Mifepristone and Misoprostol for Early Pregnancy Loss and Medication Abortion PDF

Mifepristone and Misoprostol for Early Pregnancy Loss and Medication Abortion Honor MacNaughton, MD, Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Massachusett...

Mifepristone and Misoprostol for Early Pregnancy Loss and Medication Abortion Honor MacNaughton, MD, Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Massachusetts;​Tufts University School of Medicine, Boston, Massachusetts Melissa Nothnagle, MD, MSc, Natividad Family Medicine Residency, Salinas, California;​ University of California San Francisco School of Medicine, San Francisco, California Jessica Early, MD, Tufts University Family Medicine Residency at Cambridge Health Alliance, Malden, Massachusetts;​Tufts University School of Medicine, Boston, Massachusetts Medication regimens using mifepristone and misoprostol are safe and effective for outpatient treatment of early pregnancy loss for up to 84 days’ gestation and for medication abortion up to 77 days’ gestation. Gestational age is determined using ultrasonography or menstrual history. Ultrasonography is needed when gestational dating cannot be confirmed using clinical data alone or when there are risk factors for ectopic pregnancy. The most effective regimens for medication management of early pregnancy loss and medication abortion include 200 mg of oral mifepristone (a progesterone receptor antagonist) fol- lowed by 800 mcg of misoprostol (a prostaglandin E1 analogue) administered buccally or vaginally. Cramping and bleeding are expected effects of the medications, with bleeding lasting an average of nine to 16 days. The adverse effects of misoprostol (e.g., low-grade fever, gastrointestinal symptoms) can be managed with nonsteroidal anti-inflammatory drugs or antiemetics. Ongoing pregnancy, infection, hemorrhage, undiagnosed ectopic pregnancy, and the need for unplanned uterine aspiration are rare complications. Clinical history, combined with serial quantitative beta human chorionic gonadotropin levels, urine pregnancy testing, or ultrasonography, is used to establish complete passage of the pregnancy tissue. (Am Fam Physician. 2021;103(8):​473-480. Copyright © 2021 American Academy of Family Physicians.) Medication management of early preg- longitudinal relationships with patients;​how- nancy loss and medication abortion has become ever, only 1% of abortions currently occur in cli- increasingly common since the U.S. Food and nicians’ offices.1 Drug Administration (FDA) approval of mifepri- stone (Mifeprex) in 2000. Medication abortion Determining Eligibility now accounts for 60% of all abortions completed Before prescribing mifepristone and misopros- before 10 weeks’ gestation.1 The most effective tol, clinicians should determine gestational age, medication regimens combine mifepristone, a evaluate for contraindications, provide patient- progesterone receptor antagonist that causes centered counseling on management options, decidual necrosis and uterine contractions, and and assess the need for laboratory testing. misoprostol (Cytotec), a prostaglandin E1 ana- logue that causes cervical ripening and uter- ine contractions. These regimens are safe and WHAT’S NEW ON THIS TOPIC acceptable to patients and can be prescribed by primary care clinicians in the outpatient set- Early Pregnancy Loss ting.2-4 Primary care clinicians are uniquely posi- and Medication Abortion tioned to counsel patients and provide access to Based on a 2018 review, the National Acade- medications, with their wide geographic distri- mies of Sciences, Engineering, and Medicine bution, skills in shared decision-making, and concluded that medication abortion does not increase the risk of breast cancer, mental health problems, infertility, pregnancy loss, or CME This clinical content conforms to AAFP preterm birth. criteria for CME. See CME Quiz on page 460. Author disclosure:​ No relevant financial Medication abortion accounts for 60% of all affiliations. abortions before 10 weeks’ gestation. 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Contact [email protected] for copyright questions and/or permission requests.  MIFEPRISTONE AND MISOPROSTOL SORT:​KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating Comments Mifepristone (Mifeprex) and misoprostol (Cytotec) can be safely C Consensus guideline on the safety and quality prescribed by primary care clinicians in the outpatient setting.4 of abortion care by the National Academies of Sciences, Engineering, and Medicine Menstrual dating or ultrasonography is required to confirm gesta- B Consistent results from two prospective case tional age prior to medication abortion;​ultrasonography should series and a retrospective review be performed in patients at risk of ectopic pregnancy or if gesta- tional age cannot be confirmed using clinical data alone.9-11 The most effective regimen for medication management of early A Consistent results of randomized controlled pregnancy loss is mifepristone, 200 mg orally, followed 24 to 48 trials demonstrating that mifepristone and hours later by misoprostol, 800 mcg vaginally;​when available, the misoprostol are more effective than misopros- combination should be recommended over misoprostol alone.2,3 tol alone for early pregnancy loss The recommended regimen for medication abortion up to 70 A Systematic review of using mifepristone and days’ gestation is mifepristone, 200 mg orally, followed by miso- misoprostol buccally and individual random- prostol, 800 mcg administered buccally 24 to 48 hours later or ized controlled trials of using misoprostol vaginally 0 to 72 hours later.6,13,23-27 vaginally To increase effectiveness of medication abortion, a second dose C Retrospective chart review and consensus of misoprostol four hours after the first is recommended at 71 guideline to 77 days’ gestation and should be considered at 64 to 70 days’ gestation.8,28,29 Following medication management, completed early preg- B Retrospective review and a systematic review nancy loss or abortion is confirmed using clinical history and an of lower quality clinical trials 80% decline from pretreatment in serum beta human chorionic gonadotropin levels, ultrasonography documenting the absence of a previously seen gestational sac, or a negative urine preg- nancy test result.11,35 A = consistent, good-quality patient-oriented evidence;​B = inconsistent or limited-quality patient-oriented evidence;​C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://​www.aafp.org/afpsort. Regimens using mifepristone and misopros- or cardiovascular disease, or with hemoglobin tol are effective up to 84 days’ gestation for early levels of less than 10 g per dL (100 g per L). Lab- pregnancy loss,2,3 and up to 77 days’ gestation oratory testing should be considered for patients for medication abortion.5-8 Ultrasonography is with symptoms of or at risk of anemia or sexually indicated to establish the diagnosis and confirm transmitted infections. An initial quantitative gestational dating before using medications for beta human chorionic gonadotropin (β-hCG) early pregnancy loss. Ultrasonography, if needed, level is needed if serial β-hCG will be used to con- or menstrual dating can establish that gesta- firm completed abortion. The standard of care tional age is less than 77 days before a medication has been to administer RhO(D) immune globu- abortion is provided.9-11 Ultrasonography should lin (Rhogam) to all patients who are Rh-negative be performed in patients at risk of ectopic preg- and who are undergoing early pregnancy loss or nancy or if gestational age cannot be confirmed abortion.14 However, according to preliminary using clinical data alone (Table 1).9-11 research findings, the risk of alloimmunization There are few contraindications to using in early gestation may be negligible.15 If future mifepristone and misoprostol12 (Table 24,12,13). research confirms this finding, testing for Rh sta- Medication management research has excluded tus may not be indicated when prescribing mife- patients with severe hepatic, renal, respiratory, pristone and misoprostol in the first trimester.16 474 American Family Physician www.aafp.org/afp Volume 103, Number 8 ◆ April 15, 2021  MIFEPRISTONE AND MISOPROSTOL Providing Counseling and Consent patients who are included in the decision-making Patients with early pregnancy loss or unintended process and whose treatment preferences are pregnancy should receive patient-centered honored have better mental health outcomes.17,18 counseling on all management options because The risks and benefits of treatment options for early pregnancy loss (i.e., expectant manage- ment, medication management, and uterine TABLE 1 aspiration) are reviewed at https://​w ww.aafp.org/ afp/2019/0201/p166.html. For an in-depth dis- Indications for Ultrasonography Before cussion of the options for unintended pregnancy, Medication Abortion including parenting, adoption, and medication Increased risk of ectopic pregnancy or aspiration abortion, see https://​w ww.aafp.org/ Adnexal mass or tenderness on examination afp/2015/0415/p544.html. All patients should be History of ectopic pregnancy interviewed alone to ensure they are not being History of treatment for pelvic inflammatory disease coerced by a partner or anyone else to decide History of tubal surgery, including sterilization against their will.19 The FDA requires patients who use mifepristone to sign a patient agree- Pregnancy with intrauterine device in place ment that is available on the drug manufacturers’ Vaginal bleeding or unilateral pelvic pain websites.20,21 Unable to confirm gestational age less than 11 weeks Hormonal contraceptive use within the past two months Using Mifepristone and Misoprostol REGIMENS FOR EARLY PREGNANCY LOSS Last menstrual period more than 10 weeks ago The most effective regimen for medication man- Unsure date of last menstrual period agement of early pregnancy loss is 200 mg of oral Uterine size/date discrepancy on bimanual examination mifepristone followed by 800 mcg of misopros- Information from references 9-11. tol administered vaginally 24 to 48 hours later.2,3 Regimens with misoprostol alone can be used if mifepristone is not available;​however, rates of effectiveness are lower.2,3 One common regimen TABLE 2 is misoprostol, 800 mcg vaginally, with a repeat dose in 48 hours if no bleeding has occurred22 Contraindications to Mifepristone (Table 32,5-8,21-28). (Mifeprex) and Misoprostol (Cytotec) Use Absolute contraindications REGIMENS FOR MEDICATION ABORTION Adrenal insufficiency The FDA regimen for medication abortion up to Allergy to mifepristone or misoprostol 70 days’ gestation is 200 mg of oral mifepristone Chronic systemic glucocorticoid use followed by 800 mcg of misoprostol administered buccally 24 to 48 hours later.13,23 Evidence-based Confirmed or suspected ectopic pregnancy regimens, however, demonstrate safety and effec- Hemodynamic instability tiveness up to 77 days’ gestation.7,8,28,29 Effective- Hemorrhagic disorder or current anticoagulant use ness between 64 and 77 days’ gestation increases (excluding aspirin) with the addition of a second dose of misoprostol, Inherited porphyrias 800 mcg four hours after the first dose.8,28,29 Other Intrauterine device in place (remove, then proceed with studies show that evidence-based regimens using medications) vaginal misoprostol 0 to 72 hours after mifepri- Septic abortion stone administration are as safe, tolerable, and Relative contraindications effective as the FDA regimen6,24-27 (Table 32,5-8,21-28). Hemoglobin less than 10 g per dL (100 g per L) PRESCRIBING LOGISTICS Inability to access emergency or follow-up services Mifepristone must be ordered from the man- Information from references 4, 12, and 13. ufacturer and dispensed to the patient under the supervision of a clinician. Information on April 15, 2021 ◆ Volume 103, Number 8 www.aafp.org/afp American Family Physician 475  MIFEPRISTONE AND MISOPROSTOL ordering mifepristone and resources for imple- abortion and may increase access.30 The patient menting medication management of early preg- may swallow the mifepristone in the office or at nancy loss or medication abortion are provided home. Home dosing allows for more flexible tim- in Table 4. Telehealth has been shown to be a safe ing of subsequent misoprostol use and related and effective model for providing medication cramping and bleeding. TABLE 3 Comparison of Mifepristone (Mifeprex) and Misoprostol (Cytotec) Regimens Interval between Gestational age Mifepristone mifepristone and in days dose and route Misoprostol dose and route misoprostol use Effectiveness Early pregnancy loss Up to 84 200 mg orally 800 mcg vaginally, single dose 24 hours 83.8% Up to 84 (miso- Not 800 mcg vaginally, single dose Not applicable 67.1% to 70.8% prostol alone) applicable Medication abortion Up to 63 200 mg orally 800 mcg buccally, single dose 24 to 48 hours 96.7% 800 mcg vaginally, single dose 0 to 72 hours 94.0% to 96.9% 64 to 70 200 mg orally 800 mcg buccally, single dose 24 to 48 hours 93.1% 800 mcg vaginally, single dose 24 to 48 hours 94.9% 800 mcg buccally, two doses 24 to 48 hours 99.6% four hours apart 71 to 77 200 mg orally 800 mcg buccally, single dose 24 to 48 hours 86.7% 800 mcg buccally, two doses 24 to 48 hours 97.7% four hours apart Information from references 2, 5-8, and 21-28. TABLE 4 Resources for Early Pregnancy Loss and Medication Abortion Resource Website Comments National Abortion Federation https://​prochoice.org/providers/quality-standards/ Clinical guideline 2020 Clinical Policy Guide- lines for Abortion Care Reproductive Health Access https://​www.reproductiveaccess.org/resource/order-mifepristone/ Patient handouts and Project https://​www.reproductiveaccess.org/abortion/ provider resources https://​www.reproductiveaccess.org/resource/miscarriage- treatment-medication/ https://​www.reproductiveaccess.org/resource/mabfactsheet/ Reproductive Health Educa- https://​rhedi.org/education/medication-abortion/ Curricular resources for tion in Family Medicine medication abortion 476 American Family Physician www.aafp.org/afp Volume 103, Number 8 ◆ April 15, 2021  MIFEPRISTONE AND MISOPROSTOL Misoprostol is available by prescription, or it persists for an average of nine to 16 days.4 Pain can be stocked in the office. Patients using miso- can usually be managed with nonsteroidal prostol buccally should place two tablets between anti-inflammatory drugs and a heating pad. the cheek and gums on each side of the mouth Clinicians should inform patients that gastro- and allow them to dissolve for 30 minutes before intestinal symptoms such as nausea, vomiting, swallowing any remaining medication. Patients and diarrhea are common with misoprostol use. using misoprostol vaginally should place four Oral antiemetics may be helpful. Low-grade fever pills in the vagina and lie down for 30 minutes to and chills are less common and can be managed allow the medication to be absorbed. with antipyretics.23 MANAGING EXPECTED AND ADVERSE Safety EFFECTS Complications following treatment are rare and Mifepristone is generally well tolerated, with include hemorrhage, infection, ongoing preg- the most common adverse effect being nausea.23 nancy, and undiagnosed ectopic pregnancy Misoprostol causes strong uterine cramping (Table 5).2,22,23,31,32 For early pregnancy loss, the and heavier bleeding than menses, often with rate of unplanned aspiration attributed to per- blood clots. Cramping and bleeding typically sistent pain or bleeding is 8.8% when using com- begin within several hours of using misoprostol bined regimens of mifepristone and misoprostol and last for three to five hours. Lighter bleeding and 23.5% when using misoprostol alone.2 For patients undergoing medication abortion, rates of unanticipated uterine aspiration attributed to TABLE 5 persistent pain or bleeding range from 1.8% to 4.2%.23 Prophylactic antibiotics are not recom- Complication Rates of the Management mended for medication management of early of Early Pregnancy Loss and Medication pregnancy loss or abortion.33 Abortion Patients should be instructed to call if they Complication Rate experience symptoms of potential complications, including heavy bleeding, no bleeding following Early pregnancy loss using mifepristone (Mifeprex) and misoprostol (Cytotec) misoprostol use, pain not relieved by analgesics, Need for unplanned uterine aspiration 8.8% purulent vaginal discharge, or fever or feeling ill more than 24 hours after using misoprostol. The Hemorrhage requiring transfusion 2.0% differential diagnoses and triage for these symp- Pelvic infection 1.3% toms are listed in Table 6. Based on a 2018 review, the National Acade- Early pregnancy loss using misoprostol alone mies of Sciences, Engineering, and Medicine con- Need for unplanned uterine aspiration 23.5% cludes that medication abortion does not increase the risk of breast cancer, mental health problems, Hemorrhage requiring transfusion 0.7% infertility, pregnancy loss, or preterm birth.4 Pelvic infection 0.6% to 1.3% Long-term fertility rates and pregnancy outcomes are similar for medication compared with surgi- Medication abortion using mifepristone and misoprostol cal management of early pregnancy loss.34 Need for unplanned uterine aspiration for 1.8% to 4.2% reason other than ongoing pregnancy Patient Follow-up Successful passage of pregnancy tissue after early Ongoing pregnancy 0.8% pregnancy loss or medication abortion should be Hemorrhage requiring transfusion 0.03% to 0.6% confirmed by combining clinical history with a Undiagnosed ectopic pregnancy 0.02% negative urine pregnancy test result, an adequate decline in serial serum β-hCG levels, or ultra- Pelvic infection 0.01% to 0.5% sonography documenting the absence of a pre- Information from references 2, 22, 23, 31, and 32. viously visible gestational sac.35 Serum β-hCG levels should fall by at least 50% in the first April 15, 2021 ◆ Volume 103, Number 8 www.aafp.org/afp American Family Physician 477  MIFEPRISTONE AND MISOPROSTOL 24 hours or 80% by seven days after misoprostol use. The etonogestrel implant (Nexplanon) can use.11,35 Heterogeneous echogenicity, a thickened be inserted on the same day mifepristone is taken endometrial stripe, and the presence of Doppler without increasing the risk of ongoing preg- flow on ultrasonography are not signs of incom- nancy.36 Medroxyprogesterone (Depo-Provera) plete abortion and, in the absence of symptoms, and intrauterine devices may be used after con- do not warrant further intervention. firmation of completed abortion.37 Patients who Patients may start oral, transdermal, or vaginal wish to conceive again can try as soon as they contraception any time following misoprostol feel ready.38 TABLE 6 Differential Diagnoses and Triage of Symptoms Following Medication Management of Early Pregnancy Loss and Medication Abortion Symptom Differential diagnosis Response Fever, purulent vaginal dis- Endometritis Assess in person charge, or feeling sick more Septic abortion than 24 hours after using Condition unrelated to early misoprostol (Cytotec) pregnancy loss or abortion No bleeding within 24 hours Ongoing pregnancy Urgent ultrasonography if intrauterine pregnancy not previ- of using misoprostol Ectopic pregnancy ously documented If ectopic pregnancy excluded, repeat dose of misoprostol Ongoing pregnancy symp- Ongoing pregnancy Ultrasonography, if not done, to rule out ongoing or ectopic toms:​nausea, vomiting, Ectopic pregnancy pregnancy breast pain, positive urine If ongoing pregnancy, counsel on teratogenicity of medica- Expected resolution of preg- pregnancy test, amenorrhea tions, offer repeat dose of medications if < 77 days’ gestation nancy symptoms or aspiration procedure Condition unrelated to early pregnancy loss or abortion Counsel that breast tenderness typically resolves in two weeks, urine pregnancy test should be negative by four weeks, men- ses should return in four to six weeks Soaking through two maxi Expected bleeding If no symptoms of anemia, push oral fluids, rest, nonsteroidal pads per hour for two hours Retained products of anti-inflammatory drugs, and follow-up by phone in one hour in a row conception If symptomatic anemia or persistent heavy bleeding, assess in Hemorrhage person, ensure hemodynamic stability, check hemoglobin, and consider ultrasonography Uncontrolled abdominal or Retained products of Ultrasonography, if not done, to ensure intrauterine pregnancy pelvic pain more than 24 conception If signs or symptoms of infection, assess in person for hours after misoprostol use Ectopic pregnancy endometritis Endometritis If persistent pain despite recommended analgesic use, assess Condition unrelated to early in person for retained products of conception pregnancy loss or abortion If retained products of conception, offer uterine aspiration or, in a stable patient, repeat dose of misoprostol, 800 mcg Uncontrolled abdominal or Misoprostol effect Ultrasonography, if not done, to ensure intrauterine pregnancy pelvic pain within 24 hours Ectopic pregnancy If signs or symptoms of infection, assess in person for of misoprostol use endometritis Endometritis Ensure proper analgesic use Vomiting after using Vomiting of pregnancy Offer antiemetic mifepristone (Mifeprex) Adverse effect of mifepristone Repeat dose if vomiting within 60 minutes 478 American Family Physician www.aafp.org/afp Volume 103, Number 8 ◆ April 15, 2021  MIFEPRISTONE AND MISOPROSTOL Data Sources:​ A PubMed search was completed in 6. Hsia JK, Lohr PA, Taylor J, et al. Medical abortion with Clinical Queries using the following key terms:​med- mifepristone and vaginal misoprostol between 64 and ication abortion, early pregnancy loss, mifepristone, 70 days’ gestation. Contraception. 2019;​100(3):​178-181. and misoprostol. The search included meta-analysis, 7. Dzuba IG, Chong E, Hannum C, et al. A non-inferiority randomized controlled trials, clinical trials, guidelines, study of outpatient mifepristone-misoprostol medical abortion at 64-70 days and 71-77 days of gestation. Con- and reviews. Also searched were the Cochrane data- traception. 2020;​101(5):​302-308. base, the Agency for Healthcare Research and Quality, 8. Dzuba IG, Castillo PW, Bousiéguez M, et al. A repeat dose and DynaMed. An evidence summary, generated from of misoprostol 800 mcg following mifepristone for out- Essential Evidence Plus, was reviewed, and relevant patient medical abortion at 64-70 and 71-77 days of ges- studies were referenced. 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Department of Family Medicine at Tufts University 12. Guiahi M, Davis A;​Society of Family Planning. First-trimes- School of Medicine, Boston, Mass. ter abortion in women with medical conditions:​release date October 2012 SFP guideline #20122. Contraception. MELISSA NOTHNAGLE, MD, MSc, is the program 2012;​86(6):​622-630. director of the Natividad Family Medicine Resi- 13. DailyMed. Drug label information:​mifepristone tab- dency, Salinas, Calif., and clinical professor in the let. Updated June 18, 2020. Accessed September 23, Department of Family and Community Medicine at 2020. https://​dailymed.nlm.nih.gov/dailymed/drugInfo. the University of California San Francisco School cfm?setid=b63fad9b-7f12-4400-9019-b0586054e534 of Medicine. 14. Silver RM;​Committee on Practice Bulletins–Obstetrics. Practice bulletin no. 181:​Prevention of Rh D alloimmuni- JESSICA EARLY, MD, is faculty at the Tufts Uni- zation. 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