Danderyd, Stockholm, Linkoping, Goteborg, Gavle, Umea, Skovde, Sweden, Quia, Finland, and Aalborg, Denmark

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1 FERTILITY AND STERILITY Vol. 63, No.4, April 1995 Copyright 1995 American Society for Reproductive Medicine Printed on acid-free paper in U. S. A. The efficacy of Interceed(TC7)* for prevention of reformation of postoperative adhesions on ovaries, fallopian tubes, and fimbriae in microsurgical operations for fertility: a multicenter studyt* Nordic Adhesion Prevention Study Group ll Danderyd, Stockholm, Linkoping, Goteborg, Gavle, Umea, Skovde, Sweden, Quia, Finland, and Aalborg, Denmark Objective: To evaluate the efficacy of Interceed as an adjuvant in the prevention of postoperative adhesion reformation to the ovary, fallopian tube, and fimbria when used together with microsurgical techniques, Design: Prospective, randomized, multicenter, controlled clinical study. Setting: Normal human volunteers in an academic research environment, Patients: Sixty-six women suffering from infertility due at least in part to bilateral tubal disease with bilateral adhesions attached to ovaries, fallopian tubes, and fimbriae, Intervention: Adhesiolysis bilaterly through laparotomy with microsurgical techniques, application of Interceed on one of the sides randomly assigned not known by the surgeon before application, follow-up laparoscopy 4 to 10 weeks postoperatively, with each patient serving as her own control Main Outcome Measures: Adhesion severity scores at all sites and number of adhesion free organs after laparotomy and follow-up laparoscopy. Results: When the initial scores registered at the operation for fertility were compared with those registered at the second-look laparoscopy, the results indicated that gentle microsurgical techniques resulted in a significant reduction of postoperative adhesions, Adnexa, which were covered with Interceed, had significantly lower adhesion scores than the control adnexa, representing an improvement of 39% compared with microsurgery alone (control) in reducing adhesion reformation scores. When combined with microsurgical techniques, Interceed reduced adhesion reformation scores by 70%, The number of ovaries, fallopian tubes, and fimbriae without adhesions at the time of second-look laparoscopy was significantly increased by approximately twofold when organs were covered with Interceed, Conclusion: In a prospective, randomized, multicenter, controlled clinical study using a protocol in which other adjuvants have been shown not to be efficacious, Interceed was shown to reduce significantly the incidence and severity of adhesion reformation to the ovary, fallopian tube, and fimbria after infertility surgery, Fertil Steril 1995;63: Key Words: Adhesions, adhesion prevention, fertility surgery, Interceed, ovary, fallopian tube, fimbria Received April 27, 1994; revised and accepted November 1, * Johnson & Johnson AB, Stockholm, Sweden. t Presented at the Meeting of The American Fertility Society conjointly with the Canadian Fertility and Andrology Society October 11 to 14, 1993, Montreal, Quebec, Canada. :j: Sponsored by Johnson & Johnson AB, Stockholm, Sweden. Reprint requests: Bertil Larsson, M.D., Department of Obstetrics and Gynecology, Danderyds University Hospital, S Danderyd, Sweden (FAX: ). 11 The investigators for this study were Bertil Larsson, M.D., Coordinator, Department of Obstetrics and Gynecology, Karolinska Institutet, Danderyds University Hospital, Stockholm, Sweden; Anders Aison Berg, M.D., Department of Obstetrics and Gynecology, Linkoping University Hospital, Linkoping, Sweden; Inger Bryman, M.D. and Jane Thorburn, M.D., Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Goteborg, Sweden; Katarina Hogset, M.D., Department of Obstetrics and Gynecology, Central Hospital, Gavle, Sweden; Timo Laatikainen, M.D. and Hannu Martikainen, M.D., Department of Obstetrics and Gynecology, Oulo University Hospital, Oulo, Finland; Othon Lalos, M.D., Department of Obstetrics and Gynecology, Umea University Hospital, Umea, Sweden; J. Glenn Lauritsen, M.D., Department of Obstetrics and Gynecology, Aalborg University Hospital, Aalborg, Denmark; Svein-Erik Tronstad, M.D., Department of Obstetrics and Gynecology, Central Hospital, Skovde, Sweden. Vol. 63, No.4, April 1995 Nordic Adhesion Prevention Study Group Interceed in operations for fertility 709

2 The formation of adhesions after reconstructive pelvic surgery involves the development of fibrin bands that connect pelvic structures (1, 2). A barrier that separates tissues during mesothelial healing would therefore be expected to prevent adhesion formation at the site of application. Interceed (Johnson & Johnson AB, Stockholm, Sweden) is an absorbable material that was shown to work as an adhesion barrier in some (3-8) but not all (9-11) animal studies to prevent adhesion formation after peritoneal injury. The major evidence for clinical efficacy of Interceed is derived from sidewall studies in infertility patients (12-14). As important as these studies are, they do not address the prevention of adhesions to organs primarily involved in reconstructive pelvic surgery including the ovary, fallopian tube, and fimbria. The first author and some of the other surgeons taking part in the present study previously participated in multicenter clinical trials to assess the efficacy of treatments shown in animal studies to prevent formation of postsurgical pelvic adhesions. These studies included dextran (15) and corticosteroids (Larsson B, Berg.Aison A, Carlsborg L, Holmgren E, Jensen P, Larsson G, et al., unpublished data), neither of which proved to be effective. The aim of the present study was to evaluate the efficacy of Interceed as an adjuvant therapy in prevention of postoperative adhesions to specific reproductive organs when used together with microsurgical techniques. The present multicenter study evaluated separately the potential benefit of Interceed on the ovary, fallopian tube, and fimbria for prevention of adhesion reformation. Patients MATERIALS AND METHODS Between October 1991 and January 1993, 66 patients with infertility due at least in part to bilateral tubal disease involving bilateral adhesions to ovaries, fallopian tubes, and fimbriae, were operated upon at eight centers. Patients with endometriosis were excluded. The distribution of the patients between the different centers was as follows: Danderyd University Hospital, 14; Link6ping University Hospital, 5; Sahlgrenska University Hospital, 7; Gavle Central Hospital, 9; Oulo University Hospital, 4; Umea University Hospital, 10; Aalborg University Hospital, 8; and Sk6vde Central Hospital, 9. The study was approved by the local ethical committees. All patients gave informed consent. Surgical Procedure All the surgeons who participated in this study were experienced in microsurgery, some of them also having participated previously in similar studies testing other adjuvant therapies. The same techniques were used as in our previous series (15) and have been described in detail (16). Nonwoven sponges soaked in saline or sodium acetate solution were used to keep the uterus and adnexa elevated, constantly moist, and out of contact with blood. To avoid drying ofthe pelvic and abdominal serosa, the peritoneal surfaces were irrigated continuously with saline or sodium acetate solution. All adhesions, including those attached to parietal peritoneum, bowel, uterus, and/or the adnexa, were excised with the aid of a microelectrode. Care was taken not to denude the serosa. Efforts were made to ensure complete hemostasis. If blood escaped into the peritoneal cavity, it was aspirated in saline or acetate solution and was not absorbed by operation towels. Bleeding capillaries were identified during irrigation, and hemostasis was secured by pinpoint electrocoagulation. If hemostasis was not achieved, a small suture (10-0 to 6-0) was used. The use of suture material was kept to a minimum. The hydrosalpinges were reconstructed by electrocoagulation with a pinpoint unipolar epilation needle by incising the whitish avascular scars between the fimbria. Further incisions were made from inside the oviduct during inspection of the oviduct. Hemostasis was achieved by pinpoint electrocoagulation. A tubal ostium, approximately 2 cm in diameter, was created when the mucosal edges were folded back and secured to the tubal serosa with 7-0 sutures (S&T, Stockholm, Sweden). Follow-up laparoscopy was performed 4 to 10 weeks postoperatively. Adhesions were registered at the laparotomy for fertility, as well as at the postoperative laparoscopy, according to the scoring system (Table 1) previously used in similar studies (15, 16). Application of Interceed Interceed was applied on either the right or left adnexa. The side of application was assigned randomly and was not known by the surgeon before application. A sealed envelope disclosed assignment of which side was to be treated with the adjuvant therapy. Interceed was applied in a single 710 Nordic Adhesion Prevention Study Group Interceed in operations for fertility Fertility and Sterility

3 Table 1 Score o Adhesion Scoring System* Description No adhesions 1 One minimal adhesion 2 Mild adhesions: one or two simple thin strands <1 cm in width 3 Moderate adhesions: more than two adhesions of type 2 or at least one solid adhesion 4 Severe adhesions: more severe than type 3 * Each ovary, fallopian tube, and fimbria, respectively, was assigned an adhesion score as described previously (15, 16). layer. The ovary was wrapped using one half of a sheet of Interceed barrier and then moistened with 2 to 3 ml of irrigating solution. The end of the fallopian tube was completely covered with a "bag" of Interceed by placing the fimbria at the middle of a piece of Interceed, and then draping the remaining portion back with an amount sufficient to cover all serosal defects completely. The other adnexa was left uncovered, thereby serving as the control side. Hemostasis was achieved with fine pinpoint electrocoagulation before application of Interceed. If the Interceed fabric turned black after application, it was removed, hemostasis was re-established, and a new piece of Interceed was applied. An attempt was made to aspirate residual irrigation fluid from the cul-de-sac before application of Interceed. Statistical Analysis Adhesion scores are expressed as mean ± SEM. Separate analyses were performed on the scores for each individual organ (ovary, tube, fimbria) as well as on the aggregate scores (score for all three organs combined). The reduction in adhesion scores from first- to second-look procedures for treated and control sites, as well the difference between the reduction for the treated and control groups, were compared using a paired Student's t-test. Differences in the severity and incidence of adhesions were assessed using X 2 analysis. P value < 0.05 was considered statistically significant. t-test; Fig. 1, Table 2). Separate analyses of adhesion scores for ovaries, the fallopian tubes, and the fimbriae also indicated that gentle microsurgical techniques per se resulted in a significant reduction of postoperative adhesions (P < 0.01, t-test; Table 2). Adnexa treated with Interceed showed significantly lower aggregate adhesion scores at the second-look laparoscopy than adnexa undergoing microsurgery alone by 39% (P < 0.01, t-test; Fig. 1, Table 2). Considering the ovaries, tubes, and fimbriae separately, application of Interceed per se resulted in an enhanced and statistically significant reduction in adhesion reformation scores on the ovaries by 36%, on the fallopian tubes by 39%, and on the fimbriae by 42% (P < 0.01, t-test; Table 2; P < 0.05, X2; Table 3). When combined with microsurgical techniques, Interceed reduced aggregate and individual site adhesion scores by almost 70%. An additionally significant benefit in the number of organs without adhesions at the time of secondlook laparoscopy (Fig. 2, Table 3) was provided by the use of Interceed on the ovaries (47.0% versus 25.8%; P < 0.02, X2), fallopian tubes (50.0% versus 24.2%; P < 0.01, X2), and fimbria (57.6% versus 37.9%; P < 0.05, X2). In all, adhesions were prevented from reforming in 102 or 51.5% of the 198 adnexal organs in which Interceed was used, com- Adhesion Score ~ RESULTS The total adhesion scores, i.e., that of the oviduct added to that of the corresponding ovary and fimbria recorded at the second-look laparoscopy, were significantly reduced irrespective of treatment when compared with the initial scores (P < 0.01, INTERCEED Control Figure 1 Mean aggregate adhesion scores for ovaries, fallopian tubes, and fimbriae. Compared with scores at first-look laparotomy (0), adhesion scores at second-look laparoscopy (_) were significantly lower regardless of treatment (P < 0.01, t-test). At second-look laparoscopy, the aggregate adhesion score was significantly lower at sites treated with Interceed barrier compared with untreated controls (P < 0.01, t-test). Vol. 63, No.4, April 1995 Nordic Adhesion Prevention Study Group Interceed in operations for fertility 711

4 Table 2 Adhesion Scores for Ovaries, Fallopian Tubes, and Fimbriae*t Ovaries:j: Fallopian tubes:j: Fimbriae:j: Aggregate:j: Interceed Control Interceed Control Interceed Control Interceed Control Laparotomy 3.38 ± ± ± ± ± ± ± ± 0.02 Follow-up laparoscopy 1.11 ± ± ± ± ± ± ± ± 0.06 Difference 2.27 ± ± ± ± ± ± ± ± 0.05 * Values are means ± SEM. t Total adhesion scores for each organ as well as an aggregate score for all three organs. Significant reductions in adhesion scores were obtained at follow-up laparoscopy regardless of treatment (P < 0.01, Student's paired t-test). Compared with microsurgical technique alone, Interceed barrier significantly enhanced the reduction in adhesion scores by 36% (ovaries), 39% (fallopian tubes), 42% (fimbriae), and 39% (all sites combined). :j: P < 0.01, paired t-test for laparotomy versus laparoscopy for both Interceed and controls. P < 0.01, paired t-test for difference of Interceed versus control. pared with 58 or 29.3 of the adnexal organs that did not reform adhesions after microsurgery alone (P < 0.01, X 2 ). All patients tolerated the surgical procedures well. No side effects of Interceed were observed. DISCUSSION This prospective, randomized, multicenter, controlled clinical study was performed by an experienced group of clinical investigators who previously studied the potential benefits of dextran (15) and corticosteroids (Larsson B, Berg Aison A, Carls- Table 3 Distribution of Patients by Adhesion Scores* Follow-up Laparotomy laparoscopy Adhesion score Interceed Control Interceed Control Ovaries 0 0(0) 0(0) 31 (47.0) 17 (25.8) 1 0(0) 0(0) 11 (16.7) 14 (21.2) 2 8 (12.1) 6 (9.1) 14 (21.2) 12 (18.2) 3 25 (37.9) 23 (34.8) 6 (9.1) 11 (16.7) 4 33 (50.0) 37 (56.1) 4 (6.1) 12 (18.2) Fallopian tubes 0 0(0) 0(0) 33 (50.0) 16 (24.2) 1 6 (9.1) 0(0) 12 (18.2) 12 (18.2) 2 4 (6.1) 9 (13.6) 12 (18.2) 19 (28.8) 3 30 (45.5) 31 (47.0) 3 (4.5) 11 (16.7) 4 26 (39.4) 26 (39.4) 6 (9.1) 8 (12.1) Fimbriae 0 0(0) 0(0) 38 (57.6) 25 (37.9) 1 3 (4.5) 4 (6.1) 12 (18.2) 11 (16.7) 2 11 (16.7) 7 (10.6) 11 (16.7) 14 (21.2) 3 22 (33.3) 31 (47.0) 1 (1.5) 7 (10.6) 4 30 (45.5) 24 (36.4) 4 (6.1) 9 (13.6) * Values are the number of patients with scores shown for each of the three sites with percentages in parentheses. borg L, Holmgren E, Jensen P, Larsson G, et ai., unpublished data) in women and found that these adjuvants did not reduce postoperative adhesion formation after reconstructive pelvic surgery. In the current study, using the same design and format for adhesion scoring, we found that Interceed significantly reduced the reformation of postoperative adhesions. We were not able to assess the effect of Interceed on de novo adhesion formation because all the adnexa contained adhesions at the initial laparotomy. Previous clinical studies found that Interceed reduced adhesions to the pelvic sidewall (12-14). Here, we found that Interceed significantly reduced the reformation of adhesions to the ovary, fallopian tube, and fimbria. Indeed, almost twice as many ovaries and fallopian tubes were completely free of % Adhesion free 60, , Number adhesion free to o I INTERCEED* 0 Control I Figure 2 The percentage and number of ovaries, fallopian tubes, and fimbriae without adhesions at second-look laparoscopy 4 to 10 weeks after adhesiolysis was performed using microsurgical techniques, with (_) and without (0) covering the organ with Interceed. Statistically significant reductions in adhesion reformation with Interceed treatment compared with surgery alone were noted at all three sites (P < 0.05, X 2 test). 712 Nordic Adhesion Prevention Study Group Interceed in operations for fertility Fertility and Sterility

5 adhesions after use of Interceed compared with microsurgical techniques alone. Our observations confirm and extend those of others. Giannacodimos et al. (Giannacodimos G, Douligeris N, Lappas K, abstract) reported that 85% ofthe patients had no ovarian adhesions when Interceed was used after ovarian drilling. However, their second-look data was only collected at the time of cesarean section and the outcome of another 20 patients who did not have cesarean sections is unknown. Thus, a potential limitation may exist in the interpretation of their results. Franklin et al. (Franklin R, Larsson B, Malinak LR, Webster B, abstract) as well as Reid et al. (Reid R, Spence J, Tulandi T, Yuzpe A, abstract) also preliminarily reported reduction in ovarian adhesion formation with the use of Interceed together with microsurgical techniques. In confirmation of our study, Franklin et al.'s study also found that, after wrapping the ovaries with Interceed, the number of ovaries free of adhesions was about twice as many as compared with the surgery control in cases when surgery was performed on both ovaries. Neither our study nor any of the three other previously mentioned ovarian surgery studies found any complications from Interceed use either immediately after surgery or anytime after that. Regarding the fimbria, Curto et al. (Curto JM, Bentolila D, Villois G, Torresgrosa G, abstract) reported a 100% incidence of adhesion-free fimbria when Interceed was used to cover the fimbria after salpingostomy. However, their series were uncontrolled and reported results in only 31 of 54 patients. Our study confirms and extends these observations to include the fimbria as well as the fallopian tube per se. Over twice as many fallopian tubes were free of adhesions after the use of Interceed compared with microsurgery alone. As with any study offallopian tube surgery, caution must be exercised until sufficient time has passed to evaluate fully the subsequent ectopic and intrauterine pregnancy rate. We specifically excluded patients with endometriosis because Sekiba et al. (17) previously reported a significant benefit with Interceed when used together with microsurgery in patients with severe (American Fertility Society grade III and IV) endometriosis. Otherwise, the general patient population we studied were patients with infertility due to adnexal adhesion and/or hydrosalpinges. Our patient population was similar to that of Li and Cooke (18) who reported a 93% benefit from Interceed used together with microsurgical techniques and the administration of intraperitoneal corticosteroids. However, the study of Li and Cooke did not allow for an organ-specific analysis of Interceed's efficacy. Although all clinical studies report a benefit from Interceed when used together with microsurgery, none of the controlled studies display a 100% absence of adhesions. The question may be asked as to why. One technique we believe may further increase the benefit of Interceed is that all irrigation fluid is removed before Interceed application. This is done to prevent Interceed from dislodging from its site. Often this would mean that the patient is placed in reverse Trendelenburg at the end of primary procedure to facilitate removal of irrigants that may have accumulated under the diaphragm or in the colonic gutters. Also, we do not know the relative degree of efficacy Interceed may add to surgical procedures performed by laparoscopy. We are looking forward to the forthcoming results from clinical studies with Interceed in this area because there are studies on one hand that indicate adhesion formation is a major problem after laparoscopic surgery (19) and studies on the other hand that indicate reduced adhesion formation after laparoscopic surgery (20). However, irrespective of the surgical procedure, to establish meticulous hemostasis before application of Interceed is of great importance. The efficacy of Interceed is compromised in the presence of bleeding (21) and meticulous hemostasis always should be obtained before application. If Interceed turns black after application, it has to be removed and hemostasis must be re-established. After that a new piece of Interceed can be applied. REFERENCES 1. Diamond MP, DeCherney AH. Pathogenesis of adhesion formation/reformation: application to reproductive pelvic surgery. Microsurgery 1987;8: dizerega GS, Rodgers KE. The peritoneum. New York: Springer Verlag, Diamond MP, Linsky CB, Cunningham T, Constantine B, dizerega GS, DeCherney AH. Development of model for sidewall adhesions in the rabbit and their reduction by an absorbable barrier. Microsurgery 1987;8: Linsky CB, Diamond MP, Cunningham T, Constantine B, DeCherney AH, dizerega GS. Adhesion reduction in the rabbit uterine horn model using an absorbable barrier, TC- 7. J Reprod Med 1987;32: Linsky CB, Diamond MP, Cunningham T, DeCherney AH, dizerega GS. Effect of blood of the effect of barrier adhesion reduction in the rabbit uterine horn model. Infertility 1988;11: Diamond MP, Linsky CB, Cunningham T, Kamp L, Vol. 63, No.4, April 1995 Nordic Adhesion Prevention Study Group Interceed in operations for fertility 713

6 McConnell RF, Gracy RW. Interceed (TC7) as an adjuvant for adhesion reduction: animal studies. Prog Clin BioI Res 1990;358: Diamond MP, Linsky CB, Cunningham T, Kamp L, Pines E, DeCherney AH, et al. Adhesion reformation: reduction by the use of Interceed (TC7) plus heparin. J Gynecol Surg 1991;7: Diamond MP, Linsky CB, Cunningham T, Kamp L, Pines E, DeCherney AH, et al. Synergistic effects of Interceed (TC7) and heparin in reducing adhesion formation in the rabbit uterine horn model. Fertil Steril 1991;55: Haney AF, Doty E. Murine peritoneal injury and de novo adhesion formation caused by oxidized-regenerated cellulose (lnterceed TC7) but not expanded polytetra-fluoroethylene (Gore-Tex Surgical Membrane). Fertil Steril 1992; 57: Pagidas K, Tulandi T. Effects of Ringer's lactate, Interceed (TC7) and Gore-Tex Surgical Membrane on postsurgical adhesion formation. Fertil Steril 1992;57: Best CL, Rittenhouse D, Vasquez C, Norng T, Subias E, Sueldo CEo Evaluation of Interceed (TC7) for reduction of postoperative adhesion in rabbits. Fertil Steril 1992;58: Interceed (TC7) Adhesion Barrier Study Group. Prevention of postsurgical adhesions by Interceed (TC7) an absorbable adhesion barrier. A prospective randomized multicenter clinical study. Fertil Steril 1989;51: Reid RL, Lie K, Spence JE, Tulandi T, Yuzpe A. Clinical evaluation of the efficacy of heparin -saturated Interceed for prevention of adhesions in the pelvic sidewall of the human. Prog Clin BioI Res 1993;381: Azziz R, Interceed (TC7) Adhesion Barrier Study Group II. Microsurgery alone or with Interceed Absorbable Adhesion Barrier for pelvic sidewall adhesion reformation. Surg Gynecol Obstet 1993;177: Larsson B, Lalos 0, Marks L, Tronstad SE, Bygdeman M, Pehrson S, et al. Effect of intraperitoneal instillation of 32% Dextran 70 on postoperative adhesion formation after tubal surgery. Acta Obstet Gynecol Scand 1985;64: Larsson B. Late results of salpingostomy combined with salpingolysis and ovariolysis by electromicrosurgery in 54 women. Fertil Steril 1982;37: Sekiba K, The Obstetrics and Gynecology Adhesion Prevention Committee. Use of Interceed (TC7) Absorbable Adhesion Barrier to reduce postoperative adhesion reformation in infertility and endometriosis surgery. Obstet Gynecol 1992;79: Li TC, Cooke ID. The value of an absorbable adhesion barrier, Interceed, in the prevention of adhesion reformation following microsurgical adhesiolysis: a prospective, randomized, controlled study. Br J Obstet Gynaecol 1994; 101: Operative Laparoscopy Study Group. Postoperative adhesion development after operative laparoscopy: evaluation at early second look procedures. Fertil Steril 1991;55: LundorffP, Hahlin M, Kallfelt B, Thorburn J, Lindblom B. Adhesion formation after laparoscopic surgery in tubal pregnancy: a randomized trial versus laparotomy. Fertil Steri! 1991;55: Wiseman DM, Gottlick LE, Diamond MP. Effect of thrombin-induced hemostasis on the efficacy of an absorbable adhesion barrier. J Reprod Med 1992;37: Nordic Adhesion Prevention Study Group Interceed in operations for fertility Fertility and Sterility