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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Key words: first trimester/misoprostol/miscarriages/sublingual/vaginal
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Introduction |
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Medical management has recently been explored as an alternative for management of miscarriage. Several studies have examined the efficacy of prostaglandins with or without mifepristone. It is difficult to make a conclusion from the available reports in the literature as to which regimen is the best, due to differences in the selection criteria, choice and dosage of medication and different criteria for the diagnosis of complete miscarriage. It would be desirable to develop a regimen without mifepristone since it is expensive and is not available in many countries. Misoprostol is the prostaglandin of choice as it is cheap and stable at room temperature. Various routes of administration including oral, vaginal and sublingual misoprostol have been studied for termination of pregnancy in the first trimester (El-Refaey et al., 1995; Tang et al., 2002a
,b). Clinical studies have shown that vaginal is superior to oral misoprostol in termination of first trimester pregnancies (El-Refaey et al., 1995
). Pilot studies have shown that sublingual misoprostol with or without mifepristone is useful in first trimester medical abortion (Tang et al., 2002a
,b). A pharmacokinetic study has shown that sublingual misoprostol has the highest bioavailability and shortest time to peak concentration among the three different routes of administration (Tang et al., 2002c
). A pilot study has shown that repeated doses of sublingual misoprostol are useful in medical management of first trimester miscarriages, with a success rate of 92% (Tang and Ho, 2001
). It is the objective of this randomized trial to compare repeated doses of sublingual with vaginal misoprostol in the medical management of first trimester miscarriages.
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Materials and methods |
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The 80 women were randomized according to computer-generated random numbers into two groups. Women in group 1 received 600 µg misoprostol sublingually every 3 h for a maximum of three doses and group 2 received 600 µg misoprostol vaginally every 3 h for a maximum of three doses. Informed consent was obtained before randomization. The women in group 1 were instructed by the investigator to put the three misoprostol tablets under the tongue themselves. They were not allowed any food or drink for the next 20 min to allow complete dissolution of the tablets. The research nurse was responsible for the administration of vaginal misoprostol in group 2 by putting the three misoprostol tablets into the posterior fornix. The blood pressure, pulse rate and side effects were recorded every hour and the body temperature was recorded every 3 h. Oral or parenteral analgesic was given if the woman complained of severe pain. The women were discharged after completion of the course of misoprostol if there was no heavy vaginal bleeding and they were not in pain. The women were asked to inform the nurse when they passed the product of conception at the hospital and they were given a bottle with formalin to collect any product of conception passed at home. The product of conception was sent for histological confirmation. Emergency surgical evacuation was performed if the blood loss or abdominal pain was uncontrolled. All the women were asked to use a barrier method for contraception if necessary. The outcome of the treatment was first assessed on day 7 after misoprostol. A transvaginal ultrasound examination of the pelvis was performed. Surgical evacuation was conducted if a gestational sac was still present or if there was a significant amount of the products of conception in the uterus together with clinical evidence of heavy vaginal bleeding. If the ultrasound examination showed evidence of complete or incomplete miscarriage without heavy vaginal bleeding, no action would be taken. The amount of bleeding was monitored and the woman was asked to come back on day 43 to ascertain the bleeding pattern and return of menstruation. The outcome of treatment was classified as complete miscarriage if surgical evacuation was not required up to the time of return of normal menstruation.
The primary outcome measure was the complete miscarriage rate. The incidence of side effects and the change in haemoglobin level were also studied. The acceptability of each method was assessed by questionnaire. Differences in continuous variables were analysed with Students t-test for normally distributed data and the MannWhitney U-tests for skewed data. Differences in discontinuous variables were analysed by 2-test and Fishers exact test as appropriate.
The difference in complete miscarriage rate was used to calculate the sample size required. According to the previous studies, the use of vaginal misoprostol would achieve a complete miscarriage rate of 60% (Chung et al., 1995). Sublingual misoprostol would be superior to vaginal misoprostol if it could achieve a complete miscarriage rate of 90%. Assuming that 5% of the data were excluded retrospectively, a sample size of 40 in each group would give 80% power in detecting a difference of 30% in the complete miscarriage rate with an alpha of 0.05.
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Results |
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Discussion |
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The acceptability of medical management was good in this study. Most of the women would choose medical treatment again if they were allowed to choose and most of the women accepted the route of administration to which they were randomized. There are two limitations in the assessment of the acceptability of the method in this study. Firstly, the subjects might not have the experience of surgical evacuation and therefore, it was difficult for them to compare the two methods and decide which was the preferred method to them. Secondly, this was an open study and the subjects knew the route of administration that they were assigned. The outcome of the treatment might affect their preference. This was demonstrated by the fact that 95% of the women who preferred medical management in both arms had a complete miscarriage whereas only about 60% of the women who preferred surgical treatment had a complete miscarriage. The situation was the same for the preference on the route of administration. Over 90% of the subjects who preferred the route of administration to which they were assigned had a complete miscarriage whereas only 7080% of the subjects who preferred the other route of administration had a complete miscarriage. This indicated that the outcome of treatment might affect the womens preference on the route of administration. A double-blinded placebo controlled trial may be able to tell us which route is more acceptable. Nevertheless, this study showed that most of the women thought that medical management was an acceptable method and both routes of administration were acceptable to those who had used them. This was especially true for those who had a successful outcome. Since the success rates for both routes of administration were high, medical management by either sublingual or vaginal routes was an acceptable method to most of the women in this study.
The use of mifepristone together with a prostaglandin analogue has been used in the termination of first trimester pregnancy with a high complete abortion rate of >95% (El-Refaey et al., 1995). The success rate was reported to be 84% in first trimester silent miscarriage using a combination of mifepristone and repeated doses of misoprostol (Wagaarachchi et al., 2001
). However, it is believed that mifepristone may not be necessary for medical management of miscarriages as the pregnancy is non-viable. Moreover, mifepristone is expensive and is not available in many countries. Regimens using prostaglandin alone would be more practical in many countries where mifepristone is not available. Misoprostol is the prostaglandin of choice as it is cheap and stable at room temperature. It has been used orally and vaginally for medical abortion and management of miscarriage (El-Refaey et al., 1995
; Chung et al., 1997
; Ngai et al., 2001
). Most studies have shown that the vaginal route of administration is more effective and gives a higher complete abortion rate. However, the oral route is more convenient and acceptable (Ho et al., 1997
). This is especially true for regimens using misoprostol alone because repeated administration is required. Recently, the sublingual route of administration of misoprostol has been investigated. This may offer an alternative for women who do not like vaginal drug administration. It may be a better way of giving the drug in cases of heavy vaginal bleeding, which may affect the absorption in vaginal administration. This is especially true for regimens that require repeated doses of misoprostol. Pilot studies have shown that it was effective for medical abortion and management of miscarriage (Tang and Ho, 2001
; Tang et al., 2002a
). A pharmacological study has also shown that sublingual misoprostol gave the shortest time to peak serum concentration and greatest systemic bioavailability (Tang et al., 2002c
). This means that sublingual misoprostol may have the most potent and fastest onset of action compared with the other routes of administration.
There have been very few randomized trials that compared different regimens of misoprostol in the management of miscarriages. Many of these studies involved subjects with incomplete miscarriages in whom the response to misoprostol may be better (Chung et al., 1995; Chung et al., 1997
; Nielsen and Hahlin, 1995
; Nielsen et al., 1999
; Ngai et al., 2001
). The studies that included silent miscarriages alone were not randomized studies (El-Refaey, 1992
; Zalanyi, 1998
; Wagaarachchi et al., 2001
). The present randomized study has demonstrated that medical management is an effective method for the management of silent miscarriages. Both vaginal and sublingual misoprostol gave a success rate of 87.5%. This compared favourably with our previous study using a different regimen of vaginal misoprostol (400 µg on days 1, 3 and 5) which resulted in a complete miscarriage rate of 83.3%. In that study, the expectant arm had a complete miscarriage rate of 48.3% over a 2 week observation period and the complete miscarriage rate for this group of women was even lower if only silent miscarriages were included (31.6%) (Ngai et al., 2001
). The advantage of the present regimen is that it can be completed over 1 day and there is no need for repeated follow-up visits for the administration of misoprostol. Most of the subjects who had complete miscarriage passed the product of conception within the first 24 h. Therefore, they would be more certain about the outcome of treatment after they had completed the course of misoprostol. The complete miscarriage rate is also similar to a study using a combination of mifepristone and repeated doses of misoprostol which resulted in a success rate of 84.1% (Wagaarachchi et al., 2001
). It seems that the addition of mifepristone does not increase the complete miscarriage rate. A randomized trial is required to confirm this.
The definition of success of treatment varies among different studies in the literature. Most of the studies used ultrasonographical evidence of an empty uterus as the definition of success of treatment (Chung et al., 1995, 1997, 1998; Nielsen et al., 1999
). It is well known that women with incomplete miscarriages diagnosed by ultrasound examination may not require surgical evacuation. It was suggested that the need for surgical evacuation after miscarriage should be indicated by clinical rather that ultrasonographical criteria (Ankum et al., 2001
). In the present study, treatment failure was defined as the presence of an intrauterine gestational sac on day 7. The need for surgical evacuation for incomplete miscarriage was dictated by clinical rather than ultrasonographical criteria. The duration of the observation period may also affect the success rate. In many of the previous studies, ultrasound examination was performed within the first day after misoprostol and surgical evacuation was carried out if there was evidence of retained product of conception (Chung et al., 1995
, 1997, 1998; Nielsen et al., 1999
). We believe that a waiting period of 7 days can optimize the success rate, as we know from medical termination of pregnancy that the passage of the product of conception may be delayed after misoprostol. The percentage of unnecessary surgical evacuation may be increased if the outcome is assessed immediately after misoprostol.
This is the first randomized trial comparing the clinical uses of sublingual versus vaginal misoprostol. The clinical efficacy of sublingual misoprostol is the same as vaginal misoprostol. The interval between misoprostol and passage of the product of conception was slightly shorter in the sublingual group and there was also a higher proportion of women in the sublingual group who had passed the product of conception within the first 24 h. However, statistically significant differences could not be demonstrated for these two parameters, probably due to the small sample size. Previous pilot studies have shown that there might be a higher incidence of side effects for sublingual misoprostol, especially for chills and fever (Tang et al., 2002a,c). In this randomized trial, the side effect profile was actually quite similar in both groups except for diarrhoea and fatigue, which were shown to be significantly more frequent in the sublingual group. However, this did not affect the acceptability of sublingual misoprostol. Most of the women in the sublingual group would still use the same method if they were allowed to choose again and would also recommend the method to others.
In conclusion, the overall efficacy and acceptability of medical management of silent miscarriage were good. Most women would like to be treated medically if both the surgical and the medical method were of the same efficacy. Both sublingual and vaginal misoprostol result in the same complete miscarriage rate. The inductionmiscarriage interval might be shorter in sublingual misoprostol but a larger randomized trial is required to confirm this. Nevertheless, sublingual misoprostol can be offered to women who do not like repeated vaginal administration. There is a potential to develop the sublingual administration of misoprostol into a self-administered out-patient regimen.
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References |
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Submitted on May 29, 2002; accepted on August 20, 2002