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Termination of second trimester pregnancy with gemeprost and misoprostol: A randomized double-blind placebo-controlled trial
ELSEVIER
Termination of Second Trimester Pregnancy with Gemeprost and Misoprostol: A Randomized Double-Blind Placebo-Controlled Trial K.S. Wang,* C.S.W. Ngai,t
K.S. Ghan,” L.C.H. Tang,* and P.C. Hot
A prospective randomized double-blind placebo-controlled trial was conducted in 70 subjects to determine whether pre-treatment with misoprostol could facilitate termination of second trimester pregnancy by gemeprost. The women received either 400 pg oral misoprostol or placebo tablets 12 hours before the administration of vaginal pessary of gemeprost 1 mg every 3 hours. There were no significant differences in induction-abortion interval and the amount of gemeprost required between the misoprostol and the placebo group. There was no significant difference in the incidence of side effects or analgesic requirement between the two groups, We conclude that oral misoprostol is not useful in facilitating termination of second trimester pregnancy by gemeprost. CONTRACEPTION 1996;54:23-25 KEY WORDS:
oral misoprostol,
gemeprost,
second trimester
termination
Introduction of second trimester pregnancy is ermination commonly performed by administration of prostaglandin or their analogues by various routes.’ However, it is associated with a significant degree of side effects such as vomiting, diarrhoea and fever. Serious complications such as cervical injury can occur. There is a need to find methods to shorten the abortion process and to reduce the incidence of side effects. It has been shown that insertion of a laminaria tent 12 hours before sulprostone injection could decrease the induction-abortion interval significantly in termination of second trimester pregnancy.2 The insertion of a laminaria tent requires trained personnel and can
T
*Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong and *Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong Name and address for correspondence: Dr. K.S. Wong, Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Kowloon, Hong Kong Submitted for publication March 5, 1996 Revised April 22, 1996 Accepted for publication April 26, 1996
0 1996 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
cause discomfort to the patient. The use of the laminaria tents can cause potential complications such as intrauterine displacement and perforation of the cervix.3 Recently, mifepristone, a progesterone antagonist, has been shown to be effective in reducing the induction-abortion interval and number of gemeprost pessaries required to terminate second trimester pregnancy.4 Unfortunately, mifepristone is only available in four countries: France, China, United Kingdom and Sweden. Misoprostol is a prostaglandin El analogue. It has been used in treatment of peptide ulcers. It can be administered orally. Recently, Fletcher et a1.5 have shown that misoprostol was an effective cervical ripening agent in term pregnancy. Peyron et a1.6 showed that the combination of mifepristone and oral misoprostol was effective for termination of early pregnancy. It has also been shown that misoprostol is capable for dilating the cervix before vacuum aspiration.‘,’ Therefore, it is possible that misoprosto1 may also have cervical ripening effect in second trimester pregnancy. The aim of the present doubleblind placebo-controlled trial was to investigate whether misoprostol pre-treatment can improve the efficacy of intravaginal gemeprost pessary in termination of second trimester pregnancy.
Materials
and Methods
Healthy women aged 16 to 40 years requesting legal termination of pregnancy at the gestational age of 14 to 20 weeks were recruited in the trial. Women who were using prescription drugs regularly, women with an intrauterine contraceptive device in situ or multiple pregnancy and nursing mothers were excluded from the study. Women who fulfilled the criteria for the study 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 mulISSN OOIO-7824/96/$15.00 PII SOOIO-7824(96)00115-l
24
Contraception
Wang et al.
1996;54:23-25
tiple pregnancy. The randomization schedule and envelopes bearing the subject number and allocation of grouping were prepared as described by Meinert.’ The tablets (either misoprostol 400 pg or placebo, vitamin Bb), in a bottle bearing the subject number, were taken at 8 pm. After 12 hours, women were given 1 mg gemeprost vaginally every 3 hours until abortion, for a maximum of five doses in the first 24 hours. The side effects, temperature, blood pressure and uterine contractions were recorded. When the women aborted, the amount of blood loss was noted. The products of conception were examined and evacuation of the uterus was performed if they were found to be incomplete. If women failed to abort in the first 24 hours, a second course of gemeprost was given at the same dosage schedule. The induction-abortion interval is defined as the interval between the time of the administration of the first dose of gemeprost to the time when the fetus aborted. The induction-abortion intervals and total dosage of gemeprost used in the treatment and placebo groups were compared by the Mann-Whitney Utest. The incidence of side effects was compared by the chi-square and Fisher exact tests. The estimation of sample size was based on the following assumptions: (1) a type I error of 10% and type II error of 20% were acceptable because the trial was a preliminary trial; (2) the reduction of the induction-abortion interval had to be at least similar to that of the laminaria tent (i.e., reduction of more than 6 hours) before misoprostol is likely to be an acceptable alternative; (3) the median induction-abortion interval in the control group was about 16 hours in our previous experience. Using the formula and table of Meinert,’ the number of subjects is 31 in each group. Assuming that 10% of the data might be excluded, the total number of subjects for the study would be 70. This trial was approved by the Ethics Committee of the Faculty of Medicine, the University of Hong Kong.
Results Altogether, 70 women were recruited into the trial (35 in each group). The characteristics of the two groups of women are shown in Table 1; these parameters are comparable in the two groups. Fifteen women (42.8%) in the misoprostol group and 22 women (62.8 % ) in the placebo group were primigravidae, but the difference was not statistically significant (p > 0.05). There was no significant difference in the incidence of complaints of nausea, vomiting, dizziness, fatigue, breast tenderness or lower abdominal pain between the two groups during the interval between the administration of misoprostol or placebo and the administration of gemeprost (Table 2).
Table 1. Characteristics
of the patients in misoprostol groun (n = 351 and nlacebo ZZTOUD In = 35)
Age (year) Weight (Kg) Height (cm)
Gestational age (week) Results are shown nificant.
Misoprostol Group
Placebo Group
23.2 * 7.5 52.4 + 9.3 156.0 i 5.2 16.8 k 2.1
21.0 * 5.8 51.7 + 8.2 156.9 + 4.3 15.9 f 2.0
as mean * SD. The differences
are not statistxally
sig-
The number of episodes of vomiting, diarrhoea and the incidence of febrile reaction after administration of gemeprost was also similar in the two groups. The induction-abortion interval in the misoprostol group and the placebo group was not significantly different. The amounts of gemeprost and pethidine required was smaller in the misoprostol group, but the differences were not statistically significant (Table 3). The successful abortion rate (abortion within 24 hours of the first dose of gemeprost) and complete abortion rate were comparable in both groups (Table 3).
Discussion Termination of second trimester pregnancy is a painful and stressful procedure for the patient. There is a need to find a method that can reduce the inductionabortion interval. Mifepristone pre-treatment can significantly shorten the induction-abortion interval and decrease the number of gemeprost pessaries reis more quired. lo It has been shown that mifepristone effective than the laminaria tent in shortening the induction-abortion interval in termination of second trimester pregnancy using gemeprost. ‘i However, mifepristone is licensed in only four countries. Misoprostol, a synthetic 15deoxy- 16-hydroxy- 16-methyl analogue of naturally occurring prostaglandin El, is Table 2. Side effects after treatment: misoprostol group (n = 35) and placebo group (n = 35), before gemeprost administration
Side Effects
Nausea Vomiting Dizziness Fatigue Breast tenderness Abdominal pain Headache Diarrhoea Incidence is shown as number significant.
Misoprostol Group n (%)
Placebo Group n (%)
3 (8.6) 3 (8.6)
0 (0) 0 (0) 2 (5.9) 0 PI 0 (0) 5 (14.7) 1 (2.9) 0 (01
: I:.;1 1 (2:9) 12 (34.3) 0 (0) 3 (8.6) 1%). None of the differences
is statlstically
Contraception 1996;54:23-25
Termination
of Second
Table 3. Characteristics of the abortion process and outcome of abortion in misoprostol group (n = 35) and placebo group (n = 35)
Induction-abortion interval (hr) Amount of gemeprost required (mg) Amount of pethidine required (mg) Successful abortion* Complete abortion
Misoprostol Group
Placebo Group
27.3 zt34.4 (14.3) 4.9 + 3.1 (4) 45.0 f 52.1 (50.0)
28.2 _+28.9 (18.3) 5.7 rt 2.6 (51 54.3 + 52.7 (75.0) 24 (68.6) 24 (68.6)
E /kg
P 0.0863 0.0957 0.4229 0.7942 0.6145
*Abortion within 24 hours of the first dose of gemeprost. Results are shown as mean * SD and median in the bracket or as number [%). p-value calculated with Mann-Whitney U-test or chi-square test. The differences are not statistically significant.
taken orally for the prevention and treatment of gastroduodenal ulcers. El-Refaey et a1.i2 have shown that vaginal misoprostol (600 ug) is effective in cervical priming before surgical evacuation in first trimester termination of pregnancy. In 1993, Peyron6 reported that oral misoprostol was effective in first trimester termination of pregnancy. Women with pregnancy less than 50 days received oral 400 ug misoprosto148 hours after taking 600 mg mifepristone; the success rate was 96.9%. It has also been shown that 400 pg of oral misoprostol given 12 hours before suction evacuation is effective in dilating the cervix with only minimal side effects.‘js Despite the previous evidence that oral misoprostol can dilate the cervix during pregnancy,‘!’ our results showed that it was not effective in shortening the induction-abortion interval in second trimester termination of pregnancy. Thong and Baird13 had shown that although Dilapan could effectively dilate the cervix, it did not shorten the induction-abortion interval in termination of pregnancy in second trimester. All these data suggest that it takes more than cervical dilatation to facilitate termination of pregnancy with prostaglandin analogues. Misoprostol is more convenient than other prostaglandins because it is given orally and compliance is good. The drug is less expensive than gemeprost and it can be stored at room temperature. Chung et a1.14 showed that oral misoprostol 400 ug every 4 hours for a total of three doses was effective in the management of first trimester spontaneous abortion. Although the present trial did not show that the regimen of pre-treatment with oral misoprostol 400 pg 12 hours before gemeprost could shorten the induction-abortion interval or decrease the pessaries re-
Trimester
Pregnancy
with Gemeprost
and Misoprostol
25
quired, it does not mean this drug is not useful in this aspect. Misoprostol might be effective with alteration of routes of administration (e.g., vaginal route) or other dosage regimens. Further clinical trial on use of misoprostol for pre-treatment of second trimester abortion might prove its effectiveness.
References 1. Karim SMM. Termination of second trimester pregnancy with prostaglandins. In: Karim SMM, ed. Practical applications of prostaglandins and their synthesis inhibitors. Pennsylvania: MTP Press Limited, 1979: 375-409. 2. Karim SMM, Ratnam SS,Lein AL, Yeo KC, Choo HT. Termination of secondtrimester pregnancy with laminaria and intramuscular 16-phenoxy-w- 17,18,19,20tetranor PGE2 methyl sulphonylamide (sulprostone): a randomised study. Prostaglandin 1982;23:257-63. 3. Johnson N. Intracervical tents: usageand mode of action. Obstet Gynecol Surv 1989;44:410-20. 4. Thong KJ, Baird DT. Second trimester abortion with mifepristone and gemeprost. Br J Obstet Gynaecol 1993;100:758-61. 5. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641-4. 6. Peyron R, Aubeny E, Targosz V, et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993; 328:1509-13. 7. Ngai SK,Au Yeung KC, Lao T, Ho PC. Oral misoprostol versus vaginal gemeprost for cervical dilatation prior to vacuum aspiration in women in the sixth to twelfth week of gestation. Contraception 1995;51:347-50. 8. Ngai SK, Tang 01, Lao T, Ho PC, Ma HK. Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy. Human Reproduction 1995;10:1220-2. 9. Meinert CL. Randomization and the mechanics of treatment masking. In: Meinert CL, et al., eds. Clinical Trials: Design, Conduct and Analysis. Oxford University Press:Oxford, 1986:90-l 12. 10. RodgerMW, Baird DT. Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41-5. 11. Ho PC, Tsang SSK, Ma HK. Reducing the induction to abortion interval in termination of second trimester pregnancies: a comparison of mifepristone and laminaria tent. Br J Obstet Gynaecol 1995;102:648-51. 12. El-Refaey H, Calder L, Wheatley DN, Templeton A. Cervical priming with prostaglandin El analogues,misoprostol and gemeprost. Lancet 1994;343:1207-9. 13. Thong KJ, Baird DT. A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy. Contraception 1992;46:11-7. 14. Chung TKH, Cheung LP, Leung TY, Haines CJ, Chang AMZ. Misoprostol in the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102:832-5.
Termination of Second Trimester Pregnancy with Gemeprost and Misoprostol: A Randomized Double-Blind Placebo-Controlled Trial K.S. Wang,* C.S.W. Ngai,t
K.S. Ghan,” L.C.H. Tang,* and P.C. Hot
A prospective randomized double-blind placebo-controlled trial was conducted in 70 subjects to determine whether pre-treatment with misoprostol could facilitate termination of second trimester pregnancy by gemeprost. The women received either 400 pg oral misoprostol or placebo tablets 12 hours before the administration of vaginal pessary of gemeprost 1 mg every 3 hours. There were no significant differences in induction-abortion interval and the amount of gemeprost required between the misoprostol and the placebo group. There was no significant difference in the incidence of side effects or analgesic requirement between the two groups, We conclude that oral misoprostol is not useful in facilitating termination of second trimester pregnancy by gemeprost. CONTRACEPTION 1996;54:23-25 KEY WORDS:
oral misoprostol,
gemeprost,
second trimester
termination
Introduction of second trimester pregnancy is ermination commonly performed by administration of prostaglandin or their analogues by various routes.’ However, it is associated with a significant degree of side effects such as vomiting, diarrhoea and fever. Serious complications such as cervical injury can occur. There is a need to find methods to shorten the abortion process and to reduce the incidence of side effects. It has been shown that insertion of a laminaria tent 12 hours before sulprostone injection could decrease the induction-abortion interval significantly in termination of second trimester pregnancy.2 The insertion of a laminaria tent requires trained personnel and can
T
*Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Hong Kong and *Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong Name and address for correspondence: Dr. K.S. Wong, Department of Obstetrics and Gynaecology, Kwong Wah Hospital, Kowloon, Hong Kong Submitted for publication March 5, 1996 Revised April 22, 1996 Accepted for publication April 26, 1996
0 1996 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
cause discomfort to the patient. The use of the laminaria tents can cause potential complications such as intrauterine displacement and perforation of the cervix.3 Recently, mifepristone, a progesterone antagonist, has been shown to be effective in reducing the induction-abortion interval and number of gemeprost pessaries required to terminate second trimester pregnancy.4 Unfortunately, mifepristone is only available in four countries: France, China, United Kingdom and Sweden. Misoprostol is a prostaglandin El analogue. It has been used in treatment of peptide ulcers. It can be administered orally. Recently, Fletcher et a1.5 have shown that misoprostol was an effective cervical ripening agent in term pregnancy. Peyron et a1.6 showed that the combination of mifepristone and oral misoprostol was effective for termination of early pregnancy. It has also been shown that misoprostol is capable for dilating the cervix before vacuum aspiration.‘,’ Therefore, it is possible that misoprosto1 may also have cervical ripening effect in second trimester pregnancy. The aim of the present doubleblind placebo-controlled trial was to investigate whether misoprostol pre-treatment can improve the efficacy of intravaginal gemeprost pessary in termination of second trimester pregnancy.
Materials
and Methods
Healthy women aged 16 to 40 years requesting legal termination of pregnancy at the gestational age of 14 to 20 weeks were recruited in the trial. Women who were using prescription drugs regularly, women with an intrauterine contraceptive device in situ or multiple pregnancy and nursing mothers were excluded from the study. Women who fulfilled the criteria for the study 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 mulISSN OOIO-7824/96/$15.00 PII SOOIO-7824(96)00115-l
24
Contraception
Wang et al.
1996;54:23-25
tiple pregnancy. The randomization schedule and envelopes bearing the subject number and allocation of grouping were prepared as described by Meinert.’ The tablets (either misoprostol 400 pg or placebo, vitamin Bb), in a bottle bearing the subject number, were taken at 8 pm. After 12 hours, women were given 1 mg gemeprost vaginally every 3 hours until abortion, for a maximum of five doses in the first 24 hours. The side effects, temperature, blood pressure and uterine contractions were recorded. When the women aborted, the amount of blood loss was noted. The products of conception were examined and evacuation of the uterus was performed if they were found to be incomplete. If women failed to abort in the first 24 hours, a second course of gemeprost was given at the same dosage schedule. The induction-abortion interval is defined as the interval between the time of the administration of the first dose of gemeprost to the time when the fetus aborted. The induction-abortion intervals and total dosage of gemeprost used in the treatment and placebo groups were compared by the Mann-Whitney Utest. The incidence of side effects was compared by the chi-square and Fisher exact tests. The estimation of sample size was based on the following assumptions: (1) a type I error of 10% and type II error of 20% were acceptable because the trial was a preliminary trial; (2) the reduction of the induction-abortion interval had to be at least similar to that of the laminaria tent (i.e., reduction of more than 6 hours) before misoprostol is likely to be an acceptable alternative; (3) the median induction-abortion interval in the control group was about 16 hours in our previous experience. Using the formula and table of Meinert,’ the number of subjects is 31 in each group. Assuming that 10% of the data might be excluded, the total number of subjects for the study would be 70. This trial was approved by the Ethics Committee of the Faculty of Medicine, the University of Hong Kong.
Results Altogether, 70 women were recruited into the trial (35 in each group). The characteristics of the two groups of women are shown in Table 1; these parameters are comparable in the two groups. Fifteen women (42.8%) in the misoprostol group and 22 women (62.8 % ) in the placebo group were primigravidae, but the difference was not statistically significant (p > 0.05). There was no significant difference in the incidence of complaints of nausea, vomiting, dizziness, fatigue, breast tenderness or lower abdominal pain between the two groups during the interval between the administration of misoprostol or placebo and the administration of gemeprost (Table 2).
Table 1. Characteristics
of the patients in misoprostol groun (n = 351 and nlacebo ZZTOUD In = 35)
Age (year) Weight (Kg) Height (cm)
Gestational age (week) Results are shown nificant.
Misoprostol Group
Placebo Group
23.2 * 7.5 52.4 + 9.3 156.0 i 5.2 16.8 k 2.1
21.0 * 5.8 51.7 + 8.2 156.9 + 4.3 15.9 f 2.0
as mean * SD. The differences
are not statistxally
sig-
The number of episodes of vomiting, diarrhoea and the incidence of febrile reaction after administration of gemeprost was also similar in the two groups. The induction-abortion interval in the misoprostol group and the placebo group was not significantly different. The amounts of gemeprost and pethidine required was smaller in the misoprostol group, but the differences were not statistically significant (Table 3). The successful abortion rate (abortion within 24 hours of the first dose of gemeprost) and complete abortion rate were comparable in both groups (Table 3).
Discussion Termination of second trimester pregnancy is a painful and stressful procedure for the patient. There is a need to find a method that can reduce the inductionabortion interval. Mifepristone pre-treatment can significantly shorten the induction-abortion interval and decrease the number of gemeprost pessaries reis more quired. lo It has been shown that mifepristone effective than the laminaria tent in shortening the induction-abortion interval in termination of second trimester pregnancy using gemeprost. ‘i However, mifepristone is licensed in only four countries. Misoprostol, a synthetic 15deoxy- 16-hydroxy- 16-methyl analogue of naturally occurring prostaglandin El, is Table 2. Side effects after treatment: misoprostol group (n = 35) and placebo group (n = 35), before gemeprost administration
Side Effects
Nausea Vomiting Dizziness Fatigue Breast tenderness Abdominal pain Headache Diarrhoea Incidence is shown as number significant.
Misoprostol Group n (%)
Placebo Group n (%)
3 (8.6) 3 (8.6)
0 (0) 0 (0) 2 (5.9) 0 PI 0 (0) 5 (14.7) 1 (2.9) 0 (01
: I:.;1 1 (2:9) 12 (34.3) 0 (0) 3 (8.6) 1%). None of the differences
is statlstically
Contraception 1996;54:23-25
Termination
of Second
Table 3. Characteristics of the abortion process and outcome of abortion in misoprostol group (n = 35) and placebo group (n = 35)
Induction-abortion interval (hr) Amount of gemeprost required (mg) Amount of pethidine required (mg) Successful abortion* Complete abortion
Misoprostol Group
Placebo Group
27.3 zt34.4 (14.3) 4.9 + 3.1 (4) 45.0 f 52.1 (50.0)
28.2 _+28.9 (18.3) 5.7 rt 2.6 (51 54.3 + 52.7 (75.0) 24 (68.6) 24 (68.6)
E /kg
P 0.0863 0.0957 0.4229 0.7942 0.6145
*Abortion within 24 hours of the first dose of gemeprost. Results are shown as mean * SD and median in the bracket or as number [%). p-value calculated with Mann-Whitney U-test or chi-square test. The differences are not statistically significant.
taken orally for the prevention and treatment of gastroduodenal ulcers. El-Refaey et a1.i2 have shown that vaginal misoprostol (600 ug) is effective in cervical priming before surgical evacuation in first trimester termination of pregnancy. In 1993, Peyron6 reported that oral misoprostol was effective in first trimester termination of pregnancy. Women with pregnancy less than 50 days received oral 400 ug misoprosto148 hours after taking 600 mg mifepristone; the success rate was 96.9%. It has also been shown that 400 pg of oral misoprostol given 12 hours before suction evacuation is effective in dilating the cervix with only minimal side effects.‘js Despite the previous evidence that oral misoprostol can dilate the cervix during pregnancy,‘!’ our results showed that it was not effective in shortening the induction-abortion interval in second trimester termination of pregnancy. Thong and Baird13 had shown that although Dilapan could effectively dilate the cervix, it did not shorten the induction-abortion interval in termination of pregnancy in second trimester. All these data suggest that it takes more than cervical dilatation to facilitate termination of pregnancy with prostaglandin analogues. Misoprostol is more convenient than other prostaglandins because it is given orally and compliance is good. The drug is less expensive than gemeprost and it can be stored at room temperature. Chung et a1.14 showed that oral misoprostol 400 ug every 4 hours for a total of three doses was effective in the management of first trimester spontaneous abortion. Although the present trial did not show that the regimen of pre-treatment with oral misoprostol 400 pg 12 hours before gemeprost could shorten the induction-abortion interval or decrease the pessaries re-
Trimester
Pregnancy
with Gemeprost
and Misoprostol
25
quired, it does not mean this drug is not useful in this aspect. Misoprostol might be effective with alteration of routes of administration (e.g., vaginal route) or other dosage regimens. Further clinical trial on use of misoprostol for pre-treatment of second trimester abortion might prove its effectiveness.
References 1. Karim SMM. Termination of second trimester pregnancy with prostaglandins. In: Karim SMM, ed. Practical applications of prostaglandins and their synthesis inhibitors. Pennsylvania: MTP Press Limited, 1979: 375-409. 2. Karim SMM, Ratnam SS,Lein AL, Yeo KC, Choo HT. Termination of secondtrimester pregnancy with laminaria and intramuscular 16-phenoxy-w- 17,18,19,20tetranor PGE2 methyl sulphonylamide (sulprostone): a randomised study. Prostaglandin 1982;23:257-63. 3. Johnson N. Intracervical tents: usageand mode of action. Obstet Gynecol Surv 1989;44:410-20. 4. Thong KJ, Baird DT. Second trimester abortion with mifepristone and gemeprost. Br J Obstet Gynaecol 1993;100:758-61. 5. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641-4. 6. Peyron R, Aubeny E, Targosz V, et al. Early termination of pregnancy with mifepristone (RU 486) and the orally active prostaglandin misoprostol. N Engl J Med 1993; 328:1509-13. 7. Ngai SK,Au Yeung KC, Lao T, Ho PC. Oral misoprostol versus vaginal gemeprost for cervical dilatation prior to vacuum aspiration in women in the sixth to twelfth week of gestation. Contraception 1995;51:347-50. 8. Ngai SK, Tang 01, Lao T, Ho PC, Ma HK. Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy. Human Reproduction 1995;10:1220-2. 9. Meinert CL. Randomization and the mechanics of treatment masking. In: Meinert CL, et al., eds. Clinical Trials: Design, Conduct and Analysis. Oxford University Press:Oxford, 1986:90-l 12. 10. RodgerMW, Baird DT. Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41-5. 11. Ho PC, Tsang SSK, Ma HK. Reducing the induction to abortion interval in termination of second trimester pregnancies: a comparison of mifepristone and laminaria tent. Br J Obstet Gynaecol 1995;102:648-51. 12. El-Refaey H, Calder L, Wheatley DN, Templeton A. Cervical priming with prostaglandin El analogues,misoprostol and gemeprost. Lancet 1994;343:1207-9. 13. Thong KJ, Baird DT. A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of second trimester pregnancy. Contraception 1992;46:11-7. 14. Chung TKH, Cheung LP, Leung TY, Haines CJ, Chang AMZ. Misoprostol in the management of spontaneous abortion. Br J Obstet Gynaecol 1995;102:832-5.