10
Prostaglandin analogues and their uses MARC
BYGDEMAN
INTRODUCTION The prostaglandins of both the E and F groups are potent stimulants of the human uterus in vivo at any stage of pregnancy. They are extensively used clinically for termination of pregnancy and induction of labour. The main disadvantages of these compounds are a short half-life and the occurrence of gastrointestinal side-effects. The primary prostaglandins (prostaglandin F2~ (PGF2~) and PGE2) are rapidly metabolized in the body. The initial steps in the enzymatic degradation are the oxidation of the 15-hydroxy group to a keto group and the reduction of the 13,14 double bond. The resulting 15-keto13,14-dihydro compounds are essentially biologically inactive. When it comes to termination of pregnancy, these drawbacks are partly overcome by using intrauterine administration. Another alternative has been the development of prostaglandin analogues which are not substrates for the initial steps of enzymatic degradation by 15-dehydrogenase and have a more specific effect towards uterine rather than gastrointestinal muscle. A number of such analogues have been developed, some of which are in routine clinical use. These are 15(S)-15-methyl-PGF2~ (carboprost, Upjohn Company), 16phenoxy-17,18,19,20-tetranor-PGE2 methyl sulphonylamide (sulprostone, Schering AG) and 16,16-dimethyl-trans-A2-PGE1methyl ester (gemeprost, Rh6ne-Poulenc Rover). In contrast to the primary prostaglandins, these compounds can be administered by non-invasive routes, gemeprost vaginally and sulprostone and carboprost intramuscularly. Carboprost is also available for intravenous and intrauterine administration. The fact that the analogues are administered vaginally or intramuscularly has allowed an extended clinical use for pregnancy termination. In contrast to primary prostaglandins, which are mainly used for termination of second trimester pregnancy, the analogues are useful for termination of early pregnancy, for preoperative dilatation of the cervical canal and for termination of second trimester pregnancy. Prostaglandin analogues have so far not been tried for induction of labour at or near term. In this situation, the longer duration of action isa drawback. Baillibre's Clinical Obstetrics and Gynaecology-893 Vol. 6, No. 4, December 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1694-2 All rights of reproduction in any form reserved
894
M. BYGDEMAN
T E R M I N A T I O N OF EARLY P R E G N A N C Y
The possibility of using prostaglandins for termination of very early pregnancy has been evaluated since the beginning of the 1970s. The initial trials using PGF2~ or PGE2 were mainly discouraging. The only effective route was intrauterine administration and premedication was necessary to reduce the frequency of side-effects. If analogues are used the situation is somewhat different. Repeated or single vaginal administration of the methyl ester of carboprost has been shown to be highly effective. This is also true for vaginal administration of gemeprost and meteneprost (9-deoxo-16,16-dimethyl-9methylene PGE2, Upjohn Company) or intramuscular injection of sulprostone. In a comparative study, gemeprost and meteneprost administered vaginally, and sulprostone given as intramuscular injections were found to be equally effective. The frequency of complete abortion was between 92 and 94% if the treatment was limited to the first 3 weeks following the first missed menstrual period. With the PGE analogues the side-effects were limited to occasional vomiting and diarrhoea in approximately 50% of the patients (Bygdeman et al, 1983). Even self-administration at home was shown to be possible (Bygdeman et al, 1984). The treatment results in an increase in uterine contractility followed by bleeding, which generally starts 3-6 hours after the initiation of therapy and lasts for 1-2 weeks. Most patients abort during the first 24 hours but minor residues of the conceptus without clinical importance may remain in the cavity for several weeks (Mandelin, 1978). The bleeding is described by most patients as heavier than a menstrual period but it does not generally affect the haemoglobin values. Heavy blood loss and pelvic infection occur in less than 2% of the patients (WHO Prostaglandin Task Force, 1982a). In a recent randomized study including 473 women, in whom repeated intramuscular injections of 0.5 mg of sulprostone were administered, this administration was shown to be equally effective as vacuum aspiration in terminating early pregnancy (WHO Prostaglandin Task Force, 1987). In spite of the fact that in an acceptability study both prostaglandin and vacuum aspiration was equally appreciated (Rosdn et al, 1984), no pharmaceutical company has introduced a prostaglandin analogue for termination of early pregnancy. It was not until the introduction of antiprogestin and its use in combination with prostaglandin analogues that a medical method to terminate pregnancy started to be accepted. The only antiprogestin in clinical use is R U 486 (mifepristone, Roussel Uclaf). Mifepristone is a progesterone receptor blocker which interferes with the action of progesterone at the target organ level (Baulieu, 1985). Treatment with mifepristone during early pregnancy will, after a latency period of 24-36 hours, result in increased uterine contractility due to withdrawal of progesterone inhibition of myometrial activity (Swahn and Bygdeman, 1988). It is possible that this treatment also to some extent stimulates endogenous PGF2~ production (Smith and Kelly, 1987), and the sensitivity of the myometrium to prostaglandin will be significantly increased (Swahn and Bygdeman, 1988). Although progesterone is regarded as essential for the maintenance of early pregnancy, treatment with mifepristone alone will
895
PROSTAGLANDIN ANALOGUES
not be sufficiently effective in terminating early pregnancy to compete with vacuum aspiration. However, if a small dose of prostaglandin analogue is added, the efficacy of treatment increases to almost 100% (Bygdeman and Swahn, 1985). The difference in efficacy of the different procedures to terminate early pregnancy is illustrated in a comparative study by Cameron and Baird (1988). Complete abortion occurred more often in women treated with vacuum aspiration (96%), gemeprost alone (97%) and mifepristone plus gemeprost (95%) than in those treated with mifepristone alone (60%). The treatments used were 1.0 mg of gemeprost every third hour five times; 150 mg of mifepristone daily for 4 days plus 1.0 mg gemeprost on day 3; and 150 mg mifepristone alone given daily for 4 days, respectively. While the combined treatment was equally effective as gemeprost alone, side-effects and analgesic requirements were much reduced in the women who received mifepristone alone or in combination with a single gemeprost pessary. Mifepristone is at present registered for clinical use in France and the UK. Registration is expected in the Scandinavian countries by late 1992. Approximately 30% of all early abortions in France are treated with a combination of mifepristone and a prostaglandin analogue. A common treatment is a single dose of 600 mg of mifepristone followed 48 hours later by either 1.0 mg of gemeprost or an intramuscular injection of 0.25--0.50 mg of sulprostone. Silvestre et al (1990) have recently summarized the French experience of routine clinical use of the procedure, including 2115 early pregnant women (Table 1). The overall frequency of complete abortion was 96% with very little difference between the different dose schedules. Table 1. Termination of early pregnancy with 600mg of mifepristone followed 48 hours later by either 1,0mg of cervagem or 0,250.5 mg of sulprostone (Silvestre et al, 1990). Outcome of therapy Complete abortion Incomplete abortion Pregnancy continuation Haemostatic procedure Fever (infection)
Patients (%) 96.0 2.1 1.0 0.9 0.3
However, the frequency of uterine pain was significantly lower with 0.25 mg of sulprostone and 1.0 mg of cervagem (14.9 and 21.3%, respectively) than with 0.375 and 0.5 mg of sulprostone (33.3 and 51.2%, respectively). Almost all patients started to bleed on the second day following mifepristone treatment and the mean duration of bleeding was between 7 and 12 days. The frequency of heavy bleeding needing curettage was, however, low (0.9%). Fever as a sign of infection was also very uncommon (0.3%) in the French study. The frequency of heavy bleeding and fever compares favourably with that often reported after vacuum aspiration performed during the first trimester of pregnancy. Serious complications associated with the therapy are very rare. However, one death has been reported. It occurred in
896
M. BYGDEMAN
association with the administration of sulprostone and the cause was a spasm in the coronary artery resulting in a massive infarction. The reason for this was unclear, but, since the woman was a heavy smoker, the pharmaceutical company has recommended that heavy smokers should not be treated with this therapy. The best dose schedule of mifepristone and a prostaglandin analogue remains to be established. It is very likely, however, that the dose of mifepristone may be significantly reduced to 200 or even 50 mg. It is also likely that 0.5 mg of gemeprost would be sufficient. Very recently, the combination of mifepristone and the orally active prostaglandin analogue misoprostol (15(S)-15-methyl-PGE2 methyl ester, Searle AG) has been evaluated. Misoprostol is used in many countries for the treatment of gastric ulcers. It is considerably cheaper and more stable than cervagem and sulprostone. Preliminary studies indicate that a combination of 200 mg of mifepristone and 600 ~xg of misoprostol may be equally effective as previously described combinations (Aubernu and Baulieu, 1991; Norman et al, 1991). A potential problem with misoprostol is the risk of fetal malformations if the pregnancy continues in spite of treatment (Sch6nh6fer, 1991). PREOPERATIVE CERVICAL DILATATION Vacuum aspiration is the preferred method for termination of first and early second trimester pregnancy in many countries. If the procedure is performed after the seventh week of gestation, dilatation of the cervical canal is necessary. The need for greater mechanical dilatation of the cervix causes an increased risk of cervical laceration and uterine perforation and may have an adverse long-term effect on subsequent fertility. In addition, complications such as haemorrhage and incomplete evacuation of the products of conception may arise as a result of insufficient or difficult dilatation. For these reasons a variety of procedures has been investigated with the aim of developing a simple and safe method for preparing the cervix before dilatation and suction or mechanical curettage. Two alternatives are mainly used, either administration of prostaglandins or a cervical dilator such as a laminaria tent or lamicel, a synthetic hydrophilic polymer impregnated with magnesium sulphate. That prostaglandins can be used for this purpose was suggested at the start of the 1970s. A large number of studies have been published illustrating the advantages and disadvantages of prostaglandin treatment. In this review, reference will mainly be made to two large World Health Organization (WHO) studies. For more detailed references, the reader is referred to Lauersen (1986) and Herczeg (1990). The first large clinical study was published some 10 years ago by the WHO Prostaglandin Task Force (1981). In this multicentre study with over 1000 patients, pretreatment with a vaginal suppository containing 1.0mg of 15-methyl-PGF2~ methyl ester was randomly compared with placebo. The pretreatment time was either 3 or 12 hours. The study showed that a 3 hour pretreatment period resulted in a significant degree of cervical dilatation,
897
PROSTAGLANDIN ANALOGUES
fewer operative complications, shorter duration of postoperative bleeding and a lower frequency of recurettage and treatment of infection in comparison with pretreatment with placebo. The drawback of the treatment was a higher frequency of uterine pain and gastrointestinal side-effects with the active suppositories. These problems seem to be substantially reduced if PGE analogues are used instead. Both 1.0mg of gemeprost administered vaginally and 0.5 mg of sulprostone given as an intramuscular injection are extensively used for cervical dilatation at present. Both compounds have been randomly compared in another WHO study (WHO Prostaglandin Task Force, 1986). Included in that study were also vaginal administration of meteneprost, the methyl ester of carboprost, and one laminaria tent (Table 2). The study showed that all three PGE analogues were equally effective as Table 2. Randomized comparison between the laminaria tent, 1.0 mg of gemeprost and 0.5 mg of sulprostone for preoperative dilatation of the cervical canal. Outcome after 3 hours. Mean values + SD. Percentage of patients with Method Laminaria tent Gemeprost Sulprostone
Degree of cervical dilatation (mm)
Vomiting
Diarrhoea
Analgesic injection
Bloodloss (ml)
6.9 _+1.5" 7.4 + 2.1 7.7 + 2.2*
0* 6.4* 14.3"
0.8 0.8 4.8
0* 10.3" 4.0
67.9 _+45.8 57.5 _+56.3 57.3 + 43.2
From WHO Prostaglandin Task Force (1986). * Significant difference, p < 0.05.
one medium-sized laminaria tent and more effective than the PGF analogue after 3 hours. Both types of treatment are associated with a low frequency of side-effects. With the three PGE analogues the percentage of patients experiencing occasional episodes of vomiting varied from 6.4 to 14.3% and of diarrhoea from 0.8 to 4.8%. The frequency of vomiting was significantly higher than for a laminaria tent, but not statistically different for diarrhoea. Prostaglandin therapy has a practical advantage over the laminaria tent. The introduction of the tent, which is not always easy, has to be performed by medical staff, whereas prostaglandin treatment can be overseen by paramedical personnel. Based on these and other studies, The Medical Advisory Committee of the International Planned Parenthood Federation has recommended either prostaglandin therapy or a laminaria tent to be used prior to vacuum aspiration in first trimester abortion (Editorial, 1984). Pretreatment with, for instance, gemeprost followed by vacuum aspiration may also be used during the first 2 weeks of the second trimester instead of conventional two-stage procedures. In a recent study comprising 1000 patients, the outcome of vacuum aspiration up to the 15th week of gestation was evaluated. All late first trimester primipara patients were pretreated with prostaglandin for 3 hours and the patients in early second trimester for 12 hours (Fried et al, 1989). Normally, the frequency of complications increases with gestational age. In this study, the overall complication rate
898
M. BYGDEMAN
was around 5% and the same in all stages of pregnancy, indicating that, if pretreatment with prostaglandin is used, vacuum aspiration can be safely carried out even in early second trimester abortion. SECOND TRIMESTER PREGNANCY
Intra-amniotic and extra-amniotic administration of PGF2, and extraamniotic administration of PGE2 is widely used for termination of second trimester pregnancy. An alternative is intra-amniotic injection of carboprost. This PGF2~ analogue is more potent and has a longer duration of action. The half-life of the analogue in amniotic fluid is approximately double that of PGF2~ itself (Gr6en et al, 1976). Intra-amniotic administration of this analogue has been evaluated on a large scale in two multicentre studies involving 2506 subjects. A single dose of 2.5 mg of carboprost was compared randomly with either 40 or 50 mg of PGF2~ (WHO Prostaglandin Task Force, 1977a; Tejuja et al, 1978). With a success rate of almost 95%, the analogue was significantly more effective than PGF2~ (81-88%). The mean inductionto-abortion interval (18-20 hours) and the frequency of complete abortion (about 50%) were similar with both compounds, and gastrointestinal sideeffects were within clinically acceptable limits. Injuries to the cervix were observed in 2.9 % of the patients with both compounds in the WHO study, but were more common following treatment with 50 mg of PGF2, in the Indian study. If a single-injection method is aimed at, carboprost seems to be a better alternative than the parent compound. The most important advantage of the analogues carboprost, sulprostone and gemeprost is that these compounds can be administered by non-invasive routes. Some of the major complications associated with second trimester abortion are due to an inadvertent intravenous injection of the compound when it is administered intra-amniotically. If the vaginal or intramuscular route is used, such complications are avoided. These routes offer the additional advantage that the treatment is equally useful during both the early and late parts of the second trimester. All three analogues have been used for termination of second trimester pregnancy. The results of a multicentre study performed by the WHO Prostaglandin Task Force (1977b) showed that repeated intramuscular injections of carboprost (initial dose 0.2mg followed by 0.3mg every 3 hours) was an effective method. About 85% of the patients aborted within 30 hours. The treatment was, however, associated with a high frequency of gastrointestinal side-effects. It was therefor.e concluded that this method has limited value as a primary abortion method but can be useful in order to complete the abortion process when another method has failed. If sulprostone is used instead, the efficacy seems equally good, but the frequency of gastrointestinal side-effects are lower (WHO Prostaglandin Task Force, 1982). The efficacy of the treatment can be increased if the patients are pretreated with one laminaria tent. In a multicentre study performed by the WHO Prostaglandin Task Force (1988) 529 patients in the 13th to 22nd week of pregnancy who received this pretreatment were then randomly allocated
PROSTAGLANDIN ANALOGUES
899
either 0.25 mg of carboprost every second hour or 0.5 mg of sulprostone every fourth hour. Both treatment schedules were equally effective. The success rate was 95.6 and 94.5% for the PGE and PGF analogues, respectively, within 24 hours from start of prostaglandin therapy. The mean duration of prostaglandin administration was 10.8 hours and 11.3 hours, respectively. The study also showed that the treatment with sulprostone was associated with a significantly lower frequency of gastrointestinal sideeffects than carboprost. With the former compound, 16.8% of the patients experienced occasional episodes of diarrhoea. The corresponding figure for vomiting was 41.1%. These figures are only slightly higher than those normally reported for intra-amniotic administration of hypertonic saline and comparable to those following intrauterine administration of PGEa or PGF2~. Although studies randomly comparing vaginal administration of gemeprost and intramuscular injection of sulprostone have not been performed, available data indicate that the vaginal approach is an equally good alternative. The dose of gemeprost mainly used is 1.0 mg every 3 hours five times. If the abortion has not occurred within 24 hours, a further course of five pessaries is prescribed. When this treatment was given to 113 women in the 12th to 16th week of pregnancy, 82% of the patients aborted within 24 hours and an additional 14% during the second 24 hour period, giving an overall success rate of 96%. Vomiting and diarrhoea occurred in 14 and 20%, respectively (Cameron et al, 1987). In a more recent study, pregnancies up to the 18th week were included with equally good results (Rodger and Baird, 1990). Vaginal administration of gemeprost has also been shown to be equally effective as extra-amniotic administration of PGE2. The treatment with gemeprost was less painful, and the simplicity of the treatment was another advantage appreciated by both patients and staff (Cameron and Baird, 1984) (Table 3). Some recent studies indicate that pretreatment with an antiprogestin will increase the efficacy of prostaglandin treatment during the second trimester. If 200 mg of mifepristone was administered 24 hours prior to extra-amniotic administration of PGE2 both the induction-to-abortion interval and total dose of PGE2 were significantly reduced in comparison to pretreatment with placebo (Urquhart and Templeton, 1987). In another study patients were randomly allocated to receive either 600 mg of mifepristone or placebo prior to vaginal administration of 1.0mg of cervagem every third hour. In the mifepristone pretreated group, 94% of the patients aborted within 24 hours compared with 80% of the placebo group. The median interval between administration of prostaglandin and abortion was significantly shorter in the mifepristone group (6.8 hours) compared with the placebo group (15.8 hours). The women pretreated with mifepristone also reported significantly less pain than the women who received placebo (Rodger and Baird, 1990). The outcome of a third study indicates that a combination of mifepristone and vaginal prostaglandin therapy may be highly effective even in late second trimester pregnancy (up to the 23rd week of gestation). In this study the patients were treated with either 200 mg of mifepristone orally or 0.5 mg of PGE2 administered into the cervical canal. Twenty-four hours later the
Intracervical Intramuscular Vaginal Oral Vaginal Oral Vaginal
0.5 mg every 4th hour
1.0 mg every 3rd hour 600 mg L 0 mg every 3rd hour 200 mg 5.0 mg every 4th hour
Laminaria + sulprostone
Cervagem Mifepristone + cervagem
Mifepristone + metheneprost
Intra-amniotic
Route of administration
Dose
2,5 mg
Compound
Carboprost
100
82 94
95.6
24 hours
96
94.4
48 hours
Success rate (%)
Gottlieb and Bygdeman (1991)
WHO Prostaglandin Task Force (1977a) WHO Prostaglandin Task Force (1988) Cameron et al (1987) Rodger and Baird (1990)
Reference
Table 3. Termination of second trimester pregnancy by different prostaglandin analogues. Selected studies.
:z
c~ ~J
',D
PROSTAGLANDIN ANALOGUES
901
patients received 5 mg of meteneprost every fourth hour for up to 24 hours. All patients pretreated with mifepristone aborted within 24 hours while, following pretreatment with intracervical PGE2, three patients out of 21 needed additional treatment. Pretreatment with mifepristone resulted in a shorter induction-to-abortion interval, a reduction in the total dose of meteneprost and less pain in comparison with pretreatment with intracervical PGE2 gel (Gottlieb and Bygdeman, 1991). CONCLUSIONS The development of prostaglandin analogues represents a major breakthrough in abortion technology. In combination with the antiprogestin mifepristone, both vaginal administration of gemeprost and intramuscular injection of sulprostone have been demonstrated to be highly effective in terminating early pregnancy. This non-surgical method is increasingly used as an alternative to vacuum aspiration. In late first and early second trimester abortion, pretreatment with these analogues will significantly facilitate vacuum aspiration and reduce the frequency of both operative and postoperative complications. Both vaginal administration of gemeprost and intramuscular injections of sulprostone are highly effective methods of terminating mid- and late second trimester pregnancy. The simplicity of the therapy is an important advantage in comparison with intrauterine administration of abortifacient drugs. Preliminary data indicate that if the patients are pretreated with mifepristone the efficacy of the analogues will be further enhanced and both duration of labour and frequency of side-effects reduced. REFERENCES Auberny B & Baulieu EE (1991) Contragestion with RU 486 and an orally active prostaglandin. Comptes Rendus Hebdomadaires des SOances de l'AcadOmie des Sciences 312: 539-564. Baulieu EE (1985) RU 486: an antiprogestin steroid with contragestive activity in women. In Baulieu EE & Segal SJ (eds) The Antiprogestin Steroid RU 486 and Human Fertility Control, pp 1-25. New York: Plenum Press. Bygdeman M & Swahn ML (1985) Progesterone receptor blockage. Effect on uterine contractility in early pregnancy. Contraception 32: 45-51. Bygdeman M, Christensen NJ & Gr6en K (1983) Termination of early pregnancy--future development. Acta Obstetrica et Gynecologica Scandinavica supplement 113: 125-129. Bygdeman M, Christensen N J, Gr6en K & Vesterqvist O (1984) Self-administration at home of prostaglandin for termination of early pregnancy. In Toppozada M, Bygdeman M & Hafez ESE (eds) Advances in Reproductive Health Care, pp 83-90. Lancaster: MTP Press. Cameron IT & Baird DT (1984) The use of 16,16-dimethyl-trans-Az prostaglandin E1 methyl ester (gemeprost) vaginal pessaries for the termination of pregnancy in the early second trimester. A comparison with extra-amniotic prostaglandin E2. British Journal of Obstetrics and Gynaecology 91" 1136--1140. Cameron IT & Baird DT (1988) Early pregnancy termination--a comparison between vacuum aspiration and medical abortion using prostaglandin (16,16-dimethyl-trans-A2 PGE1 methyl ester) or the antiprogestogen RU-486. British Journal of Obstetrics and Gynaecology 95: 271-276.
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M. BYGDEMAN
Cameron IT, Micbie A F & Baird DT (1987) Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16-dimethyl-trans-A 2 PGE1 methyl ester) vaginal pessaries in the early second trimester. Prostaglandins 34: 111-117. Editorial .(1984) 1PPF Medical Bulletin 18: 2-4. Fried G, Ostlund E, Ullberg C & Bygdeman M (1989) Somatic complications and contraceptive techniques following legal abortion. Aeta Obstetrica et Gynecologica Scandinavica 68: 515-521. Gottlieb C & Bygdeman M (1991) The use of antiprogestin (RU 486) for termination of second trimester pregnancy. Acta Obstetrica et Gynecologica Scandinavica 70: 199-203. Gr6en K, Granstr6m E, Bygdeman M & Wiqvist N (1976) Kinetic and metabolic studies of 15-methyl PGF2~ administered intraamniotically for induction of abortion. Prostaglandins 11: 69%711. Herczeg J (1990) Pretreatment of the cervix prior to surgical evacuation of the uterus in the late first and early second trimester of pregnancy. Bailli~re's Clinical Obstetrics and Gynaecology 4(2): 307-326. Lauersen NH (1986) Induced abortion. In Bygdeman M, Berger GS & Keith L (eds) Prostaglandins and their Inhibitors in Clinical Obstetrics and Gynaecology, pp 271-314. Lancaster: MTP Press. Mandelin M (1978) Termination of early pregnancy by a single-dose of 3.0 mg 15-methyl PGF2~ methyl ester vaginal suppository. Prostaglandins 16: 143-152. Norman JE, Thong KJ & Baird DT (1991) Uterine contractility and induction of abortion in early pregnancy by mesoprostol and mifepristone. Lancet 338: 1231-1236. Rodger MW & Baird DT (1990) Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. British Journal of Obstetrics and Gynaecology 97: 41-45. Ros6n A-S, yon Knorring K, Bygdeman M & Christensen NJ (1984) Randomized comparison of prostaglandin treatment in hospital or at home with vacuum aspiration for termination of early pregnancy. Contraception 29: 423-435. Sch6nh6fer PS (1991) Misuse of misoprostol as an abortifacient may induce malformations. Lancet 337: 1534-1535. Silvestre L, Dubois C, Renault M, Rezvani Y, Baulieu EE & Ulmann A (1990) Voluntary interruption of pregnancy with mifepristone (RU 486) and a prostaglandin analogue. New England Journal of Medicine 322: 645-648. Smith SK & Kelly RW (1987) The effect of the antiprogestins RU-486 and ZK 98.734 on the synthesis and metabolism of prostaglandins F2~ and E2 in separated cells from early human decidua. Journal of Clinical Endocrinology and Metabolism 65: 527-534. Swahn ML & Bygdeman M (1988) The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin. British Journal of Obstetrics and Gynaecology 95: 126--134. Tejuja S, Choudhury SD & Manchanda PK (1978) Use of intra- and extra-amniotic prostaglandin for the termination of pregnancies. Report of multicentric trial in India. Contraception 18: 641-652. Urquhart DR & Templeton AA (1987) Mifepristone (RU 486) and second trimester pregnancy. Lancet ii: 1405. WHO Prostaglandin Task Force (1977a) Comparison of single intra-amniotic injection of 15-methyl prostaglandin F2~ and prostaglandin F2~ for termination of second trimester pregnancy. An international multicentre study. American Journal of Obstetrics and Gynecology 129: 597-600. WHO Prostaglandin Task Force (1977b) Intramuscular administration of 15-methyl prostaglandin F2~ for induction of abortion in weeks 10 to 20 of pregnancy. American Journal of Obstetrics and Gynecology 129: 593-600. WHO Prostaglandin Task Force (1981) Vaginal administration of 15-methyl PGF2, methyl ester for preoperative cervical dilatation. Contraception 23: 251-259. WHO Prostaglandin Task Force (1982a) Termination of early first trimester pregnancy by vaginal administration of 16,16-dimethyl-trans-A 2 PGE1 methyl ester. Asia Oceania Journal of Obstetrics and Gynaecology 8: 263-268. WHO Prostaglandin Task Force (1982b) Termination of second trimester pregnancy by intramuscular injection of 16-phenoxy-~o-17,18,19,20-tetranor PGE2 methyl sulfonylamide. International Journal of Obstetrics and Gynecology 20: 383-386.
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903
WHO Prostaglandin Task Force (1986) Randomized comparison of different prostaglandin analogues and laminaria tent for preoperative cervical dilatation. Contraception 34: 237251. WHO Task Force on Postovulatory Methods for Fertility Regulation (1987) Menstrual regulation by intramuscular injections of 16-phenoxy-tetranor PGE2 methyl sulfonylamide or vacuum aspiration. A randomized, multicenter study. British Journal of Obstetrics and Gynaecology 94: 949-956. WHO Prostaglandin Task Force (1988) Termination of second trimester pregnancy with laminaria and intramuscular 15-methyl PGF2~ or 16-phenoxy-~o-17,18,19,20-tetranor PGEz methyl sulfonylamide. A randomized multicentre study. International Journal of Obstetrics and Gynecology 26: 129-135.
Prostaglandin analogues and their uses MARC
BYGDEMAN
INTRODUCTION The prostaglandins of both the E and F groups are potent stimulants of the human uterus in vivo at any stage of pregnancy. They are extensively used clinically for termination of pregnancy and induction of labour. The main disadvantages of these compounds are a short half-life and the occurrence of gastrointestinal side-effects. The primary prostaglandins (prostaglandin F2~ (PGF2~) and PGE2) are rapidly metabolized in the body. The initial steps in the enzymatic degradation are the oxidation of the 15-hydroxy group to a keto group and the reduction of the 13,14 double bond. The resulting 15-keto13,14-dihydro compounds are essentially biologically inactive. When it comes to termination of pregnancy, these drawbacks are partly overcome by using intrauterine administration. Another alternative has been the development of prostaglandin analogues which are not substrates for the initial steps of enzymatic degradation by 15-dehydrogenase and have a more specific effect towards uterine rather than gastrointestinal muscle. A number of such analogues have been developed, some of which are in routine clinical use. These are 15(S)-15-methyl-PGF2~ (carboprost, Upjohn Company), 16phenoxy-17,18,19,20-tetranor-PGE2 methyl sulphonylamide (sulprostone, Schering AG) and 16,16-dimethyl-trans-A2-PGE1methyl ester (gemeprost, Rh6ne-Poulenc Rover). In contrast to the primary prostaglandins, these compounds can be administered by non-invasive routes, gemeprost vaginally and sulprostone and carboprost intramuscularly. Carboprost is also available for intravenous and intrauterine administration. The fact that the analogues are administered vaginally or intramuscularly has allowed an extended clinical use for pregnancy termination. In contrast to primary prostaglandins, which are mainly used for termination of second trimester pregnancy, the analogues are useful for termination of early pregnancy, for preoperative dilatation of the cervical canal and for termination of second trimester pregnancy. Prostaglandin analogues have so far not been tried for induction of labour at or near term. In this situation, the longer duration of action isa drawback. Baillibre's Clinical Obstetrics and Gynaecology-893 Vol. 6, No. 4, December 1992 Copyright © 1992, by Bailli~re Tindall ISBN 0-7020-1694-2 All rights of reproduction in any form reserved
894
M. BYGDEMAN
T E R M I N A T I O N OF EARLY P R E G N A N C Y
The possibility of using prostaglandins for termination of very early pregnancy has been evaluated since the beginning of the 1970s. The initial trials using PGF2~ or PGE2 were mainly discouraging. The only effective route was intrauterine administration and premedication was necessary to reduce the frequency of side-effects. If analogues are used the situation is somewhat different. Repeated or single vaginal administration of the methyl ester of carboprost has been shown to be highly effective. This is also true for vaginal administration of gemeprost and meteneprost (9-deoxo-16,16-dimethyl-9methylene PGE2, Upjohn Company) or intramuscular injection of sulprostone. In a comparative study, gemeprost and meteneprost administered vaginally, and sulprostone given as intramuscular injections were found to be equally effective. The frequency of complete abortion was between 92 and 94% if the treatment was limited to the first 3 weeks following the first missed menstrual period. With the PGE analogues the side-effects were limited to occasional vomiting and diarrhoea in approximately 50% of the patients (Bygdeman et al, 1983). Even self-administration at home was shown to be possible (Bygdeman et al, 1984). The treatment results in an increase in uterine contractility followed by bleeding, which generally starts 3-6 hours after the initiation of therapy and lasts for 1-2 weeks. Most patients abort during the first 24 hours but minor residues of the conceptus without clinical importance may remain in the cavity for several weeks (Mandelin, 1978). The bleeding is described by most patients as heavier than a menstrual period but it does not generally affect the haemoglobin values. Heavy blood loss and pelvic infection occur in less than 2% of the patients (WHO Prostaglandin Task Force, 1982a). In a recent randomized study including 473 women, in whom repeated intramuscular injections of 0.5 mg of sulprostone were administered, this administration was shown to be equally effective as vacuum aspiration in terminating early pregnancy (WHO Prostaglandin Task Force, 1987). In spite of the fact that in an acceptability study both prostaglandin and vacuum aspiration was equally appreciated (Rosdn et al, 1984), no pharmaceutical company has introduced a prostaglandin analogue for termination of early pregnancy. It was not until the introduction of antiprogestin and its use in combination with prostaglandin analogues that a medical method to terminate pregnancy started to be accepted. The only antiprogestin in clinical use is R U 486 (mifepristone, Roussel Uclaf). Mifepristone is a progesterone receptor blocker which interferes with the action of progesterone at the target organ level (Baulieu, 1985). Treatment with mifepristone during early pregnancy will, after a latency period of 24-36 hours, result in increased uterine contractility due to withdrawal of progesterone inhibition of myometrial activity (Swahn and Bygdeman, 1988). It is possible that this treatment also to some extent stimulates endogenous PGF2~ production (Smith and Kelly, 1987), and the sensitivity of the myometrium to prostaglandin will be significantly increased (Swahn and Bygdeman, 1988). Although progesterone is regarded as essential for the maintenance of early pregnancy, treatment with mifepristone alone will
895
PROSTAGLANDIN ANALOGUES
not be sufficiently effective in terminating early pregnancy to compete with vacuum aspiration. However, if a small dose of prostaglandin analogue is added, the efficacy of treatment increases to almost 100% (Bygdeman and Swahn, 1985). The difference in efficacy of the different procedures to terminate early pregnancy is illustrated in a comparative study by Cameron and Baird (1988). Complete abortion occurred more often in women treated with vacuum aspiration (96%), gemeprost alone (97%) and mifepristone plus gemeprost (95%) than in those treated with mifepristone alone (60%). The treatments used were 1.0 mg of gemeprost every third hour five times; 150 mg of mifepristone daily for 4 days plus 1.0 mg gemeprost on day 3; and 150 mg mifepristone alone given daily for 4 days, respectively. While the combined treatment was equally effective as gemeprost alone, side-effects and analgesic requirements were much reduced in the women who received mifepristone alone or in combination with a single gemeprost pessary. Mifepristone is at present registered for clinical use in France and the UK. Registration is expected in the Scandinavian countries by late 1992. Approximately 30% of all early abortions in France are treated with a combination of mifepristone and a prostaglandin analogue. A common treatment is a single dose of 600 mg of mifepristone followed 48 hours later by either 1.0 mg of gemeprost or an intramuscular injection of 0.25--0.50 mg of sulprostone. Silvestre et al (1990) have recently summarized the French experience of routine clinical use of the procedure, including 2115 early pregnant women (Table 1). The overall frequency of complete abortion was 96% with very little difference between the different dose schedules. Table 1. Termination of early pregnancy with 600mg of mifepristone followed 48 hours later by either 1,0mg of cervagem or 0,250.5 mg of sulprostone (Silvestre et al, 1990). Outcome of therapy Complete abortion Incomplete abortion Pregnancy continuation Haemostatic procedure Fever (infection)
Patients (%) 96.0 2.1 1.0 0.9 0.3
However, the frequency of uterine pain was significantly lower with 0.25 mg of sulprostone and 1.0 mg of cervagem (14.9 and 21.3%, respectively) than with 0.375 and 0.5 mg of sulprostone (33.3 and 51.2%, respectively). Almost all patients started to bleed on the second day following mifepristone treatment and the mean duration of bleeding was between 7 and 12 days. The frequency of heavy bleeding needing curettage was, however, low (0.9%). Fever as a sign of infection was also very uncommon (0.3%) in the French study. The frequency of heavy bleeding and fever compares favourably with that often reported after vacuum aspiration performed during the first trimester of pregnancy. Serious complications associated with the therapy are very rare. However, one death has been reported. It occurred in
896
M. BYGDEMAN
association with the administration of sulprostone and the cause was a spasm in the coronary artery resulting in a massive infarction. The reason for this was unclear, but, since the woman was a heavy smoker, the pharmaceutical company has recommended that heavy smokers should not be treated with this therapy. The best dose schedule of mifepristone and a prostaglandin analogue remains to be established. It is very likely, however, that the dose of mifepristone may be significantly reduced to 200 or even 50 mg. It is also likely that 0.5 mg of gemeprost would be sufficient. Very recently, the combination of mifepristone and the orally active prostaglandin analogue misoprostol (15(S)-15-methyl-PGE2 methyl ester, Searle AG) has been evaluated. Misoprostol is used in many countries for the treatment of gastric ulcers. It is considerably cheaper and more stable than cervagem and sulprostone. Preliminary studies indicate that a combination of 200 mg of mifepristone and 600 ~xg of misoprostol may be equally effective as previously described combinations (Aubernu and Baulieu, 1991; Norman et al, 1991). A potential problem with misoprostol is the risk of fetal malformations if the pregnancy continues in spite of treatment (Sch6nh6fer, 1991). PREOPERATIVE CERVICAL DILATATION Vacuum aspiration is the preferred method for termination of first and early second trimester pregnancy in many countries. If the procedure is performed after the seventh week of gestation, dilatation of the cervical canal is necessary. The need for greater mechanical dilatation of the cervix causes an increased risk of cervical laceration and uterine perforation and may have an adverse long-term effect on subsequent fertility. In addition, complications such as haemorrhage and incomplete evacuation of the products of conception may arise as a result of insufficient or difficult dilatation. For these reasons a variety of procedures has been investigated with the aim of developing a simple and safe method for preparing the cervix before dilatation and suction or mechanical curettage. Two alternatives are mainly used, either administration of prostaglandins or a cervical dilator such as a laminaria tent or lamicel, a synthetic hydrophilic polymer impregnated with magnesium sulphate. That prostaglandins can be used for this purpose was suggested at the start of the 1970s. A large number of studies have been published illustrating the advantages and disadvantages of prostaglandin treatment. In this review, reference will mainly be made to two large World Health Organization (WHO) studies. For more detailed references, the reader is referred to Lauersen (1986) and Herczeg (1990). The first large clinical study was published some 10 years ago by the WHO Prostaglandin Task Force (1981). In this multicentre study with over 1000 patients, pretreatment with a vaginal suppository containing 1.0mg of 15-methyl-PGF2~ methyl ester was randomly compared with placebo. The pretreatment time was either 3 or 12 hours. The study showed that a 3 hour pretreatment period resulted in a significant degree of cervical dilatation,
897
PROSTAGLANDIN ANALOGUES
fewer operative complications, shorter duration of postoperative bleeding and a lower frequency of recurettage and treatment of infection in comparison with pretreatment with placebo. The drawback of the treatment was a higher frequency of uterine pain and gastrointestinal side-effects with the active suppositories. These problems seem to be substantially reduced if PGE analogues are used instead. Both 1.0mg of gemeprost administered vaginally and 0.5 mg of sulprostone given as an intramuscular injection are extensively used for cervical dilatation at present. Both compounds have been randomly compared in another WHO study (WHO Prostaglandin Task Force, 1986). Included in that study were also vaginal administration of meteneprost, the methyl ester of carboprost, and one laminaria tent (Table 2). The study showed that all three PGE analogues were equally effective as Table 2. Randomized comparison between the laminaria tent, 1.0 mg of gemeprost and 0.5 mg of sulprostone for preoperative dilatation of the cervical canal. Outcome after 3 hours. Mean values + SD. Percentage of patients with Method Laminaria tent Gemeprost Sulprostone
Degree of cervical dilatation (mm)
Vomiting
Diarrhoea
Analgesic injection
Bloodloss (ml)
6.9 _+1.5" 7.4 + 2.1 7.7 + 2.2*
0* 6.4* 14.3"
0.8 0.8 4.8
0* 10.3" 4.0
67.9 _+45.8 57.5 _+56.3 57.3 + 43.2
From WHO Prostaglandin Task Force (1986). * Significant difference, p < 0.05.
one medium-sized laminaria tent and more effective than the PGF analogue after 3 hours. Both types of treatment are associated with a low frequency of side-effects. With the three PGE analogues the percentage of patients experiencing occasional episodes of vomiting varied from 6.4 to 14.3% and of diarrhoea from 0.8 to 4.8%. The frequency of vomiting was significantly higher than for a laminaria tent, but not statistically different for diarrhoea. Prostaglandin therapy has a practical advantage over the laminaria tent. The introduction of the tent, which is not always easy, has to be performed by medical staff, whereas prostaglandin treatment can be overseen by paramedical personnel. Based on these and other studies, The Medical Advisory Committee of the International Planned Parenthood Federation has recommended either prostaglandin therapy or a laminaria tent to be used prior to vacuum aspiration in first trimester abortion (Editorial, 1984). Pretreatment with, for instance, gemeprost followed by vacuum aspiration may also be used during the first 2 weeks of the second trimester instead of conventional two-stage procedures. In a recent study comprising 1000 patients, the outcome of vacuum aspiration up to the 15th week of gestation was evaluated. All late first trimester primipara patients were pretreated with prostaglandin for 3 hours and the patients in early second trimester for 12 hours (Fried et al, 1989). Normally, the frequency of complications increases with gestational age. In this study, the overall complication rate
898
M. BYGDEMAN
was around 5% and the same in all stages of pregnancy, indicating that, if pretreatment with prostaglandin is used, vacuum aspiration can be safely carried out even in early second trimester abortion. SECOND TRIMESTER PREGNANCY
Intra-amniotic and extra-amniotic administration of PGF2, and extraamniotic administration of PGE2 is widely used for termination of second trimester pregnancy. An alternative is intra-amniotic injection of carboprost. This PGF2~ analogue is more potent and has a longer duration of action. The half-life of the analogue in amniotic fluid is approximately double that of PGF2~ itself (Gr6en et al, 1976). Intra-amniotic administration of this analogue has been evaluated on a large scale in two multicentre studies involving 2506 subjects. A single dose of 2.5 mg of carboprost was compared randomly with either 40 or 50 mg of PGF2~ (WHO Prostaglandin Task Force, 1977a; Tejuja et al, 1978). With a success rate of almost 95%, the analogue was significantly more effective than PGF2~ (81-88%). The mean inductionto-abortion interval (18-20 hours) and the frequency of complete abortion (about 50%) were similar with both compounds, and gastrointestinal sideeffects were within clinically acceptable limits. Injuries to the cervix were observed in 2.9 % of the patients with both compounds in the WHO study, but were more common following treatment with 50 mg of PGF2, in the Indian study. If a single-injection method is aimed at, carboprost seems to be a better alternative than the parent compound. The most important advantage of the analogues carboprost, sulprostone and gemeprost is that these compounds can be administered by non-invasive routes. Some of the major complications associated with second trimester abortion are due to an inadvertent intravenous injection of the compound when it is administered intra-amniotically. If the vaginal or intramuscular route is used, such complications are avoided. These routes offer the additional advantage that the treatment is equally useful during both the early and late parts of the second trimester. All three analogues have been used for termination of second trimester pregnancy. The results of a multicentre study performed by the WHO Prostaglandin Task Force (1977b) showed that repeated intramuscular injections of carboprost (initial dose 0.2mg followed by 0.3mg every 3 hours) was an effective method. About 85% of the patients aborted within 30 hours. The treatment was, however, associated with a high frequency of gastrointestinal side-effects. It was therefor.e concluded that this method has limited value as a primary abortion method but can be useful in order to complete the abortion process when another method has failed. If sulprostone is used instead, the efficacy seems equally good, but the frequency of gastrointestinal side-effects are lower (WHO Prostaglandin Task Force, 1982). The efficacy of the treatment can be increased if the patients are pretreated with one laminaria tent. In a multicentre study performed by the WHO Prostaglandin Task Force (1988) 529 patients in the 13th to 22nd week of pregnancy who received this pretreatment were then randomly allocated
PROSTAGLANDIN ANALOGUES
899
either 0.25 mg of carboprost every second hour or 0.5 mg of sulprostone every fourth hour. Both treatment schedules were equally effective. The success rate was 95.6 and 94.5% for the PGE and PGF analogues, respectively, within 24 hours from start of prostaglandin therapy. The mean duration of prostaglandin administration was 10.8 hours and 11.3 hours, respectively. The study also showed that the treatment with sulprostone was associated with a significantly lower frequency of gastrointestinal sideeffects than carboprost. With the former compound, 16.8% of the patients experienced occasional episodes of diarrhoea. The corresponding figure for vomiting was 41.1%. These figures are only slightly higher than those normally reported for intra-amniotic administration of hypertonic saline and comparable to those following intrauterine administration of PGEa or PGF2~. Although studies randomly comparing vaginal administration of gemeprost and intramuscular injection of sulprostone have not been performed, available data indicate that the vaginal approach is an equally good alternative. The dose of gemeprost mainly used is 1.0 mg every 3 hours five times. If the abortion has not occurred within 24 hours, a further course of five pessaries is prescribed. When this treatment was given to 113 women in the 12th to 16th week of pregnancy, 82% of the patients aborted within 24 hours and an additional 14% during the second 24 hour period, giving an overall success rate of 96%. Vomiting and diarrhoea occurred in 14 and 20%, respectively (Cameron et al, 1987). In a more recent study, pregnancies up to the 18th week were included with equally good results (Rodger and Baird, 1990). Vaginal administration of gemeprost has also been shown to be equally effective as extra-amniotic administration of PGE2. The treatment with gemeprost was less painful, and the simplicity of the treatment was another advantage appreciated by both patients and staff (Cameron and Baird, 1984) (Table 3). Some recent studies indicate that pretreatment with an antiprogestin will increase the efficacy of prostaglandin treatment during the second trimester. If 200 mg of mifepristone was administered 24 hours prior to extra-amniotic administration of PGE2 both the induction-to-abortion interval and total dose of PGE2 were significantly reduced in comparison to pretreatment with placebo (Urquhart and Templeton, 1987). In another study patients were randomly allocated to receive either 600 mg of mifepristone or placebo prior to vaginal administration of 1.0mg of cervagem every third hour. In the mifepristone pretreated group, 94% of the patients aborted within 24 hours compared with 80% of the placebo group. The median interval between administration of prostaglandin and abortion was significantly shorter in the mifepristone group (6.8 hours) compared with the placebo group (15.8 hours). The women pretreated with mifepristone also reported significantly less pain than the women who received placebo (Rodger and Baird, 1990). The outcome of a third study indicates that a combination of mifepristone and vaginal prostaglandin therapy may be highly effective even in late second trimester pregnancy (up to the 23rd week of gestation). In this study the patients were treated with either 200 mg of mifepristone orally or 0.5 mg of PGE2 administered into the cervical canal. Twenty-four hours later the
Intracervical Intramuscular Vaginal Oral Vaginal Oral Vaginal
0.5 mg every 4th hour
1.0 mg every 3rd hour 600 mg L 0 mg every 3rd hour 200 mg 5.0 mg every 4th hour
Laminaria + sulprostone
Cervagem Mifepristone + cervagem
Mifepristone + metheneprost
Intra-amniotic
Route of administration
Dose
2,5 mg
Compound
Carboprost
100
82 94
95.6
24 hours
96
94.4
48 hours
Success rate (%)
Gottlieb and Bygdeman (1991)
WHO Prostaglandin Task Force (1977a) WHO Prostaglandin Task Force (1988) Cameron et al (1987) Rodger and Baird (1990)
Reference
Table 3. Termination of second trimester pregnancy by different prostaglandin analogues. Selected studies.
:z
c~ ~J
',D
PROSTAGLANDIN ANALOGUES
901
patients received 5 mg of meteneprost every fourth hour for up to 24 hours. All patients pretreated with mifepristone aborted within 24 hours while, following pretreatment with intracervical PGE2, three patients out of 21 needed additional treatment. Pretreatment with mifepristone resulted in a shorter induction-to-abortion interval, a reduction in the total dose of meteneprost and less pain in comparison with pretreatment with intracervical PGE2 gel (Gottlieb and Bygdeman, 1991). CONCLUSIONS The development of prostaglandin analogues represents a major breakthrough in abortion technology. In combination with the antiprogestin mifepristone, both vaginal administration of gemeprost and intramuscular injection of sulprostone have been demonstrated to be highly effective in terminating early pregnancy. This non-surgical method is increasingly used as an alternative to vacuum aspiration. In late first and early second trimester abortion, pretreatment with these analogues will significantly facilitate vacuum aspiration and reduce the frequency of both operative and postoperative complications. Both vaginal administration of gemeprost and intramuscular injections of sulprostone are highly effective methods of terminating mid- and late second trimester pregnancy. The simplicity of the therapy is an important advantage in comparison with intrauterine administration of abortifacient drugs. Preliminary data indicate that if the patients are pretreated with mifepristone the efficacy of the analogues will be further enhanced and both duration of labour and frequency of side-effects reduced. REFERENCES Auberny B & Baulieu EE (1991) Contragestion with RU 486 and an orally active prostaglandin. Comptes Rendus Hebdomadaires des SOances de l'AcadOmie des Sciences 312: 539-564. Baulieu EE (1985) RU 486: an antiprogestin steroid with contragestive activity in women. In Baulieu EE & Segal SJ (eds) The Antiprogestin Steroid RU 486 and Human Fertility Control, pp 1-25. New York: Plenum Press. Bygdeman M & Swahn ML (1985) Progesterone receptor blockage. Effect on uterine contractility in early pregnancy. Contraception 32: 45-51. Bygdeman M, Christensen NJ & Gr6en K (1983) Termination of early pregnancy--future development. Acta Obstetrica et Gynecologica Scandinavica supplement 113: 125-129. Bygdeman M, Christensen N J, Gr6en K & Vesterqvist O (1984) Self-administration at home of prostaglandin for termination of early pregnancy. In Toppozada M, Bygdeman M & Hafez ESE (eds) Advances in Reproductive Health Care, pp 83-90. Lancaster: MTP Press. Cameron IT & Baird DT (1984) The use of 16,16-dimethyl-trans-Az prostaglandin E1 methyl ester (gemeprost) vaginal pessaries for the termination of pregnancy in the early second trimester. A comparison with extra-amniotic prostaglandin E2. British Journal of Obstetrics and Gynaecology 91" 1136--1140. Cameron IT & Baird DT (1988) Early pregnancy termination--a comparison between vacuum aspiration and medical abortion using prostaglandin (16,16-dimethyl-trans-A2 PGE1 methyl ester) or the antiprogestogen RU-486. British Journal of Obstetrics and Gynaecology 95: 271-276.
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M. BYGDEMAN
Cameron IT, Micbie A F & Baird DT (1987) Prostaglandin-induced pregnancy termination: further studies using gemeprost (16,16-dimethyl-trans-A 2 PGE1 methyl ester) vaginal pessaries in the early second trimester. Prostaglandins 34: 111-117. Editorial .(1984) 1PPF Medical Bulletin 18: 2-4. Fried G, Ostlund E, Ullberg C & Bygdeman M (1989) Somatic complications and contraceptive techniques following legal abortion. Aeta Obstetrica et Gynecologica Scandinavica 68: 515-521. Gottlieb C & Bygdeman M (1991) The use of antiprogestin (RU 486) for termination of second trimester pregnancy. Acta Obstetrica et Gynecologica Scandinavica 70: 199-203. Gr6en K, Granstr6m E, Bygdeman M & Wiqvist N (1976) Kinetic and metabolic studies of 15-methyl PGF2~ administered intraamniotically for induction of abortion. Prostaglandins 11: 69%711. Herczeg J (1990) Pretreatment of the cervix prior to surgical evacuation of the uterus in the late first and early second trimester of pregnancy. Bailli~re's Clinical Obstetrics and Gynaecology 4(2): 307-326. Lauersen NH (1986) Induced abortion. In Bygdeman M, Berger GS & Keith L (eds) Prostaglandins and their Inhibitors in Clinical Obstetrics and Gynaecology, pp 271-314. Lancaster: MTP Press. Mandelin M (1978) Termination of early pregnancy by a single-dose of 3.0 mg 15-methyl PGF2~ methyl ester vaginal suppository. Prostaglandins 16: 143-152. Norman JE, Thong KJ & Baird DT (1991) Uterine contractility and induction of abortion in early pregnancy by mesoprostol and mifepristone. Lancet 338: 1231-1236. Rodger MW & Baird DT (1990) Pretreatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. British Journal of Obstetrics and Gynaecology 97: 41-45. Ros6n A-S, yon Knorring K, Bygdeman M & Christensen NJ (1984) Randomized comparison of prostaglandin treatment in hospital or at home with vacuum aspiration for termination of early pregnancy. Contraception 29: 423-435. Sch6nh6fer PS (1991) Misuse of misoprostol as an abortifacient may induce malformations. Lancet 337: 1534-1535. Silvestre L, Dubois C, Renault M, Rezvani Y, Baulieu EE & Ulmann A (1990) Voluntary interruption of pregnancy with mifepristone (RU 486) and a prostaglandin analogue. New England Journal of Medicine 322: 645-648. Smith SK & Kelly RW (1987) The effect of the antiprogestins RU-486 and ZK 98.734 on the synthesis and metabolism of prostaglandins F2~ and E2 in separated cells from early human decidua. Journal of Clinical Endocrinology and Metabolism 65: 527-534. Swahn ML & Bygdeman M (1988) The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin. British Journal of Obstetrics and Gynaecology 95: 126--134. Tejuja S, Choudhury SD & Manchanda PK (1978) Use of intra- and extra-amniotic prostaglandin for the termination of pregnancies. Report of multicentric trial in India. Contraception 18: 641-652. Urquhart DR & Templeton AA (1987) Mifepristone (RU 486) and second trimester pregnancy. Lancet ii: 1405. WHO Prostaglandin Task Force (1977a) Comparison of single intra-amniotic injection of 15-methyl prostaglandin F2~ and prostaglandin F2~ for termination of second trimester pregnancy. An international multicentre study. American Journal of Obstetrics and Gynecology 129: 597-600. WHO Prostaglandin Task Force (1977b) Intramuscular administration of 15-methyl prostaglandin F2~ for induction of abortion in weeks 10 to 20 of pregnancy. American Journal of Obstetrics and Gynecology 129: 593-600. WHO Prostaglandin Task Force (1981) Vaginal administration of 15-methyl PGF2, methyl ester for preoperative cervical dilatation. Contraception 23: 251-259. WHO Prostaglandin Task Force (1982a) Termination of early first trimester pregnancy by vaginal administration of 16,16-dimethyl-trans-A 2 PGE1 methyl ester. Asia Oceania Journal of Obstetrics and Gynaecology 8: 263-268. WHO Prostaglandin Task Force (1982b) Termination of second trimester pregnancy by intramuscular injection of 16-phenoxy-~o-17,18,19,20-tetranor PGE2 methyl sulfonylamide. International Journal of Obstetrics and Gynecology 20: 383-386.
PROSTAGLANDIN ANALOGUES
903
WHO Prostaglandin Task Force (1986) Randomized comparison of different prostaglandin analogues and laminaria tent for preoperative cervical dilatation. Contraception 34: 237251. WHO Task Force on Postovulatory Methods for Fertility Regulation (1987) Menstrual regulation by intramuscular injections of 16-phenoxy-tetranor PGE2 methyl sulfonylamide or vacuum aspiration. A randomized, multicenter study. British Journal of Obstetrics and Gynaecology 94: 949-956. WHO Prostaglandin Task Force (1988) Termination of second trimester pregnancy with laminaria and intramuscular 15-methyl PGF2~ or 16-phenoxy-~o-17,18,19,20-tetranor PGEz methyl sulfonylamide. A randomized multicentre study. International Journal of Obstetrics and Gynecology 26: 129-135.
