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Mifepristone/Misoprostol Regimen
- Overview and history
- Mifepristone worldwide
- Mifepristone in the US
- Mechanism of action of mifepristone
- How to use mifepristone/misoprostol
- Efficacy
- Eligibility
- Contraindications
- Side effects and complications
- Acceptability
- Additional uses of mifepristone
- References
- Links
Mifepristone was developed during the early 1980s by researchers at the French pharmaceutical company Roussel Uclaf. While investigating glucocorticoid receptor antagonists, investigators discovered that some of the compounds blocked the similarly shaped progesterone receptor. Refinement of the compound led to the production of RU 486, the medication now known as mifepristone.
Clinical testing of mifepristone began in Europe in 1982. The results from the clinical trials showed that mifepristone, when used alone, induced a complete abortion in 60% of women with pregnancies up to 49 days' gestation. Investigators then discovered that by adding small doses of a prostaglandin analog on the last day of mifepristone treatment, the complete abortion rate increased to over 95%. France became the first country to license the mifepristone/prostaglandin analog regimen for early abortion in 1988. [1]
Since 1988, Mifepristone has been registered for medication abortion use in over twenty other countries worldwide including Austria, Belgium, China, Denmark, Finland, Great Britain, Greece, Israel, Luxembourg, the Netherlands, New Zealand, Norway, Russia, South Africa, Spain, Sweden, Switzerland, Taiwan, Tunisia, the Ukraine, and the United States. The following map shows the worldwide approval of mifepristone.
Mifepristone approval map courtesy of the Population Council
Millions of women worldwide have used mifepristone and a prostaglandin analog to terminate pregnancy with impressive safety and efficacy. In France, Sweden, and Great Britain, where mifepristone has been available for more than a decade, there has been an increase in the proportion of abortions performed at earlier gestation. [2]
Mifepristone may also be available in additional countries through the black market. The quality of mifepristone may vary in unregulated markets and thus the reliability of the source should be examined.
In September 2000, the U.S. Food and Drug Administration (FDA) approved the use of mifepristone in combination with misoprostol for early medication abortion. Since the approval of the mifepristone/misoprostol regimen, more than 130,000 women in the US have used this regimen for safe and effective early pregnancy termination. The number of abortion providers offering medication abortion alternatives to aspiration abortion has steadily increased.[3] In the US, the brand names of mifepristone and misoprostol are Mifeprex™ and Cytotec®, respectively.
Mifepristone (a synthetic steroid) is an anti-progestin that blocks the action of progesterone, a hormone necessary to maintain a pregnancy. By blocking the action of progesterone, mifepristone alters the uterine lining (the endometrium), induces menstrual bleeding, and causes the uterine lining to shed. Mifepristone also causes the cervix to soften and initiates uterine contractions.
Mifepristone is used in conjunction with misoprostol. Misoprostol is an analog of prostaglandin E1. By interacting with prostaglandin receptors, misoprostol causes the cervix to soften and the uterus to contract, resulting in the expulsion of the uterine contents.
The mifepristone/misoprostol regimen is approved up to 49 days' gestation. Women are required to orally take 600 mg of mifepristone (Mifegyne™). Thirty-six to forty eight hours later, women are required to either orally take 400µg (micrograms) of misoprostol or 1 mg of vaginally administer gemeprost (also a prostaglandin analog). Ten to fourteen days after taking mifepristone, the patient is required to return for a follow-up visit to determine whether the pregnancy has been terminated. [4]
The research that the FDA reviewed for approval was based on the original French regimen, developed more than a decade ago. The mifepristone/misoprostol regimen is approved up to 49 days' gestation. The FDA approved regimen specifies that a woman orally take 600mg of Mifeprex™ and 400µg (micrograms) of misoprostol two days later (orally). Approximately fourteen days after taking mifepristone, the patient is required to return for a follow-up visit to determine whether the pregnancy has been terminated.
A number of studies have shown that alternative regimens to the FDA approved protocol are effective and safe. The most common modification involves decreasing the dose of mifepristone to 200 mg. [5] Studies have also shown that misoprostol can be vaginally administered either one, two, or three days after mifepristone use, with no loss in efficacy, compared to the FDA-mandated two-day protocol. [6] Other studies have shown that the mifepristone/misoprostol regimen can be extended up to 63 days' gestation. [7] Vast experience also supports the safety, efficacy, and acceptability of home-administration of misoprostol. Several professional organization guidelines incorporate these modifications.
Recent studies have called into question the need for a routine, in-person post-abortion visit, especially for terminations occurring < 49 days' gestation. [8] Results from a mifepristone/misoprostol clinical trial conducted in China, Cuba, and India suggest that women who experience an incomplete abortion are able to identify their condition correctly. [9] Investigation into possible alternatives to universal in-person follow-up, such as telephone follow-up with home pregnancy testing and in-person follow-up for selected patients, is ongoing.
The following table compares the French, the FDA, and the evidence-based regimens.
Mifepristone Dosage
600 mg (Day 1)
Misoprostol Dosage
Regardless of which regimen is used, there are several steps involved in obtaining a medication abortion with mifepristone/misoprostol.
- Step I: A clinician counsels the woman, takes a medical history, performs a physical exam, and performs laboratory tests. Accurate dating of the pregnancy is crucial and can occur through either clinical assessment or ultrasound. If the woman is eligible for a medication abortion using mifepristone/misoprostol she takes mifepristone orally. Pain medication is commonly prescribed at this time, in case the woman needs it later.
- Step II: One to three days after taking mifepristone, the woman takes misoprostol to complete the abortion. This can be taken at home or in the clinic, depending on the protocol. Rarely, a woman may abort after the mifepristone alone.
- Step III: Several to fifteen days later, the woman returns to the doctor's office or clinic for an evaluation to make sure the abortion is complete. Completion is often clinically evident, but sometimes an ultrasound is necessary for confirmation. The only ultrasound finding which reliably demonstrates incompletion is the presence of a persistent gestational sac. If the abortion is not complete, the clinician will discuss treatment options with the patient. These options may include waiting and reevaluating for a complete abortion, administering additional misoprostol, or performing a vacuum aspiration to empty the uterus.
Numerous studies have now overwhelmingly demonstrated the efficacy and safety of the mifepristone/misoprostol regimen. Approximately 95% of women will have a successful abortion when using mifepristone/misoprostol within 49 days from the onset of the last menstrual period. Medication abortion completion rates appear to decline with increasing durations of pregnancy after 8 weeks gestational age. [10]
With respect to the timing of the abortion, approximately, 67% of women will have a complete abortion within four hours of using misoprostol and approximately 90% of women will have a complete abortion within 24 hours of using misoprostol.
For women who do not experience a complete abortion an aspiration intervention may be required. Reasons for aspiration intervention include prolonged or excessive bleeding, incomplete abortion (remnants of fetal tissue in the uterus), or an ongoing pregnancy. An aspiration termination may also be performed at the request of the woman or the provider. Ongoing pregnancy occurs in fewer than 1% of cases, when treatment has been started <49 days' gestation.
Most women with a pregnancy of <63 days' gestation can use the mifepristone/misoprostol regimen. If the use of mifepristone/misoprostol does not result in a complete abortion, vacuum aspiration or dilation and curettage (D&C) may be necessary. Women considering the mifepristone/misoprostol regimen should we willing to undergo such a procedure, if indicated.
According to the label, there are a number of contraindications to mifepristone/misoprostol use. These include: confirmed or suspected ectopic (extra-uterine) pregnancy; a history of allergy to either mifepristone or misoprostol; chronic systemic use of corticosteroids; chronic adrenal failure; coagulopathy or current therapy with anticoagulants; and inherited porphyria. Further, if an intrauterine device (IUD) is present, the device must be removed before a mifepristone/misoprostol termination can be performed. [11] In addition, women with chronic medical conditions, including hypertension, severe hepatic or renal disease, and severe anemia, should be evaluated individually.
Some side effects, such as abdominal cramping and bleeding, are hallmarks of the abortion process itself. Many women and clinicians report cramps and abdominal pain similar to those associated with a heavy menstrual period. Vaginal bleeding can vary significantly in both duration and severity, and many report that the bleeding resembles a heavy period or a spontaneous miscarriage. One study of mifepristone used with a vaginal prostaglandin to treat women through 63 days' gestation found that median blood loss was about 75 ml, compared with 50 ml typically lost during menses. [12] The range of bleeding is correlated to the length of gestation and can extend up to several hundred milliliters. Light bleeding and spotting can last for 1-3 weeks. Reported median bleeding times range from 9-13 days. The heaviest period of bleeding typically occurs when the abortion is occurring and persists for 1 to 4 hours. [13]
Side effects of the medications include nausea, vomiting, diarrhea, fever, and chills. In most cases, side effects can be managed with appropriate counseling and symptomatic treatments, such as oral analgesics for pain. Temperature elevation (defined as more than 100.4° F or 38° C) that is sustained (more than four hours) or begins later than 6 to 8 hours after misoprostol administration warrants clinical assessment.
To date, there is no evidence that mifepristone has teratogenic effects on the fetus. Several case reports have associated misoprostol use with limb defects and Mobius syndrome. However, an absolute causal relationship between misoprostol use and fetal deformities has yet to be demonstrated through prospective trials. Women electing to use the mifepristone/misoprostol regimen should be informed of the possible teratogenic effects of these drugs.
Complications
On rare occasions, uterine bleeding can be extremely heavy or prolonged. Some clinicians treat excessive bleeding with an ergot alkaloid such as methylergonovine maleate (Methergine) before resorting to aspiration. Bleeding significant enough to require transfusion is rare and is most likely to occur 1 to 3 weeks after taking the medications. Approximately 1% of women experience uterine bleeding that requires vacuum aspiration and about 0.1% require transfusion. [14]
In 2% to 5% of cases, the medication abortion is incomplete. Patients may require vacuum aspiration, to resolve an incomplete abortion, end a continuing pregnancy, or control bleeding.
Studies in the United States, Europe, Asia, Latin America, and the Middle East have demonstrated high rates of acceptability among patients using the mifepristone/misoprostol regimen. [15] Indeed, more than 90% of women in most studies reported being satisfied with the regimen. Several studies have found that more than 85% of women would choose the regimen again as well as recommend the regimen to a friend. [16] Even among women who experienced an incomplete abortion, more than two thirds reported that they would use the regimen again. [17]
Women consistently report that the best features of the mifepristone/misoprostol regimen include:
- The ability to avoid surgery and anesthesia;
- The perception that the process is more "natural";
- The perception of privacy; and
- The convenience
Women also consistently report that the least liked features of the process include:
- Length and degree of bleeding;
- Number of clinic visits; and
- Uncertainty as to whether or not the procedure had resulted in a complete abortion.
Research is currently underway to study other beneficial uses of mifepristone. Issues under investigation include the use of mifepristone in labor induction, infertility treatment, and fibroid and meningioma tumors treatment.
References:
[1] Creinin MD. Medical abortion regimens: historical context and overview. Am J Obstet Gynecol. 2000; 183: S3-S9.
[2] Jones R, Henshaw S. Mifepristone for Early Medical Abortion: Experiences in France, Great Britain and Sweden. Perspectives on Sexual and Reproductive Health. 2002; 34(3): 154-161
[3] Finer L, Henshaw S. Abortion Incidence and Services in the United States in 2000. Perspectives on Sexual and Reproductive Health. 2003; 35(1): 6-15.
[4] Mifegyne website: http://www.biam2.org/www/Spe5302.html
[5] Von Hertzen H. Research on regimens for early medical abortion. JAMWA. 2000; 35(3): S133-136.
[6] Schaff E, Fielding SL, Westhoff C, Ellertson C, Eisinger Stadalius LS, Fuller L. Vaginal misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: A randomized trial JAMA. 2000; 284(15): 1948-1953.
[7] Newhall E, Winikoff B. Abortion with Mifepristone and Misoprostol: Regimens, Efficacy, Acceptability and Future Directions. Am J Obstet Gyncol. 2000; 183(2): S44-53.
[8] Grossman D, Ellertson C, Grimes D, Strickler J, Walker D, Harper C. Mandatory follow-up examinations after first-trimester induced abortion: A review. (Need to have full citation at some point); Harper C, Ellertson C, Winikoff B. Could American women use mifepristone-misoprostol pills safely with less medical supervision? Contraception. 2002; 65: 133-142.
[9] Ellertson C, Elul B, Winikoff B. Can women use medical abortion without medical supervision? Reproductive Health Matters. 1997; 9: 149-161.
[10] Spitz I, Bardin C, Benton L, Robbins A. Early Pregnancy Termination with Mifepristone and Misoprostol in the United States. N Eng J Med. 1998; 338: 1241-1247.
[11] Ellertson C, Waldman S. The Mifepristone-Misoprostol Regimen for Early Medical Abortion. Current Women's Health Reports 2001; 1: 184-190.
[12] Rodger MW, Baird DT. Blood loss following induction of early abortion using mifepristone (RU 486) and a prostaglandin analog (gemeprost). Contraception. 1997; 56(3): 165-168.
[13] Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med. 1998; 338(18):1241-1247.
[14] World Health Organization Task Force on Post-ovulatory Methods of Fertility Regulation. Termination of pregnancy with reduced doses of mifepristone. British Medical Journal. 1993; 307 (6903): 532-537; Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med. 1998; 338(18):1241-1247.
[15] Clark S, Ellertson C, Winikoff B. Is medical abortion acceptable to all American women: The impact of sociodemographic characteristics on the acceptability of mifepristone-misoprostol abortion. JAMWA. 2000; 35(3): S177-182; Bygdeman M, Gemzell K, Marions L. Medical termination of early pregnancy: The Swedish experience. JAMWA. 2000; 35(3): S195-196; Shangchun, W. Medical abortion in China. JAMWA. 2000; 35(3): S197-199; Coyaji K. Early medical abortion in India: Three studies and their implications for abortion services. JAMWA. 2000; 35(3): S191-194; Newhall E, Winikoff B. Abortion with mifepristone and misoprostol: Regimens, efficacy, acceptability and future directions. Am J Obstet Gynecol. 2000; 183(2): S44-53; Elul B, Hajri S, Ngoc N, Ellertson C, Ben Slama C, Pearlman E, Winikoff B. Can women in less-developed countries use a simplified medical abortion regimen? Lancet 2001; 357: 1402-1405.
[16] Schaff E, Fielding S. A comparison of the Abortion Rights Mobilization and Population Council trials. JAMWA. 2000; 35(3): S137-140; Clark S, Ellertson C, Winikoff B. Is medical abortion acceptable to all American women: The impact of sociodemographic characteristics on the acceptability of mifepristone-misoprostol abortion. JAMWA. 2000; 35(3): S177-182.
[17] Clark S, Ellertson C, Winikoff B. Is medical abortion acceptable to all American women: The impact of sociodemographic characteristics on the acceptability of mifepristone-misoprostol abortion. JAMWA. 2000; 35(3): S177-182.