Elsevier

Contraception

Volume 74, Issue 1, July 2006, Pages 66-86
Contraception

Review article
Review of medical abortion using mifepristone in combination with a prostaglandin analogue

https://doi.org/10.1016/j.contraception.2006.03.018Get rights and content

Abstract

Induced abortion is still a major health problem in the world and the most frequently performed intervention in obstetrics and gynecology with an estimated total of 46 million worldwide each year. Medical abortion with mifepristone and prostaglandin was first introduced in 1988 and is now approved in 31 countries. This combination of drugs has recently been included in the List of Essential Medicines by the World Health Organisation. The present review summarizes the development, physiology and the development of the currently used regimens.

Introduction

Summary: The discovery of mifepristone has made a major improvement in medical abortion and is now available in 31 countries.

Inducing abortion of an unwanted pregnancy by administering drugs is not a new concept. Historic documents list an incredibly large number of drugs and other substances, which women have swallowed or inserted vaginally with the intention of inducing abortion of an unwanted pregnancy [1], [2]. However, most of these drugs have been either ineffective as an abortifaciant or dangerous to the health and/or even the life of the women.

The discovery of prostaglandins (PGs) has been an important step in the development of safer methods. The first studies were performed using intraamniotic injection of PG, which offered an advantage over hypertonic saline, the standard of that time [3]. However, these methods were only suitable for inducing abortion in the second trimester. Very quickly, a vaginally applicable PG was developed, which gave satisfying efficacy also during early pregnancy [4]. But the drawback of the PG analogues available at that time, i.e., associated pain and gastrointestinal side effects, were major obstacles for widespread use.

The turning point came when the French scientist Etienne-Emile Baulieu and colleagues from the French national institute INSERM and a group of colleagues at the French pharmaceutical company Roussel-Uclaf developed mifepristone or RU-486, as it was initially called [5] The abortifaciant potential of mifepristone was described for the first time in May 1982 [6]. This, together with a dose-finding study performed in Stockholm and Szeged in Hungary, indicated that mifepristone is a promising abortifaciant drug with very few side effects [7]. However, it became clear that mifepristone had a maximal effectiveness <80% when used alone, which was not sufficiently effective to be used as an abortifaciant drug in clinical routine. This low efficacy was confirmed by other studies [8], [9], [10], [11], [12], [13]. The final breakthrough came with the discovery that mifepristone increased the sensitivity of the pregnant myometrium to PG, which allowed use of a reduced dose of PG [14]. The maximal effect of the sensitization was seen when the interval between mifepristone and the PG analogue was 36–48 h. This led to the development of a combined treatment using mifepristone followed by a PG analogue [12], [14], [15], [16]. A protocol for medical abortion was developed from these findings, consisting of a single 600-mg oral dose of mifepristone (Europe) or repeated low doses of mifepristone (China), followed by an appropriate dose of a PG analogue 36–48 h later. The high efficacy in terminating early pregnancy and the low rate of side effects of this combined regimen were subsequently confirmed in several large multicenter studies [17], [18], [19].

Medical abortion was first approved in France in 1988 (up to 49 days of amenorrhoea), followed by approvals in the United Kingdom (1991) and Sweden (1992) (up to 63 days in both countries). Mifepristone has also been used in China since 1992. However, it was not until 1999/2000 that medical abortion with mifepristone and PG was approved in several other European countries and the United States. Today, mifepristone is marketed in 31 countries worldwide (Fig. 1). The approved protocol includes the association of 600-mg oral mifepristone with 400-μg oral misoprostol for use up to 49 days of gestation in all countries except the United Kingdom. In Sweden and Norway, the approved protocol also includes giving mifepristone 600 mg in association with gemeprost 1.0 mg vaginally for use up to 63 days of gestation. In the United Kingdom, gemeprost 1.0 mg following 600 mg of mifepristone up to 63 days of gestation is the only approved regimen. In China, a different protocol is used in most institutions, consisting of mifepristone 25-mg tablets taken twice daily for 3 days, followed by misoprostol 600 μg po for gestations up to 49 days or 800 μg vaginally in pregnancies between 50 and 63 days of gestation. However, various regimens with several days of ingestion of mifepristone are also used in China (Linan Cheng, personal communication 2005) [20].

According to the manufacturer, so far, more than 1.5 million women have been treated with mifepristone in Europe since it was first introduced in 1988 (Exelgyn, Paris). The close surveillance of the treatment allows confirmation of the very high safety of this regimen.

Furthermore, the World Health Organisation (WHO) has recently included the combination of mifepristone and misoprostol for this indication in the Essential Medicine List [21].

Since introduction of the method, research has largely focused on improving efficacy, defining the optimal type, dose and route of administration of the PG analogue. Many studies have also focused on finding the minimum effective dose of mifepristone needed to induce an abortion. An important reason for reducing the dosage of mifepristone has been the relatively high price: approximately €70 per box of three tablets in Europe and approximately US$270 per box in the United States.

However, the approved regimen has undergone only a few changes from the patients' perspective since its first marketing in 1988, for instance, changing the PG from intramuscular sulprostone (Nalador) to vaginal gemeprost (Cervagem) or oral misoprostol (Cytotec).

Currently, mifepristone is the only antiprogesterone used clinically to any extent. Before mifepristone became available in the United States, a combined regimen of methotrexate (MTX) and a PG analogue was used and is still in use in Canada because mifepristone is not on the market there. So far, no randomized control trial (RCT) has been published, comparing MTX plus PG to mifepristone plus PG. Results of different studies show a lower efficacy for the regimen with MTX, as well as a longer duration until complete abortion and a higher incidence of continuing pregnancies [22]. MTX is also teratogenic. Therefore, WHO and other authorities do not recommend MTX for medical abortion of an intrauterine pregnancy.

Section snippets

Mode of action

Summary: Mifepristone as well as its metabolites are antagonists to progesterone binding to its receptor.

Mifepristone is a 19-norsteroid substituted at the 11β position by a p-(dimethylamino)phenyl group. A hydrophobic 17α-substituent increases the binding affinity to the progesterone receptor (PR) [23]. A glycin at position 722 in the hormone-binding domain of human PR is critical for mifepristone binding [24]. Like progesterone, mifepristone enters the target cell and interacts with receptors

Prostaglandin analogues in medical abortion

Summary: E1 PG analogues like misoprostol or gemeprost have become the standard of care because of better tolerability and higher uterine specificity, as compared to other PG analogues. Today, misoprostol has replaced gemeprost due to a lower rate of side effects and costs.

When medical abortion was introduced in France in 1988, in most cases, sulprostone, a PG E2 derivative, was given intramuscularly 36 to 48 h after the administration of 600 mg of mifepristone. Providers applied different

Acceptance

Summary: It has been shown that a free choice of the available methods is highly important for the women. Up to 70% will choose medical abortion, provided they have the option.

Medical abortion is not a better method per se than vacuum aspiration. It is just another method with different characteristics [130]. Medical abortion has advantages and inconveniences. The choice of one or the other method depends not so much on medical criteria but, rather, on individual preference. An important factor

Outlook

It seems important to continue the search to find further improvements to the method. Possible future research activities could include the following:

  • Reduction in bleeding

  • Improving pain treatment

  • Evaluating the need for Rh prophylaxis in a clinical study

  • Allowing women themselves to verify successful abortion using a urinary hCG test

  • Dose-finding studies with slow-release misoprostol and development of a regimen for medical abortion.

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