Human Reproduction, Vol. 18, No. 11, 2315-2318,
November 2003
© 2003 European Society of Human Reproduction and Embryology
A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation
Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
1 To whom correspondence should be addressed at: 6/F, Professorial Block, Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Road, Hong Kong SAR, China. e-mail: ostang{at}graduate.hku.hk
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Abstract |
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BACKGROUND: A combination of mifepristone and misoprostol provides an effective method of medical abortion for early pregnancy. This is the first randomized trial comparing the use of sublingual misoprostol with vaginal misoprostol in combination with mifepristone for termination of early pregnancies up to 63 days. METHODS: A total of 224 women who requested legal termination of pregnancy up to 63 days were randomized by computer- generated list into two groups and given 200 mg of oral mifepristone followed 48 h later by either 800 µg of sublingual (n = 112) or vaginal (n = 112) misoprostol. RESULTS: Complete abortion occurred in 98.2% (95% CI: 93–99) of women in the sublingual group and 93.8% (95% CI: 88–97) in the vaginal group. There were three ongoing pregnancies in the vaginal group but none in the sublingual group. The median duration of vaginal bleeding was 17 days. There was no serious complication. Fever, chills and gastrointestinal side-effects (nausea, vomiting and diarrhoea) were significantly more common in the sublingual group. CONCLUSIONS: The combination of mifepristone and misoprostol is effective for medical abortion up to 63 days. Both the sublingual and vaginal are effective routes of administration. Further randomized trials are required to find out the optimal dose of sublingual misoprostol that can give the highest complete abortion rate and lowest incidence of side-effects.
Key words: medical abortion/misoprostol/sublingual/vaginal
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Introduction |
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The combination of mifepristone and a prostaglandin analogue is an effective and safe method of termination of pregnancy up to 63 days (UK Multicentre Trial, 1990
; World Health Organization, 1993; Baird et al., 1995). Misoprostol, a synthetic analogue of prostaglandin E1, is licensed for the prevention and treatment of peptic ulcer (Walter, 1992). It has been extensively investigated for the purpose of medical abortion (El-Refaey et al., 1995; Ashok et al., 1998; Tang et al., 2002a,b). It is the prostaglandin of choice because it is cheap, orally active and stable at room temperature. When combined with mifepristone for medical abortion in the first trimester, vaginal misoprostol is more effective and better tolerated than oral misoprostol (El-Refaey et al., 1995). Therefore, although misoprostol is licensed for oral administration, it is now often administered vaginally. A pharmacokinetic study has shown that the systemic bioavailability of vaginally administered misoprostol is three times higher than that of orally administered misoprostol when determined by the area under the plasma concentration–time curve (AUC) for 360 min (Zieman et al., 1997). The marked difference in AUC between oral and vaginal administration is likely to be the result of presystemic gastrointestinal or hepatic metabolism that occurs with oral but not with vaginal administration. The same study also showed that the absorption of misoprostol by the vaginal route was more variable and it was not uncommon to find that the misoprostol tablets were still not dissolved completely several hours after vaginal administration (Zieman et al., 1997; Singh et al., 1999). Although misoprostol is more effective when given vaginally, most women prefer the oral route because this can avoid the uncomfortable vaginal examination and provide more privacy during medical abortion (Ho et al., 1997). Recently, we have explored the possibility of sublingual administration of misoprostol. Misoprostol, being very soluble in water, was put under the tongue; it was observed that the tablet took 
10–15 min to dissolve. As previously mentioned, it has the advantage of avoiding the uncomfortable vaginal examination that is necessary for vaginal administration of misoprostol. A pharmacokinetic study has shown that sublingual administration of misoprostol resulted in the greatest bioavailibility when compared with oral or vaginal administration (Tang et al., 2002c). A pilot study has also shown that sublingual misoprostol, when combined with mifepristone, was effective in medical abortion at <9 weeks of gestation (Tang et al., 2002d). It is the aim of this study to compare the complete abortion rate of sublingual and vaginal misoprostol when combined with mifepristone. |
Materials and methods |
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A total of 224 pregnant women with gestational age
9 weeks were recruited from among women requesting legal termination of pregnancy. The study was approved by the ethics committee of the Faculty of Medicine, University of Hong Kong. The gestational age was confirmed in all the women by ultrasound examination. Women who were using prescription drugs regularly, women with an intrauterine contraceptive device in utero, nursing mothers, multiple pregnancies and heavy smokers were excluded. The women were randomized according to computer-generated random numbers into two groups, vaginal and sublingual. All women were given 200 mg of mifepristone (Mifegyne; Exelgyn, France) in the presence of the medical or nursing staff. Forty-eight hours after mifepristone administration, the women were given either 800 µg of sublingual or vaginal misoprostol (Cytotec; Searle Pharmaceutical, USA) according to the randomization. This was a double-blind placebo-controlled study. Women randomized to the sublingual group were given 4 tablets of vaginal placebo and women randomized to the vaginal group were given 4 tablets of sublingual placebo. They were instructed to put 4 tablets of misoprostol or placebo under the tongue and allow them to dissolve. The misoprostol took 10–15 min to dissolve and during this period of time the subjects were told not to swallow the tablets. The nurse was responsible for the administration of the vaginal drugs. Patients stayed in the hospital for 4 h, and blood pressure and pulse rates were recorded hourly. Vaginal examination was done at the end of 4 h. The women were given a diary card to record the days and the amount of vaginal bleeding (in comparison with their usual menstrual periods) and side-effects. The women then came back on day 15 (after mifepristone) and vaginal examination, measurement of blood pressure and pulse, ultrasound examination of pelvis and blood sampling for haemoglobin level were carried out. If pelvic ultrasound examination showed the presence of an ongoing pregnancy, vacuum aspiration would be arranged. If pelvic ultrasound examination showed that there was incomplete abortion or missed abortion, the women would be observed unless there was heavy bleeding. The women were followed up again on day 43. The examination and investigations on day 15 were repeated except the pelvic ultrasound examination, which was only performed when it was clinically indicated. The side-effects and duration of bleeding as recorded in the diary card were checked during the follow-up visits. An extra follow-up visit was arranged if the bleeding persisted or menstruation had not yet returned by 43 days after mifepristone. If no emergency or elective curettage was required during the interval up to the first menstruation, the outcome was classified as a complete abortion. All women were asked to use a barrier method for contraception up to the time of first menstruation.
The primary outcome measure was the complete abortion rate. The haemoglobin level, duration of vaginal bleeding and side-effects of treatment were also studied. The complete abortion rate was used to calculate the sample size required. From a previous study, the complete abortion rate with mifepristone and oral misoprostol was 87% while that of vaginal misoprostol was 98% (El-Refaey et al., 1995; Ashok et al., 1998). The sublingual administration of misoprostol would not be useful clinically if the complete abortion rate falls below that of oral misoprostol. Based on the above data, the total number of subjects required was calculated to be 212 in order to give a power of 80% at the 5% significance level. Allowing for 5% drop-outs, a total of 224 subjects was required.
SPSS 10.0 for Windows Statistical Package was used for statistical analysis. Differences in continuous variables were analysed with Student’s t-test for normally distributed data and the Mann–Whitney U-test for skewed data. Differences in discontinuous variables were analysed by 
2-test and the Fisher exact test as appropriate. Repeated measurements in haemoglobin levels were compared by paired t-test. Two-tailed P < 0.05 was considered statistically significant.
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Results |
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Table I shows the demographic data of the 224 women who underwent medical abortion with mifepristone and sublingual or vaginal misoprostol. There were no significant differences in the age, gestational age and parity between the two groups. Complete abortion occurred in 98.2% [95% confidence interval (CI): 93–99] of the women in the sublingual group and 93.8% (95% CI: 88–97) in the vaginal group. The difference was not statistically significant (Table II). There were three women who had ongoing pregnancy diagnosed on day 15 after mifepristone in the vaginal group but none of the women in the sublingual group had ongoing pregnancy. The induction-to-abortion interval was also similar in both groups. No significant change in the haemoglobin levels before and after abortion was found in both groups. The median days of vaginal bleeding were the same in both groups. Table III shows the side-effects of treatment for both groups of women. Women in the sublingual group had a significantly higher incidence of gastrointestinal side-effects, fever and chills.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The combination of mifepristone and a prostaglandin has been shown to be effective in medical abortion at gestational age up to 63 days. Misoprostol is a prostaglandin E1 analogue licensed for treatment of peptic ulcer. As it has been shown to be effective for termination of pregnancy up to 63 days gestation (UK Multicentre Trial, 1990
; World Health Organization, 1993; Baird et al., 1995) and is cheap and stable at room temperature, it has been used extensively for medical abortion. However, different regimens are used in different countries. Oral misoprostol has been shown to be less effective in medical abortion and resulted in more side-effects compared with vaginal misoprostol in randomized trials (El-Refaey et al., 1995). The use of 200 mg oral mifepristone followed 36–48 h later by 800 µg of vaginal misoprostol is the commonest regimen, with a complete abortion rate of 90–95% (McKinley et al., 1993; Ashok et al., 1998; Child et al., 2001). However, misoprostol is licensed for oral administration for the management of peptic ulcer disease. Therefore, the combination of mifepristone and oral misoprostol is still the only approved regimen in some countries. The higher efficacy of vaginal misoprostol is probably due to higher systemic bioavailability after vaginal administration, as indicated by the higher area under the serum level of misoprostol concentration–time curve (AUC) compared with oral misoprostol (Zieman et al., 1997). The same pharmacokinetic study also found that there is a wide variation in the absorption of vaginal misoprostol as shown by the large coefficients of variation of the AUC for vaginal misoprostol between individuals. Many clinical studies also showed that the misoprostol tablets were often not dissolved completely several hours after vaginal administration (Zieman et al., 1997; Singh et al., 1999). Thus, the efficacy of vaginal misoprostol may vary from patient to patient. Some studies suggested that adding water to the tablets may improve the absorption (Carbonell et al., 1997; Carbonell et al., 1999) but this was not supported by a randomized trial (Ngai et al., 2000).
Recently, we have explored the possibility of a new route of administration of misoprostol by giving it sublingually. The present study is the first report comparing sublingual with vaginal misprostol after mifepristone for medical abortion up to 63 days of gestation. The misoprostol is very soluble in water. This was administered by putting the tablets under the tongue and allowing them to dissolve. They usually dissolved within 15–20 min. Sublingual misoprostol is taken by mouth, and thus can avoid the uncomfortable vaginal administration. It has been shown that some women found vaginal administration painful and uncomfortable and would like drugs that can be taken by mouth (Ho et al., 1997). Sublingual administration is a convenient way of giving misoprostol and patients can easily handle it at home themselves. Therefore, it has the potential to be developed into a regimen that the women can take at home. Absorption of misoprostol tablets may be easier to ascertain as the dissolution of the tablets can be easily observed during sublingual compared with vaginal administration. Moreover, sublingual misoprostol can avoid the first-pass effect through the liver, as in the oral route, and therefore may result in a higher complete abortion rate. A pharmacokinetic study comparing sublingual, oral and vaginal route of administration of misoprostol has shown that sublingual administration can achieve the highest peak concentration and the time taken to achieve the peak concentration was shortest. The systemic bioavailability of sublingual misoprostol was also greater than among all other routes of administration (Tang et al., 2002c). A pilot study has shown that sublingual misoprostol was effective in first trimester medical abortion at <9 weeks gestation. The complete abortion rate in that study was 94% with only one ongoing pregnancy in 100 women. The incidence of gastrointestinal side-effects, fever and chills was high in that pilot study. However, it is very difficult to compare between studies and to conclude which is the best regimen.
This study was a head-to-head comparison between sublingual and vaginal misoprostol in first trimester abortion. The complete abortion rate in the vaginal group in this study agreed with previous studies using a similar regimen of vaginal misoprostol, which resulted in a complete abortion rate of 95–97.5% (El-Refaey et al., 1995; Ashok et al., 1998). The ongoing pregnancy rate is usually taken as the true failure of medical abortion in the first trimester. Sublingual misoprostol seemed to be superior to vaginal misoprostol in this aspect but the number of subjects was too small to show any statistical significance. The abortion process was similar in both groups, with no difference in the induction-to-abortion interval and the median duration of vaginal bleeding.
The side-effect profile, however, has shown that 800 µg sublingual misoprostol was associated with a higher incidence of gastrointestinal side-effects, chills and fever. The current study has proven the findings in a previous pilot study that the use of 800 µg was associated with a higher incidence of side-effects compared with the same dose of misoprostol administered vaginally (Tang et al., 2002d). This may be due to the higher peak concentration after sublingual administration. The side-effects may be improved by decreasing the dosage of misoprostol to 600 µg. However, the efficacy of a lower dosage of misoprostol needs to be assessed by further randomized trials.
In conclusion, sublingual and vaginal misoprostol after pretreatment with mifepristone are both effective methods of medical abortion at <9 weeks gestation. In order to reduce the incidence of side-effects, a lower dose of misoprostol can be considered when given sublingually. However, further randomized trials are required to find out the optimal dose of sublingual misoprostol that can give the highest complete abortion rate and lowest incidence of side-effects.
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Acknowledgements |
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This study was fully supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No: HKU 7244/01M). The investigators acknowledge the support of the Family Planning Association of Hong Kong in the recruitment of subjects in Hong Kong. We are grateful to the Research Group on Post-ovulatory Methods of Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization for the supply of mifepristone tablets used in this study.
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Submitted on June 6, 2003; accepted on August 15, 2003.
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