WOMEN'S HEALTH
May 1, 2001

The Three M's of Medical Abortion — Mifepristone, Methotrexate and Misoprostol

An IUD must be removed before taking medical abortion drugs like RU-486.
What is medical abortion? Quite simply, it is the ending of a pregnancy using drugs rather than surgery. A conventional abortion is considered a type of surgery. Although various herbal preparations that claim to cause an abortion have long been part of folk medicine in many cultures around the world, it is only in the last 20 years that modern science has developed abortion drugs that are reliable and effective.

While there are now several medical abortion drugs, as well as different ways of administering them, all of the approaches have one thing in common: they make use of one or more of three drugs: mifepristone, methotrexate and misoprostol.

The Three Medical Abortion Drugs

Mifepristone, A.K.A. RU-486
Around the year 1980, researchers at the French company, Roussel Uclaf, discovered a drug that interferes with the body's ability to utilize the hormone progesterone. They called it RU (for Roussel Uclaf) 486.

Progesterone is a key player in the body's early preparations for pregnancy, helping to prepare the wall of the uterus for the implantation of the embryo, or rapidly dividing fertilized egg. If the body does not provide sufficient amounts of progesterone, the embryo cannot be implanted in the uterus. When this occurs, the uterus expels the embryo by a series of muscular contractions and the pregnancy is terminated.

As they investigated the use of mifepristone as an abortion drug, early researchers found that the drug's success rate in causing abortion was no better than 80%. But when they combined mifepristone with other drugs, such as misoprostol that further stimulate uterine contractions, the success rate rose to almost 90%. This combination, a technique which is called the "French Protocol," has been widely and successfully used in France, Sweden, China and the United States.

The dose of mifepristone used in the French Protocol is 600 mg. Recent studies, however, have suggested that much lower doses can be just as effective and may be safer. In the U.S., the most common protocols are two variations on the French Protocol called the Population Council, or PC, Protocol and the Abortion Rights Movement, or ARM, Protocol. These are named for two large-scale studies of medical abortion that were done in the United States.

A key benefit of these protocols is that they can be done very early in pregnancy. This is also an important limitation because medical abortion drugs do not work as well after the seventh week of pregnancy when other hormones and mechanisms, including the growth of the placenta (the organ formed in the uterus during pregnancy), support the pregnancy. The seventh week is up to the 49th day after the first day of the last menstrual period.

Methotrexate
Methotrexate is not new; it was approved as an anticancer drug in the U.S. in 1953. It has also been used in treating other diseases, including rheumatoid arthritis and psoriasis. Methotrexate works by interfering with the development of rapidly dividing cells in the human body.

In 1982, researchers discovered that methotrexate was an effective treatment for ectopic pregnancy. Ectopic pregnancy is a dangerous condition in which a fertilized human egg implants in the wrong place, usually in one of the two fallopian tubes that transport eggs from the ovaries to the uterus. While an ectopic pregnancy cannot produce a baby, it can threaten the health, fertility and even the life of the woman.

Before methetrexate, the only treatment for an ectopic pregnancy was surgery. The surgery, unfortunately, often results in fertility problems because the fallopian tube, sometimes also an ovary or, in the worst cases, the entire uterus may need to be removed. Methotrexate doesn't interfere with progesterone but, instead, prevents the growth of the rapidly dividing cells of the developing placenta. The drug has proven to have the same effect on normal pregnancies in the uterus.

Once researchers saw the potential of methotrexate as a medical abortion drug, they tried it in combination with misoprostol, usually given as a vaginal suppository. They found that the methotrexate/misoprotol combination had a 90% success rate, which was comparable to that achieved with mifepristone/misopristol.

Misoprostol
Misoprostol is a drug with many uses; for one, it is given to people who are taking certain anti-inflammatory drugs in order to prevent stomach ulcers. Because it can also cause uterine contractions, it has become a second component of medical abortion along with either methotrexate or mifepristone.

In the French Protocol, misoprostol is given in pill form (400 mcg) 48 hours after a woman has taken mifepristone. It is sometimes prescribed as a vaginal suppository (800 mcg) because this route can be safer and more effective, especially with pregnancies that are farther along.5 The use of misoprostol by itself for medical abortion has been studied, particularly in Brazil, where abortion is illegal and misoprostol is the easiest of the three medical abortion drugs to acquire. These studies have found that although misoprostol is about as effective as both two-drug combinations, there are many more unpleasant side effects.

Among the side effects of misoprostol are diarrhea, nausea and vomiting. Some women also get hot flashes or episodes of fever. Possibly because it enters the bloodstream more gradually, misoprostol seems to have fewer side effects when given as a suppository than by mouth.

Medical Abortion Drugs and Birth Defects
Any medical abortion drug carries with it two main risks: one, that it will not work; and two, that if an unsuccessful medical abortion is not followed up by a traditional surgical abortion, the abortion drug or combination of drugs may harm the fetus.

Based on what we know today, of the three drugs we have mentioned, misoprostol is the most likely to cause birth defects. Limb and cranial abnormalities have been reported in babies born to women who remained pregnant after using misoprostol. Obviously, the newer the drug the less information is available. For instance, there is little or no evidence that mifepristone can cause any particular problem. Although in the high doses used in cancer treatment methotrexate poses a clear risk to a developing fetus, we do not know if the low dose of methotrexate used for medical abortion has a similar effect.

It should be remembered, however, that most of the scientific data on these drugs come from studies in which women have agreed in advance to undergo a surgical abortion if medical abortion drugs fail. For this reason, it is difficult to collect enough data to determine whether these drugs will cause birth defects.

Medical Reasons Not to Have a Medical Abortion
There are a number of medical reasons why a woman might not be able to take the medical abortion drugs. The contraindications to these drugs should be discussed one-on-one between a woman and her own doctor. The most common medical conditions are long-term corticosteroid therapy, chronic adrenal failure, a disease called porphyria, conditions that cause internal bleeding or anticoagulant medication, as well as any indication of an allergy to one of the medications. If a woman has an IUD, it must be removed before taking the medications.

For many women, medical abortion is desirable because it enables them to avoid a surgical procedure. However, because of the possible birth defect risk discussed above, all patients are required to agree that they will have a surgical abortion if the medical abortion fails.

The Steps of a Medical Abortion Procedure

Mifepristone/Misoprostol
On her first visit, following examination, counseling and signed permission, a woman undergoing a medical abortion takes mifepristone (600 mg). This generally causes few noticeable symptoms. (A small percentage of women, however, usually less than 5%, will have an abortion at this point.) Two days later, she takes misoprostol in pill form (400 mcg). Note that this is the PC regimen.

In the ARM version, the woman takes mifepristone by mouth (200 mg) and two days later takes misoprostol (800 mcg) as a suppository. In both of these regimens, two-thirds of women develop cramps and bleeding and complete the abortion in the next four hours. After 24 hours, the success rate nears 90%.

The heaviest bleeding occurs on the day misoprostol is taken. For most women, bleeding and spotting continue for about two weeks. Uterine cramps also occur and vary from extremely severe to very mild. Women usually describe the bleeding and cramps as resembling a heavier than normal menstrual period.

Women having a medical abortion are normally given pain killers such as ibuprofen, acetaminophen or a stronger analgesic containing codeine.

Methotrexate/Misoprostol
The basics of a medical abortion with methotrexate are very similar to that using mifepristone, except that it takes longer. Methotrexate is given by injection (75-100 mg). At least two days later, a misoprostol suppository is given. At this point, about 60% of women abort within 24 hours. Twenty to 30% of patients do not complete their abortion for another three to three and half weeks, and the bleeding lasts longer than with mifepristone.

Follow-up Visit
In all regimens, women are asked to return after 14-20 days for an examination to determine whether the abortion has occurred. While the overall success rate for medical abortion is around 90%, studies have shown that the greater the experience of the center providing the abortion, the lower the failure rate.

Medical Abortion in the United States Today
Surveys show that medical abortion is well accepted — many phyisicans, for example, indicate they are willing to provide this option to their patients. When women are asked why they chose medical over surgical abortion and whether they found the procedure acceptable, most say they wanted to avoid a surgical procedure, felt a medical procedure was more natural and more private, and allowed them to feel 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 the increased sense of privacy and convenience, as well as having friends and family members nearby.

The political picture is less clear. In the United States, pro-life forces have focused on trying to restrict the use of mifepristone (RU-486). This is largely because the two other medical abortion drugs have been approved for other uses and are, therefore, already available. The PC and the ARM studies demonstrated the safety and efficacy of mifepristone and, despite the opposition, the drug was approved by the FDA in September of 2000.

The FDA has, however, put limits on the use of RU-486 — the medication is not sold in pharmacies but is provided directly to physicians' offices. Opponents of medical abortion continue to pursue the battle on two fronts. Upon his appointment as Health and Human Services Secretary, Tommy Thompson suggested that he might direct the FDA to reopen the approval process for RU-486.

Although Secretary Thompson has since backed away from his comment in his public statements, the possibility remains that the Bush Administration may further restrict the availability of medical abortion. Meanwhile, the U.S. Congress is debating a bill that would allow RU-486 to be prescribed only by the small minority of doctors who currently perform surgical abortions and only at clinics within an hour's drive of an hospital emergency room.

For More Information
To learn more about the practical considerations of medical abortion, click on our interview with Planned Parenthood's Jini Tanenhaus.
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