Annals of Medicine
ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
Advancing Conservative Treatment of Ectopic Pregnancy — Laparoscopic and “Non-Surgical” Management Jane Thorburn To cite this article: Jane Thorburn (1992) Advancing Conservative Treatment of Ectopic Pregnancy — Laparoscopic and “Non-Surgical” Management, Annals of Medicine, 24:1, 43-47, DOI: 10.3109/07853899209164143 To link to this article: http://dx.doi.org/10.3109/07853899209164143
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Trends in Clinical Practice
Advancing Conservative Treatment of Ectopic Pregnancy - Laparoscopic and “Non-Surgical” Management
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Jane Thorburn
Improvements in diagnostic measures have contributed to the earlier diagnosis of ectopic pregnancy which in turn has led to the development of new and alternative methods of managing tubal pregnancies. Laparoscopicsalpingotomy offers advantages such as a reduction in operating time and shorter hospital stays and convalescenseas compared with conventionalabdominal surgery. Furthermore, neither the frequency of persistent trophoblasts nor of second operations is Increased, and the subsequent fertility rate is at least equal to that after laparotomy. “Non-surgical” treatment of ectopic pregnancy, such as systemic administration of methotrexate and laparoscopic/ transvaginal ultrasonic - guided local injection of methotrexate, prostaglandins or hyperosmolar glucose, are attractive alternative methods in selected cases. These methods are safe and effective and have a high success rate and promising results for fertility. Laparoscopy is preferredto conventionalabdominalsurgery for the treatment of ectopic pregnancy. In selected cases, “non-surgical” treatment can be an attractive alternative therapy. Key words: ectopic pregnancy; conservative treatment; laparoscopic surgery; methotrexate; “non-surgical” treatment; prostaglandins. (Annals of Medicine 24: 43--47,1991)
Introduction
Salpingotomy via Laparoscopy
An increasingproportion of tubal gestations are now treated early in the pregnancy and often before rupture of the tube occurs. Improvements in diagnostic measures, such as the use of serum human chorionic gonadotrophin (hCG) and endovaginal sonography, have contributed to this early recognition, which is a prerequisite for the development of new therapeutic methods for treating ectopic pregnancy (EP). Conservativetreatment of EP implies the preservation of the tube with a subsequent possible for ovum transfer. Until recently, salpingotomy via laparotomy was considered to be the prime conservative approach. During the past decade, however, a subset of alternative and advancing conservative management methods have been introduced to increase such short term benefits as shorter hospital stays and convalecense periods and to improve subsequent fertility.
In 1986, Pouly et al. (1) reported a large series of tubal pregnancies treated conservatively via laparoscopy (Table 1). A second surgical intervention owing to persistent trophoblast was necessary in less than five percent of patients. The subsequent fertility rate was reportedto be as good as the fertility rates after conservative treatment by laparotomy. Pouly emphasized, however, that fertility results after EP treatment must be interpreted with care, especially as there may be large differences in the treated populations regarding both risk determinants and pelvic conditions, which significantlyinfluencepostoperativefertility. DeCherney and Diamond (2) later presented a series of tubal gestations treated by laparoscopic salpingotomy, with an overall subsequent conception rate of over 60 %; no apparent differences in outcome were found as compared with salpingotomies performed at laparotomy. These two studies, however, showed a high success rate, which encouraged other research groups to investigatelaparoscopic treatment of EP. A case control study from Vermont in 1988 (3) compared the short term outcome of laparoscopy and laparotomy and found that patients treated by laparoscopy had significantly shorter operatingtimes, hospital stays and
Fromthe Departmentof Obstetricsand Gynaecology, University of Goteborg, Goteborg, Sweden. This study was supported by the Swedish Medical Research Council (grant 8683). Address and reprint requests: Jane Thorburn, MD., PhD., Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden.
Ann Med 24
Thorburn
44
Table 1. Ectopic pregnancy treated by laparoscopy or laparotomy. ~
No. of
Author
Mode of cases application
Pouly et a/ (1)
321
L-SCOPY
Failure rate
Pregnancy rate
15/321 (4.8Yo)
intrauterine pregancy rate
76/118 (64.4Yo)
DeCherney & Diamond (2)
79
L-scopy
2/79
(2.5Yo)
Brumstedetal(3)
C/C
25 25
L-scopy L-torny
2/25 0
(8%)
Vermesh et al(4)
R
30 30
L-SCOPY L-tomy
3/30 (10Yo) 1/30 (3“/o)
10118 (56“/o) 11/19 (58“/o)
LundonY P (5)
R
48 57
L-SCOPY L-tomy
6/48 (12.5Yo) 2/57 (3.5Yo)
25/42 (59.5Yo) 25/45 (55.5%)
43/69 (62%)
36/69
(52%)
Ectopic pregancy rate
2611 18 (22Yo) 7/69
(10Yo)
9/18 (50Yo) 8/19 (42Yo) 22/42 20/45
(52Yo) (44.5Yo)
1/18 (6Yo) 3/19 (16%) 3/42 5/45
(7.5%) (11 70)
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L-scopy = Treatment performed by laparoscopy L-torny = Treatment performed by iaparotomy C/C = case-controlstudy R = prospective randomized trial
convalescence. Despite a potential weakness in the study design, it was suggested that laparoscopy offers economic advantages and an easier and quicker recovery. The first prospective, randomized clinical trial of laparoscopy versus laparotomy for the treatment on unruptured EPs was reportedby Vermesh et al. in 1989 (4). The incidence of persistent trophoblast was similar to that reported by Pouly (1). The rate of decline in postoperative serum hCG and the subsequent pregnancy rates did not differ between the two surgical groups. Although the two methods were shown to be equally safe and effective, laparoscopy seemed to be more economical. In another prospectiverandomizedclinicaltrial by Lundorff et al. (5),the short term benefits of laparoscopy previously were confirmed. Moreover, at a second look reported (3,4) laparoscopy, which was performedin both groups undergoing surgery, it was shown that postoperative adhesion formation was reduced in cases primarily treated by laparoscopy. The subsequent pregnancy rate did not differ betweenthe two groups, but the authors pointedout that the fertility outcome in the laparotomy group could have been favoured by the fertility technique used and by the adhesiolysis performed at the second look laparoscopy.
“Non-surgical” Treatment There is great interest today in “non-surgical” - that is, without surgical interference in the tube - management of small tubal pregnancies with low trophoblastic activity. As laparoscopy is the only method other than laparotomy for viewing the pelvis, including inspection of the ectopic gestation, adhesionformation and tubal condition, the development of local injection therapy was prompted the use of laparoscopy. Becauseof improvements in the technique of endovaginalsonographyand with more experienced investigators, local injection therapy was later introduced under transvaginal sonographic control. Although the pelvic conditions cannot be seen, and thus fertility prospects cannot be forecast, this approach implies several advantages such as management without surgery, anaesthesia or admission to hospital.
Ann Med 24
Local Injection Therapy via Laparoscopy Prostaglandins(PG): In vitrostudies on the effects of PG on the oviduct and corpus luteum led to the proposal that PGF, alpha could be useful in the pharmacological treatment of EP (6).A regimen for this purpose was initially recornmended by Lindblom et al., 1987, (7) and later presented in a study of selected cases (8).Patients were treated by local injection of PGF, alpha (1-3 mg) or 15-metyl PGF, alpha (in equipotent doses) into the tubal wall and in the corpus luteum. Both the success rate and the subsequent pregnancy rate were high and no untoward effects of the treatment were seen (Table 2). The authors concluded that patients subjected to local injection therapy should be carefully selected, with those chosen presenting with only small gestations (c2 cm) and low trophoblastic activity (el000 IU/ L)In a study by Egarter and Husslein (9). a higher total dose than the original recommended regimen was used, which may explain the three patients in their series who developed severe haemodynamic side effects, including one with pulmonary oedema. Usingthe Lindblomregimen, Vejtorp et al. (10)reported no serious side effects, and by using a slightly higher dose, Odland et al. (1 1) reported no severe adverse side effects in their series. Egarter et al. (12) recently publisheda prospective multicentre study in which patients were treated by local PGF, alpha (7-10 mg) in combinationwith oestrogen in the corpus luteum, as well as additional systemic PGE,. These patients were compared to women treated by conventional abdominal surgery. No serious side effects were noted in the PG group during this regimen and the PG group had shorter hospital stays than patients undergoing laparotomies. Future fertility seemed promising as compared with conventional surgery, and postoperative morbidity was reduced in patients whose initial serum hCG concentration was below 2500 IU/L. A high success rate for cases who had initial serum hCG concentrations below 2500 IU/L was also subsequently reported by Deckardt et al. (13). Hyperosrnolarglucose.Lang et al. (1 4) allocatedpatients randomly either to PG or hyperosmolar glucose solution, considered to be a non-toxic agent. No side effects were
Conservative Treatment
45
of Ectopic Pregnancy
Table 2. “Non-surgical” treatment of ectopic pregnancy. ~
Author
No. of cases
~
Vejtotp et a1 (1 0) €garter et a1 (12) Lindblom et a1 (8) Deckardf et a1 (1 3) Odland et al(11) Lang eta/ (74) R lchinoe et a/ (1 6) Stovall et a1 (1 7) Zakut et a1 (1 9) Kojima eta/ (20) Kooi & Kock (21) Thompson et a1 (22) feichtinger (23) Me’nard et al(24) Tulandi et al(25) fernandez et a1 (26) R
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Mode of application
Drug
L
PGF PGF +&E2 F%F PGF +&E2
Failure rate
Side effects
lpsilateral Subsequent patency pregnancies
_ _ _ _ ~ _ _ _ _
11 71 26 15 16 31 (15:16) 23 57 10 9 25 18 10 17 12 21 (12:9)
L+S L L+S
&F
L
L+S:L
S S L+S L L+(S) L Tv Tv Tv
N+S
PGF2,+E+&E2:G MTX MTX+CV MTX+CV MTX MTX+A+CV MTX MTX or PGE2 MTX+CV MTX (+PCI) MTX+CV:PGE2
0 0 0 0 1 (pain) 1 (pain, PG) 0 0 1 (stornatit) 0 5’ 0 1 (pain) 0 0 2 (stornatit :pain)
4 17119 1
718 22/24
616 -
-
5/6:7/8 10119 19/23 7/7 919
4 (1:3)
-
11/14 1
-
-
9114
313 -
-
718:6/6
3
a/a
56 (15 Yo)
372
Mode of application: L = Laparoscope-guidedinjection therapy S = Systemic administration TV = Transvaginal ultrasound-guided local injection R = randomized study
1111 21/71 2/26 7115 2/16 2/15 (PG) 1I23 0 2/10 1I9 1/25 1/18 2/10 (MTX) 4117 2/12 4/12 :3/9
Drugs: PGF PG& MTX G E CV A PCI
= Prostaglandin F alpha = Prostaglandin
d
= Methotrexate = Hyperosmolar glucose
=Estrogen = Citrovorum factor = Adrenaline = Potassium Chloride
transient elevations of serum glutarnic-oxaloacetic and glutamic-pyruvic transaminaselevels when additional systemic administration was used.
noted in patients treated by glucose, and the success rate and subsequentfertility outcomewere equally as good as in the PG group. Glucose instillationcan therefore be considered in selected cases as a low risk alternative to local treatment with more aggressive agents. Methotrexate (MTX).MTX is a folic acid antagonist that has been widely used for the treatment of gestational trophoblasticdisease. Since 1982, when Tanaka (15) first treated an ectopic gestation by systemic chemotherapy, several studies have confirmed the resolution of EPs after systemic MTX treatment (16). Stovall et al. reported in 1990 (17) that systemic MTX treatment implied a higher subsequent fertility rate than that achieved by traditional surgical methods, and was comparable to resultsafter laparoscopic salpingotomy. It has been argued, however, that MTX might not be a preferable treatment, especially in view of its possible tefatogenic and mutagenic effects (18). Side effects such as stomatitis, dermatitis and bone marrow depressioncan be partiallyavoided by the paralleladministration of citrovorum factor. To reduce the MTX dosage and minimize the high toxicity and side effects of MTX systemically administered, new techniques for local injection into the tube were introduced. In a study from Israel (19), patients with small tubal gestations were treated by an injection of MTX (12.5 mg) into the gestational sac via a laparoscopy. Additional MTX was administered systemically, followed by folinic acids. The failure rate was low, and the subsequent tubal patency high. Similar results were later presented by Kojima et al. (20) usingdoses from 5 to 25 mg and by Kooi and Kock (21) using 100 mg MTX after adrenaline injection into the mesosalpinx. Minimal side effects only appeared during supplementary systemic therapy. Kojima et al. (20) also
showed that the pattern of reduction in the concentration in urinary hCG was similar to that of serum hCG observated after conservative surgical treatment of EP (4), indicating no prolonged resolution time after MTX administered via a laparoscopy. Recently, an Australian investigation (22) reported on patients who were given 20 mg MTX around the tubal gestation; they had a low failure rate and no side effects were reported. The investigators postulatedthat local MTX injection can be performed by any operator with minimal laparoscopic skills and there may also be a better chance of preserving tubal function.
Local Injection Therapy under Transvaginal Sonographic Control In 1989, Feichtinger and Kemeter (23) reported a small series of patients with unruptured EPs who were treated by localinstillationof MTX (10 to 50 mg) into the gestational sac by sonographic control and on one patienttreated by PGE, (0.5 mg). No side effects were seen among the MTX patients, but the single patient treated with PG had vomiting and abdominal pain. A larger series of patients treated by a single 50 mg dose was recently reported in France (24). No systemic side affects of MTX were observed. In one patientwith a bilateral tubal gestation, pathological examination showed resolution on the treated side and n6 evidence that MTX had affected the contralateraltube, demonstrating its localised effect.The authors noted, however, that the effect of needle aspiration per se on the resolution of EP, independent of MTX injection, has not yet been evaluated. In a Canadian study (25),a high success rate was found
Ann Med 24
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46
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after intratubal transvaginal MTX injection (1 mg/kg body weight), and no side effects were encountered. A repeat MTX injection was, however, required in four of six women with a living embryo and, in one of these local potassium chloride was also injected with good results. So the authors concludedthat MTX treatment seemed to be more appropriate in the absence of a living embryo. The prolonged resolutiontime observed in this study is one of the disadvantages generally seen in the use of transvaginal administration. A prospective, randomized study of patients with an unrupted tubal pregnancy treated by local and systemic injection of either MTX or PGE, was recently published by Fernandez et al. (26). The success rate was high in both treatment groups, indicatingthat MTX and PGE, are equally effective.
Retrograde Selective Salpingography and lntraluminal M TX Injection This new method for the “non-surgical”treatment of EP was introducedby Risques et al. (27),who reportedfour patients treated successfully. The study was, however, too small to draw any general conclusions.
Expectant Managemeni Very early diagnosis of EP may imply treatment of some patients whose condition would otherwise have resolved spontaneously. The question has arisen whether expectant management (i.e. of patients who are followed by analyses of serum hCG until non-pregnant levels are obtained) implies advantages over local injection therapy. Only small series are reported(28,29) showing a high success rate and good subsequent fertility. Criteria for the selection of these potentialcases are still under evaluation, and no conclusion as to fertility outcome can yet be drawn.
Comments Randomized trials have proved that laparoscopic salpingotomycanoffer importantadvantages over traditional surgical laparotomy. Short term benefits are shorter operations, hospitalization and recovery times with fewer adhesions forming. Compared with conventional surgery, there is no increased rate of persistent trophoblast or of the need for a second intervention. Provided that a skilled laparoscopistis available,there seems to be no restrictions, such as size of the gestation, rupture of the tube or high hCG values, for performing laparoscopic salpingotomy. On the other hand, laparoscopymay be contraindicatedin patients in pre-shock or shock with profuse bleeding. Although no study has thus far shown improved subsequent fertility after laparoscopic salpingotomy, some data seem promisingin this respect (5,30). Fertilityoutcome after laparoscopic salpingotomy is shown to be correlated with the existence of ipsilateral adhesions, the condition of the contralateral tube and the patient‘s past history (30). This accords with two previous studies on conventional abdominal surgery (31, 32). Laparoscopic surgery, as a mode of application, would therefore improve the prospectsfor subsequent fertility owing to fever adhesions forming (5) as compared with conventional laparotomy. The mode of application-laparoscopy or laparotomyAnn Med 24
should never change the mode of treatment. Radicaltreatment (salpingectomy) or conservative treatment (salpingotomy) should be performed when indicated, irrespective of whether laparotomy or laparoscopy is used. Laparoscopic salpingectomy is still a radical operation although it offers the same short term benifits as seen after laparoscopic salpingotomy. Moreover, as it is a radical treatment there is no need for postoperative hCG controls. Which patients should then be considered for radical surgery? Recently a scoring system was proposed by Pouly et al. (30) to choose the most suitable treatment to preserve fertility and reduce the risk for repeat EP ranging from laparoscopic conservative treatment to laparoscopic salpingectomy. In selected cases, a “non-surgical” approach seems attractive. The proportion of patients considered for injection therapy may vary substantially between clinics and is dependent on an “early” diagnosis of EP, a special interest among gynecologists in this research field and the ability to follow up the patient using consecutive hCG analyses. Laparoscopic !om/ injection therapy resuIts in tangible cost benefits; the technique requires no expensive high technology equipment and can be performed by any surgeon with some laparoscopic skills (22). Neither surgery nor hospital admission is required for transvaginal injection therapy, and the treatment does not need anesthesia (24). On the other hand, experience in sonography is required for transvaginal administration and this technique is still in the investigationalstage (25). Since EPs are often located intramurally and not in the lumen, it may be difficult even for a skilled professionalto locate the gestation exactly by the transvaginal approach. Ultrasound quided therapy may therefore be less effective than laparoscopic injection therapy and in some cases it may result in a prolonged resolution time (25). The importance of postoperative serum hCG analyses must be emphasized since local injection therapy has a higher failure rate than laparoscopic salpingotomy (15 Yo versus 5 %). Recommended intervals are once or twice weekly until non-pregnant concentrations are obtained. PG can give rise to severe cardiopulmonaryside effects, e.g., pulmonary oedema, but no such severe side effects are encountered at recommended doses (7,8,10). MTX is a cytotoxic substance that can result in side effects such as alopecia, stomatitis and hepatic and bone marrow toxicity. While no systemic side effects have been noted after local injection therapy (24, 25), combined local injection and systemic administration have given rise to a few cases of stomatitis (19, 26). Furthermore, there is no evidence that MTX will cause any congenital abnormalities(33,34). Local injectiontherapy with PG or MTX can therefore be regarded as safe alternatives for the treatment of selected patients with tubal pregnancy. PG treatment is recommended for patietns showing initial hCG concentrations below 1000to 2500 IU/L (8,12,13) and with an EP less than 2 cm in size (8). Suggested limits for MTX injection are higher -5000 to 10 000 IU/L and 4 cm, respectiely (19, 20). So far, neither MTX nor PG can be recommended for patients with ruptured tubes, significant haemoperitoneum or a living embryo and MTX is contraindicated when there is a co-existing intrauterine pregnancy (24, 25, 26). The success rate after PG and MTX treatment is between 80 Yoand 90 Yo,which seems to be somewhat below that of
Conservative Treatment of Ectopic Pregnancy
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laparoscopic salpingotomy (1, 4, 5). The success rate seems to be closely relatedto the size of the EP and of the amount of trophoblastic activity. The risk fo complications and the need for a second intervention are high if recommendedlimits are exceeded, and may leadto adiscreditation of the injection method. PG and MTX are shown to be equally effective (26), but a prolonged resolution time is seen after transvaginal MTX treatment (25, 26). It is not clear if pharmacological treatment will result in increased formation of adhesions compared with laparoscopic salpingotomy but the subsequent tubal patency and pregnancy outcome after MTX are comparable to results obtained after laparoscopic salpingotomy (17). Encouraging results for fertility after PG injection have also been found compared with laparoscopic salpingotomy (8),but patient series have been small, and randomized studies for evaluatina subseauent fertilitv are warranted.
References
47
tion of hyperosmolar glucose solution or prostaglandin F :a prospective randomized study. The Lancet 1990;336:78-81. 15. Tanaka T, Hayashi H, Kutsutawa T, Fujimoto S, lchinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: a report of a successful case. Fertil Steril 1982;37:851-2. 16. lchinoe K, Wake N, Shlnkai N, Shiina Y, Mlyazakl Y,Tanaka T. Nonsurgical therapy to preserveoviduct function in patients with tubal pregnancies. Am J Obstet Gynecoll987;156:464-
7. 17. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet G necoll990;162:1620-4. 18. Egarter Methotrexate treatment of ectopic gestation and reproductiveoutcome (Lettertotheeditor)Am JObstet Gynecol 1991 : 698-9. 19. Zakut H, Sadan 0, Katz A, Dreval A, Bernstein D. Management of tubal pregnancywith methotrexate.BrJ Obstet Gynecol
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1989;96:725-8. 20. Kojlma E, Morita M, Hlrakawa S. The treatment of unruptured tubal pregnancy with intratubal methotrexate injection under laparoscopic control. Obstet Gynecol 1990;75:723-5. 21. Kool S,Kock HCL. Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: a report of 25 patients. Fertil Steril 1990;54:
580-4. 22. Thompsom GR, OShea RT, Seman E. Methotrexate injection of tubal pregnancy. A logic evolution? Med J Austr 1991 ; 154:469-71. 23. Felchtinger W, Kemeter P. Treatment of unruptured ectopic
1. Pouly JL, Mahnes H, Mage G, Canls M, Bruhat MA. Conpregnancy by needlingof sac and injection of methotrexate or servative laparoscopic treatment of 321 ectopic pregnancies. PGE2 under transvaginal sonography control. Arch Gynecol Fertil Steril 1986;46:1093-7. Obstet 1989;246:85-9. 2. DeCherney AH, Diamond MP. Laparoscopic salpingostomy 24. M6nard A, Cre'quat J, Mandelbrot L, Hauuy JP, Madelenat for ectopic pregnancy. Obstet Gynecol 1987;70:948-50. P. Treatment of unrupturedtubal pregnancy by local injection 3. Brumsted J, Kessler C, Gibson C, Nakajima S, Rlddick DH, of methotrexate under transvaginalsonographic control. Fertil Glbson M. A Comparison of Laparoscopy and Laparotomyfor Steril 1990;54:47-50. the Treatment of Ectopic Pregnancy. Obstet Gynecol 1988; 25. Tulandi T, Bret PM, Atrl M, Senterman M. Treatment of 71:889-92. Ectopic Pregnancy by Transvaginai lntratubal Methotrexate 4. Vermesh M, Sllva PD, Rosen GF, Stein AL, Fossum GT, Administration. Obstet Gynecol 1991;77:627-30. Sauer MV. Management of Unruptured Ectopic Gestation by Linear Salpingostomy: A Prospective Randomized Clinical 26. Fernandez H, Baton C, Lelaldler C, Frydman R. ConservaTrial of Laparoscopy Versus Laparotomy. Obstet Gynecol
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5. Lundorff P. Modern management of ectopic pregnancy, early recognition, laparoscopic treatment and fertility prospects. Goteborg, Sweden: University of Goteborg, 1991. ISBN 91628-0204-6. Dissertation. 6. Hahlln M, Bokstram H, Llndblom B. Ectopic pregnancy: in vitro effects of prostaglandins on the oviduct and corpus luteum. Fertil Steril 1987;47:935. 7. Lindblom B, KBllfelt B, Hahlln M, Hamberger L. Local prostaglandinF I injectionfor termination of ectopic pregnancy. Lancet 198f;1 :776. 8. Lindblom B, Hahlin M, Lundorfi P, Thorburn J. Treatment of tubal pregnancy by laparoscope-guided injection of prostaglandin FZ,. Fertil Steril 1990;54:404-8. 9. Egarter C, Husslein P. Prostaglandins in the treatment of tubal pregnancy. Eicosanoids and Fatty Acids 1988;5: 44. 10. Vejtorp M, Vejerslev LO, Ruge S. Local prostaglandin treatment of ectopic pregnancy. Human Reprod 1989;4:464-7. 11. Odland Jb, Maltau JM, Tollan A. Konservativ behandling av ektopisk graviditet. Tidsskr Nor Laegeforen1991; 1 1 1: 326-
7. 12. Egarter C, Fitz R, Spona J et al. Behandlung der Eileiterschwangerschaft mit Prostaglandinen: Eine Multizenterstudie. Geburtsh u Frauenheilk 1989;49:808-12. 13. Deckardt R, JBnlcke F, KuhnW,Zhang OH. Laparoskopische Therapie der Eileiterschwangerschaft mit Prostaglandinen. Geburtsh u Frauenheilk 1990;50: 533-7. 14. Lang PF, Welss PAM, Mayer HO, Haas JG, Htinigl W. Conservative treatment of ectopic pregnancy with local injec-
tive managementof ectopicpregnancy:prospectiverandomized clinical trial of methotrexate versus prostaglandinsulprostone bv combined transvaainal and svstemic administration. Fertil Sieril 1991; 55: 74%-50. 27. Rlsauez F. Mathieson J. Pariente D et al. Diaanosis and treaiment of ectopic pregnancy by retrograds selective salpingography and intraluminal methotrexate injection:work in progress. Human Reprod 1990;5: 759-62. 28. Garcia A, Aubert J, Sama J. Josimovich JB. Expectant management of presumed ectopic pregnancies. Fetid Steril 1987;48: 395-400. 29. Fernandez H. Ralnhorn J. PaDlernik E. Bellet D. Frvdman R. Spontaneous resolution dt ectopic' pregnancy. -0bstet Gynecoll988; 71 : 1714. 30. Pouly L, Chapron C, Mahnes H, Canls MyWattiez A, Bruhat MA. Multifactorial analysis of fertility after conservative laparoscopic treatment of ectopic pregnancy in a series of 223 patients. Fertil Steril 1991;56(3):453-60. 31. Tuomlvaara L, Kaupplla A. Radical or conservative surgery for ectopic pregnancy? A follow-up study of fertility of 323 patients. Fertil Steril 1988;50(4):580-3. 32. Thorburn J, Philipson M, Lindblom B. Fertilityafter ectopic pregnancy in relation to background factors and surgical treatment. Fertil Steril 1988;49(4):595-601. 33. Ross GT. Congenital anomalies among children born of mothers receiving chemotherapy for gestational trophoblastic neoplasms. Cancer 1979;37:1043-7. 34. Walden PA, Bagshawe KD. Reproductive performance of women successfullytreatedforgestationaltrophoblastictumors. Am J Obstet Gynecol 1976;15:1 1 08-1 4.
Ann Med 24
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Advancing Conservative Treatment of Ectopic Pregnancy — Laparoscopic and “Non-Surgical” Management Jane Thorburn To cite this article: Jane Thorburn (1992) Advancing Conservative Treatment of Ectopic Pregnancy — Laparoscopic and “Non-Surgical” Management, Annals of Medicine, 24:1, 43-47, DOI: 10.3109/07853899209164143 To link to this article: http://dx.doi.org/10.3109/07853899209164143
Published online: 08 Jul 2009.
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Trends in Clinical Practice
Advancing Conservative Treatment of Ectopic Pregnancy - Laparoscopic and “Non-Surgical” Management
Downloaded by [University of California, San Diego] at 23:29 10 March 2016
Jane Thorburn
Improvements in diagnostic measures have contributed to the earlier diagnosis of ectopic pregnancy which in turn has led to the development of new and alternative methods of managing tubal pregnancies. Laparoscopicsalpingotomy offers advantages such as a reduction in operating time and shorter hospital stays and convalescenseas compared with conventionalabdominal surgery. Furthermore, neither the frequency of persistent trophoblasts nor of second operations is Increased, and the subsequent fertility rate is at least equal to that after laparotomy. “Non-surgical” treatment of ectopic pregnancy, such as systemic administration of methotrexate and laparoscopic/ transvaginal ultrasonic - guided local injection of methotrexate, prostaglandins or hyperosmolar glucose, are attractive alternative methods in selected cases. These methods are safe and effective and have a high success rate and promising results for fertility. Laparoscopy is preferredto conventionalabdominalsurgery for the treatment of ectopic pregnancy. In selected cases, “non-surgical” treatment can be an attractive alternative therapy. Key words: ectopic pregnancy; conservative treatment; laparoscopic surgery; methotrexate; “non-surgical” treatment; prostaglandins. (Annals of Medicine 24: 43--47,1991)
Introduction
Salpingotomy via Laparoscopy
An increasingproportion of tubal gestations are now treated early in the pregnancy and often before rupture of the tube occurs. Improvements in diagnostic measures, such as the use of serum human chorionic gonadotrophin (hCG) and endovaginal sonography, have contributed to this early recognition, which is a prerequisite for the development of new therapeutic methods for treating ectopic pregnancy (EP). Conservativetreatment of EP implies the preservation of the tube with a subsequent possible for ovum transfer. Until recently, salpingotomy via laparotomy was considered to be the prime conservative approach. During the past decade, however, a subset of alternative and advancing conservative management methods have been introduced to increase such short term benefits as shorter hospital stays and convalecense periods and to improve subsequent fertility.
In 1986, Pouly et al. (1) reported a large series of tubal pregnancies treated conservatively via laparoscopy (Table 1). A second surgical intervention owing to persistent trophoblast was necessary in less than five percent of patients. The subsequent fertility rate was reportedto be as good as the fertility rates after conservative treatment by laparotomy. Pouly emphasized, however, that fertility results after EP treatment must be interpreted with care, especially as there may be large differences in the treated populations regarding both risk determinants and pelvic conditions, which significantlyinfluencepostoperativefertility. DeCherney and Diamond (2) later presented a series of tubal gestations treated by laparoscopic salpingotomy, with an overall subsequent conception rate of over 60 %; no apparent differences in outcome were found as compared with salpingotomies performed at laparotomy. These two studies, however, showed a high success rate, which encouraged other research groups to investigatelaparoscopic treatment of EP. A case control study from Vermont in 1988 (3) compared the short term outcome of laparoscopy and laparotomy and found that patients treated by laparoscopy had significantly shorter operatingtimes, hospital stays and
Fromthe Departmentof Obstetricsand Gynaecology, University of Goteborg, Goteborg, Sweden. This study was supported by the Swedish Medical Research Council (grant 8683). Address and reprint requests: Jane Thorburn, MD., PhD., Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden.
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Table 1. Ectopic pregnancy treated by laparoscopy or laparotomy. ~
No. of
Author
Mode of cases application
Pouly et a/ (1)
321
L-SCOPY
Failure rate
Pregnancy rate
15/321 (4.8Yo)
intrauterine pregancy rate
76/118 (64.4Yo)
DeCherney & Diamond (2)
79
L-scopy
2/79
(2.5Yo)
Brumstedetal(3)
C/C
25 25
L-scopy L-torny
2/25 0
(8%)
Vermesh et al(4)
R
30 30
L-SCOPY L-tomy
3/30 (10Yo) 1/30 (3“/o)
10118 (56“/o) 11/19 (58“/o)
LundonY P (5)
R
48 57
L-SCOPY L-tomy
6/48 (12.5Yo) 2/57 (3.5Yo)
25/42 (59.5Yo) 25/45 (55.5%)
43/69 (62%)
36/69
(52%)
Ectopic pregancy rate
2611 18 (22Yo) 7/69
(10Yo)
9/18 (50Yo) 8/19 (42Yo) 22/42 20/45
(52Yo) (44.5Yo)
1/18 (6Yo) 3/19 (16%) 3/42 5/45
(7.5%) (11 70)
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L-scopy = Treatment performed by laparoscopy L-torny = Treatment performed by iaparotomy C/C = case-controlstudy R = prospective randomized trial
convalescence. Despite a potential weakness in the study design, it was suggested that laparoscopy offers economic advantages and an easier and quicker recovery. The first prospective, randomized clinical trial of laparoscopy versus laparotomy for the treatment on unruptured EPs was reportedby Vermesh et al. in 1989 (4). The incidence of persistent trophoblast was similar to that reported by Pouly (1). The rate of decline in postoperative serum hCG and the subsequent pregnancy rates did not differ between the two surgical groups. Although the two methods were shown to be equally safe and effective, laparoscopy seemed to be more economical. In another prospectiverandomizedclinicaltrial by Lundorff et al. (5),the short term benefits of laparoscopy previously were confirmed. Moreover, at a second look reported (3,4) laparoscopy, which was performedin both groups undergoing surgery, it was shown that postoperative adhesion formation was reduced in cases primarily treated by laparoscopy. The subsequent pregnancy rate did not differ betweenthe two groups, but the authors pointedout that the fertility outcome in the laparotomy group could have been favoured by the fertility technique used and by the adhesiolysis performed at the second look laparoscopy.
“Non-surgical” Treatment There is great interest today in “non-surgical” - that is, without surgical interference in the tube - management of small tubal pregnancies with low trophoblastic activity. As laparoscopy is the only method other than laparotomy for viewing the pelvis, including inspection of the ectopic gestation, adhesionformation and tubal condition, the development of local injection therapy was prompted the use of laparoscopy. Becauseof improvements in the technique of endovaginalsonographyand with more experienced investigators, local injection therapy was later introduced under transvaginal sonographic control. Although the pelvic conditions cannot be seen, and thus fertility prospects cannot be forecast, this approach implies several advantages such as management without surgery, anaesthesia or admission to hospital.
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Local Injection Therapy via Laparoscopy Prostaglandins(PG): In vitrostudies on the effects of PG on the oviduct and corpus luteum led to the proposal that PGF, alpha could be useful in the pharmacological treatment of EP (6).A regimen for this purpose was initially recornmended by Lindblom et al., 1987, (7) and later presented in a study of selected cases (8).Patients were treated by local injection of PGF, alpha (1-3 mg) or 15-metyl PGF, alpha (in equipotent doses) into the tubal wall and in the corpus luteum. Both the success rate and the subsequent pregnancy rate were high and no untoward effects of the treatment were seen (Table 2). The authors concluded that patients subjected to local injection therapy should be carefully selected, with those chosen presenting with only small gestations (c2 cm) and low trophoblastic activity (el000 IU/ L)In a study by Egarter and Husslein (9). a higher total dose than the original recommended regimen was used, which may explain the three patients in their series who developed severe haemodynamic side effects, including one with pulmonary oedema. Usingthe Lindblomregimen, Vejtorp et al. (10)reported no serious side effects, and by using a slightly higher dose, Odland et al. (1 1) reported no severe adverse side effects in their series. Egarter et al. (12) recently publisheda prospective multicentre study in which patients were treated by local PGF, alpha (7-10 mg) in combinationwith oestrogen in the corpus luteum, as well as additional systemic PGE,. These patients were compared to women treated by conventional abdominal surgery. No serious side effects were noted in the PG group during this regimen and the PG group had shorter hospital stays than patients undergoing laparotomies. Future fertility seemed promising as compared with conventional surgery, and postoperative morbidity was reduced in patients whose initial serum hCG concentration was below 2500 IU/L. A high success rate for cases who had initial serum hCG concentrations below 2500 IU/L was also subsequently reported by Deckardt et al. (13). Hyperosrnolarglucose.Lang et al. (1 4) allocatedpatients randomly either to PG or hyperosmolar glucose solution, considered to be a non-toxic agent. No side effects were
Conservative Treatment
45
of Ectopic Pregnancy
Table 2. “Non-surgical” treatment of ectopic pregnancy. ~
Author
No. of cases
~
Vejtotp et a1 (1 0) €garter et a1 (12) Lindblom et a1 (8) Deckardf et a1 (1 3) Odland et al(11) Lang eta/ (74) R lchinoe et a/ (1 6) Stovall et a1 (1 7) Zakut et a1 (1 9) Kojima eta/ (20) Kooi & Kock (21) Thompson et a1 (22) feichtinger (23) Me’nard et al(24) Tulandi et al(25) fernandez et a1 (26) R
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Mode of application
Drug
L
PGF PGF +&E2 F%F PGF +&E2
Failure rate
Side effects
lpsilateral Subsequent patency pregnancies
_ _ _ _ ~ _ _ _ _
11 71 26 15 16 31 (15:16) 23 57 10 9 25 18 10 17 12 21 (12:9)
L+S L L+S
&F
L
L+S:L
S S L+S L L+(S) L Tv Tv Tv
N+S
PGF2,+E+&E2:G MTX MTX+CV MTX+CV MTX MTX+A+CV MTX MTX or PGE2 MTX+CV MTX (+PCI) MTX+CV:PGE2
0 0 0 0 1 (pain) 1 (pain, PG) 0 0 1 (stornatit) 0 5’ 0 1 (pain) 0 0 2 (stornatit :pain)
4 17119 1
718 22/24
616 -
-
5/6:7/8 10119 19/23 7/7 919
4 (1:3)
-
11/14 1
-
-
9114
313 -
-
718:6/6
3
a/a
56 (15 Yo)
372
Mode of application: L = Laparoscope-guidedinjection therapy S = Systemic administration TV = Transvaginal ultrasound-guided local injection R = randomized study
1111 21/71 2/26 7115 2/16 2/15 (PG) 1I23 0 2/10 1I9 1/25 1/18 2/10 (MTX) 4117 2/12 4/12 :3/9
Drugs: PGF PG& MTX G E CV A PCI
= Prostaglandin F alpha = Prostaglandin
d
= Methotrexate = Hyperosmolar glucose
=Estrogen = Citrovorum factor = Adrenaline = Potassium Chloride
transient elevations of serum glutarnic-oxaloacetic and glutamic-pyruvic transaminaselevels when additional systemic administration was used.
noted in patients treated by glucose, and the success rate and subsequentfertility outcomewere equally as good as in the PG group. Glucose instillationcan therefore be considered in selected cases as a low risk alternative to local treatment with more aggressive agents. Methotrexate (MTX).MTX is a folic acid antagonist that has been widely used for the treatment of gestational trophoblasticdisease. Since 1982, when Tanaka (15) first treated an ectopic gestation by systemic chemotherapy, several studies have confirmed the resolution of EPs after systemic MTX treatment (16). Stovall et al. reported in 1990 (17) that systemic MTX treatment implied a higher subsequent fertility rate than that achieved by traditional surgical methods, and was comparable to resultsafter laparoscopic salpingotomy. It has been argued, however, that MTX might not be a preferable treatment, especially in view of its possible tefatogenic and mutagenic effects (18). Side effects such as stomatitis, dermatitis and bone marrow depressioncan be partiallyavoided by the paralleladministration of citrovorum factor. To reduce the MTX dosage and minimize the high toxicity and side effects of MTX systemically administered, new techniques for local injection into the tube were introduced. In a study from Israel (19), patients with small tubal gestations were treated by an injection of MTX (12.5 mg) into the gestational sac via a laparoscopy. Additional MTX was administered systemically, followed by folinic acids. The failure rate was low, and the subsequent tubal patency high. Similar results were later presented by Kojima et al. (20) usingdoses from 5 to 25 mg and by Kooi and Kock (21) using 100 mg MTX after adrenaline injection into the mesosalpinx. Minimal side effects only appeared during supplementary systemic therapy. Kojima et al. (20) also
showed that the pattern of reduction in the concentration in urinary hCG was similar to that of serum hCG observated after conservative surgical treatment of EP (4), indicating no prolonged resolution time after MTX administered via a laparoscopy. Recently, an Australian investigation (22) reported on patients who were given 20 mg MTX around the tubal gestation; they had a low failure rate and no side effects were reported. The investigators postulatedthat local MTX injection can be performed by any operator with minimal laparoscopic skills and there may also be a better chance of preserving tubal function.
Local Injection Therapy under Transvaginal Sonographic Control In 1989, Feichtinger and Kemeter (23) reported a small series of patients with unruptured EPs who were treated by localinstillationof MTX (10 to 50 mg) into the gestational sac by sonographic control and on one patienttreated by PGE, (0.5 mg). No side effects were seen among the MTX patients, but the single patient treated with PG had vomiting and abdominal pain. A larger series of patients treated by a single 50 mg dose was recently reported in France (24). No systemic side affects of MTX were observed. In one patientwith a bilateral tubal gestation, pathological examination showed resolution on the treated side and n6 evidence that MTX had affected the contralateraltube, demonstrating its localised effect.The authors noted, however, that the effect of needle aspiration per se on the resolution of EP, independent of MTX injection, has not yet been evaluated. In a Canadian study (25),a high success rate was found
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after intratubal transvaginal MTX injection (1 mg/kg body weight), and no side effects were encountered. A repeat MTX injection was, however, required in four of six women with a living embryo and, in one of these local potassium chloride was also injected with good results. So the authors concludedthat MTX treatment seemed to be more appropriate in the absence of a living embryo. The prolonged resolutiontime observed in this study is one of the disadvantages generally seen in the use of transvaginal administration. A prospective, randomized study of patients with an unrupted tubal pregnancy treated by local and systemic injection of either MTX or PGE, was recently published by Fernandez et al. (26). The success rate was high in both treatment groups, indicatingthat MTX and PGE, are equally effective.
Retrograde Selective Salpingography and lntraluminal M TX Injection This new method for the “non-surgical”treatment of EP was introducedby Risques et al. (27),who reportedfour patients treated successfully. The study was, however, too small to draw any general conclusions.
Expectant Managemeni Very early diagnosis of EP may imply treatment of some patients whose condition would otherwise have resolved spontaneously. The question has arisen whether expectant management (i.e. of patients who are followed by analyses of serum hCG until non-pregnant levels are obtained) implies advantages over local injection therapy. Only small series are reported(28,29) showing a high success rate and good subsequent fertility. Criteria for the selection of these potentialcases are still under evaluation, and no conclusion as to fertility outcome can yet be drawn.
Comments Randomized trials have proved that laparoscopic salpingotomycanoffer importantadvantages over traditional surgical laparotomy. Short term benefits are shorter operations, hospitalization and recovery times with fewer adhesions forming. Compared with conventional surgery, there is no increased rate of persistent trophoblast or of the need for a second intervention. Provided that a skilled laparoscopistis available,there seems to be no restrictions, such as size of the gestation, rupture of the tube or high hCG values, for performing laparoscopic salpingotomy. On the other hand, laparoscopymay be contraindicatedin patients in pre-shock or shock with profuse bleeding. Although no study has thus far shown improved subsequent fertility after laparoscopic salpingotomy, some data seem promisingin this respect (5,30). Fertilityoutcome after laparoscopic salpingotomy is shown to be correlated with the existence of ipsilateral adhesions, the condition of the contralateral tube and the patient‘s past history (30). This accords with two previous studies on conventional abdominal surgery (31, 32). Laparoscopic surgery, as a mode of application, would therefore improve the prospectsfor subsequent fertility owing to fever adhesions forming (5) as compared with conventional laparotomy. The mode of application-laparoscopy or laparotomyAnn Med 24
should never change the mode of treatment. Radicaltreatment (salpingectomy) or conservative treatment (salpingotomy) should be performed when indicated, irrespective of whether laparotomy or laparoscopy is used. Laparoscopic salpingectomy is still a radical operation although it offers the same short term benifits as seen after laparoscopic salpingotomy. Moreover, as it is a radical treatment there is no need for postoperative hCG controls. Which patients should then be considered for radical surgery? Recently a scoring system was proposed by Pouly et al. (30) to choose the most suitable treatment to preserve fertility and reduce the risk for repeat EP ranging from laparoscopic conservative treatment to laparoscopic salpingectomy. In selected cases, a “non-surgical” approach seems attractive. The proportion of patients considered for injection therapy may vary substantially between clinics and is dependent on an “early” diagnosis of EP, a special interest among gynecologists in this research field and the ability to follow up the patient using consecutive hCG analyses. Laparoscopic !om/ injection therapy resuIts in tangible cost benefits; the technique requires no expensive high technology equipment and can be performed by any surgeon with some laparoscopic skills (22). Neither surgery nor hospital admission is required for transvaginal injection therapy, and the treatment does not need anesthesia (24). On the other hand, experience in sonography is required for transvaginal administration and this technique is still in the investigationalstage (25). Since EPs are often located intramurally and not in the lumen, it may be difficult even for a skilled professionalto locate the gestation exactly by the transvaginal approach. Ultrasound quided therapy may therefore be less effective than laparoscopic injection therapy and in some cases it may result in a prolonged resolution time (25). The importance of postoperative serum hCG analyses must be emphasized since local injection therapy has a higher failure rate than laparoscopic salpingotomy (15 Yo versus 5 %). Recommended intervals are once or twice weekly until non-pregnant concentrations are obtained. PG can give rise to severe cardiopulmonaryside effects, e.g., pulmonary oedema, but no such severe side effects are encountered at recommended doses (7,8,10). MTX is a cytotoxic substance that can result in side effects such as alopecia, stomatitis and hepatic and bone marrow toxicity. While no systemic side effects have been noted after local injection therapy (24, 25), combined local injection and systemic administration have given rise to a few cases of stomatitis (19, 26). Furthermore, there is no evidence that MTX will cause any congenital abnormalities(33,34). Local injectiontherapy with PG or MTX can therefore be regarded as safe alternatives for the treatment of selected patients with tubal pregnancy. PG treatment is recommended for patietns showing initial hCG concentrations below 1000to 2500 IU/L (8,12,13) and with an EP less than 2 cm in size (8). Suggested limits for MTX injection are higher -5000 to 10 000 IU/L and 4 cm, respectiely (19, 20). So far, neither MTX nor PG can be recommended for patients with ruptured tubes, significant haemoperitoneum or a living embryo and MTX is contraindicated when there is a co-existing intrauterine pregnancy (24, 25, 26). The success rate after PG and MTX treatment is between 80 Yoand 90 Yo,which seems to be somewhat below that of
Conservative Treatment of Ectopic Pregnancy
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laparoscopic salpingotomy (1, 4, 5). The success rate seems to be closely relatedto the size of the EP and of the amount of trophoblastic activity. The risk fo complications and the need for a second intervention are high if recommendedlimits are exceeded, and may leadto adiscreditation of the injection method. PG and MTX are shown to be equally effective (26), but a prolonged resolution time is seen after transvaginal MTX treatment (25, 26). It is not clear if pharmacological treatment will result in increased formation of adhesions compared with laparoscopic salpingotomy but the subsequent tubal patency and pregnancy outcome after MTX are comparable to results obtained after laparoscopic salpingotomy (17). Encouraging results for fertility after PG injection have also been found compared with laparoscopic salpingotomy (8),but patient series have been small, and randomized studies for evaluatina subseauent fertilitv are warranted.
References
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