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Medical management of early pregnancy loss is cost-effective compared with office uterine aspiration

      Background

      Early pregnancy loss, also referred to as miscarriage, is common, affecting approximately 1 million people in the United States annually. Early pregnancy loss can be treated with expectant management, medications, or surgical procedures—strategies that differ in patient experience, effectiveness, and cost. One of the medications used for early pregnancy loss treatment, mifepristone, is uniquely regulated by the Food and Drug Administration.

      Objective

      This study aimed to compare the cost-effectiveness from the healthcare sector perspective of medical management of early pregnancy loss, using the standard of care medication regimen of mifepristone and misoprostol, with that of office uterine aspiration.

      Study Design

      We developed a decision analytical model to compare the cost-effectiveness of early pregnancy loss treatment with medical management with that of office uterine aspiration. Data on medical management came from the Pregnancy Failure Regimens randomized clinical trial, and data on uterine aspiration came from the published literature. The analysis was from the healthcare sector perspective with a 30-day time horizon. Costs were in 2018 US dollars. Effectiveness was measured in quality-adjust life-years gained and the rate of complete gestational sac expulsion with no additional interventions. Our primary outcome was the incremental cost per quality-adjust life-year gained. Sensitivity analysis was performed to identify the key uncertainties.

      Results

      Mean per-person costs were higher for uterine aspiration than for medical management ($828 [95% confidence interval, $789–$868] vs $661 [95% confidence interval, $556–$766]; P=.004). Uterine aspiration more frequently led to complete gestational sac expulsion than medical management (97.3% vs 83.8%; P=.0001); however, estimated quality-adjust life-years were higher for medical management than for uterine aspiration (0.082 [95% confidence interval, 0.8148–0.08248] vs 0.079 [95% confidence interval, 0.0789–0.0791]; P<.0001). Medical management dominated uterine aspiration, with lower costs and higher confidence interval. The probability that medical management is cost-effective relative to uterine aspiration is 97.5% for all willingness-to-pay values of ≥$5600/quality-adjust life-year. Sensitivity analysis did not identify any thresholds that would substantially change outcomes.

      Conclusion

      Although office-based uterine aspiration more often results in treatment completion without further intervention, medical management with mifepristone pretreatment costs less and yields similar quality-adjust life-years, making it an attractive alternative. Our findings provided evidence that increasing access to mifepristone and eliminating unnecessary restrictions will improve early pregnancy care.

      Key words

      Introduction

      Early pregnancy loss (EPL), or miscarriage, is common, affecting more than 1 million people in the United States annually.
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      Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008.
      With an increased availability of highly sensitive pregnancy tests and early ultrasounds, many patients are diagnosed with an EPL before the onset of symptoms.
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      • Joseph K.S.
      • Galea S.
      • Bates L.M.
      • Louis G.M.
      • Ananth C.V.
      Signs and symptoms of early pregnancy loss.
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      Incidence of early loss of pregnancy.
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      Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study.
      Once diagnosed, pregnant individuals have 3 treatment routes available to them: expectant management (watching and waiting), surgical intervention (uterine aspiration in the office or operating room), or medical management (using medications to induce uterine contractions and expel tissue).
      American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology
      ACOG Practice Bulletin No. 200: early pregnancy loss.
      These 3 options differ in effectiveness, patient experience, and cost.
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      • Cubo A.M.
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      • Doyague M.J.
      • Sayagués J.M.
      Medical versus surgical treatment of first trimester spontaneous abortion: a cost-minimization analysis.
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      • Barg F.K.
      Treatment decisions at the time of miscarriage diagnosis.

      Why was this study conducted?

      This study compared the cost-effectiveness of medical management of early pregnancy loss using mifepristone and misoprostol with that of office uterine aspiration.

      Key findings

      Medical management with mifepristone and misoprostol dominated office uterine aspiration from the healthcare sector perspective because costs were lower and quality-adjusted life-years were similar.

      What does this add to what is known?

      Given the cost-effectiveness of medical management of early pregnancy loss with mifepristone and misoprostol, increasing access to mifepristone and eliminating unnecessary restrictions will substantially improve early pregnancy care.
      A 2018 multicenter randomized clinical trial (RCT) on medical management of EPL demonstrated increased clinical effectiveness when the medication mifepristone was added as a pretreatment to the standard regimen of misoprostol.
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      Before mifepristone pretreatment, as many as 15%–40% of patients opting for medical management with 800 μg of vaginal misoprostol required either additional doses of medication or a uterine evacuation procedure to complete the process.
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      With improved medication management effectiveness, patient and clinician interests in expanding access to medication management have increased,
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      • Romero D.
      • Prine L.
      • Rubin S.E.
      Barriers and enablers to family physicians’ provision of early pregnancy loss management in the United States.
      and the COVID-19 pandemic has highlighted the importance of treatment options that minimize in-person clinic visits.
      • Kohn J.E.
      • Snow J.L.
      • Simons H.R.
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      • Thompson T.A.
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      Medication abortion provided through telemedicine in four U.S. states.
      ,
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      • Raifman S.
      • Grossman D.
      Women’s experiences using telemedicine to attend abortion information visits in Utah: a qualitative study.
      However, there are barriers to mifepristone access for EPL treatment. Mifepristone was approved to induce abortion, and is used off-label for EPL treatment. Mifepristone carries a US Food and Drug Administration (FDA)-mandated Risk Evaluation and Mitigation Strategy (REMS) that requires both prescribing providers and dispensing pharmacies to be certified.
      • Srinivasulu S.
      • Yavari R.
      • Brubaker L.
      • Riker L.
      • Prine L.
      • Rubin S.E.
      US clinicians’ perspectives on how mifepristone regulations affect access to medication abortion and early pregnancy loss care in primary care.
      Approved Risk Evaluation and Mitigation Strategies (REMS)
      US Food and Drug Administration 2021.
      Mifeprex (Mifepristone): The Original Early Option Pill
      Danco.
      Furthermore, clinicians and payers may perceive cost to be a barrier to the use of mifepristone.
      The comparative cost-effectiveness of medication management and in-office management has significant implications for clinical care and reproductive health policy. If medication management is preferred by many patients, decreases the need to access in-person clinical care during a pandemic, and is found to be cost-effective, clinicians and policymakers should increase efforts to improve mifepristone availability and reduce access burdens. Given the clinical efficacy of medical management of EPL using mifepristone pretreatment, and its proven cost-effectiveness compared with misoprostol-alone treatment for EPL,
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      we developed a decision analytical model combining the Pregnancy Failure Regimens (PreFaiR) trial data and data from the published literature to assess the cost-effectiveness of medical management with mifepristone pretreatment followed by misoprostol (“medical management”) compared with an office-based uterine aspiration arm (“uterine aspiration”) for the treatment of EPL.

      Materials and Methods

      Trial design and participants

      PreFaiR is a pragmatic comparative effectiveness trial conducted at 3 US sites from May 1, 2014, to April 30, 2017, the details of which have been previously described.
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      The trial randomized 300 women with anembryonic pregnancy or fetal demise before 12 completed gestational weeks with a closed cervical os to pretreatment with 200 mg mifepristone administered orally followed by 800 μg misoprostol administered vaginally or to 800 μg misoprostol administered vaginally without pretreatment. Of note, 141 women were randomized to mifepristone pretreatment, and data from 148 patients were evaluable for the medical management arm (age [mean (standard deviation)]: 30.7 [6.3] years).
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      Participants were scheduled to return at 24 to 96 hours after misoprostol use (“day 3 visit”) for assessment of treatment success. If the gestational sac was not expelled, participants were offered expectant management, a second dose of misoprostol, or office-based uterine aspiration. All participants were followed up for 30 days after randomization to verify pregnancy expulsion and to assess adverse effects.
      We developed a secondary analysis using PreFaiR results
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      to compare the healthcare sector perspective costs and health outcomes associated with medical management vs uterine aspiration. For the medical management arm, we used the mifepristone pretreatment-misoprostol arm results from the trial.
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      The uterine aspiration arm was based on a demographically similar population, using the published literature to generate patient-level data.
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      • Cubo A.M.
      • Soto Z.M.
      • Haro-Pérez A.
      • Hernández Hernández M.E.
      • Doyague M.J.
      • Sayagués J.M.
      Medical versus surgical treatment of first trimester spontaneous abortion: a cost-minimization analysis.
      ,
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      ,
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      All uterine aspirations were assumed to be performed in the office setting with local anesthesia (without general anesthetic or sedative agents). As is standard practice and consistent with previous cost analyses, office uterine aspiration procedures were assumed to have been performed without ultrasound guidance.
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      ,
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      ,
      • Dalton V.K.
      • Harris L.
      • Weisman C.S.
      • Guire K.
      • Castleman L.
      • Lebovic D.
      Patient preferences, satisfaction, and resource use in office evacuation of early pregnancy failure.
      This study has institutional review board approval from the University of Pennsylvania (Philadelphia, PA), the University of California Davis (Davis, CA), and the Albert Einstein College of Medicine (New York, NY).

      Economic evaluation design

      Incremental cost per quality-adjusted life-year (QALY) gained and the incremental cost per complete gestational sac expulsion were calculated from the healthcare sector perspective to compare medical management and uterine aspiration for miscarriage management. This approach follows the recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine
      • Sanders G.D.
      • Neumann P.J.
      • Basu A.
      • et al.
      Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine.
      ,
      • Sanders G.D.
      • Maciejewski M.L.
      • Basu A.
      Overview of cost-effectiveness analysis.
      and the Consolidated Health Economic Evaluation Reporting Standards for health economic evaluations (Supplemental Table 1).
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated Health Economic Evaluation Reporting Standards (CHEERS)--explanation and elaboration: a report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force.
      An intent-to-treat approach was used: all participants assigned to mifepristone pretreatment in the 2018 trial, regardless of treatment response, were included in the medical management arm. We used the 30-day follow-up period of the 2018 Schreiber et al
      • Schreiber C.A.
      • Creinin M.D.
      • Atrio J.
      • Sonalkar S.
      • Ratcliffe S.J.
      • Barnhart K.T.
      Mifepristone pretreatment for the medical management of early pregnancy loss.
      trial as our time horizon. For the uterine aspiration arm, we modeled costs and outcomes for a demographically similar population choosing office uterine aspiration as their primary treatment approach.

      Costs and use of resources

      Healthcare sector perspective costs included, as recommended, costs incurred by payers and by patients for the therapies and other EPL-related healthcare costs. We used a macro-costing approach: healthcare utilization data collected during the trial (medical management arm) or estimated from the literature (uterine aspiration arm) were combined with national average Medicare reimbursement rates or published prices to reflect costs to the healthcare sector for each EPL- or therapy-related clinical event (Supplemental Table 2). For generalizability, national average Medicare reimbursement rates were used rather than institution- or region-specific costs. The original study used detailed case report forms, collected at scheduled study visits or telephone calls on study days 3, 8, and 30, for information regarding resource use. In addition, the number of EPL-related procedures performed, adverse clinical events (eg, infections, additional office visits, emergency department visits, and admissions), and other healthcare regimens for EPL (eg, medications) were collected from both case report forms and electronic medical record review during the original study. Unit cost estimates were applied to calculate the total costs for each participant. For medical management, costs included initial treatment with 200 mg mifepristone and 800 μg misoprostol. For uterine aspiration, costs included an office-based procedure with local anesthesia and estimated complication rates from the literature.
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      Results were expressed in 2018 US dollars.

      Effectiveness outcome

      The primary effectiveness outcome was the 1-month QALY. QALYs were based on a modified utility score taken from the published EPL literature of 30-day trials, with successful medical management defined as 1, successful uterine aspiration defined as 0.95, and need for uterine aspiration or repeat dosage after failed medical or procedural treatment defined as 0.90.
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      ,
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      QALYs were calculated from the utility scores, which were assumed to remain constant during the 30-day trial.
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      ,
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      Other effectiveness outcomes included treatment success, defined for medical management as gestational sac expulsion with 1 dose of misoprostol at the first follow-up visit and for uterine aspiration as a successful procedure, with no additional intervention needed within 30 days after treatment. Any uterine aspirations performed for treatment failures were assumed to be 100% completed.

      Statistical analysis

      Univariate cost and effectiveness measures were compared using unpaired t tests to assess differences between medical management and uterine aspiration. The primary cost-effectiveness measure was the incremental cost-effectiveness ratio (ICER), defined as the difference in mean cost of medical management vs uterine aspiration, divided by the difference in mean QALYs of medical management vs uterine aspiration. A secondary ICER was calculated using treatment success as the effectiveness measure; the difference in mean cost was divided by the difference in treatment success with medical management vs uterine aspiration. Uncertainty in the estimated ICER was evaluated by generating pairs of differences in mean cost and mean QALYs from 5000 replications of cost and QALY data and calculating 95% confidence intervals (CIs). The cost-effectiveness plane shows the differences between the medical management and uterine aspiration arms in mean cost on the y-axis and mean QALYs on the x-axis. The ICER was calculated for each replication and compared with a range of willingness-to-pay values ($0–$2,000,000 per QALY). Cost-effectiveness acceptability curves (CEACs) displayed the percentage of ICER replications that were cost-effective below each willingness-to-pay value. An analogous approach was used for treatment success ICER.
      • Efron B.
      • Tibshirani R.J.
      An introduction to the bootstrap.
      • Barber J.A.
      • Thompson S.G.
      Analysis of cost data in randomized trials: an application of the non-parametric bootstrap.
      • Glick H.A.
      • Doshi J.A.
      • Sonnad S.S.
      • Polsky D.
      Economic evaluation in clinical trials.
      • Ramsey S.D.
      • Willke R.J.
      • Glick H.
      • et al.
      Cost-effectiveness analysis alongside clinical trials II: an ISPOR Good Research Practices Task Force report.
      • Fenwick E.
      • O’Brien B.J.
      • Briggs A.
      Cost-effectiveness acceptability curves--facts, fallacies and frequently asked questions.
      • Fenwick E.
      • Byford S.
      A guide to cost-effectiveness acceptability curves.
      We performed sensitivity analyses to identify the effect of key variables on cost-effectiveness results, including the cost of mifepristone for medical management, cost of uterine aspiration, frequency of treatment success, and utility score assumptions.
      Statistical analyses were performed using Stata (version 14.2; StataCorp, College Station, TX). P values of <.05 indicated significance; all analyses were 2-sided.

      Results

      Resources and costs

      Estimated mean per-person costs were higher for uterine aspiration ($828 [95% CI, $789–$868]) than for medical management ($661 [95% CI, $556–$766]) (P=.004) (Table 1).
      Table 1Costs and outcomes of early pregnancy loss treatment with medical management vs uterine aspiration
      VariableMedical management (US dollar)Uterine aspiration (US dollar)P value
      Mean per-person costs
      Direct costs—formal healthcare sector
      Medical management healthcare utilization based on data from Nagendra et al17; uterine aspiration healthcare utilization based on data from Zhang et al6, Rausch et al7, and Cubo et al8. Details are shown in Supplemental Table 2
      Treatment519.34 (57.03)741.87 (0.00)<.0001
      Reaspiration41.71 (134.87)25.52 (130.37).223
      Repeat misoprostol0.22 (0.80)
      Unscheduled visits
      Unscheduled visits were categorized as visits requiring a visit to a provider and a transvaginal ultrasound
      14.13 (52.68)18.31 (59.21).468
      Other complications
      Other complications included visits to the office or emergency department related to the miscarriage, such as pelvic inflammatory disease or need for a transfusion because of hemorrhage
      84.03 (625.48)33.41 (318.87).259
      Pain control
      Pain control measures: all patients received a prescription to aid in pain management
      1.31 (1.47)9.29 (0.0)<.0001
      Total healthcare perspective costs (US dollar)
      All costs reported in 2018 US dollars ($).
      660.75 (555.88–765.62)828.40 (789.12–867.68).004
      Effects
      Average QALY per person0.082 (0.003)0.0790 (0.001)<.0001
      Completion rate after first treatment (%)83.8 (36.98)97.3 (16.22).0001
      Data are presented as mean (standard deviation) or mean (95% confidence interval), unless otherwise indicated.
      Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
      a Medical management healthcare utilization based on data from Nagendra et al
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      ; uterine aspiration healthcare utilization based on data from Zhang et al
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      , Rausch et al
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      , and Cubo et al
      • Cubo A.M.
      • Soto Z.M.
      • Haro-Pérez A.
      • Hernández Hernández M.E.
      • Doyague M.J.
      • Sayagués J.M.
      Medical versus surgical treatment of first trimester spontaneous abortion: a cost-minimization analysis.
      . Details are shown in Supplemental Table 2
      b Unscheduled visits were categorized as visits requiring a visit to a provider and a transvaginal ultrasound
      c Other complications included visits to the office or emergency department related to the miscarriage, such as pelvic inflammatory disease or need for a transfusion because of hemorrhage
      d Pain control measures: all patients received a prescription to aid in pain management
      e All costs reported in 2018 US dollars ($).

      Clinical effectiveness and quality-adjust life-year outcomes

      The effect of treatment completion was defined by complete gestational sac expulsion. With medical management, 83.8% of women had successful management after their initial treatment, compared with an estimated 97.3% of women with successful management with uterine aspiration (P=.0001) (Table 1).
      Estimated QALYs were 0.0790 (95% CI, 0.0789–0.0791) for uterine aspiration and 0.0820 (95% CI, 0.8148–0.08248) for medical management (P<.0001) (Table 1).

      Cost-effectiveness

      In comparing the cost-effectiveness of medical management with that of uterine aspiration from the healthcare sector perspective, medical management was dominant, as costs were lower and QALYs were higher for medical management than for uterine aspiration (Table 2, Figure 1). CEAC analysis demonstrated that the probability that medical management is cost-effective relative to office uterine aspiration is 97.5% (corresponding to the upper bound of 95% CI) for all willingness-to-pay values of >$5600 per QALY gained (Figure 2).
      Table 2Incremental cost-effectiveness ratio of treatment of early pregnancy loss with medical management vs uterine aspiration, by measure of health outcome
      Health outcome: quality-adjusted life-yearsHealth outcome: completion after first treatment
      Difference in mean cost per person−$167.65Difference in mean cost per person−$167.65
      Difference in mean QALY per person0.0030Difference in completion rate after first treatment−13.5%
      ICERMedical management dominant

      ICER (−55,883.33)

      95% CI (−$99,683.07 to $5531.71) per QALY
      ICER$12.42 per 1 percentage point in completion rate

      95% CI (−$1.25 to $45.64)
      CI, confidence interval; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
      Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
      Figure thumbnail gr1
      Figure 1ICER scatter plot for mifepristone pretreatment vs office uterine aspiration, by measure of health outcome
      Scatterplots of points representing pairs of mean differences in cost and mean differences in QALYs (A) and percent completion (B) for mifepristone pretreatment vs office uterine aspiration from 5000 bootstrapped replications with replacement. The healthcare sector perspective in cost per QALY gained is in panel A, and the healthcare perspective in cost per percent completion gained is in panel B. The difference in mean cost is on the y-axis, and the difference in mean QALY (A) or percent completion (B) is on the x-axis. Points that lie above the horizontal axis represent replications in which mifepristone pretreatment costs more than office uterine aspiration, whereas points below the horizontal axis indicate replications in which office uterine aspiration costs more than mifepristone pretreatment. Points to the right of the vertical axis represent replications in which mifepristone pretreatment was more effective than office uterine aspiration, whereas points on the left of the vertical axis indicate replications in which office uterine aspiration was more effective than mifepristone pretreatment. Estimates in panel A fell in the lower right quadrant; this shows that mifepristone pretreatment is “dominant,” with lower mean costs and higher mean QALYs than office uterine aspiration. In panel B, estimates fell in the lower left quadrant; this shows that mifepristone pretreatment has lower cost and lower percent completion rates than office uterine aspiration. The blue points are within the 95% CI, the red points are outside the 95% CI, and the yellow points indicate the ICER point estimates.
      CI, confidence interval; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.
      Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
      Figure thumbnail gr2
      Figure 2CEAC for mifepristone pretreatment vs uterine aspiration, by measure of health outcome
      The 5000 bootstrapped ICER replications with replacement were used to derive cost-effectiveness acceptability frontiers, which plot the probability of the optimal strategy being cost-effective across a range of WTP values per QALY gained (A) or per percent completion gained (B). These probabilities were graphed to create CEACs for mifepristone pretreatment vs uterine aspiration. The common maximum WTP threshold per QALY gained of $100,000 is indicated by the red line in panel A. Mifepristone pretreatment had a 97.5% probability of being cost-effective (corresponding to the upper bound of 95% CI) compared with office uterine aspiration at a WTP threshold per QALY gained of $5600 and at $46 per 1 percentage point in completion rate gained.
      CI, confidence interval; CEAC, cost-effectiveness acceptability curve; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year; WTP, willingness to pay.
      Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
      The cost-effectiveness of treatment success of medical management to uterine aspiration was also evaluated. Costs for medical management were lower than for uterine aspiration, but uterine aspiration had higher treatment success than medical management, resulting in an ICER of $12.42 per 1 percentage point in completion rate gained (Table 2, Figure 1). CEAC analysis demonstrated that the probability that medical management is cost-effective relative to uterine aspiration is 97.5% for all willingness-to-pay values of >$46.00 per 1 percentage point in completion rate gained (Figure 2).

      Sensitivity analyses

      Threshold analysis demonstrated the effort of key variables on mifepristone pretreatment cost-effectiveness. With a decrease in the cost of an in-office uterine aspiration procedure from $475 to $11, or an increase in the cost of mifepristone from $54 to $518 per dose, medical management would remain cost-effective at the generally accepted maximum willingness-to-pay threshold of approximately $100,000 per QALY.
      • Neumann P.J.
      • Cohen J.T.
      • Weinstein M.C.
      Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold.
      With a decrease in percentage completion rate for medical management from 83.8% to 28.4%, medical management would remain cost-effective at $100,000 per QALY. With a decrease in utility score from 1.0000 to 0.9335 for successful medical management, an increase in utility score from 0.9500 to 0.9999 for successful in-office uterine aspiration, or a decrease in utility score from 0.90 to 0.46 for retreatment after failed medical or procedural treatment, mifepristone pretreatment would remain cost-effective at $100,000 per QALY.

      Comment

      Principal findings

      Our study demonstrated that from the healthcare perspective, medical management with mifepristone pretreatment followed by misoprostol was cost-effective compared with office uterine aspiration for EPL treatment, with higher effectiveness (QALYs) and lower costs. Our analysis demonstrated that the ICER for medical management is well below the maximum willingness-to-pay threshold of approximately $100,000 per QALY gained.
      • Neumann P.J.
      • Cohen J.T.
      • Weinstein M.C.
      Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold.

      Results in the context of what is known

      The improved efficacy of mifepristone pretreatment vs misoprostol alone has changed the standard of care for medical management of EPL.
      American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology
      ACOG Practice Bulletin No. 200: early pregnancy loss.
      ,
      • Nagendra D.
      • Koelper N.
      • Loza-Avalos S.E.
      • et al.
      Cost-effectiveness of mifepristone pretreatment for the medical management of nonviable early pregnancy: secondary analysis of a randomized clinical trial.
      Previous research comparing the cost-effectiveness of medical management with that of uterine aspiration for EPL management was based on medical management protocols using misoprostol alone.
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      Our analysis provided additional information for patients seeking EPL treatment, clinicians incorporating the full range of EPL care into their practices, healthcare payers, and policymakers.

      Clinical implications

      The COVID-19 pandemic has highlighted the importance of increasing access to EPL treatment options that reduce the need for in-person clinical visits. As the pandemic has affected access to hospital services, the importance of an effective treatment option that can be offered through telemedicine has become essential.
      • Glick H.A.
      • Doshi J.A.
      • Sonnad S.S.
      • Polsky D.
      Economic evaluation in clinical trials.
      ,
      • Ramsey S.D.
      • Willke R.J.
      • Glick H.
      • et al.
      Cost-effectiveness analysis alongside clinical trials II: an ISPOR Good Research Practices Task Force report.
      This study has contributed to a growing body of literature showing medication management with mifepristone and misoprostol for EPL to be safe, effective, and cost-effective. Unfortunately, clinicians are hindered in prescribing mifepristone because of unnecessary restrictions, limiting the widespread use of this treatment strategy.
      • Srinivasulu S.
      • Yavari R.
      • Brubaker L.
      • Riker L.
      • Prine L.
      • Rubin S.E.
      US clinicians’ perspectives on how mifepristone regulations affect access to medication abortion and early pregnancy loss care in primary care.
      ,
      Approved Risk Evaluation and Mitigation Strategies (REMS)
      US Food and Drug Administration 2021.
      ,
      • Thompson A.
      • Singh D.
      • Ghorashi A.R.
      • Donovan M.K.
      • Ma J.
      • Rikelman J.
      The disproportionate burdens of the mifepristone REMS.
      We have shown that cost is not a barrier.
      The FDA initially designated mifepristone as a medication requiring REMS after its approval in September 2000 for medical termination of intrauterine pregnancy. The REMS regulations for mifepristone initially required providers to be certified to prescribe mifepristone, mifepristone to be dispensed in a clinic or hospital setting, and prescribers to obtain a signed patient agreement form before dispensing the medication.
      Approved Risk Evaluation and Mitigation Strategies (REMS)
      US Food and Drug Administration 2021.
      These restrictions have prevented many patients from accessing mifepristone and are particularly burdensome for Black and underinsured patients, who are more likely to seek treatment in emergency care settings.
      • Flynn A.N.
      • Shorter J.M.
      • Roe A.H.
      • Sonalkar S.
      • Schreiber C.A.
      The Burden of the Risk Evaluation and Mitigation Strategy (REMS) on providers and patients experiencing early pregnancy loss: a commentary.
      In April 2021, the FDA announced its intention to “exercise enforcement discretion” during the COVID-19 public health emergency, and in December 2021, the FDA modified the REMS by removing the requirement that mifepristone be dispensed only in certain healthcare settings, specifically clinics, medical offices, and hospitals (referred to as the “in-person dispensing requirement”), and adding a requirement that pharmacies that dispense the drug be certified.
      Approved Risk Evaluation and Mitigation Strategies (REMS)
      US Food and Drug Administration 2021.
      How these changes will impact patients who wish to use mifepristone “off-label” for miscarriage management remains to be seen, but evidence of cost-effectiveness and the recent reduction in regulatory barriers may result in improved care and access for patients suffering from the most common complication in pregnancy.

      Strengths and limitations

      Our study used economic data collected prospectively from a pragmatic RCT for the medical management arm. However, our analysis has some limitations. Our study used 2018 national Medicare reimbursement rates to calculate healthcare costs to improve generalization, but actual costs for healthcare and reimbursement rates may vary by region and payer. The cost of mifepristone was included in healthcare costs but may also vary by region and year purchased. The use of a uterine aspiration group modeled with data from the published literature necessitated different sources of healthcare utilization data between the comparison groups. Our sensitivity analyses were performed with these limitations in mind to demonstrate thresholds at which mifepristone pretreatment would no longer be cost-effective.
      In addition, further studies must be done to evaluate the QALYs for EPL and other obstetrical and gynecologic procedures to establish standard measures that can be used across our field. We made assumptions based on limited literature regarding the assignment of utility preference score values for successful medical management, failed medical management, successful uterine aspiration, and failed uterine aspiration. We performed sensitivity analyses to further determine the smallest difference at which medical management remained cost-effective.
      Our study examined only the healthcare perspective when comparing these 2 effective EPL treatment options. There is a need to assess the societal sector perspective of EPL management to conduct more comprehensive cost-effectiveness analyses and better identify the complete costs associated with treatment.

      Conclusion

      Medical management of EPL with mifepristone pretreatment and misoprostol has been found to be cost-effective compared with office uterine aspiration, with similar QALYs and lower costs, making it a high-value care alternative. Increasing access to mifepristone and eliminating unnecessary restrictions will improve early pregnancy care.

      Acknowledgments

      We thank the members of the Pregnancy Failure Regimens trial team and the study participants for their dedication.

      Appendix

      Supplemental Table 1Consolidated Health Economic Evaluation Reporting Standards
      SectionItem numberRecommendationReported on page number or line number
      Title and abstract
      Title1Identify the study as an economic evaluation or use more specific terms, such as “cost-effectiveness analysis,” and describe the interventions compared.1
      Abstract2Provide a structured summary of objectives, perspective, setting, methods (including study design and inputs), results (including base case and uncertainty analyses), and conclusions.3
      Introduction
      Background and objectives3Provide an explicit statement of the broader context for the study.

      Present the study question and its relevance for health policy or practice decisions.
      5 and 6
      Methods
      Target population and subgroups4Describe characteristics of the base case population and subgroups analyzed, including why they were chosen.6
      Setting and location5State relevant aspects of the system or systems in which the decision or decisions need to be made.6
      Study perspective6Describe the perspective of the study and relate this to the costs being evaluated.6 and 7
      Comparators7Describe the interventions or strategies being compared and state why they were chosen.5 and 6
      Time horizon8State the time horizon or horizons over which costs and consequences are being evaluated and say why appropriate.6
      Discount rate9Report the choice of discount rate or rates used for costs and outcomes and say why appropriate.NA

      30-day time horizon
      Choice of health outcomes10Describe what outcomes were used as the measure or measures of benefit in the evaluation and their relevance for the type of analysis performed.8
      Measurement of effectiveness11aSingle study-based estimates: Describe fully the design features of the single effectiveness study and why the single study was a sufficient source of clinical effectiveness data.5–6
      11bSynthesis-based estimates: Describe fully the methods used for identification of included studies and synthesis of clinical effectiveness data.6
      Measurement and valuation of preference-based outcomes12If applicable, describe the population and methods used to elicit preferences for outcomes.8
      Estimating resources and costs13aSingle study-based economic evaluation: Describe approaches used to estimate resource use associated with the alternative interventions. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.7
      13bModel-based economic evaluation: Describe approaches and data sources used to estimate resource use associated with model health states. Describe primary or secondary research methods for valuing each resource item in terms of its unit cost. Describe any adjustments made to approximate to opportunity costs.7
      Currency, price date, and conversion14Report the dates of the estimated resource quantities and unit costs. Describe methods for adjusting estimated unit costs to the year of reported costs if necessary. Describe methods for converting costs into a common currency base and the exchange rate.7
      Choice of model15Describe and give reasons for the specific type of decision analytical model used. Providing a figure to show model structure is strongly recommended.6
      Assumptions16Describe all structural or other assumptions underpinning the decision analytical model.6–8
      Analytical methods17Describe all analytical methods supporting the evaluation. This could include methods for dealing with skewed, missing, or censored data; extrapolation methods; methods for pooling data; approaches to validate or make adjustments (such as half cycle corrections) to a model; and methods for handling population heterogeneity and uncertainty.8 and 9
      Results
      Study parameters18Report the values, ranges, references, and, if used, probability distributions for all parameters. Report reasons or sources for distributions used to represent uncertainty where appropriate. Providing a table to show the input values is strongly recommended.Supplement Table 2
      Incremental costs and outcomes19For each intervention, report mean values for the main categories of estimated costs and outcomes of interest and mean differences between the comparator groups. If applicable, report incremental cost-effectiveness ratios.9 and 10

      Exhibit 1 and 2
      Characterizing uncertainty20aSingle study-based economic evaluation: Describe the effects of sampling uncertainty for the estimated incremental cost and incremental effectiveness parameters, together with the impact of methodological assumptions (such as discount rate and study perspective).9 and 10

      Exhibit 1–4
      20bModel-based economic evaluation: Describe the effects on the results of uncertainty for all input parameters and uncertainty related to the structure of the model and assumptions.9 and 10

      Exhibit 1–4
      Characterizing heterogeneity21If applicable, report differences in costs, outcomes, or cost-effectiveness that can be explained by variations between subgroups of patients with different baseline characteristics or other observed variability in effects that are not reducible by more information.NA
      Discussion
      Study findings, limitations, generalizability, and current knowledge22Summarize key study findings and describe how they support the conclusions reached. Discuss limitations and the generalizability of the findings and how the findings fit with current knowledge.11–13
      Other
      Source of funding23Describe how the study was funded and the role of the funder in the identification, design, conduct, and reporting of the analysis. Describe other nonmonetary sources of support.1
      Conflicts of interest24Describe any potential for conflict of interest of study contributors in accordance with journal policy. In the absence of a journal policy, we recommend authors comply with International Committee of Medical Journal Editors recommendations.1
      NA, not available.
      Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
      Supplemental Table 2Inputs and data sources for costs
      Healthcare utilizationMedical management cost, assumptions
      Healthcare utilization source: 30-day trial period analysis. For medical management, case report forms completed at baseline and 3, 8, and 30 days and unscheduled visits. Completed by study coordinator based on participant interviews
      Uterine aspiration (office) cost, assumptions
      Healthcare utilization source: from the published literature Zhang et al6 and Rausch et al7
      Price source
      Scheduled study visitsInitial visitLevel 4 new visit CPT 99204 ($167.40)

      TVUS CPT 76830 ($108.94)

      Misoprostol 800 μg ($3.12)

      Mifepristone 200 μg ($90.00)
      NA2018 Medicare fee schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.


      Costs of medications are from the 2018 NADAC
      NADAC (National Average Drug Acquisition Cost) 2018
      Data.Medicaid.gov.
      data; cost for mifepristone is from 2018 Danco wholesale cost data.
      Mifeprex (Mifepristone): The Original Early Option Pill
      Danco.
      Day 3Level 3 established visit CPT 99213 ($74.16)

      TVUS CPT 76830 ($108.94)
      NA2018 Medicare fee schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.
      Day 8Level 3 established visit CPT 99213 ($74.16)

      TVUS CPT 76830 ($108.94)
      NA2018 Medicare Fee Schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.
      Repeat misoprostol dosesMisoprostol 800 μg ($3.12)NACosts of medications are from the 2018 NADAC data.
      NADAC (National Average Drug Acquisition Cost) 2018
      Data.Medicaid.gov.
      Pain medicationIbuprofen 200 mg ($0.03)

      Codeine 15 mg ($0.33)
      NACosts of medications are from the 2018 NADAC data.
      NADAC (National Average Drug Acquisition Cost) 2018
      Data.Medicaid.gov.
      Other utilizationUnscheduled visits
      Unscheduled visits were collected from trial initiation through 30 days (medical management) or estimated from Zhang et al6 and Rausch et al7 (uterine aspiration)
      There were 10 visits.

      Level 4 established visit CPT 99214 ($109.44)

      TVUS CPT 76830 ($108.94)
      Estimated 9% visits
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.
      ,
      NADAC (National Average Drug Acquisition Cost) 2018
      Data.Medicaid.gov.


      Level 4 established visit CPT 99214 ($109.44)

      TVUS CPT 76830 ($108.94)
      2018 Medicare fee schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.
      Uterine aspiration
      For medical management, uterine aspirations were collected from trial initiation through 30 days. For uterine aspiration, all patients received initial procedure, and repeat procedures were estimated from Zhang et al6 and Rausch et al7
      There were 13 uterine aspirations.

      Uterine aspiration procedure CPT 59820 ($392.04)

      Paracervical block CPT 64450 ($82.08)

      Lidocaine ($0.06)

      Ibuprofen 600 mg ($0.09)

      Doxycycline 100 mg × 3 doses ($1.14)
      All received initial uterine aspirations

      Estimated 3% repeat procedures
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.


      Uterine aspiration procedure CPT 59820 ($392.04)

      Paracervical block CPT 64450 ($82.08)

      Lidocaine ($0.06)

      Ibuprofen 600 mg ($0.09)

      Doxycycline 100 mg × 3 doses ($1.14)
      2018 Medicare fee schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.


      Costs of medications are from the 2018 NADAC data.
      NADAC (National Average Drug Acquisition Cost) 2018
      Data.Medicaid.gov.
      Adverse events
      Adverse events were collected from trial initiation through 30 days (medical management) or estimated from Zhang et al6 and Rausch et al7 (uterine aspiration).
      Pelvic inflammatory disease office visitsThere were 2 visits.

      Level 4 established visit CPT 99214 ($109.44)

      Ceftriaxone 250 mg intramascular ($1.31)

      Doxycycline for 14 d ($10.64)
      NA2018 Medicare fee schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.


      Costs of medications are from the 2018 NADAC data.
      NADAC (National Average Drug Acquisition Cost) 2018
      Data.Medicaid.gov.
      Emergency department visits and hospitalizationsIndividual patient billing records were obtained. CPT codes were abstracted.

      There were2 hemorrhages ($4487 and $5642) and1 hemorrhage or fever ($1673)
      Estimated:

      3% emergency department visits with ultrasound ($329)
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.


      2% fever ($236)
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.


      1 endometritis ($336)
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.


      1 hemorrhage ($5160)
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      ,
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      2018 Medicare fee schedule
      Physician Fee Schedule Search. Centers for Medicare & Medicaid Services.
      CPT, Current Procedural Terminology; NA, not available; NADAC, National Average Drug Acquisition Costs; TVUS, transvaginal ultrasound.
      Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
      a Healthcare utilization source: 30-day trial period analysis. For medical management, case report forms completed at baseline and 3, 8, and 30 days and unscheduled visits. Completed by study coordinator based on participant interviews
      b Healthcare utilization source: from the published literature Zhang et al
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      and Rausch et al
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      c Unscheduled visits were collected from trial initiation through 30 days (medical management) or estimated from Zhang et al
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      and Rausch et al
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      (uterine aspiration)
      d For medical management, uterine aspirations were collected from trial initiation through 30 days. For uterine aspiration, all patients received initial procedure, and repeat procedures were estimated from Zhang et al
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      and Rausch et al
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      e Adverse events were collected from trial initiation through 30 days (medical management) or estimated from Zhang et al
      • Zhang J.
      • Gilles J.M.
      • Barnhart K.
      • et al.
      A comparison of medical management with misoprostol and surgical management for early pregnancy failure.
      and Rausch et al
      • Rausch M.
      • Lorch S.
      • Chung K.
      • Frederick M.
      • Zhang J.
      • Barnhart K.
      A cost-effectiveness analysis of surgical versus medical management of early pregnancy loss.
      (uterine aspiration).

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