Background Cyproterone acetate (CPA) is a synthetic progesterone derivative introduced in the 1970s and prescribed as antiandrogenic therapy for inoperable prostate cancer, sexual deviations in men, and signs of androgenization in women. In 2020, the CPA summary of product characteristics (SmPC) was revised to include an updated special warning and precaution about (1) the risk of meningioma with increasing cumulative dose and (2) contraindication in patients with meningioma or history of meningioma. A Direct Healthcare Professional Communication (DHPC) was distributed. The European Medicine Agency’s Pharmacovigilance Risk Assessment Committee requested that marketing authorization holders in Europe conduct a survey to assess physicians’ knowledge of the updated key safety information. The primary objective of this study was to measure physicians’ awareness (i.e., did they receive and review the revised SmPC and DHPC) and level of knowledge and understanding of the key safety information pertaining to the restricted use of CPA monotherapy because of the risk of meningioma. Methods This cross-sectional web-based survey was administered to dermatologists, endocrinologists, gynecologists, urologists, oncologists, psychiatrists, and general practitioners in France, Germany, Poland, Spain, and the Netherlands who had prescribed CPA monotherapy in the previous 12 months to assess awareness of the risk of meningioma associated with CPA monotherapy. Results Of the 613 physicians who participated, 85% correctly indicated that CPA monotherapy should be prescribed with the lowest effective dose, 75% correctly indicated that the risk of meningioma increases with increasing cumulative CPA monotherapy doses, and 73% correctly indicated that treatment with CPA-containing products must be stopped permanently if a patient is diagnosed with meningioma. Overall, 40% of physicians reported having received the DHPC, and 42% reported having received the revised SmPC. Conclusions Despite low recall of receipt of the updated SmPC and DHPC, most physicians surveyed are aware of the meningioma risk and actions to mitigate the risk.

48 Background: Anecdotal evidence suggests that some pts with mCRC experience significantly longer responses to REG in clinical care settings, including a case exceeding 9 years. However, comprehensive studies on long-term responders to REG are lacking. We evaluated demographic/clinical characteristics of pts with long-term response (LTR) to REG using duration of treatment (DOT) as a surrogate for treatment response. Methods: This was a retrospective cohort study using the US nationwide de-identified Flatiron Health Electronic Health Record-derived database. The study period was January 1, 2013 to May 31, 2023, and adult pts with mCRC who initiated REG monotherapy (index date) from July 1, 2013 to December 31, 2022 were included. DOT for pts with LTR of ≥5 months (LTR5 [primary objective]; mos) or ≥4 mos (LTR4 [secondary objective]) were determined. Results: A total of2,326 eligible pts (median age 64 yrs; 56% male) had initiated REG during the study period. Overall, 346 pts (15%; median age 65 yrs) had LTR5 and 503 pts (22%; median age 65 yrs) had LTR4. Among pts with LTR5, 46% had stage IV disease at initial diagnosis, 68% had ECOG performance status (ECOG PS) 0‒1 at index, 64% received prior bevacizumab (BEV), and of pts tested at index with results, the median carcinoembryonic antigen (CEA) level was 35 ng/mL, and 51% and 5% had a KRAS and BRAF mutation at index, respectively; pts with LTR4 had similar characteristics (Table). Median time from initial CRC diagnosis to index date was 39.2 mos for pts with LTR5 and 38.6 mos for pts with LTR4. Of pts who initiated REG before 2019 (n = 1,070), 14% had LTR5 and 21% had LTR4; of pts who initiated REG from 2019 onwards (n = 1,256), 16% had LTR5 and 22% had LTR4. Among pts with LTR5, 33% and 23% had received REG as third-line (3L) or fourth-line (4L) treatment, respectively; among pts with LTR4, 34% and 23% had received REG as 3L or 4L treatment, respectively. Median time to discontinuation of REG was 7.3 (95% CI 6.9, 7.8) mos in pts with LTR5 and 6.0 (95% CI 5.7, 6.2) mos in pts with LTR4. Median follow-up time (from index date) was 13.3 mos and 11.1 mos in pts with LTR5 and LTR4, respectively. Conclusions: This is the first large-scale RW evidence study to describe demographic/clinical characteristics of pts with LTR to REG. Pts demonstrating LTR typically had favorable ECOG PS at REG initiation, less advanced disease at initial diagnosis, and the majority had received prior BEV. [Table: see text]

45 Background: Emerging data shows that the higher incidence of mCRC in younger patients (pts) is accompanied by more aggressive front-line treatment with chemotherapies, such as FOLFOXIRI+bevacizumab (triplet+bev). We explored the use of triplet+bev and subsequent therapies in a representative sample of community practices in the USA. Methods: This was a retrospective study using the nationwide de-identified Flatiron Health Electronic Health Record-derived database from January 1, 2013, to February 28, 2023. The use of triplet+bev and subsequent treatments were analyzed in pts with newly diagnosed mCRC (≥18 years [yrs] of age) by oncologist-defined, rule-based line of treatment (LOT) and age (18–49, 50–64, and ≥65 yrs). Results: Of 24,285 eligible pts, 14%, 37%, and 49% were 18–49, 50–64, and ≥65 yrs at treatment initiation, respectively (Table). Triplet+bev use in any LOT was the most prevalent in the youngest age group (18–49 yrs) at 7% (Table). Two-thirds (67%) received triplet+bev in first line (1L) and 23% in second line (2L), 57% were male, and 34% had a KRAS mutation (23% missing). From 2013 to 2022, triplet+bev use in newly treated pts increased; this trend was more pronounced in pts 18–49 yrs (Table). Among pts not censored before the end of the respective LOT, median duration of 1L and 2L triplet+bev was 25.1 and 21.6 weeks, respectively (Table). For non-censored pts with and without a KRAS mutation, respectively, median duration of triplet+bev was 26.1 vs 23.5 weeks in 1L and 21.6 vs 16.5 weeks in 2L. Most frequently used new agents after 1L triplet+bev included anti-EGFR (panitumumab or cetuximab; 19%), TAS-102 (12%), regorafenib (10%), and capecitabine (3%). Most frequently used new agents after 2L triplet+bev were TAS-102 (21%), anti-EGFR (17%), regorafenib (15%), and pembrolizumab (8%). Conclusions: Our study shows that the use of triplet+bev has increased in pts with mCRC over time, particularly in those <50 yrs. Most frequent subsequent therapies across all pts following 1L and 2L triplet+bev included TAS-102, anti-EGFR, and regorafenib. Future research is needed to identify the optimal treatment strategies after triplet+bev. [Table: see text]

Objectives: The levonorgestrel-releasing intrauterine device containing 13.5 mg of levonorgestrel (LNG 13.5 mg IUD), Jaydess, was approved for contraception by the European Medicines Agency in 2013. We aimed to describe the characteristics of new users of LNG 13.5 mg IUD in Sweden within the first 3 years after approval (2014-2016). Study design: We conducted an observational, population -based study using data from the Swedish national registers. Women with the first pharmacy dispensation of LNG 13.5 mg IUD between 2014 and 2016 were followed until December 31, 2020. Descriptive analyses included demographic characteristics, duration of the use of first-time LNG 13.5 mg IUD, and contraceptive switching patterns. Results: We included 38,327 women, with mean age at first-time LNG 13.5 mg IUD use of 26 (SD: 7) years. Over 80% were prescribed LNG 13.5 mg IUD by a midwife. The most common comorbidities in the year prior to LNG 13.5 mg IUD use (2%-3% prevalence) were depression, anxiety, premenstrual syndrome, and menorrhagia. The median duration of first-time LNG 13.5 mg IUD use was 2.6 years, and after use, more than 50% of women opted to continue using a hormonal intrauterine device. Conclusions: In this postmarketing drug utilization study, there were over 38,000 first-time LNG 13.5 mg IUD users in Sweden between 2014 and 2016, with an estimated median duration of use of 2.6 years. Firsttime LNG 13.5 mg IUD users consisted mostly of young, healthy individuals with a history of hormonal contraceptive use. Over half of the women continued using a hormonal IUD after the first LNG 13.5 mg IUD. Implications: The median duration of LNG 13.5 mg IUD use was 2.6 years, approaching the 3 -year indicated use limit. The majority of users continued with another hormonal intrauterine device after LNG 13.5 mg IUD use. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Real-world (RW) evidence is needed to evaluate atezolizumab plus bevacizumab (atezo + bev) utilization for hepatocellular carcinoma (HCC) in clinical practice. This retrospective cohort study used administrative claims databases to evaluate treatment patterns in individuals with HCC ≥18 years of age who were initiated on atezo + bev between June 2020 and June 2022. The endpoints of this study were the proportion of individuals who discontinued atezo + bev and received subsequent systemic therapies, time to discontinuation (TTD), and time to next treatment. Overall, 825 individuals were eligible (median age 67 years; 80% male). Over a median follow-up of 15.3 months, most (72%) discontinued atezo + bev, with a median TTD of 3.5 months. A minority (19%) received subsequent therapies, with the most common second-line agents being lenvatinib (6%), cabozantinib (4%), and nivolumab (4%). The median time from index to next treatment post-atezo + bev was 5.4 months. Further research is needed to identify the patients who are most likely to benefit from atezo + bev as well as later-line HCC therapies to optimize overall survival.

ABSTRACT Intrauterine device (IUD) expulsion is more common among women with heavy menstrual bleeding, parity, higher body mass index (BMI), younger age, dysmenorrhea, or immediate postabortion or postpartum insertion. The APEX-IUD study was an observational cohort study of 326,658 individuals examining the association with breastfeeding, IUD type, and timing of postpartum IUD insertion with IUD expulsion and uterine perforation. This data set provides an opportunity to examine specific demographic, reproductive, and medical risk factors associated with IUD expulsion. This analysis of APEX-IUD data aimed to determine the associations of 6 risk factors (age, race/ethnicity, parity, BMI, heavy menstrual bleeding, and dysmenorrhea) and IUD expulsion, as well as the extent to which these associations differed for LNG-IUD compared with copper IUD users. Individuals aged 50 years or younger at the time of IUD insertion without a delivery 52 weeks or less before insertion were included. Individuals were followed from IUD insertion until IUD expulsion, uterine perforation, removal, reinsertion, expiration, pregnancy, hysterectomy, death, disenrollment from the health care system, or end of study period (June 2018). Crude incidence rates for each risk factor category were calculated using the number of expulsions during the time at risk divided by the total person-years at risk and were reported as the number of expulsions per 1000 person-years at risk. Hazards ratios (HRs) and 95% confidence intervals from Cox regression models were used to evaluate associations of the risk factors with IUD expulsion. These models were adjusted for potential confounding effects and were separately used to assess the association of covariates with IUD expulsion varied by IUD type. The total study cohort included 228,834 individuals (LNG-IUD: 184,733 [80.7%]; copper IUD: 41,123 [18.0%]; unknown type: 2978 [1/3%]). The average length of follow-up was 2.0 years, and there were 6762 expulsions with a crude incidence rate of 14.9 per 1000 person-years (95% confidence interval, 14.6–15.3). Adjusted hazards ratios (aHRs) showed the younger age groups having a higher risk of IUD expulsion and a trend toward lower aHRs with increasing age. Individuals with parity of 4 or more had the highest risk of IUD expulsion, and a parity of 2 was associated with the lowest risk on adjusted analysis. Adjusted analysis revealed a greater risk of IUD expulsion among individuals with higher BMI or heavy menstrual bleeding diagnosis compared with the comparator group. Multiple racial and ethnic groups including non-Hispanic Black, Hispanic Black, Hispanic White, Asian, or Pacific Islander were associated with a greater risk of IUD expulsion compared with non-Hispanic Whites when adjusting for covariates. When comparing aHRs by copper IUD or LNG-IUD; younger age was more strongly associated with expulsion among copper IUD users than LNG-IUD users, the risk for expulsion associated with obesity was significantly attenuated for copper IUD users compared with LNG-IUD users, and the risk of expulsion for those with heavy menstrual bleeding was partially attenuated by copper IUDs. Adjusted analysis revealed no association between dysmenorrhea and IUD expulsion. The results of this study show that, among the 6 risk factors investigated here, the risk of IUD expulsion was highest among individuals with a diagnosis of heavy menstrual bleeding, particularly in recent and past periods.

Introduction Rare disease research has specific challenges that can be addressed using registries.Areas covered There are at least three different types of registries: patient registries, disease registries, and product registries. Patient registries recruit rare disease patients, potentially including several rare diseases within a registry, while disease registries can be considered a subset of patient registries which focus on specific diseases. Product registries focus on specific drugs. These registries may be used to conduct research that is specifically requested by a regulatory authority, they may be developed by a drug company to monitor the use of a particular drug or may be developed for public health monitoring purposes.Expert Opinion Compared to other sources of real-world data (RWD), such as electronic medical records (EMRs) and claims data, registries are more likely to have a correct diagnosis and more specific information about RDs. However, registries also have their challenges. Competition between registries may lead to missing or incomplete data. Registries could also have limited information on drug and medical history, which are better captured in EMRs or claims. Nevertheless, registries remain an important source of RWD in the rare disease space and are increasingly being leveraged to comply with regulatory requirements.

Pesticides are highly tested and regulated chemicals. There is currently great interest in the role that pesticides may play in childhood neurodevelopment. The objective was to identify and describe the body of evidence and to assess the ability to synthesize effect estimates. The epidemiologic literature from 2011 to 2022 was searched for publications on the association between pesticide exposure and neurodevelopment, behavior, and/or cognition in children. We identified 114 publications, representing 67 unique studies. While organochlorine and other insecticides were the most common classes of pesticides studied, up to 159 different metabolites or active ingredients were reported. Nine pesticides or their metabolites were reported in >10 publications. Similarly, multiple assessment methods were administered across studies to evaluate outcomes in neurodevelopment at ages which ranged from birth to 18 years of age. This scoping review reveals the heterogeneity among published studies with respect to exposures and health outcomes, in the methods used to assess and classify them, and in combinations of the two. This limits the adequacy of the evidence to evaluate specific risk estimates for a particular exposure-outcome pair. Intentional coordination among researchers to increase consistency in methodologies would facilitate the synthesis of results across studies. Research opportunities also exist to validate assumptions in exposure and outcome assessment which are implicit in many of the studies reviewed. In conclusion, there are many ongoing epidemiologic studies with a focus on pesticides and neurodevelopment. The variety of exposures, exposure assessment methods and tests for each outcome can be overwhelming. Interdisciplinary collaboration is recommended to harmonize data collection and to enable meaningful interpretation of the study results across populations.

Background Intrauterine devices (IUDs) are highly effective contraception. IUDs inserted directly following delivery provide immediate birth control and may decrease unintended pregnancies, including short-interval pregnancies, thereby mitigating health risks and associated economic burden. Methods This systematic literature review included published global data on the utilisation, effectiveness, and safety of postpartum intrauterine devices (PPIUDs) of any type. English language articles indexed in MEDLINE, Embase, and Cochrane from January 2010–October 2021 were included. Results 133 articles met the inclusion criteria (46% interventional studies; 54% observational; n=87 from lower-income countries; n=46 from higher-income countries). PPIUD use was low in higher-income countries (6/10 000 US deliveries in 2013–2016) and varied widely in lower-income countries (2%-46%). Across both higher- and lower-income countries, in most studies (79%), >80% of women with PPIUDs had an IUD in place by 3 months; at 6 and 12 months, 76% and 54% of included studies reported that >80% of women had an IUD in place; reason for discontinuation was infrequently reported. Pregnancies were rare (96 pregnancies across 12 191 women from 37 studies reporting data) and were generally unrelated to device failure, but rather occurred in women no longer using a PPIUD. Expulsions occurred mainly in the early outpatient period and ranged widely (within 3 months: 0–41%). Abnormal bleeding, infections, or perforations were rare. Conclusions PPIUDs are safe and effective. Long-term follow-up data are limited. Future research elucidating reasons underlying lack of PPIUD use is warranted.

OBJECTIVE:The APEX-IUD (Association of Perforation and Expulsion of Intrauterine Devices) study evaluated the association of postpartum timing of intrauterine device (IUD) insertion, breastfeeding, heavy menstrual bleeding, and IUD type (levonorgestrel-releasing vs copper) with risks of uterine perforation and IUD expulsion in usual clinical practice. We summarize the clinically important findings to inform counseling and shared decision making.METHODS:APEX-IUD was a real-world (using U.S. health care data) retrospective cohort study of individuals aged 50 years and younger with IUD insertions between 2001 and 2018 and with electronic health record data. Cumulative incidences of uterine perforation and IUD expulsion were calculated. Adjusted hazard ratios (aHRs) and 95% CIs were estimated from proportional hazards models with control of confounding.RESULTS:Among the study population of 326,658, absolute risk of uterine perforation was low overall (cumulative incidence, 0.21% [95% CI 0.19-0.23%] at 1 year and 0.61% [95% CI 0.56-0.66% at 5 years]) but was elevated for IUDs inserted during time intervals within 1 year postpartum, particularly among those between 4 days and 6 weeks postpartum (aHR 6.71, 95% CI 4.80-9.38), relative to nonpostpartum insertions. Among postpartum insertions, IUD expulsion risk was greatest for insertions in the immediate postpartum period (0-3 days after delivery) compared with nonpostpartum (aHR 5.34, 95% CI 4.47-6.39). Postpartum individuals who were breastfeeding had a slightly elevated risk of perforation and lowered risk of expulsion than those not breastfeeding. Among nonpostpartum individuals, those with a heavy menstrual bleeding diagnosis were at greater risk of expulsion than those without (aHR 2.84, 95% CI 2.66-3.03); heavy menstrual bleeding also was associated with a slightly elevated perforation risk. There was a slightly elevated perforation risk and slightly lower expulsion risk associated with levonorgestrel-releasing IUDs compared with copper IUDs.CONCLUSION:Absolute risk of adverse outcomes with IUD insertion is low. Clinicians should be aware of the differences in risks of uterine perforation and expulsion associated with IUD insertion during specific postpartum time periods and with a heavy menstrual bleeding diagnosis. This information should be incorporated into counseling and decision making for patients considering IUD insertion.FUNDING SOURCE:Bayer AG.

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.

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 deviceeexpulsion rate (40.01 vs 10.92 per 1000 personyears) 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.

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 includedwomen 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 fewerweeks; 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.

OBJECTIVE:To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).METHODS:In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005-2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.RESULTS:Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6-1.9) in non-users and 2.0 (95% CI 1.8-2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05-1.30) compared with non-users. The risk was higher for short duration of use (<14 weeks, HR 3.64, 95% CI 2.90-4.58) than for medium duration (14 to <64 weeks, HR 1.74, 95% CI 1.48-2.05) or ≥64 weeks' use (HR 1.23, 95% CI 1.08-1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03-2.08) compared with newer AEDs.CONCLUSION:Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.

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 10,00 0 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 10,00 0 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 10,0 00 woman-years [95%CI 1.2-2.5]) or implant (2.0 per 10,00 0 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. (C) 2021ElsevierInc. Allrightsreserved.

Objectives: (a) to estimate the accuracy of International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for amyotrophic lateral sclerosis (ALS) in the Hospital Discharge Database (HDD) of the Italian region Friuli-Venezia Giulia; (b) to identify the predictors of a true positive ALS code; (c) to compare incident and prevalent cases obtained from HDD with those identified in a retrospective population-based study. Methods: Records of all patients discharged 2010-2014 with an ICD-9-CM code for ALS and other motor neuron diseases were extracted from the HDD. For each record, all the available clinical documentation was evaluated to confirm or reject the diagnosis of ALS. ALS incident and prevalent cases were identified. Validity measures were calculated both overall and stratified by patient and hospitalization characteristics. Adjusted odds ratio (aOR), with 95% confidence interval (95%CI), of a true positive code was estimated using unconditional logistic regression. Results: ALS code had sensitivity 92.9%, specificity 75.3%, positive predictive value (PPV) 92.3%, and negative predictive value (NPV) 76.8%. A true positive ALS code was predicted by concurrent codes for respiratory interventions (aOR: 3.82; 95%CI: 2.09-6.99), primary position code (2.78; 1.68-4.62), non-programed hospitalization (2.06; 1.18-3.61), male patient (1.56; 1.06-2.29), and hospitalization length <14 days (1.42; 1.07-2.84). Two hundred and thirty-six prevalent and 187 incident cases were identified, 84% of those detected in the population-based study. Conclusion: ALS code shows very good accuracy and identifies a high percentage of true positive, incident and prevalent cases, but additional sources and an algorithm based on selected variables may further improve case identification.

Objective: To determine the risk of hip-pelvis and other non-vertebral fractures in older adults using antidepressants (ADs). Methods: We conducted a case-control study nested in a cohort of new users of ADs aged >= 65 years without prior hip-pelvis or other non-vertebral fractures, identified in the German Pharmacoepidemiological Research Database (GePaRD) during 2005-2014. Cases were patients first hospitalized for hip-pelvis or other non-vertebral fractures. Up to 100 controls per case were selected using incidence density sampling. AD use was ascertained at index date (ID) based on the supply of last dispensing. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression with current users of mirtazapine as reference (active comparator). Results: A total of 39,853 cases of hip-pelvis fracture (80% women, median age 81 years) and 31,577 cases of other fractures (84% women, median age 79 years) were matched to >3 million controls. For hip-pelvis fracture, aORs in current users were about 1.3 with little variation between individual ADs, ranging from 1.33 for citalopram (95% CI 1.27-1.39) to 1.28 for amitriptyline (1.21-1.35). For other fractures, the aORs were highest in current users of citalopram (1.50; 1.42-1.58) and duloxetine (1.54; 1.39-1.71) and lowest for amitriptyline (1.18; 1.11-1.26) and trimipramine (1.16; 1.03-1.29). For all examined ADs, the aORs were higher for other fractures than for hip-pelvis fracture. Conclusion: The risk of fractures varies between ADs, but for most agents is higher than the risk for mirtazapine. When treating older adults with ADs, prescribers should carefully consider the risk profile of individual ADs regarding fractures, which are a major health problem in this population.