In this second installment of our three-part series on mifepristone (RU-486), we describe how the drug works, its track record in clinical trials, and how--step by step--a medical abortion is performed. 

Mifepristone: an antiprogestin 
Progesterone is a powerful female hormone with many roles in the body, but its primary job in human reproduction is in the establishment and maintenance of pregnancy. Progesterone prepares the uterine lining (endometrium) for implantation of a fertilized egg. It also suppresses release of prostaglandins that cause the muscles of the uterus to contract. Uterine muscular contraction helps to expel the contents of the uterus during menstruation, a spontaneous miscarriage, or a medical abortion. 

Mifepristone is a progesterone receptor blocker: its chemical structure is close enough to the structure of progesterone that it can occupy the sites in the body where progesterone "attaches" to do its job. Figuratively speaking, mifepristone parks its car in progesterone's space. There's nowhere else for progesterone to park. It cannot come to work, so it cannot do its job. 

When mifepristone blocks the action of progesterone, the nutritive lining of the uterus (endometrium) degrades and releases prostaglandins, which in turn promote uterine contraction. In some cases (between 5% and 6% in clinical trials), the action of mifepristone alone is enough to provoke a complete abortion, but in most cases the subsequent administration of a synthetic prostaglandin is needed to provide sufficient uterine contraction to expel the uterine contents. All medical abortion protocols that include mifepristone require the combined use of a prostaglandin, administered from 1 to 3 days after mifepristone. 

The process of medical abortion with mifepristone
The standard FDA approved protocol for medical abortion with mifepristone calls for three visits to the clinic or doctor's office. 

First Visit: At the first visit, the woman is screened to determine whether she is a good candidate for medical abortion; she reads an FDA-approved medication guide explaining the process and receives counseling. The duration of her pregnancy is determined by ultrasound because medical abortion is currently advisable only in early pregnancy. FDA guidelines suggest the pregnancy be of no more than seven weeks' duration (49 days), but the clinics of Planned Parenthood offer medical abortion with mifepristone up to the ninth week of pregnancy (63 days). 

If the woman meets all the criteria for medical abortion and wishes to proceed, she signs a form declaring that she has read the medication guide and understands the process. She then takes from one to three tablets containing 200 mg of mifepristone. The dose varies, depending on the treatment protocol followed at the particular office or clinic. By law, mifepristone cannot be dispensed by pharmacies; it is supplied directly to physicians who are qualified to offer medical abortion and is taken by the patient while she is still on the premises. 

Second Visit: One to three days after taking mifepristone (the interval varies by protocol), the woman returns for a check-up and to see if she is still pregnant. Around 5% to 6% of women abort after taking mifepristone only, but most will need to take a synthetic version of a prostaglandin to promote uterine contractions; in the U.S., the ulcer medication misoprostol is used. She can ingest the two 200 mcg tablets of misoprostol on site, or she can take them home. Some protocols specify 800 mcg of misoprostol inserted intravaginally. 

Misoprostol induces strong uterine contractions which expel the contents of the uterus. Some clinics require that the woman spend four hours on site before leaving; most women experience menstruation-like bleeding and passage of the uterine contents within four hours of taking misoprostol. Bleeding or spotting usually lasts from 9 to 16 days, but may persist for up to 30 days. Bleeding may be similar to or heavier than regular menstrual bleeding. Clots and tissue from the uterus may be visible at this time, just as they would in the event of a spontaneous miscarriage. 

Third visit: The purpose of the third visit, approximately 14 days after the first visit, is to assess the woman's health and confirm that the abortion is complete. Medical abortion with mifepristone and misoprostol is between 92% and 98% effective (rates vary among studies), but if it fails, a surgical abortion must be considered. Continuing a pregnancy after a failed attempt at medical abortion with mifepristone and misoprostol increases the risk of birth defects. 

How effective is medical abortion with mifepristone?
The FDA-approved labeling for mifepristone cites U.S. trials in 827 women and French trials in 1,605. In the U.S. trials the rate of complete abortion was 92.1%; in the French trials, 95.5%. It has been suggested that the lower success rate in these U.S. studies might be attributable to the fact that French physicians have better familiarity with the drug. 

The U.S. clinical trials eventually enrolled 2,121 women at 17 different sites around the country (JAMWA. 2000;55:137-140). In those trials, women who were up to 63 days pregnant took 600 mg of mifepristone, followed two days later by 400 mcg of oral misoprostol. Abortion was complete in 92% of pregnancies under 49 days' duration; 83% of pregnancies between 50 and 56 days' duration; and 77% of pregnancies between 57 and 63 days' duration. Overall, 49% of pregnancies were terminated within four hours of misoprostol administration; after 24 hours, 75% had been terminated. 

In another large U.S. study (JAMA. 2000;284:1948-1953), 2,225 women who were up to 56 days pregnant (8 weeks) took 200 mg of mifepristone followed by 800 mcg of misoprostol self-administered intravaginally, at home, either 1, 2 or 3 days after taking mifepristone. Complete abortion was achieved in 98% of the women who took misoprostol after 1 day, in 98% of women who took misoprostol after 2 days, and 96% who took misoprostol after 3 days. This flexibility in the timing of misoprostol administration means a woman could schedule her first visit (to receive mifepristone) on any weekday. The common regimen of a second visit 2 days after mifepristone administration makes Thursday and Friday appointments for mifepristone administration problematic, unless the woman's healthcare provider is open on weekends. 

How safe is medical abortion with mifepristone?
Mifepristone has been used by more than 620,000 women in Europe. To date, no deaths have been associated with mifepristone. One woman in France died of cardiac arrest after taking the prostaglandin sulprostone, but sulprostone is not available in the U.S. (and is no longer available in France). 

Excessive or prolonged bleeding is the most serious potential adverse event associated with medical abortion. Women should expect bleeding or spotting for 9 to 16 days. Up to 8% may have some form of bleeding for as long as 30 days. The duration of post-abortion bleeding is related to the duration of the pregnancy--longer pregnancy (63 days vs 49 days) is associated with a greater likelihood of prolonged bleeding. About 1% of women experience bleeding severe enough to require a surgical procedure (curettage) to stop it. In the U.S. trials, 4.8% of women required medical intervention (curettage, vasoconstrictive drugs, saline infusion, or blood transfusion) to manage excessive post-abortion bleeding. 

In one study that measured post-abortion blood loss, women up to 63 days pregnant who took mifepristone followed by an intravaginal prostaglandin had a median blood loss of 75 mL. By way of comparison, the typical volume of blood lost per menstrual period is about 50 mL, and the normal volume given in a blood donation is 500 mL. 

As for side effects, in the U.S. trials the following were reported: abdominal cramping in 96% of the women; nausea in 61%; headache, 31%; vomiting, 26%; diarrhea, 20%; dizziness, 12%; fatigue, 10%; back pain, 9%; and a variety of other non-life-threatening effects in 5% or less of women. 

Who shouldn't take mifepristone?
The FDA recommends that mifepristone be used to terminate pregnancies that are seven weeks (49 days) advanced, although as noted earlier, some providers offer medical abortion with mifepristone at up to 9 weeks (63 days). 

Other restrictions are related to the woman's health and the nature of her pregnancy: Mifepristone should never be used to terminate a tubal pregnancy (a pregnancy that occurs outside the womb). Practitioners who offer medical abortion to their patients must be able to accurately diagnose a tubal pregnancy. A woman with an intrauterine device in place should not be given mifepristone until the device has been removed. Women with adrenal-gland problems should not receive mifepristone, nor should women who have been treated for long periods of time with certain steroids. And women with bleeding problems or who are taking an anticoagulant medication are not candidates for mifepristone. 

In part three of this series, we'll examine the present status of mifepristone and the ongoing attempt to "unring the bell" of FDA approval. We'll also take a look at the drug's lukewarm reception, postapproval, and outline some of its potential alternative uses. Part one offers a history of RU-486 and its controversial introduction into the United States.