The role of mifepristone and misoprostol for medical termination of pregnancy.
Neither of the medications now used for medical termination of pregnancy were first developed for that role. In the case of misoprostol, its effect on the pregnant uterus was initially regarded as an unwanted side effect of an anti-ulcer medication, while mifepristone was initially designed to strongly bind to progesterone receptors for experimental reasons, without regard to any clinical use. Today, a combination of these medications provides a reliable method of pregnancy termination used widely throughout the world.
The first steps in the development of mifepristone grew out of research done at the French pharmaceutical laboratories of Roussel Uclaf, conducted by chemists Georges Teutsch and Alain Belanger in the late 1970s. At the research facility in Paris, Teutsch and Belanger were investigating steroid receptors and how to modify binding. To assist their work, they developed synthetic steroids that would bind to steroid receptors. One of the compounds the group synthesised was named RU-486 and a member of their team found that RU-486 occupied the progesterone receptor with a strong affinity, not allowing natural progesterone to bind and have its physiological effect. RU-486 was synthesised by taking a 19-norsteroid moiety and substituting a p-dimethylamino phenyl group at the 11b position. Its binding affinity for the progesterone receptor is up to five times that of progesterone.1
This ‘anti-progesterone’ function of RU-486 was duly noted, but the full significance of the results did not become apparent to the team at the time. It was not until an endocrinologist also working for Roussel Uclaf, Etienne-Emile Baulieu, recognised that RU- 486 could play a role in fertility regulation that further work was undertaken. Baulieu used RU-486 in various laboratory animals and found that it prevented the physiological change from proliferative to secretory endometrium during the animals’ oestrus cycle, and led to spontaneous pregnancy loss if given after pregnancy was established. Perhaps most importantly, RU-486 did not appear to have toxic side effects, even in relatively high doses. Encouraged by these animal data, Roussel Uclaf funded further testing of RU-486 in human subjects, with very similar results to the animal studies. Subsequent large studies across Europe and Asia confirmed that low oral doses of RU-486 provoked early pregnancy loss with few complications and minimal side effects.
It should not be surprising that RU-486, or mifepristone as it is now usually known, has such a profound effect once it blocks the progesterone receptor. Progesterone maintains pregnancy through a number of physiological actions. It prevents the typical cervical changes that lead to labour – interstitial hydration, apoptosis of smooth muscle cells, denaturation of the collagen framework and opening of elastin fibres. It also reduces synthesis and release of prostaglandins from the decidual cells, and stabilises myocytes and inhibits the formation of a muscle bundle syncytium with gap junction formation that is necessary for co-ordinate contraction during labour.
When the progesterone receptor is blocked endogenous progesterone cannot bind and this leads to vascular injury, necrosis of the decidual tissue and these effects ultimately result in bleeding.2 3 Mifepristone administration will thus counteract all of the progesterone actions, leading to cervical softening, increased sensitivity to prostaglandins and increased spontaneous contractility.4 Indeed, mifepristone administration increases myometrial sensitivity with increases in frequency and amplitude of contractions of up to five times and its effects peak at between 36 and 48 hours after administration.5
Misoprostol was originally synthesised in 1973, by Paul Collins, a chemist working with American pharmaceutical giant Searle. It had long been recognised that prostaglandin-E series compounds inhibited gastric acid secretion, hence Collins’ research. However, its potential went unrecognised until it was first licenced by Searle in 1985, at the same time the company was embroiled in controversy and was in the process of withdrawing its Copper-7 intrauterine device from sale in the wake of the Dalkon Shield disaster. At the time, gastric ulcers associated with non-steroidal anti-inflammatory drug (NSAID) use were a major problem and the original H2- antagonists, cimetidine and ranitidine, were making huge profits for other companies. Searle was keen to enter this lucrative market and misoprostol, as a synthetic PGE1 analogue, had been licenced specifically for the prevention and treatment of peptic ulcer disease in patients on long-term therapy with NSAIDs, such as naproxen and aspirin, for conditions such as rheumatoid arthritis. Misoprostol was the first compound to receive formal FDA approval for that indication, giving Searle a major commercial advantage.
Collins and his group knew well that prostaglandins affected uterine smooth muscle and conducted experiments using misoprostol only to find they were unable to counter the potentially disastrous side effect. Misoprostol induces cervical ripening and labour by direct action on the cervix and by the stimulation of myometrial activity. Thus, misoprostol was released with strong warnings about its potential effect in women of childbearing age, and especially in pregnancy. The significance of this effect was not lost on other researchers and misoprostol was subsequently used ‘off-licence’ as an abortifacient.6 Today, misoprostol, either alone or in combination with other drugs, may be used to deliberately induce uterine contractions at any stage of pregnancy.
Misoprostol has a number of very useful properties: it is inexpensive; it is very stable at room temperature; it can be stored in austere conditions for long periods of time; and tablets are readily absorbed and effective if taken orally or used vaginally or rectally. Following oral administration, the plasma concentration of misoprostol peaks at about 30 minutes, but declines rapidly thereafter with a terminal half-life of between 20 and 40 minutes. In contrast, after vaginal administration, the levels increase gradually and peak after about 75 minutes, but remain detectable for a significantly longer time. In medical termination of pregnancy, both the oral and vaginal routes are effective, but patient acceptability has led to oral administration being most commonly used, particularly in early pregnancy. Importantly, misoprostol has minimal effects on airways and has few side effects.
For termination of pregnancy
Despite mifepristone increasing uterine contractility and causing cervical softening, less than one per cent of women proceed to abortion after administration of mifepristone alone.7 For this reason, medical termination of pregnancy is usually undertaken using a combination of mifepristone and a prostaglandin analogue, in most cases misoprostol. In effect, mifepristone primes the myometrium to potentiate the effect of the misoprostol, resulting in abortion. A combination of mifepristone and misoprostol is approved for medical termination of early intrauterine pregnancy in both Australia and New Zealand (see Table 1).
The timing of the misoprostol dosage does not appear critically different between 24 and 48 hours following the mifepristone, with both intervals resulting in a similar induction to abortion time and comparable efficacy.8 Mifepristone reaches peak plasma concentrations within one-to-two hours of administration and slowly decreases with a mean half-life of 24 hours9, which could account for the lack of difference in efficacy despite timing differences. The effectiveness of this combination of mifepristone and misoprostol for medical termination of pregnancy is at least 93 per cent if performed before 49 days gestation. Less than five per cent of women who receive mifepristone followed by misoprostol require surgical intervention: in between two and four per cent of women it is required for retained products; and in about one per cent it is necessary for ongoing pregnancy. Women undergoing medical termination must to be followed up to three weeks after medication, to ensure complete expulsion of the pregnancy and cessation of bleeding.
Currently, GyMiso is licensed in Australia for use up to 49 days gestation, however, in many other countries – including, upon the recommendations of the Royal College of Obstetricians and Gynaecologists, the UK – the combination is recommended for use for medical termination until 63 days gestation. The priming effect of mifepristone on the myometrium may also be used in mid trimester termination of pregnancy with misoprostol. Mifepristone 200mg is administered 36–48 hours prior to the start of a misoprostol regime designed to induce a mid-trimester abortion. In this case, mifepristone has been shown to reduce the total dose of misoprostol required.
Worldwide, 47 000 maternal deaths occur owing to unsafe abortion each year10 and medical management provides an alternative to the previously favoured surgical termination, that is not always readily available. Fortunately in Australia there is access to safe options and, though such decisions can never be easy, the remarkable synergistic combination of mifepristone and misoprostol provides a therapeutic option with a number of advantages at a very difficult time. These advantages include: increased options for the patient a misoprostol induction of a labour in later pregnancy, including intrauterine fetal death; an effective alternative to surgical termination in early gestations; an option that can be undertaken as an outpatient with the support of loved ones; and simply the ability of the patient to be involved in choice, permitting patient preference and increased satisfaction in this difficult time.11
Table 1. Mifepristone and misoprostol regimens for termination of intrauterine pregnancy up to 49 days gestation.
|Country||Mifepristone dose||Misoprostol dose|
|Australia||200mg oral single dose||800μg single oral dose OR two 400μg oral doses two hours apart, 36–48 hours post mifepristone|
|New Zealand||200mg oral single dose||800μg vaginally 36–48 hours post mifepristone|
Lalitkumar S, Bygdeman M, Gemzell-Danielsson K. Mid-trimester induced abortion: a review. Hum Reprod Update 2007; 13: 37-52.