Fertility outcome after conservative surgical treatment of ectopic pregnancy evaluated in a randomized trial*

Transcription

1 FERTLTY AND STERLTY Copyright 1992 The American Fertility Society Printed on acid-free paper in U.S.A. Fertility outcome after conservative surgical treatment of ectopic pregnancy evaluated in a randomized trial* Per Lundorff, M.D.t Jane Thorburn, M.D., Ph.D. Bo Lindblom, M.D., Ph.D. Department of Obstetrics and Gynecology, University of GOteborg, G6teborg, Sweden Objective: To evaluate the fertility outcome after laparoscopic surgery for ectopic pregnancy. Design: A randomized trial versus laparotomy was performed between May 1987 and June Setting: The study was conducted in a clinical university center, the Sahlgrens Hospital. Patients: A group of 105 patients with tubal pregnancy were stratified with regard to risk determinants and age and randomized to laparoscopy or laparotomy. Eighty-seven patients who desired pregnancy were evaluated for subsequent fertility outcome. nterventions: Linear salpingotomy was performed in both surgical groups. Main Outcome Measure: We evaluated the fertility outcome after laparoscopic salpingotomy for comparison with the outcome after laparotomy. Results: There was no difference between the groups in the overall fertility outcome. A substantially higher proportion of patients in the laparotomy group were subjected to adhesiolysis performed at a second-look laparoscopy. Conclusions: The fertility prospects are not impaired by laparoscopic surgery. Adhesiolysis at a second-look laparoscopy, especially after laparotomy, might be beneficial in selected cases and may serve to improve subsequent fertility. Fertil Steril1992;57: Key Words: Ectopic pregnancy, laparoscopic surgery, fertility outcome Despite improved diagnostic methods and surgical treatment of ectopic pregnancy (EP), subsequent fertility is still poor. The cumulative frequency of live births is reported in several studies to be approximately 60%, and a recurrence of EP between 10% and 30% (1-6). The fertility outcome is correlated to a great extent with risk factors, regardless of the method of surgery (4), and is influenced by the presence and status of the contralateral tube rather than the op- Received February 18, 1991; revised and accepted January 16, * Supported by grant 8683 from The Swedish Medical Research Council, Sweden and by the Giiteborg Medical Society, Giiteborg, Sweden. t Reprint requests and present address: Per Lundorff, M.D., Department of Obstetrics and Gynecology, Viborg Sygehus, DK Viborg, Denmark. 998 Lundorff et al. Fertility after EP eration methods per se (3). On the other hand, some investigators stress the importance of conservative treatment by linear salpingotomy, as compared with radical surgery, to enhance the fertility, and the method is recommended even when both tubes are present (7). The presence of adhesions is also suggested to be of great importance for subsequent fertility (8), and adhesiolysis among infertility patients is recommended (9, 10). Efforts have consequently concentrated on minimizing the formation of adhesions, e.g., by using laparoscopic treatment (11). n the light of this, we initiated a prospective randomized trial to evaluate the subsequent fertility in women with tubal pregnancy conservatively treated either by laparoscopy or laparotomy. Attention was focused on the impact of periadnexal adhesions, tubal patency, and adhesiolysis in connection with a second-look laparoscopy.

2 MATERALS AND METHODS During a 2-year period between May 1987 and June 1989, 105 women with tubal pregnancies fulfilling the entry criteria were stratified on the basis of age and risk determinants (12) (previous EP, previous abdominal surgery, history of infertility or intrauterine device in situ), to establish comparable groups for future fertility evaluation and randomized in a prospective trial to either surgery by laparoscopy (n = 48) or laparotomy (n = 57) by sealed envelopes. All operations were performed under general anesthesia with endotracheal intubation. For the laparoscopic surgery, an 8 to 10-mm laparoscope was used, introduced through the umbilicus. Two additiona15-mm trocars were inserted suprapubic in the right and left side of the lower pelvis for introduction of a grasping forceps, a diathermy knife, and, intermittently, a suction-irrigation unit (Aquapurator; Wisap, Sauerlach, Germany). A diluted solution of vasopressin, 5 V in 10 ml of saline was injected into the mesosalpinx for hemostasis via a 0.8-mm syringe. The tube was opened with a fine diathermy knife over the implantation site with a longitudinal incision (10 to 15 mm), and the pregnancy products were removed either with the Aquapurator or with lo-mm spoon forceps. n case of laparotomy, vasopressin injection and a salpingotomy with a similar diathermy knife was performed and the pregnancy products squeezed through the opening. All surgical interventions were performed by one of the authors with the aim of performing a linear salpingotomy regardless of the operative approach. An atraumatic, gentle technique was always used. rrespective of the operative approach, the affected tube was left open for secondary healing. Entry criteria were: (1) diameter ofthe tubal gestation < 4 cm; (2) ampullary gestation accessible for laparoscopic approach; (3) a trained laparoscopist on duty; and (4) hemodynamic stability. f the preoperative human chorionic gonadotropin level was known, cases with titers > 10,000 V jl were excluded. A gross anatomy evaluation of the periadnexal and tubal status was undertaken during surgery. A second-look laparoscopy was performed in 64 patients who desired pregnancy 12 weeks after primary surgery (range 1 to 29 weeks), and the periadnexal and tubal status was compared with the status at primary surgery. Twenty-nine patients in the laparoscopy group and 35 patients in the laparotomy group underwent a second-look laparoscopy. At this procedure, adhesiolysis by careful electrocautery was performed in 33 of 45 cases in which adhesions were found. The results of the second-look laparoscopy have also been reported recently (13). Questionnaires including items such as wish for pregnancy and outcome, use of contraceptives during the study period and time at risk for pregnancy were sent to all 105 patients 1 year after surgery and at the end of the study period in August Eightyfive patients immediately answered the final questionnaire. n 20 cases, a repeat letter that drew 19 responses was sent. One patient was lost in the follow-up, making the response rate 99%. Seventeen patients had no future desire for pregnancy. The remaining 87 patients, 42 from the laparoscopy group and 45 from the laparotomy group, desired a pregnancy. Statistics Fischer's exact test was used for the statistical analysis. A P value < 0.05 was considered significant. Fertility Outcome RESULTS n the total material of 87 patients, 50 conceived during the study period. Twelve of these had a second pregnancy, and 1 patient had two subsequent pregnancies, bringing the total to 64 pregnancies (Fig. 1). Of all 87 women, 30 (35%) had at least one delivery or a late ongoing pregnancy during the follow-up period. Eight (16%) were EPs among the first 50 subsequent pregnancies, whereas 42 (84%) were intrauterine pregnancies (VPs). The rate of miscarriage among the latter was 17 of 42. None of the patients whose first pregnancy was ectopic had a second pregnancy. n one case, a miscarriage after EP surgery was followed by a second EP (Fig. 1). The average period at risk in all 87 patients who desired pregnancy ranged from 1 to 36 months with a mean of 14 months. Thirteen women were at risk for pregnancy < 18 months and 5 for >30 months (Fig. 2). The first subsequent pregnancy in the total material as it relates to months at risk for pregnancy is illustrated in a cumulative frequency distribution in the form of a modified life table in Figure 3. Seventy percent of the first subsequent pregnancies occurred within 1 year of the at risk period and 95% within 18 months. After 21 months at risk, no further successful pregnancies were seen. Only EPs were observed after 28 months at risk. As seen in Figure 3, the EP jvp ratio increased parallel to the time at risk. Lundorff et al. Fertility after EP 999

3 No Tot,l""teri,l ] f Lool for ton..., up ill Responden ~ W.h for pr..,no""v ~ ~@] ~ No Pl'9nonev [Tl Finl pl'9 nev ~ ~ E Ectopic Pl'9no""v[) ntnuttrtne prt9nencj ~... uc... krllo. 2 MllClrrl. 9 ollljll"'lup[!) Term pregnel'lcy[!] ollljll"'lup Z ' o1.hf,r Pl'9nonev ~ l.porolomv ~ ~ NoP'9.. nev~ Flrll Eclopic pr..,no""v 0 nlrou\'rlb= -.~m. ~ o"""'lup m T,rm prtt.. ftcj _l1li pr.,no""y [!] 3 los ollljoi"'lup z Thin! pr"no",v [!] o"""'lup Figure 1 Total fertility outcome of all 105 patients in the randomized trial. Conception Rates Related to Surgical Methods Laparoscopy Group Twenty-five of 42 patients conceived (59.5%). Among the first subsequent pregnancies, 22 of 25 (88%) were UPs, and a recurrence of EP was seen in 3 of 25 (12%). Eleven of these 22 pregnancies (50%) were either ongoing or full-term pregnancies, 2 of 22 (9%) were induced abortions, and 9 of 22 (41%) resulted in miscarriage. The ratio between EP and UP was thus 1:7 (Fig. 3). Eleven of 42 patients (26.2%) in this group thus had a late ongoing or full-term pregnancy. Five women conceived a second time, the results of which were 1 ectopic and 4 UPs. n total, 14 women (33%) had a term delivery or a late ongoing pregnancy. Number of patients 8r---~--~~--~--~--~--~--~ o Month, Figure 2 Number of women in relation to months at risk for pregnancy. Months at risk for pregnancy before a first conception in women who became pregnant (0). Months at risk for pregnancy in women who did not become pregnant (~). nancy. Seven women had one subsequent pregnancy, and 1 patient had two subsequent pregnancies. No EPs were seen as a second or third pregnancy. A total of 16 women (36%) had a term delivery or late ongoing pregnancy (Fig. 1). The rate of first subsequent UP and the ratio of EP /UP did not differ significantly between the two surgical methods. mpacts of Adhesions and Adhesiolysis The possible importance of adhesions and adhesiolysis was further analyzed regardless of the treatment to which the patients belonged. Forty-five of the 64 patients who underwent second-look laparoscopy after EP surgery had adhesions of varying degrees. The subsequent conception rate did not differ significantly between patients with or without adhesions (Table 1). n patients without adhesions and with bilateral patency, UPs were observed exclusively. Further- Number of potlents laperoscopy Leplfotomy Laparotomy Group Twenty-five patients of 45 conceived (55.5%). Among the first pregnancies, 20 of 25 (80%) were UPs, and a recurrence of EP was seen in 5 cases (20%). Twelve of these 20 UPs were ongoing or full-term pregnancies (60%), and 8/20 (40%) resulted in miscarriage. The ratio between EP and UP was 1:4 (Fig. 3). Twelve of 45 patients (26.7%) in this group thus had a late ongoing or term preg- Months at risk Months at rl sk Figure 3 Cumulative frequency of a first subsequent pregnancy in 87 patients who desired pregnancy as related to months at risk and to method of surgery. Term delivery/late ongoing pregnancy (dark gray area); Spontaneous abortion (empty bars); EP (light gray area) Lundorff et a1. Fertility after EP

4 Table 1 Subsequent Fertility at First Conception After EP Surgery in 64 Patients Who Desired Pregnancy Considering Surgical Method and Periadnexal and Tubal Status at Second-Look Laparoscopy Total no. of pregnancies UP EP EP/UP EP/EP + UP Laparoscopy group (n = 42) 25 (60) * 22 (52) t Laparotomy group (n = 45) 25 (56) 20 (44) No adhesion (n = 19) 11 (58) 10 (53) Adhesions (n = 45) 24 (55) 17 (39) Bilateral patency (n = 30) 20 (67) 18 (60) No bilateral patency (n = 31) 13 (42) 8 (26) Contralateral patency (n = 40) 25 (63) 22 (55) No contralateral patency (n = 19) 6 (32) 4 (21) psilateral patency only (n = 15) 5 (33) 2 (13) All other cases (n = 46) 28 (61) 24 (52) P < 0.01 P < 0.05 P < (7.1) 1/ (11.1) 1/ (5.3) 1/ (15.9) 1/ (6.5) 1/ (16.1) 1/ (7.5) 1/ (10.5) 1/ (20) 3/ (8.9) 1/6 14 % * Values in parentheses are percents. t, not significant. more, both patients with contralateral patency and patients with bilateral patency had a higher frequency of UPs. Among patients with only ipsilateral patency, the UP rate was significantly lower than in all other cases. Adhesiolysis was performed at second-look laparoscopy in 10 of 29 patients in the laparoscopy group and in 23 of 35 patients in the laparotomy group (not significant). DSCUSSON n recent years, conservative surgery in cases of EP has been considered the operation of choice, especially in women who desire pregnancy. Laparoscopic salpingotomy is suggested to be a simple and safe surgical method with minimal complications (12). Although it has been suggested that laparoscopic treatment of EP may improve future fertility (1), this randomized study could not confirm a statistically improved fertility rate in patients treated by this method. t should be observed, however, that patients in both groups were operated on by surgeons trained in tuboplasty and microsurgery using an atraumatic technique. The procedures performed on the tube were in principle the same regardless of the mode of entrance. The overall subsequent pregnancy rate (PR) after conservative management in the treatment of EP is reported to be between 50% and 80% (2, 3, 14). n this investigation, the overall conception rate of <60% is somewhat lower in comparison with a previous study from our clinic (4). One plausible explanation could be the high proportion of patients (54%) with known risk determinants for EP, such as previous EP, history of infertility, and previous abdominal surgery. The patients were stratified according to risk determinants when randomized to laparoscopy or laparotomy, and the fertility outcome between the surgical methods is thus not biased in this regard. Another explanation for the low overall subsequent fertility rate is the short follow-up period. Our patients were at risk for pregnancy for an average of only 14 months. To our knowledge, no other longitudinal study has described future fertility after EP considering months at risk. As seen from Figure 2, 13 patients were followed for <18 months with no conception, and some of these would probably have conceived ifthe follow-up period had been extended. The observed miscarriage frequency among the first subsequent pregnancy was 17 of 87 (19.5%) in the total material, a rate somewhat higher than described by others (4, 6, 15). This is difficult to explain, but can partly be because of the high mean age ofthe women joining the study. t is noteworthy is that 7 of 17 women having miscarriage as a first subsequent pregnancy later gave birth, that 4 women had a second miscarriage, and 1 a repeat EP. These figures indicate that a subsequent spontaneous abortion after an EP still implies a reasonable chance for the woman to experience a future term pregnancy. On the other hand, according to our study, the potential for a future term pregnancy after a repeat EP is extremely poor. The results from our study agree with the conclusions of Tuomivaara and Kauppila (3) that an intact contralateral tube implies a higher subsequent UP rate and a lower EP rate. n addition, the present study could verify the suggestions of Caspi et al. (8) that an inverse relationship exists between the grade of adhesions and the PR. Lundorff et al. Fertility after EP 1001

5 Patients without patency on the contralateral tube at second-look laparoscopy have a significantly lower UP rate than patients with patency. The EP rates did not differ. t is also seen that patients with only ipsilateral patency at second-look laparoscopy have a significantly decreased UP rate and are at extremely high risk for a subsequent EP. Bronson and Wallach (9) observed that adhesiolysis among infertility patients improved the subsequent fertility rate, and Tulandi et al. (10) recently suggested an increased PR in women with periadnexal adhesions after adhesiolysis. n the present study, adhesiolysis at second-look laparoscopy was performed in 24% of patients in the laparoscopy group and in 51% in the laparotomy group. The higher rate of adhesiolysis in the laparotomy group probably reflects an increased adhesion formation after laparotomy (14). Among all subsequent UPs in the laparoscopy group, 18% had been subjected to adhesiolysis versus 45% in the laparotomy group. To what extent the adhesiolysis has contributed to subsequent fertility is difficult to say because the adhesiolysis was not performed as a randomized trial. According to the design of the study, the surgeons' aim was to re-establish normal anatomy by adhesiolysis at a second-look laparoscopy. Complete adhesiolysis was achieved in 75% of cases. n the remaining cases, the adhesiolysis could not be successfully performed because of anatomical and/ or technical factors. This study thus shows that the prospects for fertility are similar in the laparoscopy and laparotomy group when a second-look laparoscopy with adhesiolysis is performed. t is possible that this adhesiolysis performed in half of the laparotomy cases compensates for the better adhesion scores after second-look laparoscopy and thus for more UPs in this group. To conclude, this randomized clinical trial showed that the fertility outcome after laparoscopy is equivalent to that observed after atraumatic laparotomy including adhesiolysis at second-look laparoscopy. The results may have been positively influenced, especially in the laparotomy group, by the large proportion of cases undergoing second-look laparoscopy, including patency test and adhesiolysis. The latter question should be further analyzed in a randomized trial including cases subjected or not subjected to a second-look laparoscopy with adhesiolysis. REFERENCES 1. Bruhat MA, Manhes H, Mage G, Pouly JL. Treatment of ectopic pregnancy by means of laparoscopy. Fertil Steril 1980;33: Badawy SZA, Taymour E, Shaykh ME, Dorwitt D, Gaudino S, Finnerty JF, et al. Conservative surgical treatment of tubal pregnancy: Factors affecting future fertility. nt J Fertil 1986;31: Tuomivaara L, Kauppila A. Radical or conservative surgery for ectopic pregnancy? A follow-up study of fertility of 323 patients. Fertil Steril 1988;50: Thorburn J, Philipson M, Lindblom B. Fertility after ectopic pregnancy in relation to background factors and surgical treatment. Fertil Steril 1988;49: Mitchell DE, McSwain HF, Peterson HE. Fertility after ectopic pregnancy. Am J Obstet Gynecol 1989;161: Langer R, Raziel A, Ron-E R, Golan A, Bukovsky, Caspi E. Reproductive outcome after conservative surgery for unruptured tubal pregnancy, a 15-year experience. Fertil Steril 1990;53: DeCherney AH, Kase N. The conservative surgical management of unruptured ectopic pregnancy. Obstet Gynecol 1979;54: Caspi E, Halperin Y, Bukowsky. The importance of peri adnexal adhesions in tubal reconstructive surgery for infertility. Fertil Steril 1979;31: Bronson RA, Wallach EE. Lysis of periadnexal adhesions for correction of infertility. Fertil Steril 1977;28: Tulandi T, Collins JA, Burrows E, Jarrell JF, Mcnnes RA, Wrixon W, et al. Treatment-dependent and treatment-independent pregnancy among women with periadnexal adhesions. Am J Obstet Gyneco1990;162: Pouly JL, Mahnes H, Mage G, Canis M, Bruhat MA. Conservative laparoscopic treatment of 321 ectopic pregnancies. Fertil Steri1986;46: Thorburn J, Berntsson C, Philipson M, Lindblom B. Background factors of ectopic pregnancy.. Frequency distribution in a case-control study. Eur J Obstet Gynecol Reprod Bioi 1986;23: Lundorff P, Thorburn J, Hahlin M, Kallfelt B, Lindblom B. Adhesion formation after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy. Fertil Steril 1991;55: Makinen J, Salmi TA, Nikkanen VPJ. Encouraging rates of fertility after ectopic pregnancy. nt J Fertil 1989;34: Timonen S, Nieminen U. Tubal pregnancy, choice of operative method of treatment. Acta Obstet Gynecol Scand 1967;46: Lundorff et al. Fertility after EP