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.

Optimization and characterization of electrospun polycaprolactone coated with gelatin-silver nanoparticles for wound healing application.

Bacterial infection and damage caused by dressing removal are two concerning problems which prolong the healing process in treatment of skin injuries. In this study, plasma treated electrospun polycaprolactone (PCL) scaffold was coated with silver nanoparticles (AgNPs) embedded in gelatin (Gel) by multi-immersion technique to optimize its antibacterial performance and reduce wound-scaffold adhesion. Water interaction test was used to examine the hydrophilization of PCL electrospun fibers after plasma treatment. Scanning Electron Microscopy (SEM) and weight calculation were employed to investigate the morphology and absorptive ability of the GelAg multi-coated PCL membrane (EsPCLGelAg). Antibacterial property of the membrane was evaluated using agar diffusion method against gram positive and gram negative bacteria. Mice model was also used to examine the efficiency of the membrane in healing process and its ability to prevent damage of newly formed tissue when peeling off. SEM results showed that the thickness of GelAg layer on EsPCL membrane increases correspondingly to the number of coating times. In vitro and in vivo data also demonstrated that the greater number of GelAg coating times, the more significant the antibacterial property of the membrane while not sticking to the wound site. These results suggest that multi-coating technique can be applied to optimize the antibacterial property of EsPCLGelAg scaffold and prevent removal-induced damage for wound dressing applications.

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.

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.

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.

Impact of estrogen type on cardiovascular safety of combined oral contraceptives.

OBJECTIVES: The International Active Surveillance study "Safety of Contraceptives: Role of Estrogens" (INAS-SCORE) investigated the cardiovascular risks associated with the use of a combined oral contraceptive (COC) containing dienogest and estradiol valerate (DNG/EV) compared to established COCs in a routine clinical setting. STUDY DESIGN: Transatlantic, prospective, noninterventional cohort study conducted in the United States 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). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. RESULTS: A total of 50,203 new COC users were followed up for up to 5.5years (mean value, 2.1years). Overall 20.3% and 79.7% of these women used DNG/EV and oCOC (including 11.5% LNG users), respectively. A low loss to follow-up of 3.1% was achieved. Based on 47 (VTE) and 233 (SCE) events, the primary analysis (European data set) yielded adjusted hazard ratios for DNG/EV vs. oCOC of 0.4 and 0.5, respectively. The upper bounds of the 95% confidence intervals were 0.98 (VTE) and 0.96 (SCE). The corresponding hazard ratios for DNG/EV vs. LNG showed similar point estimates but the confidence intervals included unity. CONCLUSION: DNG/EV is associated with similar or even lower cardiovascular risk compared to oCOC and LNG. IMPLICATION STATEMENT: A COC containing DNG and EV is associated with similar or even lower cardiovascular risk compared to COCs containing levonorgestrel or other progestogens.

Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen.

OBJECTIVE: To estimate real-life effectiveness of oral contraceptive pills by progestogen, length of pill-free interval, and body mass index while focusing on the effect of progestogens with a long half-life and on 24-day oral contraceptive pills regimens. METHODS: Outcome data from 52,218 U.S. participants in the International Active Surveillance of Women Taking Oral Contraceptives­a large, prospective, controlled, noninterventional, long-term cohort study with active surveillance of the study participants­were used to analyze contraceptive failure in association with oral contraceptive pills use. Low loss to follow-up is ensured by a comprehensive follow-up procedure. Contraceptive failure rates are described by Pearl Index and life-table analysis. Inferential statistics for contraceptive failure are based on Cox regression models. RESULTS: Analyses are based on 1,634 unintended pregnancies during 73,269 woman-years of oral contraceptive pills exposure. Life-table estimates of contraceptive failure for a 24-day regimen of drospirenone and ethinyl estradiol and 21-day regimens of other progestogens were 2.1% and 3.5% after the first study year, and 4.7% and 6.7% after the third year. The adjusted hazard ratio was 0.7 (95% confidence interval 0.6­0.8). Direct comparisons of the 24-day and 21-day regimens of drospirenone and norethisterone, respectively, showed also lower contraceptive failure rates for 24-day regimens. Contraceptive failure rates adjusted for age, parity and educational level showed a slight increase with higher body mass index. CONCLUSION: The 24-day oral contraceptive regimens containing a progestogen with a long half-life show higher contraceptive effectiveness under routine medical conditions compared with conventional 21-day regimens. Obesity seems to be associated with a slight reduction of contraceptive effectiveness. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00335257. LEVEL OF EVIDENCE: II

Explorative evaluation of the impact of premenstrual disorder on daily functioning and quality of life.

OBJECTIVES: : To assess the effects of premenstrual disorders on health-related quality of life (HR-QOL), hobbies and social activities, and relationships with others in the multinational IMPACT study. METHODS: : Women aged 15-45 years were screened for suspected premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS) and invited to participate in this web-based study. Based on the Daily Record of Severity of Problems (DRSP), prospectively assessed over two observational cycles, participants were grouped into two categories: no perceived symptoms/mild PMS or moderate-to-severe PMS/PMDD. HR-QOL was assessed retrospectively at baseline using the SF-12. RESULTS: : Overall, 1477 women started the study. Of these, 822 (56%) completed the DRSP and SF-12 questionnaires as planned. Moderate-to-severe PMS/PMDD was associated with a reduction in HR-QOL compared with no perceived symptoms/mild PMS for both mental component scores (34.5 ± 8.7 vs 39.0 ± 9.5) and physical component scores (48.9 ± 7.9 vs 51.1 ± 7.2). Women with moderate-to-severe PMS/PMDD experienced a significantly greater mean number of days with at least moderate interference with hobbies or social activities (5.6 vs 1.1 day; p < 0.05, t-test), and relationships with others (5.4 vs 1.1 day) than those with no perceived symptoms/mild PMS. CONCLUSIONS: : Moderate-to-severe PMS/PMDD has a negative impact on HR-QOL, hobbies and social activities, and relationships with others. Studies with a confirmatory design are needed to confirm these results.

The Menopause Rating Scale (MRS) scale: a methodological review.

BACKGROUND: This paper compiles data from different sources to get a first comprehensive picture of psychometric and other methodological characteristics of the Menopause Rating Scale (MRS) scale. The scale was designed and standardized as a self-administered scale to (a) to assess symptoms/complaints of aging women under different conditions, (b) to evaluate the severity of symptoms over time, and (c) to measure changes pre- and postmenopause replacement therapy. The scale became widespread used (available in 10 languages). METHOD: A large multinational survey (9 countries in 4 continents) from 2001/ 2002 is the basis for in depth analyses on reliability and validity of the MRS. Additional small convenience samples were used to get first impressions about test-retest reliability. The data were centrally analyzed. Data from a postmarketing HRT study were used to estimate discriminative validity. RESULTS: Reliability measures (consistency and test-retest stability) were found to be good across countries, although the sample size for test-retest reliability was small. VALIDITY: The internal structure of the MRS across countries was astonishingly similar to conclude that the scale really measures the same phenomenon in symptomatic women. The sub-scores and total score correlations were high (0.7-0.9) but lower among the sub-scales (0.5-0.7). This however suggests that the subscales are not fully independent. Norm values from different populations were presented showing that a direct comparison between Europe and North America is possible, but caution recommended with comparisons of data from Latin America and Indonesia. But this will not affect intra-individual comparisons within clinical trials. The comparison with the Kupperman Index showed sufficiently good correlations, illustrating an adept criterion-oriented validity. The same is true for the comparison with the generic quality-of-life scale SF-36 where also a sufficiently close association has been shown. CONCLUSION: The currently available methodological evidence points towards a high quality of the MRS scale to measure and to compare HRQoL of aging women in different regions and over time, it suggests a high reliability and high validity as far as the process of construct validation could be completed yet.