Trends in the Use of Mifepristone for Medical Management of Early Pregnancy Loss From 2016 to 2020

Abstract

This study assesses the use of mifepristone plus misoprostol for miscarriage management among commercially insured adults in the US.

Early pregnancy loss (miscarriage) is failure of an intrauterine pregnancy before 13 weeks of gestation. In November 2018, the American College of Obstetricians and Gynecologists (ACOG) recommended combination therapy of mifepristone plus misoprostol (similar to that used for induced medication abortion) for the medical management of miscarriage rather than using misoprostol alone.¹ Mifepristone plus misoprostol has been shown in randomized clinical trials to be more effective than misoprostol alone (success rate of 84% vs 67%, respectively) in expelling the gestational sac by the first follow-up visit.²

In addition, combination therapy with mifepristone plus misoprostol is safe and more cost-effective than misoprostol alone.^3,4 Yet, mifepristone is highly regulated under the US Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, and the requirements of the program dissuade clinicians from stocking and using mifepristone.⁵ In this study, we assessed the use of mifepristone plus misoprostol for miscarriage management among commercially insured adults in the US.

Methods

We conducted a retrospective cohort study of commercially insured individuals aged 15 to 49 years receiving medical management of miscarriage using Merative MarketScan data from January 1, 2016, through December 31, 2020. MarketScan includes deidentified patient-level health care claims from approximately 350 payers of primarily large employers. Using both prescription and outpatient medical service claims, we identified those receiving misoprostol alone or mifepristone plus misoprostol within 28 days after a diagnosed miscarriage (eFigure in Supplement 1). Vanderbilt University Medical Center institutional review board deemed the study exempt.

We used a log-binomial model to examine the relationship between time and use rates of misoprostol alone or in combination with mifepristone. Although miscarriage management is distinct from abortion care, it is possible that some claims may not be observed in states with restrictions on abortion care. To account for this, we separately estimated rates of medication use for miscarriage both overall and excluding states with abortion care restrictions on fully insured private plans (a list of the states excluded appears in footnote c in Table 1). We estimated risk ratios (RRs) with 99% CIs for medication use over time, including before (January 2016-November 2018) and after (December 2018-December 2020) the release of the ACOG guideline. We applied sparse patient clustering to account for repeated events among individuals.

Table 1. Individual-Level Characteristics of the Study Cohort.

	Guideline from the American College of Obstetricians and Gynecologists on early pregnancy loss managementa				Total
	Before release (Jan 2016-Nov 2018) (n = 13 594)		After release (Dec 2018-Dec 2020) (n = 8532)
	Mifepristone plus misoprostol	Misoprostol alone	Mifepristone plus misoprostol	Misoprostol alone
All states
Total	74 (0.54)	13 520 (99.46)	152 (1.78)	8380 (98.22)	22 126b
Patient age, median (IQR), y	33.5 (30-39)	33 (29-37)	34 (32-37)	33 (29-37)	33 (29-37)
US region
Midwest	7 (0.2)	2234 (61.3)	8 (0.2)	1397 (38.3)	3646
Northeast	35 (1.1)	1981 (60.9)	61 (1.9)	1176 (36.2)	3253
South	6 (0.1)	6617 (60.6)	17 (0.2)	4274 (39.2)	10 914
West	26 (0.6)	2681 (62.5)	65 (1.5)	1519 (35.4)	4291
Unknown	0	7 (31.8)	1 (4.5)	14 (63.6)	22
Source of medications
Prescription	0	13 322 (61.7)	1 (<1)	8272 (38.3)	21 595
Clinic	47 (11.5)	198 (48.3)	57 (13.9)	108 (26.3)	410
Multiple sources	27 (22.3)	0	94 (77.7)	0	121
Unrestricted states c
	Before Nov 2018 (n = 18 828)		After Nov 2018 (n = 6697)
Total	73 (0.67)	10 755 (99.33)	148 (2.21)	6549 (97.79)	17 525d
Patient age, median (IQR), y	34 (30-39)	33 (29-37)	34 (32-37)	33 (29-37)	33 (29-37)
US region
Midwest	7 (0.3)	1359 (63.8)	7 (0.3)	758 (35.6)	2131
Northeast	35 (1.1)	1981 (60.9)	61 (1.9)	1176 (36.2)	3253
South	5 (0.1)	4925 (60.8)	14 (0.2)	3161 (39.0)	8105
West	26 (0.6)	2483 (61.9)	65 (1.6)	1440 (35.9)	4014
Unknown	0	7 (31.8)	1 (4.5)	14 (63.6)	22
Source of medications
Prescription	0	10 592 (62.1)	1 (<1)	6461 (37.9)	17 054
Clinic	47 (13.3)	163 (46.0)	56 (15.8)	88 (24.9)	354
Multiple sources	26 (22.2)	0	91 (77.8)	0	117

^a Data are expressed as No. (%) unless otherwise indicated.

^b Data represent 22 116 unique first-time patients receiving mifepristone plus misoprostol or misoprostol alone (22 116 had ≥1 miscarriage; 524 had ≥2 miscarriages [10 of whom received both treatments for different miscarriages, representing 22 126 patients receiving both treatments over time]; and 21 had 3 miscarriages) and 22 661 claims for mifepristone plus misoprostol and misoprostol alone. In 2016, 0.40% received mifepristone plus misoprostol and 99.60% received misoprostol alone; and in 2020, these percentages were 2.50% and 97.50%, respectively.

^c The 11 excluded states with restrictions on abortion care for fully insured private plans as of May 1, 2022, were Idaho, Indiana, Kansas, Kentucky, Michigan, Missouri, Nebraska, North Dakota, Oklahoma, Texas, and Utah.

^d Data represent 17 515 unique first-time patients receiving mifepristone plus misoprostol or misoprostol alone (17 515 had ≥1 miscarriage; 434 had ≥2 miscarriages [10 of whom received both treatments for different miscarriages, representing 17 525 patients receiving both treatments over time]; and 16 had 3 miscarriages) and 17 965 claims for mifepristone plus misoprostol and misoprostol alone. In 2016, 0.51% received mifepristone plus misoprostol and 99.49% received misoprostol alone; and in 2020, these percentages were 3.08% and 96.92%, respectively.

A 2-sided P < .01 defined statistical significance. We used SAS Analytics version 9.4 (SAS Institute Inc) and R version 3.6.3 (R Foundation for Statistical Computing) for the analyses.

Results

A total of 30 169 patients with medically managed miscarriages were identified. After exclusions, the final cohort comprised 22 661 medically managed miscarriages across 22 116 unique patients. The median age was 33 years (IQR, 29-37 years) with most residing in the southern US.

One percent received mifepristone plus misoprostol, whereas 99% received misoprostol alone (Table 1). The receipt of mifepristone plus misoprostol increased over time (from 0.40% in 2016 to 2.50% in 2020; RR, 1.04 [99% CI, 1.03-1.06 per month increase]; P < .001) (Table 2). Before the ACOG guideline update, 0.54% received mifepristone plus misoprostol and 99.46% received misoprostol alone (Table 1). After the ACOG guideline update, 1.78% received mifepristone plus misoprostol and 98.22% received misoprostol alone (Table 1). After the release of the ACOG guideline, individuals with a miscarriage undergoing medical management were more likely to receive mifepristone plus misoprostol than before the release (RR, 3.20 [99% CI, 2.22-4.61]; P < .001) (Table 2).

Table 2. Association Between Month of Treatment and Use of Mifepristone Plus Misoprostol.

	Received mifepristone plus misoprostol, %		Risk ratio (99% CI)a
	Before release of ACOG guideline (or 2016)	After release of ACOG guideline (or 2020)
All states
Month of treatment	0.40	2.50	1.04 (1.03-1.06)b
Release of the ACOG guideline	0.54	1.78	3.20 (2.22-4.61)c
Unrestricted states d
Month of treatment	0.51	3.08	1.04 (1.03-1.06)b
Release of the ACOG guideline	0.67	2.21	3.20 (2.22-4.63)c

Abbreviation: ACOG, American College of Obstetricians and Gynecologists.

^a P<.001 for all comparisons.

^b Per month increase after release of the ACOG guideline.

^c Increase after release of the ACOG guideline.

^d The 11 excluded states with restrictions on abortion care for fully insured private plans as of May 1, 2022, were Idaho, Indiana, Kansas, Kentucky, Michigan, Missouri, Nebraska, North Dakota, Oklahoma, Texas, and Utah.

When limiting the analyses to states without restrictions on insurance coverage of abortion care, there was minimal variation from the primary analyses. Before the ACOG update, 0.67% received mifepristone plus misoprostol and 99.33% received misoprostol alone (Table 1). After the ACOG update, 2.21% received mifepristone plus misoprostol and 97.79% received misoprostol alone (Table 1). The RRs per month and before and after the guideline change did not vary from the primary analyses.

Discussion

This research found commercially insured individuals undergoing medical management of miscarriage rarely received the recommended combination treatment of mifepristone plus misoprostol. Even though treatment with mifepristone plus misoprostol increased after the ACOG updated recommendations, it remained underused over the study period.

This study is limited by focusing on commercially insured patients and might not generalize to other insured or uninsured populations, and by the short period of analyses after release of the guideline. The long-standing politicization of mifepristone, and its availability, may worsen as a result of the increasing polarity of reproductive health care after the Dobbs v Jackson Women’s Health Organization decision in 2022 eliminated the constitutional right to abortion.⁶ Continued efforts are needed to promote the use and availability of mifepristone for efficient medical management of miscarriage.

Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Senior Editor.

Supplement 1.

eFigure. Flow diagram of the study cohort

Supplement 2.

Data sharing statement