Emergency contraception for individuals weighing 80kg or greater: a randomized trial of 30 mg ulipristal acetate and 1.5 mg or 3.0 mg levonorgestrel.

OBJECTIVE: To compare the efficacy of oral emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing >80 kg. STUDY DESIGN: We enrolled healthy women aged 18-40 years with a weight of at least 80 kg requesting EC in a multi-center, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, unprotected intercourse within 72 hours of enrollment, no use of hormonal contraception since last menstrual period, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. Study staff directly observed EC ingestion. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in person visit with quantitative serum human chorionic gonadotropin (hCG) and ultrasound. RESULTS: We enrolled and randomized 532; 44 were not dosed or not evaluable for primary end-point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups [mean age 29.6 years (5.74), BMI 37.09 kg/m2 (6.95)]. Five pregnancies occurred during the study (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window relative to estimated day of ovulation (day of ovulation and the 3 days prior). We closed the study prior to achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis. CONCLUSION: Although slow enrollment limited our study power, we found no differences in pregnancy rates between oral EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the three treatment arms. IMPLICATIONS: Women weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist.

Safety testing of Ovaprene: An investigational nonhormonal monthly vaginal contraceptive.

OBJECTIVES: Evaluate the safety of Ovaprene, an investigational nonhormonal vaginal contraceptive designed for monthly use. STUDY DESIGN: Open-label, multicenter study enrolling heterosexually-active women with previous permanent contraception who underwent assessments during five menstrual cycles: baseline postcoital test cycle, diaphragm postcoital test cycle, Ovaprene safety cycle, and two Ovaprene postcoital test cycles. Safety outcomes included treatment-emergent adverse events, systemic laboratory findings, pelvic examinations, colposcopies, Nugent scores, determination of community state types of vaginal microbiota, and anti-Escherichia coli activity and inflammatory markers in cervicovaginal fluids. RESULTS: We enrolled 38 participants. Of these, 33 used Ovaprene and completed 77 Ovaprene cycles. The most common product-related urogenital treatment-emergent adverse events were bacterial vaginosis and vaginal odor. The frequency of transitioning from Lactobacillus-dominated community state type to community state type IV (not Lactobacillus-dominated) was similar before Ovaprene use and afterwards. Mean Nugent scores were <4 at each visit without a discernible upward trend. Inflammatory markers showed wide variation but no upward trend, and E. coli inhibitory activity of cervical secretions did not change. We found no Staphylococcus aureus, the causative agent in toxic shock syndrome, on used Ovaprenes or in vaginal samples. No clinically important changes in systemic laboratory findings, pelvic examinations, or colposcopies occurred during Ovaprene use. CONCLUSIONS: Ovaprene use did not result in cervicovaginal irritation or adverse effects on resident vaginal microbiota and did not impact transitions from a Lactobacillus-dominated community state type to community state type IV. IMPLICATIONS: The finding that the use of Ovaprene, an investigational monthly user-controlled nonhormonal vaginal contraceptive, does not appear to result in adverse changes in vaginal health during short-term use supports further evaluation of the contraceptive potential of the device.

Successful postcoital testing of Ovaprene: An investigational non-hormonal monthly vaginal contraceptive.

OBJECTIVE: Evaluate reduction in progressively motile sperm per high power field (HPF) in midcycle cervical mucus after intercourse with Ovaprene: an investigational monthly non-hormonal vaginal contraceptive consisting of a vaginal ring and mechanical barrier, releasing spermiostatic ferrous gluconate. STUDY DESIGN: Open-label, multicenter study enrolling heterosexually-active women with previous permanent contraception. Participants underwent a baseline postcoital test cycle with no device to confirm the presence of sperm, followed by one diaphragm postcoital test cycle, one Ovaprene safety cycle, and two Ovaprene postcoital test cycles. In each postcoital test cycle, participants underwent a midcycle cervical mucus evaluation to confirm an Insler score ≥10 and absence of sperm, and then returned two to four hours after vaginal intercourse for repeat cervical mucus evaluation. We considered <5 progressively motile sperm/HPF indicative of preliminary contraceptive effectiveness. RESULTS: We enrolled 38 participants; 23 completed the study. All participants had ≥5 progressively motile sperm/HPF in the baseline cycle and <5 progressively motile sperm/HPF in all 49 Ovaprene cycles and all 35 diaphragm cycles, meeting the definition of a successful postcoital test. This was true regardless of examiner blinding, prior vaginal delivery or vaginal ring use, body mass index, or dislodgements noted by the participant or investigator. The mean of 27.2 (±17.9) progressively motile sperm/HPF in baseline postcoital test cycles was reduced to 0.5 (±1.1) and 0.5 (±1.3) progressively motile sperm/HPF in the first and second Ovaprene cycles, respectively. Ovaprene fit all participants and all could insert, position, and remove it. CONCLUSION: Use of Ovaprene resulted in meeting the prespecified criterion for contraceptive effect by all participants during all postcoital test cycles. IMPLICATIONS: The finding that use of Ovaprene, an investigational monthly non-hormonal vaginal contraceptive, resulted in postcoital testing of cervical mucus that met the pre-specified definition of success (<5 progressively motile sperm/HPF) supports further evaluation of contraceptive efficacy of the device in users at risk for pregnancy.

Changes in hair cortisol concentration in intrauterine device initiators: A prospective cohort study.

OBJECTIVES: Prior studies found increased hair cortisol concentration (a surrogate marker for hypothalamic-pituitary-adrenal axis activation) in users of the levonorgestrel intrauterine device (LNG 52 mg IUD). We evaluated change in hair cortisol and psychometric tests in women initiating a copper (CuT380 IUD) or LNG 52 mg IUD. STUDY DESIGN: We prospectively enrolled healthy women initiating an LNG 52 mg IUD or CuT380 IUD. Participants provided hair and blood samples and completed psychometric inventories (Patient Health Questionnaire-9, Positive and Negative Affect Schedule, and Psychological General Well-Being Index) after IUD insertion and at 6 and 12 months. We used liquid chromatography with tandem mass spectrometry to measure hair cortisol concentrations. We compared hair cortisol concentrations and psychometric test changes from baseline to 6 and 12 months using independent two-sample t tests. RESULTS: We enrolled 39 of our targeted 86 participants (LNG 52 mg IUD 26, CuT380 IUD 13). Thirty-eight subjects (LNG 52 mg IUD 25, CuT380 IUD 13) completed 6 months of follow-up. We found no difference between cohorts in the mean change in hair cortisol concentrations at 6 months (LNG 52 mg IUD n = 21 [-0.01 pg/mg (95% CI -1.26, 1.23); CuT380 IUD n = 13 [-1.31 pg/mg (-3.36, 0.73)]). While psychometric inventory results remained within normal ranges, LNG 52 mg IUD users reported a trend toward more favorable changes over time. CONCLUSIONS: We did not find clinically important differences in hair cortisol concentrations following initiation of a CuT380 IUD or LNG 52 mg IUD; psychometric inventories demonstrated no adverse effect of hormonal IUDs on mood. IMPLICATIONS: Our findings of similar hair cortisol concentrations following the initiation of either the LNG 52 mg IUD or CuT380 IUD suggest that hormonal IUDs do not increase cortisol concentrations or alter stress reactivity, and favorable effects on psychometric inventories provide further reassurance that the LNG 52 mg IUD has no adverse impact on mood. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03499379.

Development and validation of an expanded panel of progestins using liquid chromatography-tandem triple quadrupole mass spectrometry to monitor protocol compliance in hormonal contraceptive pharmacokinetic/pharmacodynamic studies.

We developed and validated the use of ultra-high-performance liquid chromatography-heated electrospray ionization-tandem triple quadrupole mass spectrometry to simultaneously analyze serum concentrations of ethinylestradiol, dienogest, norelgestromin, norethindrone, gestodene, levonorgestrel, etonogestrel, segesterone acetate, medroxyprogesterone acetate, and drospirenone. The calibration range for all targets was 0.009-10 ng/mL, with lower limit of quantification of 0.009 ng/mL for all analytes except gestodene (0.019 ng/mL). We used our assay to check compliance among participants in a clinical trial, confirmed the use of drospirenone in 11 of 13 study participants, and evidence of noncompliant progestins in 2 (levonorgestrel = 1, norethindrone = 1). We conclude that this approach provides an accurate method to check protocol compliance in contraceptive clinical trials. IMPLICATIONS: The availability of a liquid chromatography-tandem triple quadrupole mass spectrometry multiprogestin analysis panel for simultaneous evaluation of the most common contraceptive steroids approved worldwide could improve monitoring of compliance and protocol adherence in clinical trials.

Satisfaction with a Segesterone Acetate and Ethinyl Estradiol Contraceptive Vaginal System Among Recent Oral Contraceptive or Hormonal Contraceptive Vaginal Ring Users.

Background: We evaluated satisfaction with use of a segesterone acetate and ethinyl estradiol (0.15/0.013 mg) contraceptive vaginal system (CVS) among women who had recently used a monthly contraceptive vaginal ring or contraceptive pills. The CVS is a ring-shaped device used in a 21-days-in/7-days-out regimen for 13 cycles. Materials and Methods: We analyzed post hoc satisfaction responses at cycle 3 and end of study (EOS) from a subset of participants with documented recent use of the monthly ring or daily pills before enrollment in a multinational, phase 3, 13-cycle trial evaluating the CVS. EOS included results from participants who had completed ≥10 cycles. Results were summarized descriptively. Results: We identified 128 recent ring and 219 recent pill users at cycle 3 (of 1033 survey participants), and 92 and 148, respectively, at EOS (of 622 survey participants); overall satisfaction with CVS use was high (≥90%). At EOS, most ring (89%) and pill (97%) users liked the CVS as much/better than any previous method. The two most-liked CVS features included ease of use and 1-year duration; the two most disliked features included ring insertion and feeling it coming out. At EOS, ≥88% of both groups reported no concern about using the same CVS for a year, and most (>80%) had recommended it to friends or family members. Conclusion: The CVS clinical trial participants who were recent ring/pill users reported high satisfaction and liked it as much/better than any previously used contraceptive; the CVS may be a good contraceptive option for switchers. Clinical trial registration NCT00263341.

Heavy Menstrual Bleeding Treatment With a Levonorgestrel 52-mg Intrauterine Device.

OBJECTIVE: To evaluate heavy menstrual bleeding treatment outcomes with levonorgestrel 52-mg intrauterine device (IUD) use in participants without body mass index (BMI) or parity restrictions. METHODS: Investigators included participants aged 18-50 years with no pelvic or systemic pathology causing heavy menstrual bleeding at 29 U.S. centers in a prospective trial. Participants had up to three screening cycles with menstrual product collection for alkaline hematin blood-loss measurements. Investigators enrolled those with two menses with blood loss of 80 mL or more (values averaged for baseline blood loss), placed the IUD, and followed participants for up to six 28-day cycles. Participants collected any menstrual products used during cycles 3 and 6 for blood-loss measurement. We evaluated outcomes in participants with at least one follow-up assessment for the primary outcome of median absolute blood-loss change and, secondarily, treatment success , defined as the proportion with a final measured blood loss less than 80 mL and at least 50% reduction from baseline. We evaluated exploratory outcomes of differences in blood-loss changes by BMI and parity using Wilcoxon rank sum test. RESULTS: Of 105 enrolled participants, 47 (44.8%) had obesity (BMI 30.0 or higher) and 29 (27.6%) were nulliparous. Baseline mean blood loss ranged from 73 to 520 mL (median 143 mL, interquartile range 112-196 mL). Eighty-nine (84.8%) had at least one evaluable follow-up evaluation. Participants had median (interquartile range) absolute blood-loss decreases at cycles 3 (n=86) and 6 (n=81) of 93.3% (86.1-97.7%) and 97.6% (90.4-100%), respectively. At cycle 6, participants without obesity (n=43) and with obesity (n=38) had similar median [interquartile range] decreases (97.6% [91.8-100%] and 97.5% [90.3-100%], respectively; P =.89), with comparable findings for nulliparous (n=25) and parous (n=56) participants (97.0% [91.7-99.1%] and 98.1% [89.9-100%], respectively; P =.43). Treatment success occurred in 81.8% (95% CI 74.2-89.4%) of 99 participants, excluding those with no outcomes due to lost to follow-up or consent withdrawal, and did not vary by BMI or parity. The most common adverse events leading to discontinuation were bleeding or cramping (n=6 [5.7%]) and expulsion (n=5 [4.8%]). CONCLUSION: This levonorgestrel 52-mg IUD reduces blood loss by more than 90% over 6 months compared with baseline for most users with heavy menstrual bleeding. FUNDING SOURCE: Medicines360. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03642210.

Combined Oral Contraceptive Adherence and Pregnancy Rates.

OBJECTIVE: To assess the relationship of adherence and pregnancy in participants using an estetrol and drospirenone combined oral contraceptive. METHODS: We performed a secondary analysis for which we pooled data from two parallel, multicenter, phase 3 trials (United States and Canada, Europe and Russia) that enrolled participants 16-50 years of age to receive estetrol 15 mg and drospirenone 3 mg in a 24 hormone and four placebo pills regimen for up to 13 cycles. Participants reported pill intake, sexual intercourse, and other contraceptive use on paper diaries. We limited this efficacy analysis to at-risk cycles (one or more reported acts of intercourse and no other contraceptive use) in participants 16-35 years of age at screening. We excluded cycles with other contraceptive use unless pregnancy occurred in that cycle. We assessed primarily the relationship between number of pills not taken per cycle and pregnancies and, secondarily, when pregnancies occurred during product use with a test for trend and χ 2 analyses as appropriate. RESULTS: Among 2,837 participants in this analysis, 31 on-treatment pregnancies occurred during 26,455 at-risk cycles. Pregnancies occurred in 0.09%, 0.25%, 0.83%, and 1.6% of cycles in which participants reported they took all hormone pills (n=25,613 cycles) or did not take one (n=405 cycles), two (n=121 cycles), and more than two (n=314 cycles) hormone-containing pills, respectively ( P <.001). No pregnancies occurred in 2,216 cycles when one or more pills were missed and missed-pill instructions were followed. All pregnancies related to not taking pills occurred in the first three cycles. Pregnancy rates ranged from 0% to 0.21% per cycle with no significant trend by cycle ( P =.45). CONCLUSION: Pregnancy occurs more frequently when combined oral contraceptive users report not taking all hormone-containing pills per 28-day cycle and exceeds 1% only when more than two pills are not taken. Pregnancies in participants who reported missed pills occurred only when missed-pill instructions were not followed. A 0.09% pregnancy risk per cycle among users of a 24 hormone and four placebo pills formulation who report taking all pills likely approximates a true method-failure rate. FUNDING SOURCE: Estetra SRL, an affiliate company of Mithra Pharmaceuticals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02817828 and NCT02817841.

Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin.

BACKGROUND: Some users of the etonogestrel contraceptive implant experience bothersome bleeding, which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown, but it is likely multifactorial (eg, impaired angiogenesis, "leaky" fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, antiproliferative, and antiangiogenic properties, which may make it a useful agent for implant-associated bothersome bleeding. OBJECTIVE: This study aimed to evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users. STUDY DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Here, etonogestrel implant users with frequent or prolonged bleeding or spotting were enrolled and randomized to either 600-mg Theracurmin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. The term "frequent" was defined as ≥2 independent bleeding or spotting episodes, and the term "prolonged" was defined as ≥7 consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical examination and negative gonorrhea and chlamydia and pregnancy tests. Enrolled participants initiated study treatment after 3 consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30 days of enrollment, the participants were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. Bleeding was defined as a day that required the use of protection with a pad, tampon, or liner, and spotting was defined as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. The secondary outcomes included total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha level of .05 to demonstrate a 6-day difference between groups. RESULTS: From February 2021 to November 2022, 58 individuals enrolled in the study with 54 participants (93%) completing 30 days of treatment (26 in the curcumin group and 28 in the placebo group). Of note, 1 individual in the curcumin arm did not experience a qualifying bleeding event and, thus, never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups, including length of implant use at study enrollment (placebo, 521±305 days; curcumin, 419±264 days). The study groups did not differ concerning any bleeding-related outcome (mean days without bleeding or spotting: curcumin, 16.7±6.9; placebo, 17.5±4.8; P=.62; mean bleeding-free days: curcumin, 23.4±4.9; placebo, 22.4±4.5; P=.44; bleeding episodes: curcumin, 2.0±0.8; placebo, 2.1±0.8; P=.63). In addition, satisfaction with the implant as contraception and acceptability of bleeding over the study period did not differ by study group (P=.54 and P=.30, respectively). CONCLUSION: Daily use of curcumin did not improve bleeding patterns in users of the etonogestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.

Hormonal regulation of non-cystic fibrosis transmembrane conductance regulator ion channels in the endocervix.

OBJECTIVE: To characterize ion channel expression and localization in the endocervix under different hormonal conditions using a nonhuman primate primary endocervical epithelial cell model. DESIGN: Experimental. SETTING: University-based, translational science laboratory. INTERVENTIONS: We cultured and treated conditionally reprogrammed primary rhesus macaque endocervix cells with estradiol and progesterone and measured gene expression changes for several known ion channel and ion channel regulators of mucus secreting epithelia. Using both rhesus macaque endocervical samples and human samples, we localized channels in the endocervix using immunohistochemistry. MAIN OUTCOME MEASURES: The relative abundance of transcripts was evaluated using real-time polymerase chain reaction. Immunostaining results were evaluated qualitatively. RESULTS: Compared with controls, we found that estradiol increased gene expression for ANO6, NKCC1, CLCA1, and PDE4D. Progesterone down-regulated gene expression for ANO6, SCNN1A, SCNN1B, NKCC1, and PDE4D (P≤.05). Immunohistochemistry confirmed endocervical cell membrane localization of ANO1, ANO6, KCNN4, LRR8CA, and NKCC1. CONCLUSIONS: We found several ion channels and ion channel regulators that are hormonally sensitive in the endocervix. These channels, therefore, may play a role in the cyclic fertility changes in the endocervix and could be further investigated as targets for future fertility and contraceptive studies.

Efficacy of Tubal Surgery for Permanent Contraception: Considerations for the Clinician.

Permanent contraception meets the needs of many people certain in their decision to never become pregnant in the future. Female permanent contraception procedures became more common than male procedures during the 1970s and 1980s, when laparoscopic surgery became widely available. To better understand the efficacy of these new procedures, the US Centers for Disease Control and Prevention conducted a prospective cohort study, known as the Collaborative Review of Sterilization (CREST). For decades, results of this study have defined perioperative counseling around failure risks of such surgeries. However, laparoscopic technology and techniques have changed significantly in recent decades and evidence has emerged supporting noncontraceptive benefits of tubal excision. Therefore, we present here a review of updated information regarding permanent contraception failure in the modern context and implications for clinical practice and future research directions.

Extended use of levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg: A population pharmacokinetic approach to estimate in vivo levonorgestrel release rates and systemic exposure including comparison with two other LNG-IUSs.

OBJECTIVE: To characterize performance of levonorgestrel-releasing intrauterine system (LNG-IUS) 52mg (Mirena) over 8 years of use and facilitate comparisons with LNG-IUS 19.5mg and LNG-IUS 13.5mg. STUDY DESIGN: We estimated in vivo levonorgestrel (LNG) release rates and LNG plasma/serum concentrations for LNG-IUS 52mg up to 8 years of use with a population pharmacokinetic (popPK) approach using data from the Mirena Extension Trial (MET) and earlier clinical trials. We compared these with previously published release rates and exposure data for LNG-IUS 19.5mg and 13.5mg. Our 8-year popPK and release models were developed based on measured plasma/serum LNG and sex hormone-binding globulin concentrations and residual LNG content from removed LNG-IUS 52mg devices. RESULTS: Model-based estimated LNG release rates for LNG-IUS 52mg decreased from ∼21 µg/d after insertion to ∼7.0 µg/d after 8 years, similar to LNG-IUS 19.5mg after 5 years (7.6 µg/d) and higher than LNG-IUS 13.5mg after 3 years (5.5 µg/d). Model-based estimated and measured plasma/serum LNG concentrations showed satisfactory agreement. Average model-based estimated LNG concentrations after 8 years of LNG-IUS 52mg use (100 ng/L [coefficient of variance 39.9%]) were similar to LNG-IUS 19.5mg after 5 years (84.8 ng/L [39.9%]) and higher than LNG-IUS 13.5mg after 3 years (58.1 ng/L [40.8%]). CONCLUSIONS: The 8-year release and popPK models provide reliable in vivo LNG release rates and concentration estimates, respectively, facilitating direct comparisons between the 3 studied LNG-IUSs. LNG release rates from LNG-IUS 52mg at 8 years are similar to LNG-IUS 19.5mg at 5 years and higher than LNG-IUS 13.5mg at 3 years. IMPLICATIONS: Levonorgestrel release from intrauterine system reservoirs declines with duration of use in a predictable way, and in relation to the initial load. As release rates and plasma concentrations of levonorgestrel may influence endometrial and systemic side effects, these data may assist clinical decision-making.

Systemic polidocanol from intravenous or pressurized intrauterine administration produces reversible cardiovascular toxicity.

Objective: Fatal allergic responses and cardiac arrhythmias have been reported with the intravenous (IV) administration of polidocanol. We sought to identify the physiologic mechanism of systemic cardiovascular response after transcervical (TC) and IV administration of polidocanol. Methods: We continuously monitored blood pressure (BP) and heart rate using an arterial line during IV and intraperitoneal (IP) administration of polidocanol solution (PS) and polidocanol doxycycline solution in female rats and TC and IP administration of polidocanol foam (PF) and PDF (TC only) in female baboons. We performed TC procedures using a catheter with (pressurized) and without (nonpressurized) balloon inflation. Baboons also underwent monitoring during IV PS administration with and without pretreatment with antihistamines. We performed cardiac echo and electrocardiograms during selected experiments. We defined a refractory hypotension as a sustained decrease of more than 30% from baseline that prevented delivery of the target dose. Results: We found a dose-related increase in the proportion of baboons that developed refractory hypotension during TC administration of 5% PDF and PF, an effect confined to pressurized administration. The infusion of 0.5% PS in rats induced a rapid and dramatic refractory hypotension. The inclusion of doxycycline did not improve or deteriorate these outcomes, and doxycycline solution or saline (control) alone did not affect BP. All five female baboons that received up to 20 mL of 1% PS (200 mg) developed refractory hypotension. Pretreatment with diphenhydramine, ranitidine, or both did not block the refractory hypotension induced by IV administration of 1% PS (100 mg). In contrast, only one of the six female baboons treated with IP PF 400 mg developed a decrease of more than 30% in BP, and this response was not sustained. Cardiac echocardiography done in four baboons during TC treatment demonstrated a decrease in cardiac output as the physiologic mechanism of hypotension. We did not observe important changes on the electrocardiograms. Conclusions: Adverse cardiovascular effects of polidocanol treatment occur owing to a direct myocardial effect of polidocanol and not as a result of a hypersensitivity reaction. Pressurized TC administration of PF results in refractory hypotension owing to endometrial vascular uptake of polidocanol and not as a result of uptake from peritoneal surfaces.

Tolerability and safety of the estetrol/drospirenone combined oral contraceptive: Pooled analysis of two multicenter, open-label phase 3 trials.

OBJECTIVES: To evaluate tolerability and safety of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg oral contraceptive using pooled data from two, multicenter, phase 3 trials. STUDY DESIGN: The two trials enrolled participants aged 16-50 years with a body mass index ≤35.0 kg/m2 to use E4/DRSP in a 24/4-day regimen for up to 13 cycles. We pooled data from participants who used at least one E4/DRSP dose and had a follow-up assessment to analyze adverse events (AEs), vital signs, and laboratory parameters, including serum lipids, glucose, glycated hemoglobin, and potassium. We consolidated similar Medical Dictionary for Regulatory Activities preferred terms into groupings. RESULTS: Of 3725 participants enrolled, we included 3417 in the analyses of whom 1786 (52.3%) reported ≥1 AE. Most participants with reported AEs had AEs that investigators rated as mild or moderate (n = 1665, 93.2%); of participants reporting AEs, 1105 (61.9%) did so during cycles 1 to 3. In total, 981 (28.7%) participants experienced ≥1 treatment-related AE, most frequently related to bleeding complaints (n = 323, 9.5%), breast pain or tenderness (n = 136, 4.0%), acne (n = 113, 3.3%), and mood disturbance (n = 111, 3.2%). Discontinuation due to treatment-related AEs occurred in 272 participants (8.0%), with only bleeding complaints (n = 97, 2.8%) and mood disturbance (n = 38, 1.1%) at rates exceeding 1%. Three participants experienced serious AEs, which the site investigators considered treatment-related: one venous thromboembolism, one worsening of depression, and one ectopic pregnancy. We found no clinically relevant changes in weight, blood pressure, heart rate, or laboratory parameters during treatment. CONCLUSIONS: E4/DRSP is associated with a favorable tolerability and safety profile. IMPLICATIONS STATEMENT: Pooling data allowed for a robust assessment of tolerability and safety, including relatively infrequent events. Other than bleeding complaints and mood disturbance, no adverse event resulted in E4/DRSP discontinuation at rates >1%. Post-marketing surveillance studies are needed to evaluate long-term safety of the E4/DRSP COC and population-based venous thromboembolism risks.

Contraceptive efficacy and safety of the 52-mg levonorgestrel intrauterine system for up to 8 years: findings from the Mirena Extension Trial.

BACKGROUND: The 52-mg levonorgestrel-releasing intrauterine system is an established, long-acting contraceptive option with approved use for up to 7 years. OBJECTIVE: The Mirena Extension Trial evaluated the efficacy and safety of the 52-mg levonorgestrel-releasing intrauterine system during extended use beyond 5 and up to 8 years. STUDY DESIGN: This was a multicenter, single-arm study in the United States, enrolling existing users of the 52-mg levonorgestrel-releasing intrauterine system, aged 18 to 35 years, who have had the system for 4.5 to 5 years. We assessed the contraceptive efficacy (Pearl Index) and cumulative failure rate (using the Kaplan-Meier method) of the 52-mg levonorgestrel-releasing intrauterine system during extended use. We also evaluated bleeding outcomes and adverse events. RESULTS: Of the 362 participants starting year 6, 243 entered and 223 completed 8 years of 52-mg levonorgestrel-releasing intrauterine system use. Just more than half the participants were parous. The mean (standard deviation) age was 29.2 (±2.9) years, and all participants were aged ≤36 years at the end of year 8. Two pregnancies occurred, both with the device in situ. The year 6 pregnancy was of undetermined location and resolved spontaneously. The pregnancy in year 7 was ectopic and resolved with methotrexate treatment. In both cases, the 52-mg levonorgestrel-releasing intrauterine system was removed and the participants left the trial. For years 6 to 8, the 3-year Pearl Index (95% confidence interval) was 0.28 (0.03-1.00) with a 3-year cumulative failure rate of 0.68% (0.17-2.71). Pearl Indexes for years 6, 7, and 8 were 0.34 (0.01-1.88), 0.40 (0.01-2.25), and 0.00 (0.00-1.90), respectively. The 3-year (years 6-8) ectopic pregnancy Pearl Index was 0.14 (0.00-0.77). We found treatment-emergent adverse events in 249 of 362 participants (68.8%), with 65 (18.0%) events considered to be related to the 52-mg levonorgestrel-releasing intrauterine system. The discontinuation rate was 38.4% (139/362), most commonly because of desire for pregnancy (12.2%, 44/362). During extended use beyond 5 years and up to 8 years, participants reported a decrease in the mean number of bleeding or spotting days with approximately half of the women experiencing amenorrhea or infrequent bleeding. We did not enroll a sufficient number of women using the 52-mg levonorgestrel-releasing intrauterine system for contraception and heavy menstrual bleeding to assess extended use for that indication. At the end of year 8, most (98.7%, 220/223) of the participants who completed the study remained satisfied with the continued use of the 52-mg levonorgestrel-releasing intrauterine system. Of the 31 women who discontinued early because of desire for pregnancy with evaluable data for return-to-fertility analysis, 24 reported a posttreatment pregnancy within 1 year, giving a 12-month return-to-fertility rate of 77.4%. CONCLUSION: The 52-mg levonorgestrel-releasing intrauterine system, initially approved for 5 years, maintains high contraceptive efficacy, user satisfaction, and a favorable safety profile through 8 years of use. Participants reported 26 posttreatment pregnancies in total, of which 24 occurred in women who had discontinued the 52-mg levonorgestrel-releasing intrauterine system because of a desire for pregnancy. Of note, among women who elected to continue use through 8 years, bleeding patterns remained highly favorable. These findings support continued 52-mg levonorgestrel-releasing intrauterine system use for up to 8 years in women who wish to continue treatment.

Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials.

OBJECTIVE: To evaluate overall and subgroup efficacy of an estetrol (E4) 15 mg drospirenone (DRSP) 3 mg oral contraceptive in a 24/4-day regimen. STUDY DESIGN: We pooled efficacy outcomes from 2 pivotal phase 3 contraceptive trials with E4/DRSP conducted in the United States/Canada and Europe/Russia. We assessed Pearl Index (PI; pregnancies per 100 participant-years) and 13-cycle life-table pregnancy rates in at-risk cycles (confirmed intercourse and no other contraceptive use) among participants 16 to 35 years. We calculated PI by age and further subcategorization (contraceptive history and body mass index [BMI]). We performed multivariable analysis using Cox regression to assess impact of potential confounding factors. RESULTS: Analyses included 3027 participants, of whom 451 (14.9%) had a BMI ≥30 kg/m2. The pooled PI was 1.52 (95% confidence interval 1.04-2.16) and the 13-cycle life-table pregnancy rate was 1.28% (0.83%-1.73%). We calculated unadjusted pooled PI in participants 16 to 25 years and 26 to 35 years of 1.61 (0.94-2.57) and 1.43 (0.78-2.40), respectively; in new starters and switchers of 1.88 (1.09-3.00) and 1.24 (0.68-2.08), respectively; and by BMI <25 kg/m2, 25 to 29.9 kg/m2, and ≥30 kg/m2 of 1.14 (0.64-1.88), 2.19 (1.05-4.03), and 2.27 (0.83-4.94), respectively. In multivariable analysis, we found associations of prior pregnancy (hazard ratio [HR] 3.61[1.56-8.38]), Black race (HR 4.61[1.97-10.80]), age 16 to 25 years (HR 2.37[1.09-5.15]) and compliance <99% of expected pills (HR 4.21[2.04-8.66]) with conception. CONCLUSION: E4/DRSP is an effective oral contraceptive overall and across subgroups stratified by age, contraceptive history, and BMI. Other than compliance, predictors of contraceptive failure are nonmodifiable. IMPLICATIONS STATEMENT: Pooled results from two phase 3 trials demonstrate high contraceptive efficacy of the novel estetrol-drospirenone oral contraceptive. Several non-modifiable risk factors, including prior pregnancy, race, and age, are associated with higher pregnancy risk. Additional research is needed to better understand predictors of combined oral contraceptive failure.

Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women.

OBJECTIVE: To evaluate the bleeding patterns of a new combined oral contraceptive containing estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in a 24/4-day regimen. STUDY DESIGN: We pooled bleeding data from two parallel, open-label, 13-cycle phase 3 trials that enrolled participants 16 to 50 years old with body mass index (BMI) ≤35 kg/m2. Participants reported vaginal bleeding/spotting in daily diaries. For this bleeding analysis, we included participants with at least one evaluable cycle. We calculated mean frequencies of scheduled and unscheduled bleeding/spotting episodes and median duration of bleeding/spotting episodes, and assessed associations between treatment compliance, BMI and recent hormonal contraceptive use on bleeding/spotting outcomes. RESULTS: We included 3409 participants with 33,815 cycles. Scheduled bleeding/spotting occurred in 87.2% to 90.4% of participants/cycle, with a median duration of 4 to 5 days. Unscheduled bleeding/spotting decreased from 27.1% in Cycle 1 to 20.6% in Cycle 2 to ≤17.5% from Cycle 5 onwards. Most (66.5%) unscheduled bleeding/spotting episodes were spotting-only. Between 5.8% and 7.8% of users/cycle experienced absence of any scheduled or unscheduled bleeding/spotting. Missing one or more active pills resulted in a higher occurrence of unscheduled bleeding/spotting (adjusted odds ratio [aOR] 2.13 [95% confidence interval 1.68-2.70]) and absence of scheduled bleeding/spotting (aOR 2.36 [1.82-3.07]). Participants with a BMI ≥30 kg/m2 reported more absence of scheduled bleeding/spotting (aOR 1.68 [1.37-2.05]). Switchers and starters reported similar frequencies of unscheduled bleeding/spotting (aOR 0.94 [0.83-1.07]) and absence of scheduled bleeding/spotting (aOR 1.00 [0.85-1.19]). Three percent of participants discontinued for a bleeding-related adverse event. CONCLUSION: E4/DRSP use results in a predictable bleeding pattern with limited unscheduled bleeding/spotting. Noncompliance and BMI affect bleeding patterns. IMPLICATIONS STATEMENT: Most estetrol/drospirenone users experience a predictable and regular bleeding pattern. Providers can educate patients about the expected bleeding patterns and should advise users that they may infrequently experience no scheduled bleeding/spotting. This information may improve user acceptability and continuation of this new oral contraceptive.

Continuation rates of two different-sized copper intrauterine devices among nulliparous women: Interim 12-month results of a single-blind, randomised, multicentre trial.

Background: The most widely used copper intrauterine device (IUD) in the world (the TCu380A), and the only product available in many countries, causes side effects and early removals for many users. These problems are exacerbated in nulliparous women, who have smaller uterine cavities compared to parous women. We compared first-year continuation rates and reasons/probabilities for early removal of the TCu380A versus a smaller Belgian copper IUD among nulliparous users. Methods: This 12-month interim report is derived from a pre-planned interim analysis of a sub population and focused on key secondary comparative endpoints. In this participant-blinded trial at 16 centres in the USA, we randomised participants aged 17-40 in a 4:1 ratio to the NT380-Mini or the TCu380A. In the first year, participants had follow-up visits at 6-weeks and 3, 6, and 12-months, and a phone contact at 9 months; we documented continued use, expulsions, and reasons for removal. Among participants with successful IUD placement, we compared probabilities of IUD continuation and specific reasons for discontinuation using log-rank tests. This trial is registered with ClinicalTrials.gov number NCT03124160 and is closed to recruitment. Findings: Between June 1, 2017, and February 25, 2019, we assigned 927 nulliparous women to either the NT380-Mini (n = 744) or the TCu380A (n = 183); the analysis population was 732 (NT380-Mini) and 176 (TCu380A). Participants using the NT380-Mini, compared to the TCu380A, had higher 12-month continuation rates (78·7% [95% CI: 72·9-84·5%] vs. 70·2% [95% CI: 59·7-80·7], p = 0·014), lower rates of removal for bleeding and/or pain (8·1% vs. 16·2%, p = 0·003) and lower IUD expulsion rates (4·8% vs. 8·9%, p = 0·023), respectively. Interpretation: The NT380-Mini offers important benefits for a nulliparous population compared to the TCu380A in the first twelve months, when pivotal experiences typically occur. Higher continuation rates with the NT380-Mini may avert disruptions in contraceptive use and help users avoid unintended pregnancy. Funding: Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Mona Lisa, N.V. (Belgium).