Randomized comparison of vaginal (200 µg every 3 h) and oral (400 µg every 3 h) misoprostol when combined with mifepristone in termination of second trimester pregnancy
Suk Wai Ngai1,
Oi Shan Tang and
Pak Chung Ho
Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China
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Abstract
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It is known that when misoprostol is given at 200 µg every 3 h after mifepristone pretreatment, the vaginal route is more effective than the oral route. However, women prefer the oral route. This randomized study was to test our hypothesis that oral misoprostol 400 µg is as effective as vaginal misoprostol 200 µg when given every 3 h in termination of second trimester pregnancy after priming with mifepristone. A total of 142 patients was randomly assigned to group 1 (200 mg mifepristone + 400 µg oral misoprostol every 3 h up to five doses) or group 2 (200 mg mifepristone + 200 µg vaginal misoprostol every 3 h up to five doses). The incidence of side-effects and the preference study were assessed through a standardized questionnaire during and after the abortion. For the oral group, both the incidence of diarrhoea (40.0 versus 23.2%, P = 0.03) and the amount of drug used (1734 compared with 812 µg, P < 0.0001) were significantly higher than that of the vaginal group but the incidence of fever appeared to be lower (not significant). There was no significant difference in complete abortion rate: 81.4% in the oral group and 75.4% in the vaginal group. The median inductionabortion interval was similar in the two groups (10.4 versus 10.0 h). The percentage of women who aborted in 24 h was also similar: 57/70 (81.4%) in the oral group and 58/69 (87.0%) in the vaginal group. Overall, 82.0% of women preferred the oral route. Oral misoprostol (400 µg) given every 3 h up to five doses, when combined with mifepristone, was as effective as the vaginal (200 µg) route in second trimester termination of pregnancy. This regimen could also be offered to those women who found repeated vaginal administration unacceptable.
Key words:
mifepristone/misoprostol/second trimester abortion
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Introduction
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Termination of pregnancy in the second trimester is often carried out by the administration of prostaglandins. Mifepristone, a progesterone-receptor antagonist, has been shown to be effective in shortening the inductionabortion interval (Urquahart et al., 1989; Urquahart and Templeton, 1990). It has been shown that oral misoprostol (400 µg every 3 h) given after priming with mifepristone is as effective as vaginal gemeprost (Ho et al., 1996
). At a lower dose (200 µg every 3 h), vaginal misoprostol is more effective than oral misoprostol in termination of second trimester pregnancy when combined with mifepristone (Ho et al., 1997
). However, most women prefer the oral route. The inductionabortion interval of the vaginal misoprostol at a dose of 200 µg every 3 h (Ho et al., 1997
) was similar to that of the oral route when given at the same dosage (Ho et al., 1996
). There are several advantages in using the oral route: (i) it is more convenient to administer; (ii) it is preferred by the majority of women; (iii) misoprostol is manufactured for administration by the oral route. The cost of increasing the dose of oral misoprostol is minimal because it is cheap. We decided to use a lower dose of mifepristone here. Although the manufacturer's recommended regimen for second trimester abortion is mifepristone 600 mg followed by gemeprost, it has been shown that a 200 mg dose of mifepristone is as effective as a 600 mg dose for first and mid-trimester abortion (WHO Task force, 1993; Webster et al., 1996 respectively). The objective of this randomized study was to test our hypothesis that oral misoprostol given at 400 µg every 3 h is as effective as vaginal misoprostol 200 µg every 3 h in termination of second trimester pregnancy when combined with 200 mg oral mifepristone.
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Materials and methods
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Healthy women (aged between 16 and 35 years) requesting legal second trimester (1420 weeks) termination of pregnancy were recruited in this study. Women who were using prescription drugs regularly, women with an intrauterine device in utero, nursing mothers, multiple pregnancies and heavy smokers were excluded. After taking medical history and a physical examination, an ultrasound examination was performed to confirm the gestational age of the pregnancy. The study was explained to the woman and a written consent was obtained.
After recruitment, the subjects were randomized into two groups (Meinert, 1986
). Sealed envelopes were prepared with serial numbers in front and the allocated grouping inside. When a subject was recruited into the study, she was given a serial number according to the sequence of entry into the study. The sealed envelope bearing the serial number of the subject was opened, and the woman was allocated to the grouping in the envelope. For women allocated to group 1, 200 mg of mifepristone was taken by the subject in the morning. About 3648 h later, the patient was admitted into the hospital. Misoprostol 400 µg was given orally every 3 h up to a maximum of five doses starting at 0800 h. The side-effects, uterine contractions, blood pressure and pulse rate were recorded every 3 h. Pelvic examination was performed every 3 h and a vitamin B6 tablet (which resembled misoprostol) was inserted as placebo. If abortion did not occur after 24 h, a second course of oral misoprostol was given. If abortion still failed to occur, the pregnancy was terminated with vaginal gemeprost. After abortion, the products of conception were examined. If the abortion process was considered to be incomplete, evacuation of the uterus was carried out. For women in group 2, the pregnancies were terminated with vaginal misoprostol. Mifepristone 200 mg was taken in the morning on day 1. About 3648 h later, misoprostol 200 µg was administered vaginally every 3 h for a maximum of five doses. In order to mimic the first group, two oral placebo tablets (vitamin B6) were given every 3 h. The management and monitoring of the subjects were the same as for group 1. On discharge from the hospital, all subjects were asked to indicate which route of drug administration they preferred and the reasons for their preference. The patients did not know whether they received oral or vaginal misoprostol.
The main outcome measure was the percentage of women who aborted within 24 h. Our previous experience was that with mifepristone followed by vaginal misoprostol, 85% of women would abort within 24 h. A sample size of 142 would have the power of 0.8 to detect a difference of 15% at 5% significance level.
The MannWhitney U test was used to compare the differences in inductionabortion intervals (the interval between the first dose of misoprostol and the expulsion of the products of conception) and the total doses of misoprostol required. The
2 test or Fisher's exact test was used to compare the differences in incidence of failure and side-effects, and the preference for the oral or vaginal route.
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Results
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Altogether 142 women were recruited. Three women had to be excluded. One woman was excluded because she defaulted after administration of mifepristone and she had termination of pregnancy in another hospital. The second subject was excluded because after administration of mifepristone, she informed the doctor that she had drug sensitivity. Therefore, the pregnancy was terminated with gemeprost. The third woman was excluded because the misoprostol was administered by the wrong route on the second day of administration of misoprostol. The characteristics of the women in the two groups were comparable (Table I
). Side-effects related to mifepristone were similar between the two groups (Table II
). The incidence of side-effects after administration of misoprostol is shown in Table III
. The incidence of diarrhoea in the oral misoprostol group was significantly higher (P = 0.033) than that in the vaginal misoprostol group. The mean number of episodes of diarrhoea in the oral group (1.44) was also significantly higher than the vaginal group (0.54) while the mean number of episodes of vomiting was similar in both groups. The incidence of fever (temperature >38°C) was apparently higher in the vaginal misoprostol (but the difference was not statistically significant). The median highest temperature during the period of administration of prostaglandin was significantly higher in the vaginal group than that in the oral misoprostol group (37.5°C versus 37.2°C, P < 0.05).
The characteristics of the abortion process are shown in Table IV
. The amount of misoprostol used in the oral group was significantly higher than that in the vaginal group (P < 0.0001). There was no significant difference between the groups for the other parameters. When women in the two groups with (n = 23 and 27 respectively) or without (n = 47 and 41 respectively) previous pregnancies were analysed separately, the results were similar. There was no significant difference in complete abortion rate in the two groups: 57/70 (81.4%) women in the oral misoprostol group and 58/69 (84.0%) women in the vaginal misoprostol group aborted within 24 h. There were no significant complications in either group of women. Eleven women in the oral group and nine women in the vaginal group went onto the second day and required a second course of misoprostol. Two women in each group went onto the third day and required gemeprost. Overall, 13 women (18.6%) in the oral group and 17 women (24.6%) in the vaginal group required suction evacuation for incomplete abortion. No women in the study had failed medical abortion requiring surgical treatment.
When they were asked which route they preferred, 11 women had no particular preference. For those who had positive responses, 116 (90%) preferred the oral route. The reasons given were: it was more convenient (n = 58); it was less painful (n = 51); it offered more privacy (n = 3); it was more effective (n = 3); it would be absorbed better (n = 1). Only 12 women preferred the vaginal route. The reasons were: it was more effective (n = 7) and it might cause less gastro-intestinal upset (n = 5).
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Discussion
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Our previous study showed that misoprostol was more effective than gemeprost in termination of second trimester pregnancy (Wong et al., 1998
). We showed that after pretreatment with mifepristone, vaginal misoprostol (200 µg) caused a significantly shorter inductionabortion interval than when the same dose was given orally (15.2 h versus 32.0 h, P < 0.05). However, patients preferred the oral route because they felt it was more private and convenient. The results of this study showed that after pretreatment with mifepristone, oral misoprostol given at the dose of 400 µg was of similar efficacy when compared with 200 µg vaginal dose given at every 3 h. The inductionabortion interval was 20.8 h in the oral group and 17.4 h in the vaginal group. With the same regimen of vaginal misoprostol given after mifepristone, the inductionabortion interval was similar to that of our previous study (Ho et al., 1997
). In contrast, the inductionabortion interval was significantly reduced when the dose of oral misoprostol was increased from 200 to 400 µg every 3 h. Thus, by increasing the oral dosage, the efficacy as well as the acceptability of this treatment regimen can be improved.
In our study, about 80% of women aborted within 24 h of misoprostol administration. El-Refaey et al. (1995) and Ashok and Templeton (1999) have shown that using a combination of vaginal and oral misoprostol, up to 97% of women aborted within 15 h of administration. The inductionabortion interval was also shorter when compared with the regimen from our study. This was probably due to the difference in treatment regimen. In the first study (El-Refaey et al., 1995), women were pretreated with 600 mg oral mifepristone. After 3648 h, they were randomized to group 1: vaginal misoprostol 600 µg followed by vaginal misoprostol 400 µg given at a 3 h interval; group 2: vaginal misoprostol 600 µg followed by oral misoprostol 400 µg doses given at a 3 h interval. They achieved an overall successful abortion rate of 97% and a mean induction to abortion time of 6.4 h (95% confidence interval 5.67.0 h). Ashok et al. (1999) reviewed 500 women who underwent second trimester termination of pregnancy. Women were given a single oral dose of mifepristone 200 mg and 3648 h later, vaginal misoprostol 800 µg. Three hours following the first dose of misoprostol, 400 µg doses were administered orally at 3 h intervals, to a maximum of four doses, and 97% aborted successfully. The median induction-to-abortion interval after the first prostaglandin administration was 6.5 h. It seems that the first dose of misoprostol, when it is given vaginally at high dose, is important in reducing the inductionabortion interval. Further randomized trials comparing different regimens are essential to confirm this hypothesis.
The safety of misoprostol in termination of pregnancy must not be overlooked. In our study, we used relatively low doses of misoprostol. No patient suffered from any significant sequelae. In El-Refaey's study (1995), there was one patient who developed sudden onset of rigor, vomiting and eruption of maculopapular rash following the vaginal administration of 600 µg misoprostol. The side-effects of regimens using higher doses of vaginal misoprostol must be assessed in any future studies.
In Hong Kong, one tablet of 200 µg of misoprostol costs HK$ 2.10 (US$ 0.27). The increase in drug cost by using oral misoprostol was thus about four-fold (HK$9.68 or US$1.24). This amount, however, was actually small when compared with the cost of mifepristone. As in our previous study, the majority of the women preferred the oral route. The reasons were also similar to those quoted previously.
In conclusion, the combination of mifepristone and oral misoprostol provides a safe and effective regimen for medical termination of second trimester pregnancy. The oral regimen should be offered to those women who consider vaginal administration unacceptable.
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Notes
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1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, People's Republic of China. 
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References
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Submitted on January 31, 2000;
accepted on June 15, 2000.