Course Authors
Susan C. Stewart, M.D.
Dr. Stewart reports no commercial conflict of interest.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the mechanism of action of mifepristone, methotrexate and misoprostol
Outline the steps involved in medical abortion: counseling, medication and follow-up
List the contraindications to medical abortion
Describe the expected course of medical abortion and the complications and their management.
My goal in this Cyberounds® is to inform health care providers about the research on medical abortion so that you have a general understanding of the medications involved, the procedure and what a woman who is terminating a pregnancy might expect.
What is medical abortion? Quite simply, it is termination of a pregnancy using medication rather than surgery. Although there have been rumors of ancient herbal remedies that were effective, it is really only during the last 20 years that truly efficacious medications and regimens have been developed.
The Drugs
Mifepristone or RU 486
Around 1980, researchers at Roussel Uclaf in France were investigating compounds that interacted with glucocorticoid receptors and identified compounds that also attached to the progesterone receptor. These were further refined and one compound, designated RU (Roussel Uclaf) 486, was recognized for its potential for early pregnancy interruption, and was tested in research trials starting in 1981.(1),(2)
Progesterone is an essential hormone for the establishment of early pregnancy. If the level of progesterone is inadequate, the embryo is expelled through the action of endogenous prostaglandins, causing myometrial contraction to empty the uterus. The key effects of progesterone in early pregnancy are the following:
- production of decidual factors that facilitate implantation (secretory endometrium)
- maintenance of myometrial relaxation
- decrease in prostaglandin synthesis (through downregulating estrogen)
- stimulation of prostaglandin dehydrogenase, which metabolizes and removes prostaglandins.(3)
Mifepristone blocks progesterone action by occupying progesterone receptor sites. The affinity of mifepristone for the progesterone receptor site has been found to be five times that of progesterone. The results of this blockade are changes in the uterine lining, making it less hospitable to implantation, and also an increased sensitivity of the myometrium to prostaglandin induced contractions. With decreased progesterone action, prostaglandin levels increase, and cervical softening and uterine contraction occur. Investigators found that the highest rate of complete abortion with mifepristone alone was 80%, though most studies reported a lower rate. When compounds like prostaglandin analogs, that cause uterine contraction, were added to the regimen, high rates of complete abortion, generally over 90%, resulted. Extensive testing and usage of this regimen has occurred in France, Sweden, China and the United States. The regimen has been found to be highly effective, as well as acceptable, to women using it.(1)
The dose of mifepristone used in the "French Protocol" has been 600 mg. Other studies have shown that much lower doses can be employed.
In the normal course of pregnancy, human chorionic gonadotropin (HCG) is secreted by the trophoblast. HCG starts the chain of events that leads to progesterone production by the corpus luteum in the ovary. The pregnancy is dependent on this source of progesterone until about the seventh week, when the developing placenta begins to supply adequate progesterone. This is why the protocol for mifepristone focuses on using the drug up to the 49th day after the first day of the last menstrual period or the seventh week of pregnancy.
As you know, pregnancy is dated from the first day of the last menstrual period, not from fertilization or implantation, which are impossible to determine in an individual woman, except in a research study. Although seven weeks may be the theoretical ideal, many studies include patients up to nine weeks or 63 days. As expected, the efficacy decreases with the length of gestation.(3)
One of the most important facts to remember about mifepristone is that it also blocks glucocorticoid receptors. Therefore, it is contraindicated in patients with adrenal failure or long-term corticosteroid treatment.
There is certainly potential for the use of this drug in the treatment of steroid mediated diseases like Cushing's disease, as well as tumors with progesterone receptors such as breast cancer.
Methotrexate
Methotrexate was approved as an anticancer drug in the U.S. in 1953. It has been used in gestational trophoblastic neoplasia (hydatidiform mole and choriocarcinoma), as well as chronic proliferative conditions like rheumatoid arthritis and psoriasis. Methotrexate blocks dihydrofolic acid reductase, a crucial enzyme in deoxyribonucleic acid synthesis and, thus, inhibits rapidly dividing cellular growth.
In 1982, researchers began reporting the efficacy of methotrexate in the medical treatment of ectopic pregnancy. Methotrexate exerts its antimetabolite effect on the cytotrophoblast, the rapidly dividing cells involved in establishing implantation and developing the placenta, stopping their invasive growth. Its use in ectopic pregnancy has permitted regression of that condition without the necessity of surgical intervention. In contrast, mifepristone would not work for ectopic pregnancy because:
- it acts to interrupt implantation by changing the desidual lining, which results in separation of the developing embryo and
- there are no progesterone receptors in the fallopian tubes. It is also helpful to realize that ectopic pregnancies are anembryonic, hence nonviable, though the growth of the cytotrophoblast can invade tissue and rupture blood vessels.(4)
After the prostaglandin analogue misoprostol became available in the United States as Cytotec®, an ulcer drug, research began on the combination of methotrexate and misoprostol for medical abortion. The first published study, on women with pregnancies 56 days (eight weeks) or less, was in 1993 and showed that misoprostol was more effective when administered intravaginally than orally. The dose of methotrexate was 50 mg/m(2), followed in three to seven days by 800 mcg of misoprostol intravaginally. Most subsequent studies have reported abortion rates around 90%, with a decreasing success rate as gestational age increases.(4)
Misoprostol
Misoprostol is a synthetic prostaglandin E1 analog that exerts a protective effect on the gastric mucosa in patients on NSAIDs and has been found to have a significant preventive effect on the development of gastric ulcers in these patients. It is amusing to read the PDR description of Cytotec® with the warnings about use in pregnancy and its FDA pregnancy rating "X" -- "contraindicated." Misoprostol stimulates uterine contractions and has become the second component of the medical abortion regimen for both methotrexate and mifepristone in an off label usage.
On the French Protocol, it is given in a dose of 400 mcg orally 48 hours after the dose of mifepristone. It can also be given intravaginally in an 800 mcg dose and has been used both with methotrexate and with mifepristone. Vaginal administration results in a lower peak level after administration and a longer sustained high blood level, and is associated with greater efficacy in later gestations.(5) The use of misoprostol as the only drug for medical abortion has also been studied. Doses of intravaginal misoprostol were given at 24-48 hour intervals. Although completion rates were comparable to the two-drug regimens, the rate of side effects was extremely high.(4) There is extensive experience with the use of misoprostol only in countries where abortion is illegal, particularly Brazil.(6)
Some of misoprostol's advantages are that it is in pill form and is stable. Some of the other prostaglandins used in the European studies were injectable or not stable at room temperature, a disadvantage in locations where clean syringes or refrigeration are not available.
Medical Abortion Drugs and Congenital Anomalies
Of the three drugs just discussed, based on current knowledge, misoprostol has the most potential for teratogenicity. Limb and cranial abnormalities have been reported in babies born to women who had a continued pregnancy after using misoprostol. With mifepristone, there is very little information and no clear-cut association with any particular anomaly. Although methotrexate could be considered quite teratogenic in chemotherapy doses, the dose of methotrexate used for medical abortion is considered low dose therapy, which has not yet been associated with the development of such anomalies.(4)
Obviously, much of the data we have comes from tightly controlled studies in which a surgical abortion is performed if the pregnancy is not terminated by the medical regimen. Therefore, there is little information about ongoing pregnancy after the administration of these drugs.
Timing, Medication Administration and Course of Medical Abortion
There are many, many studies and variations on medication, dosages and results. I will try to summarize.
Abortion with Mifepristone and Misoprostol
In the United States, there were two large multi-center study groups, the Population Council PC (1994-1995) and the Abortion Rights Mobilization--ARM (1996-1997). The PC used mifepristone 600 mg with misoprostol 400 mcg orally; ARM studied mifepristone 200 mcg with misoprostol 800 mcg intravaginally.
Determining the Duration of Pregnancy
The medical abortion procedure is most effective within the first seven weeks of the pregnancy. Time from the last menstrual period is the first criterion. Signs and symptoms of pregnancy can be helpful. Physical findings, such as enlargement of the uterus, softening of the cervix, and changes in the appearance of the cervix, can also confirm the diagnosis. Transvaginal ultrasound has been used in the American studies to verify pregnancy duration. The gestational sac can be identified at 4.5 weeks, the yolk sac at five to six weeks and the first sign of the embryo at six weeks.(7)
Counseling and Contraindications
The provider must review the woman's medical history for long term corticosteroid therapy, chronic adrenal failure, porphyria, hemorrhagic disorder or anticoagulant medication, as well as any indication of an allergy to the procedure medications. If an IUD is in place, it must be removed before administering the medications. Finally, if there is any suspicion of an ectopic pregnancy, it must be investigated and treated accordingly.(8)
Many patients have chosen the medical abortion option because they would like to avoid a surgical procedure. However, all patients must agree that they will have a surgical evacuation procedure if the medical abortion fails. If a patient will not agree to surgery under any circumstances, it is best not to attempt the medical abortion.
Any provider who does not perform surgical abortions must make arrangements for surgical back up (urgent or nonurgent) to care for any patient who needs it. Also there should be a 24-hour hotline for patients to call for any reason. The more thorough the initial counseling is, the less likely the patient will need to use the hotline.
Medication and Clinical Events
On the first visit, after examination, counseling and signed permission, the patient takes the mifepristone dose of 600 mg. She generally has few symptoms. A small percentage, usually less than 5% of patients, will abort on mifepristone alone. Two days later, she takes misoprostol 400 mcg orally. This is the PC regimen. In the ARM regimen, the patient takes an oral dose of 200 mg of mifepristone and two days later takes misoprostol, 800 mcg, intravaginally. In both these regimens two-thirds of women develop cramps and bleeding and complete the abortion in the next four hours. By 24 hours, the completion rate is almost 90%.(9)
The heaviest bleeding is on the day of misoprostol administration. On average, bleeding and spotting continue for about two weeks. The amount of bleeding varies considerably from patient to patient. In some cases, it may go on for a month or more, with an increase around the time of the next menstrual period. Uterine cramps vary in severity, from extremely severe to minimal. As in spontaneous abortion, both bleeding and cramps are usually described as heavier than a normal menstrual period.(10)
Misoprostol causes significant GI side effects, primarily diarrhea, nausea and vomiting. Thermoregulatory effects, hot flashes or fever, are also described and may be due to misoprostol, but they can also be ascribed to endogenous hormonal variations.(11) Possibly because of the lower peak blood levels, vaginal misoprostol has been observed to cause fewer side effects than oral.(5)
Analgesic medications should be prescribed at the time of the first visit. Ibuprofen, acetominophen and a stronger analgesic containing codeine are most commonly used. Nonsteroidal anti-inflammatory drugs do not interfere with the action of misoprostol because NSAIDs inhibit endogenous prostaglandin synthesis and misoprosol is a preformed and exogenous prostaglandin.
Methotrexate
The efficacy and course of the medical abortion with methotrexate is similar to mifepristone, except that it is slower. Methotrexate is administered intramuscularly in a dose of 50 mg/m(2) (75-100 mg). At least two days later, vaginal misoprostol is used and about 60% of women abort within 24 hours. Twenty to thirty per cent of patients do not complete their abortion until three to three and half weeks, and the total time of bleeding is longer than with mifepristone.(4)
Follow-up visit
In all regimens, a revisit is requested at 14-20 days to determine whether the abortion is complete. In the United States studies, transvaginal ultrasound was the method of choice, and can determine whether the gestational sac is absent from the uterus, present and nonviable or present and viable.(7)
Failure
Failure of the medical regimen was defined as the necessity to perform surgical uterine evacuation for any reason. This included on-going pregnancy (<1% in gestations of <49 days), excessive bleeding (<1%), choice by patient or rule of the protocol. Studies have shown that the greater the experience of the center, the lower the failure rate. Many centers offer the procedure of Manual Vacuum Aspiration, which can be used to empty the uterus if needed.(12)
Reactions of Patients
When patients are asked why they chose medical over surgical abortion and whether they found the procedure acceptable, they commonly say they wanted to avoid a surgical procedure, they felt a medical procedure was more natural, and they felt the procedure was more private and they were more in control. When the option of taking the misoprostol at home, rather in the clinic, was available, women who took their medication at home liked having privacy, convenience and friends and family members available. Having a hotline increased their sense of security.
Medical Abortion in the United States
In the United States, the battle to get mifepristone approved by the FDA has been long and tortuous. In 1996, the FDA issued an "approvable letter." The Population Council, which holds the U.S. patent on the drug, designated the Danco Group as the manufacturer. The PC studies and the ARM studies have demonstrated safety and efficacy, supporting results from the large European and Asian trials. The problem is politics, and the U.S. is not unique in this regard. Mifepristone was approved by the FDA in September of 2000 and is now available in the United States. The medication is not in pharmacies, but provided directly to physicians' offices.
Obstetrician/gynecologists, family physicians and other clinicians delivering women's health care have been polled about their interest in providing medical abortions. One survey indicated that around half of those questioned were either "very likely" or "somewhat" likely" to offer this option to their patients.(13) Educational courses are being developed for those who are interested.
I would like to thank Dr. Carolyn Westhoff for her review and comments for this conference. Carolyn Westhoff, MD, MSc, is a Professor, Obstetrics/Gynecology and Public Health, Director, Division of Prevention and Ambulatory Care, Columbia University College of Physicians and Surgeons, and Chair or the American Medical Women's Association Reproductive Health Initiative.
For further information:
The National Abortion Federation
The National Abortion Federation (NAF) is the professional organization of abortion providers in the United States and Canada. To learn more about NAF see their website or call 202-667-5881. NAF has set up a special website that provides information about the mifepristone and misoprostol combination for medical abortion. There is both consumer and provider information.
Danco Laboratories
For more information on mifepristone.
The American Medical Women's Association Reproductive Health Initiative
The American Medical Women's Association Reproductive Health Initiative (RHI) produces educational resources and programs to expand the capacity of medical schools, residency programs, physicians and other health professionals to provide comprehensive reproductive health services. Among RHI activities is the Medical Abortion Education Project (MAEP), an innovative collaborative program with Physicians for Reproductive Choice and Health and the National Abortion Federation, which will train physician educators who will give continuing medical education workshops to prepare health care professionals for medical abortion services. For more information on RHI and MAEP, please contact Susan Eisendrath, MPH, RHI Director at 703-838-0500 or seisendr@amwa-doc.org.