Does the shape of the copper intrauterine device play a role in expulsion? Results from the ongoing European Active Surveillance Study on LCS12.

OBJECTIVE: To compare the incidence of expulsion for different copper intrauterine device (IUD) shapes. STUDY DESIGN: We conducted a secondary analysis of the ongoing, prospective, non-interventional European Active Surveillance Study on LCS12 (EURAS-LCS12). Users of newly inserted IUDs were recruited in 10 European countries via a network of approximately 1200 clinicians. We restricted the analysis to copper IUD users. In the main analysis, we classified copper IUDs by shape [Nova-T frame, Tatum-T frame, Multiload frame, frameless IUDs and intrauterine balls], without differentiation of size. We calculated the cumulative incidence, crude, and adjusted hazard ratios for expulsion. Covariates included in the adjusted analyses were age, BMI, parity, education, income, IUD user status, marital status, length of device, heavy menstrual bleeding, and clinician's experience. RESULTS: We included 26,381 copper IUD users from the EURAS-LCS12 dataset for this study. The most frequently used IUD shape was the Nova-T frame (14,724 [55.8%]) followed by the Tatum-T frame (4276 [16.2%]), frameless IUDs (3374 [12.8%]), Multiload frame (2962 [11.2%]), and intrauterine balls (IUBs) (1045 [4.0%]). Cox regression analysis regarding expulsions yielded an adjusted hazard ratio of 0.8 (95% CI, 0.7-1.0), 1.3 (95% CI, 1.0-1.8), 1.6 (95% CI, 1.2-2.1) and 3.6 (95% CI, 2.7-4.9) for Nova-T frame IUD, frameless IUDs, Multiload frame IUDs and IUBs versus Tatum-T frame IUD, respectively. CONCLUSION: The risk of expulsion following placement of a copper IUD is related to IUD shape, with Nova-T frame and Tatum-T frame IUDs demonstrating the lowest risk. IMPLICATIONS: Our finding of a higher risk of expulsion observed with Multiload frame, frameless, and intrauterine ball copper IUDs compared to Tatum-T frame and Nova-T frame devices during real world use has clinical importance. Clinicians may choose to use these data when counseling patients.

Venous Thromboembolic Risk of Estradiol Valerate-Dienogest Compared with Ethinyl Estradiol-Levonorgestrel Combined Oral Contraceptives.

This pooled analysis compared the risk of venous thromboembolism (VTE) associated with combined oral contraceptives (COCs) containing estradiol (E2) valerate-dienogest with those containing ethinyl E2-levonorgestrel. Data were retrieved from two large, prospective, observational cohort studies. Propensity score subclassification was applied to balance baseline parameters between the COC user cohorts. Crude and adjusted hazard ratios (HRs) were calculated based on the extended Cox model. The pooled data set included 11,616 E2 valerate-dienogest users and 18,681 ethinyl E2-levonorgestrel users, contributing 17,932 and 29,140 women-years of observation, respectively. A significantly decreased VTE risk in E2 valerate-dienogest COCs compared with ethinyl E2-levonorgestrel COCs was observed (propensity score-stratified HR 0.46, 95% CI, 0.22-0.98). This pooled analysis expands data from a previous postauthorization safety study and provides valuable real-world safety information on the relative safety of current COCs.

Systematic analysis of combined oral contraceptive prescription patterns in psychotropic drug users across twelve European countries.

OBJECTIVE: To investigate prescription patterns of combined oral contraceptives (COC) among psychotropic drug users compared to non-psychotropic drug users in routine clinical practice in Europe. STUDY DESIGN: A pooled analysis of three large, prospective, multinational cohort studies including women with a new prescription of COC from 12 European countries. We calculated standardized mean differences (SMD) to investigate whether the status of psychotropic drug use (use/no use) or the psychotropic drug class (psycholeptics/psychoanaleptics) is associated with the healthcare professional's choice of a specific type of COC progestin. RESULTS: Our analysis comprised 143,069 non-psychotropic drug users and 2174 psychotropic drug users. Progestins with the highest frequency in the cohorts were levonorgestrel (non-psychotropic drug users: 33.8%; psychotropic drug users: 32.4%), nomegestrol/nomegestrol acetate (non-psychotropic drug users: 19.1%; psychotropic drug users: 26.4%), and drospirenone (non-psychotropic drug users: 15.9%; psychotropic drug users: 14.8%). SMD analysis indicated no substantial differences in COC prescription patterns between the two cohorts. However, we observed association signals for users of the herbal antidepressant St. John's wort in that those individuals more often received a prescription for drospirenone and less frequently for nomegestrol/nomegestrol acetate compared to non-psychotropic drug users. CONCLUSIONS: Psychotropic drug user status does not seem to affect healthcare professionals' decisions when prescribing COC. However, limited evidence suggests that the risk for drug interactions might differ by progestin type, and some COC might be more suitable for psychotropic drug users than others. Specific guidelines should be conveyed to healthcare professionals to assist them in contraceptive counseling. IMPLICATIONS: With exception of St. John's wort, our analysis showed no differential prescription behavior of combined oral contraceptives in psychotropic drug users and non-users. However, healthcare professionals should carefully consider psychotropic drug use in contraceptive counseling as it is still unclear whether drug interactions exist when co-administered with certain oral contraceptives.

TEMPORARILY WITHDRAWN: Does the shape of the copper intrauterine device play a role in expulsion? Results from the ongoing European Active Surveillance Study on LCS12.

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How did regional lockdowns during the COVID-19 pandemic affect recruitment into a large multinational cohort study of intrauterine device users?

OBJECTIVES: To investigate the impact of lockdown policies on the recruitment of an ongoing cohort study. STUDY DESIGN: We performed descriptive analyses of recruitment, dropout, and baseline characteristics over time. Oxford Stringency Index was used to assess the impact of regional constraints on recruitment. RESULTS: Drop in recruitment clearly reflected the Stringency Index within the first months of the pandemic. Unexpectedly, drop-out rates declined in 2020/2021. Baseline characteristics were comparable, yet younger women were recruited more frequently during the pandemic. CONCLUSIONS: There was no strong evidence of recruitment bias due to the pandemic. IMPLICATIONS: The COVID-19 pandemic is a potential source of bias for ongoing studies and its influence on the study conduct (e.g., recruitment, drop-out) should be thoroughly evaluated to ensure that study results are not biased in this regard. The Oxford's Government Stringency Index can be used to identify pandemic-affected time periods.

NOMAC-E2 shows a better contraceptive effectiveness than LNG combined oral contraceptives in women under 25: real-world PRO-E2 study.

Objective: To investigate unintended pregnancy and changes in mood, acne, and weight in NOMAC-E2 vs levonorgestrel-containing COC (COCLNG) users under 25 years.Methods: In this large, observational study, new users (first-ever users of an eligible COC or restarting with the same or a new eligible COC after a break of at least 2 months) of NOMAC-E2 and COCLNG were recruited in 12 countries in Europe, Australia, and Latin America and followed up via questionnaires for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 women-years). Crude (HRcrude) and adjusted hazard ratios (HRadj) were calculated. Mood and acne changes were defined as change of score from baseline. Weight change was defined as percent change of body weight.Results: Overall, 12,829 NOMAC-E2 users and 17,095 COCLNG users under 25 were followed-up. The risk of unintended pregnancy was statistically significantly lower in the NOMAC-E2 cohort; confirmed events: 30 NOMAC-E2 (PI 0.24; 95% CI, 0.16-0.35) vs 94 COCLNG (PI 0.51; 95% CI, 0.41-0.62). The HRcrude for unintended pregnancy comparing NOMAC-E2 to COCLNG was 0.47 (95% CI, 0.31-0.71) and the HRadj was 0.52 (95% CI, 0.34-0.78). No differential effect on acne, mood, and weight was observed between cohorts.Conclusions: NOMAC-E2 shows a significantly better contraceptive effectiveness in young women and has no differential effect on acne, mood, and weight compared to COCLNG.

NOMAC-E2 compares to LNG combined oral contraceptives in women over forty: real-world PRO-E2 study.

OBJECTIVE: To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COCLNG) in users over 40. METHODS: In this large, observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/104 women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight. RESULTS: Overall, 7,762 NOMAC-E2 and 6,059 COCLNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COCLNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9-13.7) vs 4 COCLNG (IR 5.9; 95% CI, 1.6-15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01-0.13) vs 5 COCLNG (PI 0.08; 95% CI, 0.03-0.18). No differential effect on mood and weight was observed between cohorts. CONCLUSIONS: NOMAC-E2 can be considered a valid alternative to COCLNG in perimenopausal women.

Pregnancy and pregnancy outcomes in a prospective cohort study: Final results from the Nexplanon Observational Risk Assessment Study (NORA).

OBJECTIVES: To monitor pregnancy occurrence and outcomes among Nexplanon users in the United States during standard clinical practice. STUDY DESIGN: The Nexplanon Observational Risk Assessment (NORA) study was a large prospective cohort study conducted in the United States (US). Study participants with a newly inserted Nexplanon implant were recruited by health care professionals (HCPs) who had completed the Nexplanon clinical training. Via a survey, study participants were followed up at 6-month intervals for 36 months and 6 months after implant removal. Reported unintended pregnancies were validated and classified as noninsertion, preinsertion, during-use, or postremoval. RESULTS: Four hundred and twenty-eight HCPs in 47 states recruited 7364 Nexplanon users. Pregnancies included one noninsertion, eight preinsertion, three during-use, and 14 postremoval pregnancies; of these 26 pregnancies, 22 resulted in the birth of a healthy child, two resulted in an induced abortion, one resulted in a spontaneous abortion, and one resulted in an ectopic pregnancy. Six pregnancies occurred during-use (n = 3) or within 7 days following implant removal (n = 3), yielding a Pearl Index of 0.04 (95% CI, 0.02-0.09). CONCLUSIONS: Nexplanon is an effective contraceptive in real-world users; the Pearl Index was 0.02 (95% CI, 0.00-0.06) for during-use pregnancies, and 0.04 when including pregnancies that occurred within 7 days following implant removal. IMPLICATIONS: This large real-world-use study indicates that Nexplanon is as effective as shown in the preapproval clinical trials.

Thromboembolic safety of norethisterone vs levonorgestrel in combined oral contraceptive users: a pooled analysis of 4 large prospective cohort studies.

BACKGROUND: Norethisterone (acetate) and levonorgestrel are marketed globally as components of combined oral contraceptives. Although guidelines recommend both as first-line combined oral contraceptives, no direct, comparative safety studies are available. OBJECTIVE: We directly compared the thromboembolic event risk associated with the use of norethisterone acetate-containing and levonorgestrel-containing combined oral contraceptives. STUDY DESIGN: Data regarding the cohorts of interest, norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg) and levonorgestrel (ethinylestradiol ≤30 µg), were retrieved from a pooled dataset comprising 4 prospective, noninterventional, active-surveillance cohort studies in 14 European countries, the United States, and Canada, with similar study design but differing medication cohorts. Baseline characteristics and parameters of reproductive, contraceptive, and medical history were summarized using descriptive statistics. Propensity score subclassification was applied to balance baseline parameters between cohorts. Time-to-event analysis of venous thromboembolic events was performed on the basis of the extended Cox model to calculate crude and adjusted hazard ratios, including 95% confidence intervals. The time of venous thromboembolic events was censored at the end of the observation period for women who did not have an event. Women who dropped out or were lost to follow-up without reported venous thromboembolic events were censored at the time they last confirmed that they did not have an event. RESULTS: The pooled dataset included 235,437 combined oral contraceptive users who were followed up for a total of 571,163 women years. Among these, 40,142 women were users of norethisterone/norethisterone acetate (ethinylestradiol ≤30 µg), and 39,098 women were users of levonorgestrel (ethinylestradiol ≤30 µg), contributing 61,976 and 84,816 women years of observation, respectively. The observed prevalence of prognostic factors at baseline showed typical features of US and European combined oral contraceptive users. Both cohorts showed a similar, low rate of thromboembolic events, and we could exclude a 1.5-fold increased venous thromboembolism risk for norethisterone/norethisterone acetate relative to levonorgestrel (adjusted hazard ratio, 0.73; 95% confidence interval, 0.48-1.11). CONCLUSION: These data confirm the similar risk profiles of norethisterone/norethisterone acetate and levonorgestrel regarding thromboembolic events in routine combined oral contraceptive use of around 80,000 women from Europe and the United States/Canada. The analysis provides reassurance for both combined oral contraceptive users and clinicians regarding the safety of oral contraceptives and potentially opens discussion on norethisterone acetate as a potential gold standard therapy in clinical and postmarket research alongside levonorgestrel-combined oral contraceptives.

Real world data on symptomology and diagnostic approaches of 27,840 women living with endometriosis.

Endometriosis is a chronic disease that requires a suitable, lifelong treatment. To our knowledge, the Visanne Post-approval Observational Study (VIPOS) is to date the largest real-world, non-interventional study investigating hormonal management of endometriosis. We describe women's experiences of endometriosis in the real world by considering their symptoms and the diagnostic process in their healthcare setting. Overall, 27,840 women were enrolled from six European countries via networks of gynecologists or specialized centers. Of these, 87.8% of women were diagnosed based on clinical symptoms; the greatest and lowest proportions of women were in Russia (94.1%) and Germany (61.9%), respectively. Most women (82.8%) experienced at least one of the triad of endometriosis-associated pain symptoms: pelvic pain, pain after/during sexual intercourse, and painful menstrual periods. The most frequently reported endometriosis-associated symptoms were painful periods (61.8%), heavy/irregular bleeding (50.8%), and pelvic pain (37.2%). Women reported that endometriosis impacted their mood; 55.6% reported feeling "down", depressed, or hopeless, and 53.2% reported feeling like a failure or having let down family/friends. VIPOS broadens our understanding of endometriosis based on real-world data by exploring the heterogeneity of symptoms women with endometriosis experience and the differences in diagnostic approaches between European countries.Trial registration: ClinicalTrials.gov, NCT01266421; registered 24 December 2010. Registered in the European Union electronic Register of Post-Authorisation Studies as number 1613.

Unintended pregnancy in users of nomegestrol acetate and 17ß-oestradiol (NOMAC-E2) compared with levonorgestrel-containing combined oral contraceptives: final results from the PRO-E2 study.

OBJECTIVE: To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COCLNG) users in clinical practice. STUDY DESIGN: In this observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (contraceptive failures per 100 women-years [WY]), crude hazard ratios (HRcrude) and adjusted hazard ratios (HRadj). RESULTS: Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COCLNG user cohorts, respectively. There were 64 unintended pregnancies in NOMAC-E2 users (0.15 per 100 WY; 95% CI, 0.11-0.19) and 200 in COCLNG users (0.41 per 100 WY; 95% CI, 0.35-0.47). The unintended pregnancy risk was statistically significantly lower in the NOMAC-E2 cohort (p<.0001) compared to the COCLNG user cohort. The HRadj of NOMAC-E2 vs COCLNG was 0.45 (95% CI, 0.34-0.60; adjusted for age, body mass index, gravidity, COC user status, education level). CONCLUSIONS: NOMAC-E2 demonstrated superior contraceptive effectiveness compared to COCLNG, likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC.

Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17ß-oestradiol (1.5mg) (PRO-E2 study): risk of venous and arterial thromboembolism.

OBJECTIVE: To assess and compare the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in NOMAC-E2 users with levonorgestrel-containing combined oral contraceptive (COCLNG) users. STUDY DESIGN: This large, prospective, observational active surveillance study used a non-inferiority design. New users of NOMAC-E2 and COCLNG were recruited in 12 countries in Australia, Europe, and Latin America. Women were followed up directly and self-reported outcomes of interest were validated via treating physicians. The main outcome of interest was VTE, specifically deep venous thrombosis of the lower extremities (DVT) and pulmonary embolism (PE). Secondary outcomes included all VTE and ATE. Data on confounders were captured and independent blinded adjudication assessed the classification of events. Incidence rates, crude (HRcrude), and adjusted (HRadj) hazard ratios were calculated. RESULTS: A total of 101,498 women (49,598 NOMAC-E2 users and 51,900 COCLNG users) were enrolled and followed for up to 2 years (144,901 WY of observation). NOMAC-E2 users had a higher mean age (31.0 ± 8.63 years) than COCLNG users (29.3 ± 8.53 years) but other baseline characteristics were similar between the cohorts. The main analysis comparing the risk of DVT of the lower extremities and PE in NOMAC-E2 users versus COCLNG users yielded an HRadj of 0.59 (95% CI, 0.25-1.35) (adjusted for age, BMI, family history of VTE, and current duration of use). The risk of all VTE and ATE was not higher in NOMAC-E2 users compared with COCLNG users. CONCLUSION(S): NOMAC-E2 use was not associated with a higher risk of VTE or ATE compared with COCLNG.

Risk of depression and anemia in users of hormonal endometriosis treatments: Results from the VIPOS study.

OBJECTIVE: Dienogest (DNG) 2 mg (Visanne) was launched for endometriosis treatment in Europe in 2010. The Visanne Post-approval Observational Study (VIPOS) was designed to assess the safety of DNG 2 mg/day compared to other hormonal endometriosis treatments, focusing especially on clinically relevant depression and anemia. STUDY DESIGN: Large, prospective, non-interventional, active surveillance study in six European countries. Participants were recruited via gynecologists or specialized centers routinely prescribing endometriosis medication. Self-administered questionnaires during study entry and follow-up collected information on baseline characteristics, health status and endometriosis treatment. Patient-reported anemia and depression cases were validated by health care professionals. Inferential statistics were based on Cox proportional hazards models and crude and adjusted hazard ratios (HR) between cohorts were calculated (including 95% confidence intervals [CI]). Adjustment for potential confounding was performed by including predefined prognostic factors as covariates in the Cox models. RESULTS: Out of 26,430 participants, 11.4% used DNG, 12.8% used other approved endometriosis medications (OAED) and 75.7% used hormonal treatments not approved but frequently used for endometriosis treatment (NAED). At baseline, DNG users more frequently reported a surgically confirmed endometriosis diagnosis, severe endometriosis-associated pain and a history of depression, compared to the other cohorts. Baseline characteristics showed large inter-country variability. Overall, the number of confirmed anemia and depression events were substantially lower than expected. The adjusted HRs for anemia were 1.1 (95% CI, 0.4-2.6) for DNG vs OAED and 1.3 (95% CI, 0.7-2.4) for DNG vs NAED. The adjusted HRs for new or worsening depression were 1.8 (95% CI, 0.3-9.4) for DNG vs OAED and 1.5 (95% CI, 0.8-2.8) for DNG vs NAED. CONCLUSION: The main limitations encountered (low number of confirmed events and considerable inter-country variability) made a robust statistical analysis and a solid interpretation of the results challenging. However, no safety signal regarding anemia for DNG users could be detected, whereas a slight increase in depression risk cannot be excluded but might be explained by baseline severity of endometriosis or unknown country-specific confounding variables. VIPOS reflected routine use of hormonal endometriosis medications and provided real-world insights into endometriosis management in Europe.

Safety of Dienogest and Other Hormonal Treatments for Endometriosis in Real-World Clinical Practice (VIPOS): A Large Noninterventional Study.

INTRODUCTION: Endometriosis is a common gynecologic disease associated with a significant burden on women's health and healthcare systems. Currently approved hormonal treatments for endometriosis can be effective in controlling symptoms, but may have clinically relevant side effects that limit their long-term use. Dienogest 2 mg (Visanne; Bayer AG, Berlin, Germany) is a 19-nortestosterone derivative that significantly reduces menstrual bleeding, dysmenorrhea, premenstrual pain, dyspareunia, and pelvic pain in women with endometriosis. Although dienogest 2 mg has demonstrated efficacy in clinical trials, data regarding long-term and real-world use are limited. METHODS: To our knowledge, the Visanne Post-approval Observational Study (VIPOS) is the largest real-world, noninterventional study performed examining the safety of dienogest and other hormonal treatments for the management of endometriosis in routine clinical practice. Patients self-reported medical and gynecologic history and symptoms and treatment information. Primary clinical outcomes were clinically validated and subject to independent blinded adjudication. Loss to follow-up was minimized through active contact with participating women at 6 months post-enrollment and annually thereafter to ensure almost all clinically relevant outcomes were captured. PLANNED OUTCOMES: VIPOS planned to enroll approximately 25,000 women initiating a new treatment for endometriosis, including those prescribed dienogest 2 mg/day and other hormonal medications for endometriosis (approved or nonapproved), from approximately 1000 centers in six European countries. The main clinical outcomes of interest for follow-up are anemia requiring medical intervention, de novo or clinically worsening depression, and treatment-failure patterns that result in drug discontinuation. Additional analyses will characterize the baseline risk factors of medically managed patients with endometriosis and assess treatment utilization patterns. VIPOS was designed to provide real-world information on endometriosis treatment and associated clinical outcomes, while not affecting the prescribing physician's decisions or the classification of patient diagnoses. TRIAL REGISTRATION: European Union Electronic Register of Post-Authorisation Studies (EU PAS) no. 1613, Clinicaltrials.gov: NCT01266421.

Unintended pregnancy rates differ according to combined oral contraceptive - results from the INAS-SCORE study.

Objectives: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive (COC) containing dienogest and oestradiol valerate (DNG/oEV) compared to other combined oral contraceptives (oCOC) and particularly, levonorgestrel-containing OCs (LNG). Methods: Prospective, non-interventional cohort study with two main exposure groups and one exposure subgroup: new users of DNG/oEV and oCOC, with the subgroup, LNG. In a planned secondary analysis, pregnancy outcomes were investigated, including contraceptive failure. The influence of age, parity and OC-type were assessed. Results: 30,098 COC users were followed for a total oral contraceptive exposure time of 68,362 woman-years (WY) and 287 unintended pregnancies were reported. The overall contraceptive failure rate in the European population was 0.4 events/100 WY (95% CI, 0.4-0.5). DNG/oEV showed lower contraceptive failure rates compared to the comparators. This difference was maintained when the study population was restricted to women aged 18-35 years; the pearl index (PI) for this demographic for DNG/oEV was 0.37 (95% CI 0.24-0.54) and 0.76 (95% CI 0.56-1.01) for LNG. The hazard ratios (HRs) adjusted for age, parity, smoking and BMI were 0.7 (95% CI, 0.5-0.98, p = .04) and 0.5 (95% CI, 0.3-0.8, p < .01) for DNG/oEV versus oCOC and LNG, respectively. The corresponding adjusted HRs in women aged 25 years or younger were 0.6 (95% CI 0.4-1.1) and 0.4 (95% CI, 0.2-0.8), respectively. Conclusions/discussion: DNG/oEV showed improved contraceptive effectiveness compared with oCOC and particularly LNG-COC when adjusted for age, parity, user status and smoking.

Real world data on Nexplanon® procedure-related events: final results from the Nexplanon Observational Risk Assessment study (NORA).

OBJECTIVES: We conducted this study to characterize the frequency of insertion-, localization- and removal-related events and their clinically significant consequences among Nexplanon® (etonogestrel radiopaque contraceptive implant) users in the United States during standard clinical practice. STUDY DESIGN: The Nexplanon Observational Risk Assessment (NORA) study was a large, prospective cohort study conducted in the United States. A total of 428 Health Care Professionals (HCPs) who had completed the Nexplanon clinical training program recruited women who were newly prescribed Nexplanon. We collected data on insertion-, localization- and removal-related events experienced during routine clinical practice via questionnaires completed by patients and HCPs. Recruitment began in December 2011 and follow-up ended in October 2017. Data analysis characterized the frequency of procedure-related events. RESULTS: We collected data on 7364 insertion procedures. The incidence of incorrect insertion (i.e., initially unrecognized non-insertion, partial insertion or deep insertion) was 12.6 per 1000 insertions (95% CI, 10.2-15.5). Pins and needles/numbness in the arm/hand/fingers was the most common patient-reported event. We obtained data on 5159 removal procedures, of which all were successful but one (due to the location of the implant in deep muscle tissue). No implants were localized outside the arm. The most common challenge reported by HCPs during implant removal was encasement of the implant within fibrotic tissue. CONCLUSIONS: Events associated with the insertion, localization and removal of the Nexplanon contraceptive implant were rare and their clinical consequences were generally not suggestive of serious injury. IMPLICATIONS: This study is the largest prospective evaluation of events associated with insertion and removal of Nexplanon during routine clinical practice. It demonstrates that complications associated with insertion and removal of Nexplanon are rare when performed by trained clinicians.

IUD use among parous women and risk of uterine perforation: a secondary analysis.

OBJECTIVE: The objective of the study was to determine if delivery and lactation are risk factors for complete intrauterine device perforations. STUDY DESIGN: We performed a reanalysis of the European Active Surveillance Study on Intra-Uterine Devices data set using complete penetration of the myometrium as the definition for perforation. RESULTS: Of the 61,448 women enrolled (70% levonorgestrel, 30% copper devices), we identified 58 complete perforations, 30 of which occurred in lactating women. Incidence per 1000 insertions was 4.5 (95% confidence interval [CI]: 3.0-6.4) for lactating and 0.6 (95% CI: 0.4-0.9) for nonlactating women. Time since delivery was also associated with perforation risk. CONCLUSIONS: Lactation and delivery are independent cofactors for perforation. Results do not differ when restricting the definition of perforation.

Perforation risk and intra-uterine devices: results of the EURAS-IUD 5-year extension study.

OBJECTIVES: The objective of this analysis was to identify intra-uterine devices (IUD) perforations detected from 12 to 60 months following IUD insertion, and to combine this information with (our previously published) data about perforations detected in the first 12 months to calculate cumulative perforation rates. METHODS AND MATERIALS: Prospective, non-interventional cohort study with new users of levonorgestrel-releasing intra-uterine systems (LNG-IUS) and copper-IUD. The original cohort included 61,448 women followed for 12 months. Of these, we had sufficient resources to perform an additional follow-up and analysis at 60 months in 39,009 women. Inclusion criteria for this analysis was insertion prior to 31 July 2010. All potential cases were validated via the health care professional or medical records. Crude and adjusted relative risks were calculated using a logistic regression model. RESULTS: We identified 23 additional perforations (19 LNG-IUS and 4 copper-IUD) more than 12 months after insertion. Added to perforations detected at 12 months, the overall perforation rate was 2.1 per 1000 insertions (95% CI: 1.6-2.8) for LNG-IUS users (40 + 19 perforations/27,630 insertions) and 1.6 per 1000 insertions (95% CI: 0.9-2.5) for copper-IUD users (14 + 4 perforations/11,379 insertions). LNG-IUS users had a borderline higher risk of perforation compared with copper-IUD users (ORadj 1.7; 95% CI: 1.0-2.8). Forty-five (58%) of the 77 perforations were associated with suspected risk factors. Breastfeeding (RR 4.9, 95% CI: 3.0-7.8) and time since delivery (RR 3.0, CI: 1.5-5.4) remained significant risk factors in perforations detected after 12 months. No perforations resulted in serious injury to intra-abdominal or pelvic structures. CONCLUSIONS: The incidence of uterine perforations in this study was low, although higher than the commonly reported rate. Approximately one third of perforations are detected 12 months after insertion. Clinical sequalae of perforations are generally mild and associated with a very low risk of injury to intra-abdominal and pelvic structures. Implications Uterine perforation is a rare risk associated with intra-uterine device use. Late diagnosed perforations can occur, although women can be reassured that the morbidity associated with detection and removal is low.

Fertility and combined oral contraceptives - unintended pregnancies and planned pregnancies following oral contraceptive use - results from the INAS-SCORE study.

OBJECTIVES: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive containing dienogest and estradiol valerate (DNG/EV) and whether DNG/EV compared to other combined oral contraceptives (oCOC) has a negative effect on return to fertility. METHODS: Transatlantic, prospective, non-interventional cohort study conducted in the USA and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). In a planned secondary analysis, pregnancy outcomes were investigated including contraceptive effectiveness and pregnancy following contraceptive cessation. The influence of age, parity and OC-type were assessed. RESULTS: 50,203 COC users were followed for 105,761 woman-years (WY). There were 677 unintended pregnancies reported: 451 in the USA and 226 in Europe. The contraceptive failure rate in Europe was 0.5 events/100 WY (95% CI: 0.4-0.5) and in the USA 1.9 events/100 WY (95% CI: 1.7-2.1). Differences in compliance (1.3 pregnancies/100 WY) accounted for 90% of the geographical difference seen between Europe and the USA. DNG/EV showed lower contraceptive failure rates compared to the comparators; 0.9% DNG/EV, 2.1% oCOC and 2.8% LNG after 4 years. Overall, 1167 (2.3%) of women stopped contraceptive use with the intention of becoming pregnant with 89% conceiving within 2 years. No significant differences were seen between groups after adjusting for age. CONCLUSION/DISCUSSION: DNG/EV is associated with similar contraceptive effectiveness in typical-use settings when compared to oCOC and LNG. There was no difference observed between cohorts in fertility following OC use.