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Termination of second trimester pregnancy with sulprostone and mifepristone: A randomized double-blind placebo-controlled trial
Contraception
1993
47~123-129,
TERMINATION
OF
SECOND
WITH EULPROBTONE A RANDONIEED
DOUBLE-BLIND
TRINESTER
PREGNANCY
AND NIFEPRIBTONE: PLACEBO-CONTROLLED
TRIAL
P.C. Ho and H. K. Ma Department of Obstetrics and Gynaecology, University of Hong Kong, Pokfulam Road, Hong Kong
Abstract A prospective randomized double-blind placebocontrolled trial was conducted in 13 subjects to find out whether mifepristone treatment could facilitate termination of second trimester pregnancy by sulprostone. The women received either 600 mg oral mifepristone or placebo tablets 36 hours before the administration of intramuscular sulprostone 0.5 mg every 6 hours. The median interval between the administration of sulprostone and abortion in the mifepristone group (4.6 hours) was significantly shorter than that in the placebo group (20 hours). The amount of sulprostone required was also significantly less in the mifepristone group. There was no significant difference in the incidence of side effects or analgesic requirement between the two groups. We conclude that oral mifepristone is useful in facilitating termination of second trimester pregnancies by sulprostone.
Submitted for publication August 5, 1992 Accepted for publication November 20, 1992
CopyrightO1993Butterworth-Heinemann
124
Contraception
Introduction Termination of second trimester pregnancy is frequently performed by administration of prostaglandins by various routes with a significant degree of However, it is associated (1) Serious side effects such as vomiting, diarrhoea and fever. There complications such as cervical laceration may also occur. is a need to look for methods to improve the efficacy of the This may prostaglandins so that a lower dosage may be used. reduce the incidence of side effects or serious complications. Shortening of induction-abortion interval will also make the process less distressful for the patients. The insertion of a laminaria tent 8 hours before sulprostone injection has been shown to reduce the inductionabortion interval from 16.7 hours to 10.4 hours in termination of The insertion of a laminaria second trimester pregnancy (2). tent requires a trained personnel. It also carries the theoretical risk of introducing infection. Therefore, it is necessary to continue the search for other methods to improve the efficacy of prostaglandins in termination of second trimester pregnancy. Mifepristone(RU486) is an antagonist to progesterone and glucocorticoids at the receptor level (3). Repeated administration of 25 mg of mifepristone twice daily induces uterine contractions and sensitizes the uterus to the stimulatory action of the prostaglandin E analogue, sulprostone (4). Combination of prostaglandins and mifepristone is effective in termination of pregnancies less than 49 days(4). Results of recent studies suggested that mifepristone might also be useful in termination of second trimester pregnancies. Urquhart and Templeton (5) reported that the administration of 200 mg of mifepristone 24 hours before extra-amniotic infusion of prostaglandin E2 reduced the induction-abortion interval and the total dose of prostaglandin required. Rodger and Baird (6) also found that the use of mifepristone would reduce the inductionabortion interval in second trimester pregnancy using vaginal gemeprost. Sulprostone has also been used to terminate second There is the advantage that the trimester pregnancy (2). adjustment of dosage is easier than gemeprost. Combination of mifepristone and sulprostone in the second trimester has not so far been evaluated. Therefore, we have conducted a double-blind placebo-controlled trial to investigate whether mifepristone pre-treatment can also improve the efficacy of intramuscular sulprostone in termination of second trimester pregnancy.
Contraception
125
Patients and methods Subjects for this study were recruited from women 18 to 35 years old requesting legal termination of pregnancy at the gestational age of 14 to 20 weeks. They were interviewed and examined. They were excluded if they had any significant past or present medical disorder or if they were using prescription drugs regularly. Nursing mothers or women who had used hormonal contraception during the conception cycle or the cycle just before conception or women with intrauterine contraceptive device in situ were also excluded. An ultrasound examination was performed and the patients were recruited only if there was a singleton pregnancy with fetal parameters corresponding to the gestational age and there was no gross fetal abnormality. The protocol was explained to the patient and written consent was obtained. The mifepristone and placebo tablets were obtained through the World Health Organization. The randomization schedule was produced by the World Health Organization. The subject was given a subject number on admission into the study. The tablets (either mifepristone or placebo) in the bottle bearing the subject number were taken at 8 pm. Sulprostone 0.5 mg was given intramuscularly every 6 hours starting at 36 hours after ingestion of the tablets. Subsequent doses would be withheld if the patient had strong uterine contractions. The side effects, uterine contractions, blood pressure and pulse were recorded every 2 hours. If the patient did not abort after 24 hours, the patient was reassessed and a decision made as to whether sulprostone should be continued with or without oxytocin infusion. After abortion, the products of gestation were examined to see whether the abortion was complete. If necessary, exploration and evacuation of the uterus were performed under general anaesthesia. This study was approved by the Ethics Committee of the Faculty of Medicine, University of Hong Kong.
Contraception
126 Results
Altogether 13 subjects were recruited into the study, 6 in the placebo group and 7 in the mifepristone group. There was no significant difference in the mean age of the patients, the gestational age on the day of admission to study, the weight and All the patients were height of the patients (Table I). subjects However, despite the small number of nulliparous. the induction-abortion interval (i.e. the interval studied, between the first injection of sulprostone and the abortion) in the mifepristone group was significantly shorter than the placebo group. The total amount of sulprostone used was also lower in the All the patients in the mifepristone group (Table II). mifepristone group aborted within 10 hours of the first injection Three patients in the placebo group did not of sulprostone. abort at 24 hours after the first injection of sulprostone. Of these three patients, one aborted at 27 hours after an additional injection of sulprostone while the other two patients required oxytocin infusion in addition to further injections of The abortion was incomplete and required evacuation sulprostone. of uterus under general anaesthesia in 2 patients (28.6%) in the mifepristone group and 4 patients (66.7%) in the placebo group. The difference was not statistically significant.
Table I
Chuacteristios
of PAthAtS
Placebo aroun n=6 Age (years) Gestational (days)
Age
Mifenristone n=7
21.0 * 4.4 (20.5)
19.5 + 3.9 (18)
109.7 -+ 10.0 (107)
115.3 -+ 10.1 (120)
Weight
(Kg)
51.2 + 5.1 (52.0)
50.8 + 5.8 (50.1)
Height
(Cm)
156.3 + 4.9 (154)
157.1 + 5.4 (158)
Results are expressed as means + standards deviations. The figures in brackets represent the medians.
aroun
127
Contraception Table II
Remits
of termin8tion
with
proataglandin
Placebo urouo n=6
Mifepristone arouo n=7
Induction-abortion Interval (hrs)
33.8 + 31.0 (20.0)
5.9 + 2.3 (4.6)
0.018
Total amount of sulpro8tone(pg) required
2333.3 + 1966.4 (2000)
585.7 + 318.5 (500)
0.007
Results are expressed as means + standard deviation. in brackets represent the medians. P value calculated with Mann-Whitney U test.
E
The figures
The highest temperature during treatment was similar in both groups of patients. The number of episodes of vomiting and diraahoea and the analgesic requirement were higher in the placebo group (Table III) but the difference was not statistically significant by the Mann Whitney U test, probably because of the in each group. small number of patients both groups of No serious complication was encountered in patients and none of the patients required blood transfusion. Table III
Incidence of side effects and analgesic Placebo urouo
Higheat temperature during treatment
(Oc)
requirement
Mifewristone
urouw
37.2 + 0.3 (37.1)
37.2 -+ 0.2 (37.1)
No. of episodes of vomiting
0.7 * 1.0 (0.0)
0.3 * 0.5 (0.0)
No. of episodes
2.5 + 3.4 (1.5)
0.7 -+ 1.3 (0.0)
of diarrhoea Dosage of Pethidine given (mg)
67.9
?r 67.3 (75)
25 + 38.7 (0)
Results are expressed as means t standard deviations. The figures in brackets represent the medians.
128
Contraception
Discussion Our results show that mifepristone pre-treatment would shorten significantly the induction-abortion interval and reduce Although the number of the amount of sulprostone required. subjects in this study is small, the difference is quite big and already statistically significant. This agrees with the results of studies using other types of prostaqlandins to terminate second trimester pregnancy (5,6). Mifepristone has been shown to sensitize the uterus to the action of prostaglandins by releasing the endogenous prostaglandins from the decidua. This could explain the results of this study. The number of subjects in this study was small because the study was terminated early on receipt of the news from France that a woman had died from cardiovascular shock after termination of pregnancy by sulprostone and mifepristone (7). It is possible that the sudden increase in the serum level of sulprostone after an intramuscular injection may be responsible for the complications. Subsequently, Schering, the cardiovascular company producing sulprostone, advised against the administration of sulprostone by intramuscular route or by an intravenous bolus injection. An intravenous infusion should be used instead. Termination of second trimester pregnancies is a painful and stressful event for the patient. There is a need to find a method which can shorten the process. Although laminaria tent can shorten the induction-abortion interval to about IO hours, there are certain disadvantages associated with the use of laminaria tent. First of all, it requires a trained personnel to insert the laminaria tent. Secondly, there is the potential risk of introducing infection. Thirdly, the laminaria tent may be displaced and become embedded in the myometrium leading to difficulty in removing the tent (8). In contrast, the use of mifepristone involves only the use of oral tablets and no special skill is required. It also avoids the potential complications of laminaria tent. Although cardiovascular complications may occur with the combination of sulprostone and mifepristone, similar complications have not been reported with the combination of vaginal prostaglandin and mifepristone. Our study shows that mifepristone is effective in shortening the induction-abortion interval in termination of second trimester pregnancies by prostaglandins. In view of the potential advantages of mifepristone over laminaria tent, further studies should be conducted to compare the efficacy of these two methods in facilitating termination of second trimester pregnancies.
Acknowledaement This study was supported by the Task Force on Post-ovulatory Methods for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organization.
Contraception
129
References 1.
Karim SMM.Termination of second trimester pregnancy with prostaglandins. In : Karim SMM, eds Practical applications of prostaglandins and their synthesis inhibitors. 1979:375-409. Pensylvania, USA : MTP Press Limited,
2.
Karim SWM, Ratnam SS, Lein AL, Ye0 KC, Choo HT. Termination of second trimester pregnancy with laminaria and intramuscular 16-phenoxy-w-17,18,19, 20-tetranor-PGE2 methylsulfonylamide (sulprostone) A randomised study. Prostaglandins 1982;23:257-63.
3.
Baulieu EE. An antiprogestin steroid with RU486 : contragestive In: SJ Segal, Baulieu EE, activity in women. eds. The antiprogestin steroid : RU 486 and human fertility control Paris: Plenum Press, 1984: 1-25.
4.
Bydeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception 1985: 32;45-51.
5.
Urguhart DR, Templeton AA. The use of mifepristone prior to prostaglnadin-induced mid-trimester abortion. Human Reproduction 1990;5:883-86.
6.
Rodger WW, Baird DT. Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41-45.
7.
Anonymous. A death associated Lancet 337:969-70.
8.
Liang ST, Woo JSK, Tang GWK. displaced laminaria tent. 146:988-89.
with mifepristone/sulprostone. Ultrasonic localization of a Am J Obstet Gynecol 1983,
1993
47~123-129,
TERMINATION
OF
SECOND
WITH EULPROBTONE A RANDONIEED
DOUBLE-BLIND
TRINESTER
PREGNANCY
AND NIFEPRIBTONE: PLACEBO-CONTROLLED
TRIAL
P.C. Ho and H. K. Ma Department of Obstetrics and Gynaecology, University of Hong Kong, Pokfulam Road, Hong Kong
Abstract A prospective randomized double-blind placebocontrolled trial was conducted in 13 subjects to find out whether mifepristone treatment could facilitate termination of second trimester pregnancy by sulprostone. The women received either 600 mg oral mifepristone or placebo tablets 36 hours before the administration of intramuscular sulprostone 0.5 mg every 6 hours. The median interval between the administration of sulprostone and abortion in the mifepristone group (4.6 hours) was significantly shorter than that in the placebo group (20 hours). The amount of sulprostone required was also significantly less in the mifepristone group. There was no significant difference in the incidence of side effects or analgesic requirement between the two groups. We conclude that oral mifepristone is useful in facilitating termination of second trimester pregnancies by sulprostone.
Submitted for publication August 5, 1992 Accepted for publication November 20, 1992
CopyrightO1993Butterworth-Heinemann
124
Contraception
Introduction Termination of second trimester pregnancy is frequently performed by administration of prostaglandins by various routes with a significant degree of However, it is associated (1) Serious side effects such as vomiting, diarrhoea and fever. There complications such as cervical laceration may also occur. is a need to look for methods to improve the efficacy of the This may prostaglandins so that a lower dosage may be used. reduce the incidence of side effects or serious complications. Shortening of induction-abortion interval will also make the process less distressful for the patients. The insertion of a laminaria tent 8 hours before sulprostone injection has been shown to reduce the inductionabortion interval from 16.7 hours to 10.4 hours in termination of The insertion of a laminaria second trimester pregnancy (2). tent requires a trained personnel. It also carries the theoretical risk of introducing infection. Therefore, it is necessary to continue the search for other methods to improve the efficacy of prostaglandins in termination of second trimester pregnancy. Mifepristone(RU486) is an antagonist to progesterone and glucocorticoids at the receptor level (3). Repeated administration of 25 mg of mifepristone twice daily induces uterine contractions and sensitizes the uterus to the stimulatory action of the prostaglandin E analogue, sulprostone (4). Combination of prostaglandins and mifepristone is effective in termination of pregnancies less than 49 days(4). Results of recent studies suggested that mifepristone might also be useful in termination of second trimester pregnancies. Urquhart and Templeton (5) reported that the administration of 200 mg of mifepristone 24 hours before extra-amniotic infusion of prostaglandin E2 reduced the induction-abortion interval and the total dose of prostaglandin required. Rodger and Baird (6) also found that the use of mifepristone would reduce the inductionabortion interval in second trimester pregnancy using vaginal gemeprost. Sulprostone has also been used to terminate second There is the advantage that the trimester pregnancy (2). adjustment of dosage is easier than gemeprost. Combination of mifepristone and sulprostone in the second trimester has not so far been evaluated. Therefore, we have conducted a double-blind placebo-controlled trial to investigate whether mifepristone pre-treatment can also improve the efficacy of intramuscular sulprostone in termination of second trimester pregnancy.
Contraception
125
Patients and methods Subjects for this study were recruited from women 18 to 35 years old requesting legal termination of pregnancy at the gestational age of 14 to 20 weeks. They were interviewed and examined. They were excluded if they had any significant past or present medical disorder or if they were using prescription drugs regularly. Nursing mothers or women who had used hormonal contraception during the conception cycle or the cycle just before conception or women with intrauterine contraceptive device in situ were also excluded. An ultrasound examination was performed and the patients were recruited only if there was a singleton pregnancy with fetal parameters corresponding to the gestational age and there was no gross fetal abnormality. The protocol was explained to the patient and written consent was obtained. The mifepristone and placebo tablets were obtained through the World Health Organization. The randomization schedule was produced by the World Health Organization. The subject was given a subject number on admission into the study. The tablets (either mifepristone or placebo) in the bottle bearing the subject number were taken at 8 pm. Sulprostone 0.5 mg was given intramuscularly every 6 hours starting at 36 hours after ingestion of the tablets. Subsequent doses would be withheld if the patient had strong uterine contractions. The side effects, uterine contractions, blood pressure and pulse were recorded every 2 hours. If the patient did not abort after 24 hours, the patient was reassessed and a decision made as to whether sulprostone should be continued with or without oxytocin infusion. After abortion, the products of gestation were examined to see whether the abortion was complete. If necessary, exploration and evacuation of the uterus were performed under general anaesthesia. This study was approved by the Ethics Committee of the Faculty of Medicine, University of Hong Kong.
Contraception
126 Results
Altogether 13 subjects were recruited into the study, 6 in the placebo group and 7 in the mifepristone group. There was no significant difference in the mean age of the patients, the gestational age on the day of admission to study, the weight and All the patients were height of the patients (Table I). subjects However, despite the small number of nulliparous. the induction-abortion interval (i.e. the interval studied, between the first injection of sulprostone and the abortion) in the mifepristone group was significantly shorter than the placebo group. The total amount of sulprostone used was also lower in the All the patients in the mifepristone group (Table II). mifepristone group aborted within 10 hours of the first injection Three patients in the placebo group did not of sulprostone. abort at 24 hours after the first injection of sulprostone. Of these three patients, one aborted at 27 hours after an additional injection of sulprostone while the other two patients required oxytocin infusion in addition to further injections of The abortion was incomplete and required evacuation sulprostone. of uterus under general anaesthesia in 2 patients (28.6%) in the mifepristone group and 4 patients (66.7%) in the placebo group. The difference was not statistically significant.
Table I
Chuacteristios
of PAthAtS
Placebo aroun n=6 Age (years) Gestational (days)
Age
Mifenristone n=7
21.0 * 4.4 (20.5)
19.5 + 3.9 (18)
109.7 -+ 10.0 (107)
115.3 -+ 10.1 (120)
Weight
(Kg)
51.2 + 5.1 (52.0)
50.8 + 5.8 (50.1)
Height
(Cm)
156.3 + 4.9 (154)
157.1 + 5.4 (158)
Results are expressed as means + standards deviations. The figures in brackets represent the medians.
aroun
127
Contraception Table II
Remits
of termin8tion
with
proataglandin
Placebo urouo n=6
Mifepristone arouo n=7
Induction-abortion Interval (hrs)
33.8 + 31.0 (20.0)
5.9 + 2.3 (4.6)
0.018
Total amount of sulpro8tone(pg) required
2333.3 + 1966.4 (2000)
585.7 + 318.5 (500)
0.007
Results are expressed as means + standard deviation. in brackets represent the medians. P value calculated with Mann-Whitney U test.
E
The figures
The highest temperature during treatment was similar in both groups of patients. The number of episodes of vomiting and diraahoea and the analgesic requirement were higher in the placebo group (Table III) but the difference was not statistically significant by the Mann Whitney U test, probably because of the in each group. small number of patients both groups of No serious complication was encountered in patients and none of the patients required blood transfusion. Table III
Incidence of side effects and analgesic Placebo urouo
Higheat temperature during treatment
(Oc)
requirement
Mifewristone
urouw
37.2 + 0.3 (37.1)
37.2 -+ 0.2 (37.1)
No. of episodes of vomiting
0.7 * 1.0 (0.0)
0.3 * 0.5 (0.0)
No. of episodes
2.5 + 3.4 (1.5)
0.7 -+ 1.3 (0.0)
of diarrhoea Dosage of Pethidine given (mg)
67.9
?r 67.3 (75)
25 + 38.7 (0)
Results are expressed as means t standard deviations. The figures in brackets represent the medians.
128
Contraception
Discussion Our results show that mifepristone pre-treatment would shorten significantly the induction-abortion interval and reduce Although the number of the amount of sulprostone required. subjects in this study is small, the difference is quite big and already statistically significant. This agrees with the results of studies using other types of prostaqlandins to terminate second trimester pregnancy (5,6). Mifepristone has been shown to sensitize the uterus to the action of prostaglandins by releasing the endogenous prostaglandins from the decidua. This could explain the results of this study. The number of subjects in this study was small because the study was terminated early on receipt of the news from France that a woman had died from cardiovascular shock after termination of pregnancy by sulprostone and mifepristone (7). It is possible that the sudden increase in the serum level of sulprostone after an intramuscular injection may be responsible for the complications. Subsequently, Schering, the cardiovascular company producing sulprostone, advised against the administration of sulprostone by intramuscular route or by an intravenous bolus injection. An intravenous infusion should be used instead. Termination of second trimester pregnancies is a painful and stressful event for the patient. There is a need to find a method which can shorten the process. Although laminaria tent can shorten the induction-abortion interval to about IO hours, there are certain disadvantages associated with the use of laminaria tent. First of all, it requires a trained personnel to insert the laminaria tent. Secondly, there is the potential risk of introducing infection. Thirdly, the laminaria tent may be displaced and become embedded in the myometrium leading to difficulty in removing the tent (8). In contrast, the use of mifepristone involves only the use of oral tablets and no special skill is required. It also avoids the potential complications of laminaria tent. Although cardiovascular complications may occur with the combination of sulprostone and mifepristone, similar complications have not been reported with the combination of vaginal prostaglandin and mifepristone. Our study shows that mifepristone is effective in shortening the induction-abortion interval in termination of second trimester pregnancies by prostaglandins. In view of the potential advantages of mifepristone over laminaria tent, further studies should be conducted to compare the efficacy of these two methods in facilitating termination of second trimester pregnancies.
Acknowledaement This study was supported by the Task Force on Post-ovulatory Methods for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction of the World Health Organization.
Contraception
129
References 1.
Karim SMM.Termination of second trimester pregnancy with prostaglandins. In : Karim SMM, eds Practical applications of prostaglandins and their synthesis inhibitors. 1979:375-409. Pensylvania, USA : MTP Press Limited,
2.
Karim SWM, Ratnam SS, Lein AL, Ye0 KC, Choo HT. Termination of second trimester pregnancy with laminaria and intramuscular 16-phenoxy-w-17,18,19, 20-tetranor-PGE2 methylsulfonylamide (sulprostone) A randomised study. Prostaglandins 1982;23:257-63.
3.
Baulieu EE. An antiprogestin steroid with RU486 : contragestive In: SJ Segal, Baulieu EE, activity in women. eds. The antiprogestin steroid : RU 486 and human fertility control Paris: Plenum Press, 1984: 1-25.
4.
Bydeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception 1985: 32;45-51.
5.
Urguhart DR, Templeton AA. The use of mifepristone prior to prostaglnadin-induced mid-trimester abortion. Human Reproduction 1990;5:883-86.
6.
Rodger WW, Baird DT. Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41-45.
7.
Anonymous. A death associated Lancet 337:969-70.
8.
Liang ST, Woo JSK, Tang GWK. displaced laminaria tent. 146:988-89.
with mifepristone/sulprostone. Ultrasonic localization of a Am J Obstet Gynecol 1983,