Menstrual cup use and intrauterine device expulsion in a copper intrauterine device randomized trial.

OBJECTIVE: To evaluate menstrual cup use and intrauterine device (IUD) expulsion. STUDY DESIGN: We performed a secondary analysis of a 3-year contraceptive efficacy trial comparing two copper 380 mm2 IUDs. Investigators randomized participants approximately 1:4 to the TCu380A or NTCu380-Mini IUD. Approximately 12 months after enrollment began, we advised participants against menstrual cup use due to observed IUD expulsions in cup users. We evaluated IUD expulsion (including spontaneous partial and complete expulsion and accidental self-removal) at 12 and 36 months. We used multivariable logistic regression to evaluate IUD expulsion by age, baseline menstrual volume, body mass index, IUD type, menstrual cup use, parity, and uterine length. RESULTS: This analysis included 1046 participants (203 TCu380A and 843 NTCu380-Mini), with 879 (84.0%) nulliparas. Through 12 and 36 months, expulsion occurred in 74 (7.1%, 95% CI 5.5-8.6%) and 133 (12.7%, 95% CI 10.7-14.7%) participants, respectively. Overall, 250 (23.9%) reported menstrual cup use. More menstrual cup users than non-users experienced expulsion through 12 months (32/203 [15.8%] vs. 42/843 [5.0%]) and 36 months (58/250 [23.2%] vs. 75/796 [9.4%]). Through 36 months, NTCu380-Mini menstrual cup users had higher expulsion odds, while TCu380A cup users did not. Menstrual cup users more frequently experienced accidental self-removal than non-users in participants using the TCu380A (3/53 [5.7%] vs. 0/150 [0.0%]) and the NTCu380-Mini (20/197 [10.2%] vs. 7/646 [1.1%]). In multivariable regression, we found increased odds of expulsion through 36 months in participants using menstrual cups with the NTCu380-Mini (aOR 3.13, 95% CI 1.16-8.46) and <25 years (aOR 1.59, 95% CI 1.07-2.34). CONCLUSIONS: We found higher odds of IUD expulsion with menstrual cup and concurrent NTCu380-Mini IUD use over 36 months of use, but not with concurrent TCu380A IUD use. Menstrual cup users experienced higher likelihood of accidental self-removal regardless of IUD type. IMPLICATIONS: Menstrual cup and NTCu380-Mini use may increase IUD expulsion risk and may increase accidental self-removal risk with TCu380A and NTCu380-Mini use. Clinicians should advise patients of these risks and consider warning patients using an IUD shaped like the NTCu380-Mini (Nova-T frames) of expulsion risk with menstrual cup use.

Understanding the mechanical behavior of intrauterine devices during simulated removal.

OBJECTIVE: To evaluate differences based on intrauterine device (IUD) frame geometry in force, and stress, and strain at the stem/arms junction during simulated IUD removal. STUDY DESIGN: We manufactured injection-molded frame models for three Nova-T IUDs (Mirena [model M]; Liletta [model L]; Kyleena [model K]) and a Tatum-T IUD (Paragard [model P]) at two-times scaling. We created a custom fixture to simulate the uterus and used a screw-driven machine to pull models at various displacement rates through the 10 cm fixture cavity to measure force and strain and calculate stress at the IUD stem/arms junction. We tested models at 30 mm/min and higher displacement rates for exploratory analyses. We used Mann-Whitney U test for statistical testing. RESULTS: We completed testing at 30 mm/min using five of each Nova-T model and nine model P samples. Resistance against the cavity walls created significantly more force on model P (11.83, interquartile range [IQR] 11.61-12.31) than any Nova-T model samples (p < 0.001). The smaller model K created slightly more median stress (MPa) than the larger model M (0.36 [IQR 0.33-0.38] and 0.79 [IQR 0.76-0.80], respectively, p = 0.008); model P samples generated significantly more median stress than other models (1.70 [IQR 1.67-1.77], p < 0.001). Strain plots demonstrated permanent deformation for some samples during IUD removal simulation. We tested 20 samples at various higher displacement rates up to 2500 mm/min, with stress notably increasing for model P samples with increasing rates. No fractures occurred. CONCLUSIONS: Force and stress at the stem/arms junction are higher with Tatum-T-shaped compared to Nova-T-shaped IUD models under the same testing conditions, and a higher speed of extraction causes more stress. IMPLICATIONS: Sharp corners create vulnerability under static and fatigue loading in structural components due to increased local stresses. Our findings suggest that IUDs with Tatum-T frames should be removed slowly to minimize the stress at the stem/arms junction. Future studies can provide more information if performed with commercially available products.

The benefits of estetrol addition to drospirenone for contraception.

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

The efficacy, safety, and tolerability of an estrogen-free oral contraceptive drospirenone 4 mg (24/4-day regimen) in obese users.

OBJECTIVES: This study aimed to compare contraceptive efficacy and safety of drospirenone 4 mg in a 24/4-day regimen in nonobese and obese users and describe pharmacokinetics according to bodyweight. STUDY DESIGN: We analyzed data from three drospirenone 4 mg trials (2 European and 1 United States) to report outcomes in nonobese (body mass index <30 kg/m2) and obese (body mass index ≥30 kg/m2) users. We used data from the US trial to calculate the Pearl Index (pregnancies per 100 woman-years) in nonbreastfeeding participants aged ≤35 years at enrollment for confirmed pregnancies. We assessed safety outcomes from all trials based on reported treatment-emergent adverse events. We evaluated pharmacokinetics by bodyweight in the US trial. RESULTS: The three trials combined comprised 2152 nonobese and 425 obese participants, including 590 nonobese and 325 obese participants in the US trial. Eight nonobese and four obese participants had confirmed pregnancies in the US trial, resulting in Pearl Indices of 3.0 (95% CI: 1.3-5.8) and 2.9 (95% CI: 0.8-7.3), respectively. Two-hundred forty-four (11.3%) nonobese and 39 (9.2%) obese participants discontinued due to a treatment-emergent adverse event. The pharmacokinetic analysis included 814 participants with a median weight of 73 (interquartile range 61-89) kg and median plasma drospirenone exposure (AUC0-24ss) of 661.3 (interquartile range 522-828) ng∙h/mL. Changing bodyweight from the median to the fifth percentile (51 kg) or 95th percentile (118 kg) changed drospirenone exposure (AUC0-24,ss) by 22.2% and -23.6%, respectively. CONCLUSIONS: Drospirenone 4 mg demonstrated similar contraceptive efficacy for both nonobese and obese users despite a difference in exposure based on bodyweight. IMPLICATIONS: Our limited comparison between obese and nonobese users of drospirenone-only oral contraception demonstrated no evidence that efficacy or discontinuation for adverse events differs between groups. Serum drospirenone levels vary by bodyweight and may correlate with bleeding outcomes.

Early pregnancy loss medical management in clinical practice.

OBJECTIVES: This study aimed to review clinical practice outcomes of early pregnancy loss (EPL) medical management using mifepristone and misoprostol outside of a clinical trial setting. STUDY DESIGN: In this retrospective cohort study, we reviewed a deidentified database of patients who received mifepristone-misoprostol for EPL from May 2018 to May 2021 at our academic center-based clinic, which was a study site for a multicenter mifepristone-misoprostol EPL trial completed in March 2018. All patients received mifepristone 200 mg orally and misoprostol 800 mcg vaginally or buccally, with clinic follow-up typically scheduled within 1 week. The primary outcome was successful medical management, defined as management without the need for aspiration, and the secondary outcomes included additional interventions and indications, follow-up ultrasonography findings, and adverse events requiring treatment. RESULTS: We treated 90 patients with a median ultrasound-measured gestational size of 49 (range 30-80) days and median time from mifepristone to misoprostol of 24 (range 8-66) hours. Follow-up was completed in clinic by 80 (88.9%), completed remotely by five (5.6%), and not completed by five (5.6%) patients. Overall, 76 (95% CI 82.9%-96.0%) of 85 patients (89.4%) with follow-up were successfully managed without uterine aspiration. Eighty patients had initial follow-up ultrasonography interpreted as gestational sac expulsion; seven (8.8%) of these ultimately underwent aspiration, including one patient who had a previously undiagnosed cesarean scar ectopic pregnancy. Two patients had significant safety outcomes: one pelvic infection and one blood transfusion during aspiration in the patient with a cesarean scar ectopic pregnancy. CONCLUSIONS: Outside of a clinical trial setting, medical management of EPL with mifepristone and misoprostol remains effective and safe. IMPLICATIONS: Medical management of EPL with mifepristone and misoprostol is effective and safe outside of a clinical trial setting. A standardized protocol based on the best available clinical trial evidence can be used in clinical practice for the medical management of EPL.

Levonorgestrel 52-mg Intrauterine Device Efficacy and Safety After More Than 8 Years of Use.

FUNDING SOURCE: Medicines360. The Sponsor, Medicines360, designed the study and oversaw its conduct, including funding the trial and providing all study product free of charge to participants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00995150.

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.

Complex Family Planning fellowship graduates' intended practice plans and barriers to practicing in areas of unmet need.

OBJECTIVES: To describe practice patterns and challenges encountered by Complex Family Planning (CFP) fellowship graduates. STUDY DESIGN: We invited all 110 obstetrics and gynecology physicians who graduated from the CFP fellowship from 2017-2020 via email to complete an anonymous online survey. We inquired about demographics, intended and obtained postfellowship positions, and successes and challenges in obtaining jobs. We used Fisher's exact test to assess if the proportion of graduates who grew up, attended residency, and completed fellowship in a US region (Northeast, Midwest, South, and West) and practiced in that same region differed. RESULTS: Ninety-nine (90.0%) graduates completed the survey. When entering fellowship, most (n = 92 [92.9%]) expected to practice in an academic environment. About half (n = 49 [49.5%]) pursued fellowship with the intent to practice in a location with an unmet need for abortion providers, of which 22 (44.9%) did so. Forty-nine (49.5%) respondents did not practice after fellowship where they initially intended, citing common challenges of job availability, family-related concerns, safety concerns, and relationship status changes. We found associations between regions where graduates completed residency and currently practice (p = 0.004), driven primarily by higher associations in the South (76.9%) and West (70.6%) and a lower association in the Midwest (22.7%). We found no association between current practice region and where graduates grew up (p = 0.15) or completed fellowship (p = 0.23). CONCLUSIONS: CFP fellowship graduates from 2017-2020 primarily intended to practice in academic environments with half planning to practice in underserved locations. However, more than half of those who entered fellowship hoping to fill an unmet need for abortion providers did not do so. IMPLICATIONS: About half of CFP fellowship graduates from 2017-2020 intended to obtain positions in areas they defined as having an unmet need for abortion provision. Personal life and job barriers prevented many from serving in such positions after fellowship. Practice location intentions and outcomes may be different in a post-Dobbs environment.

Management of cesarean scar ectopic pregnancies at an academic referral center: A case series.

OBJECTIVES: To describe treatment and outcomes of patients with confirmed cesarean scar ectopic pregnancy (CSEP) at a tertiary referral center. STUDY DESIGN: We reviewed a deidentified family planning clinical database for patients seen by our subspecialty service for CSEP from January 2017 through December 2021 in this case series. We extracted referral information, final diagnosis, management, and outcome measures including estimated blood loss, secondary procedures, and treatment complications. RESULTS: Of 57 cases referred for suspected CSEPs, 23 (40%) had confirmed diagnoses; one additional case was diagnosed during clinic evaluation for early pregnancy loss. Most (n = 50 [88%]) referrals occurred in the last 2 years of the 5-year study period. Of 24 confirmed CSEP cases, eight were pregnancy losses at the time of diagnosis. Fourteen cases were ≤50 days gestation or gestational size (7 [50%] pregnancy losses) and 10 >50 days gestation (range 39-66 days). We treated all 14 patients ≤50 days primarily with suction aspiration under ultrasound guidance in an operating room with no complications and estimated blood loss of 14 ± 10 mL. Of the 10 patients>50 days (maximum 66 days), seven were managed with primary aspiration of which five were uncomplicated. We treated one patient (57 days) had primary intrauterine double-catheter balloon with immediate hemorrhage requiring uterine artery embolization followed by an uncomplicated suction aspiration. CONCLUSIONS: Patients with confirmed CSEPs at 50 days or less gestation or gestational size can likely be primarily treated with suction aspiration with low risk for significant adverse outcomes. Treatment success and complications are directly related to gestational age at treatment. IMPLICATIONS: Ultrasound-guided suction aspiration monotherapy should be considered for primary CSEP treatment up to 50 days and, with continued experience, may be reasonable beyond 50 days gestation. Invasive treatments or those that require multiple days and visits, such as methotrexate or balloon catheters, are not necessary for early CSEPs.

Texas Senate Bill 8 and Abortion Experiences in Patients With Fetal Diagnoses: A Qualitative Analysis.

OBJECTIVE: To describe experiences with abortion counseling and access in patients with lethal or life-limiting fetal diagnoses in Texas after enactment of Senate Bill 8 (SB8). METHODS: In this qualitative study, we interviewed patients who obtained abortions after enactment of SB8, using semi-structured interviews to explore how restrictions affected abortion care. Two researchers coded all transcripts using an inductive technique and analyzed themes in an iterative approach. RESULTS: We interviewed 16 participants who reported gestational durations from 13 to 29 weeks at the time of abortion. Participants described loss of the therapeutic patient-physician relationship and feelings of isolation while pursuing abortion due to the limitations imposed by SB8. For example, participants felt there was a physician "gag rule" regarding abortion ("the unspoken word of termination"), resulting in the need to find information about pregnancy options outside of the medical community and further highlighting the privilege of financial resources necessary to obtain an abortion on their own. Participants also expressed fears regarding confidentiality with their support systems and clinicians ("I would joke around and say, well don't sue me, but halfway mean it") and personal safety when self-referring for abortion ("…am I making the right choice on where I need to go? Is it safe?"). CONCLUSION: Abortion restrictions and bans such as SB8 erode the patient-physician relationship, evoking fear and safety concerns during a vulnerable time for those undergoing abortion for lethal or life-limiting fetal diagnoses. They force patients to shoulder the significant burden of understanding pregnancy options and navigating the process of abortion alone, which is likely to have greater effects on those with fewer resources.

Clinical interventions are more accurate than quantitative measurements for defining hemorrhage with dilation and evacuation.

OBJECTIVES: To assess if quantitative blood loss (QBL) with dilation and evacuation (D&E) procedures correlated with clinically relevant outcomes or hemorrhage. STUDY DESIGN: We used a de-identified database to review D&E procedures performed at UC Davis Health from April 2019 through March 2020. Surgeons determined QBL during procedures and estimated blood loss, when excessive, during post-procedure recovery. We extracted patient demographic and procedure-related information. We defined clinically relevant bleeding as cases with bleeding-related interventions within 24 hours post-procedure including use of ≥2 uterotonics, tranexamic acid administration, cervical injury requiring repair, uterine balloon tamponade, blood transfusion, uterine artery embolization, hospitalization, or return to operating room; the latter 5 criteria defined hemorrhage. We used χ2 test for trend to evaluate bleeding outcomes. RESULTS: We evaluated 431 procedures with a mean gestational age of 19 weeks and 3 days. Clinically relevant bleeding outcomes occurred in 6/319 (2%), 15/97 (15%) and 7/12 (58%) patients with total blood loss <250mL, 250-500mL and >500mL, respectively (p<0.0001); 11 had bleeding related to cervical injuries. Hemorrhage occurred in 0, 4/97 (4%) and 5/12 (42%) patients, respectively (p<0.0001). Patients with relevant bleeding outcomes had QBLs ranging from 150-1800mL (median QBL 312.5mL, interquartile range [IQR] 250-550mL) while those without clinically relevant bleeding ranged from 10-900mL (median QBL 150mL, IQR 75-200mL). CONCLUSION: Most patients (75%) with clinically relevant bleeding outcomes had QBL ≤500mL. Although higher QBL correlates with clinical interventions, the need for significant interventions rather than a single blood loss amount should be used to define hemorrhage with D&E procedures. IMPLICATIONS: Clinical hemorrhage is best defined by the necessary clinical interventions required to manage bleeding rather than any quantified amount of blood loss.