1 Department of Obstetrics and Gynaecology, Kwong Wah Hospital and 2 Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong SAR, China
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Abstract |
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Key words: misoprostol/second trimester abortion
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Introduction |
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Misoprostol, a synthetic 15-deoxy-16-hydroxy-16-methyl analogue of naturally occurring prostaglandin E1, is taken orally for the prevention and treatment of gastroduodenal ulcers. The drug is inexpensive (HK$4/tablet) and can be stored at room temperature. Previous study has shown that pre-treatment with mifepristone together with vaginally or orally administered misoprostol was an effective and non-invasive method for second trimester termination of pregnancy (El-Refaey and Templeton, 1995). But mifepristone is currently only available in four countries: France, UK, China and Sweden.
Our recent study showed that vaginal misoprostol 400 µg every 3 h is more effective than gemeprost 1 mg every 3 h in termination of second trimester pregnancy (Wong et al., 1998). However, from the pharmacokinetic study of vaginal administration of 400 µg misoprostol, the plasma concentration of misoprostol acid after administration reached maximum values between 60 and 120 min and declined slowly to an average of 60% of the peak at 240 min after administration (Zieman et al., 1997
). Assuming that the pharmacological effect of misoprostol is related to its concentration in the plasma, the results suggest that vaginal administration could be dosed at longer intervals than 3 h. This regimen may have fewer side-effects and still be effective.
The aim of our randomized trial was to compare the efficacy and side-effects of 400 µg misoprostol administered intravaginally every 3 h with a regimen of 400 µg misoprostol vaginally every 6 h in termination of second trimester pregnancy.
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Materials and methods |
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The women were randomly allocated to receive either intravaginal misoprostol (Cytotec; Searle, Crows Nest, NSW, Australia) 400 µg every 3 h for a maximum of five doses or 400 µg every 6 h for a maximum of three doses in 24 h. The randomization schedule and envelopes bearing the subject number and allocation of grouping were prepared as described elsewhere (Meinert, 1986). The schedule was constructed so that the number in each group would be balanced for every 10 women recruited. The group assignments were put into sealed envelopes. The envelopes were opened when the women were recruited.
Women assigned to group 1 were given misoprostol 400 µg (two tablets of 200 µg Cytotec) in the posterior vaginal fornix every 3 h, up to a maximum of five doses in 24 h. Women in group 2 were given misoprostol 400 µg in the posterior vaginal fornix every 6 h, up to a maximum of three doses over 24 h. The side-effects including nausea, vomiting, diarrhoea and fever (temperature >38°C) were recorded. The blood pressure, pulse, temperature and frequency of uterine contractions were monitored every 3 h. Pethidine hydrochloride 75 mg (Pethidine; Antigen Pharmaceuticals Limited, Roscrea, Ireland) was given for pain relief if women requested. After abortion, the products of gestation (fetus and placenta) were examined to see whether the abortion was complete, but ultrasound examination was not performed. Evacuation of the uterus was performed under general anaesthesia if the placenta was found to be incomplete. The amount of blood loss during abortion was assessed clinically. If a woman in either group failed to abort 24 h after initiation of the treatment, she was given a second course of misoprostol with the same regimen. If a woman failed to abort after 48 h, the regimen of gemeprost (Cervagem; Ono Pharmaceutical Company Limited, Osaka, Japan) 1 mg every 3 h for a maximum of five doses in 24 h would be used.
The inductionabortion interval was defined as the interval between the time of administration of the first dose of misoprostol to the time when the fetus aborted. Complete abortion was defined as the expulsion of both the fetus and the placenta without operative intervention. The inductionabortion interval, the rates of successful abortion (abortion within 24 and 48 h after initial administration of misoprostol) and complete abortion and then the incidences of side-effects were compared in both groups.
The estimation of sample size was based on the following assumptions: (i) a type I error of 10% and type II error of 20% were acceptable because this trial was preliminary; (ii) the primary outcome indicator was abortion rate within 24 h; (iii) from a previous study (Wong et al., 1998), the successful abortion rate in 24 h of women using misoprostol 400 µg every 3 h with a maximum of five doses was 80%. The successful abortion rate in group B should be at least 60% which was the successful rate of gemeprost (Wong et al., 1998
), in order to consider the regimen of vaginal misoprostol 400 µg every 6 h as an acceptable method. Using the program EPI 6 (Centers for Disease Control and Prevention, USA), the number of subjects in each group was 74. Therefore, the total number of subjects for the study was 148. The trial was approved by the Ethics Committees of the hospital.
The differences in the means of continuous variables were analysed with the Student's t-test for normally distributed data and with MannWhitney U-test for skewed data. Differences in proportions were analysed with the 2 or Fisher's exact test as appropriate.
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Results |
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Discussion |
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There are different regimens for use of misoprostol in termination of pregnancy in second trimester. With mifepristone pre-treatment, the abortion rate with misoprostol in the first 24 h was 97% (El-Refaey and Templeton, 1995). But mifepristone is currently available only in France, UK, Sweden and China. Therefore, it is necessary to explore the use of misoprostol alone in termination of second trimester pregnancy.
It has been reported that the abortion rate within 24 h of the regimen of 200 µg misoprostol given vaginally every 12 h in second trimester abortion was 89% (Jain and Mishell, 1994). However, a subsequent study reported that the success rate was only 69.7% with the same regimen (Jain and Mishell, 1996
). Patients with missed abortion were included in the study and the fetus was killed with potassium chloride injection before administration of misoprostol. Therefore, it is not certain whether this regimen was effective in termination of second trimester pregnancy with a live fetus.
Recently, we have reported that a regimen of vaginal 400 µg misoprostol every 3 h with maximum of five repeated doses in 24 h results in termination of second trimester pregnancy with live fetus. The successful abortion rate within 24 h was 80% (Wong et al., 1998). The results of the present study were comparable. Other authors reported the results of the regimen of vaginal 200 µg misoprostol every 12 h until abortion or for 36 h. The abortion rates in 24 and 48 h were 40% and 92% respectively (Nuutila et al., 1997
). In that study, only 86% of the fetuses were alive.
The results in the present study showed that the regimen of vaginal misoprostol 400 µg every 3 h is more effective than that with 400 µg every 6 h. The overall inductionabortion interval was shorter and the success rate within 48 h was higher in the group with 400 µg every 3 h. There was no significant difference between the two regimens in primigravidae. It seems that women with previous pregnancy can have better results using misoprostol 400 µg every 3 h as opposed to 6 h, whereas the primigravidae should have the regimen of misoprostol 400 µg every 6 h in 24 h because this regimen was associated with a lower incidence of fever and yet was equally effective in abortion.
The reported incidences of vomiting and diarrhoea were 57% and 29% respectively in one of the studies on vaginal misoprostol (El-Refaey and Templeton, 1995). The median dosage required in that study was 1000 µg. The incidences of vomiting and diarrhoea in the present study were low. The median dosages of misoprostol required in group 1 and group 2 were ~2000 µg and ~1200 µg respectively. It seems that the incidence of side-effects is not related to total amount of misoprostol used. Another common side-effect after administration of misoprostol is fever. Our previous study reported that the incidence of patients having a temperature >38°C is 50% (Wong et al., 1998
). Similar findings (32.4 and 12.2% in groups 1 and 2 respectively) were noted in the present study. Another study using vaginal misoprostol reported that incidence of fever ranged from 0 to 8.8% (Jain and Mishell, 1996
; Nuutila et al., 1997
). This may be due to difference in dose (400 µg versus 200 µg) or frequency (every 3 h versus every 12 h) of administration of the misoprostol.
In this study we have shown that dosages of misoprostol up to 4000 µg over 48 h were well tolerated. Side-effects were mainly gastrointestinal and fever but these were mild. In conclusion, the regimens of vaginal misoprostol 400 µg every 3 h or 400 µg every 6 h are safe and effective methods for second trimester abortion. The regimen with misoprostol 400 µg every 3 h seems more effective in multigravidae.
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Notes |
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References |
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Submitted on June 1, 1999; accepted on November 25, 1999.