Abstract. Introduction. RBMOnline - Vol 8. No Reproductive BioMedicine Online; on web 5 April 2004

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1 RBMOnline - Vol 8. No Reproductive BioMedicine Online; on web 5 April 2004 Article Live delivery rates in subfertile women with Asherman s syndrome after hysteroscopic adhesiolysis using the resectoscope or the Versapoint system Dr Konstantinos Zikopoulos is Assistant Professor of Obstetrics and Gynaecology at the University Hospital of Ioannina, Greece. In 1990 he obtained his PhD degree on the topic of male infertility. Subsequently he went on to sub-specialize in reproductive medicine at the Royal Infirmary Hospital in Edinburgh. He has published several papers in international journals. Since September 2002 he has been a clinical research fellow at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University. Dr Konstantinos Zikopoulos Konstantinos A Zikopoulos, Efstratios M Kolibianakis 1, Peter Platteau, Luc de Munck, Herman Tournaye, Paul Devroey, Michel Camus Centre for Reproductive Medicine, Dutch-Speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium 1 Correspondence: Fax: ; stratis@easynet.be Abstract The purpose of this study was to report on a 10-year experience in the treatment of subfertile women with intrauterine adhesions using the resectoscope or the Versapoint system. Forty-six subfertile women with stage I (n = 6), stage II (n = 25) and stage III (n = 15) intrauterine adhesions underwent adhesiolysis with the use of the resectoscope (n = 21) or the Versapoint system (n = 26). Synechiolysis was successful in 43 women (93.5%) after the first attempt. In 13 out of 14 women (92.9%) with oligo/amenorrhoea at presentation, restoration of menses was reported after adhesiolysis (Versapoint: 9/9, resectoscope: 4/5). Overall live delivery rates according to stage of intrauterine adhesions were 33.3, 44.4 and 46.7% for stages I, II and III respectively. Similar cumulative delivery rates were achieved in patients with no additional infertility factors who attempted to conceive naturally after adhesiolysis using the Versapoint (71.7%) or the resectoscope (60%). Ten gestations ended in preterm delivery (50%), while in two of the women who delivered, a hysterectomy was performed due to placenta accreta. In conclusion, hysteroscopic adhesiolysis offers a real chance of parenthood in a substantial proportion of infertile couples either by using the Versapoint system or the resectoscope. Keywords: Asherman s syndrome, cumulative delivery rates, intrauterine adhesiolysis, subfertility 720 Introduction Aetiology, clinical characteristics and therapy of intrauterine adhesions (IUA) were first reported by Asherman (1948). Their prevalence is difficult to determine and ranges from 3.7 to 23.4% in women with post-partum bleeding (Eriksen and Kaestel, 1960; Bergman, 1961) and from 5 to 39% in women with recurrent miscarriages (Rabau and David, 1963; Toaff, 1966). In addition, a prevalence of 2.7% has been reported in women undergoing hysterosalpingography (Sweeney, 1966; Dmowski and Greenblatt, 1969), while in subfertile couples intrauterine adhesions are encountered in 4% of cases (Sirbu et al., 1957). Asherman s syndrome can result from intrauterine injury leading to endometrial sclerosis and adhesion formation (March, 1995), especially in a pregnant or recently pregnant uterus. Intrauterine adhesions associated with endometrial tuberculosis and the use of intrauterine contraceptive device have also been reported (Corson, 1992). Findings leading to diagnosis of the syndrome range from the presence of minimal adhesions to complete obliteration of the uterine cavity (Al-Inany, 2001). Women with Asherman s syndrome may have minimal menstrual disturbances, while subfertility may be the main complaint. Treatment of

2 intrauterine adhesions involves both their removal as well as prevention of their recurrence (Chen et al., 1997). Hysteroscopic surgery is currently the optimal treatment approach for Asherman s syndrome, and several techniques have been used so far (Valle and Sciarra, 1988) that allow easy and rapid dissection of adhesions (Magos, 2002). This study reports on a 10-year experience in the treatment of subfertile women with intrauterine adhesions using the resectoscope or the Versapoint system. Materials and methods Patient population Forty-six subfertile women who underwent hysteroscopic treatment of intrauterine adhesions at the Centre for Reproductive Medicine of the Dutch-Speaking Brussels Free University from December 1992 to December 2002 were included in the study. The mean age of the women at the time of adhesiolysis was 33.6 ± 0.7 years, while the mean duration of infertility prior to adhesiolysis was 35.8 ± 3.1 months. Aetiologies of intrauterine adhesions and symptoms at presentation appear in Table 1. The most frequent cause of intrauterine adhesions was curettage either after abortion or after delivery. The main complaint of the majority of the couples was subfertility. The diagnosis of IUA was carried out using hysterosalpingography (HSG) and was confirmed using hysteroscopy in all cases. Synechiae were classified according to the American Fertility Society (1988). Stage I was present in six women (13.0%), stage II in 25 women (54.3%) and stage III in 15 women (32.6%). Six women with stage III had complete obliteration of the uterine cavity. Thirty-five women (76.1%) had attempted to conceive naturally before diagnosis of IUA, while 11 couples (23.9%) had already been treated by IVF/intracytoplasmic sperm injection (ICSI). Procedure of intrauterine adhesiolysis Operative hysteroscopy was performed under general anaesthesia in the early proliferative phase of the menstrual cycle in those women who were menstruating. In 21 women (45.7%) from 1992 until 1997, adhesiolysis was carried out using transcervical resectoscopy (TCR) with continuous flow (27 French, 9 mm outer sheath and 8 mm inner sheath, Olympus Optical Company). The adhesions were incised with a high frequency resection electrode needle (A2193; Olympus Optical Co. Ltd., Shinku-ku, Tokyo, Japan). The uterine cavity was distended with sorbitol solution to allow visualization. In 25 women (54.3%) between 1998 and 2002 adhesions were lysed with the Versapoint electrosurgical system (Versapoint Electro-Surgical System; Gynecare Inc., Menlo Park, CA, USA). Saline solution was used to distend the uterine cavity. In both methods fluid balance was recorded in all women. Simultaneous laparoscopy was performed in all women with stage II and stage III intrauterine adhesions, due to the increased risk of uterine perforation. When it was difficult to distinguish between adhesions and endometrial lining, methylene blue was injected through the inflow channel (Valle and Sciarra, 1988). Adhesiolysis begun inferiorly and was carried cephalic until a panoramic view of the endometrial cavity was obtained and tubal ostia were visualized. In the case of stage III disease, a hysterometer was carefully introduced into the cavity after the uterine axis was assessed through vaginal examination and laparoscopy. The hysterometer helps to find a plane of cleavage corresponding to the pre-existing uterine cavity. It then allows the introduction of the operating hysteroscope and the initiation of adhesiolysis starting at the level of the internal os. In some cases, adhesiolysis was stopped for safety reasons before visualization of the ostia was achieved. In those patients, however, a methylene blue test confirmed tubal patency at that stage through the laparoscope. In the case of stage III disease, an intrauterine contraceptive device (IUCD; Multiload Cu 375; homesteel Achel P.V.B.A., Odilialaan, Belgium) was introduced into the uterine cavity at the end of the operation and kept in-situ for 1 month. Post-operative management Post-operatively, all women received sequential estroprogestative treatment with oestradiol valerate 4 mg/daily (Progynova; Schering, Berlin, Germany) and micronized progesterone (Utrogestan; Besins, Brussels, Belgium) 600 mg/daily for a period of 2 months. The IUCD was removed 1 month after adhesiolysis. Control hysteroscopy was repeated 2 months after the operation in all women. Table 1. Aetiology of intrauterine adhesions and symptoms at presentation. Aetiology of n (%) Symptoms at n (%) adhesions presentation Curettage after abortion 28 (60.9) Subfertility only 19 (41.3) Curettage after delivery 11 (23.9) Subfertility + 12 (26.1) amenorrhoea Myomectomy 1 (2.2) Subfertility + 13 (28.3) recurrent abortions Tuberculosis 1 (2.2) Subfertility + 2 (4.3) oligomenorrhoea Unknown 5 (10.9) 721

3 722 Reproductive outcome All women were contacted in July 2003 and information was obtained regarding mode of conception and the occurrence of live delivery. Statistical analysis Values are presented as mean ± SEM, unless stated otherwise. Cumulative delivery rates were calculated according to the Kaplan Meier procedure. Results Procedure A total of 46 women underwent hysteroscopic adhesiolysis during the study period. Synechiolysis was successful in 43 women (93.5%) after the first attempt. In three women with stage III disease treated by the Versapoint, a repeat hysteroscopy demonstrated the presence of intrauterine adhesions and further resection was carried out. A third adhesiolysis was necessary in one case. Though no bleeding or fluid absorption problems were recorded during the procedures that were performed, uterine perforation occurred in one case during hysterometry. No women required admission for post-operative complications. Restoration of menses In 13 out of 14 women (92.9%) with oligo/amenorrhoea at presentation restoration of menses was reported following adhesiolysis (Versapoint: 9/9, resectoscope: 4/5). Reproductive outcome All patients Twenty-five women underwent IVF following successful adhesiolysis (54.3%), while 21 women attempted to conceive naturally (45.7%). Indications for IVF after adhesiolysis were male factor infertility (n = 10), tubal factor (n = 5), endometriosis (n = 1) or advanced maternal age (n = 9). Live delivery rate following adhesiolysis was 43.5% (20/46) during a mean follow-up period of 39.2 ± 4.5 months. Overall live delivery rates according to stage of intrauterine adhesions were 33.3, 44.4 and 46.7% for stages I, II and III respectively. Three deliveries occurred in the group of patients with stage III intrauterine adhesions and no cavity at initial hysteroscopy (n = 6). In patients who attempted to conceive naturally, live delivery rate was 61.9% (13/21), while in patients who were treated by IVF/ICSI live delivery rate was 28.0% (7/25). Patients with no additional infertility factors who attempted to conceive naturally The age of the patients treated with the resectoscope or the Versapoint was similar (32.7 ± 1.4 years versus 32.5 ± 1.6 years respectively). In addition no significant differences were present considering the stage of adhesions between the two groups compared (resectoscope: stage I, 10%; stage II, 60%; stage III, 30%; Versapoint: stage I, 9.1%; stage II, 36.4%; stage III, 54.5%, P = 0.51). Cumulative delivery rates in patients with no additional infertility factors who attempted to conceive naturally, according to the method of adhesiolysis used appear in Figure 1. Similar cumulative delivery rates were achieved by using either of the two methods (Versapoint: 71.7% resectoscope: 60%). The overall cumulative delivery rate in these patients was 64.7%. Most of the pregnancies in patients with no additional infertility factors who attempted to conceive naturally were achieved in less than 2 years from the operation. Mean time to conception leading to live delivery was 12.2 months (95% CI: months). Live delivery rates according to the stage of disease and type of operation in patients who attempted to conceive naturally are shown in Table 2. Obstetric complications Ten gestations ended in term delivery (prematurity rate: 50%). All premature deliveries occurred after 32 weeks. In two of the women who delivered, a hysterectomy was performed. In one case hysterectomy had already been planned during gestation, as a diagnosis of placenta accreta had been made by ultrasound, while in the second case, hysterectomy was performed because of perforation of the uterus during manual extraction of placenta accreta. Discussion The current study shows that adhesiolysis in subfertile patients with Asherman s syndrome using the Versapoint system or the resectoscope can lead to live deliveries even in patients with stage III syndrome and complete obliteration of the uterine cavity. As expected, the probability of delivery appears to be lower in couples with additional infertility factors compared with those with IUA only. An overall cumulative delivery rate of 64.7% is expected within 2 years after the operation in patients with no additional infertility factors who attempt to conceive naturally. So far as is known, cumulative delivery rates have not been reported in the literature after hysteroscopic adhesiolysis in the absence of additional infertility factors. By reviewing ten studies published between 1974 and 1987 in women with IUA treated by various adhesiolysis methods, Siegler and Valle (1988) reported that out of 775 women, 302 achieved a term delivery (38.9%). Table 3 shows that in seven studies performed in the last decade, delivery rates after adhesiolysis using various hysteroscopic methods are very similar to those reported by Siegler and Valle (1988). Overall, out of 126 patients, 48 delivered (38.1% delivery rate). Therefore, despite limitations due to lack of uniform classification of IUA, the application of different techniques for adhesiolysis and/or differences in the population analysed, it can probably be claimed that about 40% of patients with intrauterine adhesions can be expected to deliver following adhesiolysis. In the current study after adhesiolysis in patients with no additional infertility factors, 13 out of 21 patients

4 Table 2. Live delivery rates according to stage of intrauterine adhesions and method of adhesiolysis in patients who attempted to conceive naturally (delivery rates are not significantly different between Resectoscope and Versapoint). Method of Live delivery rate [n (%)] adhesiolysis Stage I Stage II Stage III Figure 1. Cumulative delivery rates in subfertile patients with Asherman s syndrome who attempted to conceive by natural means according to the method of adhesiolysis used. Resectoscope 1/1 (100.0) 4/6 (66.7) 1/3 (33.3) Versapoint 1/1 (100.0) 3/4 (75.0) 3/6 (50) Table 3. Delivery rates after adhesiolysis using various hysteroscopic methods. Study Patients (n) Hysteroscopic Method of Follow-up Delivery rate method conception period (%) (no. deliveries) Pabuccu et al. 24 a Scissors or Intercourse Not stated 70.8 (17/24) (1997) monopolar probe 16 b 16 months 37.5 (6/16) Chen et al. 7 Resectoscope Intercourse Not stated 28.5 (2/7) (1997) McComb and 5 Scissors Intercourse Not stated 60.0 (3/5) Wagner (1997) Protopapas 7 Myometrial Intercourse: Mean 28.5 (2/7) et al. (1998) scoring 6 patients, 12.4 months IVF: 1 patient (range: 2 30 months) Capella-Alloue 28 Monopolar knife Intercourse: 31 months 32.1 (9/28) et al. (1999) 27 patients, (range: 2 84) IVF: 1 patient Goldenberg 36 Not stated Intercourse 21.1 months 22.2 (8/36) et al. (1995) Coccia et al. 3 Pressure lavage Intercourse Not stated 33.3 (1/3) (2001) under ultrasound guidance Total (48/126) a With recurrent abortions. b Infertile. 723

5 724 delivered (61.3%). The higher delivery rate might be attributed to the fact that a simultaneous laparoscopy was performed in all patients during adhesiolysis, which made it possible to identify co-existing infertility factors and directed a proportion of patients to assisted reproduction treatment. It is interesting to note that 11 women (23.9%) with IUA in the current study had been previously treated using IVF/ICSI before diagnosis of Asherman s syndrome was established. Apparently, the omission of hysteroscopy in the initial infertility workup led to unjustified treatment for these patients. The mean time to conception leading to live delivery is not mentioned in any of the reports in Table 3. The current study suggests that in patients with no additional infertility factors deliveries following adhesiolysis are expected to occur in less than 2 years from operation. It has been reported that the severity of adhesions affects the chance of pregnancy following adhesiolysis (Valle and Scierra, 1988). In the current study, the delivery rate was quite encouraging in patients with stage III disease in whom a normal cavity was present at follow up hysteroscopy, in agreement with March (1995). Treatment of IUA using the Versapoint system has been previously reported in pilot studies. Villos (1999) described synechiotomy in two patients, of whom one delivered at term, while Marwah and Bhandari (2003) reported treatment of 11 patients with IUA using the Versapoint system that were not, however, followed up post-operatively for the occurrence of delivery. So far as is known, this is the largest series of patients with IUA that have been treated using the Versapoint system. The probability of live delivery appears to be similar to that which is achieved using the resectoscope, regardless of the stage of IUA (Table 2). The resectoscope has been widely used to treat Asherman s syndrome. It uses a monopolar electrosurgical system and the distension medium is a non-electrolyte solution, usually sorbitol or glycine. The bipolar electrosurgical system (Versapoint) was introduced in recent years to treat intrauterine pathologies (Zikopoulos et al., 2003). The saline solution which is used with the Versapoint as a distension medium is iso-osmolar and therefore safer than those used in electrosurgery. The cost of Versapoint, however, is relatively high. Theoretically, Versapoint might be safer that the resectoscope if uterine perforation occurs, as the activated Versapoint tip must be bathed in a saline (i.e. conducting) environment for the circuit to be completed. On the contrary, if perforation occurs while using the resectoscope, the potential risk of damaged intra-abdominal contents is increased as energy spreads beyond the electrode tip. The current series shows that restoration of fertility in patients with IUA comes at a price. Fifty per cent of all deliveries achieved in this series were preterm, while two hysterectomies had to be performed in patients with IUA after adhesiolysis and delivery (10%, 2/20). Placenta accreta is the most common complication reported after the treatment of IUA with an incidence of about 8% (Siegler and Valle, 1988). Its occurrence might be associated with a defective lamina basalis after adhesiolysis, which allows abnormal placentation. Subfertile patients with IUA undergoing adhesiolysis should be appropriately informed about the occurrence of this lifethreatening complication if they become pregnant. In conclusion, hysteroscopic adhesiolysis can be performed using the Versapoint system with safety and efficacy comparable to that using the resectoscope and offers a real chance of parenthood in a substantial proportion of infertile couples. Live deliveries in couples with no additional infertility factors are expected to occur in 64.7% in less than 2 years from adhesiolysis. Subfertile patients with IUA should be counselled about the potential risks that the restoration of infertility might be associated with. Acknowledgement This study was supported from Funds For Scientific Research Flanders. References Al-Inany H 2001 Intrauterine adhesions. An update. Acta Obstetrica et Gynecologica Scandinavica 80, American Fertility Society 1988 The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, mullerian anomalies and intrauterine adhesions. Fertility and Sterility 49, Asherman J 1948 Amenorrhea atraumatica (atretica) American Journal of Obstetrics and Gynecology 55, Bergman P 1961 Traumatic intra-uterine lesions. Acta Obstetrica et Gynecologica Scandinavica 40, Capella-Allouc S, Morsad F, Rongieres-Bertrand C et al Hysteroscopic treatment of severe Asherman s syndrome and subsequent fertility. Human Reproduction 14, Chen FP, Soong YK, Hui YL 1997 Successful treatment of severe uterine synechiae with transcervical resectoscopy combined with laminaria tent. Human Reproduction 12, Coccia ME, Becattini C, Bracco GL et al Pressure lavage under ultrasound guidance: a new approach for outpatient treatment of intrauterine adhesions. Fertility and Sterility 75, Corson SL 1992 Operative hysteroscopy for infertility. Clinical Obstetrics and Gynecology 35, Dmowski WP, Greenblatt RB 1969 Asherman s syndrome and risk of placenta accreta. Obstetrics and Gynecology 34, Eriksen J, Kaestel C 1960 The incidence of uterine atresia after postpartum curettage. A follow-up examination of 141 patients. Danish Medical Bulletin 7, Goldenberg M, Sivan E, Sharabi Z et al Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions. Human Reproduction 10, Magos A 2002 Hysteroscopic treatment of Asherman s syndrome. Reproductive BioMedicine Online 4, March CM 1995 Intrauterine adhesions. Obstetrics and Gynecology Clinics of North America 22, Marwah V, Bhandari SK 2003 Diagnostic and interventional microhysteroscopy with use of the coaxial bipolar electrode system. Fertility and Sterility 79, McComb PF, Wagner BL 1997 Simplified therapy for Asherman s syndrome. Fertility and Sterility 68, Pabuccu R, Atay V, Orhon E et al Hysteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation and fertility. Fertility and Sterility 68, Protopapas A, Shushan A, Magos A 1998 Myometrial scoring: a new technique for the management of severe Asherman s syndrome. Fertility and Sterility 69,

6 Rabau E, David A 1963 Intrauterine adhesions: etiology, prevention, and treatment. Obstetrics and Gynecology 22, Siegler AM, Valle RF 1988 Therapeutic hysteroscopic procedures. Fertility and Sterility 50, Sirbu P, Coman A, Vexler E 1957 Gynecol Obstet (Paris) 56, Sweeney WJ 1966 Intrauterine synechiae. Obstetrics and Gynecology 27, Toaff, R Some remarks on post-traumatic uterine adhesions Revue Francaise de Gynecologie et d Obstetrique 61, Valle RF, Sciarra JJ 1988 Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. American Journal of Obstetrics and Gynecology 158, Villos GA 1999 Intrauterine surgery using a new coaxial bipolar electrode in normal saline solution (Versapoint): a pilot study. Fertility and Sterility 72, Zikopoulos K, Kolibianakis EM, Tournaye H et al Hysteroscopic septum resection using the Versapoint system in subfertile women. Reproductive BioMedicine Online 7, Received 29 January 2004; refereed 19 February 2004; accepted 8 March