A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial

K.S. Wong1,3, C.S.W. Ngai2, E.L.K. Yeo1, L.C.H. Tang1 and P.C. Ho2

1 Department of Obstetrics and Gynaecology, Kwong Wah Hospital and 2 Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong SAR, China


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A prospective randomized trial was conducted in 148 women to compare the efficacy of two regimens of vaginal misoprostol for termination of second trimester pregnancy. Women aged 16–40 years requesting termination of second trimester pregnancy were randomized into two groups. Women in group 1 were given vaginal misoprostol 400 µg every 3 h for a maximum of five doses in 24 h. Women in group 2 were given vaginal misoprostol 400 µg every 6 h for a maximum of three doses in 24 h. If women did not abort in 24 h, the same regimen was repeated. The median induction–abortion interval in group 1 (15.2 h) was significantly shorter (P < 0.01) than that in the group 2 (19.0 h). The percentage of women who achieved successful abortion within 48 h in group 1 (90.5%) was also significantly higher (P < 0.02) than that in group 2 (75.7%). The incidence of fever was more common in group 1 (P = 0.01). It is concluded that the regimen of vaginal misoprostol 400 µg every 3 h with maximum of five doses in 24 h was more effective than the regimen of misoprostol every 6 h in termination of second trimester pregnancy.

Key words: misoprostol/second trimester abortion


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Termination of second trimester pregnancy is frequently performed by administration of prostaglandins or their analogues by various routes (Karim, 1979Go). It has been shown that administration of vaginal gemeprost is an effective and safe method in termination of second trimester pregnancy. However, it is associated with significant side-effects such as vomiting, diarrhoea and fever (Wong et al., 1996Go). Moreover, it must be given vaginally every 3 h and it is expensive (HK$180 per pessary).

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, 1995Go). 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., 1998Go). 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., 1997Go). 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.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Healthy women requesting legal termination of second trimester pregnancy between 14 and 20 weeks were recruited to the trial. Women who were using prescription drugs regularly or who had cardiac disorders, an intrauterine contraceptive device in situ, missed abortion (pregnancy with a dead fetus), or multiple pregnancy and nursing mothers were excluded from the study. Women who fulfilled the criteria for the trial were interviewed and given an explanation of the trial. An informed written consent was obtained. A pelvic ultrasound examination was performed to confirm the gestation and to exclude multiple pregnancy and missed abortion.

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, 1986Go). 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 induction–abortion 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 induction–abortion 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., 1998Go), 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., 1998Go), 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 Mann–Whitney U-test for skewed data. Differences in proportions were analysed with the {chi}2 or Fisher's exact test as appropriate.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 148 women who were to have second trimester legal termination of pregnancy, with gestation between 14 and 20 weeks, was recruited into the study with 74 subjects in each group. The two groups of patients were comparable in age, height, weight and gestational age of pregnancy (Table IGo). Twenty-four (32.4%) women in group 1 and 19 (25.7%) in group 2 were primigravidae. The difference was not statistically significant.


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Table I. Characteristics of patients
 
The incidences of side-effects in both groups after the administration of misoprostol are shown in Table IIGo. Before administration of misoprostol, the incidences of complaints were similar in both groups. After the administration of drugs, the incidence of complaints was similar in both groups, but the incidence of fever with temperature higher than 38°C was statistically higher (P = 0.003) in the group receiving misoprostol every 3 h. The temperatures returned to normal within 24 h after the last dose of misoprostol.


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Table II. Incidence of side effects after misoprostol administration
 
The characteristics of the abortion process are shown in Table IIIGo. A total of 54 (73.0 %) women in group 1 and 45 (60.8%) women in group 2 aborted within 24 h. The difference was not statistically significant ({chi}2-test). After the second course of misoprostol in women who failed to abort in 24 h, the overall successful abortion rate in group 1 was statistically higher than that in group 2 (P <= 0.02). When the patients were divided into primigravidae and multigravidae, the successful rate within 48 h in group 1 was significantly higher in multigravidae (90.0% and 70.9%, P = 0.015). There were seven and 18 women in groups 1 and 2 respectively who required an additional course(s) of gemeprost to achieve abortions subsequently.


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Table III. Characteristics of the abortion process
 
The median induction–abortion interval in group 1 was significantly shorter than that in group 1 (P < 0.01). Also this difference only appeared in multigravidae. The mean amount of misoprostol administered in group 1 was statistically significantly larger than in group 2 (2021 ± 890 and 1546 ± 663 µg, P = 0.002). Considering analgesic requirements, 25 (33.8%) and 27 (36.5%) women had pethidine injection in groups 1 and 2 respectively. The abortion was complete in 34 women (45.9%) in group 1 and in 31 women (41.9%) in group 2; the difference was not statistically significant. There was no difference in complete abortion rates in primigravidae and multigravidae. The estimated blood loss during abortion was comparable in both groups. The mean blood loss in group 1 was 100.7 ml (SD 98.2) and that in group 2 was 140.4 ml (SD 163.3); the difference was not statistically significant.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There are a number of advantages to using misoprostol instead of other prostaglandins for termination of pregnancy. Misoprostol is substantially less expensive than gemeprost. Misoprostol does not require refrigerated transport and storage facilities. This drug can be given vaginally, orally or in combination in different dosages. The combination of the mifepristone and prostaglandin analogue (gemeprost and misoprostol) provides an effective and safe medical method for abortion at gestation up to 63 days. The complete abortion rate is >95% (Ashok et al., 1998Go; Gupta, 1998Go; Tang et al., 1999Go). There is also good evidence that misoprostol is useful in second trimester abortion.

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, 1995Go). 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, 1994Go). However, a subsequent study reported that the success rate was only 69.7% with the same regimen (Jain and Mishell, 1996Go). 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., 1998Go). 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., 1997Go). 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 induction–abortion 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, 1995Go). 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., 1998Go). 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, 1996Go; Nuutila et al., 1997Go). 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.


    Notes
 
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Kwong Wah Hospital, 25 Waterloo Road, Kowloon, Hong Kong SAR, China Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ashok, P.W., Penney, G.C., Flett, G.M.M. et al. (1998) An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum. Reprod., 13, 2962–2965.[Abstract/Free Full Text]

El-Refaey, H. and Templeton, A. (1995) Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: a randomized comparison between two misoprostol regimens. Hum. Reprod., 10, 475–478.[Abstract]

Gupta, S. (1998) Early non-surgical abortion—give women the choice. Hum. Reprod., 13, 2379–2381.[Abstract]

Jain, J.K. and Mishell, D.R. Jr (1994) A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N. Engl. J. Med., 331, 290–293.[Abstract/Free Full Text]

Jain, J.K. and Mishell, D.R. Jr (1996) A comparison of misoprostol with and without laminaria tents for induction of second-trimester abortion. Am. J. Obstet. Gynecol., 175, 173–177.[ISI][Medline]

Karim, S.M.M. (1979) Termination of second trimester pregnancy with prostaglandins. In Karim, S.M.M. (ed.), Practical Applications of Prostaglandins and their Synthesis Inhibitors. MTP Press, Pennsylvania, pp. 375–409.

Meinert, C.L. (1986) Randomization and the mechanics of treatment masking. In Meinert, C.L. (ed.), Clinical Trials: Design, Conduct and Analysis. Oxford University Press, New York, pp. 90–112.

Nuutila, M., Toivonen, J., Ylikorkala, O. et al. (1997) A comparison between two doses of intravaginal misoprostol and gemeprost for induction of second trimester abortion. Obstet. Gynecol., 90, 896–900.[Abstract/Free Full Text]

Tang, O.S., Gao, P.P., Cheng, et al. (1999) A randomized double-blind placebo-controlled study to assess the effect of oral contraceptive pills on the outcome of medical abortion with mifepristone and misoprostol. Hum. Reprod., 14, 722–725.[Abstract/Free Full Text]

Wong, K.S., Wong, A.Y.K. and Tang, L.C.H. (1996) Second trimester pregnancy termination using gemeprost. Hong Kong Med. J., 2, 19–24.

Wong, K.S., Ngai, C.S.W., Wong, A.Y.K. et al. (1998) Vaginal misoprostol compared with vaginal gemeprost in termination of second trimester pregnancy. Contraception, 58, 207–210.[ISI][Medline]

Zieman, M., Fong, S.K., Benowitz, N.L. et al. (1997) Absorption kinetics of misoprostol with oral or vaginal administration. Obstet. Gynecol., 90, 88–92.[Abstract/Free Full Text]

Submitted on June 1, 1999; accepted on November 25, 1999.