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.

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.

Comparative contraceptive effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices.

OBJECTIVES: The objective was to measure the rate of unintended pregnancies in women using levonorgestrel-releasing intrauterine systems (LNG IUSs, releasing 20 mcg LNG daily) and copper intrauterine devices (IUDs) in a typical population of IUD users and to describe associated complications. METHODS: A multinational, prospective, non-interventional cohort study of new users of LNG IUS and copper IUDs was performed. Following a baseline survey, study participants and their physicians completed one follow-up questionnaire after 12 months. A multifaceted four-level follow-up procedure minimized loss to follow-up. Patient-reported outcomes were validated by the treating physicians. RESULTS: A total of 61,448 women with a newly inserted IUD were enrolled in six European countries between 2006 and 2012. The copper IUD cohort contained more than 30 different types. Validated 1-year follow-up information for 58,324 users between 18 and 50 years of age (70% using LNG IUS, 30% using copper IUDs) was collected. A total of 118 contraceptive failures occurred (26 LNG, 92 copper). Both types of IUD were highly effective, with overall Pearl indices of 0.06 [95% confidence interval (CI): 0.04-0.09] and 0.52 (95% CI: 0.42-0.64) for LNG IUS and copper IUDs, respectively. The adjusted hazard ratio for LNG IUS vs. copper IUDs was 0.16 (95% CI: 0.10-0.25). Tenty-one pregnancies (7 LNG IUS, 14 copper IUD) were ectopic, yielding an adjusted hazard ratio for ectopic pregnancy of 0.26 (95% CI: 0.10-0.66). CONCLUSIONS: The contraceptive failure rate was low with both IUDs. However, the LNG IUS was associated with a significantly lower risk of pregnancy, including ectopic pregnancy, than the copper IUDs. IMPLICATIONS: To our knowledge, this is the first large-scale, multinational, prospective epidemiological study to measure and compare the contraceptive effectiveness of LNG IUSs and copper IUDs during routine clinical practice. Clinicians and patients should be aware of differences in rates of unintended pregnancies and associated complications in relation to IUD us.

Risk of uterine perforation with levonorgestrel-releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine Devices.

OBJECTIVES: The objectives were to identify and compare the incidence of uterine perforation and other medically adverse events associated with levonorgestrel-releasing intrauterine systems (LNG-IUSs, releasing 20 mcg LNG daily) and copper intrauterine devices (IUDs) under routine conditions of use in a study population representative of typical users. METHODS AND MATERIALS: This is a multinational, prospective, non-interventional cohort study with new users of LNG-IUSs and copper IUDs. In addition to a baseline questionnaire, women and their treating health care professional completed a single follow-up questionnaire after 12 months. All patient-reported outcomes were validated by the treating physicians. RESULTS: A total of 61,448 women in six European countries were followed between 2006 and 2013 for more than 68,000 women-years of observation (70% LNG, 30% copper devices). Overall, 81 uterine perforations were reported: 61 for LNG-IUSs [1.4 per 1000 insertions (95% confidence interval {CI}: 1.1-1.8)] and 20 for copper IUDs [1.1 per 1000 insertions (95% CI: 0.7-1.7)], for an adjusted risk ratio (RRadj) of 1.6 (95% CI: 1.0-2.7) when adjusted for age, body mass index, breastfeeding at time of insertion and parity. Breastfeeding at time of insertion was associated with a sixfold increase (RR 6.1, 95% CI: 3.9-9.6), with no differences between LNG and copper IUD users. Sixty-three of the total 81 perforations were associated with previously suspected risk factors (e.g., breastfeeding, time since last delivery ≤36 weeks). No perforations led to serious illness or to injury of intra-abdominal or pelvic structures. CONCLUSIONS: Uterine perforation incidence in this study was low, with a benign clinical course thereafter. The LNG-IUSs and copper IUDs did not have clinically important differences in perforation rates. IMPLICATIONS: The European Active Surveillance Study on Intrauterine Devices is the first large-scale, prospective, non-interventional study to compare the perforation risk in LNG-IUS and copper IUD users. It is the first to examine the independent roles that breastfeeding status and postpartum status have on perforation risk. Conducted during routine clinical practice, the findings are generalizable to broader populations.

Intercountry assessment of the impact of severe premenstrual disorders on work and daily activities.

We explored the effects of premenstrual symptoms in women suffering from moderate-to-severe premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD) on work productivity, absenteeism, and daily life activities in a large, worldwide exploratory study. Women aged 15-45 years from 19 countries in North America, Latin America, Europe, Asia, and Australia were screened for suspected PMS and PMDD and invited to participate in this 2-month web-based survey. Overall, 4,032 women completed all administered questionnaires and represent the analysis set. Women suffering from moderate-to-severe PMS/PMDD had increased work absenteeism and work productivity impairment due to premenstrual symptoms relative to those with mild PMS/no perceived symptoms.

Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer.

BACKGROUND: This study compares the risk of breast cancer for levonorgestrel-releasing intrauterine devices (LNG(IUD)) versus copper IUDs (CU(IUD)) in women younger than 50 years of age. STUDY DESIGN: Retrospective, population-based, case-control study using cancer registers in Finland and Germany, powered to exclude a 1.5-fold risk of breast cancer. RESULTS: Analysis of 5113 breast cancer cases diagnosed 2000-2007 and 20,452 controls - matched by year of birth and area of residence - yielded relative risk estimates approaching unity with 95% CI crossing 1.0 for all comparisons, including ever-use of LNG(IUD) versus CU(IUD) (adjusted OR, 0.99; 95% CI, 0.88-1.12) and current use at time of diagnosis (adjusted OR, 0.85; 95% CI, 0.52-1.39), as well as for sub-analyses by country, age, tumor characteristics and period, recency and duration of use prior to diagnosis. CONCLUSION: This study does not indicate an increased risk of breast cancer for users of LNG(IUD). No indications for tumor promotion or tumor induction were found.

Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study.

OBJECTIVE: The primary objective of the study was to clarify whether the use of the oral contraceptive 2 mg dienogest/30 microg ethinylestradiol (DNG/EE) is associated with a higher risk of venous thromboembolism (VTE) than the use of other combined oral low-dose contraceptives (i.e. containing < or =30 microg EE), particularly oral contraceptives containing levonorgestrel (LNG). The secondary objective was to investigate the VTE risk associated with drospirenone/ethinylestradiol (DRSP/EE) in comparison to low-dose LNG/EE. METHODS: This German community-based, case-control study recruited VTE cases from the primary care sector. Eligible cases were women aged 15-49 years with a VTE between January 2002 and February 2008. Four controls (women without a confirmed or potential VTE before the index date) were matched by age and region to each case. Medical information relevant for the assessment of VTE was abstracted from patient charts. Data on personal characteristics of the patients were collected via self-administered questionnaires. At the end of the study a blinded adjudication of the reported VTE was conducted. Conditional logistic regression techniques were used, adjusting for nine potential confounders, including personal history of VTE, family history of VTE, body mass index, duration of current combined oral contraceptive (COC) use and smoking. RESULTS: A total of 680 VTE cases and 2720 corresponding controls were analysed. The mean age of cases and controls was - as a result of matching - almost identical (36.1 years). A total of 35, 25, and 60 of the cases had used DNG-, DRSP- and LNG-containing low-dose COCs, respectively, at the time of the VTE diagnosis. The crude odds ratio (OR) for VTE associated with current COC use in comparison to women who had never used a COC before the index date was 1.9 (95% CI 1.5-2.5), the adjusted OR was 2.3 (95% CI 1.7-3.0). The point estimate of the crude OR of DNG/EE vs any other low-dose COCs was 0.9 (95% CI 0.6-1.3), the adjusted OR was 0.9 (95% CI 0.6-1.4). The crude ORs for DNG/EE and DRSP/EE vs low-dose LNG/EE were 1.1 (95% CI 0.7-1.8) and 1.0 (95% CI 0.6-1.6), respectively; the adjusted ORs were 1.1 (95% CI 0.7-1.9) and 1.0 (95% CI 0.6-1.8). CONCLUSIONS: The study confirms that COC use is associated with an increased risk of VTE. The VTE ORs (adjusted and crude) that compared DNG/EE and DRSP/EE with other low-dose COCs (including LNG/EE) were close to unity and do not indicate a higher risk for users of DNG/EE or DRSP/EE.

Use of oral contraceptives containing gestodene and risk of venous thromboembolism: outlook 10 years after the third-generation "pill scare".

BACKGROUND: This study investigated whether gestodene-containing oral contraceptives (OCs) carry a higher risk of venous thromboembolism (VTE) than OCs containing progestins other than desogestrel and gestodene. The study was conducted based on the hypothesis that the biases and confounding factors that were present initially after the introduction of new so-called "third-generation" OCs (i.e., those containing desogestrel and gestodene) in the 1990s, which likely contributed to the alleged increased risk of VTE, may have vanished after 10 years. STUDY DESIGN: This was a matched case-control study using data identified for women (aged 15-49 years) with suspected or diagnosed VTE (deep vein thrombosis or pulmonary embolism) that occurred between January 2002 and February 2006 in Austria. All VTE cases were validated by an attending/relevant physician(s), a detailed review of medical records and patient-completed questionnaires. Data were analyzed using an unconditional logistic regression model with adjustment for relevant confounders. RESULTS: Overall, 451 VTE cases and 1,920 controls without VTE were identified. The adjusted odds ratios for confirmed VTE with OC use versus nonuse were: 3.39 (95% CI 2.36-4.87) for OCs containing gestodene and 3.14 (2.1-4.47) for OCs containing progestins other than desogestrel and gestodene. Adjusted odds ratios for a head-to-head comparison of OCs containing gestodene versus OCs containing progestins other than desogestrel and gestodene were: 0.99 (0.68-1.45) for all cases; 1.01 (0.69-1.47) for confirmed cases and 1.11 (0.73-1.69) for confirmed and idiopathic VTE cases, respectively. CONCLUSION: The risk of VTE is not elevated in users of gestodene-containing OCs relative to users of OCs containing progestins other than desogestrel and gestodene. Our study supports the view that (i) the majority of previous results may be explained by differences in the user populations of so-called "third-generation" OCs (containing desogestrel and gestodene) and "second-generation" OCs (containing progestins other than desogestrel and gestodene) that were present shortly after market introduction of gestodene-containing OCs and that (ii) these differences seem to have disappeared over time.

Explorative evaluation of the impact of severe premenstrual disorders on work absenteeism and productivity.

PURPOSE: To assess the effects of premenstrual disorders on work productivity and absenteeism in the multinational Impact study. METHODS: Women aged 15-45 years were screened for suspected premenstrual dysphoric disorders (PMDD) and premenstrual syndrome (PMS) and invited to participate in this web-based study. Based on the Daily Record of Severity of Problems (DRSP) questionnaire, symptoms were assessed prospectively over 2 months. Participants were categorized as having no perceived symptoms/mild PMS or moderate-to-severe PMS/PMDD based on a validated algorithm. Work productivity impairment and absenteeism were assessed retrospectively using the Premenstrual Symptoms Screening Tool (PSST) and a modified version of the Work Productivity and Activity Impairment (WPAI) questionnaire. Work productivity impairment was also assessed prospectively over 2 months using the DRSP questionnaire. RESULTS: Overall 1,477 women started the study-of these, 822 (56%) completed the study as planned and represent the full analysis set. Employed women with moderate-to-severe PMS/PMDD had higher rate of productivity impairment on the modified version of the WPAI questionnaire (values >/=7) relative to those with no perceived symptoms/mild PMS (adjusted odds ratio, 3.12; 95% confidence interval, 1.75-5.57). Similar outcomes were obtained for impairment of working productivity or efficiency using the PSST scale (value 4). The mean number of days on the DRSP with at least moderate reduction in productivity or efficiency in daily routine was higher for women with moderate-to-severe PMS/PMDD (5.6 vs. 1.1). Women with moderate-to-severe PMS/PMDD had a higher rate of absenteeism (>8hours per cycle; 14.2% vs. 6.0%). CONCLUSION: Moderate-to-severe PMS/PMDD seems to be associated with work productivity impairment and increased absenteeism, and thus poses a potential economic burden.

Oral contraceptive effectiveness according to body mass index, weight, age, and other factors.

OBJECTIVE: The purpose of this study was to assess the use-effectiveness of oral contraceptives (OCs) in Europe according to body mass index (BMI), weight, age, and other factors. STUDY DESIGN: In a planned secondary analysis, we used data from the European Active Surveillance Study on Oral Contraceptives, which was a prospective active cohort surveillance study of 59,510 OC users, to assess the effectiveness of OCs overall and by BMI, weight, age, duration of use, ethinylestradiol dose, regimen type, starting/switching status, and parity. Self-reported unplanned pregnancies during OC use were confirmed by interview. RESULTS: An analysis of OC effectiveness (112,659 women-years of exposure and 545 unplanned pregnancies) found little variation in effectiveness by BMI/weight. Failure rates decreased after 30 years of age and with an increasing duration of use. CONCLUSION: OC users in Europe reported high contraceptive effectiveness with "typical use." Failure rates decreased with age and duration of use. BMI and weight had little, if any, influence on effectiveness.