Misoprostol for all?

Authors


There can be few drugs whose use has been taken up so enthusiastically by obstetricians and gynaecologists. The most recent Medline Database produced 169 publications using the subject headings ‘pregnancy’ and ‘misoprostol’. This is all the more unusual as misoprostol, a PGE1, analogue, was developed for the treatment of peptic ulcer by Searle in 1973. When the drug came before the Advisory Committee of the United States Food and Drug Administration in 19851, it was felt by one reviewer that the gastrointestinal effects were overshadowed by the abortifacient effect of the drug and he warned of ‘the potential for inadvertent or deliberate misuse by pregnant women’. And so it turned out in Brazil, where, in the absence of legalised abortion, there was widespread abuse over a number of years for the purpose of inducing illegal abortion2,3. The therapeutic potential of misoprostol as an abortifacient was clearly demonstrated in 1987 in a randomised studf. Subsequent studies, many carried out in France and the UK, have since indicated the effectiveness of the drug in this respect5–10. Its use administered both orally and vaginally, continues to be developed11–21, particularly with the antiprogesterone mifepristone, and the drug now forms the basis of a number of first and second trimester regimens for medical (non-surgical) evacuation of the uterus used around the world22–25.

Misoprostol is a viscous oil which is susceptible to the same types of chemical degradation as natural E prostaglandins. However dispersion on hydroxy-propyl methyl cellulose is considerably more stable than the pure chemical, and tablets of solid dispersion have a shelf life of several years at room temperature26. This means that the drug is easily stored and transported, and when these advantages are combined with its extremely low cost, it has particular relevance for use in the developing world. In the UK most therapeutic doses will cost less than £l. The manufacturer's oral preparation can be administered vaginally with good effect, and perhaps fewer side effects than the equivalent dose administered orally19, albeit there are significant differences in the pharmacokinetics of the drug when administered by these two routes27, which have relevance for the timing of intermittent dose regimens, such as those used for the induction of labour or second trimester abortion. The pregnant uterus becomes progressively more sensitive to the drug with advancing gestation. Single doses of 400–800 pg are considered therapeutic in the first trimester (following mifepristone) while doses of 50 pg or even 25 pg are being used for the induction of labour28–30.

At present the drug would appear to have established therapeutic uses in a number of areas including the induction of labour31–33, first and second trimester induced abortion, evacuation of the uterus following miscarriage34–38 and even possibly for the prevention of postpartum haemorrhage39. Two of these issues are further described in this issue of the Journal. In addition, the drug is increasingly used for cervical predilatation prior to surgical termination of pregnancy40–41. The place of cervical priming before surgical evacuation of the uterus is well established. Easier entry to the uterine cavity reduces the risk of both cervical injury and uterine perforation43,44. Recent guidelines of the Royal College of Obstetricians and Gynaecologists recommend that cervical preparation should be routine where the woman was under 18 years of age or the gestation greater than 10 weeks45.

A number of effective methods of cervical dilatation are available. Recent publications attest to the continuing effectiveness of mechanical method46,47 which may be particularly advantageous prior to second trimester surgical abortion, although their use is not entirely problem free48. The cervical effect of the antiprogesterone drug mifepristone has been assessed in a number of studies and shown to compare favourably with prostaglandins49–52. More recently, it has been demonstrated that the nitric oxide donors, isosorbide mononitrate and glycerol trinitrate, can induce cervical ripening, although not as effectively as the standard dose of gemeprost53. The therapeutic effect of these compounds may be better suited to the induction of labour in cases with unfavourable cervix, as they induce cervical ripening, while apparently maintaining the myometrium in a relaxed state54,55.

Prostaglandins remain the most widely used method of cervical preparation prior to surgical abortion. Until recently gemeprost has been the main preparation used in the UK, but there is increasing interest in the use of misoprostol. A number of randomised studies have now been published demonstrating both effectiveness40,56,57 and comparable efficacy to gemeprost41,58. The issues that remain to be resolved are the optimum route, dose and timing of administration, and attempts to address two of these issues have already been reported42. This study would appear to have enough power to deal with the dose issue, and here is it clear that a vaginal dose of 400 pg is better than 200 pg, certainly at gestations of 7–11 weeks. What is not so clear is whether there is any added benefit or risk in giving a higher dose such as 600 or 800 μg as recommended in the recent RCOG guideline45. A further trial is probably needed to resolve this issue which should assess both efficacy and side effects. The oral administration of misoprostol for cervical dilation has also been studied59,60 and is highly effective, although concern has been raised about the possibility of premature uterine evacuation when the oral dose is given as much as 12 hours prior to operations59. Experience indicates that when given orally, the therapeutic effect on the cervix can be anticipated in much less than 12 hours61, due to rapid absorption and swift onset of action.

These uncertainties notwithstanding, it is now clear that where surgical abortion is being carried out, cervical predilatation should be considered in almost all cases, and misoprostol has established itself as one of a range of effective options. The place of misoprostrol for other reproductive indications will also become clearer in the near future. At present, there is both considerable interest and much continuing research.

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