Original Research ajog.

org

GYNECOLOGY
Medical management of early pregnancy loss
is cost-effective compared with office uterine aspiration
Divyah Nagendra, MD, MSHP; Sarah M. Gutman, MD, MSPH; Nathanael C. Koelper, MPH; Sandra E. Loza-Avalos, MPH;
Sarita Sonalkar, MD, MPH; Courtney A. Schreiber, MD, MPH; Heidi S. Harvie, MD, MSCE, MBA

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 manage-
ment, medications, or surgical procedures—strategies that differ in pa-
tient 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 preg-
nancy 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 ran-
domized 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,
$789e$868] vs $661 [95% confidence interval, $556e$766]; P¼.004).
Uterine aspiration more frequently led to complete gestational sac
expulsion than medical management (97.3% vs 83.8%; P¼.0001);
however, estimated quality-adjust life-years were higher for medical
management than for uterine aspiration (0.082 [95% confidence interval,
0.8148e0.08248] vs 0.079 [95% confidence interval, 0.0789e0.0791];
P<.0001). Medical management dominated uterine aspiration, with lower
costs and higher confidence interval. The probability that medical man-
agement 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: health economics, mifepristone pretreatment, miscarriage,
misoprostol, quality-adjusted life-years, uterine aspiration

Introduction in the office or operating room), or to medication management have

Early pregnancy loss (EPL), or miscar-
riage, is common, affecting more than 1
million people in the United States
annually.1 With an increased availability
of highly sensitive pregnancy tests and
early ultrasounds, many patients are
diagnosed with an EPL before the onset
of symptoms.2e4 Once diagnosed,
pregnant individuals have 3 treatment
routes available to them: expectant
management (watching and waiting),
surgical intervention (uterine aspiration
Cite this article as: Nagendra D, Gutman SM, Koelper
NC, et al. Medical management of early pregnancy loss is
cost-effective compared to office uterine aspiration. Am J
Obstet Gynecol 2022;227:737.e1-11.
0002-9378/$36.00
ª 2022 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2022.06.054
medical management (using medica-
tions to induce uterine contractions and
expel tissue).5 These 3 options differ in
effectiveness, patient experience, and
cost.6e9
A 2018 multicenter randomized clin-
ical trial (RCT) on medical management
of EPL demonstrated increased clinical
effectiveness when the medication
mifepristone was added as a pretreat-
ment to the standard regimen of
misoprostol.10 Before mifepristone pre-
treatment, as many as 15%e40% of
patients opting for medical management
with 800 mg of vaginal misoprostol
required either additional doses of
medication or a uterine evacuation
procedure to complete the process.6,7
With improved medication manage-
ment effectiveness, patient and clinician
interests in expanding access
increased,11 and the COVID-19
pandemic has highlighted the impor-
tance of treatment options that mini-
mize in-person clinic visits.12,13
However, there are barriers to mifepris-
tone access for EPL treatment. Mife-
pristone 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 Mitiga-
tion Strategy (REMS) that requires both
prescribing providers and dispensing
pharmacies to be certified.14e16
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 implica-
tions for clinical care and reproductive

NOVEMBER 2022 American Journal of Obstetrics & Gynecology 737.e1

Original Research GYNECOLOGY ajog.org

institutional review board approval from

AJOG at a Glance the University of Pennsylvania (Philadel-
Why was this study conducted? phia, PA), the University of California
This study compared the cost-effectiveness of medical management of early Davis (Davis, CA), and the Albert Einstein
pregnancy loss using mifepristone and misoprostol with that of office uterine College of Medicine (New York, NY).
aspiration.
Economic evaluation design
Key findings Incremental cost per quality-adjusted
Medical management with mifepristone and misoprostol dominated office life-year (QALY) gained and the incre-
uterine aspiration from the healthcare sector perspective because costs were lower mental cost per complete gestational sac
and quality-adjusted life-years were similar. expulsion were calculated from the
healthcare sector perspective to compare
What does this add to what is known? medical management and uterine aspi-
Given the cost-effectiveness of medical management of early pregnancy loss with ration for miscarriage management.
mifepristone and misoprostol, increasing access to mifepristone and eliminating This approach follows the recommen-
unnecessary restrictions will substantially improve early pregnancy care. dations of the Second Panel on
Cost-Effectiveness in Health and Medi-
cine19,20 and the Consolidated Health
Economic Evaluation Reporting Stan-
health policy. If medication manage- vaginally without pretreatment. Of note, dards for health economic evaluations
ment is preferred by many patients, de- 141 women were randomized to mife- (Supplemental Table 1).21 An intent-to-
creases the need to access in-person pristone pretreatment, and data from treat approach was used: all partici-
clinical care during a pandemic, and is 148 patients were evaluable for the pants assigned to mifepristone pretreat-
found to be cost-effective, clinicians and medical management arm (age [mean ment in the 2018 trial, regardless of
policymakers should increase efforts to (standard deviation)]: 30.7 [6.3] treatment response, were included in the
improve mifepristone availability and years).10 Participants were scheduled to medical management arm. We used the
reduce access burdens. Given the clinical return at 24 to 96 hours after miso- 30-day follow-up period of the 2018
efficacy of medical management of EPL prostol use (“day 3 visit”) for assessment Schreiber et al10 trial as our time hori-
using mifepristone pretreatment, and its of treatment success. If the gestational zon. For the uterine aspiration arm, we
proven cost-effectiveness compared with sac was not expelled, participants were modeled costs and outcomes for a
misoprostol-alone treatment for EPL,17 offered expectant management, a second demographically similar population
we developed a decision analytical dose of misoprostol, or office-based choosing office uterine aspiration as
model combining the Pregnancy Failure uterine aspiration. All participants were their primary treatment approach.
Regimens (PreFaiR) trial data and data followed up for 30 days after randomi-
from the published literature to assess zation to verify pregnancy expulsion and Costs and use of resources
the cost-effectiveness of medical man- to assess adverse effects. Healthcare sector perspective costs
agement with mifepristone pretreatment We developed a secondary analysis us- included, as recommended, costs
followed by misoprostol (“medical ing PreFaiR results10 to compare the incurred by payers and by patients for the
management”) compared with an office- healthcare sector perspective costs and therapies and other EPL-related health-
based uterine aspiration arm (“uterine health outcomes associated with medical care costs. We used a macro-costing
aspiration”) for the treatment of EPL. management vs uterine aspiration. For approach: healthcare utilization data
the medical management arm, we collected during the trial (medical man-
Materials and Methods used the mifepristone pretreatment- agement arm) or estimated from the
Trial design and participants misoprostol arm results from the trial.10 literature (uterine aspiration arm) were
PreFaiR is a pragmatic comparative The uterine aspiration arm was based on combined with national average Medicare
effectiveness trial conducted at 3 US sites a demographically similar population, reimbursement rates or published prices
from May 1, 2014, to April 30, 2017, the using the published literature to generate to reflect costs to the healthcare sector for
details of which have been previously patient-level data.6e8,10,17 All uterine as- each EPL- or therapy-related clinical
described.10 The trial randomized 300 pirations were assumed to be performed event (Supplemental Table 2). For
women with anembryonic pregnancy or in the office setting with local anesthesia generalizability, national average Medi-
fetal demise before 12 completed gesta- (without general anesthetic or sedative care reimbursement rates were used
tional weeks with a closed cervical os to agents). As is standard practice and rather than institution- or region-specific
pretreatment with 200 mg mifepristone consistent with previous cost analyses, costs. The original study used detailed
administered orally followed by 800 mg office uterine aspiration procedures were case report forms, collected at scheduled
misoprostol administered vaginally or to assumed to have been performed without study visits or telephone calls on study
800 mg misoprostol administered ultrasound guidance.7,17,18 This study has days 3, 8, and 30, for information

737.e2 American Journal of Obstetrics & Gynecology NOVEMBER 2022

ajog.org GYNECOLOGY Original Research

regarding resource use. In addition, the management vs uterine aspiration. A cost-effective below each willingness-to-
number of EPL-related procedures per- secondary ICER was calculated using pay value. An analogous approach was
formed, adverse clinical events (eg, in- treatment success as the effectiveness used for treatment success ICER.22e27
fections, additional office visits, measure; the difference in mean cost was We performed sensitivity analyses to
emergency department visits, and ad- divided by the difference in treatment identify the effect of key variables on
missions), and other healthcare regimens success with medical management vs cost-effectiveness results, including the
for EPL (eg, medications) were collected uterine aspiration. Uncertainty in the cost of mifepristone for medical man-
from both case report forms and elec- estimated ICER was evaluated by agement, cost of uterine aspiration, fre-
tronic medical record review during the generating pairs of differences in mean quency of treatment success, and utility
original study. Unit cost estimates were cost and mean QALYs from 5000 repli- score assumptions.
applied to calculate the total costs for each cations of cost and QALY data and Statistical analyses were performed
participant. For medical management, calculating 95% confidence intervals using Stata (version 14.2; StataCorp,
costs included initial treatment with 200 (CIs). The cost-effectiveness plane shows College Station, TX). P values of <.05
mg mifepristone and 800 mg misoprostol. the differences between the medical indicated significance; all analyses were
For uterine aspiration, costs included an management and uterine aspiration 2-sided.
office-based procedure with local anes- arms in mean cost on the y-axis and
thesia and estimated complication rates mean QALYs on the x-axis. The ICER Results
from the literature.6,7 Results were was calculated for each replication and Resources and costs
expressed in 2018 US dollars. compared with a range of willingness-to- Estimated mean per-person costs were
pay values ($0e$2,000,000 per QALY). higher for uterine aspiration ($828 [95%
Effectiveness outcome Cost-effectiveness acceptability curves CI, $789e$868]) than for medical
The primary effectiveness outcome was (CEACs) displayed the percentage management ($661 [95% CI,
the 1-month QALY. QALYs were based on of ICER replications that were $556e$766]) (P¼.004) (Table 1).
a modified utility score taken from the
published EPL literature of 30-day trials,
with successful medical management
defined as 1, successful uterine aspiration TABLE 1
defined as 0.95, and need for uterine Costs and outcomes of early pregnancy loss treatment with medical
aspiration or repeat dosage after failed management vs uterine aspiration
medical or procedural treatment defined Medical management Uterine aspiration
as 0.90.7,17 QALYs were calculated from Variable (US dollar) (US dollar) P value
the utility scores, which were assumed to Mean per-person costs
remain constant during the 30-day
trial.7,17 Other effectiveness outcomes Direct costs—formal
healthcare sectora
included treatment success, defined for
medical management as gestational sac Treatment 519.34 (57.03) 741.87 (0.00) <.0001
expulsion with 1 dose of misoprostol at Reaspiration 41.71 (134.87) 25.52 (130.37) .223
the first follow-up visit and for uterine Repeat misoprostol 0.22 (0.80) — —
aspiration as a successful procedure, with b
Unscheduled visits 14.13 (52.68) 18.31 (59.21) .468
no additional intervention needed within
30 days after treatment. Any uterine as- Other complicationsc 84.03 (625.48) 33.41 (318.87) .259
pirations performed for treatment fail- Pain control d
1.31 (1.47) 9.29 (0.0) <.0001
ures were assumed to be 100% Total healthcare perspective 660.75 (555.88e765.62) 828.40 (789.12e867.68) .004
completed. costs (US dollar)e
Effects
Statistical analysis
Univariate cost and effectiveness mea- Average QALY per person 0.082 (0.003) 0.0790 (0.001) <.0001
sures were compared using unpaired t Completion rate after first 83.8 (36.98) 97.3 (16.22) .0001
tests to assess differences between med- treatment (%)
ical management and uterine aspiration. Data are presented as mean (standard deviation) or mean (95% confidence interval), unless otherwise indicated.
The primary cost-effectiveness measure a
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; b Unscheduled
was the incremental cost-effectiveness visits were categorized as visits requiring a visit to a provider and a transvaginal ultrasound; c Other complications included
ratio (ICER), defined as the difference 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;
in mean cost of medical management vs e
All costs reported in 2018 US dollars ($).
uterine aspiration, divided by the dif- Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.
ference in mean QALYs of medical

NOVEMBER 2022 American Journal of Obstetrics & Gynecology 737.e3

Original Research GYNECOLOGY ajog.org

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 man-
agement after their initial treatment,
compared with an estimated 97.3% of
women with successful management
with uterine aspiration (P¼.0001)
(Table 1).
Estimated QALYs were 0.0790 (95%
CI, 0.0789e0.0791) for uterine aspira-
tion and 0.0820 (95% CI,
0.8148e0.08248) for medical manage-
ment (P<.0001) (Table 1).
Cost-effectiveness
In comparing the cost-effectiveness of
medical management with that of uter-
ine aspiration from the healthcare sector
perspective, medical management was
dominant, as costs were lower and
QALYs were higher for medical man-
agement 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).
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 anal-
ysis 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 uter-
ine aspiration procedure from $475 to
$11, or an increase in the cost of mife-
pristone 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.28
With a decrease in percentage comple-
tion 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 suc-
cessful 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 man-
agement 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.28
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.5,17 Previous
research comparing the cost-effective-
ness of medical management with that of
uterine aspiration for EPL management
was based on medical management
protocols using misoprostol alone.7 Our
analysis provided additional information
for patients seeking EPL treatment, cli-
nicians incorporating the full range of
EPL care into their practices, healthcare
payers, and policymakers.
Clinical implications
The COVID-19 pandemic has high-
lighted the importance of increasing ac-
cess to EPL treatment options that
reduce the need for in-person clinical
visits. As the pandemic has affected

TABLE 2
Incremental 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-years Health outcome: completion after first treatment
Difference in mean $167.65 Difference in mean cost per person $167.65
cost per person
Difference in mean 0.0030 Difference in completion rate after first 13.5%
QALY per person treatment
ICER Medical management dominant ICER $12.42 per 1 percentage point in
ICER (55,883.33) completion rate
95% CI ($99,683.07 to $5531.71) 95% CI ($1.25 to $45.64)
per QALY
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.

737.e4 American Journal of Obstetrics & Gynecology NOVEMBER 2022

ajog.org GYNECOLOGY Original Research

FIGURE 1
ICER scatter plot for mifepristone pretreatment vs office uterine aspiration, by measure of health outcome

A Mifepristone Pretreatment vs Office Uterine Aspiration B Mifepristone Pretreatment vs Office Uterine Aspiration
Healthcare Perspective − QALYs Healthcare Perspective − Percent Completion
500

500
Higher Costs and Lower QALYs for Mifepristone Higher Costs and Higher QALYs for Mifepristone Higher Costs and Lower % Completion for Mifepristone Higher Costs and Higher % Completion for Mifepristone
Incremental Cost of Mifepristone + Misoprostol

Incremental Cost of Mifepristone + Misoprostol

400

400
300

300
200

200
95% CI, Upper
100

100
95% CI, Upper
0

0
−500 −400 −300 −200 −100

−500 −400 −300 −200 −100

95% CI, Lower
95% CI, Lower

Lower Costs and Lower QALYs for Mifepristone Lower Costs and Higher QALYs for Mifepristone Lower Costs and Lower % Completion for Mifepristone Lower Costs and Higher % Completion for Mifepristone

−.005 −.004 −.003 −.002 −.001 0 .001 .002 .003 .004 .005 −50 −40 −30 −20 −10 0 10 20 30 40 50
Incremental QALY of Mifepristone + Misoprostol Incremental Percent Completion of Mifepristone + Misoprostol

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.

access to hospital services, the impor- medical termination of intrauterine in December 2021, the FDA modified the
tance of an effective treatment option pregnancy. The REMS regulations for REMS by removing the requirement that
that can be offered through telemedicine mifepristone initially required providers mifepristone be dispensed only in certain
has become essential.24,25 This study has to be certified to prescribe mifepristone, healthcare settings, specifically clinics,
contributed to a growing body of litera- mifepristone to be dispensed in a clinic medical offices, and hospitals (referred to
ture showing medication management or hospital setting, and prescribers to as the “in-person dispensing require-
with mifepristone and misoprostol for obtain a signed patient agreement form ment”), and adding a requirement that
EPL to be safe, effective, and cost- before dispensing the medication.15 pharmacies that dispense the drug be
effective. Unfortunately, clinicians are These restrictions have prevented many certified.15 How these changes will
hindered in prescribing mifepristone patients from accessing mifepristone and impact patients who wish to use mife-
because of unnecessary restrictions, are particularly burdensome for Black pristone “off-label” for miscarriage
limiting the widespread use of this and underinsured patients, who are management remains to be seen, but
treatment strategy.14,15,29 We have more likely to seek treatment in emer- evidence of cost-effectiveness and the
shown that cost is not a barrier. gency care settings.30 In April 2021, the recent reduction in regulatory barriers
The FDA initially designated mife- FDA announced its intention to “exercise may result in improved care and access
pristone as a medication requiring REMS enforcement discretion” during the for patients suffering from the most
after its approval in September 2000 for COVID-19 public health emergency, and common complication in pregnancy.

NOVEMBER 2022 American Journal of Obstetrics & Gynecology 737.e5

Original Research GYNECOLOGY ajog.org

FIGURE 2
CEAC for mifepristone pretreatment vs uterine aspiration, by measure of health outcome

A Cost effec veness acceptability curve of Mifepristone pretreatment vs Office Uterine

Aspira on - Healthcare Perspec ve QALYs
B Cost effec veness acceptability curve of Mifepristone pretreatment vs Office Uterine
Aspira on - Healthcare perspec ve percent comple on
1 1
97.5%
Probability
0.98 0.9
97.5%
Probability
0.96 0.8

0.94 0.7
Probability of Cost-effec veness

Probability of Cost-effec veness

0.92 0.6

0.9 0.5

0.88 0.4

0.86 0.3

0.84 0.2

0.82 0.1

0.8 0
$- $100,000 $200,000 $300,000 $400,000 $500,000 $600,000 $700,000 $800,000 $900,000 $1,000,000 $- $100,000 $200,000 $300,000 $400,000 $500,000 $600,000 $700,000 $800,000 $900,000 $1,000,000
Willingness-to-pay Willingness-to-pay

Mifepristone-pretreatment vs Uterine Aspira on Mifepristone-pretreatment vs Uterine Aspira on

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.

Strengths and limitations that can be used across our field. We lower costs, making it a high-value care
Our study used economic data collected made assumptions based on limited alternative. Increasing access to mife-
prospectively from a pragmatic RCT for literature regarding the assignment of pristone and eliminating unnecessary
the medical management arm. However, utility preference score values for suc- restrictions will improve early pregnancy
our analysis has some limitations. Our cessful medical management, failed care. n
study used 2018 national Medicare medical management, successful uterine
reimbursement rates to calculate aspiration, and failed uterine aspiration. Acknowledgments
healthcare costs to improve generaliza- We performed sensitivity analyses to We thank the members of the Pregnancy Failure
tion, but actual costs for healthcare and further determine the smallest difference Regimens trial team and the study participants
for their dedication.
reimbursement rates may vary by region at which medical management remained
and payer. The cost of mifepristone was cost-effective.
included in healthcare costs but may also Our study examined only the health- References
vary by region and year purchased. The care perspective when comparing these 2 1. Ventura SJ, Curtin SC, Abma JC,
effective EPL treatment options. There is Henshaw SK. Estimated pregnancy rates and
use of a uterine aspiration group
rates of pregnancy outcomes for the United
modeled with data from the published a need to assess the societal sector States, 1990-2008. Natl Vital Stat Rep 2012;60:
literature necessitated different sources perspective of EPL management to 1–21.
of healthcare utilization data between conduct more comprehensive cost- 2. Sapra KJ, Joseph KS, Galea S, Bates LM,
the comparison groups. Our sensitivity effectiveness analyses and better iden- Louis GM, Ananth CV. Signs and symptoms of
tify the complete costs associated with early pregnancy loss. Reprod Sci 2017;24:
analyses were performed with these
502–13.
limitations in mind to demonstrate treatment. 3. Wilcox AJ, Weinberg CR, O’Connor JF, et al.
thresholds at which mifepristone pre- Incidence of early loss of pregnancy. N Engl J
treatment would no longer be cost- Conclusion Med 1988;319:189–94.
effective. Medical management of EPL with 4. Wang X, Chen C, Wang L, Chen D, Guang W,
mifepristone pretreatment and miso- French J. Conception, early pregnancy loss, and
In addition, further studies must be
time to clinical pregnancy: a population-based
done to evaluate the QALYs for EPL and prostol has been found to be cost- prospective study. Fertil Steril 2003;79:577–84.
other obstetrical and gynecologic pro- effective compared with office uterine 5. American College of Obstetricians and Gy-
cedures to establish standard measures aspiration, with similar QALYs and necologists’ Committee on Practice Bulletins—

737.e6 American Journal of Obstetrics & Gynecology NOVEMBER 2022

ajog.org
Gynecology. ACOG Practice Bulletin No. 200:
early pregnancy loss. Obstet Gynecol 2018;132:
e197–207.
6. Zhang J, Gilles JM, Barnhart K, et al.
A comparison of medical management with
misoprostol and surgical management for early
pregnancy failure. N Engl J Med 2005;353:
761–9.
7. 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. Fertil Steril 2012;97:
355–60.
8. Cubo AM, Soto ZM, Haro-Pérez A, Hernández
Hernández ME, Doyague MJ, Sayagués JM.
Medical versus surgical treatment of first trimester
spontaneous abortion: a cost-minimization anal-
ysis. PLoS One 2019;14:e0210449.
9. Schreiber CA, Chavez V, Whittaker PG,
Ratcliffe SJ, Easley E, Barg FK. Treatment de-
cisions at the time of miscarriage diagnosis.
Obstet Gynecol 2016;128:1347–56.
10. Schreiber CA, Creinin MD, Atrio J,
Sonalkar S, Ratcliffe SJ, Barnhart KT. Mifepris-
tone pretreatment for the medical management
of early pregnancy loss. N Engl J Med 2018;378:
2161–70.
11. deFiebre G, Srinivasulu S, Maldonado L,
Romero D, Prine L, Rubin SE. Barriers and en-
ablers to family physicians’ provision of early
pregnancy loss management in the United
States. Womens Health Issues 2021;31:57–64.
12. Kohn JE, Snow JL, Simons HR, Seymour JW,
Thompson TA, Grossman D. Medication abortion
provided through telemedicine in four U.S. states.
Obstet Gynecol 2019;134:343–50.
13. Ehrenreich K, Kaller S, Raifman S,
Grossman D. Women’s experiences using tele-
medicine to attend abortion information visits in
Utah: a qualitative study. Womens Health Issues
2019;29:407–13.
14. Srinivasulu S, Yavari R, Brubaker L, Riker L,
Prine L, Rubin SE. US clinicians’ perspectives on
how mifepristone regulations affect access to
medication abortion and early pregnancy loss
care in primary care. Contraception 2021;104:
92–7.
15. Approved Risk Evaluation and Mitigation
Strategies (REMS). US Food and Drug Admin-
GYNECOLOGY
istration 2021. Available at: https://www.
accessdata.fda.gov/scripts/cder/rems/index.
cfm. Accessed December 21, 2021.
16. Mifeprex (Mifepristone): The Original Early
Option Pill. Danco. Available at: https://www.
earlyoptionpill.com. Accessed July 11, 2022.
17. Nagendra D, Koelper N, Loza-Avalos SE,
et al. Cost-effectiveness of mifepristone pre-
treatment for the medical management of
nonviable early pregnancy: secondary analysis
of a randomized clinical trial. JAMA Netw Open
2020;3:e201594.
18. Dalton VK, Harris L, Weisman CS, Guire K,
Castleman L, Lebovic D. Patient preferences,
satisfaction, and resource use in office evacua-
tion of early pregnancy failure. Obstet Gynecol
2006;108:103–10.
19. Sanders GD, Neumann PJ, Basu A, et al.
Recommendations for conduct, methodological
practices, and reporting of cost-effectiveness
analyses: second panel on cost-effectiveness
in health and medicine. JAMA 2016;316:
1093–103.
20. Sanders GD, Maciejewski ML, Basu A.
Overview of cost-effectiveness analysis. JAMA
2019;321:1400–1.
21. 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. Value
Health 2013;16:231–50.
22. Efron B, Tibshirani RJ. An introduction to the
bootstrap. Boca Raton, FL: CRC Press; 1994.
23. Barber JA, Thompson SG. Analysis of cost
data in randomized trials: an application of the
non-parametric bootstrap. Stat Med 2000;19:
3219–36.
24. Glick HA, Doshi JA, Sonnad SS, Polsky D.
Economic evaluation in clinical trials, 2nd ed.
Oxford, United Kingdom: Oxford University
Press; 2013.
25. Ramsey SD, Willke RJ, Glick H, et al. Cost-
effectiveness analysis alongside clinical trials II:
an ISPOR Good Research Practices Task Force
report. Value Health 2015;18:161–72.
26. Fenwick E, O’Brien BJ, Briggs A. Cost-
effectiveness acceptability curves–facts,
NOVEMBER 2022 American Journal of Obstetrics & Gynecology
Original Research
fallacies and frequently asked questions. Health
Econ 2004;13:405–15.
27. Fenwick E, Byford S. A guide to cost-
effectiveness acceptability curves. Br J Psychi-
atry 2005;187:106–8.
28. Neumann PJ, Cohen JT, Weinstein MC.
Updating cost-effectiveness–the curious resil-
ience of the $50,000-per-QALY threshold.
N Engl J Med 2014;371:796–7.
29. Thompson A, Singh D, Ghorashi AR,
Donovan MK, Ma J, Rikelman J. The dispro-
portionate burdens of the mifepristone REMS.
Contraception 2021;104:16–9.
30. Flynn AN, Shorter JM, Roe AH, Sonalkar S,
Schreiber CA. The Burden of the Risk Evaluation
and Mitigation Strategy (REMS) on providers
and patients experiencing early pregnancy loss:
a commentary. Contraception 2021;104:29–30.
Author and article information
From the Department of Obstetrics and Gynecology,
Cambridge Health Alliance, Cambridge, MA (Dr Nagen-
dra); Department of Obstetrics and Gynecology, Perelman
School of Medicine at the University of Pennsylvania,
Philadelphia, PA (Drs Nagendra and Gutman, Mr Koelper,
Ms Loza-Avalos, and Drs Sonalkar, Schreiber, and Har-
vie); and Leonard Davis Institute of Health Economics,
University of Pennsylvania, Philadelphia, PA (Drs Sonal-
kar, Schreiber, and Harvie).
Received Jan. 28, 2022; revised June 17, 2022;
accepted June 26, 2022.
C.A.S. and H.S.H contributed equally to this work.
The authors report no conflict of interest.
This study was supported by the National Institute of
Child Health and Human Development of the National
Institutes of Health (Eunice Kennedy Shriver award
number R01-HD0719-20 [C.A.S.] and Women’s Repro-
ductive Health Research award number K12-HD001265-
20 [S.S.]) and a Society of Family Planning Research Fund
Midcareer Mentor Award (C.A.S.). The funding sources
were not involved in the study design; collection, analysis,
and interpretation of data; writing of the report; or deci-
sion to submit the article for publication.
This study was registered on ClinicalTrials.gov
(registration number: NCT02012491; www.clinicaltrials.
gov)
Corresponding author: Sarah M. Gutman, MD, MSPH.
sarah.gutman@pennmedicine.upenn.edu
737.e7
Original Research GYNECOLOGY ajog.org

SUPPLEMENTAL TABLE 1
Consolidated Health Economic Evaluation Reporting Standards
Reported on page
number or line
Section Item number Recommendation number
Title and abstract
Title 1 Identify the study as an economic evaluation or use more specific terms, 1
such as “cost-effectiveness analysis,” and describe the interventions
compared.
Abstract 2 Provide a structured summary of objectives, perspective, setting, 3
methods (including study design and inputs), results (including base case
and uncertainty analyses), and conclusions.
Introduction
Background and 3 Provide an explicit statement of the broader context for the study. 5 and 6
objectives Present the study question and its relevance for health policy or practice
decisions.
Methods
Target population and 4 Describe characteristics of the base case population and subgroups 6
subgroups analyzed, including why they were chosen.
Setting and location 5 State relevant aspects of the system or systems in which the decision or 6
decisions need to be made.
Study perspective 6 Describe the perspective of the study and relate this to the costs being 6 and 7
evaluated.
Comparators 7 Describe the interventions or strategies being compared and state why 5 and 6
they were chosen.
Time horizon 8 State the time horizon or horizons over which costs and consequences 6
are being evaluated and say why appropriate.
Discount rate 9 Report the choice of discount rate or rates used for costs and outcomes NA
and say why appropriate. 30-day time
horizon
Choice of health 10 Describe what outcomes were used as the measure or measures of 8
outcomes benefit in the evaluation and their relevance for the type of analysis
performed.
Measurement of 11a Single study-based estimates: Describe fully the design features of the 5e6
effectiveness single effectiveness study and why the single study was a sufficient
source of clinical effectiveness data.
11b Synthesis-based estimates: Describe fully the methods used for 6
identification of included studies and synthesis of clinical effectiveness
data.
Measurement and 12 If applicable, describe the population and methods used to elicit 8
valuation of preference- preferences for outcomes.
based outcomes
Estimating resources and 13a Single study-based economic evaluation: Describe approaches used to 7
costs 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.
13b Model-based economic evaluation: Describe approaches and data 7
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.
Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022. (continued)

737.e8 American Journal of Obstetrics & Gynecology NOVEMBER 2022

ajog.org GYNECOLOGY Original Research

SUPPLEMENTAL TABLE 1
Consolidated Health Economic Evaluation Reporting Standards (continued)
Reported on page
number or line
Section Item number Recommendation number
Currency, price date, and 14 Report the dates of the estimated resource quantities and unit costs. 7
conversion 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.
Choice of model 15 Describe and give reasons for the specific type of decision analytical 6
model used. Providing a figure to show model structure is strongly
recommended.
Assumptions 16 Describe all structural or other assumptions underpinning the decision 6e8
analytical model.
Analytical methods 17 Describe all analytical methods supporting the evaluation. This could 8 and 9
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.
Results
Study parameters 18 Report the values, ranges, references, and, if used, probability Supplement
distributions for all parameters. Report reasons or sources for Table 2
distributions used to represent uncertainty where appropriate. Providing a
table to show the input values is strongly recommended.
Incremental costs and 19 For each intervention, report mean values for the main categories of 9 and 10
outcomes estimated costs and outcomes of interest and mean differences between Exhibit 1 and 2
the comparator groups. If applicable, report incremental cost-
effectiveness ratios.
Characterizing 20a Single study-based economic evaluation: Describe the effects of 9 and 10
uncertainty sampling uncertainty for the estimated incremental cost and incremental Exhibit 1e4
effectiveness parameters, together with the impact of methodological
assumptions (such as discount rate and study perspective).
20b Model-based economic evaluation: Describe the effects on the results of 9 and 10
uncertainty for all input parameters and uncertainty related to the Exhibit 1e4
structure of the model and assumptions.
Characterizing 21 If applicable, report differences in costs, outcomes, or cost-effectiveness NA
heterogeneity 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.
Discussion
Study findings, 22 Summarize key study findings and describe how they support the 11e13
limitations, conclusions reached. Discuss limitations and the generalizability of the
generalizability, and findings and how the findings fit with current knowledge.
current knowledge
Other
Source of funding 23 Describe how the study was funded and the role of the funder in the 1
identification, design, conduct, and reporting of the analysis. Describe
other nonmonetary sources of support.
Conflicts of interest 24 Describe any potential for conflict of interest of study contributors in 1
accordance with journal policy. In the absence of a journal policy, we
recommend authors comply with International Committee of Medical
Journal Editors recommendations.
Checklist available at http://www.ispor.org/TaskForces/EconomicPubGuidelines.asp.
NA, not available.
Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.

NOVEMBER 2022 American Journal of Obstetrics & Gynecology 737.e9

Original Research GYNECOLOGY ajog.org

SUPPLEMENTAL TABLE 2
Inputs and data sources for costs
Medical management cost, Uterine aspiration (office)
Healthcare utilization assumptionsa cost, assumptionsb Price source
Scheduled study Initial visit Level 4 new visit CPT 99204 NA 2018 Medicare fee schedule1
visits ($167.40) Costs of medications are from the 2018
TVUS CPT 76830 ($108.94) NADAC2 data; cost for mifepristone is
Misoprostol 800 mg ($3.12) from 2018 Danco wholesale cost
Mifepristone 200 mg ($90.00) data.16
Day 3 Level 3 established visit CPT NA 2018 Medicare fee schedule1
99213 ($74.16)
TVUS CPT 76830 ($108.94)
Day 8 Level 3 established visit CPT NA 2018 Medicare Fee Schedule1
99213 ($74.16)
TVUS CPT 76830 ($108.94)
Repeat Misoprostol 800 mg ($3.12) NA Costs of medications are from the 2018
misoprostol NADAC data.2
doses
Pain medication Ibuprofen 200 mg ($0.03) NA Costs of medications are from the 2018
Codeine 15 mg ($0.33) NADAC data.2
Other utilization Unscheduled There were 10 visits. Estimated 9% visits1,2 2018 Medicare fee schedule1
visitsc Level 4 established visit CPT Level 4 established visit
99214 ($109.44) CPT 99214 ($109.44)
TVUS CPT 76830 ($108.94) TVUS CPT 76830 ($108.94)
Uterine There were 13 uterine All received initial uterine 2018 Medicare fee schedule1
aspirationd aspirations. aspirations Costs of medications are from the 2018
Uterine aspiration procedure Estimated 3% repeat NADAC data.2
CPT 59820 ($392.04) procedures6,7
Paracervical block CPT 64450 Uterine aspiration procedure
($82.08) CPT 59820 ($392.04)
Lidocaine ($0.06) Paracervical block CPT
Ibuprofen 600 mg ($0.09) 64450 ($82.08)
Doxycycline 100 mg  3 Lidocaine ($0.06)
doses ($1.14) Ibuprofen 600 mg ($0.09)
Doxycycline 100 mg  3
doses ($1.14)
Adverse eventse Pelvic There were 2 visits. NA 2018 Medicare fee schedule1
inflammatory Level 4 established visit Costs of medications are from the 2018
disease office CPT 99214 ($109.44) NADAC data.2
visits Ceftriaxone 250 mg
intramascular ($1.31)
Doxycycline for 14 d ($10.64)
Emergency Individual patient billing Estimated: 2018 Medicare fee schedule1
department records were obtained. CPT 3% emergency department
visits and codes were abstracted. visits with ultrasound ($329)6,7
hospitalizations There were2 hemorrhages 2% fever ($236)6,7
($4487 and $5642) and1 1 endometritis ($336)6,7
hemorrhage or fever ($1673) 1 hemorrhage ($5160)6,7
CPT, Current Procedural Terminology; NA, not available; NADAC, National Average Drug Acquisition Costs; TVUS, transvaginal ultrasound.
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 al6 and Rausch et al7; c Unscheduled visits were collected from trial initiation
through 30 days (medical management) or estimated from Zhang et al6 and Rausch et al7 (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 al6 and Rausch et al7; e Adverse events were collected from trial
initiation through 30 days (medical management) or estimated from Zhang et al6 and Rausch et al7 (uterine aspiration).
Nagendra. Cost-effective early pregnancy loss management. Title. Am J Obstet Gynecol 2022.

737.e10 American Journal of Obstetrics & Gynecology NOVEMBER 2022

ajog.org GYNECOLOGY Original Research

f e e - s c h e d u l e / o v e r v i e w . a s p x . Accessed 73c5-552b-b84e-ac795f34d056. Accessed

Supplemental References December 28, 2018. December 28, 2018.
1. Physician Fee Schedule Search. Centers 2. NADAC (National Average Drug Acquisition
for Medicare & Medicaid Services. Available at: Cost) 2018. Data.Medicaid.gov. Available at:
h t t p s :/ / w w w . c m s .g o v / a p p s / p h y s i c i a n - https://data.medicaid.gov/dataset/8de1b213-

NOVEMBER 2022 American Journal of Obstetrics & Gynecology 737.e11