Human Reproduction, Vol. 16, No. 11, 2283-2287,
November 2001
© 2001 European Society of Human Reproduction and Embryology
Incomplete miscarriage: a randomized controlled trial comparing oral with vaginal misoprostol for medical evacuation
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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BACKGROUND: A prospective randomized controlled trial was conducted to compare the efficacy and side-effects of vaginal versus oral misoprostol in the medical management of incomplete miscarriage. METHODS: Two hundred and one patients who miscarried consented to randomization using computer-generated randomization model prior to treatment. A total of 800 µg of misoprostol was given either vaginally or orally to the randomized subjects. A second dose was repeated 4 h later if the product of conception had not been passed. RESULTS: The incidence of complete uterine evacuation following vaginal and oral misoprostol was similar [(58/95) 61.1% versus (67/103) 64.4%]. There was a significantly decreased incidence of diarrhoea [(12/95) 13.6% versus (62/103) 65.3%, P < 0.01] with the use of vaginal misoprostol. CONCLUSIONS: Vaginal misoprostol was as effective as oral misoprostol in medical uterine evacuation in patients with incomplete miscarriage. There was also a reduction in the incidence of diarrhoea with the use of vaginal misoprostol.
Key words: incomplete miscarriage/misoprostol/side-effects/vaginal
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Introduction |
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TopAbstractIntroductionMaterials and methodsDiscussionReferences |
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Incomplete miscarriage has traditionally been managed since the 1930s with surgical evacuation. The role of medical treatment has been shown to be a reasonable alternative in the past decade to universal surgical evacuation of the uterus in incomplete miscarriage (Henshaw et al., 1993
; Chung et al., 1995; Goldberg et al., 2001). There is a plethora of different combinations of medical treatment regimes for the management of incomplete miscarriage. Investigations to date mainly focused on the use of synthetic prostaglandin analogues (Henshaw et al., 1993; Chung et al., 1995; De Jonge et al., 1995). One safe, inexpensive agent used is misoprostol. Misoprostol alone, given orally, reduced the incidence of surgical evacuation of retained product of conception by 50%, even when the criteria for ascertaining success of evacuation was very strict and done by routine transvaginal sonography (Chung et al., 1995). Moreover, for those patients who subsequently required a surgical evacuation, the risk of surgery-related complications and short-term complications were also found to be significantly lower in patients who had had misoprostol prior to surgical evacuation (Chung et al., 1998a). Misoprostol is justified as a first line treatment in the management of miscarriage in all cases because firstly it will avoid surgical intervention altogether in a proportion and secondly, in those who need it, misoprostol reduces surgery-related morbidity, mainly by priming the cervix (Chung et al., 1998a).
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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Protocol
All patients admitted to the gynaecological unit from September 1998 to March 1999 with a clinical diagnosis of incomplete miscarriage, supported by a positive urinary pregnancy test and confirmed by transvaginal ultrasonography (TVS) with evidence of retained product of conception (POC) were invited to consent to randomization before treatment. Patients with an intrauterine dimension measuring <11 cm2 (sagittal plus transverse plane) were considered to have an empty uterus and excluded from randomization (Chung et al., 1998b
). Other exclusion criteria were severe blood loss, sepsis, a known allergy to prostaglandin or their analogues, a history of asthma or any reason that the attending clinician thought may make the patient unsuitable for misoprostol administration. Participants were given 800 µg misoprostol either orally or vaginally according to study protocol. The dose was repeated 4 h after the initial dose if the patient had not passed products of conception. A repeat TVS was performed on all subjects the following day. Patients who had an intrauterine dimension of <11 cm2 (transverse plus sagittal plane) were considered to have an empty uterus and were discharged (Chung et al., 1998b). The remainder underwent surgical evacuation. All patients were assessed clinically 2 weeks after discharge to review their symptoms and a urinary pregnancy test was performed. The discharge management protocol has previously been reported (Chung et al., 1998a). Written consent was obtained according to the misoprostol protocol approved by the institutional review board.
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. Mann–Whitney 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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Analysis
The baseline clinical characteristics of the study subjects are shown in Table I
. There was a statistically significant higher incidence of subjects who had past history of termination of pregnancies in the oral misoprostol group (P < 0.01).
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The efficacies of vaginal and oral misoprostol are shown in Table II
. Thirty-seven out of 95 (39%) in the vaginal misoprostol versus 36/103 (35%) in the oral misoprostol group required surgical evacuation of their uterus before discharge, although this difference was not statistically significant. The median time lapse between the administration of the first dose of misoprostol and the passage of tissue mass was 7.7 h for both treatment groups (not significant). Among the patients who had surgical evacuation because of failure of medical treatment, 36/37 from the vaginal group and 32/36 of the oral group had an open cervical os at surgical evacuation (not significant).
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The immediate side-effects of vaginal and oral misoprostol are shown in Table III
. There were no differences in the incidence of fever, nausea and vomiting between the vaginal and oral misoprostol group. However, the incidence of diarrhoea was significantly increased in the oral misoprostol group compared with the vaginal group [62/103 (60.2%) versus 12/95 (12.6%), P < 0.01)]. There was no significant difference in the number of patients who had a drop in haemoglobin 
1 g/dl.
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Table IV
shows the complications of vaginal and oral misoprostol at 2 weeks follow-up. The number of days of pelvic pain was significantly longer in the vaginal misoprostol group compared with oral misoprostol (P = 0.02). However, the analgesic requirement in both groups was the same. None of the patients who underwent surgical evacuation suffered from any surgical complications such as haemorrhage, uterine perforation, blood transfusion or infection. However, one patient who had failed evacuation after oral misoprostol required a second surgical evacuation 2 weeks after discharge because of persistent vaginal bleeding and retained product of conception.
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Table V
shows the details of the patients who defaulted follow-up at 2 weeks. Four of them were contacted via telephone. They remained asymptomatic after discharge. Eight patients could not be contacted.
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Discussion |
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TopAbstractIntroductionMaterials and methodsDiscussionReferences |
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Most of the randomized clinical trials comparing the use of oral and vaginal misoprostol in medical evacuation of the uterus come from the experiences of cases for termination of pregnancies (El-Refaey et al., 1995
; Ho et al., 1997). It was found that the combination of mifepristone together with vaginal misoprostol improves the success rate of uterine evacuation compared with that of the use of mifepristone and oral misoprostol. At the same time, the systemic side-effects were reduced after vaginal administration (El-Refaey et al., 1995; Ho et al., 1997). The role of oral and vaginal misoprostol was also evaluated in cervical priming before suction termination of pregnancy (Lawrie et al., 1996; MacIsaac et al., 1999). However, the findings from these studies were more inconsistent.
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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1 To whom correspondence should be addressed: E-mail: mwpang{at}cuhk.edu.hk
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References |
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Submitted on February 27, 2001; accepted on July 13, 2001.
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