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Aligning mifepristone regulation with evidence: driving policy change using 15 years of excellent safety data

      Mifepristone was approved for sale in the United States 15 years ago this month. Use of mifepristone has steadily increased since its introduction; medical abortions now account for approximately 36% of the 1.1 million induced abortions that occur in the United States each year [
      • Jones R.K.
      • Jerman J.
      Abortion incidence and service availability in the United States, 2011.
      ,
      • Nash E.
      • Gold R.B.
      • Rathbum G.
      • Vierboom Y.
      Laws affecting reproductive health and rights: 2014 state policy review.
      ]. As clinical experience and research with mifepristone have expanded, the gold standard for medical abortion care has evolved beyond the protocol indicated in the FDA-approved label. Currently, the most common evidence-based protocols involve 200 mg mifepristone and 800 mcg misoprostol, and allow for use up to at least 63 days of gestation; these regimens are recommended by the World Health Organization [
      • World Health Organization
      Safe abortion: technical and policy guidance for health systems.
      ], the American College of Obstetricians and Gynecologists and the Society of Family Planning [
      • Creinin M.D.
      • Grossman D.A.
      Medical management of first-trimester abortion.
      ] and the Planned Parenthood Federation of America [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ]. The experiences of the hundreds of thousands of women who have had medical abortions using these protocols provide strong reassurance that mifepristone is extraordinarily safe; recent studies that include more than 423,000 women undergoing medical abortion with evidence-based regimens demonstrate that serious adverse outcomes are exceedingly rare [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ,
      • Shannon C.
      • Brothers L.P.
      • Philip N.M.
      • Winikoff B.
      Infection after medical abortion: a review of the literature.
      ,
      • Henderson J.T.
      • Hwang A.C.
      • Harper C.C.
      • Stewart F.H.
      Safety of mifepristone abortions in clinical use.
      ,
      • Sitruk-Ware R.
      Mifepristone and misoprostol sequential regimen side effects, complications and safety.
      ,
      • Winikoff B.
      • Dzuba I.G.
      • Creinin M.D.
      • Crowden W.A.
      • Goldberg A.A.
      • Gonzales J.
      • et al.
      Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial.
      ,
      • Niinimaki M.
      • Pouta A.
      • Bloigu A.
      • Gissler M.
      • Hemminki E.
      • Suhonen S.
      • et al.
      Immediate complications after medical compared with surgical termination of pregnancy.
      ,
      • Raymond E.G.
      • Shannon C.
      • Weaver M.A.
      • Winikoff B.
      First-trimester medical abortion with mifepristone 200 mg and misoprostol: a systematic review.
      ,
      • Gatter M.
      • Cleland K.
      • Nucatola D.L.
      Efficacy and safety of medical abortion using mifepristone and buccal misoprostol through 63 days.
      ,
      • Upadhyay U.D.
      • Desai S.
      • Zlidar V.
      • Weitz T.A.
      • Grossman D.
      • Anderson P.
      • et al.
      Incidence of emergency department visits and complications after abortion.
      ].
      Most complications associated with medical abortion are minor and include (but are not limited to) bleeding, cramping, fever and chills [
      • Winikoff B.
      • Dzuba I.G.
      • Creinin M.D.
      • Crowden W.A.
      • Goldberg A.A.
      • Gonzales J.
      • et al.
      Two distinct oral routes of misoprostol in mifepristone medical abortion: a randomized controlled trial.
      ,
      • Upadhyay U.D.
      • Desai S.
      • Zlidar V.
      • Weitz T.A.
      • Grossman D.
      • Anderson P.
      • et al.
      Incidence of emergency department visits and complications after abortion.
      ]. The outcomes of greatest clinical concern are heavy bleeding requiring transfusion, serious infection resulting in hospital admission, ongoing pregnancy, undiagnosed ectopic pregnancy and death attributable to the medical abortion regimen. In one large study [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ], 0.10% (238/233,805) of patients presented to the emergency department for treatment following medical abortion; another recent study found that that, in the majority of cases, when women sought care in emergency departments following medical abortion, the complications were typically minor and expected [
      • Upadhyay U.D.
      • Desai S.
      • Zlidar V.
      • Weitz T.A.
      • Grossman D.
      • Anderson P.
      • et al.
      Incidence of emergency department visits and complications after abortion.
      ]. Rates of hospital admission due to any medical-abortion-related complications are extremely low, with reports ranging from 0.04% (6/13,373) to 0.3% (119/45,528) [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ,
      • Raymond E.G.
      • Shannon C.
      • Weaver M.A.
      • Winikoff B.
      First-trimester medical abortion with mifepristone 200 mg and misoprostol: a systematic review.
      ,
      • Gatter M.
      • Cleland K.
      • Nucatola D.L.
      Efficacy and safety of medical abortion using mifepristone and buccal misoprostol through 63 days.
      ]. Bleeding is an expected consequence of medical abortion, and it is only in the most extreme of circumstances that women require transfusion to replace excessive blood loss. Recent studies report that blood transfusion was required in 0.03% (4/13,373) to 0.14% (16/11,319) of medical abortion patients [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ,
      • Henderson J.T.
      • Hwang A.C.
      • Harper C.C.
      • Stewart F.H.
      Safety of mifepristone abortions in clinical use.
      ,
      • Sitruk-Ware R.
      Mifepristone and misoprostol sequential regimen side effects, complications and safety.
      ,
      • Raymond E.G.
      • Shannon C.
      • Weaver M.A.
      • Winikoff B.
      First-trimester medical abortion with mifepristone 200 mg and misoprostol: a systematic review.
      ,
      • Gatter M.
      • Cleland K.
      • Nucatola D.L.
      Efficacy and safety of medical abortion using mifepristone and buccal misoprostol through 63 days.
      ]. Serious infection requiring hospitalization following medical abortion is also rare; recent estimates range from 0.01% (2/13,373) to 0.23% (26/11,319) [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ,
      • Henderson J.T.
      • Hwang A.C.
      • Harper C.C.
      • Stewart F.H.
      Safety of mifepristone abortions in clinical use.
      ,
      • Gatter M.
      • Cleland K.
      • Nucatola D.L.
      Efficacy and safety of medical abortion using mifepristone and buccal misoprostol through 63 days.
      ,
      • Upadhyay U.D.
      • Desai S.
      • Zlidar V.
      • Weitz T.A.
      • Grossman D.
      • Anderson P.
      • et al.
      Incidence of emergency department visits and complications after abortion.
      ]. Infection is more prevalent when misoprostol is administered through a vaginal, rather than an oral or buccal, route [
      • Fjerstad M.
      • Trussell J.
      • Sivin I.
      • Lichtenberg E.S.
      • Cullins V.
      Rates of serious infection after changes in regimens for medical abortion.
      ]. Five deaths have been attributed to septic shock associated with serious bacterial infections after using misoprostol vaginally [
      • Sinave C.
      • Le Templier G.
      • Blouin D.
      • Leveille F.
      • Deland E.
      Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease.
      ,
      • Fischer M.
      • Bhatnagar J.
      • Guarner J.
      • Reagan S.
      • Hacker J.K.
      • Van Meter S.H.
      • et al.
      Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion.
      ], prompting the Planned Parenthood Federation of America to adopt new guidelines in 2006 that include buccal administration of misoprostol.
      Ongoing pregnancy does not pose health risks to the woman per se but is important to monitor because surgical intervention may be required to complete the abortion and because misoprostol can be teratogenic [
      • Orioli I.
      • Castilla E.
      Epidemiological assessment of misoprostol teratogenicity.
      ,
      • Brasil R.
      • Coelho H.
      • D'Avanzo B.
      • La Vecchia C.
      Misoprostol and congenital anomalies.
      ]. However, medical abortion using mifepristone and misoprostol is highly effective, with recent studies reporting very low rates of ongoing pregnancy ranging from 0.13% (70/13,373) to 1.1% (499/45,528) [
      • Cleland K.
      • Creinin M.D.
      • Nucatola D.
      • Nshom M.
      • Trussell J.
      Significant adverse events and outcomes after medical abortion.
      ,
      • Raymond E.G.
      • Shannon C.
      • Weaver M.A.
      • Winikoff B.
      First-trimester medical abortion with mifepristone 200 mg and misoprostol: a systematic review.
      ,
      • Gatter M.
      • Cleland K.
      • Nucatola D.L.
      Efficacy and safety of medical abortion using mifepristone and buccal misoprostol through 63 days.
      ,
      • Upadhyay U.D.
      • Desai S.
      • Zlidar V.
      • Weitz T.A.
      • Grossman D.
      • Anderson P.
      • et al.
      Incidence of emergency department visits and complications after abortion.
      ].
      Ectopic pregnancy is a serious, but rare, event; ectopic pregnancies make up 1.3% to 2.0% of pregnancies in the United States [
      • Centers for Disease Control
      MMWR weekly: current trends in ectopic pregnancy — United States, 1990–1992.
      ,
      • Saraiya M.
      • Berg C.J.
      • Shulman H.
      • Green C.A.
      • Atrash H.K.
      Estimates of the annual number of clinically recognized pregnancies in the United States, 1981–1991.
      ]. Half of the pregnancies in the United States are unintended [
      • Finer L.B.
      • Zolna M.R.
      Shifts in intended and unintended pregnancies in the United States, 2001–2008.
      ], and therefore, many women may not even be aware that they are pregnant, which could delay diagnosis of an ectopic pregnancy. However, women seeking abortion services, by definition, know that they are pregnant and may therefore be more likely to receive an early diagnosis of ectopic pregnancy. Furthermore, some studies show that rates of ectopic pregnancy are substantially lower among women seeking abortion services compared with overall rates in the general population [
      • Creinin M.D.
      • Grossman D.A.
      Medical management of first-trimester abortion.
      ,
      • Grossman D.
      • Ellertson C.
      • Grimes D.A.
      • Walker D.
      Routine follow-up visits after first-trimester induced abortion.
      ,
      • Bracken H.
      • Clark W.
      • Lichtenberg E.
      • Schweikert S.
      • Tanenhaus J.
      • Barajas A.
      • et al.
      Alternatives to routine ultrasound for eligibility assessment prior to early termination of pregnancy with mifepristone–misoprostol.
      ].
      Updated evidence-based regimens for medical abortion have increased options and lowered costs for women seeking abortion, all while maintaining an excellent safety profile. Research and practice in medical abortion continue to evolve, creating the potential to expand the medical option to even more women seeking abortion services. New studies demonstrate safe and effective use of mifepristone for medical abortion up to 70 days of gestation [
      • Boersma A.A.
      • Meyboom-de Jong B.
      • Kleiverda G.
      Mifepristone followed by home administration of buccal misoprostol for medical abortion up to 70 days of amenorrhoea in a general practice in Curacao.
      ,
      • Winikoff B.
      • Dzuba I.G.
      • Chong E.
      • Goldberg A.B.
      • Lichtenberg E.S.
      • Ball C.
      • et al.
      Extending outpatient medical abortion services through 70 days of gestational age.
      ,
      • Smith P.S.
      • Peña M.
      • Dzuba I.G.
      • Martinez M.L.G.
      • Peraza A.G.A.
      • Bousiéguez M.
      • et al.
      Safety, efficacy and acceptability of outpatient mifepristone-misoprostol medical abortion through 70 days since last menstrual period in public sector facilities in Mexico City.
      ]. In addition, a growing body of research supports the safety of moving medical abortion away from clinic-centered models of care, allowing women to use mifepristone and misoprostol in the privacy and comfort of their home and to use technologies such as semiquantitative pregnancy tests to assess whether clinic follow-up is needed [
      • Ngo T.D.
      • Park M.H.
      • Shakur H.
      • Free C.
      Comparative effectiveness, safety and acceptability of medical abortion at home and in a clinic: a systematic review.
      ,
      • Conkling K.
      • Karki C.
      • Tuladhar H.
      • Bracken H.
      • Winikoff B.
      A prospective open-label study of home use of mifepristone for medical abortion in Nepal.
      ,
      • Blum J.
      • Shochet T.
      • Lynd K.
      • Lichtenberg E.S.
      • Fischer D.
      • Arnesen M.
      • et al.
      Can at-home semi-quantitative pregnancy tests serve as a replacement for clinical follow-up of medical abortion? A US study.
      ].
      The current FDA-approved label for mifepristone limits its use to 49 days of gestation and indicates a 600-mg dose of mifepristone. In addition, mifepristone is not available in pharmacies; unlike other medications for which a doctor writes a prescription that the patient fills at a pharmacy, the prescriber’s agreement specifies that mifepristone can be dispensed only in medical offices, clinics and hospitals. Furthermore, the FDA-approved label for mifepristone requires that patients make three office visits to receive the medications and complete extensive follow-up [
      • Food and Drug Administration
      ,
      • Food and Drug Administration
      Mifeprex tablets, 200 mg; label and medication guide.
      ]. Although the safety and efficacy of updated evidence-based regimens for medical abortion are clear, some states require that providers follow the original FDA-approved protocol for medical abortion [
      • Guttmacher Institute
      Facts on induced abortion in the United States.
      ]. Requiring adherence to the FDA label does not serve the best interests of women; rather, it restricts the population of eligible women because of gestational age limits, directs women to take three times more mifepristone than evidence has shown to be necessary and requires that they make repeat visits to the clinic, demanding that increasing numbers of women travel great distances to receive services [
      • Boonstra H.
      Medication abortion restrictions burden women and providers and threaten US trend toward very early abortion.
      ]. An extensive and rigorous literature supports the safety of both the current evidence-based regimens as well as innovative expanded protocols, providing a strong foundation for improving access to medical abortion by aligning the mifepristone label with the evidence.

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        Medical management of first-trimester abortion.
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        Significant adverse events and outcomes after medical abortion.
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        Safety of mifepristone abortions in clinical use.
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