Medical methods for first trimester abortion

Medical methods for first trimester abortion have been demonstrated to be both safe and effective. Regimens that combine mifepristone or methotrexate with a prostaglandin such as misoprostol are more efficacous than a prostaglandin alone.

RHL Commentary by Grossman D

1. EVIDENCE SUMMARY

Medical methods for first trimester abortion have been demonstrated to be both safe and effective. Regimens that combine mifepristone or methotrexate with a prostaglandin such as misoprostol are more efficacous than a prostaglandin alone. In the case of regimens that combine mifepristone with a prostaglandin, the dose of mifepristone may be reduced from 600 mg to 200 mg without affecting efficacy; in 4 trials that compared the efficacy of the 200-mg dose with the 600-mg dose of mifepristone the relative risk (RR) of failure was 1.07 with the 95% confidence interval (CI) being 0.87–1.32. In combination with mifepristone, vaginally administered misoprostol in a 800-µg dose , appears to be more efficacious compared with a prostaglandin E1 analogue 0.5 mg. When mifepristone is used with misoprostol to terminate pregnancies of up to 63 days’ gestation, misoprostol administered vaginally is more efficacious than when administered orally (2 trials, RR 4.41 of failure with oral misoprostol compared with vaginal adminstration, 95% CI 2.32–8.38). Data were insufficient in the meta-analysis to determine the effect of gestational age on the efficacy of the various regimens. Oral administration of misoprostol was found to be associated more frequently with nausea and diarrhoea compared with vaginal administration (2 trials, RR 1.13, 95% CI 1.0–1.25; RR 1.80, 95% CI 1.49–2.18, respectively). With regard to the timing of administration of the prostaglandin following the administration of mifepristone on day 0, one trial indicated that misoprostol administered on day 3 was less effective compared with its administration on day 1 (RR of failure 1.94, 95% CI 1.05–3.58). However, in the three trials included in the review (but not pooled), there was no difference in efficacy when comparing prostaglandin administration on day 3 with day 2, day 2 with day 1, and day 2 with day 0.

With the combined methotrexate-misoprostol regimen, one study compared intramuscular administration with oral administration of methotrexate and found no statistically significant difference in efficacy . The review also found no statistically significant difference in efficacy between the administration of misoprostol on day 3 compared with day 5, or on day 4 compared with day 5, after methotrexate.

The review does not include two recent trials as they were published after the review was submitted for publication. The first is a WHO multinational study (1), of mifepristone combined with three different misoprostol regimens-(a) 800 µg vaginally on day 3 only; (b) 800 µg vaginally on day 3 followed by 400 µg orally twice daily for 7 days; or (c) 800 µg orally on day 3 followed by 400 µg orally twice daily for 7 days; n=2219. This study found that in women with gestation periods ≥57 days, the risk of failure was higher in group c compared with group b (RR 2.8, 95% CI 1.3-5.8), but there were no significant differences in efficacy in women with gestation periods <57 days.

The second study not included in the current version of the review is a randomized controlled trial of mifepristone followed by either sublingual or vaginal misoprostol (2). The dose of mifepristone was 200 mg, and that of misoprostol was 800 µg, administered 48 hours after mifepristone. The study included women with gestation periods up to 63 days (n=224). The authors found no significant difference in efficacy between the two regimens (sublingual: 98.2%; vaginal: 93.8%), although women in the sublingual group experienced significantly more nausea, vomiting, diarrhoea, fever and chills. While more research is needed to identify the optimal dosage of sublingual misoprostol, it appears that this route is another effective option that may be offered to women, especially given the evidence that women often prefer oral administration over vaginal (3).

One of the outcomes this review aimed to address was “women’s dissatisfaction with the procedure,” yet in the discussion the authors state that acceptability has not been sufficiently assessed in the identified trials.

The WHO multinational trial referred to above reported data on side-effects and acceptability and found that 85% of participants with a successful outcome for the procedure would choose medical abortion again should the need arise (4). Significantly higher acceptability was found among parous women (compared to nulliparous women) and those whose procedures were successful (compared with those in whom the procedure failured).

Two reviewers selected trials for inclusion from the results of the search and performed data extraction independently. The quality of the trials included was assessed appropriately, and there was adequate justification to exclude the studies that were left out. Study location is not always specified for the included trials, which would have been useful. Data were appropriately analysed and presented clearly. It is especially useful that data were presented for trials even when their methodologies were not similar enough to allow for combined analysis using meta-analytic techniques. The presentation of the data is user-friendly for such a review that includes many trials with dissimilar interventions and methods.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

It is estimated that in 2000 27 million legal and 19 million illegal abortions were performed worldwide(5). Up to 95% of illegal abortions (unsafe abortions) were performed in developing countries and 99% of deaths from these abortions also occurred in those countries (5). Access to safe abortion is limited in many developing countries because of legal restrictions, administrative barriers to access legal abortion services, financial barriers and lack of adequately trained providers (6, 7. 8), In Latin America, rural women with limited financial resources disproportionately suffer from complications of illegal abortion (9).

2.2. Applicability of the results

Although the majority of the studies included in the review were conducted in developed countries, many of the findings should be relevant to under-resourced settings. The authors point out that some of the conditions under which the trials were carried out (such as routine use of ultrasound and easy access to emergency back-up facilities) as well as the high relative cost of mifepristone may make the review less applicable to under-resourced setting. While these concerns are valid, several non-randomized trials in developing countries that included rural sites and that were done in settings where ultrasonography was not routinely used, have documented the safety, efficacy and acceptability of medical abortion using mifepristone and misoprostol (10, 11, 12, 13, 14). In most of these studies, as well as those in the review, the proportion of women followed up is very high, and more outcome information is needed from under-resourced settings where follow-up may be more difficult. In settings where mifepristone is not available, the review’s comparisons related to methotrexate and prostaglandins used alone are particularly relevant.

2.3. Implementation of the intervention

Wherever abortion is legally allowed for at least one indication and misoprostol and mifepristone are available, it should be possible to provide services offering first trimester medical abortion. Cost remains an important barrier to providing mifepristone medical abortion, although Asian manufacturers have significantly reduced the price of the medication. Furthermore, because of the limited indications for use of mifepristone, it is registered and available in a small number of countries, of which only a few are developing countries. Both methotrexate and misoprostol are more widely available and less costly than mifepristone, and in settings where the latter is not accessible, they represent safe, effective and acceptable alternatives. While one study found that misoprostol alone was associated with an increased risk of failure compared with mifepristone plus misoprostol (RR 2.86, 95%CI 1.07–7.61), (15), it should be noted that misoprostol alone was 88% effective and was not associated with more side-effects or complications. Where methotrexate is available, the finding that oral administration appears to be as effective as intramuscular administration with similar side effects particularly in relevant to under-resourced settings.

Prior to initiating medical abortion services, providers will require training in assessment of gestational age, use of the medications, assessment of completion of abortion, and management of complications. However, these educational barriers should be minimal. In facilities that do not currently offer aspiration abortion, there may be cultural barriers to offering abortion services of any kind, and these will need to be addressed in a comprehensive manner. In developed countries, provider acceptability of medical abortion is high, (16), (17) and it seems reasonable to expect that at least some practitioners will begin to offer services once the medications and training are made available.

3. RESEARCH

Several research questions remain unanswered regarding medical methods for first trimester abortion. With regimens that include mifepristone, more well-designed studies are needed to determine the optimal dose of misoprostol administered via the sublingual (more side-effects) or buccal routes in order to minimize side-effects while maintaining efficacy. More data comparing oral and vaginal misoprostol after mifepristone among women in early pregnancy (≤49 or ≤56 days) would be helpful to clarify the relative efficacy of these regimens in this period.

As the Cochrane Review notes, additional studies comparing the efficacy of the mifepristone and methotrexate regimens are needed. One non-blinded randomized trial found the regimens to be equally effective, although methotrexate took significantly longer to complete the abortion process (18).

Also as noted in the review, additional acceptability trials are needed to understand better women’s preferences, although these studies might not involve treatment allocation concealment. As mifepristone-based medical abortion becomes more widely available in developing countries such as India, South Africa, Tunisia and Viet Nam, more data about its use outside of research settings will be critical to inform programmes in similar under-resourced locations.

Until mifepristone is widely available at an affordable price more research is needed to perfect medical abortion regimens using methotrexate and misoprostol alone, including studies to test further oral methotrexate and to evaluate alternative routes of administration for misoprostol. While these studies are less relevant in countries with access to mifepristone, they are critical to improving services in developing countries without such access. These studies are also difficult to perform in countries where abortion is legally restricted. Similarly, well-designed trials are needed to evaluate medical methods of late first trimester abortion (between 9 and 12 weeks of gestation) in order to increase access to services in areas with few surgical abortion providers.

Further research also is needed to evaluate the extent to which medical abortion regimens—regardless of the medications used—can be simplified for use in under-resourced settings. A recent randomized controlled trial found that the interval between mifepristone and vaginal misoprostol may be shortened to 6–8 hours without affecting efficacy, (19), and more studies of varying intervals—including immediate misoprostol administration—would be welcome. Several non-randomized trials have demonstrated the safety, efficacy and acceptability of home use of misoprostol after mifepristone. (12, 13, 14, 20). Further research is needed to prospectively evaluate clinical determination of gestational age and abortion completion without the use of ultrasound, as well as the possible use of low sensitivity urine pregnancy tests to confirm completion. Well-designed studies of the management of incomplete abortion after medical abortion regimens are also needed, including trials to assess the utility of repeat dosing of misoprostol.

Sources of support: Population Council, Gynuity Health Projects, an anonymous donor

Acknowledgements: I would like to thank Beverly Winikoff, Batya Elul and Kelly Blanchard for their insightful comments on earlier drafts of this commentary.

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This document should be cited as: Grossman D. Medical methods for first trimester abortion: RHL commentary (last revised: 3 September 2004). The WHO Reproductive Health Library; Geneva: World Health Organization.

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