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PART XI. EARLY PREGNANCY, PRENATAL DIAGNOSIS, AND ABORTION
Conservative Treatment of Ectopic Pregnancy" P. YLOSTALO, B. CACCIATORE, A. KOSKIMIES, M. KAARIAINEN, P. LEHTOVIRTA, P. MAKELA, R. SIEGBERG, U.-H. STENMAN, A. TENHUNEN, AND 0. YLIKORKALA Departments I and II of Obstetrics and Gynecology University of Helsinki Helsinki, Finland The development of diagnostic modalities, particularly the combined use of serum hCG assays and vaginal sonography, has improved diagnostic accuracy in early ectopic pregnancy' and consequently the possibilities of developing a treatment for this condition. Various nonsurgical methods have been used in the conservative treatment of ectopic pregnancy, such as puncture and aspiration, local potassium chloride, local prostaglandin, parenteral or local methotrexate, local hyperosmolar glucose, and expectant management only. In this context, salpingotomy made by laparoscopy is not considered conservative treatment. Of the treatments used, prostaglandins, methotrexate, hyperosmolar glucose solution, and expectant management have been successful. Puncture and aspiration seem insufficient, but large studies have not been reported. Potassium chloride has also been unsatisfactory.2 In five studies consisting of 124 treatment of ectopic pregnancy with local prostaglandin was successful in 81-100% of patients (TABLE1). A dose of0.5- 10 mg of prostaglandin F-2 alfa was injected by laparoscopy locally and in some studies also into the ovary and corpus luteum. Alternatively, 500 pg of prostaglandin E-2 was given parenterally twice daily for 3 days. With this treatment tubal patency was preserved in 88-92%. After injection into the ovary, hypotony, hypertension, and tachycardia related to the dose have been reported. Parenteral methotrexate has been given intramuscularly in doses of 0.4- 1.0 mg/kg usually four times every second day in combination with 0.1 mg/kg of citrovorum factor rescue every second day. In seven studies8-I4consisting of 171 patients the success rate was 83-10070 (TABLE2) and tubal patency after treatment 53-83%. As side effects, stomatitis and transient signs of impaired liver function were found in 18% of the patients on the average. Methotrexate has also been given by local injection during In laparoscopy or by ultrasound-guided vaginal puncture using a dose of 5-50 mg.15-21 seven studies consisting of 95 patients (TABLE3) the success rate was 78- 100%. Tubal patency was retained in 86- 100%. Side effects like stomatitis have occurred only when parenteral methotrexate was also given. In a study by Lang et aLZ250% glucose was injected locally by laparoscopy in 16 patients with a success rate of 100%. Tubal patency after this treatment was 88%, and no side effects occurred. Prostaglandin was used in 15 patients with a success rate of 87%, but severe abdominal pains occurred in 60% of the patients. Thus, local treatment of ectopic pregnancy with hyperosmolar glucose is an interesting alternative, requiring further studies. 'The study was supported by grants from the Academy of Finland and the Paul0 Foundation.
516
YLOSTALO et ai.: ECTOPIC PREGNANCY
517
In 1955 Lundz3studied expectant management of ectopic pregnancy in 119 patients. This study also included severe cases (TABLE4), and many patients were hospitalized for a long time. The success rate was 57%. Of those patients who desired pregnancy, 61% later became pregnant, and 46% had an intrauterine and 15% an ectopic pregnancy. In six other studies11*2k2* consisting of 84 patients the entry criteria were usually a size of the ectopic pregnancy of less than 3-5 cm in diameter, no signs of rupture, and no acute bleeding. In these the success rate was 71 - 100%. Resolution time varied considerably, and tuba1 patency after treatment was 70- 100%. The aim of our study was to evaluate expectant management and the frequency of spontaneous resolution in ectopic pregnancy. TABLE 1. Local Prostaglandin (PG) Treatment by Laparoscopy Author Lindblom et aL,’ 1987
Lindblom et al..‘ 1988 Egarter and Husslein, 1988
No. of Patients
Tubal Patency
Side Effects
100%
...
...
96%
...
...
90%
...
Elevated temperatures, hypertension, hypotony
81%
22/24
...
91%
7/8
...
Success
PG
9 F 2-alfa 0.5-1.5 mg or 15-methyl PGF 2-alfa 75 (+ into ovary) 23 F 2-alfa 10 F 2-alfa 10 mg (+2.5 mg into ovary) +PGE-2 2 X 500 Pg im daily for 3
Rate
S
Egarter et al..6 1989
71 F 2-alfa 7-10 mg (+ 25 mg conj. estrogene into ovary) PGE-2 der. 2 X 500 pg im daily for 3 days 11 F 2-alfa 0.75-1.5 mg (+ into ovarv)
+
Vejtorp et aL,’ 1989
MATERIALS AND METHODS From January 1989 to May 1990,207 patients were treated for ectopic pregnancies in the Helsinki University Central Hospital, and 48 of them were selected for expectant management (FIG. 1). The patients were examined by sonography using a vaginal transducer with an emission frequency of 5.0 mHz, and by estimation of serum hCG concentrations by an immunofluorometric assay (DELFIA, Pharmacia-Wallac, Turku, Finland) calibrated against the first International Reference Preparation (IRP).
ANNALS NEW YORK ACADEMY OF SCIENCES
518 TABLE 2.
Parenteral Methotrexate (MTX)Treatment
Author
No. of Patients
OW et a L 8 1986
6
Rodi et alL9 1986
7
Ichinoe et a1..lo 1987 Sauer et al.," 1987
23
Carson et al.,'= 1989 Stovall et a1.,l3 1989 Stovall et al..I4 1990
21
Success Rate
MTX 1 mg/kg im every 2nd day x 4 ( + CF) 1 mg/kg im every 2nd day x 4 ( + CF) 0.4 mg/kg im daily for 5 days 1 mg/kg im every 2nd day x 4 ( + CF) 1 mg/kg im X 1-4(+ CF) 1 mg/kg im X 1 - 4 ( + CF) 1 mg/kg im X 1-4(+ CF)
21
36 57
Tubal Patency
Side Effects
83%
...
100%
4/5
96%
10/19
95%
15/20
5 stomatitis SGOT elevation
91%
...
...
94%
...
1 stomatitis 2 SGOT elevation
95%
19/23
...
3 stomatitis 2 transient SGOT elevation 1 stomatitis 2 transient SGOT elevation 4 SGOT elevation
ABBREVIATIONS: CF = citrovorum factor; im = intramuscularly.
TABLE 3.
Local Methotrexate (MTX)Treatment
Author Leeton and Da~ison,'~ 1988 Feichtinger and Kerneter,l6 1989 Pansky et al,, I' 1989 Pansky et al.,ls 1989 Zakut et a1.,I9 1989
Kojima et al.," 1990 MCnard et a1.,l1 1990
No. of Patients
MTX
LAP/TV
Success Rate
Tubal Patency
Side Effects
2
50mg
TV
100%
...
...
9
10-50 mg
TV
78%
2/2
...
27
12.Ymg
LAP
89%
6/7
...
37
12.5-25 mg
LAP
...
19/21
...
10
12.5 mg 0.5 mg/kg im after 24 h 5-25 mg
+
LAP
80%
7/7
Stomatitis
LAP
100%
9/9
...
50 mg
TV
16%
...
...
9 17
ABBREVIATIONS: LAP = laparoscopy; TV = transvaginal
YLOSTALO et 01.: ECTOPIC PREGNANCY
519
TABLE 4. Expectant Management Author
Lurid:' 1955 Mashiach et al.." 1982 Carp et aZ.,25 1986 Garcia et 1987 Sauer et aL,I' 1987 Fernandez et a1..17 1988 Makinen et a1..281990
No. of Patients
Success Rate
Tuba1 Patency
119
57%
...
5
80%
2/2
14
79%
5/5
13
92%
7/10
5
100%
3/4
14
71%
6/6
33
82%
...
The selection criteria of patients with ectopic pregnancy were as follows: a falling level of serum hCG in two estimations at 2 days' interval, no signs of intrauterine pregnancy by vaginal sonography, a diameter of the ectopic pregnancy of less than 4 cm, and no signs of rupture or acute bleeding. The patients visited our outpatient department every 2-7 days for assay of hCG and vaginal sonography.
RESULTS In 68 patients (32.8%), salpingotomy or salpingectomy was performed by emergency laparotomy and in 91 (44.0%) by laparoscopy. In the 48 patients treated by expectant management, spontaneous resolution occurred in 3 1 (64.6%)patients corresponding to 15% of all ectopic pregnancies. In 17 (35.4%)patients salpingotomy was performed by laparoscopy (FIG.1) because of clinical symptoms such as abdominal pain, increasing adnexal mass or peritoneal fluid, or a constant or rising level of serum
pregnancy
68 (32.8%)
48 (23.2%)
91 (44.0%)
17 (35.4%)
Expectant
31 (64.6%)
1 Laparoscopy 52.2%
Spontaneous resolution 15.0%
FIGURE 1. Outcome of ectopic pregnancies in 207 patients.
ANNALS NEW YORK ACADEMY OF SCIENCES
520
hCG. In the expectant management group with spontaneous resolution serum hCG levels mostly normalized within 40 days (FIG.2). In three cases expectant management was continued despite a transiently increasing hCG level. In patients subjected to laparoscopy after an expectant management time of 2- 18 days, hCG levels decreased more slowly than in those with spontaneous resolution, and in many cases an increasing or constant level of serum hCG was observed (FIG.3). The volume of the abnormal adnexal mass measured by vaginal sonography was 0.5-35 cm3.The mass disappeared or diminished greatly within 25 days (5-45 days) in those with spontaneous resolution. In the group requiring laparoscopy after expectant management the volume of the adnexal mass was 1- 35 cm3at admission and it increased during follow-up. Other reasons for laparoscopy were clinical symptoms such as pain and an increasing volume of fluid in the cul-de-sac. Salpingotomy by laparoscopy was easy to perform in these cases. If the patients had had infertility problems, laparoscopy or hysterosalpingography (HSG) was performed 3 months later. Of our study group 60% of the patients did not have infertility problems. Three patients are already pregnant and have an intrauterine pregnancy. Tubal patency has been observed by HSG in two patients and by laparoscopy in two.
DISCUSSI 0N In the present study expectant treatment was initially used in 23% of the patients with ectopic pregnancy. In one third of the cases surgery was later performed. However, with increasing experience this figure can be reduced. In many patients spontaneous resolution would have occurred without surgery. Another advantage of expectant management was that surgery was more easily performed after 1-2 weeks than in the acute phase. Tubal patency has been observed after different kinds of conservative
ooooo
m
10000
-.
c 1000
1 v
(3
2
100 10
1
I
0
10
20 30 40 50 Day after start of follow-up
FIGURE 2. Serum hCG levels during follow-up of patients subjected to successful expectant treatment.
521
YLOSTALO et al.: ECTOPIC PREGNANCY
10000 -j
1000
100
1 0
10
20
30
Day after start of follow-up FIGURE 3. Serum hCG levels in patients initially selected for expectant management but later treated by salpingotomy.
treatment of ectopic pregnancy on average in 72-93% of the patients (TABLES1-4). These results are obviously at least as good as those obtained by conservative surgical treatment. However, tubal patency has seldom been tested after surgical treatment. In the study of Mitchell et aLZ9it was observed that conservative surgical treatment left a patent tube on the treated side in only 9 of 18 patients. In another study30postoperative hysterosalpingography showed patency of the involved tube in 80% and 89% of patients after linear salpingotomy by laparoscopy and laparotomy, respectively. Fertility after conservative surgical treatment was reviewed by Lavy et al. 31 After salpingostomy or salpingotomy, 45% had an intrauterine pregnancy and 12% a recurrent ectopic pregnancy. These figures correspond to those of Lundz3obtained by expectant management, 46% and 15%, respectively. On the basis of our experience we suggest the following management of ectopic pregnancy. If emergency surgery is not needed, hCG estimations and vaginal sonography are performed two times at 1-2 days' interval. If the hCG level is falling, expectant management can be used. During follow-up repeated hCG estimations and vaginal sonography are performed at an interval of 2-7 days until the hCG level becomes normal (below 10 U/L). If the patient has infertility problems or if vaginal sonography shows a persisting abnormal adnexal mass, HSG or laparoscopy is performed. If the hCG level starts to rise, active management is recommended. Of the treatments currently available, the recently described local delivery of methotrexate by transuterine tubal ~atheterizatiod~ appears attractive. The role of this treatment in relation to earlier mentioned medical and surgical procedures has to be established by further studies.
SUMMARY As a conservative nonsurgical treatment of an early ectopic pregnancy, local prostaglandin, parenteral or local methotrexate, local hyperosmolar glucose, and also expec-
522
ANNALS NEW YORK ACADEMY OF SCIENCES
tant management have been used successfully in selected cases. The success rate of conservative treatment has been 71%-100% and that of tubal patency after different kinds of conservative treatment 72-93% of patients. In the present study of expectant management in early ectopic pregnancy in patients with decreasing serum hCG levels, spontaneous resolution was observed in 64.6% of patients and in the total series of 207 ectopic pregnancies in 15.0% of patients. Expectant management of early ectopic pregnancy is recommended when emergency surgery is not needed on admission and the serum hCG level is decreasing as noted in two consecutive estimations with an interval of 1-2 days.
REFERENCES 1. CACCIATORE, B., U.-H. STENMAN& P. YLOSTALO.1989. Comparison of abdominal and vaginal sonography in suspected ectopic pregnancy. Obstet. Gynecol. 73: 770-774. 2. ROBERTSON, D. E., W. SMITH & I. CRAFT. 1987. Reduction of ectopic pregnancy by ultrasound methods. Lancet ii: 1524. B., M. HAHLIN,B. KALLFELT& L. HAMBERGER. 1987. Local prostaglandin 3. LINDBLOM, F-2 alfa injection for termination of ectopic pregnancy. Lancet i: 776-777. B., L. ENK,M. HAHLIN,B. KALLFELT,P. LUNDORFF & J. THORNBURN. 1988. 4. LINDBLOM, Non-surgical treatment of ectopic pregnancy. Lancet i: 1403. 5. EGARTER, CH. & P. HUSSLEIN.1988. Behandlung der Tubargraviditat durch lokale und systemische Applikation von Prostaglandin. Geburtsh. Frauenheilk. 48.361 -363. 6. EGARTER,C., R. FITZ,J. SPONA,W. GRUNBERGER, P. WAGENBICHLER, R. HAIDBAUER, K. BAUMGARTEN, A. BECK,S. LEODOLTER, H. KISS& P. HUSSLEIN.1989. Behandlung der Eileiterschwangerschaft mit Prostaglandinen: Eine Multizenterstudie. Geburtsch. u. Frauenheilk. 4 9 808-812. 7. VEJTORP.M., L. 0.VUERSLEV& S. RUGE.1989. Local prostaglandin treatment of ectopic pregnancy. Hum. Reprod. 4 464-467. P. K. SAND& R. K. TAMURA. 1986. Conservative treatment 8. ORY,S. J., A. L. VILLANUEVA, of ectopic pregnancy with methotrexate. Am. J. Obstet. Gynecol. 1 5 4 1299-1306. M. BUSTILLO,J. E. GUNNING, J. R. MARSHALL 9. RODI,I. A., M.V. SAUER,M. J. GORRILL, & J. E. BUSTER.1986. The medical treatment of unruptured ectopic pregnancy with methotrexate and citrovorum rescue: Preliminary experience. Fertil. Steril. 46: 81 1-813. 10. ICHINOE, K., N. WAKE, N. SHINKAI,Y. SHIINA,Y. MIYAZAKI& T. TANAKA.1987. 11.
12. 13. 14.
15.
Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancies. Am. J. Obstet. Gynecol. 1 5 6 484-487. SAUER,M. V., L. H. GREENBERG, M. J. GORRILL,M. BUSTILLO,I. A. RODI, J. E. GUNNING, T. R. YEKO& J. E. BUSTER.1987. Nonsurgical management of unruptured ectopic pregnancy: An extended clinical trial. Fertil. Steril. 48: 752-755. CARSON,S. A., R. ANDERSEN,T. STOVALL,F. LING, E. UMSTOT& J. E. BUSTER.1989. Rising human chorionic somatomammotropin predicts ectopic pregnancy rupture following methotrexate chemotherapy. Fertil. Steril. 51: 593-597. STOVALL, T. G., F. W. LING& J. E. BUSTER.1989. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil. Steril. 51: 435-438. STOVALL,T. G., F. W. LING & J. E. BUSTER. 1990. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am. J. Obstet. Gynecol. 162: 1620- 1624. LEETON,J. & G. DAVISON. 1988. Nonsurgical management of unruptured tubal pregnancy with intra-amniotic methotrexate: Preliminary report of two cases. Fertil. Steril. 5 0
167-169. 16. FEICHTINGER, W. & P. KEMETER.1989. Treatment of unruptured ectopic pregnancy by
needling of sac and injection of methotrexate or P G E2 under transvaginal sonography control. Arch. Gynecol. Obstet. 246: 85-89. 17. PANSKY, M., I. BUKOVSKY, A. GOLAN,R.LANGER,D. SCHNEIDER, S. ARIELI& E. CASPI.
YLOSTALO et al.: ECTOPIC PREGNANCY
18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
523
1989. Local methotrexate injection: A nonsurgical treatment of ectopic pregnancy. Am. J. Obstet. Gynecol. 161:393-396. PANSKY,M., I. BUKOVSKY, A. GOLAN,Z. WEINTRAUB, D. SCHNEIDER, R. LANCER,S. ARIELI& E. CASPI. 1989. Tuba1 patency after local methotrexate injection for tubal pregnancy. Lancet ii: 967-968. ZAKUT,H., 0. SADAN,A. KATZ,D. DREVAL& D. BERNSTEIN.1989. Management of tubal pregnancy with methotrexate. Br. J. Obstet. Gynaecol. 96: 725-728. KOJIMA,E., Y. ABE, M. MORITA,M. ITO, S. HIRAKAWA & K. MOMOSE.1990. The treatment of unruptured tubal pregnancy with intratubal methotrexate injection under laparoscopic control. Obstet. Gynecol. 75 723-725. M ~ N A R DA., , J.-P. HAUUY,J. C R ~ Q U A P. T , MADELENAT & L. MANDELBROT. 1990. Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control. Fertil. Steril. 54: 47-50. LANG,P. F., P. A. M. WEISS,H. 0. MAYER,J. G. HAAS& W. HONIGL.1990. Conservative treatment of ectopic pregnancy with local injection of hyperosmolar glucose solution or orostanlandin F-2 alfa: A Drosoective randomised studv. Lancet ii: 78-81. L&D, JT 1955. Early ectopic pregnancy. Comments on ionservative treatment. J. Obstet. Gynaecol. Br. Emp. 62 70-76. S., H. J. A. CARP& D. M. SERR.1982. Nonoperative management of ectopic MASHIACH, pregnancy: A preliminary report. J. Reprod. Med. 27: 127-132. CARP,H. J. A., G. OELSNER, D. M. SERR& S. MASHIACH. 1986. Fertility after nonsurgical treatment of ectopic pregnancy. J. Reprod. Med. 31: 119- 122. 1987. Expectant management GARCIA,A. J., J. M. AUBERT,J. SAMA& J. B. JOSIMOVICH. of presumed ectopic pregnancies. Fertil. Steril. 48: 395-400. E. PAPIERNIK,D. BELLET& R. FRYDMAN. 1988. FERNANDEZ, H., J. D. RAINHORN, Spontaneous resolution of ectopic pregnancy. Obstet. Gynecol. 71: 171 - 174. MAKINEN,J. I., A. K. KIVIJARVI& K. M. A. IRJALA.1990. Lancet i: 1099. MITCHELL, D. E., H. F. MCSWAIN, J. A. MCCARTHY & H. B. PETERSON. 1987. Hysterosalpingographic evaluation of tubal patency after ectopic pregnancy. Am. J. Obstet. Gynecol. 157: 618-622. VERMESH, M., P. D. SILVA,G. F. ROSEN,A. L. STEIN,G. T. FOSSUM & M. V. SAUER. 1989. Management of unruptured ectopic gestation by linear salpingotomy: A prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet. Gynecol. 73 400-404. LAVY,G., M. P. DIAMOND & A. H. DECHERNEY. 1987. Ectopic pregnancy: Its relationship to tubal reconstructive surgery. Fertil. Steril. 47: 543-556. RISQUEZ,F., J. MATHIESON, D. PARIENTE, H. FOULOT,J. B. DUBUISSON, A. BONNIN,L. CEDARD & J. R. ZORN.1990. Diagnosis and treatment of ectopic pregnancy by retrograde selectivesalpingography and intraluminal methotrexate injection: Work in progress. Hum. Reprod. 5: 759-762.
PART XI. EARLY PREGNANCY, PRENATAL DIAGNOSIS, AND ABORTION
Conservative Treatment of Ectopic Pregnancy" P. YLOSTALO, B. CACCIATORE, A. KOSKIMIES, M. KAARIAINEN, P. LEHTOVIRTA, P. MAKELA, R. SIEGBERG, U.-H. STENMAN, A. TENHUNEN, AND 0. YLIKORKALA Departments I and II of Obstetrics and Gynecology University of Helsinki Helsinki, Finland The development of diagnostic modalities, particularly the combined use of serum hCG assays and vaginal sonography, has improved diagnostic accuracy in early ectopic pregnancy' and consequently the possibilities of developing a treatment for this condition. Various nonsurgical methods have been used in the conservative treatment of ectopic pregnancy, such as puncture and aspiration, local potassium chloride, local prostaglandin, parenteral or local methotrexate, local hyperosmolar glucose, and expectant management only. In this context, salpingotomy made by laparoscopy is not considered conservative treatment. Of the treatments used, prostaglandins, methotrexate, hyperosmolar glucose solution, and expectant management have been successful. Puncture and aspiration seem insufficient, but large studies have not been reported. Potassium chloride has also been unsatisfactory.2 In five studies consisting of 124 treatment of ectopic pregnancy with local prostaglandin was successful in 81-100% of patients (TABLE1). A dose of0.5- 10 mg of prostaglandin F-2 alfa was injected by laparoscopy locally and in some studies also into the ovary and corpus luteum. Alternatively, 500 pg of prostaglandin E-2 was given parenterally twice daily for 3 days. With this treatment tubal patency was preserved in 88-92%. After injection into the ovary, hypotony, hypertension, and tachycardia related to the dose have been reported. Parenteral methotrexate has been given intramuscularly in doses of 0.4- 1.0 mg/kg usually four times every second day in combination with 0.1 mg/kg of citrovorum factor rescue every second day. In seven studies8-I4consisting of 171 patients the success rate was 83-10070 (TABLE2) and tubal patency after treatment 53-83%. As side effects, stomatitis and transient signs of impaired liver function were found in 18% of the patients on the average. Methotrexate has also been given by local injection during In laparoscopy or by ultrasound-guided vaginal puncture using a dose of 5-50 mg.15-21 seven studies consisting of 95 patients (TABLE3) the success rate was 78- 100%. Tubal patency was retained in 86- 100%. Side effects like stomatitis have occurred only when parenteral methotrexate was also given. In a study by Lang et aLZ250% glucose was injected locally by laparoscopy in 16 patients with a success rate of 100%. Tubal patency after this treatment was 88%, and no side effects occurred. Prostaglandin was used in 15 patients with a success rate of 87%, but severe abdominal pains occurred in 60% of the patients. Thus, local treatment of ectopic pregnancy with hyperosmolar glucose is an interesting alternative, requiring further studies. 'The study was supported by grants from the Academy of Finland and the Paul0 Foundation.
516
YLOSTALO et ai.: ECTOPIC PREGNANCY
517
In 1955 Lundz3studied expectant management of ectopic pregnancy in 119 patients. This study also included severe cases (TABLE4), and many patients were hospitalized for a long time. The success rate was 57%. Of those patients who desired pregnancy, 61% later became pregnant, and 46% had an intrauterine and 15% an ectopic pregnancy. In six other studies11*2k2* consisting of 84 patients the entry criteria were usually a size of the ectopic pregnancy of less than 3-5 cm in diameter, no signs of rupture, and no acute bleeding. In these the success rate was 71 - 100%. Resolution time varied considerably, and tuba1 patency after treatment was 70- 100%. The aim of our study was to evaluate expectant management and the frequency of spontaneous resolution in ectopic pregnancy. TABLE 1. Local Prostaglandin (PG) Treatment by Laparoscopy Author Lindblom et aL,’ 1987
Lindblom et al..‘ 1988 Egarter and Husslein, 1988
No. of Patients
Tubal Patency
Side Effects
100%
...
...
96%
...
...
90%
...
Elevated temperatures, hypertension, hypotony
81%
22/24
...
91%
7/8
...
Success
PG
9 F 2-alfa 0.5-1.5 mg or 15-methyl PGF 2-alfa 75 (+ into ovary) 23 F 2-alfa 10 F 2-alfa 10 mg (+2.5 mg into ovary) +PGE-2 2 X 500 Pg im daily for 3
Rate
S
Egarter et al..6 1989
71 F 2-alfa 7-10 mg (+ 25 mg conj. estrogene into ovary) PGE-2 der. 2 X 500 pg im daily for 3 days 11 F 2-alfa 0.75-1.5 mg (+ into ovarv)
+
Vejtorp et aL,’ 1989
MATERIALS AND METHODS From January 1989 to May 1990,207 patients were treated for ectopic pregnancies in the Helsinki University Central Hospital, and 48 of them were selected for expectant management (FIG. 1). The patients were examined by sonography using a vaginal transducer with an emission frequency of 5.0 mHz, and by estimation of serum hCG concentrations by an immunofluorometric assay (DELFIA, Pharmacia-Wallac, Turku, Finland) calibrated against the first International Reference Preparation (IRP).
ANNALS NEW YORK ACADEMY OF SCIENCES
518 TABLE 2.
Parenteral Methotrexate (MTX)Treatment
Author
No. of Patients
OW et a L 8 1986
6
Rodi et alL9 1986
7
Ichinoe et a1..lo 1987 Sauer et al.," 1987
23
Carson et al.,'= 1989 Stovall et a1.,l3 1989 Stovall et al..I4 1990
21
Success Rate
MTX 1 mg/kg im every 2nd day x 4 ( + CF) 1 mg/kg im every 2nd day x 4 ( + CF) 0.4 mg/kg im daily for 5 days 1 mg/kg im every 2nd day x 4 ( + CF) 1 mg/kg im X 1-4(+ CF) 1 mg/kg im X 1 - 4 ( + CF) 1 mg/kg im X 1-4(+ CF)
21
36 57
Tubal Patency
Side Effects
83%
...
100%
4/5
96%
10/19
95%
15/20
5 stomatitis SGOT elevation
91%
...
...
94%
...
1 stomatitis 2 SGOT elevation
95%
19/23
...
3 stomatitis 2 transient SGOT elevation 1 stomatitis 2 transient SGOT elevation 4 SGOT elevation
ABBREVIATIONS: CF = citrovorum factor; im = intramuscularly.
TABLE 3.
Local Methotrexate (MTX)Treatment
Author Leeton and Da~ison,'~ 1988 Feichtinger and Kerneter,l6 1989 Pansky et al,, I' 1989 Pansky et al.,ls 1989 Zakut et a1.,I9 1989
Kojima et al.," 1990 MCnard et a1.,l1 1990
No. of Patients
MTX
LAP/TV
Success Rate
Tubal Patency
Side Effects
2
50mg
TV
100%
...
...
9
10-50 mg
TV
78%
2/2
...
27
12.Ymg
LAP
89%
6/7
...
37
12.5-25 mg
LAP
...
19/21
...
10
12.5 mg 0.5 mg/kg im after 24 h 5-25 mg
+
LAP
80%
7/7
Stomatitis
LAP
100%
9/9
...
50 mg
TV
16%
...
...
9 17
ABBREVIATIONS: LAP = laparoscopy; TV = transvaginal
YLOSTALO et 01.: ECTOPIC PREGNANCY
519
TABLE 4. Expectant Management Author
Lurid:' 1955 Mashiach et al.." 1982 Carp et aZ.,25 1986 Garcia et 1987 Sauer et aL,I' 1987 Fernandez et a1..17 1988 Makinen et a1..281990
No. of Patients
Success Rate
Tuba1 Patency
119
57%
...
5
80%
2/2
14
79%
5/5
13
92%
7/10
5
100%
3/4
14
71%
6/6
33
82%
...
The selection criteria of patients with ectopic pregnancy were as follows: a falling level of serum hCG in two estimations at 2 days' interval, no signs of intrauterine pregnancy by vaginal sonography, a diameter of the ectopic pregnancy of less than 4 cm, and no signs of rupture or acute bleeding. The patients visited our outpatient department every 2-7 days for assay of hCG and vaginal sonography.
RESULTS In 68 patients (32.8%), salpingotomy or salpingectomy was performed by emergency laparotomy and in 91 (44.0%) by laparoscopy. In the 48 patients treated by expectant management, spontaneous resolution occurred in 3 1 (64.6%)patients corresponding to 15% of all ectopic pregnancies. In 17 (35.4%)patients salpingotomy was performed by laparoscopy (FIG.1) because of clinical symptoms such as abdominal pain, increasing adnexal mass or peritoneal fluid, or a constant or rising level of serum
pregnancy
68 (32.8%)
48 (23.2%)
91 (44.0%)
17 (35.4%)
Expectant
31 (64.6%)
1 Laparoscopy 52.2%
Spontaneous resolution 15.0%
FIGURE 1. Outcome of ectopic pregnancies in 207 patients.
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hCG. In the expectant management group with spontaneous resolution serum hCG levels mostly normalized within 40 days (FIG.2). In three cases expectant management was continued despite a transiently increasing hCG level. In patients subjected to laparoscopy after an expectant management time of 2- 18 days, hCG levels decreased more slowly than in those with spontaneous resolution, and in many cases an increasing or constant level of serum hCG was observed (FIG.3). The volume of the abnormal adnexal mass measured by vaginal sonography was 0.5-35 cm3.The mass disappeared or diminished greatly within 25 days (5-45 days) in those with spontaneous resolution. In the group requiring laparoscopy after expectant management the volume of the adnexal mass was 1- 35 cm3at admission and it increased during follow-up. Other reasons for laparoscopy were clinical symptoms such as pain and an increasing volume of fluid in the cul-de-sac. Salpingotomy by laparoscopy was easy to perform in these cases. If the patients had had infertility problems, laparoscopy or hysterosalpingography (HSG) was performed 3 months later. Of our study group 60% of the patients did not have infertility problems. Three patients are already pregnant and have an intrauterine pregnancy. Tubal patency has been observed by HSG in two patients and by laparoscopy in two.
DISCUSSI 0N In the present study expectant treatment was initially used in 23% of the patients with ectopic pregnancy. In one third of the cases surgery was later performed. However, with increasing experience this figure can be reduced. In many patients spontaneous resolution would have occurred without surgery. Another advantage of expectant management was that surgery was more easily performed after 1-2 weeks than in the acute phase. Tubal patency has been observed after different kinds of conservative
ooooo
m
10000
-.
c 1000
1 v
(3
2
100 10
1
I
0
10
20 30 40 50 Day after start of follow-up
FIGURE 2. Serum hCG levels during follow-up of patients subjected to successful expectant treatment.
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YLOSTALO et al.: ECTOPIC PREGNANCY
10000 -j
1000
100
1 0
10
20
30
Day after start of follow-up FIGURE 3. Serum hCG levels in patients initially selected for expectant management but later treated by salpingotomy.
treatment of ectopic pregnancy on average in 72-93% of the patients (TABLES1-4). These results are obviously at least as good as those obtained by conservative surgical treatment. However, tubal patency has seldom been tested after surgical treatment. In the study of Mitchell et aLZ9it was observed that conservative surgical treatment left a patent tube on the treated side in only 9 of 18 patients. In another study30postoperative hysterosalpingography showed patency of the involved tube in 80% and 89% of patients after linear salpingotomy by laparoscopy and laparotomy, respectively. Fertility after conservative surgical treatment was reviewed by Lavy et al. 31 After salpingostomy or salpingotomy, 45% had an intrauterine pregnancy and 12% a recurrent ectopic pregnancy. These figures correspond to those of Lundz3obtained by expectant management, 46% and 15%, respectively. On the basis of our experience we suggest the following management of ectopic pregnancy. If emergency surgery is not needed, hCG estimations and vaginal sonography are performed two times at 1-2 days' interval. If the hCG level is falling, expectant management can be used. During follow-up repeated hCG estimations and vaginal sonography are performed at an interval of 2-7 days until the hCG level becomes normal (below 10 U/L). If the patient has infertility problems or if vaginal sonography shows a persisting abnormal adnexal mass, HSG or laparoscopy is performed. If the hCG level starts to rise, active management is recommended. Of the treatments currently available, the recently described local delivery of methotrexate by transuterine tubal ~atheterizatiod~ appears attractive. The role of this treatment in relation to earlier mentioned medical and surgical procedures has to be established by further studies.
SUMMARY As a conservative nonsurgical treatment of an early ectopic pregnancy, local prostaglandin, parenteral or local methotrexate, local hyperosmolar glucose, and also expec-
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tant management have been used successfully in selected cases. The success rate of conservative treatment has been 71%-100% and that of tubal patency after different kinds of conservative treatment 72-93% of patients. In the present study of expectant management in early ectopic pregnancy in patients with decreasing serum hCG levels, spontaneous resolution was observed in 64.6% of patients and in the total series of 207 ectopic pregnancies in 15.0% of patients. Expectant management of early ectopic pregnancy is recommended when emergency surgery is not needed on admission and the serum hCG level is decreasing as noted in two consecutive estimations with an interval of 1-2 days.
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