British Journal of Obstetrics and Gynaecology December 1992, Vol. 99, pp. 1004-1007
FE RTILITY CO NTRO L
Induction of abortion with mifepristone and misoprostol in early pregnancy ABSTRACT
K. JOO T H O N G D A V I D T. B A I R D Department of Obstetrics and G ynaecology University of Edinburgh Centre for Reproductive Biology 37 Chalmers Street Edinburgh E H 3 9EW, U K
Objective To investigate the clinical efficacy of the combination of mifepristone and an orally active prostaglandin, misoprostol, for early medical termination. Design Women with amenorrhoea ~ 5 days 6 were given 200 mg mifepristone. 48 h later, 600 pg misoprostol was given orally. Setting Medical Termination Unit, Simpson Memorial Maternity Pavilion, Edinburgh. Subjects 100 women requesting medical termination of pregnancy. Interventions Evacuation of uterus for incomplete abortion or on-going pregnancies. Results O n e woman had an incomplete abortion prior to administration of misoprostol. 92 (93%) out of 99 women had complete abortion following administration of misoprostol. There were three on-going pregnancies (3.0%, 95% confidence limits (CL) 0.6-86) and four incomplete abortions with this regimen (4.0%, 95% C L 1.1-10.0). 24% women vomited and 7 % had diarrrhoea following administration of misoprostol. 62% did not require any analgesia. Conclusions The combination of misoprostol with mifepristone is inexpensive, simple, effective, noninvasive and an acceptable alternative to current regimens for medical termination.
Medical termination of pregnancy using a combination of mifepristone and prostaglandin is a safe, effective alternative to vacuum termination up to the first 9 weeks of pregnancy (Sylvestre et al. 1990; UK Multicentre Trial 1990). The two most widely used prostaglandins, gemeprost and sulprostone, are administered as a vaginal pessary or by intramuscular injection, respectively. In practice, both routes of administration of prostaglandin are not ideal. These prostaglandins are expensive, require refrigeration before use and cardiovascular complications including a maternal death from myocardial infarction after administration of sulprostone have been reported (Kalra et al. 1989; Anonymous 1991). A n oral prostaglandin that could be used in combination with mifepristone for early medical termination may be more acceptable to women undergoing the procedure. The results of oral PGE, in combination with mifepristone was disappointing (Swahn et al. 1989) but a 95% complete abortion rate was achieved following administration of 9-methylene PGE, (Swahn et al. 1990). However, the fact that the latter was administered in solution would limit its use in clinical practice. Misoprostol is a stable, orally active synthetic analogue of prostaglandin E , which is used for the prophylaxis and treatment of peptic ulcer. It is cheap, effective and associated with fewer gastrointestinal side effects (Herting & Nissen 1986). Misoprostol has a uterotonic effect and it is contraindicated Correspondence: Protessor David
1004
'r. Baird.
for women in early pregnancy. 800 pg misoprostol when administered to pregnant women between 9-12 weeks gestation within 12 h of vacuum aspiration resulted in 11% partial or complete abortion (Rabe et al. 1987). 400 pg misoprostol administered 4 hourly to 20 women in the second and third trimester induced expulsion of the fetus in all of these women (Neto et al. 1988). We previously demonstrated that the uterotonic effect of misoprostol was markedly enhanced in women who had been treated 24-48 h previously with 200 mg mifepristone (Norman et al. 1991). Preliminary reports suggest that misoprostol in combination with mifepristone at a dose of 200 mg (Norman et al. 1991) or 600 mg (Aubeny & Baulieu 1991) may be as effective as gemeprost or sulprostone for inducing early abortion but with fewer side effects. In this study we report our experience in the use of misoprostol in combination with mifepristone for induction of abortion in 100 women in early pregnancy.
Subjects and methods O n e hundred pregnant women (amenorrhoea s.56 days) who were referred to the Edinburgh Royal Infirmary requesting a medical termination were recruited for this study. Informed consent was obtained from all women whose age ranged from 1 7 4 1 years. The gestational age was assessed by the menstrual history, pelvic examination and by pelvic ultrasound. Approval for the study was granted by the
ABORTION WlTH MIFEPRISTONE AND MISOPROSTOL
Table 1. Characteristics of the women. Characteristics
Table 2. Analgesic requirements. Median
(range) ~
Age (yrs) Height (cm) Weight (kg) Gestation (days) Maximum diameter of sac (mm) Parous
1005
26 164 60 50 26 51
It
(%)
61 21 14 3
(62) (21) (14) (3)
~~~~
(1741) (148-178) (42-98) (36-56) (9-52) (51 %)
Local Ethical Subcommittee. All of these women had grounds for termination of pregnancy under the 1967 Abortion Act. Routine endocervical swabs for bacteriological culture, including chlamydia screening, were carried out. When a decision was made to terminate the pregnancy, arrangements were made for the women to come into hospital for the administration of mifepristone. On the first day of treatment (day l ) , blood was taken for estimation of haemoglobin concentration and blood group. A pelvic ultrasound scan was carried out. After receiving 200 mg mifepristone, the women returned home and were readmitted 48 h (day 3) later for the oral administration of 600 pg of misoprostol. On day 3, the symptom questionnaire was completed before administration of misoprostol, and 2 and 4 h later. Blood pressure, pulse and temperature were measured hourly. Women who required analgesia were given paracetamol (1 g), dihydrocodeine (30 mg) or diamorphine ( 5 mg). Four hours following the administration of misoprostol, a vaginal examination was carried out to exclude excessive bleeding and to confirm whether the fetus had been expelled. Anti-D was administered to rhesus negative women prior to discharge from hospital. A menstrual calendar was given to each of these women to record the number of days of bleeding and they were advised to use a barrier method of contraception until the next period. These women were followed up on day 8,15 and 43 after the administration of the misoprostol or until the next menstrual period. Statistical analyses were carried out using the test, Mann-Whitney U test and the paired t test. Values were expressed as median (range).
x2
Results Table 1 shows the characteristics of the women. An emergency curettage of the uterus was necessary on one woman admitted 48 h after administration of mifepristone because of heavy bleeding as a result of incomplete abortion. Of the remaining 99 women who were given misoprostol, 92 (93%) had complete abortion. There were three ongoing pregnancies which were terminated by vacuum aspiration. In addition, four women had incomplete abortions which required a curettage of the uterus. Within 4 h of administration of misoprostol, all women had vaginal bleeding and 79% patients passed the fetus and/or placental tissue. There was no apparent difference in clinical efficacy in relation to gestation. There was one ongoing pregnancy and two incomplete abortions in 49 women with ame-
None Paracetamol only Dihydrocodeine f paracetamol Diamorphine ? dihydrocodeine It paracetarnol
norrhoea of up to 49 days. The solitary woman with an ongoing pregnancy in this category was a 32 year old para 1+0 who was 38 days pregnant; vacuum aspiration was carried out 2 weeks later. In 50 women with pregnancies in the gestational age range of 50-56 days, there were two ongoing pregnancies and two incomplete abortions. With the exception of one woman, histological examination of the curettings confirmed residual trophoblastic material. In the whole group of 99 women the ongoing pregnancy rate was 3.0% (95% CL 0.6-8.6) and the incomplete abortion rate was 4.0% (95% CL 1.1-10). 62% of women did not require any analgesia and only 3% women required diamorphine (Table 2). There was a significant decrease in nausea and breast tenderness following administration of misoprostol (Table 3). Over a 4 h period, there was a significant increase in vomiting, abdominal pain, faintness and diarrhoea. No significant change was noted in women for dizziness and none of the women in this study had hypotension. Complete abortion occurred in all women (24%) who vomited in the 4 h following swallowing misoprostol. The median (range) body mass index of women who aborted successfully and women who did not were 21.8 (16.839.7) kg/m2 and 22.4 (17.9-31.2) kg/m2, respectively. The median (range) duration for bleeding was 14 (1-69) days. The mean interval from induction of abortion to menstruation was 37 (18-69) days. There was a small but significant fall in the concentration of haemoglobin between day 1 and day 8 (12.6k0.08 versus 11.9_+0.09g/dl; P
FE RTILITY CO NTRO L
Induction of abortion with mifepristone and misoprostol in early pregnancy ABSTRACT
K. JOO T H O N G D A V I D T. B A I R D Department of Obstetrics and G ynaecology University of Edinburgh Centre for Reproductive Biology 37 Chalmers Street Edinburgh E H 3 9EW, U K
Objective To investigate the clinical efficacy of the combination of mifepristone and an orally active prostaglandin, misoprostol, for early medical termination. Design Women with amenorrhoea ~ 5 days 6 were given 200 mg mifepristone. 48 h later, 600 pg misoprostol was given orally. Setting Medical Termination Unit, Simpson Memorial Maternity Pavilion, Edinburgh. Subjects 100 women requesting medical termination of pregnancy. Interventions Evacuation of uterus for incomplete abortion or on-going pregnancies. Results O n e woman had an incomplete abortion prior to administration of misoprostol. 92 (93%) out of 99 women had complete abortion following administration of misoprostol. There were three on-going pregnancies (3.0%, 95% confidence limits (CL) 0.6-86) and four incomplete abortions with this regimen (4.0%, 95% C L 1.1-10.0). 24% women vomited and 7 % had diarrrhoea following administration of misoprostol. 62% did not require any analgesia. Conclusions The combination of misoprostol with mifepristone is inexpensive, simple, effective, noninvasive and an acceptable alternative to current regimens for medical termination.
Medical termination of pregnancy using a combination of mifepristone and prostaglandin is a safe, effective alternative to vacuum termination up to the first 9 weeks of pregnancy (Sylvestre et al. 1990; UK Multicentre Trial 1990). The two most widely used prostaglandins, gemeprost and sulprostone, are administered as a vaginal pessary or by intramuscular injection, respectively. In practice, both routes of administration of prostaglandin are not ideal. These prostaglandins are expensive, require refrigeration before use and cardiovascular complications including a maternal death from myocardial infarction after administration of sulprostone have been reported (Kalra et al. 1989; Anonymous 1991). A n oral prostaglandin that could be used in combination with mifepristone for early medical termination may be more acceptable to women undergoing the procedure. The results of oral PGE, in combination with mifepristone was disappointing (Swahn et al. 1989) but a 95% complete abortion rate was achieved following administration of 9-methylene PGE, (Swahn et al. 1990). However, the fact that the latter was administered in solution would limit its use in clinical practice. Misoprostol is a stable, orally active synthetic analogue of prostaglandin E , which is used for the prophylaxis and treatment of peptic ulcer. It is cheap, effective and associated with fewer gastrointestinal side effects (Herting & Nissen 1986). Misoprostol has a uterotonic effect and it is contraindicated Correspondence: Protessor David
1004
'r. Baird.
for women in early pregnancy. 800 pg misoprostol when administered to pregnant women between 9-12 weeks gestation within 12 h of vacuum aspiration resulted in 11% partial or complete abortion (Rabe et al. 1987). 400 pg misoprostol administered 4 hourly to 20 women in the second and third trimester induced expulsion of the fetus in all of these women (Neto et al. 1988). We previously demonstrated that the uterotonic effect of misoprostol was markedly enhanced in women who had been treated 24-48 h previously with 200 mg mifepristone (Norman et al. 1991). Preliminary reports suggest that misoprostol in combination with mifepristone at a dose of 200 mg (Norman et al. 1991) or 600 mg (Aubeny & Baulieu 1991) may be as effective as gemeprost or sulprostone for inducing early abortion but with fewer side effects. In this study we report our experience in the use of misoprostol in combination with mifepristone for induction of abortion in 100 women in early pregnancy.
Subjects and methods O n e hundred pregnant women (amenorrhoea s.56 days) who were referred to the Edinburgh Royal Infirmary requesting a medical termination were recruited for this study. Informed consent was obtained from all women whose age ranged from 1 7 4 1 years. The gestational age was assessed by the menstrual history, pelvic examination and by pelvic ultrasound. Approval for the study was granted by the
ABORTION WlTH MIFEPRISTONE AND MISOPROSTOL
Table 1. Characteristics of the women. Characteristics
Table 2. Analgesic requirements. Median
(range) ~
Age (yrs) Height (cm) Weight (kg) Gestation (days) Maximum diameter of sac (mm) Parous
1005
26 164 60 50 26 51
It
(%)
61 21 14 3
(62) (21) (14) (3)
~~~~
(1741) (148-178) (42-98) (36-56) (9-52) (51 %)
Local Ethical Subcommittee. All of these women had grounds for termination of pregnancy under the 1967 Abortion Act. Routine endocervical swabs for bacteriological culture, including chlamydia screening, were carried out. When a decision was made to terminate the pregnancy, arrangements were made for the women to come into hospital for the administration of mifepristone. On the first day of treatment (day l ) , blood was taken for estimation of haemoglobin concentration and blood group. A pelvic ultrasound scan was carried out. After receiving 200 mg mifepristone, the women returned home and were readmitted 48 h (day 3) later for the oral administration of 600 pg of misoprostol. On day 3, the symptom questionnaire was completed before administration of misoprostol, and 2 and 4 h later. Blood pressure, pulse and temperature were measured hourly. Women who required analgesia were given paracetamol (1 g), dihydrocodeine (30 mg) or diamorphine ( 5 mg). Four hours following the administration of misoprostol, a vaginal examination was carried out to exclude excessive bleeding and to confirm whether the fetus had been expelled. Anti-D was administered to rhesus negative women prior to discharge from hospital. A menstrual calendar was given to each of these women to record the number of days of bleeding and they were advised to use a barrier method of contraception until the next period. These women were followed up on day 8,15 and 43 after the administration of the misoprostol or until the next menstrual period. Statistical analyses were carried out using the test, Mann-Whitney U test and the paired t test. Values were expressed as median (range).
x2
Results Table 1 shows the characteristics of the women. An emergency curettage of the uterus was necessary on one woman admitted 48 h after administration of mifepristone because of heavy bleeding as a result of incomplete abortion. Of the remaining 99 women who were given misoprostol, 92 (93%) had complete abortion. There were three ongoing pregnancies which were terminated by vacuum aspiration. In addition, four women had incomplete abortions which required a curettage of the uterus. Within 4 h of administration of misoprostol, all women had vaginal bleeding and 79% patients passed the fetus and/or placental tissue. There was no apparent difference in clinical efficacy in relation to gestation. There was one ongoing pregnancy and two incomplete abortions in 49 women with ame-
None Paracetamol only Dihydrocodeine f paracetamol Diamorphine ? dihydrocodeine It paracetarnol
norrhoea of up to 49 days. The solitary woman with an ongoing pregnancy in this category was a 32 year old para 1+0 who was 38 days pregnant; vacuum aspiration was carried out 2 weeks later. In 50 women with pregnancies in the gestational age range of 50-56 days, there were two ongoing pregnancies and two incomplete abortions. With the exception of one woman, histological examination of the curettings confirmed residual trophoblastic material. In the whole group of 99 women the ongoing pregnancy rate was 3.0% (95% CL 0.6-8.6) and the incomplete abortion rate was 4.0% (95% CL 1.1-10). 62% of women did not require any analgesia and only 3% women required diamorphine (Table 2). There was a significant decrease in nausea and breast tenderness following administration of misoprostol (Table 3). Over a 4 h period, there was a significant increase in vomiting, abdominal pain, faintness and diarrhoea. No significant change was noted in women for dizziness and none of the women in this study had hypotension. Complete abortion occurred in all women (24%) who vomited in the 4 h following swallowing misoprostol. The median (range) body mass index of women who aborted successfully and women who did not were 21.8 (16.839.7) kg/m2 and 22.4 (17.9-31.2) kg/m2, respectively. The median (range) duration for bleeding was 14 (1-69) days. The mean interval from induction of abortion to menstruation was 37 (18-69) days. There was a small but significant fall in the concentration of haemoglobin between day 1 and day 8 (12.6k0.08 versus 11.9_+0.09g/dl; P
