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Termination of early pregnancy through a combination of the antiprogestin and prostaglandin analogue
European Journal of Obstetrics & Gynecology and Reproductive Elsevier
35
Biology, 31 (1990) 35-40
EUROBS 00977
Termination of early pregnancy through a combination of the antiprogestin and prostaglandin analogue * Bernard
Maria
‘, Franqoise Stampf ‘, Anne Goepp and Catherine Dubois 3
2
’ Service de GynPcologie-ObstPtrique,
2 Laboratoire de Biochimie, Centre Hospitalier Intercommunal, Viileneuve Saint Georges, and 3 Laboratoire Roussel-Uclaf, Romainville, France Accepted for publication 8 November 1989
Termination of early pregnancy (less than 49 days of amenorrhea) was induced in 75 patients with the combination of the antigestagen mifepristone and a prostaglandin analogue, meteneprost. After 48 h a single oral dose of 600 mg of mifepristone was followed by a 10 mg meteneprost vaginal pessary. Pregnancy was confirmed by clinical and ultrasound examinations and plasma HCG assessment. Complete abortion occurred in 72 patients (96%) and the three others required a surgical uterine aspiration. Bleeding continued for 4 to 12 days (mean = 8). Uterine pain and side effects occurred during the 3 h following the use of prostaglandin. Only minor analgesic were required in 30 patients. The combination of mifepristone and meteneprost is a safe and effective method to terminate an early pregnancy. Termination of early pregnancy; Abortion; Antiprogesterone;
Mifepristone; Prostaglandin analogue
Introduction Abortion is still the most frequently used method of fertility regulation. Uterine vacuum aspiration is performed widely to induce legal abortion. It is a safe surgical procedure; however, failures and complications can occur. If an effective abortion
* This study was presented at the First European Congress on Prostaglandins in reproduction, Vienna, Austria, 6-9 July 1988. Correspondence: Dr. B. Maria, Service de Gynkologie-Obstttrique, Centre Hospitalier Intercommunal, 94190 Villeneuve Saint Georges, France. 0028-2243/90/.$03.50
8 1990 Elsevier Science Publishers B.V. (Biomedical Division)
36
medical method were available, the operative complications would be reduced and an ambulatory induced abortion would become possible. Prostaglandins have been investigated for the termination of early pregnancy [l]. Several studies have shown that administration of prostaglandin E, (PGE,) analogues may be as effective as vacuum aspiration, however, they have gastro-intestinal side effects, pelvic pains and prolonged bleeding [2-41. An antiprogestin would be of interest, since progesterone is indispensable to maintain early pregnancy [5]. Mifepristone is a synthetic 19-nor-steroid with antiprogesterone activity. When used in early pregnancy, it acts as an abortifacient. Mifepristone induces decidual necrosis without any alteration of trophoblast and endometrial prostaglandin synthesis [6,7]. Previous studies have been reported using Mifepristone alone in very early pregnancy with a 80% rate of complete abortion [8,9]. Recently, it has been reported that the combination of mifepristone and a low dose of prostaglandin increases the efficacy of the procedure [lo-121. The purpose of our study was to evaluate the effect of a single dose of 600 mg of mifepristone in combination with a PGE, analogue, meteneprost (9-deoxo-16,16-dimethyl-9-methylene, PGE,), on early pregnancy. Methods
Subjects The study included 75 healthy women applying for a legal abortion according to the French Regulation. Women with any signs of abnormal pregnancy, pelvic inflammatory disease, use of glucocorticoids in the previous 3 months, a history of liver, gastrointestinal or renal disease or prostaglandin contra-indications (asthma) were excluded from the study. The procedure was limited to pregnancies of less than 7 weeks from the last menstrual period, i.e., 49 days of amenorhea. Pregnancy was confirmed by pelvic ultrasound examination and plasma HCG assessment. The study was approved by the Ethical Committee of Institut Roussel-Uclaf (Paris). The nature of the study was explained to each subject in detail and a written consent was obtained. Each patient had to agree to abortion by aspiration if the procedure failed. Protocol On day 1, each patient underwent a careful clinical pelvic and ultrasound examination. Blood samples were drawn to measure plasma HCG, complete blood count, creatinine, glycemia, bilirubine, cholesterol, triglycerides and liver enzymes. Mifepristone was delivered as 200 mg tablets. Each patient swallowed three tablets (600 mg) under supervision. The clinical events that should occur were carefully explained to each woman and a permanent telephone number was available for emergencies. On day 3, the patients had to come back. First the same blood sampling, except HCG assay, were performed again. If there was no evidence of ovular expulsion, the prostaglandin (Meteneprost 10 mg vaginal pessary) was used. Then, the patients were observed over the next three hours to note whether bleeding or any side effects occurred. After that time they went back home.
37
On day 10, a follow-up visit was scheduled. Clinical and ultrasound examinations and same blood sampling were performed. Success was assumed if vaginal bleeding occurred, ultrasonic examination confirmed uterine vacuity and a decrease in plasma HCG level, under the initial value, was observed. On the other hand on-going pregnancies and missed abortions were failures, as well as the patients who needed a blood transfusion or a curettage for heavy bleeding. In case of failure, a uterine vacuum aspiration was performed. After that check, a contraceptive method was proposed. Technical points Ultrasound examinations were all carried out with a Hitachi-Diasonics DRF 100 apparatus with a 3.5 MHz probe. Plasma HCG level were determined by immunoenzymoassay (B HCG EIA Roche Diagnostica). The results are expressed as means k SE.
Study group The 75 women present the following characteristics: mean age: 28.44 + 5.93 years (from 18 to 42 years); mean weight: 58.51 + 10.41 kg (from 40 to 110 kg); mean height: 163.9 f 5.9 cm (from 150 to 180 cm); 32 patients (43%) were nulliparous; mean amenorrhea: 43.56 f 3.74 days (from 33 to 49 days); mean diameter of intrauterine sac: 15.81 f 8.33 mm (from 0 to 43 mm); and mean crown-rump length of embryo: 3.18 + 3.80 (from 0 to 12 mm); only 36 embryos (48%) were clearly measurable. - mean HCG level on day 1: 42.615 f 28.244 IU/l and mean level of haemoglobin: 12.89 f 0.85 g/dl. Efficacy 72 patients out of the 75 were considered to have a complete abortion, that is an abortion rate of 96%. The three failures included one developing pregnancy and two missed abortions. In the success group, the mean HCG level on day 10 was 1.455 f 2.881 IU/l. The difference with the level of day one is significant (p < 0.01) (Table 1).
TABLE I HCG and haemoglobin concentrations before (day 1) and after treatment (day 10)
HCG (IU/l) HB (g/d0
Day 1
Day 10
r-test
42,615 f 28,244 12.89k0.85
1,485 f 2,281 12.38 f 1.03
p < 0.01 NS
38 TABLE II Number of prostaglandin side effects Side effects
Before PG
After PG
(Mild-moderate-severe)
Pain Nausea and vomiting Diarrhea
33
13
(18-25-30)
33 6
44 10
(19-17-8) (10-0-O)
Tolerance The mean duration of bleeding was 8.04 f 2.14 days (from 4 to 12 days). No transfusion and no curettage for heavy bleeding were necessary. In 63 patients (84%), the ovular expulsion occurred on day 3 after the prostaglandin use. The mean haemoglobin level on day 10 was 12.38 f 1.03 g/dl, which is not different from day 1 (Table I). The other side effects are prostaglandin dependent. As we used a single pessary of meteneprost, they only occurred during the next three hours. To evaluate the intensity of those side effects, we classified them in mild, moderate or severe (Table II). The severe group lead to medication. 73 patients complained of painful uterine contractions. Only 30 of them (41%) needed treatment. We never used any other drug than antispasmodic (phloroglucinol = Spasfon* ). Nausea and vomiting occurred in 44 patients, but only 8 of them (17%) needed treatment (metoclopramid = Primperan * ). Diarrhea only happened to 10 patients (14%). All the biological tests remained in the normal range, without any significant variation between day 1, 3 and 10.
Discussion Mifepristone had been used alone in previous reports concerning termination of early pregnancy in sequential doses during a few days [8,13]. For pregnancies of less than 49 days of amenorrhea, the reported success rates run from 60 to 82%. We have reported our experience of the 600 mg single dose with a success rate of 84% for such pregnancies [14]. However, if we consider the pregnancies of less than 42 days (6 weeks) the success ratio is 87% [9,14], and for the pregnancies between 43 and 49 days (7 weeks) it is only 64% [14]. So, in clinical practice, mifepristone, when used alone, has shown an unacceptable rate of failures requiring vacuum aspiration in nearly 20% of the cases. Prostaglandin analogues effectively induced early abortion. Some comparative studies have shown that the success rates were comparable (95%) either with prostaglandin or with vacuum aspiration [2-41. But the doses required are associated with a high incidence of side effects such as pelvic pain requiring analgesia, vomiting and diarrhea. The induction of abortion by mifepristone involves a direct antiprogesterone effect on the endometrium (per-i-ovular decidual necrosis), inducing ovum detach-
39
ment [6,7], and a secondary endometrial prostaglandin synthesis [7,15], stimulating myometrial contractility and softening of the cervix, leading to ovum expulsion [16]. There is evidence that mifepristone sensitises the uterus to the oxytocic action of prostaglandin [15]. Bygdeman [lo] has confirmed that the addition of small dose of prostagkmdin (0.25 mg sulprostone) to treatment with mifepristone increases the frequency of complete abortion to 94%. We observed good results with the same combination [17]. Such good results are also reported by Cameron [11,18], Rodger [12] and Dubois [19], using a vaginal pessary of 1 mg of gemeprost. Our study confirmed these results, using another prostaglandin analogue, meteneprost. 72 patients out of 75 completely aborted after treatment. No heavy bleeding was reported during treatment, and the haemoglobin concentration did not decrease. The postaglandin-induced side effects occurred only during the 3 hours following prostaglandin use. The pain intensity never required opioid analgesia. About 60% of our patients needed no analgesic drug at all and 40% only a minor analgesic or antispasmodic drug. Nausea and vomiting, which are common symptoms in early pregnancy, were moderate, 33 patients complained of nausea before prostaglandin, and 44 after; only 8 required a symptomatic treatment (Table II). Is medical termination of pregnancy better than vacuum aspiration? The answer is not easy. Surgical aspiration needs an operating room and a skilled operator. In most of cases, local or general anaesthesia is necessary with their own risk. The results of large series (20) point out a failure rate of 2% and a complication rate of 4%. The occurrence of an incomplete abortion after medical termination needs careful supervision. The acceptability of medical termination has been assessed with prostaglandins [3]. The comparative study of Cameron and Baird [18] shows that gemeprost, alone or in combination with mifepristone, is as effective as vacuum aspiration; but the side effects were greatly reduced when combined with mifepristone and prostaglandin. Conclusion The use of mifepristone in combination with meteneprost is an effective and safe means of terminating an early pregnancy. The low rate of painful uterine contractions and gastro-intestinal side effects suggests that it is an acceptable method and a good alternative to surgical abortion. Nevertheless, a close medical supervision is necessary to assess the efficacy of the method. Acknowledgements Mifepristone tablets and Meteneprost pessaries were kindly provided by laboratoires Roussel-Uclaf, Romainville, France. We are grateful to all the members of our outpatient gynecological unit for carrying out this study. References 1 Bygdeman M, Christensen N, Green K, Zheng S, Lundstrom V. Termination of early pregnancy. Future development. Acta Obstet Gynecol Stand 1983; (suppl.) 113;125-129.
40
2 Smith SK, Baird DT. The use of 16,16-dimethyl-trarr.rA*-PGE, methyl ester (ON0 802) vaginal suppositories for the termination of early pregnancy; a comparative study. Br J Obstet Gynecol 1980;87:712-727. 3 Rosen AS, Von Knorring K, Bygdeman M, Christensen NJ. Randomized comparison of PG treatment in hospital or at home with vacuum aspiration for termination of early pregnancy. Contraception 1984;29:423-435. 4 World Health Organization. Menstrual regulation by intramuscular injections of lCphenoxytetranorPGE, methyl sulfanylamide or vacuum aspiration. A randomized multicenter study. Br J Obstet Gynecol 1987;94:949-956. 5 Csapo AI, Pulki~en M. Indispensability of the human corpus luteum in the maintenance of early pregnancy: lutectomy evidence. Obstet Gynecol Surv 1978;33:69-81. 6 Secchi J, Lelaque D, Toumemine C, Philibert D. Histopharmacology of RU 486. In: Baulieu EE, Segal SJ eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985;79-86. 7 Hermann WL, Schindler AM, Wyss R, Bischof P. Effects of the antiprogesterone RU 486 in early pregnancy and during the menstrual cycle. In: Baulieu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985; 179-198. 8 Courinet B, Lestrat N, Ulmann A, Baulieu EE, Schaison G. Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone). N Eng J Med 1986;325:1565-1570. 9 Maria B, Stampf F, Goepp A, Uhnann A. Termination of early pregnancy by a single dose of Mifepristone (RU 486), a progesterone antagonist. Eur J Obstet Gynecol Reprod Biol 1988;28:249255. 10 Bygdeman M, Swahn ML, Progesterone receptor blockage. Contraception 1985;32:45-51. 11 Cameron T, Michie AF, Baird DT. Therapeutic abortion in early pregnancy with antiprogestogen RU 486 alone or in combination with PG analogue. Contraception 1986;34:459-468. 12 Rodger MW, Baird DT. Induction of therapeutic abortion in early pregnancy with Mifepristone in combination with PG pessary. Lancet 1987;ii:1415-1418. 13 Kovacs L, Sas M, Resch BA et al. Termination of early pregnancy by RU 486, an antiprogestational compound. Contraception 1984;29:399-410. 14 Maria B, Chaneac M, Stampf F, Ulmamr A. Interruption pr6coce de la grossesse par un steroide antiprogesterone: la Mifepristone (RU 486). J Gynecol Obstet Biol Rep 1988;17:1089-1094. 15 Kelly RW, Healy DL, Cameron MJ, Cameron IT, Baird DT. RU 486 stimulation of PGF, production in isolated endometrial cells in short-term cultures. In: Baulieu EE, Segal SJ, eds.. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985;259-262. 16 Swahn ML, Cekan S, Wang G, Lundstrom V, Bygdeman M. Pharmacokinetic and clinical studies of RU 486 for fertility regulation. In: Baulieu EE, Segal SJ. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985;249-258. 17 Maria B, Stampf F. Interruption de la grossesse par l’association Mif&pristonssulprostone Presse Med 1987;16:2128. 18 Cameron T, Baird, DT. Early pregnancy termination: a comparison between vacuum aspiration and medical abortion using PG or the antigestagen RU 486. Br. J. Obstet Gynecol 1988;95:271-276. 19 Dubois C, Ulmann A, Aubeny E et al. Contragestion par le RU 486: i&r& de l’association a un derive prostaglandine. CR Acad Sci Paris 1988;306:57-61. 20 Laufe LE, The menstrual regulation procedure. Studies in Family Planning 1977;8:253-256.
35
Biology, 31 (1990) 35-40
EUROBS 00977
Termination of early pregnancy through a combination of the antiprogestin and prostaglandin analogue * Bernard
Maria
‘, Franqoise Stampf ‘, Anne Goepp and Catherine Dubois 3
2
’ Service de GynPcologie-ObstPtrique,
2 Laboratoire de Biochimie, Centre Hospitalier Intercommunal, Viileneuve Saint Georges, and 3 Laboratoire Roussel-Uclaf, Romainville, France Accepted for publication 8 November 1989
Termination of early pregnancy (less than 49 days of amenorrhea) was induced in 75 patients with the combination of the antigestagen mifepristone and a prostaglandin analogue, meteneprost. After 48 h a single oral dose of 600 mg of mifepristone was followed by a 10 mg meteneprost vaginal pessary. Pregnancy was confirmed by clinical and ultrasound examinations and plasma HCG assessment. Complete abortion occurred in 72 patients (96%) and the three others required a surgical uterine aspiration. Bleeding continued for 4 to 12 days (mean = 8). Uterine pain and side effects occurred during the 3 h following the use of prostaglandin. Only minor analgesic were required in 30 patients. The combination of mifepristone and meteneprost is a safe and effective method to terminate an early pregnancy. Termination of early pregnancy; Abortion; Antiprogesterone;
Mifepristone; Prostaglandin analogue
Introduction Abortion is still the most frequently used method of fertility regulation. Uterine vacuum aspiration is performed widely to induce legal abortion. It is a safe surgical procedure; however, failures and complications can occur. If an effective abortion
* This study was presented at the First European Congress on Prostaglandins in reproduction, Vienna, Austria, 6-9 July 1988. Correspondence: Dr. B. Maria, Service de Gynkologie-Obstttrique, Centre Hospitalier Intercommunal, 94190 Villeneuve Saint Georges, France. 0028-2243/90/.$03.50
8 1990 Elsevier Science Publishers B.V. (Biomedical Division)
36
medical method were available, the operative complications would be reduced and an ambulatory induced abortion would become possible. Prostaglandins have been investigated for the termination of early pregnancy [l]. Several studies have shown that administration of prostaglandin E, (PGE,) analogues may be as effective as vacuum aspiration, however, they have gastro-intestinal side effects, pelvic pains and prolonged bleeding [2-41. An antiprogestin would be of interest, since progesterone is indispensable to maintain early pregnancy [5]. Mifepristone is a synthetic 19-nor-steroid with antiprogesterone activity. When used in early pregnancy, it acts as an abortifacient. Mifepristone induces decidual necrosis without any alteration of trophoblast and endometrial prostaglandin synthesis [6,7]. Previous studies have been reported using Mifepristone alone in very early pregnancy with a 80% rate of complete abortion [8,9]. Recently, it has been reported that the combination of mifepristone and a low dose of prostaglandin increases the efficacy of the procedure [lo-121. The purpose of our study was to evaluate the effect of a single dose of 600 mg of mifepristone in combination with a PGE, analogue, meteneprost (9-deoxo-16,16-dimethyl-9-methylene, PGE,), on early pregnancy. Methods
Subjects The study included 75 healthy women applying for a legal abortion according to the French Regulation. Women with any signs of abnormal pregnancy, pelvic inflammatory disease, use of glucocorticoids in the previous 3 months, a history of liver, gastrointestinal or renal disease or prostaglandin contra-indications (asthma) were excluded from the study. The procedure was limited to pregnancies of less than 7 weeks from the last menstrual period, i.e., 49 days of amenorhea. Pregnancy was confirmed by pelvic ultrasound examination and plasma HCG assessment. The study was approved by the Ethical Committee of Institut Roussel-Uclaf (Paris). The nature of the study was explained to each subject in detail and a written consent was obtained. Each patient had to agree to abortion by aspiration if the procedure failed. Protocol On day 1, each patient underwent a careful clinical pelvic and ultrasound examination. Blood samples were drawn to measure plasma HCG, complete blood count, creatinine, glycemia, bilirubine, cholesterol, triglycerides and liver enzymes. Mifepristone was delivered as 200 mg tablets. Each patient swallowed three tablets (600 mg) under supervision. The clinical events that should occur were carefully explained to each woman and a permanent telephone number was available for emergencies. On day 3, the patients had to come back. First the same blood sampling, except HCG assay, were performed again. If there was no evidence of ovular expulsion, the prostaglandin (Meteneprost 10 mg vaginal pessary) was used. Then, the patients were observed over the next three hours to note whether bleeding or any side effects occurred. After that time they went back home.
37
On day 10, a follow-up visit was scheduled. Clinical and ultrasound examinations and same blood sampling were performed. Success was assumed if vaginal bleeding occurred, ultrasonic examination confirmed uterine vacuity and a decrease in plasma HCG level, under the initial value, was observed. On the other hand on-going pregnancies and missed abortions were failures, as well as the patients who needed a blood transfusion or a curettage for heavy bleeding. In case of failure, a uterine vacuum aspiration was performed. After that check, a contraceptive method was proposed. Technical points Ultrasound examinations were all carried out with a Hitachi-Diasonics DRF 100 apparatus with a 3.5 MHz probe. Plasma HCG level were determined by immunoenzymoassay (B HCG EIA Roche Diagnostica). The results are expressed as means k SE.
Study group The 75 women present the following characteristics: mean age: 28.44 + 5.93 years (from 18 to 42 years); mean weight: 58.51 + 10.41 kg (from 40 to 110 kg); mean height: 163.9 f 5.9 cm (from 150 to 180 cm); 32 patients (43%) were nulliparous; mean amenorrhea: 43.56 f 3.74 days (from 33 to 49 days); mean diameter of intrauterine sac: 15.81 f 8.33 mm (from 0 to 43 mm); and mean crown-rump length of embryo: 3.18 + 3.80 (from 0 to 12 mm); only 36 embryos (48%) were clearly measurable. - mean HCG level on day 1: 42.615 f 28.244 IU/l and mean level of haemoglobin: 12.89 f 0.85 g/dl. Efficacy 72 patients out of the 75 were considered to have a complete abortion, that is an abortion rate of 96%. The three failures included one developing pregnancy and two missed abortions. In the success group, the mean HCG level on day 10 was 1.455 f 2.881 IU/l. The difference with the level of day one is significant (p < 0.01) (Table 1).
TABLE I HCG and haemoglobin concentrations before (day 1) and after treatment (day 10)
HCG (IU/l) HB (g/d0
Day 1
Day 10
r-test
42,615 f 28,244 12.89k0.85
1,485 f 2,281 12.38 f 1.03
p < 0.01 NS
38 TABLE II Number of prostaglandin side effects Side effects
Before PG
After PG
(Mild-moderate-severe)
Pain Nausea and vomiting Diarrhea
33
13
(18-25-30)
33 6
44 10
(19-17-8) (10-0-O)
Tolerance The mean duration of bleeding was 8.04 f 2.14 days (from 4 to 12 days). No transfusion and no curettage for heavy bleeding were necessary. In 63 patients (84%), the ovular expulsion occurred on day 3 after the prostaglandin use. The mean haemoglobin level on day 10 was 12.38 f 1.03 g/dl, which is not different from day 1 (Table I). The other side effects are prostaglandin dependent. As we used a single pessary of meteneprost, they only occurred during the next three hours. To evaluate the intensity of those side effects, we classified them in mild, moderate or severe (Table II). The severe group lead to medication. 73 patients complained of painful uterine contractions. Only 30 of them (41%) needed treatment. We never used any other drug than antispasmodic (phloroglucinol = Spasfon* ). Nausea and vomiting occurred in 44 patients, but only 8 of them (17%) needed treatment (metoclopramid = Primperan * ). Diarrhea only happened to 10 patients (14%). All the biological tests remained in the normal range, without any significant variation between day 1, 3 and 10.
Discussion Mifepristone had been used alone in previous reports concerning termination of early pregnancy in sequential doses during a few days [8,13]. For pregnancies of less than 49 days of amenorrhea, the reported success rates run from 60 to 82%. We have reported our experience of the 600 mg single dose with a success rate of 84% for such pregnancies [14]. However, if we consider the pregnancies of less than 42 days (6 weeks) the success ratio is 87% [9,14], and for the pregnancies between 43 and 49 days (7 weeks) it is only 64% [14]. So, in clinical practice, mifepristone, when used alone, has shown an unacceptable rate of failures requiring vacuum aspiration in nearly 20% of the cases. Prostaglandin analogues effectively induced early abortion. Some comparative studies have shown that the success rates were comparable (95%) either with prostaglandin or with vacuum aspiration [2-41. But the doses required are associated with a high incidence of side effects such as pelvic pain requiring analgesia, vomiting and diarrhea. The induction of abortion by mifepristone involves a direct antiprogesterone effect on the endometrium (per-i-ovular decidual necrosis), inducing ovum detach-
39
ment [6,7], and a secondary endometrial prostaglandin synthesis [7,15], stimulating myometrial contractility and softening of the cervix, leading to ovum expulsion [16]. There is evidence that mifepristone sensitises the uterus to the oxytocic action of prostaglandin [15]. Bygdeman [lo] has confirmed that the addition of small dose of prostagkmdin (0.25 mg sulprostone) to treatment with mifepristone increases the frequency of complete abortion to 94%. We observed good results with the same combination [17]. Such good results are also reported by Cameron [11,18], Rodger [12] and Dubois [19], using a vaginal pessary of 1 mg of gemeprost. Our study confirmed these results, using another prostaglandin analogue, meteneprost. 72 patients out of 75 completely aborted after treatment. No heavy bleeding was reported during treatment, and the haemoglobin concentration did not decrease. The postaglandin-induced side effects occurred only during the 3 hours following prostaglandin use. The pain intensity never required opioid analgesia. About 60% of our patients needed no analgesic drug at all and 40% only a minor analgesic or antispasmodic drug. Nausea and vomiting, which are common symptoms in early pregnancy, were moderate, 33 patients complained of nausea before prostaglandin, and 44 after; only 8 required a symptomatic treatment (Table II). Is medical termination of pregnancy better than vacuum aspiration? The answer is not easy. Surgical aspiration needs an operating room and a skilled operator. In most of cases, local or general anaesthesia is necessary with their own risk. The results of large series (20) point out a failure rate of 2% and a complication rate of 4%. The occurrence of an incomplete abortion after medical termination needs careful supervision. The acceptability of medical termination has been assessed with prostaglandins [3]. The comparative study of Cameron and Baird [18] shows that gemeprost, alone or in combination with mifepristone, is as effective as vacuum aspiration; but the side effects were greatly reduced when combined with mifepristone and prostaglandin. Conclusion The use of mifepristone in combination with meteneprost is an effective and safe means of terminating an early pregnancy. The low rate of painful uterine contractions and gastro-intestinal side effects suggests that it is an acceptable method and a good alternative to surgical abortion. Nevertheless, a close medical supervision is necessary to assess the efficacy of the method. Acknowledgements Mifepristone tablets and Meteneprost pessaries were kindly provided by laboratoires Roussel-Uclaf, Romainville, France. We are grateful to all the members of our outpatient gynecological unit for carrying out this study. References 1 Bygdeman M, Christensen N, Green K, Zheng S, Lundstrom V. Termination of early pregnancy. Future development. Acta Obstet Gynecol Stand 1983; (suppl.) 113;125-129.
40
2 Smith SK, Baird DT. The use of 16,16-dimethyl-trarr.rA*-PGE, methyl ester (ON0 802) vaginal suppositories for the termination of early pregnancy; a comparative study. Br J Obstet Gynecol 1980;87:712-727. 3 Rosen AS, Von Knorring K, Bygdeman M, Christensen NJ. Randomized comparison of PG treatment in hospital or at home with vacuum aspiration for termination of early pregnancy. Contraception 1984;29:423-435. 4 World Health Organization. Menstrual regulation by intramuscular injections of lCphenoxytetranorPGE, methyl sulfanylamide or vacuum aspiration. A randomized multicenter study. Br J Obstet Gynecol 1987;94:949-956. 5 Csapo AI, Pulki~en M. Indispensability of the human corpus luteum in the maintenance of early pregnancy: lutectomy evidence. Obstet Gynecol Surv 1978;33:69-81. 6 Secchi J, Lelaque D, Toumemine C, Philibert D. Histopharmacology of RU 486. In: Baulieu EE, Segal SJ eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985;79-86. 7 Hermann WL, Schindler AM, Wyss R, Bischof P. Effects of the antiprogesterone RU 486 in early pregnancy and during the menstrual cycle. In: Baulieu EE, Segal SJ, eds. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985; 179-198. 8 Courinet B, Lestrat N, Ulmann A, Baulieu EE, Schaison G. Termination of early pregnancy by the progesterone antagonist RU 486 (Mifepristone). N Eng J Med 1986;325:1565-1570. 9 Maria B, Stampf F, Goepp A, Uhnann A. Termination of early pregnancy by a single dose of Mifepristone (RU 486), a progesterone antagonist. Eur J Obstet Gynecol Reprod Biol 1988;28:249255. 10 Bygdeman M, Swahn ML, Progesterone receptor blockage. Contraception 1985;32:45-51. 11 Cameron T, Michie AF, Baird DT. Therapeutic abortion in early pregnancy with antiprogestogen RU 486 alone or in combination with PG analogue. Contraception 1986;34:459-468. 12 Rodger MW, Baird DT. Induction of therapeutic abortion in early pregnancy with Mifepristone in combination with PG pessary. Lancet 1987;ii:1415-1418. 13 Kovacs L, Sas M, Resch BA et al. Termination of early pregnancy by RU 486, an antiprogestational compound. Contraception 1984;29:399-410. 14 Maria B, Chaneac M, Stampf F, Ulmamr A. Interruption pr6coce de la grossesse par un steroide antiprogesterone: la Mifepristone (RU 486). J Gynecol Obstet Biol Rep 1988;17:1089-1094. 15 Kelly RW, Healy DL, Cameron MJ, Cameron IT, Baird DT. RU 486 stimulation of PGF, production in isolated endometrial cells in short-term cultures. In: Baulieu EE, Segal SJ, eds.. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985;259-262. 16 Swahn ML, Cekan S, Wang G, Lundstrom V, Bygdeman M. Pharmacokinetic and clinical studies of RU 486 for fertility regulation. In: Baulieu EE, Segal SJ. The antiprogestin steroid RU 486 and human fertility control. New York: Plenum Press, 1985;249-258. 17 Maria B, Stampf F. Interruption de la grossesse par l’association Mif&pristonssulprostone Presse Med 1987;16:2128. 18 Cameron T, Baird, DT. Early pregnancy termination: a comparison between vacuum aspiration and medical abortion using PG or the antigestagen RU 486. Br. J. Obstet Gynecol 1988;95:271-276. 19 Dubois C, Ulmann A, Aubeny E et al. Contragestion par le RU 486: i&r& de l’association a un derive prostaglandine. CR Acad Sci Paris 1988;306:57-61. 20 Laufe LE, The menstrual regulation procedure. Studies in Family Planning 1977;8:253-256.