Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research to advance the health of people with inherited bleeding disorders with the potential to menstruate.

BACKGROUND: People who have or had the potential to menstruate (PPM) with inherited bleeding disorders (BD) face particular challenges receiving appropriate diagnosis and care and participating in research. As part of an initiative to create a National Research Blueprint for future decades of research, the National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive all-stakeholder consultations to identify the priorities of PPM with inherited BDs and those who care for them. RESEARCH DESIGN AND METHODS: Working group (WG) 4 of the NHF State of the Science Research Summit distilled community-identified priorities for PPM with inherited BDs into concrete research questions and scored their feasibility, impact, and risk. RESULTS: WG4 identified important gaps in the foundational knowledge upon which to base optimal diagnosis and care for PPM with inherited BDs. They defined 44 top-priority research questions concerning lifespan sex biology, pregnancy and the post-partum context, uterine physiology and bleeding, bone and joint health, health care delivery, and patient-reported outcomes and quality-of-life. CONCLUSIONS: The needs of PPM will best be advanced with research designed across the spectrum of sex and gender biology, with methodologies and outcome measures tailored to this population, involving them throughout.

Up to 1% of cisgender women and girls have an inherited bleeding disorder (BD). Common symptoms include heavy menstrual bleeding (HMB), heavy bleeding after giving birth known as post-partum hemorrhage (PPH), nose bleeds, bleeding from the mouth, and excessive bleeding after surgery or procedures. They can also experience bleeding into their muscles, joints, and even into the brain. Uterine bleeding, such as from HMB and PPH, can impact the lives of anyone who has or had a uterus, a group we designate as people who have or had the potential to menstruate (PPM).Many PPM with an inherited BD do not receive diagnosis, treatment, and care needed due to a lack of expertise among health care professionals and the public, misunderstanding, and bias. Uncertainty about "normal" versus "abnormal" bleeding can contribute to a lack of diagnosis, treatment, and care. Language, such as the label of "carrier," can be a barrier to accessing treatment and care for PPM.People with inherited BDs, health care professionals with various expertise and focus, and researchers worked together to identify the research that would most improve the lives of PPM, in six focus areas where there are major gaps in knowledge and the lack of standards required for accurate diagnosis.

Evaluation of a new, low-dose levonorgestrel intrauterine contraceptive system over 5 years of use.

OBJECTIVE: To evaluate the efficacy and safety of a new, low-dose levonorgestrel intrauterine contraceptive system (LNG-IUS 12) for up to 5 years of use. STUDY DESIGN: In this Phase III study, 2885 nulliparous and parous women aged 18-35 years were randomized to LNG-IUS 8 or LNG-IUS 12 for 3 years. After 3 years, women using LNG-IUS 12 could continue for up to 2 additional years (5 years total). The primary outcome was occurrence of pregnancy (Pearl Index). Secondary outcomes included safety, bleeding, dysmenorrhea, discontinuations, and user satisfaction. RESULTS: From August 2007 through May 2008, out of 2885 women who were enrolled, 1453 were randomized to LNG-IUS 12. Placement was attempted in 1452/1453 (full analysis set). Mean age at baseline was 27.1 years; 39.5% were nulliparous. The cumulative 5-year Pearl Index (PI) was 0.29; the 5-year cumulative failure rate was 1.4%. The 5-year PI for ectopic pregnancy was 0.18. Over 5 years, 55.3% of women reported study drug-related treatment-emergent adverse events (TEAEs). Crude incidences of pelvic inflammatory disease, uterine perforation, and complete/partial LNG-IUS 12 expulsion were 0.6%, 0.2%, and 3.7%, respectively. Women using LNG-IUS 12 generally experienced less frequent bleeding over time. The incidence of amenorrhea during the last 90-day reference interval (end of Year 5) was 22.6%. Overall, 870 (59.9%) and 550 (37.9%) women completed 3 and 5 years of treatment, respectively; 77.8% of women who entered the extension phase completed 5 years of use. Over 5 years, 22.6% discontinued due to TEAEs, including 13 women who discontinued due to pregnancy; 76 discontinued due to bleeding problems including amenorrhea; and 163 discontinued due to desire for pregnancy, 71.2% of whom conceived within 12 months. CONCLUSION: In this study including parous and nulliparous women, LNG-IUS 12 was highly effective over 5 years of use and associated with a favorable safety profile. LNG-IUS 12 offers women a low-dose contraceptive option for up to 5 years.

A multicentre, open-label, randomised phase III study comparing a new levonorgestrel intrauterine contraceptive system (LNG-IUS 8) with combined oral contraception in young women of reproductive age.

OBJECTIVES: To compare user satisfaction and adverse events (AEs) with a levonorgestrel intrauterine system (LNG-IUS 8; average levonorgestrel release rate approximately 8 µg/24 h over the first year [total content 13.5 mg]) and a 30 µg ethinyl estradiol/3 mg drospirenone (EE/DRSP) combined oral contraceptive (COC) in a population of young women. METHODS: Nulliparous and parous women (aged 18-29 years) with regular menstrual cycles (21-35 days) were randomised to LNG-IUS 8 or EE/DRSP for 18 months. The primary endpoint was the overall user satisfaction rate at month 18/end of study visit. RESULTS: Overall, 279 women were randomised to LNG-IUS 8 with attempted placement and 281 women were randomised to EE/DRSP and took ≥1 pill; the mean age was 23.7 and 23.9 years, and 77.4% and 73.3% were nulliparous, respectively. At month 18/end of study, 82.1% and 81.9% of women, respectively, reported being 'very satisfied' or 'satisfied' with their treatment; however, significantly more LNG-IUS 8 users reported a preference to continue their treatment post-study (66.2% vs 48.8%; p = 0.0001). There were two pregnancies (one ectopic pregnancy, one spontaneous abortion) reported in the LNG-IUS 8 group and six (three live births, two spontaneous abortions, one induced abortion) in the EE/DRSP group. CONCLUSIONS: LNG-IUS 8 and EE/DRSP were associated with similarly high user satisfaction rates. However, LNG-IUS 8 users were significantly more likely to prefer to continue their contraceptive method post-study, indicating that a levonorgestrel intrauterine system is an appealing contraceptive option for young women.

The Effect of Age, Parity and Body Mass Index on the Efficacy, Safety, Placement and User Satisfaction Associated With Two Low-Dose Levonorgestrel Intrauterine Contraceptive Systems: Subgroup Analyses of Data From a Phase III Trial.

OBJECTIVE: Two low-dose levonorgestrel intrauterine contraceptive systems (LNG-IUSs; total content 13.5 mg [average approx. 8 µg/24 hours over the first year; LNG-IUS 8] and total content 19.5 mg [average approx. 13 µg/24 hours over the first year; LNG-IUS 13]) have previously been shown to be highly effective (3-year Pearl Indices: 0.33 and 0.31, respectively), safe and well tolerated. The present subgroup analyses evaluated whether or not outcomes were affected by parity, age (18-25 vs 26-35 years), or body mass index (BMI, <30 vs ≥30 kg/m2). METHODS: Nulliparous and parous women aged 18‒35 years with regular menstrual cycles (21‒35 days) requesting contraception were randomized to 3 years of LNG-IUS 8 or LNG-IUS 13 use. RESULTS: In the LNG-IUS 8 and LNG-IUS 13 groups, 1432 and 1452 women, respectively, had a placement attempted and were included in the full analysis set; 39.2%, 39.2% and 17.1% were 18-25 years old, nulliparous and had a BMI ≥30 kg/m2, respectively. Both systems were similarly effective regardless of age, parity or BMI; the subgroup Pearl Indices had widely overlapping 95% confidence intervals. Placement of LNG-IUS 8 and LNG-IUS 13 was easier (p < 0.0001) and less painful (p < 0.0001) in women who had delivered vaginally than in women who had not. The complete/partial expulsion rate was 2.2-4.2% across all age and parity subgroups and higher in parous than in nulliparous women (p = 0.004). The incidence of pelvic inflammatory disease was 0.1-0.6% across all age and parity subgroups: nulliparous and younger women were not at higher risk than parous and older women, respectively. The ectopic pregnancy rate was 0.3-0.4% across all age and parity subgroups. Across all age and parity subgroups, the 3-year completion rate was 50.9-61.3% for LNG-IUS 8 and 57.9-61.1% for LNG-IUS 13, and was higher (p = 0.0001) among older than younger women in the LNG-IUS 8 group only. CONCLUSIONS: LNG-IUS 8 and LNG-IUS 13 were highly effective, safe and well tolerated regardless of age or parity. TRIAL REGISTRATION: Clinical trials.gov NCT00528112.

Ovarian cysts: presence and persistence with use of a 13.5mg levonorgestrel-releasing intrauterine system.

OBJECTIVE: The aim of this study was to assess the presence of ovarian cysts in women using a new low-dose levonorgestrel-releasing intrauterine contraceptive system (LNG-IUS 13.5mg [total content]). STUDY DESIGN: A Phase 3 study assessed LNG-IUS 13.5mg use in healthy women with regular menstrual cycles who requested contraception. Transvaginal ultrasonography was performed at screening, baseline, and 3, 6, 9, 12, 18, 24, 30, and 36 months after placement. RESULTS: A total of 1432 women, mean age 27.2±4.8 years, were studied. A total of 10,446 transvaginal ultrasound examinations were performed over 3 years. Ovarian cysts were present in 1.6, 1.1, 2.3, 2.1, 2.4, 2.0, 2.1, 2.2, 1.9, and 2.1% of participants at screening, baseline, and Months 3, 6, 9, 12, 18, 24, 30, and 36, respectively. One hundred first-time ovarian cysts were identified from baseline through Month 9. The size distribution through Month 12 was ≤30 mm (13%), >30 to ≤50 mm (74%), >50 to ≤80 mm (11%), and >80 mm (0%). The overall persistence of ovarian cysts from one examination to the next in Year 1 was 12% (11/90 with follow-up). Cyst persistence was 36% from baseline to 3 months, 13% from 3 to 6 months, 10% from 6 to 9 months, and 0% from 9 to 12 months. The likelihood of cyst persistence increased for cysts >50mm (36%) as compared to those ≤50 mm (8%). CONCLUSION: Ovarian cysts were present in 1.6% of women at screening, 2.0 to 2.4% of LNG-IUS 13.5mg users during Year 1, and 1.9 to 2.1% during Years 2 and 3. The majority were >30 to ≤50 mm in size. The small and diminishing number of persistent cysts-decreasing to 0% from 9 to 12 months-suggests that they were functional in nature. IMPLICATIONS: Transvaginal ultrasound follow-up of women during a 3-year clinical trial of LNG-IUS 13.5mg showed that ovarian cysts were present in 1.6% of participants at screening and 1.1-2.4% at each subsequent visit. Eighty-eight percent were ≤5cm, with none >8cm. No ovarian cysts persisted beyond Month 9, suggesting a functional etiology.

EVAPIL-R Scale: Continuous development and validation of a tool to assess patient-reported tolerability of different contraceptive methods in longitudinal studies.

OBJECTIVE: The objective of this study was to modify the EVAPIL, a questionnaire designed to assess user-reported tolerability of combined oral contraceptives (COCs) in cross-sectional studies, to make it appropriate for assessing the tolerability of intrauterine systems (IUSs), subdermal implants, and COCs in longitudinal studies. METHODS: Development of the EVAPIL-Revised (EVAPIL-R) was informed by a targeted literature review, qualitative interviews with IUS-prescribing gynecologists (n = 5), and IUS and implant users in the United States, Germany, and France (n = 36). RESULTS: Evidence generated supports the content validity of the EVAPIL-R for assessing user-reported tolerability of COCs, IUSs, and implants. Modifications to improve the relevance and usability of the questionnaire in longitudinal studies included specification of a defined recall period, addition of separate assessments of frequency and intensity (where relevant), and inclusion of additional items measuring concepts of importance to IUS and implant users (eg, vaginal discharge). CONCLUSIONS: The EVAPIL-R is a valuable tool for use in research and clinical practice to identify tolerability concerns in hormonal contraceptive users. Future research will evaluate the psychometric validity and responsiveness of the EVAPIL-R. Understanding of user-reported tolerability of contraceptive methods is critical for facilitating patient adherence and potentially reducing the number of unintended pregnancies. The EVAPIL-R may be used to facilitate "women-centered" research and contraceptive counseling and provision.

Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies.

OBJECTIVE: To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content). DESIGN: Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies. SETTING: Randomized, open-label, multicenter studies. PATIENT(S): Nulliparous and parous women. INTERVENTION(S): Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 µg/24 h (total content 52 mg). MAIN OUTCOME MEASURE(S): Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects. RESULT(S): The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 µg/24 h after 24 days, declining progressively to 5 µg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 µg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 µg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups. CONCLUSION(S): Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in alower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 µg/24 h.

Two low-dose levonorgestrel intrauterine contraceptive systems: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of two low-dose levonorgestrel intrauterine contraceptive systems. METHODS: Nulliparous and parous women aged 18-35 years with regular menstrual cycles (21-35 days) requesting contraception were randomized to 3 years of treatment with one of two levonorgestrel intrauterine contraceptive systems: 13.5 mg total content or 19.5 mg total content. The primary outcome was the pregnancy rate, calculated as the Pearl Index. RESULTS: Overall, 1,432 and 1,452 women in the 13.5 mg intrauterine contraceptive system and 19.5 mg intrauterine contraceptive system groups, respectively, had a placement attempted and were included in the full analysis set to evaluate efficacy and safety. Mean (standard deviation) age was 27.1 (4.8) years; 39.2% were nulliparous. Over the 3-year study period, 0.33 pregnancies per 100 women-years (95% confidence interval [CI] 0.16-0.60) were observed with the 13.5 mg intrauterine contraceptive system compared with 0.31 per 100 women-years (95% CI 0.15-0.57) with the 19.5 mg intrauterine contraceptive system. Kaplan-Meier estimates for that period were 0.009 and 0.010, respectively. At least partial expulsions occurred in 4.56% and 3.58% and discontinuation rates resulting from a reported adverse event occurred in 21.9% and 19.1%, respectively. Ten of the 20 pregnancies were ectopic. Serious adverse events included six cases of pelvic inflammatory disease and one partial uterine perforation. CONCLUSIONS: Both lower-dose levonorgestrel intrauterine contraceptive systems were highly effective for 3 years of use and generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00528112. LEVEL OF EVIDENCE: : I.

Safety and efficacy of a single-rod etonogestrel implant (Implanon): results from 11 international clinical trials.

OBJECTIVE: To present efficacy, safety, and bleeding profile results from the clinical trials that supported the U.S. Food and Drug Administration filing for the approval of a single-rod etonogestrel (ENG) contraceptive implant (Implanon). DESIGN: Integrated analysis of 11 international clinical trials. SETTING: Contraceptive clinics in U.S., Chile, Asia, and Europe. PATIENT(S): A total of 942 healthy women, aged 18 to 40 years. INTERVENTION(S): Insertion of an ENG implant. Most women were enrolled in studies lasting either 2 or 3 years. MAIN OUTCOMES MEASURE(S): Efficacy was measured by the cumulative Pearl Index in women