diagnostic and seven studies on prognostic factors had a low risk of bias and a low risk concerning applicability. CONCLUSION: Most of the DPFs identified require additional evaluation and validation in properly designed studies before they can be recommended for use in clinical practice. The PIONEER online search tool for DPFs for PCa will enable researchers to understand the quality of the current research and help them design future studies. ETHICS AND DISSEMINATION: There are no ethical implications.

Demographic, Reproductive, and Medical Risk Factors for Intrauterine Device Expulsion.

OBJECTIVE: To explore to what extent intrauterine device (IUD) expulsion is associated with demographic and clinical risk factors. METHODS: The APEX-IUD (Association of Perforation and Expulsion of IntraUterine Devices) study was a U.S. cohort study using electronic health records from three integrated health care systems (Kaiser Permanente Northern California, Southern California, and Washington) and a health care information exchange (Regenstrief Institute). These analyses included individuals aged 50 years or younger with IUD insertions from 2001 to 2018. Intrauterine device expulsion cumulative incidence and incidence rates were estimated. Using Cox regression models, hazard ratios with 95% CIs were estimated before and after adjustment for risk factors of interest (age, race and ethnicity, parity, body mass index [BMI], heavy menstrual bleeding, and dysmenorrhea) and potential confounders. RESULTS: In total, 228,834 individuals with IUD insertion and no delivery in the previous 52 weeks were identified (184,733 [80.7%] with levonorgestrel-releasing intrauterine system). Diagnosis of heavy menstrual bleeding-particularly a diagnosis in both recent and past periods-was the strongest risk factor for IUD expulsion. Categories with the highest risk of IUD expulsion within each risk factor included individuals diagnosed with overweight, obesity, and morbid obesity; those in younger age groups, especially among those aged 24 years or younger; and in those with parity of four or more. Non-Hispanic White individuals had the lowest incidence and risk, and after adjustment, Asian or Pacific Islander individuals had the highest risk. Dysmenorrhea was not independently associated with expulsion risk when adjusting for heavy menstrual bleeding. CONCLUSION: Most risk factors for expulsion identified in this study appear consistent with known physiologic factors that affect uterine anatomy and physiology (age, BMI, heavy menstrual bleeding, parity). The increased risk of IUD expulsion among individuals of color warrants further investigation. Intrauterine devices are an effective long-term contraceptive; expulsion is uncommon, but patients should be counseled accordingly. FUNDING SOURCE: Bayer AG. CLINICAL TRIAL REGISTRATION: EU PAS register, EUPAS33461.