Prostaglandins Leukotrienes and Essential 0 Longman Group UK Ltd 1991
Fatty Acids
(1991) 42, 177-179
Prostaglandin versus Expectant Management in Early Tubal Pregnancy C. Egarter,
H. Kiss and P. Husslein
1. Univ. Frauenklinik, Spitalgasse 23, A-1090 Vienna/Austria (Reprint requests to CE) ABSTRACT. Since ectopic pregnancy may terminate in spontaneous recovery we compared treatment by means of prostaghmdin (PG) application with expectant management in laparoscopically verified tubal gestations. Twelve patients received local and systemic PG, 4 patients were treated with sodium chloride and in 7 patients laparoscopy was discontinued without medical therapy. The comparison between the PG group and the placebo groups revealed a highly significant difference with regard to a subsequent necessary surgical intervention and hospitaliition. Expectant management may only be recommended in very selected cases, whereas PG treatment seems to produce favourable results in cases of early tubal pregnancy.
and participation in this study which was approved by an Ethical Committee. According to the principles defined by this Ethical Committee, all the patients gave informed written consent to be treated according to the protocol of this study. The patients were informed of the preliminary character of the procedure, the possibility of laparotomy in case of sudden pain or a rise in serum hCG concentration and agreed to comply with the requirements for clinical and biologic monitoring. If the diagnosis of an unruptured ectopic pregnancy exhibiting no acute bleeding was confirmed by a’laparoscopy, the patients were randomised into three groups. In 12 patients (group A) 10 mg PGF2alpha (1.5-2 ml; Minprostin F2alpha, Upjohn, Vienna, Austria) were injected transabdominally into the tubal extension using a 17 gauge needle. During this slow application, heart frequency and blood pressure were closely monitored (8). An additional dose of 25 mg conjugated estrogens was injected into the ipsilateral ovary. During the first 3 postoperative days, the patients received 500 mg twice daily of a synthetic PGE2 derivative (Sulprostone, Nalador, Schering, Berlin, FRG) administered intramuscularly. The comparison group was randomised as follows: 4 patients (group B) received an intratubal dose of 1.5-2 ml isotonic sodium chloride (NaCl) solution; another 7 patients (group C) received no medical therapy with laparoscopy being terminated after verification of the tubal pregnancy. In all patients hCG serum levels were determined at l-3 day intervals on an outpatient basis by
Ectopic pregnancy can be treated successfully without surgical intervention to the tube. These methods are often used in conjunction with a diagnostic laparoscopic procedure or ultrasound. Methotrexate (1, 2)) hypertonic sodium chloride solutions (3) and, although still without success, antiprogesterone (4) have been described in several studies to manage unruptured ectopic pregnancies. Based on in vitro studies (5, 6) and on the observation that termination of early pregnancy with prostaglandin (PG) analogues was not associated related to tubal pregnancies, with problems PGF2alpha was used as a new approach in preliminary studies (7-9). Since in various studies spontaneous resolution of tubal pregnancy could be demonstrated (lO-12), the purpose of this study was to compare our combined local and systemic PG application with expectant nonintervention.
PATIENTS AND METHODS The patients included in this study presented with suspected unruptured ectopic pregnancy suggested by history, clinical examination and ultrasound. The initial plasma human chorionic gonadotropin (hCG) concentration had to be less than 2500 mIU/ml serum. After detailed information the patient had to choose between conventional management such as the use of laparoscopic techniques or laparotomy
Date received 18 July 1990 Date accepted 20 November 1990 177
178
Prostaglandins Leukotrienes
and Essential Fatty Acids
means of a kit that is specific for the P-subunit of hCG (Serono, 1251 anti-hCG, Freiburg, FRG). Postoperatively the patients were informed as to their individual situation and - if possible - released on the 2nd postoperative day. The P-hCG determinations were performed at longer intervals in patients showing a definite decline in P-hCG level. Because of the unconventional procedure and the possible occurrence of very risky situations for the patients, intermediate analyses were planned in order to stop the study as soon as a statistical trend for any of the groups could be demonstrated. Statistically it was estimated that a sample of about 20 patients per group would be initially required. The data are expressed as mean + standard deviation and statistical comparison was done by the chisquare test.
PGF,a 2500 II-hCG ImlUlmlt
1
Fig. la
10
5
15
days
B-hCG values in tubal pregnancies treated by means removal of pregnancy
RESULTS The study was terminated after the first intermediate analysis when 23 patients had been enrolled. Of the 12 patients in group A only 3 had to undergo a second operation with surgical removal of the involved tube. In 2 patients this was because of postoperatively rising P-hCG values and in 1 patient because of clinical symptoms. Severe side effects of the PG application were not observed. The only patient in the control groups, who did not require laparotomy exhibited an initial P-hCG of 121 mIU/ml and was treated by NaCl. In all other patients rising @hCG values or an increase in abdominal symptoms necessitated surgical removal of the tubal pregnancy. However, intraoperatively only 1 patient exhibited an imminent rupture showing the tubal tumor covered by peritoneum only. In the other patients the size of the tubal bulge did not differ significantly from the former laparoscopic estimation. The therapeutic results in the different treatment groups are summarised in Table 1. Groups B and C differed highly significantly (p < 0.0015; chi-square test) from the prostaglandin group. On subdividing the results according to the initial highest P-hCG value, a relatively even distribution within the entire spectrum of 2500 mIE/ml P-hCG could be demonstrated (Figs la & b). Table 1 Success rate in the different treatment
B NaCl
C nihil
9
1
-
3
3
7
Group PGF>GE&, Success Secondary operation
groups
Difference between Group A versus B/C statistically significant (p < 0.0015; chi-square test)
2500
-
2000
-
1500
-
IODO
-
500
7
fl-HCC (muirnIl
I-
I
1
5
10
15
20
days
Fig. lb j%hCG values in tubal pregnancies with NaCl or expectant management J. indicates surgical removal of pregnancy
Hospitalisation in group A patients was significantly reduced (2-5 days) in comparison to groups B and C where 10 of the 11 patients had to undergo secondary laparotomy (5-14 days). The interval between laparoscopic verification of the tubal pregnancy and a necessary operation was between 3-19 days and exhibited a wide range of scatter in all groups. The postoperative course was uneventful in all surgically treated patients.
DISCUSSION For a long time it has been known that ectopic pregnancy may terminate in spontaneous recovery. The first such extrauterine gestation was described by Albucazis in 963 AD; he recorded a case in which the fetal parts escaped through the abdominal wall by suppuration and the patient recovered. Also Te-
Prostaglandins vs Expectant Management in Early Tubal Pregnancy
Linde (13) mentioned the spontaneous healing of tubal pregnancy in his textbook which appeared in 1946. However, strictly expectant management was not evaluated until recently. Mashiach (10) and Fernandez (11) reported a few cases in which selected, laparoscopically verified tubal pregnancies whose phCG showed static or falling levels and whose diameter did not exceed 2 cm were treated expectantly by continuous clinical and biologic monitoring. In some of these patients no further surgical procedure was necessary and some exhibited tubal patency later. In contradistinction, Cole and Corlett (14) found dense adhesions in 72% of patients with ‘chronic ectopic gestations’, and Gomel and Filmar (15) demonstrated that chorionic villi are capable of surviving and causing tubal destruction for at least 15 months after the demise of a pregnancy, which is why they argued against expectant management. The possible spontaneous resolution of some tubal pregnancies is beyond doubt; however, it is still unclear which group of patients may profit from such management. Since the risk of treatment is negligible today, awaiting spontaneous resolution is only interesting from a theoretical point of view and should only be recommended in very selected cases. The present study, which wds terminated for ethical reasons, does not support strictly expectant management. There was a highly significant difference between the PG treated group and the expectant and NaCl-treated group. Only 1 of 11 patients demonstrated a spontaneous recovery of her ectopic pregnancy in these series. The fact that success rates are reported to be higher in other studies (10, 11, 16, 17) may be explained by the unselected entry criteria in the present study. The therapeutic effect of PG in this indication requires further evaluation. Since our initial favourable results were based on the combined application of local and systemic PG we did not change the scheme in this investigation. However, further studies are needed to determine whether such combined application is necessary. Acknowledgements This study was partly supported by the Medizinisch - wissenschaftlicher Fonds des Biirgermeisters der Bundeshauptstadt Wien and by the Japan Society for the Promotion of Science.
References 1. Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto T, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982; 37: 851. 2. Ichinoe K, Wake N, Shinkai N, Shiina Y, Miyazaki Y, Tanaka T. Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancy. Am J Obstet Gynecol 1987; 156: 484. 3. Lang P F, Weiss P A M, Mayer H 0, Haas J G, Hnigl W. Conservative treatment of ectopic pregnancy with local injection of hyperosmolar glucose solution or prostaglandin F%lpha: a orosoective randomized studv. Lancet 1990: 336: 78. 4. Kenigsberg D, Porte J, Hull’M, Spitz I M. ‘Medical treatment of residual ectopic pregnancy: RU 486 and methotrexate. Fertil Steril 1987; 47: 702. 5. Hahlin M, Bokstrom H, Lindblom B. Ectopic pregnancy: in vitro effects of prostaglandins on the oviduct and corpus luteum. Fertil Steril 1987; 47: 935. 6. Lindblom B, Hamberger L, Wiqvist N. Differentiated contractile effects of prostaglandins E and F on the isolated circular and longitudinal smooth muscle of the human oviduct. Fertile Steril 1978; 30: 553. ’ 7. Lindblom B, Kallfelt B, Hahlin M, Hamberger L. Local prostaglandin F2alpha-injection for termination of ectopic pregnancy. Lancet 1987; 4: 776. 8. Egarter Ch. Husslein P. Treatment of Ectopic Pregnancy by Means of Prostaglandins. Prostagl Leucotr 1989; 35: 91. 9. Egarter Ch, Fitz R, Husslein P. New treatment of tubal pregnancy by PC F2alpha and PG E,. Arch Ohstet Gynecol 1989; 245: 413. 10. Mashiach S, Carp H J, Serr D M. Nonoperative management of ectopic pregnancy: preliminary report. J Reprod Med 1982; 27: 127. 11. Fernandez H, Rainhom J D, Papiernik E, Bellet D, Frydman R. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988; 71: 171. 12. Garcia A J, Aubert J M, Sama J, Josimovich J B. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987; 48: 395. 13. TeLinde R W. Operative Gynecology, JB Lippincott, Philadelphia, 1946. 14. Cole T, Corlett R C. Chronic ectopic pregnancy. Obstet Gynecol 1982; 59: 63. 15. Gomel V, Filmar S. Arrested tubal pregnancy. Fertil Steril 1987; 48: 1043. 16. Kamrava M M, Taymor M L, Berger M J, Thompson I E, Seihel M M. Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy. Obstet Gynecol 1983; 62: 486. 17. Dericks-Tan J S E, Scholz C, Taubert H D. Spontaneous recovery of ectopic pregnancy: a preliminary report. Eur J Obstet -Gynecol -Reprod Biol 1987: 25: 181.
179
Fatty Acids
(1991) 42, 177-179
Prostaglandin versus Expectant Management in Early Tubal Pregnancy C. Egarter,
H. Kiss and P. Husslein
1. Univ. Frauenklinik, Spitalgasse 23, A-1090 Vienna/Austria (Reprint requests to CE) ABSTRACT. Since ectopic pregnancy may terminate in spontaneous recovery we compared treatment by means of prostaghmdin (PG) application with expectant management in laparoscopically verified tubal gestations. Twelve patients received local and systemic PG, 4 patients were treated with sodium chloride and in 7 patients laparoscopy was discontinued without medical therapy. The comparison between the PG group and the placebo groups revealed a highly significant difference with regard to a subsequent necessary surgical intervention and hospitaliition. Expectant management may only be recommended in very selected cases, whereas PG treatment seems to produce favourable results in cases of early tubal pregnancy.
and participation in this study which was approved by an Ethical Committee. According to the principles defined by this Ethical Committee, all the patients gave informed written consent to be treated according to the protocol of this study. The patients were informed of the preliminary character of the procedure, the possibility of laparotomy in case of sudden pain or a rise in serum hCG concentration and agreed to comply with the requirements for clinical and biologic monitoring. If the diagnosis of an unruptured ectopic pregnancy exhibiting no acute bleeding was confirmed by a’laparoscopy, the patients were randomised into three groups. In 12 patients (group A) 10 mg PGF2alpha (1.5-2 ml; Minprostin F2alpha, Upjohn, Vienna, Austria) were injected transabdominally into the tubal extension using a 17 gauge needle. During this slow application, heart frequency and blood pressure were closely monitored (8). An additional dose of 25 mg conjugated estrogens was injected into the ipsilateral ovary. During the first 3 postoperative days, the patients received 500 mg twice daily of a synthetic PGE2 derivative (Sulprostone, Nalador, Schering, Berlin, FRG) administered intramuscularly. The comparison group was randomised as follows: 4 patients (group B) received an intratubal dose of 1.5-2 ml isotonic sodium chloride (NaCl) solution; another 7 patients (group C) received no medical therapy with laparoscopy being terminated after verification of the tubal pregnancy. In all patients hCG serum levels were determined at l-3 day intervals on an outpatient basis by
Ectopic pregnancy can be treated successfully without surgical intervention to the tube. These methods are often used in conjunction with a diagnostic laparoscopic procedure or ultrasound. Methotrexate (1, 2)) hypertonic sodium chloride solutions (3) and, although still without success, antiprogesterone (4) have been described in several studies to manage unruptured ectopic pregnancies. Based on in vitro studies (5, 6) and on the observation that termination of early pregnancy with prostaglandin (PG) analogues was not associated related to tubal pregnancies, with problems PGF2alpha was used as a new approach in preliminary studies (7-9). Since in various studies spontaneous resolution of tubal pregnancy could be demonstrated (lO-12), the purpose of this study was to compare our combined local and systemic PG application with expectant nonintervention.
PATIENTS AND METHODS The patients included in this study presented with suspected unruptured ectopic pregnancy suggested by history, clinical examination and ultrasound. The initial plasma human chorionic gonadotropin (hCG) concentration had to be less than 2500 mIU/ml serum. After detailed information the patient had to choose between conventional management such as the use of laparoscopic techniques or laparotomy
Date received 18 July 1990 Date accepted 20 November 1990 177
178
Prostaglandins Leukotrienes
and Essential Fatty Acids
means of a kit that is specific for the P-subunit of hCG (Serono, 1251 anti-hCG, Freiburg, FRG). Postoperatively the patients were informed as to their individual situation and - if possible - released on the 2nd postoperative day. The P-hCG determinations were performed at longer intervals in patients showing a definite decline in P-hCG level. Because of the unconventional procedure and the possible occurrence of very risky situations for the patients, intermediate analyses were planned in order to stop the study as soon as a statistical trend for any of the groups could be demonstrated. Statistically it was estimated that a sample of about 20 patients per group would be initially required. The data are expressed as mean + standard deviation and statistical comparison was done by the chisquare test.
PGF,a 2500 II-hCG ImlUlmlt
1
Fig. la
10
5
15
days
B-hCG values in tubal pregnancies treated by means removal of pregnancy
RESULTS The study was terminated after the first intermediate analysis when 23 patients had been enrolled. Of the 12 patients in group A only 3 had to undergo a second operation with surgical removal of the involved tube. In 2 patients this was because of postoperatively rising P-hCG values and in 1 patient because of clinical symptoms. Severe side effects of the PG application were not observed. The only patient in the control groups, who did not require laparotomy exhibited an initial P-hCG of 121 mIU/ml and was treated by NaCl. In all other patients rising @hCG values or an increase in abdominal symptoms necessitated surgical removal of the tubal pregnancy. However, intraoperatively only 1 patient exhibited an imminent rupture showing the tubal tumor covered by peritoneum only. In the other patients the size of the tubal bulge did not differ significantly from the former laparoscopic estimation. The therapeutic results in the different treatment groups are summarised in Table 1. Groups B and C differed highly significantly (p < 0.0015; chi-square test) from the prostaglandin group. On subdividing the results according to the initial highest P-hCG value, a relatively even distribution within the entire spectrum of 2500 mIE/ml P-hCG could be demonstrated (Figs la & b). Table 1 Success rate in the different treatment
B NaCl
C nihil
9
1
-
3
3
7
Group PGF>GE&, Success Secondary operation
groups
Difference between Group A versus B/C statistically significant (p < 0.0015; chi-square test)
2500
-
2000
-
1500
-
IODO
-
500
7
fl-HCC (muirnIl
I-
I
1
5
10
15
20
days
Fig. lb j%hCG values in tubal pregnancies with NaCl or expectant management J. indicates surgical removal of pregnancy
Hospitalisation in group A patients was significantly reduced (2-5 days) in comparison to groups B and C where 10 of the 11 patients had to undergo secondary laparotomy (5-14 days). The interval between laparoscopic verification of the tubal pregnancy and a necessary operation was between 3-19 days and exhibited a wide range of scatter in all groups. The postoperative course was uneventful in all surgically treated patients.
DISCUSSION For a long time it has been known that ectopic pregnancy may terminate in spontaneous recovery. The first such extrauterine gestation was described by Albucazis in 963 AD; he recorded a case in which the fetal parts escaped through the abdominal wall by suppuration and the patient recovered. Also Te-
Prostaglandins vs Expectant Management in Early Tubal Pregnancy
Linde (13) mentioned the spontaneous healing of tubal pregnancy in his textbook which appeared in 1946. However, strictly expectant management was not evaluated until recently. Mashiach (10) and Fernandez (11) reported a few cases in which selected, laparoscopically verified tubal pregnancies whose phCG showed static or falling levels and whose diameter did not exceed 2 cm were treated expectantly by continuous clinical and biologic monitoring. In some of these patients no further surgical procedure was necessary and some exhibited tubal patency later. In contradistinction, Cole and Corlett (14) found dense adhesions in 72% of patients with ‘chronic ectopic gestations’, and Gomel and Filmar (15) demonstrated that chorionic villi are capable of surviving and causing tubal destruction for at least 15 months after the demise of a pregnancy, which is why they argued against expectant management. The possible spontaneous resolution of some tubal pregnancies is beyond doubt; however, it is still unclear which group of patients may profit from such management. Since the risk of treatment is negligible today, awaiting spontaneous resolution is only interesting from a theoretical point of view and should only be recommended in very selected cases. The present study, which wds terminated for ethical reasons, does not support strictly expectant management. There was a highly significant difference between the PG treated group and the expectant and NaCl-treated group. Only 1 of 11 patients demonstrated a spontaneous recovery of her ectopic pregnancy in these series. The fact that success rates are reported to be higher in other studies (10, 11, 16, 17) may be explained by the unselected entry criteria in the present study. The therapeutic effect of PG in this indication requires further evaluation. Since our initial favourable results were based on the combined application of local and systemic PG we did not change the scheme in this investigation. However, further studies are needed to determine whether such combined application is necessary. Acknowledgements This study was partly supported by the Medizinisch - wissenschaftlicher Fonds des Biirgermeisters der Bundeshauptstadt Wien and by the Japan Society for the Promotion of Science.
References 1. Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto T, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982; 37: 851. 2. Ichinoe K, Wake N, Shinkai N, Shiina Y, Miyazaki Y, Tanaka T. Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancy. Am J Obstet Gynecol 1987; 156: 484. 3. Lang P F, Weiss P A M, Mayer H 0, Haas J G, Hnigl W. Conservative treatment of ectopic pregnancy with local injection of hyperosmolar glucose solution or prostaglandin F%lpha: a orosoective randomized studv. Lancet 1990: 336: 78. 4. Kenigsberg D, Porte J, Hull’M, Spitz I M. ‘Medical treatment of residual ectopic pregnancy: RU 486 and methotrexate. Fertil Steril 1987; 47: 702. 5. Hahlin M, Bokstrom H, Lindblom B. Ectopic pregnancy: in vitro effects of prostaglandins on the oviduct and corpus luteum. Fertil Steril 1987; 47: 935. 6. Lindblom B, Hamberger L, Wiqvist N. Differentiated contractile effects of prostaglandins E and F on the isolated circular and longitudinal smooth muscle of the human oviduct. Fertile Steril 1978; 30: 553. ’ 7. Lindblom B, Kallfelt B, Hahlin M, Hamberger L. Local prostaglandin F2alpha-injection for termination of ectopic pregnancy. Lancet 1987; 4: 776. 8. Egarter Ch. Husslein P. Treatment of Ectopic Pregnancy by Means of Prostaglandins. Prostagl Leucotr 1989; 35: 91. 9. Egarter Ch, Fitz R, Husslein P. New treatment of tubal pregnancy by PC F2alpha and PG E,. Arch Ohstet Gynecol 1989; 245: 413. 10. Mashiach S, Carp H J, Serr D M. Nonoperative management of ectopic pregnancy: preliminary report. J Reprod Med 1982; 27: 127. 11. Fernandez H, Rainhom J D, Papiernik E, Bellet D, Frydman R. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988; 71: 171. 12. Garcia A J, Aubert J M, Sama J, Josimovich J B. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987; 48: 395. 13. TeLinde R W. Operative Gynecology, JB Lippincott, Philadelphia, 1946. 14. Cole T, Corlett R C. Chronic ectopic pregnancy. Obstet Gynecol 1982; 59: 63. 15. Gomel V, Filmar S. Arrested tubal pregnancy. Fertil Steril 1987; 48: 1043. 16. Kamrava M M, Taymor M L, Berger M J, Thompson I E, Seihel M M. Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy. Obstet Gynecol 1983; 62: 486. 17. Dericks-Tan J S E, Scholz C, Taubert H D. Spontaneous recovery of ectopic pregnancy: a preliminary report. Eur J Obstet -Gynecol -Reprod Biol 1987: 25: 181.
179
