Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR
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Abstract |
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Key words: incomplete miscarriage/misoprostol/side-effects/vaginal
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Introduction |
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Most research into the use of misoprostol for the medical evacuation of incomplete miscarriage has concentrated on its effect after oral administration. Recent evidence suggested that there might be an improved efficacy of uterine evacuation and a reduced incidence of side-effects if misoprostol was administered vaginally (Herabutya and O-Prasertsawat, 1997; Zalanyi, 1998
). Apart from clinical studies, investigations into the absorption kinetics and uterine activity also suggested that vaginal administration should be more effective in uterine evacuation and, at the same time, had less systemic side-effects compared with oral administration (Zieman et al., 1997
; Danielsson et al., 1999
). However, whether this difference in pharmacological effect would be reflected in the clinical usage in the medical management of incomplete miscarriage has not been adequately evaluated. We report a randomized, controlled trial comparing the efficacy, side-effects and short-term complications associated with oral and vaginal administration of misoprostol as the initial management of incomplete miscarriage.
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Materials and methods |
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Sample size calculation
From our earlier studies, the efficacy of oral misoprostol was ~50%. A trial with a power of 90% and to detect a 50% change in efficacy in the administration of vaginal misoprostol with an alpha of 0.05 would require a sample size of 95 in each arm.
Statistical tests
A two-sample t-test was used to analyse the baseline differences in the two treatment groups in terms of their age and gestation by last menstrual period. A 2 analysis was used to detect any differences in the cervical os status on admission, the parity, number of previous miscarriages, termination of pregnancies and ectopic pregnancies. The efficacy, presence of side-effects such as fever, nausea, vomiting, diarrhoea and drop in haemoglobin were analysed with the
2 test. MannWhitney U-test was used to compare the time required for the passage of the tissue mass, the number of days of bleeding and abdominal pain between the two treatment groups.
Assignment
Patients were randomized according to a computer-generated set of random numbers in blocks of five. Each number was put in an opaque envelope, labelled serially. Randomization was for either oral or vaginal misoprostol.
Results
Participant flow and follow-up
Figure 1 summarizes the trial profile. Two hundred and one cases consented and underwent randomization. Two subjects declined treatment after randomization, before the assigned treatment commenced. One patient developed a rash after the first dose of misoprostol and further medical treatment was abandoned. Eventually, 198 patients completed the medical treatment regime. Twelve subjects were lost to follow-up at 2 weeks after discharge.
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Discussion |
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The only randomized trial comparing the use of oral misoprostol and vaginal misoprostol in the medical evacuation of incomplete miscarriage was performed by Crenin et al. (Crenin et al., 1997). They found that vaginal misoprostol was associated with a significant improvement in uterine evacuation but at the same time, an increase in systemic side-effects. However, the dosage of vaginal misoprostol used was twice as high as the oral group, therefore making the interpretation of the results difficult.
Unlike previous studies performed in cases of termination of pregnancies, we were unable to demonstrate a difference in the efficacy of uterine evacuation in the vaginal and oral routes of administration (El-Refaey et al., 1995; Ho et al., 1997
). The reasons we postulate for this difference are, firstly, the contractility behaviour of the uterus in incomplete miscarriage could be different from that of termination of pregnancy. In addition, apart from misoprostol, mifepristone was also used in those cases for termination of pregnancy. In animal studies, it was found that the administration of mifepristone increased endometrial PGE2 and PGF2
concentrations (Arkaravichien and Kendle, 1992
). It is not known whether mifepristone primed myometrium would respond differently to misoprostol than those cases exposed to misoprostol alone. However, the delay of treatment that is required with mifepristone may not be acceptable to patients with a failed pregnancy.
On the other hand, our study has shown a significant increase in the incidence of diarrhoea with oral misoprostol administration. The finding is consistent with other clinical studies and the absorption kinetics studies of misoprostol (Zieman et al., 1997; Danielsson et al., 1999
). Although the overall bioavailability was higher in vaginal misoprostol, the peak plasma concentration of oral misoprostol was 1.6 times higher with oral misoprostol compared with vaginal administration (Zieman et al., 1997
). It was believed that the higher peak plasma concentration of misoprostol was the cause of the increased systemic side-effects.
In our study, the success rate for complete uterine evacuation rate was found to be ~60% with either route of administration, which is relatively low compared with other studies (Crenin et al., 1997). This is a consequence of the different definition of successful evacuation used. In our study, we used intrauterine dimension obtained on TVS (sagittal + transverse) of <11 cm2 as indicating complete abortion (Chung et al., 1998b
). We have found that this criterion is associated with a low complication rate of
3% (Chung et al., 1999
). Most other investigators have relied on clinical assessment alone (De Jonge et al., 1995
; El-Refaey et al., 1995
; Ho et al., 1997
). We have not seen comparable follow-up clinical information, especially in regard to complications, using only clinical assessment as distinct to the TVS criterion we use. Complication rates as high as 14% in small case series have been reported (Cetin and Cetin, 1998
). Our experience with this criterion, which has now been used in managing more than 3000 cases, is such that we are reluctant to change without evidence that clinical assessment alone is associated with a similarly low complication rate. This is an area for future research.
To conclude, vaginal misoprostol was as effective as oral misoprostol in medical evacuation of incomplete miscarriage. Vaginal administration was also associated with a significant decrease in the incidence of diarrhoea compared with oral administration. Because of this, we propose that the vaginal route of administration for misoprostol in patients with incomplete miscarriage should be preferred. However, vaginal administration of misoprostol may not be as acceptable to patients compared with the oral route. Nevertheless, both are equally effective.
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Notes |
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References |
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Submitted on February 27, 2001; accepted on July 13, 2001.