Medical abortion has been shown to be an effective alternative to surgery for termination of pregnancy in the late as well as the early first trimester of pregnancy. This review discusses the development, application and the current issues with medical and surgical abortion in the first trimester. Studies comparing the two approaches are also assessed as well as potential research directions in this area.
Introduction
Surgical termination of pregnancy by vacuum aspiration was established as the method of choice for abortion in the 1960s. However, since the introduction of mifepristone in the 1980s, the uptake of medical abortion has been steadily increasing in countries where it has been available for routine use, and this has probably been one of the most significant developments in fertility control in recent years.
Medical termination of pregnancy
In the early 1970s, studies reported the successful use of natural prostaglandins (PGs) in inducing abortion in early pregnancy. Subsequently, PG analogues were used for this purpose. However, the doses required with PG-only regimens were associated with a high frequency of side effects. Pre-treatment with mifepristone was shown to shorten the induction to abortion interval, improve the efficacy of the regimen and reduce the amount of pain experienced. A more effective application was found with PG in lower doses given in combination with mifepristone, and this forms the mainstay of most current regimens used in clinical practice. However, in many parts of the world, mifepristone might not be available due to cost or licensing implications and, in such situations, a misoprostol-only regimen could offer an alternative.
Uterotonic compounds: PGs
PGs are naturally occurring fatty acids that are produced by virtually all tissues in the body and function as local hormones. They are synthesised from essential fatty acids and are not normally stored in the tissues. A problem with the naturally occurring PG is their rapid breakdown by the enzyme 15-hydroxyprostaglandin dehydrogenase. It was noted that the incorporation of methyl groups protected from destruction by this enzyme, and this was the concept used in the PG analogues: carboprost, (PGF2α), gemeprost (PGE1), sulprostone (PGE2) and misoprostol (PGE1). Misoprostol was discovered in 1973 by scientists at Searle Pharmaceuticals and was licensed for the management of peptic ulcers. It exerts an anti-secretory activity, inhibiting the secretion of acid and pepsin in the stomach. The PG analogues are more stable, have a longer half-life and a more selective uterotonic effect compared to the parent compounds.
Absorption pharmacokinetics for the different routes of misoprostol administration
Tang et al. reported on the absorption kinetics of misoprostol 400 μg administered sublingually, orally and vaginally. The study showed significantly higher peak serum concentrations of misoprostol acid with sublingual administration. The time to peak concentration was shorter in the sublingual group and oral groups, while the area under the misoprostol acid concentration versus time curve was significantly greater for the sublingual group. The results suggested that the systemic bioavailability for the sublingual route is comparable to that with the vaginal route of misoprostol administration. The higher peak levels and shorter time to peak concentration may explain the increased prevalence of side effects noted with oral and sublingual administration. More recently, the same group reported on the absorption kinetics of five repeated doses of misoprostol 400 μg given sublingually or vaginally at 3-hourly intervals. The peak plasma levels of misoprostol acid decreased with repeated vaginal doses, but remained the same with sublingual administration. The area under the misoprostol acid concentration versus time curve was higher in the sublingual group, although subgroup analysis showed the reduction in plasma levels with vaginal administration only occurred in women with significant vaginal bleeding.
Aronsson et al. assessed uterine contractility with the oral, sublingual and vaginal administration of misoprostol. Regular uterine contractions were noted in all women in the sublingual and vaginal groups, but not after oral administration. The increase in the uterine activity was significantly higher from 2 h onwards with sublingual and vaginal administration. These findings are consistent with the absorption kinetics reported by Tang et al.
Misoprostol-only regimens for abortion in the first trimester
Moreno-Ruiz et al. reported a systematic review of 13 studies between 1997 and 2003 that assessed a misoprostol-only regimen for medical termination of pregnancy up to 63 days of gestation. In most of these studies, misoprostol was given vaginally in a dose of 800 μg and repeated every 24 h, up to three doses. The complete abortion rate ranged from 84% to 96%, and the median induction to abortion interval was 6–9 h. Surgical intervention for excessive bleeding was required in 0.3–3.3%.
In a randomised study on medical abortion up to 56 days gestation, a misoprostol-only regimen following placebo administration was compared to a combined regimen of mifepristone followed by misoprostol 48 h later. Misoprostol 800 μg was given vaginally followed by two further doses of 800 μg at 24-h intervals. The complete abortion rate was higher in the mifepristone and misoprostol group (95.7%) compared with 88% for the placebo and misoprostol group.
These reports show that abortion could be successfully induced with PG alone, but the doses required were associated with a high frequency of side effects, suggesting that PG would be less suitable for use as sole agents to induce abortion.
The anti-progesterones (mifepristone)
Development of mifepristone
In 1980, the scientists at Rousel-Uclaf (Romainville-France), while investigating glucocorticoid antagonists, discovered a C-19 derivative of norethindrone with high affinity for the progesterone receptor. The company’s code for this drug was RU 38486 (subsequently shortened to RU 486) and the generic name, mifepristone. This discovery began a new era in fertility control and has shaped much of our current practice. In 1988, France became the first country to license the use of mifepristone in combination with a PG analogue for termination of pregnancy up to 49 days of gestation. Recent figures show that mifepristone is now licensed in 40 countries worldwide for use in the context of medical abortion.
Mechanism of action in pregnancy termination
Mifepristone blocks the progesterone receptors within the decidua, leading to ultra-structural changes in the endothelium of the decidual capillaries, vascular damage followed by decidual necrosis and detachment of the conceptus. Mifepristone has also been reported to result in an increase in uterine contractility 24–36 h after its administration. It also increases the myometrial sensitivity to exogenous PG. The effect of mifepristone administration on uterine contractility is shown in Fig. 1 .
Mifepristone was initially assessed for use as a single agent for termination of pregnancy, with varied success rates of 60–80%. Subsequently, a more effective application was found in combination with PG, and this forms the mainstay of most current regimens used in clinical practice.
Safety and side effects
Worldwide, millions of women are reported to have used mifepristone, with seven reported deaths in the US related to medical abortion: one ruptured ectopic pregnancy and six related to infection (five caused by Clostridium sordellii ). This gives a case-fatality rate of 1 per 100 000 medical abortions and is comparable to that associated with spontaneous miscarriage (0.7 per 100 000) or induced abortion overall, medical and surgical (0.7 per 100 000). There have been no deaths from infection for women taking mifepristone in Europe.
As mifepristone crosses the placental barrier, this raises concerns about the possible teratogenic effects on the foetus in cases where the pregnancy continues. The long-term safety data are limited, but animal data are largely reassuring. A report on 21 women who continued their pregnancy following mifepristone administration included one case with sirenomelia and cleft palate. In a further report, multiple foetal abnormalities were noted following mifepristone administration for termination of pregnancy at 18 weeks of gestation for severe oligohydramnios. It remains difficult to ascertain whether this was related to mifepristone or co-incidental. However, there have been reports of normal development in human foetuses exposed to mifepristone.
Combined regimens of mifepristone followed by PG analogues
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Medical abortion up to 9 weeks of gestation
Type of PG
Currently, the two commonly used PGs are the PGE1 analogues gemeprost and misoprostol. The conventional PG analogue used for medical abortion is gemeprost. A 1-mg pessary costs ∼£20 and is unstable at room temperature. Studies have demonstrated that the PGE1 analogue misoprostol is an effective alternative to gemeprost. Misoprostol is cheap (£1 per dose) and, unlike gemeprost, does not require specific storage conditions.
In Table 1 , a summary of randomised trials that have evaluated the use of the combined regimen is presented.
| Study | Gestation (days) | Regimen | Numbers | Complete abortion (%) | p -value |
|---|---|---|---|---|---|
| Baird et al. | ≤63 | Mifepristone 200 mg Misoprostol 600 μgm orally | 386 | 94.6 | >0.05 |
| Mifepristone 200 mg Gemeprost 0.5 mg vaginally | 391 | 96.7 | |||
| Bartley et al. | ≤63 | Mifepristone 200 mg Misoprostol 800 μgm vaginally | 500 | 98.7 | 0.02 |
| Mifepristone 200 mg Gemeprost 0.5 mg vaginally | 499 | 96.2 | |||
| El Refaey et al. | ≤63 | Mifepristone 600 mg Misoprostol 800 μgm orally | 130 | 87.0 | 0.02 |
| Mifepristone 600 mg Misoprostol 800 μgm vaginally | 133 | 95.0 |
The study by Baird et al. showed no significant difference in efficacy between the two regimens, although the continuing pregnancy rate was significantly higher in the misoprostol group (2.3%) compared with the gemeprost group (0.2%). The study by Bartley et al. showed the complete abortion rate was significantly higher with misoprostol (98.7%) compared with gemeprost (96.2%), and the continuing pregnancy rates significantly lower (0.2%) compared with gemeprost (1.8%). The former study adopted a lower dose of misoprostol (600 μg) and used the oral route of administration and this might explain the lower efficacy noted in the misoprostol group.
The manufacturer’s recommended regimen continues to be gemeprost 1 mg given in combination with mifepristone 600 mg, while the use of misoprostol constitutes an out-of-license use. The Royal College of Obstetricians and Gynaecologists (RCOG) Guideline on induced abortion, however, states that misoprostol is a cost-effective alternative to gemeprost in this context.
Dose and interval of mifepristone/dose of PG
A Cochrane review reported a meta-analysis of four randomised trials comparing mifepristone in doses of 200–600 mg. Similar efficacy was reported and the review concluded that the dose of mifepristone can be lowered to 200 mg without significantly decreasing efficacy. A more recent systematic review of four randomised trials comparing mifepristone 200 and 600 mg again showed similar efficacy, but a 1%-higher continuing pregnancy rate with mifepristone 200 mg compared with 600 mg of mifepristone. However, the interpretation of these data has been questioned as the type, dose and interval of administration of PG varied in these studies, with two administering misoprostol orally. Furthermore, the complete abortion rates (88–94%) was lower, and the continuing pregnancy rates (0.3–2.8%) were considerably higher than those in large case series administering mifepristone in doses of 200 mg (complete abortion 97.7% and continuing pregnancy 0.3% in a series of 4132 women ). The manufacturer’s summary of product characteristics recommends an interval of 36–48 h between administering mifepristone and the PG analogue. Studies have reported high efficacy with shorter intervals of 24 h, 6–8 h and even the simultaneous administration of mifepristone and misoprostol, although one study carried out in Scotland showed reduced efficacy with a shorter interval of 6 h compared to a 36–48-h interval.
Misoprostol has been used in doses of 400–800 μg in combination with mifepristone. Ashok et al. reported a review of the outcomes of medical abortion up to 63 days gestation in 4132 women. The initial 2000 cases received mifepristone 200 mg followed by a single dose of misoprostol 800 μg administered vaginally. They had a complete abortion rate of 97.5%, and efficacy significantly decreased at gestations >49 days. The regimen was subsequently modified to offer a second dose of misoprostol 400 μg to women who had not aborted within 4 h of the initial dose. There was no difference in efficacy with the modified two-dose regimen compared to the initial regimen (97.9% and 97.5%, respectively). However, there was a significant reduction in the continuing pregnancy rates from 0.6% to 0.1%.
In 2004, the RCOG Guideline for induced abortion , recommended a regimen of mifepristone 200 mg followed by misoprostol 800 μg given vaginally 1–3 days later for women up to 49 days of gestation, and a second dose of misoprostol 400 μg (vaginally or orally) 4 h later for women who had not aborted.
Route of misoprostol administration
Earlier medical termination of pregnancy protocols used misoprostol in doses of 400 μg administered orally. El Refaey et al. reported a randomised trial that compared the vaginal administration with the oral administration of misoprostol 800 μg following mifepristone 600 mg with medical abortion up to 63 days of gestation. This showed superior efficacy and lower side effects with vaginal administration (complete abortion rate of 95% compared to 87% for the oral group).
It has, however, been suggested that women preferred the oral route of administration and valued having additional choice. Studies from Hong Kong and Aberdeen have since evaluated the feasibility of sublingual misoprostol administration in this context. Tang et al. reported a randomised trial that compared the sublingual and vaginal routes of misoprostol administration using a single dose of 800 μg for medical abortion up to 9 weeks of gestation following mifepristone administration. In the sublingual group, 98.2% had complete abortion. There was no significant difference between the two groups, although more side effects were noted in the sublingual group.
Winikoff et al. reported a randomised study of 966 women undergoing medical abortion up to 63 days of gestation comparing buccal with oral administration of misoprostol 800 μg 24–36 h after mifepristone 200 mg. A total of 96.2% of patients in the buccal group had a complete abortion compared to 91.3% in the oral group. Efficacy decreased in the oral group as gestation increased, while side effects were higher with buccal administration.
Medical abortion at 9–13 weeks of gestation
To date, the medical regimen is not licensed for use at 9–13 weeks of gestations, and the majority of these cases are undertaken surgically.
A randomised trial that compared medical abortion and surgical vacuum aspiration at 10–13 weeks of gestation, showed a complete abortion rate of 94.6% in the medical group and 97.9% in the surgical group. A subsequent review reported on the outcomes of medical abortion at 64–91 days of gestation in 1076 consecutive cases. The complete abortion rate for the medical regimen was 95.8%. Efficacy decreased and the continuing pregnancy rates increased as the gestational age increased, particularly for women with >12 weeks of gestation.
Furthermore, a randomised trial in Aberdeen compared the sublingual route of misoprostol administration to the vaginal route of administration in the context of medical abortion at all gestations up to 13 weeks in 340 women. Complete abortion occurred in 98.1% of women in the sublingual group compared to 97.4% in the vaginal group. Over two-thirds of women in each group expressed satisfaction with the method, although more side effects were experienced by women in the sublingual group. A prospective series reported on medical abortion at 64–84 days of gestation in 321 women. Mifepristone 200 mg was followed by misoprostol 800 μg given vaginally followed by two further doses of 400 μg at 3-hourly intervals. The complete abortion rate was 89% with high reported acceptability (93%).
The RCOG Guideline on induced abortion states that the medical regimen using mifepristone in combination with misoprostol would be a safe and effective alternative to surgery for women undergoing abortion at 9–13 weeks gestation.
Anti-metabolites (methotrexate)
Methotrexate inhibits dihydrofolate reductase, the enzyme necessary for purine and pyrimidine synthesis. Its effect on pregnancy appears to be predominantly on the rapidly dividing cytotrophoblast and has been shown to be effective for the treatment of gestational trophoblastic disease. It has also been used in the context of termination of pregnancy.
A regimen of methotrexate and misoprostol 800 μg given vaginally was compared to a regimen of mifepristone and oral misoprostol 400 μg in a randomised trial. A total of 75% of women in the methotrexate group aborted by day 8 compared with 91% in the latter group. However, the overall complete abortion rate was comparable (surgical evacuation: 4.0% and 3.9%, respectively).
Methotrexate is potentially teratogenic and there have been several reports of limb-reduction defects in foetuses following its use. The toxicity of methotrexate is dose dependent, although serious complications have been reported with low-dose methotrexate. Methotrexate is no longer seen as an alternative to the combined mifepristone/PG-analogue regimen and its use is now restricted to places where mifepristone is unavailable.
Side effects and complications of medical termination of pregnancy
Clinical trials on patients with peptic ulcers treated with misoprostol in daily doses of 400–800 μg have reported gastrointestinal side effects, abdominal pain and fever as the most frequent side effects. Side effects experienced by women using a regimen of 800 μg in three doses included nausea (24%), vomiting (23%), diarrhoea (50%), dizziness (15%), headache (11%), pyrexia (18%), chills (50%) and pelvic pain (96%). These did not differ significantly when misoprostol was given at 48-h intervals compared with 24-h intervals. It is not known whether the active metabolite of misoprostol (misoprostol acid) is secreted in the breast milk or not. This could potentially cause diarrhoea in nursing infants and, hence this has been given as a contraindication for its use by the manufacturer. However, it has been suggested that avoiding breast feeding for 4 h after oral administration of misoprostol and 6 h after vaginal administration would allow sufficient time for misoprostol levels in the breast milk to fall.
Shannon et al. reported a systematic review of 65 studies and showed that the frequency of diagnosed or treated infection after medical abortion was estimated to be 0.92%. The RCOG Guideline on induced abortion recommends testing for lower genital tract infection, providing antibiotic prophylaxis or both. More recently, Fjerstad et al. reported on the infection rates after the joint change to buccal misoprostol from vaginal misoprostol and routine provision of antibiotics with medical abortion. Serious infections declined by 73%, from 0.93/1000 abortions to 0.25/1000, while the subsequent change to routine provision of antibiotics led to a further significant reduction in the rate of serious infection by 76%, from 0.25/1000 abortions to 0.06/1000. The rate of serious infections declined by 93% after a change from vaginal to buccal administration of misoprostol combined with routine administration of antibiotics.
Excessive bleeding at the time of abortion is rare. However, there is more observed blood loss with medical abortion when compared with surgical abortion. Blood transfusion has been reported to occur in 0.1–0.2% of women undergoing medical abortion up to 63 days of gestation. Medical regimens carry a small risk of failure to terminate the pregnancy, and in such cases surgical intervention is needed. Ashok et al. reported a surgical evacuation rate of 2.3% with a regimen of mifepristone in combination with misoprostol for termination of pregnancy up to 63 days of gestation. Indications for surgery included continuing pregnancy (0.3%), missed abortion (0.3%) and incomplete abortion (1.6%). Bartley et al. reported a surgical evacuation rate of 3.6% using a regimen of mifepristone and gemeprost for termination of pregnancy up to 63 days of gestation. Of these, 1.4% had continuing pregnancy while 2.2% had incomplete abortion. For termination of pregnancy at 64–91 days of gestation, a review of 1076 cases showed that 4.2% of women required surgical evacuation. Of these, 16 (1.5%) had a continuing pregnancy, five (0.5%) had missed abortion, 20 (1.9%) had incomplete abortion, while four (0.4%) required emergency evacuation for bleeding. Serious complications including uterine rupture, cervical lacerations and major haemorrhage are rare.
Exposure to misoprostol in early pregnancy has been associated with multiple congenital defects including skull defects, cranial nerve palsies, facial malformations, constriction rings, equinovarus, erythrogryposis and congenital transverse limb defects. These are thought to be secondary to uterine contractions leading to vasoconstriction and distal ischaemia. Much of this evidence has come from Brazil where misoprostol had been available over the counter in pharmacies and used in an illegal manner to self-induce abortion. Several reports have suggested an association between misoprostol exposure in early pregnancy and the Mobius syndrome (congenital facial paralysis, with or without limb defects). This may be due to vascular disruption of the subclavian artery during the fourth to sixth weeks of embryonic development. The absolute risk of these abnormalities following exposure to misoprostol, however, could not be evaluated from these reports, and would be difficult to estimate due to the illegal nature of using misoprostol in the context of abortion in these countries and the likely underreporting of use.
Both anti-progesterones and PG have contraindications to their use including: allergy to mifepristone or PG, adrenal insufficiency, severe asthma, long-term treatment with corticosteroids, haemorrhagic disorders or treatment with anticoagulants, porphyria, history of cardiovascular disease and women >35 years of age who are heavy smokers.
Acceptability of medical abortion
The provision of medical abortion offers additional choice to women. In a review on the acceptability of medical abortion in early pregnancy, Winikoff reported that, in most trials that offered women a choice between medical and surgical methods, 60–70% of women chose medical methods, with high reported acceptability of 88–97%.
Furthermore, a multi-centre study in the UK assessed the perceived acceptability of home medical abortion in women undergoing conventional hospital-based early medical abortion. The majority of women (75.7%) said they could have managed the pain at home with oral analgesia, and 78.9% said they would have coped with the bleeding at home. Approximately one-third of women (36.0%) said they would have preferred to have the abortion at home.
Analgesia requirements with medical abortion
Abdominal pain is one of the most common adverse effects of medical abortion. Analgesia use and, hence presumably, the perception of pain is higher in women of younger age, higher gestation, those who had a longer induction to abortion interval and with an increased number of misoprostol doses, while women with a previous live birth require less analgesia. The majority of women undergoing medical abortion require oral analgesia or no analgesia and only a small proportion use intramuscular opiates.
Westhoff et al. also reported on the use of advance analgesia use with medical abortion. Women who were given analgesia supplies were more likely to use it compared to those given a prescription. In turn, the latter group had higher analgesia use compared to those asked to use analgesia only as required.
Home administration of misoprostol
Studies from the United States have reported high efficacy and good acceptability for medical abortion carried out in home settings and home care is becoming the standard approach there. Studies have also reported the feasibility and high acceptability of the home regimen in Guadeloupe and, more recently, in the UK, Sweden, France, Vietnam and Tunisia with high efficacy and acceptability.
The provision of medical abortion at home allows the procedure to be carried out in the privacy of a familiar environment and avoids the inconvenience of an additional visit to the hospital. It might also have major cost-saving implications for health-service provision. Research is needed to compare the acceptability and efficacy of home medical abortion with that carried out in hospital settings.
Follow-up
The main reason for follow-up after medical termination of pregnancy is to confirm successful abortion and to identify possible complications following the procedure. Abortion is usually confirmed through identifying the products of conception or by carrying out a transvaginal ultrasound of the uterus. Follow-up is usually offered within 2 weeks of abortion. It has been suggested, however, that giving women simple instructions and advice about detecting complications would be a suitable alternative, with little evidence that mandatory follow-up visits detect conditions that women could not learn to recognise themselves. Follow-up, however, remains essential for women who do not expel recognisable products of conception, to exclude the risk of continuing pregnancy.
Licensing
The use of misoprostol in the context of termination of pregnancy represents an out-of-licence use for the product, while administering it through the vaginal route also constitutes an unlicensed route of administration. The European Union (EU) Pharmaceutical Directive 65/65/EEC specifically permits doctors to use “licensed medicines for indications or in doses or by routes of administration outside the recommendations given in the product licence.” In the United Kingdom, the licensing authority working through the Medicines Control Agency and under the Medicines Act Regulations of 1968 can provide exemptions to prescribe unlicensed medicines or to use or advise the use of licensed medicines for indications, or in doses, or by routes of administration, outside the terms of the product licence. In each case, however, the doctor should be able to justify this use in accordance with a responsible body of professional opinion. The RCOG Guideline on induced abortion has indicated that misoprostol would be a cost-effective and acceptable alternative for all abortion procedures where the E1 analogue gemeprost is conventionally used. Patients should be properly informed that this represents an unlicensed indication for use of the product.
Medical termination of pregnancy
In the early 1970s, studies reported the successful use of natural prostaglandins (PGs) in inducing abortion in early pregnancy. Subsequently, PG analogues were used for this purpose. However, the doses required with PG-only regimens were associated with a high frequency of side effects. Pre-treatment with mifepristone was shown to shorten the induction to abortion interval, improve the efficacy of the regimen and reduce the amount of pain experienced. A more effective application was found with PG in lower doses given in combination with mifepristone, and this forms the mainstay of most current regimens used in clinical practice. However, in many parts of the world, mifepristone might not be available due to cost or licensing implications and, in such situations, a misoprostol-only regimen could offer an alternative.
Uterotonic compounds: PGs
PGs are naturally occurring fatty acids that are produced by virtually all tissues in the body and function as local hormones. They are synthesised from essential fatty acids and are not normally stored in the tissues. A problem with the naturally occurring PG is their rapid breakdown by the enzyme 15-hydroxyprostaglandin dehydrogenase. It was noted that the incorporation of methyl groups protected from destruction by this enzyme, and this was the concept used in the PG analogues: carboprost, (PGF2α), gemeprost (PGE1), sulprostone (PGE2) and misoprostol (PGE1). Misoprostol was discovered in 1973 by scientists at Searle Pharmaceuticals and was licensed for the management of peptic ulcers. It exerts an anti-secretory activity, inhibiting the secretion of acid and pepsin in the stomach. The PG analogues are more stable, have a longer half-life and a more selective uterotonic effect compared to the parent compounds.
Absorption pharmacokinetics for the different routes of misoprostol administration
Tang et al. reported on the absorption kinetics of misoprostol 400 μg administered sublingually, orally and vaginally. The study showed significantly higher peak serum concentrations of misoprostol acid with sublingual administration. The time to peak concentration was shorter in the sublingual group and oral groups, while the area under the misoprostol acid concentration versus time curve was significantly greater for the sublingual group. The results suggested that the systemic bioavailability for the sublingual route is comparable to that with the vaginal route of misoprostol administration. The higher peak levels and shorter time to peak concentration may explain the increased prevalence of side effects noted with oral and sublingual administration. More recently, the same group reported on the absorption kinetics of five repeated doses of misoprostol 400 μg given sublingually or vaginally at 3-hourly intervals. The peak plasma levels of misoprostol acid decreased with repeated vaginal doses, but remained the same with sublingual administration. The area under the misoprostol acid concentration versus time curve was higher in the sublingual group, although subgroup analysis showed the reduction in plasma levels with vaginal administration only occurred in women with significant vaginal bleeding.
Aronsson et al. assessed uterine contractility with the oral, sublingual and vaginal administration of misoprostol. Regular uterine contractions were noted in all women in the sublingual and vaginal groups, but not after oral administration. The increase in the uterine activity was significantly higher from 2 h onwards with sublingual and vaginal administration. These findings are consistent with the absorption kinetics reported by Tang et al.
Misoprostol-only regimens for abortion in the first trimester
Moreno-Ruiz et al. reported a systematic review of 13 studies between 1997 and 2003 that assessed a misoprostol-only regimen for medical termination of pregnancy up to 63 days of gestation. In most of these studies, misoprostol was given vaginally in a dose of 800 μg and repeated every 24 h, up to three doses. The complete abortion rate ranged from 84% to 96%, and the median induction to abortion interval was 6–9 h. Surgical intervention for excessive bleeding was required in 0.3–3.3%.
In a randomised study on medical abortion up to 56 days gestation, a misoprostol-only regimen following placebo administration was compared to a combined regimen of mifepristone followed by misoprostol 48 h later. Misoprostol 800 μg was given vaginally followed by two further doses of 800 μg at 24-h intervals. The complete abortion rate was higher in the mifepristone and misoprostol group (95.7%) compared with 88% for the placebo and misoprostol group.
These reports show that abortion could be successfully induced with PG alone, but the doses required were associated with a high frequency of side effects, suggesting that PG would be less suitable for use as sole agents to induce abortion.
The anti-progesterones (mifepristone)
Development of mifepristone
In 1980, the scientists at Rousel-Uclaf (Romainville-France), while investigating glucocorticoid antagonists, discovered a C-19 derivative of norethindrone with high affinity for the progesterone receptor. The company’s code for this drug was RU 38486 (subsequently shortened to RU 486) and the generic name, mifepristone. This discovery began a new era in fertility control and has shaped much of our current practice. In 1988, France became the first country to license the use of mifepristone in combination with a PG analogue for termination of pregnancy up to 49 days of gestation. Recent figures show that mifepristone is now licensed in 40 countries worldwide for use in the context of medical abortion.
Mechanism of action in pregnancy termination
Mifepristone blocks the progesterone receptors within the decidua, leading to ultra-structural changes in the endothelium of the decidual capillaries, vascular damage followed by decidual necrosis and detachment of the conceptus. Mifepristone has also been reported to result in an increase in uterine contractility 24–36 h after its administration. It also increases the myometrial sensitivity to exogenous PG. The effect of mifepristone administration on uterine contractility is shown in Fig. 1 .
