Keywords: Mifepristone; Misoprostol; Abortion; History; Review

Article Outline

1. Introduction

1.1. A brief history

2. An evolving regimen

2.1. Increasing the gestational age from 49 to 63 days

2.2. Shortening the process

2.3. Decreasing costs and increasing flexibility of regimen

2.4. Reducing failures, side effects and complications

2.5. Increasing the numbers and types of clinicians

3. Other uses of mifepristone

4. Discussion

Acknowledgements

References

1. Introduction

Approved in the US in 2000, mifepristone has had an extraordinary journey. Supporters of the medication had hoped that it would rectify the inequities in abortion care. While almost 70,000 women die [1] and 5 million suffer from temporary or permanent disability from unsafe abortion in developing countries each year [2], early first-trimester surgical abortion has a mortality rate of 0.1/100,000 in developed countries where abortion is accessible, legal and safe [3]. If extrapolated to the World Health Organization's estimated 50 million abortions worldwide, the worldwide death rate could decrease to 50! Millions of women around the world have used mifepristone for early abortion. In refute to the concern that medical abortion would increase abortion, the evidence is that the number of abortions in the US [4], France and Sweden [5] continue to decline. Despite the World Health Organization having added mifepristone to the list of essential medicines for developing countries [6], the potential for medical abortion to dramatically expand safe abortion services where unsafe practices still occur has yet to be realized.  

1.1. A brief history

In the early 1980s, the identification of mifepristone was both an important milestone in steroid research and a laboratory mistake. Researchers could claim that they now had agonists and antagonists for the five major classes of steroid hormones: estrogens, androgens, mineralocorticoids and, now, progestins, and glucocorticoids. While the French researchers from Roussel-Uclaff were hoping for a pure anti-glucocorticoid, their compound RU 36486, shortened to RU 486, also had anti-progesterone properties, making it a likely abortifacient with all the accompanying moral, political and economic problems. Researchers also understood the other potential clinical applications for a drug that had both anti-glucocorticoid and anti-progesterone properties.

French trials began in the 1980s and news about mifepristone spread. While studies demonstrated mifepristone had abortifacient properties, it was only 65% effective in ending pregnancies up to 49 days gestation [7]. When combined with the uterotonic properties of a prostaglandin 2 days later, effectiveness reached 95% that made it clinically acceptable.

In 1988, mifepristone was approved and brought to market in France. In the same year, the Reagan administration banned the drug from importation as “a dangerous drug.” The Vatican had already labeled it as “a new, serious threat to human life.” Anti-abortion advocates in the US and Europe mounted lobbying efforts to warn away pharmaceutical companies that might want to develop and market mifepristone in the US and abroad with threats of boycotts of their other products. After 1 month on the French market, these groups succeeded in pressuring Roussel-Uclaff to withdraw mifepristone. Only after a counter protest by health care professionals and the French minister of health's declaration that mifepristone was now “the moral property of women” backed by the threat to take the patent away did the company relent. Mifepristone was now securely established in France, though under strict guidelines for prescribing, administering, storing, and dispensing.

The first synthetic prostaglandin used with mifepristone was sulprostone administered intramuscularly. Reinforcing the need for a supervised setting, sulprostone was associated with three serious episodes of angina with one death in women with additional cardiovascular risk factors. Sulprostone was discontinued and gemeprost, a prostaglandin vaginal suppository, was substituted. Gemeprost worked well but was relatively expensive, required refrigeration and not available in the US. Misoprostol, another prostaglandin approved as an oral tablet to prevent stomach ulcers, also was a potent uterotonic. Misoprostol has become the recommended prostaglandin because it is generic, inexpensive, stable at room temperature and active both orally and absorbed through a mucosal epithelial surface.

Because of the Reagan and first Bush administrations' ban from 1988 to 1993, US researchers turned to an alternative medication, methotrexate, a generic, inexpensive and readily available antimetabolite also used as an effective treatment for early ectopic pregnancy. In the mid-1990s, US studies demonstrated that methotrexate followed in several days by misoprostol was also effective as an abortifacient [8]. To achieve success rates of 90–95%, women often needed several doses of misoprostol and as long as 2–4 weeks of waiting for a complete abortion [9], making the procedure cumbersome and the timing of the abortion unpredictable.

While methotrexate and misoprostol and misoprostol-alone regimens have been evaluated, neither have shown any advantage when mifepristone is available (except methotrexate is indicated if an occult ectopic pregnancy is possible). Several important findings emerged from methotrexate abortion research that were applied to mifepristone: (1) misoprostol was more effective when given vaginally compared with orally [10], (2) repeated doses of misoprostol improved effectiveness [11], and (3) women could safely have their abortion at home rather than require a supervised setting.

In 1993, President Clinton directed the Food and Drug Administration (FDA) to review the scientific basis for the previous import ban on RU486, essentially ending the ban. The French company, weary of controversy, did not want to be involved with the US. They gave the US mifepristone license, at no cost, to the New York nonprofit research organization, the Population Council, and provided the FDA with the necessary toxicology and chemical data required for approval.

The Population Council performed the requisite clinical study in 1994–1995 for FDA approval [12]. In 1996, the FDA provided an initial approval letter indicating that mifepristone was safe and effective, but required further information prior to a final approval, in particular, the need for an approved US manufacturer. Since none of the US pharmaceutical companies were interested in bringing mifepristone to market due to the threat of boycott, there was a delay until a new company, Danco, was formed. For fear of violence, Danco's headquarters remains unpublished.

To not delay the approval process further, the FDA was purposely not given current evidence-based regimens to review. In 2000, the FDA gave its final approval for mifepristone based on the regimen studied by the Population Council and France. The label required (1) women to be no more than 49 days from the first day of their last menstrual period, (2) the mifepristone dose be 600 mg orally followed in 2 days by misoprostol 400 mcg orally dispensed in a clinic setting and (3) a final appointment in 2 weeks to confirm the abortion was complete.

From the onset, there were concerns with the FDA's approved regimen. The gestational age limit of 49 days from the last menstrual period restricted the number of women who could access a medical abortion. Danco's charge for the three-tablet 600 mg mifepristone dose of $270 as well as the requirement of multiple visits would be cost-prohibitive for some. The 2-day wait between medications, the return to the medical facility in 2 days for misoprostol administration and the waiting for the 2-week follow-up visit to confirm a complete abortion made for a long process and much anxiety. Researchers set out to increase the gestational age limit, shorten the process, decrease the costs, simplify the regimen, reduce the failures, side effects and complications, and increase the numbers and types of clinicians offering mifepristone.

2. An evolving regimen

2.1. Increasing the gestational age from 49 to 63 days

Though mifepristone was approved for use up to 49 days gestation by the FDA, there have been multiple US and international studies that demonstrated that it was effective through 63 days gestation [13], [14] and [15]. Applying the knowledge from methotrexate abortion research that misoprostol given vaginally was more effective and had fewer side effects, mifepristone studies followed by misoprostol vaginally also demonstrated consistent effectiveness rates of >95% that allowed researchers to increase the gestational age from 49 to 63 days. The pharmacokinetic studies of different doses and different routes of misoprostol provided the explanations of what was apparent clinically. Misoprostol 400 mcg given orally is rapidly absorbed from the intestine providing a quick serum peak concentration that is associated with gastrointestinal side effects such as nausea, vomiting and diarrhea [14]. This 400-mcg dose of oral misoprostol has a relatively short bioactive time for uterine contractility. Misoprostol 800 mcg vaginally or in the buccal pouch of the cheek for 30 min is more slowly absorbed, bypasses the enterohepatic circulation slowing the metabolism and causes a lower peak serum concentration associated with fewer gastrointestinal side effects. The higher 800-mcg dose has prolonged blood levels, more bioactive time and more uterine contractions that are necessary for completing abortions up to 63 days [15].

The FDA-approved label of mifepristone 600 mg orally and misoprostol 400 mcg orally up to 49 days gestation is highly effective and tolerated well as noted in France for the past two decades. The off-label use of mifepristone followed by misoprostol 800 mcg vaginally or buccally for medical abortion to 63 days is routine in Great Britain, Sweden, and the US and found in guidelines by the American College of Obstetrics and Gynecology [16], the National Abortion Federation [17], the Royal College of Obstetricians and Gynecologists [18], and the World Health Organization [19].

A new antiabortion legislative strategy to decrease access to medical abortion is to prevent “off-label” use of mifepristone by penalizing US physicians who do not follow the FDA's label [20]. Off-label prescribing (i.e., allowing physicians to use their professional judgment in treating patients) is common practice and sanctioned by the FDA since drug labels often lag behind science and are delayed due to the high costs of changes for the pharmaceutical industry [21]. Under the doctrine of informed consent and under federal law, US women who chose an evidence-based regimen must also be informed about the FDA-approved mifepristone regimen [22].

2.2. Shortening the process

One study found that women were more interested in accessing any type of available abortion without delays than whether the method was by surgery or medications [23]. Women also prefer the shortest interval between mifepristone and misoprostol [24]. Same day use of mifepistrone and misoprostol, whether 6–8 h apart [25], or at the same time, look promising though more study is required [26].

Having a predictable, short interval from misoprostol to abortion would allow women to plan appropriately. Newer regimens using misoprostol either vaginally or buccally induce expulsion within 4 h in over 90% of women which is higher than with misoprostol orally [27].

According to the US label, women must return 14 days later to document a complete abortion when most women have experienced resolution of their pregnancy symptoms. In France, since ultrasonography was not used routinely, clinicians relied upon their medical history of miscarriage-like symptoms and a bimanual examination documenting the uterus had returned to a nonpregnant size. Clinicians in the US have relied on ultrasonography at the follow-up visit to document the absence of the gestational sac to confirm a complete abortion. Serial serum human chorionic gonadotropin (hCG) levels demonstrating a decrease greater than 50% by 48 h post misoprostol is also consistent with a complete abortion [28] and only requires a follow-up lab visit. With ultrasonography or serial hCG levels, the final office or lab visit can occur as short as 1–2 days after misoprostol.

2.3. Decreasing costs and increasing flexibility of regimen

The cost of a medical alternative to a surgical procedure is usually less expensive but not so with medical abortion, at least in the US. This is because a medical abortion can require as many as four visits: primary care for a referral, an abortion provider for initial assessment and mifepristone administration, visit for misoprostol administration, and a final follow-up appointment. In addition, the FDA-recommended mifepristone 600-mg dose was expensive. If the time and costs were not streamlined, cost of a medical abortion would be prohibitive.

While ultrasonography provides accurate pregnancy dating, rules out ectopic pregnancy and documents the absent gestational sac at follow-up, it can be expensive and may not be needed routinely. France only used ultrasonography for dating when there was a discrepancy between the last menstrual period and uterine size by bimanual examination. Other countries have used mifepristone safely without routine ultrasonography [29] and [30]. Because of the concern about missing an ectopic pregnancy, some advocate routine ultrasonography [31]. Routine ultrasonography has led to unnecessary surgical interventions when normal intrauterine echogenic findings have been interpreted as retained tissue requiring intervention. As noted earlier, if hCG levels are obtained on Day 1 and at follow-up, a precipitous drop confirms a complete abortion [32]. A persistent elevated serum hCG is helpful in identifying retained tissue, trophoblastic malignancy and an ectopic or heterotopic pregnancy.

A sensitive pregnancy test measuring around 25 IU/L may remain positive up to a month after either a surgical or medical abortion [33]. Low-sensitive pregnancy tests are available measuring 500–2000 IU/L, and these will be negative after a complete surgical and medical abortions at 2 weeks [34]. Women could be sent home with instructions (1) to expect bleeding as much as a menses with passage of pregnancy tissue within 4–24 h of misoprostol, (2) to perform a low sensitivity test in 2 weeks and (3) to return for evaluation if their test is positive [35].

Randomized control trials have demonstrated that mifepristone can be reduced from 600 to 200 mg without loss in efficacy, thereby reducing the medication costs in the US by a two thirds [36]. The 200-mg dose is also practical since mifepristone comes as an unscored 200-mg tablet. The dose may be decreased even further to 100 mg [37] or 75 mg [38] in the earliest gestations, though 50 mg is ineffective [39].

Using misoprostol in the vagina is awkward for some women and culturally unacceptable to others [40]. Women prefer an oral route compared with a vaginal route, making the buccal route more acceptable [41]. Preliminary reports also show that the sublingual route for misoprostol is highly effective but has more prostaglandin side effects such as nausea, vomiting and chills [42].

Eliminating the need for a misoprostol-administration visit at 48 h after mifepristone has resulted in one less visit. Home use of misoprostol has become routine in the US [43], Great Britain and Sweden and is becoming more common in developing countries [44] and [45].

2.4. Reducing failures, side effects and complications

The reasons given most often by women for choosing a medical abortion are to avoid the invasiveness and risks of a surgical abortion and anesthesia [46] and [47]. As clinicians gained more experience with medical abortion, the number of unnecessary surgical interventions has decreased [48]. The reason for surgical intervention after mifepristone typically included 1% on-going pregnancies [49], 1% heavy bleeding, 1–2% retained pregnancy tissue and persistent bleeding and 1–2% nonmedical indications. For women returning with either retained nonviable products of conception or an ongoing pregnancy, repeating the misoprostol dose at 1 week was successful in completing the abortion in half of these women [50] or more.

In about 1% of women, the medications fail and pregnancy continues requiring either another dose(s) of misoprostol or surgical completion. There is no evidence that mifepristone is teratogenic. Misoprostol causes uterine contractions and fetal compression, which is the likely cause of Mobius' syndrome, fetal limb defects and other birth defects noted [51].

The two most serious adverse events are hemorrhage and sepsis. In a study of 95,163 women using mifepristone, the complication rate was 2.2/1000 women [52]. The need for transfusion for excessive bleeding is estimated to be about 1/1000. Heavy bleeding is unpredictable, though more likely in later gestations. There are two time periods when heavy bleeding occurs, that is, the immediate 24 h after misoprostol and 3–5 weeks later related to retained pregnancy tissue [53]. Women need to know how to access emergency medical care if needed. Heavy bleeding can often be controlled by uterotonics such as misoprostol or methergine, though suction aspiration may be required. Early intervention decreases blood loss and the need for transfusion.

There have been seven deaths following mifepristone–misoprostol related to overwhelming sepsis and toxic shock from Clostridium sordellii or perfringens and all occurred in the US [54] and [55]. Six of the infectious deaths were in women who used vaginal misoprostol and one in a woman who used buccal misoprostol. The case fatality is about 1/100,000 [52]. Infections from these organisms also occur after other obstetrical and gynecologic procedures including term birth and spontaneous abortion [56]. None of the women who died used prophylactic antibiotics that are routinely given after surgical abortion [57]. In Great Britain and Sweden, antibiotics are routinely used with mifepristone and vaginal misoprostol [58] and are advocated by some in the US. On the other side, prophylactic antibiotics can be problematic and increase drug resistance [59]. Because these infections are very rare, it is impractical to perform a randomized control trial of routine antibiotics versus placebo because of the large number of participants needed. A retrospective review at Planned Parenthood of America centers found a significant reduction in serious infections in 37,488 women treated with mifepristone followed by vaginal misoprostol and no antibiotics of 1.15 per 1000 (95% CI of 0.83–1.54) to a rate of 0 per 1000 (95% CI 0–0.13) in 22,302 women treated with mifepristone followed by buccal misoprostol with routine doxycycline for 1 week [60].

2.5. Increasing the numbers and types of clinicians

The number of US abortion sites continues to decrease and is currently less than 1900. Many women desiring abortion must travel a considerable distance because one third of women aged 15–44 years live in the 87% of counties with no abortion services [61]. Medical abortion, because it does not require surgical skills, could increase the numbers and types of providers. Ten years after approval in France, their ministry of health removed the regulations requiring medical abortion to be performed only in hospitals and clinics and now allow gynecologists and general practitioners to offer medical abortion in their private practices as long as they can refer for consultation. These private practitioners have the same success rates as hospitals and about 5% of women have required referral for consultation [62].

One barrier to increasing providers in the US is medial liability insurance, a necessity to practice medicine. Medical liability coverage for medical abortion has been denied or been cost-prohibitive disproportionately affecting nonspecialists [63]. The result is that primary care physicians are unable to afford the incremental costs of liability insurance to offer medical abortion. This problem needs to be addressed.

Advance practice clinicians (i.e., nurse practitioners, physician assistants and nurse midwives) have the requisite skills to offer medical abortion but are unwilling to risk their professional licenses because of old state laws that allow only physicians to provide abortions [64]. These laws need to be challenged and changed in consideration of the availability of medical abortion.

Medical abortion can be easily incorporated into primary practices that do not provide uterine aspiration when referral services for surgical completion are available [65]. There is on-going interest and training of family medicine physicians and some interest among internists in providing medical abortion [66]. Mifepristone has also been dispensed by telemedicine when local services are not available [67].

3. Other uses of mifepristone

In other countries, mifepristone has been approved for reproductive-related services such as emergency contraception [68], and for both late first trimester (9–14 weeks) [69] and [70] and second trimester (14–22 weeks) abortions [71] and [72]. Mifepristone can be used to evacuate the uterus for embryonic or fetal demise [73] and induce labor at term for fetal death in utero [74]. Mifepristone can prime the cervix for surgical abortion [75] and is under study for menstrual regulation [76].

The antiglucocorticoid properties of mifepristone have been effective in treating acute psychotic depression [77] and Cushing's syndrome [78], and may be helpful in high stress-related conditions including HIV [79]. Mifepristone has helped in other conditions with progesterone receptors such as uterine leiomyomas [80], endometriosis and certain tumors such as meningiomas [81], leiomyosarcoma [82] and some breast cancers.

4. Discussion

Ten years later, medical abortion has been integrated in abortion care (though not primary care) in the US. Around the world, more than 30 countries have approved mifepristone to induce abortion. When access is readily available, many women within the approved gestational limits are choosing a medical abortion: about 50% in Scotland, Sweden and Switzerland [83].

Mifepristone can be provided in a wide range of primary care practices, expanding the pool of providers and making targeting for protest more difficult. While surgical abortion may be needed for the rare medical abortion failure, mifepristone provides the best alternative when a surgical abortion cannot be easily or safely performed. Examples include obstructing leiomyomas, cervical stenosis, orthopedic problems limiting lying on an exam table and extreme fear of surgery.

Costs continue to be a barrier in the US, though the reduction to one 200-mg tablet of mifepristone has helped. A generic brand of mifepristone would reduce costs more. Women can elect a shortened 1-day interval between mifepristone and misoprostol, use misoprostol buccally or vaginally at home for a predictable 4 h time to expulsion. Women can have a final visit within 1 to 2 days of using misoprostol when office ultrasonography is used or return to a lab when serial hCGs are employed. The future looks promising for avoiding the final visit if a low-sensitivity pregnancy test is negative at 2 weeks. Women can opt for repeat doses of misoprostol for the rare on-going pregnancy to avoid a surgical intervention. Though the science is not definitive, many practitioners have adopted a conservative approach and use prophylactic antibiotics similar to surgical abortion to prevent infection.

When all systems are in place and working, and skilled surgical providers are available, a surgical abortion is quick, simple and safe. But even when all the systems are in place, many of us would prefer to control our bodily functions in a more private, less invasive manner, especially women who are seeking an abortion. Women have waited a long time for a safe abortifacient. Fortunately, mifepristone has arrived.

Acknowledgments

The author would like to thank Lawrence Lader, Richard Hausknecht (both recently deceased), Mitchell Creinin, Beverly Winikoff, and Irving Spitz for their vision, advocacy and perseverance in making mifepristone a reality in the US.