FDA Restrictions on Mifepristone: Time for a Change?

Mifepristone, a drug used to manage early miscarriage or end an early pregnancy, carries unique restrictions imposed by the U.S. Food and Drug Administration (FDA). Patients are required to pick up the drug in person from a doctor or a clinic, even though they can take the drug at home. In July, a federal court ruled that the FDA must suspend these restrictions during the COVID-19 pandemic, for patients seeking an early abortion, although the ruling did not apply to women with an early pregnancy loss. But the challenges to FDA restrictions on mifepristone predate the pandemic. This Issue Brief provides the context for this ongoing controversy, and reviews recent evidence on the clinical and cost effectiveness of mifepristone for the medical management of first trimester miscarriage

Bleeding changes after levonorgestrel 52-mg intrauterine system insertion for contraception in women with self-reported heavy menstrual bleeding.

BackgroundThe levonorgestrel 52-mg intrauterine system has proven efficacy for heavy menstrual bleeding treatment in clinical trials, but few data exist to demonstrate how rapidly the effects occur and the effects in women with self-reported heavy bleeding, as seen commonly in clinical practice.ObjectiveEvaluate changes in bleeding patterns in women with self-reported heavy menstrual bleeding before levonorgestrel 52-mg intrauterine system insertion.Study designA total of 1714 women aged 16-45 years old received a levonorgestrel 52-mg intrauterine system in a multicenter trial evaluating contraceptive efficacy and safety for up to 10 years. At screening, participants described their baseline menstrual bleeding patterns for the previous 3 months. Participants completed daily diaries with subjective evaluation of bleeding information for the first 2 years. For this analysis, we included women with at least 1 complete 28-day cycle of intrauterine system use and excluded women using a hormonal or copper intrauterine contraception in the month prior to study enrollment. We evaluated changes in menstrual bleeding and discontinuation for bleeding complaints per 28-day cycle over 26 cycles (2 years) in women who self-reported their baseline pattern as heavy. We also compared rates of amenorrhea, defined as no bleeding or spotting, within the entire study population in women with subjective heavy menstrual bleeding at baseline compared with those who did not complain of heavy menstrual bleeding.ResultsOf the 1513 women in this analysis, 150 (9.9%) reported baseline heavy menstrual bleeding. The majority of women reported no longer experiencing heavy menstrual bleeding by the end of cycle 1 (112/150, 74.7%) with even greater rates by cycle 2 (124/148, 83.8%). At the end of cycles 6, 13, and 26, 129 of 140 (92.1%; 95% confidence interval, 87.7%-96.6%), 114 of 123 (92.7%; 95% confidence interval, 88.1%-97.3%), and 100 of 103 (97.1%; 95% confidence interval, 93.8%-100%) women reported no heavy menstrual bleeding, respectively. After cycles 13 and 26, 63 of 123 (51.2%; 95% confidence interval, 42.4%-60.1%) and 66 of 103 (64.1%; 95% confidence interval, 54.8%-73.3%), respectively, reported their bleeding as amenorrhea or spotting only. A lower proportion of women with baseline self-reported heavy menstrual bleeding reported amenorrhea as compared with women in the overall study cohort without heavy menstrual bleeding at the end of 6 cycles (319 [25.5%] vs 21 [15.0%], P=.005) and 13 cycles (382 [34.4%] vs 26 [21.1%], P=.003); differences were not significant after 19 cycles (367 [37.2%] vs 36 [31.0%], P=.022) and 26 cycles (383 [43.5%] vs 38 [36.9%], P=.21). Only 4 (2.7%) women with baseline heavy menstrual bleeding discontinued for bleeding complaints (2 for heavy menstrual bleeding and 2 for irregular bleeding), all within the first year.ConclusionMost women who self-report heavy menstrual bleeding experience significant improvement quickly after levonorgestrel 52-mg intrauterine system insertion. Discontinuation for bleeding complaints among women with baseline heavy menstrual bleeding is very low

Management of early pregnancy loss with mifepristone and misoprostol: clinical predictors of treatment success from a randomized trial.

BackgroundEarly pregnancy loss is a common event in the first trimester, occurring in 15%-20% of confirmed pregnancies. A common evidence-based medical regimen for early pregnancy loss uses misoprostol, a prostaglandin E1 analog, with a dosage of 800 μg, self-administered vaginally. The clinical utility of this regimen is limited by suboptimal effectiveness in patients with a closed cervical os, with 29% of patients experiencing early pregnancy loss requiring a second dose after 3 days and 16% of patients eventually requiring a uterine aspiration procedure.ObjectiveThis study aimed to evaluate clinical predictors associated with treatment success in patients receiving medical management with mifepristone-misoprostol or misoprostol alone for early pregnancy loss.Study designWe performed a planned secondary analysis of a randomized trial comparing mifepristone-misoprostol with misoprostol alone for management of early pregnancy loss. The published prediction model for treatment success of single-dose misoprostol administered vaginally included the following variables: active bleeding, type of early pregnancy loss (anembryonic pregnancy or embryonic and/or fetal demise), parity, gestational age, and treatment site; previous significant predictors were vaginal bleeding within the past 24 hours and parity of 0 or 1 vs >1. To determine if these characteristics predicted differential proportions of patients with treatment success or failure, we performed bivariate analyses; given the small proportion of treatment failures in the combined treatment arm, both arms were combined for analysis. Thereafter, we performed a logistic regression analysis to assess the effect of these predictors collectively in each of the 2 treatment groups separately as well as in the full cohort as a proxy for the combined treatment arm. Finally, by using receiver operating characteristic curves, we tested the ability of these predictors in association with misoprostol treatment success to discriminate between treatment success and treatment failure. To quantify the ability of the score to discriminate between treatment success and treatment failure in each treatment arm as well as in the entire cohort, we calculated the area under the curve. Using multivariable logistic regression, we then assessed our study population for other predictors of treatment success in both treatment groups, with and without mifepristone pretreatment.ResultsOverall, 297 evaluable participants were included in the primary study, with 148 in the mifepristone-misoprostol combined treatment group and 149 in the misoprostol-alone treatment group. Among patients who had vaginal bleeding at the time of treatment, 15 of 17 (88%) in the mifepristone-misoprostol combined treatment group and 12 of 17 (71%) in the misoprostol-alone treatment group experienced expulsion of pregnancy tissue. Among patients with a parity of 0 or 1, 94 of 108 (87%) in the mifepristone-misoprostol treatment group and 66 of 95 (69%) in the misoprostol-alone treatment group experienced expulsion of pregnancy tissue. These clinical characteristics did not predict treatment success in the combined cohort alone (area under the curve=0.56; 95% confidence interval, 0.48-0.64). No other baseline clinical factors predicted treatment success in the misoprostol-alone treatment arm or mifepristone pretreatment arm. In the full cohort, the significant predictors of treatment success were pretreatment with mifepristone (adjusted odds ratio=2.51; 95% confidence interval, 1.43-4.43) and smoking (adjusted odds ratio=2.15; 95% confidence interval, 1.03-4.49).ConclusionNo baseline clinical factors predicted treatment success in women receiving medical management with misoprostol for early pregnancy loss. Adding mifepristone to the medical management regimen of early pregnancy loss improved treatment success; thus, mifepristone treatment should be considered for management of early pregnancy loss regardless of baseline clinical factors

Mucosal Integrity and Inflammatory Markers in the Female Lower Genital Tract as Potential Screening Tools for Vaginal Microbicides

Background—In the female genital tract, vaginal colposcopy, endometrial mucosal integrity and inflammatory mediators are potential in vivo biomarkers of microbicide and contraceptive safety. Study Design—A randomized, blinded crossover trial of 18 subjects comparing effects of Gynol II (putative inflammatory gel), HEC (putative inert gel) and no gel exposure on endometrial and vaginal epithelial integrity and endometrial and vaginal inflammatory markers (IL-1β, IL-6, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, TNF-α, IL-1RA, IL-10, SLPI). Results—Gynol II was associated with more vaginal lesions. No endometrial disruptions were observed across conditions. In the vagina, RANTES (p=0.055) and IL-6 (p=0.04) were higher after HEC exposure than at baseline. In the endometrium, IL-1β (p=0.003) and IL-8 (p=0.025) were lower after Gynol II cycles than after no gel. Conclusions—Gynol II and HEC may modulate inflammatory markers in the vagina and endometrium. How these changes relate to infection susceptibility warrants further study

Six-month Expulsion of Postplacental Copper Intrauterine Devices Placed After Vaginal Delivery

Background Immediate placement of an intrauterine device after vaginal delivery is safe and convenient, but longitudinal data describing clinical outcomes have been limited. Objective We sought to determine the proportion of TCu380A (copper) intrauterine devices expelled, partially expelled, malpositioned, and retained, as well as contraceptive use by 6 months postpartum, and determine risk factors for expulsion and partial expulsion. Study Design In this prospective, observational study, women who received a postplacental TCu380A intrauterine device at vaginal delivery were enrolled postpartum. Participants returned for clinical follow-up at 6 weeks, and for a research visit with a pelvic exam and ultrasound at 6 months. We recorded intrauterine device outcomes and 6-month contraceptive use. Partial expulsion was defined as an intrauterine device protruding from the external cervical os, or a transvaginal ultrasound showing the distal end of the intrauterine device below the internal os of the cervix. Multinomial logistic regression models identified risk factors associated with expulsion and partial expulsion by 6 months. The area under the receiver operating characteristics curve was used to assess the ability of a string check to predict the correct placement of a postplacental intrauterine device. The primary outcome was the proportion of intrauterine devices expelled at 6 months. Results We enrolled 200 women. Of 162 participants with follow-up data at 6 months, 13 (8.0%; 95% confidence interval, 4.7–13.4%) experienced complete expulsion and 26 (16.0%; 95% confidence interval, 11.1–22.6%) partial expulsion. Of 25 malpositioned intrauterine devices (15.4%; 95% confidence interval, 10.2–21.9%), 14 were not at the fundus (8.6%; 95% confidence interval, 5.2–14.1%) and 11 were rotated within the uterus (6.8%; 95% confidence interval, 3.8–11.9%). Multinomial logistic regression modeling indicated that higher parity (odds ratio, 2.05; 95% confidence interval, 1.21–3.50; P = .008) was associated with expulsion. Provider specialty (obstetrics vs family medicine; odds ratio, 5.31; 95% confidence interval, 1.20–23.59; P = .03) and gestational weight gain (normal vs excess; odds ratio, 9.12; 95% confidence interval, 1.90–43.82; P = .004) were associated with partial expulsion. Long-acting reversible contraceptive method use at 6 months was 80.9% (95% confidence interval, 74.0–86.6%). At 6 weeks postpartum, 35 of 149 (23.5%; 95% confidence interval, 16.9–31.1%) participants had no intrauterine device strings visible. Sensitivity of a string check to detect an incorrectly positioned intrauterine device was 36.2%, and specificity of the string check to predict a correctly positioned intrauterine device was 84.5%. This corresponds to an area under the receiver operating characteristics curve of 0.5. Conclusion This prospective assessment of postplacental TCu380A intrauterine device placement, with ultrasound to confirm device position, finds a complete intrauterine device expulsion proportion of 8.0% at 6 months. The association of increasing parity with expulsion is consistent with prior research. The clinical significance of covariates associated with partial expulsion (provider specialty and gestational weight gain) is unclear. Due to the observational study design, any associations cannot imply causality. The proportion of partially expelled and malpositioned intrauterine devices was high, and the area under the receiver operating characteristics curve of 0.5 indicates that a string check is a poor test for assessing device position. Women considering a postplacental intrauterine device should be counseled about the risk of position abnormalities, as well as the possibility of nonvisible strings, which may complicate clinical follow-up. The clinical significance of intrauterine device position abnormalities is unknown; future research should evaluate the influence of malposition and partial expulsion on contraceptive effectiveness and side effects

Effects of Long-Term Use of Nonoxynol-9 on Vaginal Flora

OBJECTIVE—Products containing nonoxynol-9 have been used as spermicidal contraceptives for many years, but limited data have been published describing the long-term effects of nonoxynol-9 use on the vaginal microbial ecosystem. This longitudinal study was conducted to examine the effects of nonoxynol-9 on the vaginal ecology. METHODS—Vaginal swabs were obtained from 235 women enrolled in a randomized clinical trial before initiation of use of 1 of 5 different formulations of nonoxynol-9 for contraception, and up to 3 more samples were gathered over 7 months of use. The swab samples were evaluated in a single laboratory. The prevalence of several constituents of the normal vaginal flora was evaluated. The associations between nonoxynol-9 dosage, formulation, average product use per week, and number of sex acts per week were calculated. RESULTS—The changes in prevalence of vaginal microbes after nonoxynol-9 use were minimal for each of the different nonoxynol-9 formulations. However, when both nonoxynol-9 concentration and number of product uses are taken into account, nonoxynol-9 did have dose-dependant effects on the increased prevalence of anaerobic gram-negative rods (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1–5.3), H2O2-negative lactobacilli (OR 2.0, 95% CI 1.0–4.1), and bacterial vaginosis (OR 2.3, 95% CI 1.1–4.7). CONCLUSION—This study demonstrated that most nonoxynol-9 users experienced minimal disruptions in their vaginal ecology. There were no differences between the different formulations evaluated with respect to changes in vaginal microflora. However, independent of the nonoxynol-9 formulation, there was a dose-dependent effect with increased exposure to nonoxynol-9 on the risk of bacterial vaginosis and its associated flora

Tear Osmolarity and Dry Eye Symptoms in Women Using Oral Contraception and Contact Lenses

Purpose—To examine the relationship between oral contraceptive pill (OCP) use, contact lens wear, and dry eye signs and symptoms in healthy young females. Methods—Fifty-two women using OCPs and forty-five women not using any form of hormonal contraception were enrolled. Medical, menstrual, and contact lens histories were obtained and dry eye symptoms were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment iN Dry Eye (SANDE) questionnaires. Tear osmolarity testing was performed using the TearLab™ Osmolarity System. Results—Mean age of all subjects was 26.0 ± 3.7 years. There were no significant differences in any of the measurements between the follicular and luteal phases. While SANDE scores were significantly higher in subjects with OCP and recent contact lens use (p\u3c0.01), there were no significant differences in OSDI and tear osmolarity amongst the same subject groups. Subjects who reported both OCP and recent contact lens use had significantly higher OSDI and SANDE scores (p=0.015 and p\u3c0.001, respectively). Conclusions—There were no differences between the phases of the menstrual cycle. Tear osmolarity was not affected by OCP or contact lens use in young females. However, the combination of OCP use and contact lens wear may increase the severity of dry eye symptoms

An Exploratory, Randomized, Crossover MRI Study of Microbicide Delivery with the SILCS Diaphragm Compared to a Vaginal Applicator

Background—Microbicide gels studied for HIV prevention often are delivered via a single-use vaginal applicator. Using a contraceptive diaphragm such as the SILCS diaphragm for gel delivery could have advantages, including lower cost and additional pregnancy prevention. Study Design—We performed an exploratory, nonblinded, randomized, crossover study among healthy, sexually active, nonpregnant women. Using BufferGel®, we evaluated three microbicide delivery methods for gel distribution and retention: SILCS single-sided gel delivery, SILCS double-sided gel delivery and a vaginal applicator (without SILCS). Magnetic resonance images were taken at baseline, after gel insertion, and immediately and 6 h after simulated intercourse. Three women completed all gel delivery methods described in this article. Results—Magnetic resonance imaging analysis indicated similar gel spread in the vagina among all three methods. SILCS single-sided gel application resulted in the most consistent longitudinal coverage; SILCS double-sided gel application was the most consistent in the transverse dimension. Conclusions—Gel coverage was similar with all three methods. These results suggest that the SILCS microbicide delivery system is comparable to vaginal applicators for delivery of gel products intravaginally

Mifepristone Pretreatment for the Medical Management of Early Pregnancy Loss

BACKGROUND Medical management of early pregnancy loss is an alternative to uterine aspira-tion, but standard medical treatment with misoprostol commonly results in treat-ment failure. We compared the efficacy and safety of pretreatment with mifepris-tone followed by treatment with misoprostol with the efficacy and safety of misoprostol use alone for the management of early pregnancy loss. METHODS We randomly assigned 300 women who had an anembryonic gestation or in whom embryonic or fetal death was confirmed to receive pretreatment with 200 mg of mifepristone, administered orally, followed by 800 µg of misoprostol, adminis-tered vaginally (mifepristone-pretreatment group), or 800 µg of misoprostol alone, administered vaginally (misoprostol-alone group). Participants returned 1 to 4 days after misoprostol use for evaluation, including ultrasound examination, by an in-vestigator who was unaware of the treatment-group assignments. Women in whom the gestational sac was not expelled were offered expectant management, a second dose of misoprostol, or uterine aspiration. We followed all participants for 30 days after randomization. Our primary outcome was gestational sac expulsion with one dose of misoprostol by the first follow-up visit and no additional intervention within 30 days after treatment. RESULTS Complete expulsion after one dose of misoprostol occurred in 124 of 148 women (83.8%; 95% confidence interval [CI], 76.8 to 89.3) in the mifepristone-pretreat-ment group and in 100 of 149 women (67.1%; 95% CI, 59.0 to 74.6) in the miso-prostol-alone group (relative risk, 1.25; 95% CI, 1.09 to 1.43). Uterine aspiration was performed less frequently in the mifepristone-pretreatment group than in the misoprostol-alone group (8.8% vs. 23.5%; relative risk, 0.37; 95% CI, 0.21 to 0.68). Bleeding that resulted in blood transfusion occurred in 2.0% of the women in the mifepristone-pretreatment group and in 0.7% of the women in the misoprostol-alone group (P = 0.31); pelvic infection was diagnosed in 1.3% of the women in each group. CONCLUSIONS Pretreatment with mifepristone followed by treatment with misoprostol resulted in a higher likelihood of successful management of first-trimester pregnancy loss than treatment with misoprostol alone. (Funded by the National Institute of Child Health and Human Development; PreFaiR ClinicalTrials.gov number, NCT02012491.