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MEDICAL ABORTION/History and Overview


Mifepristone was developed during the early 1980s by a team of researchers working for the French pharmaceutical company Roussel Uclaf under the direction of Étienne-Émile Baulieu. While investigating glucocorticoid receptor antagonists, the team discovered compounds that blocked the similarly shaped progesterone receptor. Further refinement led to the production of RU-486, the medication that is now known as mifepristone.

Early Clinical Studies

Clinical testing of mifepristone as a means of inducing medical abortion began in France in 1982. Results from these trials showed that when used as a single agent, mifepristone induced a complete abortion in up to 80% of women up to 49 days' gestation.1 By adding small doses of a prostaglandin analogue a few days later to stimulate uterine contractions, investigators discovered that they could induce a complete medical abortion in nearly 100 percent of women. 2,3

Worldwide Experience

In 1988, France became the first country to license the combination of mifepristone and a prostaglandin analogue for abortion during early pregnancy. Since then, this means of medical abortion has been approved in nearly thirty countries worldwide including Austria, Belgium, China, Denmark, Great Britain, Israel, Norway, Russia, South Africa, Sweden and Taiwan. In September 2000, the U.S. Food and Drug Administration (FDA) approved the use of mifepristone in the United States. Millions of women worldwide have used mifepristone and a prostaglandin analogue to terminate pregnancy with impressive safety and efficacy. 1

Bringing Mifepristone to the United States

While France first licensed the use of this combination of drugs in 1988, the politics of abortion delayed the introduction of mifepristone in the United States. Initial research in the United States was interrupted when Roussel Uclaf, the French manufacturer, stopped supplying the drug. In 1989 the FDA, under pressure from the first Bush administration, banned the import of mifepristone for personal use. President Clinton signed an executive order shortly after his inauguration in early 1993 to encourage the testing, licensing, and manufacturing of mifepristone and similar medications in the United States. Roussel Uclaf donated the U.S. patent rights for mifepristone to the Population Council, a private nonprofit research organization.

The Population Council conducted clinical trials using mifepristone in combination with the prostaglandin analogue misoprostol for medical abortion. (Misoprostol is widely available as Cytotec®.) Efficacy results and safety profiles from these studies and clinical trials in France led the FDA to grant "approvable" status for this combination medical abortion regimen in 1996. For final approval, the FDA requested further information on issues such as how the drug would be manufactured and distributed. Danco Laboratories, LLC, a women's health pharmaceutical company, was granted an exclusive license from the Population Council to manufacture, market, and distribute mifepristone in the United States. However, it was difficult for Danco to identify a manufacturer willing to become involved in the politically charged area of abortion, which led to substantial delays in final approval. Ultimately, Danco secured a manufacturer for production of mifepristone in accordance with FDA manufacturing standards. In September 2000, the FDA approved the mifepristone and misoprostol combination for medical abortion.

The Methotrexate Alternative

During the extended struggle to make mifepristone available in the United States, some physicians began to study the use of low doses of methotrexate in combination with misoprostol for medical abortion. Results were comparable to the rates seen with mifepristone and misoprostol up to 49 days' gestation (complete medical abortion, 94% to 96%; incomplete medical abortion completed with surgical abortion, 2% to 4%; and ongoing pregnancy requiring surgical abortion, 1% to 3%). The methotrexate/misoprostol regimen, however, generally takes longer to effect abortion and the timing of bleeding is less predictable than with mifepristone and misoprostol.4,5 While not approved in the United States as an abortifacient, methotrexate is approved for other indications, so physicians can prescribe this medication legally for the "off-label" evidence-based indication of abortion.

Mechanism of Action

Mifepristone blocks the progesterone receptor, leading to changes in the endometrial blood supply.6,7 In contrast, methotrexate inhibits DNA synthesis and primarily affects rapidly dividing cells. In early pregnancy, methotrexate interferes with the process of implantation through its effect on trophoblastic tissue.8 The net effect of mifepristone and methotrexate - detachment of the trophoblast from the uterine decidua - is the same. Mifepristone also softens the cervix to facilitate expulsion of the pregnancy. The prostaglandin analogue misoprostol accelerates the process of expulsion by stimulating uterine contractions as well as softening the cervix.9

Eligibility for Medical Abortion with Mifepristone and Misoprostol

The clinical trials conducted in the United States and France that formed the clinical basis of the new drug application (NDA) for mifepristone involved a single oral dose of 600 mg of mifepristone followed 48 hours later by a 400-µg dose of misoprostol administered orally. Using this regimen, the highest rates of complete abortion (about 95%) are seen in women up to 49 days' gestation.10,11

For this reason, FDA-approved indications specify this gestational age as the "cut-off" for eligibility for medical abortion. Research conducted independently of the NDA has demonstrated the safety and efficacy of several evidence-based alternative regimens of mifepristone and misoprostol. These include a lower dose of mifepristone, different administration of misoprostol, home use of misoprostol, and flexibility in the timing of the regimen. These evidence-based alternative regimens are widely accepted clinical practice, but were not under consideration as part of the FDA's initial approval process.

Contraindications to medical abortion with mifepristone and misoprostol include allergy to either of these medications, chronic systemic use of corticosteroids, chronic adrenal failure, coagulopathy or current therapy with anticoagulants, confirmed or suspected ectopic pregnancy or an undiagnosed adnexal mass, inherited porphyrias, and the presence of an intrauterine device (removal of the IUD eliminates this contraindication). In addition, women who do not have access to a telephone or who could not arrange transportation to a medical facility should not have a medical abortion, as they would not be able to secure appropriate care in the event of an emergency.

Side Effects and Complications

Side effects are expected with medical abortion. Some side effects, such as pain and bleeding, result from the abortion process itself. 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. Complications of medical abortion are rare; vaginal bleeding requiring transfusion occurs in approximately 1 in 500 cases. 4 Uterine infection (endometritis) is also rare because medical abortion usually does not require insertion of an instrument into the uterus. Approximately 2%-5% of women undergoing medical abortion will require vacuum aspiration to complete the abortion, to control bleeding, or to abort a continuing pregnancy.4,12

Availability

Physicians interested in providing mifepristone abortion services are able to obtain the drug through selected distributors. Information on how to obtain mifepristone is available through the Danco Laboratories website, www.earlyoptionpill.com. Women and health care professionals who would like referrals to providers of mifepristone should contact the National Abortion Federation's toll-free Hotline (800-772-9100).

Medical Abortion in the United States

It is unusual for a drug to be introduced with such a wealth of clinical experience available to providers. Abundant evidence from studies conducted in the United States and abroad indicates that medical abortion with mifepristone and misoprostol is safe, effective, and well-accepted by women.

References

  1. Creinin MD. Medical abortion regimens: Historical context and overview. Am J Obstet Gynecol. 2000; 183: S3-S9.
  2. Swahn ML, Cekan S, Wang G, Lujndstron V, Bygdeman M. Pharmacokinetics and clinical studies of RU 486 for fertility regulation. In: Baulieu EE, Siegel S, ed. The Antiprogestin Steroid RU 486 and Human Fertility Control. New York, NY: Plenum; 1985:249-258.
  3. Bydgeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception. 1985;32:45-51.
  4. Kahn JG, Becker BJ, MacIsaac L, et al. The efficacy of medical abortion: a meta-analysis. Contraception. 2000;61:29-40.
  5. Pymar HC, Creinin MD. Alternatives to mifepristone regimens for medical abortion. Am J Obstet Gynecol. 2000; 183: s54-s64.
  6. Gravanis A, Schaison G, George M, et al. Endometrial and pituitary responses to the steroidal anti-progestin RU 486 in post-menopausal women. J Clin Endocrinol Metab. 1985;60:156-163.
  7. Schindler AM, Zanon P, Obradovic D, Wyss R, Graff P, Herrmann WL. Early ultrastructural changes in RU-486-exposed decidua. Gynecol Obstet Invest. 1985;20:62-67.
  8. DeLoia JA, Stewart-Akers AM, Creinin MD. Effects of methotrexate on trophoblast proliferation and local immune responses. Hum Reprod. 1998;13:1063-1069.
  9. Koopersmith TB, Mishell DR Jr. The use of misoprostol for termination of early pregnancy. Contraception. 1996;53:238-242.
  10. Peyron R, Aubény E, Targosz V, et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med. 1993;328:1509-1513.
  11. Aubény E, Peyron R, Turpin CL, et al. Termination of early pregnancy (up to 63 days of amenorrhea) with mifepristone and increasing doses of misoprostol. Int J Fertil Menopausal Stud. 1995;40(suppl 2):85-91.
  12. Kruse B, Poppema S, Creinin MD, Paul M. Management of side effects and complications in medical abortion. Am J Obstet Gynecol. 2000; 183: S65-S75.

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