Management of early pregnancy loss with mifepristone and misoprostol: clinical predictors of treatment success from a randomized trial.
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ABSTRACT:
SUBMITTER: Sonalkar S
PROVIDER: S-EPMC7529708 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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Management of early pregnancy loss with mifepristone and misoprostol: clinical predictors of treatment success from a randomized trial.
Sonalkar Sarita S Koelper Nathanael N Creinin Mitchell D MD Atrio Jessica M JM Sammel Mary D MD McAllister Arden A Schreiber Courtney A CA
American journal of obstetrics and gynecology 20200417 4
<h4>Background</h4>Early 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 ...[more]
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Project description:ImportanceMedication management of early pregnancy loss (EPL), or miscarriage, typically involves the administration of misoprostol with or without pretreatment with mifepristone. Combination treatment with mifepristone plus misoprostol is more effective than misoprostol alone but is underutilized in the US.ObjectiveTo describe differences in clinical outcomes after EPL management with mifepristone plus misoprostol vs misoprostol alone using commercial claims data.Design, setting, and participantsThis retrospective cohort study used national insurance claims data from the IBM MarketScan Research Database. Participants included pregnant people (aged 15-49 years) with private insurance who presented with an initial EPL diagnosis between October 1, 2015, and December 31, 2022.ExposuresThe primary exposure was the medication used to manage EPL (ie, mifepristone plus misoprostol or misoprostol alone). Other exposures of interest included demographic characteristics and location of service.Main outcomes and measuresThe primary outcome was subsequent procedural management (eg, uterine aspiration) after EPL diagnosis and medication management. Other outcomes of interest included return visits, hospitalizations, and complications occurring in the subsequent 6 weeks. Descriptive statistics and bivariate analyses were used, and a multivariable logistic regression model was created to examine factors associated with subsequent procedural management.ResultsThis study included 31 977 patients (mean [SD] age, 32.7 [5.6] years) with claims for EPL who received medication management. Of these patients, 3.0% received mifepristone plus misoprostol and 97.0% received misoprostol alone. Patients who received misoprostol with pretreatment with mifepristone were less likely to have subsequent uterine aspiration (10.5% vs 14.0%; P = .002), and they were also less likely to have subsequent emergency department (ED) visits for EPL (3.5% vs 7.9%; P < .001). In multivariable analysis, use of mifepristone plus misoprostol was associated with decreased odds of subsequent procedural management (adjusted odds ratio, 0.71 [95% CI, 0.57-0.87]).Conclusions and relevanceThe findings of this study suggest that mifepristone is underutilized for the medication management of EPL, but its use is associated with a lower need for subsequent uterine aspiration and a decrease in the number of subsequent visits to an ED. Increasing access to mifepristone for EPL management may decrease health care utilization and expenditures.
| S-EPMC11581616 | biostudies-literature
Project description:BackgroundIn case of early pregnancy loss (EPL) women can either choose for expectant, medical or surgical management. One week of expectant management is known to lead to spontaneous abortion in approximately 50% of women. Medical treatment with misoprostol is known to be safe and less costly than surgical management, however less effective in reaching complete evacuation of the uterus. Recently, a number of trials showed that prompt treatment with the sequential combination of mifepristone with misoprostol is superior to misoprostol alone in reaching complete evacuation. In this analysis we evaluate whether the sequential combination of mifepristone with misoprostol is cost-effective compared to misoprostol alone, in the treatment of EPL.Methods and findingsA cost-effectiveness analysis (CEA) from a healthcare perspective was performed alongside a randomised controlled trial (RCT) in which standard treatment with misoprostol only was compared with a combination of mifepristone and misoprostol, in women with EPL after a minimum of one week of unsuccessful management. A limited societal perspective scenario was added. This RCT, the Triple M trial, was a multicentre, randomized, double-blinded, placebo-controlled trial executed at 17 hospitals in the Netherlands. The trial started on June 27th 2018, and ended prematurely in January 2020 due to highly significant outcomes from the predefined interim-analysis. We included 351 women with a diagnosis of EPL between 6 and 14 weeks gestation after at least one week of unsuccessful expectant management. They were randomized between double blinded pre-treatment with oral mifepristone 600mg (N = 175) or placebo (N = 176) taken on day one, both followed by misoprostol orally. In both groups, an intention-to-treat analysis was performed for 172 patients, showing a significant difference in success rates between participants treated with mifepristone and misoprostol versus those treated with misoprostol alone (79.1% vs 58.7% respectively). In this cost-effective analysis we measured the direct, medical costs related to treatment (planned and unplanned hospital visits, medication, additional treatment) and indirect costs based on the IMTA Productivity Cost Questionnaire (iPCQ). Quality Adjusted Life Years (QALY's) were calculated from participants' scores on the SF-36 questionnaires sent digitally at treatment start, and one, two and six weeks later. We found medical treatment with placebo followed by misoprostol to be 26% more expensive compared to mifepristone followed by misoprostol (p = 0.001). Mean average medical costs per patient were significantly lower in the mifepristone group compared to the placebo group (€528.95 ± 328.93 vs €663.77 ± 456.03, respectively; absolute difference €134.82, 95% CI 50,46-219,18, p = 0.002). Both indirect costs and QALY's were similar between both groups.ConclusionThe sequential combination of mifepristone with misoprostol is cost-effective compared with misoprostol alone, for treatment of EPL after a minimum of one week of unsuccessful expectant management.
| S-EPMC8827447 | biostudies-literature
Project description:ObjectiveEvidence strongly supports the use of mifepristone-misoprostol combination treatment for early pregnancy loss (EPL) among pregnancies conceived without assisted reproductive technologies. No literature exists, however, regarding the efficacy of this treatment in the medical management of EPL among pregnancies after in vitro fertilization and embryo transfer (IVF-ET). These patients differ as some use exogenous hormonal supplementation to provide pregnancy support. Thus, the management for EPL may differ between unassisted conceptions and those after ET. Mifepristone, a progesterone receptor antagonist, may demonstrate an altered treatment effect when used with misoprostol to manage EPL in assisted reproductive technologie-conceived pregnancies.ObjectiveTo describe our institution's experience using mifepristone-misoprostol to manage EPL after in vitro fertilization with embryo transfer IVF-ET.DesignRetrospective case series.SettingSingle academic institution from 2020 to 2022.PatientssNine patients with ultrasound confirmed EPL after IVF-ET.InterventionsAll 9 patients underwent in vitro fertilization followed by fresh or frozen embryo transfer. All 9 received 200 mg of mifepristone 24 hours before 800 μg of misoprostol.Main outcome measurementsIncomplete abortion, need for surgical management, number of days to negative serum human chorionic gonadotropin (hCG).ResultsOf the 9 subjects included, one had a programmed frozen embryo transfer cycle, 6 had modified natural frozen embryo transfer cycles, and 2 underwent fresh ET. Eight subjects had successful expulsion of tissue with one dose of treatment, and one required uterine aspiration. No subjects required additional dosing of misoprostol. The mean number of days elapsed from mifepristone treatment to tissue expulsion was 4.89 ± 11.30 days and the mean days to negative-range serum hCG was 36.89 ± 18.59 days. At the initial ultrasound, all pregnancies had one gestational sac seen; 5/9 had a yolk sac; only 3 had fetal cardiac activity. The mean gestational age at the time of EPL diagnosis was 55.22 ± 8.77 days, with the majority (8/9) having completed 7 weeks gestation.ConclusionsMifepristone-misoprostol combination treatment appears to be a reasonable option for those with EPL after IVF-ET. Future, larger-scale studies are needed comparing combination treatment with misoprostol only among various ET protocols.
| S-EPMC10028465 | biostudies-literature
Project description:PurposeTo improve counseling of women by reporting bleeding characteristics at home after medical management of an early pregnancy loss (EPL) with mifepristone and misoprostol, and to evaluate occurring bleeding patterns as a prognostic tool.MethodsThis prospective two-center observational cohort study enrolled 197 women who presented with an EPL (embryonic or anembryonic miscarriage) from December 2017 to April 2019 and chose a home-based medical management with 200 mg mifepristone and 800 mcg misoprostol. From the day of mifepristone intake, the strength of vaginal bleeding was recorded daily for 2 weeks by the patient herself using a diary sheet. Treatment success was defined as no histologically confirmed retained products of conception (RPOC) within 3 months. After considering all drop-out criteria, 154 women were included in the analysis.Results40.0% of patients (95% CI 30.4-49.6) already reported bleeding onset in the time period between the intake of mifepristone and misoprostol. The median duration of vaginal bleeding including spotting was 13 days. The chance of RPOC was about sixfold (OR 6.06, 95% CI 2.15-17.10) in the group of persistent bleeding after 2 weeks compared to the group with a terminated bleeding at that time. Exploratory regression analysis indicated association of higher serum levels of leukocytes at treatment start with RPOC (p = 0.013).ConclusionsTerminated bleeding after 2 weeks is a useful indicator for successful medical induction of EPL. Women undergoing medical treatment with mifepristone must be informed about the high frequency of bleeding onset before misoprostol intake.Clinical trial registrationDRKS-German Clinical Trials Register, ID: DRKS00013515, registration date 05.12.2017. http://www.drks.de/DRKS00013515 .
| S-EPMC9349076 | biostudies-literature
Project description:BackgroundMedical management of early pregnancy loss is an alternative to uterine aspiration, but standard medical treatment with misoprostol commonly results in treatment failure. We compared the efficacy and safety of pretreatment with mifepristone followed by treatment with misoprostol with the efficacy and safety of misoprostol use alone for the management of early pregnancy loss.MethodsWe 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, administered 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 investigator 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.ResultsComplete 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-pretreatment group and in 100 of 149 women (67.1%; 95% CI, 59.0 to 74.6) in the misoprostol-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.ConclusionsPretreatment 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 .).
| S-EPMC6437668 | biostudies-literature
Project description:BackgroundWorldwide, millions of women seek treatment for early pregnancy loss (EPL) annually. Medical management with misoprostol is widely used, but only effective 60% of the time. Pre-treatment with mifepristone prior to misoprostol might improve the success rate of medical management.MethodsThis was a multi-centre, double-blind, placebo-controlled randomised trial in 17 Dutch hospitals. Women with a non-viable pregnancy between 6 and 14 weeks of gestation were eligible for inclusion after at least one week of expectant management. Participants were randomised (1:1) between oral mifepristone 600 mg or an oral placebo tablet. Participants took 400 μg misoprostol orally, repeated after four hours on day two and, if necessary, day three. Primary outcome was expulsion of gestational sac and endometrial thickness <15 mm after 6-8 weeks. Analyses were done according to intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT03212352.FindingsBetween June 28th 2018 and January 8th 2020, 175 women were randomised to mifepristone and 176 to placebo, including 344 in the intention-to-treat analysis. In the mifepristone group 136 (79•1%) of 172 participants reached complete evacuation compared to 101 (58•7%) of 172 participants in the placebo group (p<0•0001, RR 1•35, 95% CI 1•16-1•56). Incidence of serious adverse events was significantly lower in the mifepristone group with 24 (14%) patients affected versus 55 (32%) in the placebo group (p = 0•0005) (Table 3).InterpretationPre-treatment with mifepristone prior to misoprostol was more effective than misoprostol alone in managing EPL.FundingHealthcare Insurers Innovation Foundation, Radboud University Medical Centre, Canisius Wilhelmina Hospital.
| S-EPMC7910666 | biostudies-literature
Project description:BACKGROUND:Early pregnancy failure (EPF) is a common complication of pregnancy. If women do not abort spontaneously, they will undergo medical or surgical treatment in order to remove the products of conception from the uterus. Curettage, although highly effective, is associated with a risk of complications; medical treatment with misoprostol is a safe and less expensive alternative. Unfortunately, after 1 week of expectant management in case of EPF, medical treatment with misoprostol has a complete evacuation rate of approximately 50%. Misoprostol treatment results may be improved by pre-treatment with mifepristone; its effectiveness has already been proven for other indications of pregnancy termination. This study will test the hypothesis that, in EPF, the sequential combination of mifepristone with misoprostol is superior to the use of misoprostol alone in terms of complete evacuation (primary outcome), patient satisfaction, complications, side effects and costs (secondary outcomes). METHODS:The trial will be performed multi-centred, prospectively, two-armed, randomised, double-blinded and placebo-controlled. Women with confirmed EPF by ultrasonography (6-14 weeks), managed expectantly for at least 1 week, can be included and randomised to pre-treatment with oral mifepristone (600 mg) or oral placebo (identical in appearance). Randomisation will take place after receiving written consent to participate. In both arms pre-treatment will be followed by oral misoprostol, which will start 36-48 h later consisting of two doses 400 μg (4 hrs apart), repeated after 24 h if no tissue is lost. Four hundred sixty-four women will be randomised in a 1:1 ratio, stratified by centre. Ultrasonography 2 weeks after treatment will determine short term treatment effect. When the gestational sac is expulsed, expectant management is advised until 6 weeks after treatment when the definitive primary endpoint, complete or incomplete evacuation, will be determined. A sonographic endometrial thickness < 15 mm using only the allocated therapy by randomisation is considered as successful treatment. Secondary outcome measures (patient satisfaction, complications, side effects and costs) will be registered using a case report form, patient diary and validated questionnaires (Short Form 36, EuroQol-VAS, Client Satisfaction Questionnaire, iMTA Productivity Cost Questionnaire). DISCUSSION:This trial will answer the question if, in case of EPF, after at least 1 week of expectant management, sequential treatment with mifepristone and misoprostol is more effective than misoprostol alone to achieve complete evacuation of the products of conception. TRIAL REGISTRATION:Clinicaltrials.gov (d.d. 02-07-2017): NCT03212352. Trialregister.nl (d.d. 03-07-2017): NTR6550. EudraCT number (d.d. 07-08-2017): 2017-002694-19. File number Commisie Mensgebonden Onderzoek (d.d. 07-08-2017): NL 62449.091.17.
| S-EPMC6880504 | biostudies-literature
Project description:BackgroundThe anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone.MethodsMifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024.FindingsBetween Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups.InterpretationTreatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery.FundingUK National Institute for Health Research Health Technology Assessment Programme.
| S-EPMC7493715 | biostudies-literature
Project description:BackgroundA wide range of drugs have been studied for first trimester medical abortion. Studies evaluating different regimens, including combination mifepristone and misoprostol and misoprostol alone regimens, show varying results related to safety, efficacy and other outcomes. Thus, the objectives of this systematic review were to compare the safety, effectiveness and acceptability of medical abortion and to compare medical with surgical methods of abortion ≤63 days of gestation.MethodsPubmed and EMBASE were systematically searched from database inception through January 2019 using a combination of MeSH, keywords and text words. Randomized controlled trials on induced abortion at ≤63 days that compared different regimens of medical abortion using mifepristone and/or misoprostol and trials that compared medical with surgical methods of abortion were included. We extracted data into a pre-designed form, calculated effect estimates, and performed meta-analyses where possible. The primary outcomes were ongoing pregnancy and successful abortion.ResultsThirty-three studies composed of 22,275 participants were included in this review. Combined regimens using mifepristone and misoprostol had lower rates of ongoing pregnancy, higher rates of successful abortion and satisfaction compared to misoprostol only regimens. In combined regimens, misoprostol 800 μg was more effective than 400 μg. There was no significant difference in dosing intervals between mifepristone and misoprostol and routes of misoprostol administration in combination or misoprostol alone regimens. The rate of serious adverse events was generally low.ConclusionIn this systematic review, we find that medical methods of abortion utilizing combination mifepristone and misoprostol or misoprostol alone are effective, safe and acceptable. More robust studies evaluating both the different combination and misoprostol alone regimens are needed to strengthen existing evidence as well as assess patient perspectives towards a particular regimen.
| S-EPMC7339463 | biostudies-literature
Project description:ObjectivesTo compare participant-reported bleeding and pain with two medication regimens for early pregnancy loss (EPL).Study designWe performed a secondary analysis of a randomized trial in which participants took either mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later or misoprostol alone for medical management of EPL. Participants reported bleeding and pain (Numeric Pain Rating Scale, NPRS, 0-10) with daily paper diaries and at study visits on trial days 3, 8, and 30. We used, Fisher's exact, Pearson chi-square, Wilcoxon rank sum, and Student's t-tests to compare onset, duration, and severity of bleeding and pain symptoms between trial arms after misoprostol administration.ResultsAmong 291 participants who submitted diary data, 143 received mifepristone pretreatment. A larger proportion of this group reported moderate or heavy bleeding on trial day 2, the day of misoprostol administration, compared with those who did not receive pretreatment (73% vs 47%, p < 0.01). Between days 4 and 8, more mifepristone-pretreatment participants reported mild or no bleeding, compared with the misoprostol-only arm (78% vs 61%, p < 0.01). Average pain score for trial days 2-4 was higher for the pretreatment group compared with the misoprostol-only group (6.9 vs 6.0, p = 0.01), and there was a trend toward shorter total duration of pain (15 vs 19 hours, p = 0.08). These differences remained after controlling for treatment success across arms.ConclusionsMifepristone pretreatment increased the severity of pain but not bleeding and resulted in a shorter trajectory of symptoms during medical management of EPL.ImplicationsMifepristone pretreatment decreases the duration of heavy bleeding and there was a trend toward decreased duration of pain during medical management of miscarriage, indicating that this medication improves the efficiency, in addition to the efficacy, of this treatment.
| S-EPMC10302372 | biostudies-literature