Article Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure

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1 RBMOnline - Vol 8. No Reproductive BioMedicine Online; on web 24 March 2004 Article Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure Dr Aygul Demirol obtained her medical degree and further degree in the specialization of Obstetrics and Gynecology at Hacettepe University, School of Medicine, Ankara, Turkey. She is Clinical Director of the CLINIC Women Health, Infertility and IVF Center and she is currently working in the clinical and laboratory site of the IVF Unit. She is participating in research projects related to infertility and IVF. Dr Aygul Demirol Dr Timur Gurgan Professor Timur Gurgan is the Head of the Division of Reproductive Endocrinology and Infertility, University of Hacettepe, Ankara, Turkey. He is the founder of the University IVF and Andrology Center which is the one of the most successful and academically well established centres in the Country. He trained in reproductive endocrinology, IVF and endoscopic surgery in UK, Canada, USA and Israel. His main interests are PCOS, endometriosis, assisted reproductive technology and reproductive surgery. He has over 100 national and international publications. He is acting as the Scientific Director of the Private CLINIC for Women Health, Infertility and IVF Unit in Ankara. He is also the President of 13th World Congress on IVF, Assisted Reproduction and Genetics, which will take place in 2005 in Istanbul. Aygul Demirol 1, Timur Gurgan CLINIC of Women s Health, Infertility and IVF Centre, Cankaya caddesi, 20/3, Ankara/Turkey 1 Correspondence: Tel: ; Fax: ; ademirol@gurganclinic.com; ayguldr@yahoo.com Abstract The study was conducted to evaluate if the diagnosis and treatment of intrauterine lesions with office hysteroscopy is of value in improving the pregnancy outcome in patients with recurrent in-vitro fertilization and embryo transfer failure. Four hundred and twenty-one patients who had undergone two or more failed IVF-embryo transfer cycles were prospectively randomized into two groups. Group I (n = 211) did not have office hysteroscopic evaluation, Group II (n = 210) had office hysteroscopy. The patients who had normal hysteroscopic findings were included in Group IIa (n = 154) and patients who had abnormal hysteroscopic findings were included in Group IIb (n = 56). Intrauterine lesions diagnosed were operated during the office procedure. Fifty-six (26%) patients in Group II had intrauterine pathologies and the treatment was performed at the same time. No difference existed in the mean number of oocyte retrieved, fertilization rate, number of embryos transferred or first trimester abortion rates among the patients in groups. Clinical pregnancy rates in Group I, Group IIa and Group IIb were 21.6%, 32.5% and 30.4% respectively. There was a significant difference in the clinical pregnancy rates between patients in Group I and Group IIa (21.6% and 32.5%, P = 0.044, respectively) and Group I and Group IIb (21.6% and 30.4%, P = 0.044, respectively). There was no significant difference in the clinical pregnancy rate of patients in Groups IIa and IIb. Patients with normal hysterosalpingography but recurrent IVF-embryo transfer failure should be evaluated prior to commencing IVF-embryo transfer cycle to improve the clinical pregnancy rate. 590 Keywords: assisted reproduction, infertility, intrauterine pathology, office hysteroscopy

2 Introduction The major determinant of the success of IVF treatment is embryo quality; on the other hand uterine receptivity and uterine integrity have also an important impact for the achievement and continuation of pregnancy. It has been well established that implantation of fertilized eggs is affected by intrauterine environment. Benign endometrial pathologies, such as endometrial polyps, adhesions, hyperplasia, endometritis and uterine mullerian abnormalities can have a negative effect on pregnancy rates (PR) (Valle, 1980; Kirsop et al., 1991; Shamma et al., 1992; Balmaceda and Ciuffardi, 1995; La Sala et al., 1998; Lass et al., 1999; Varasteh et al., 1999). Frequently, hysterosalpingography (HSG) has been performed during the course of infertility evaluation before IVF treatment. In the detection of intrauterine abnormalities, however, HSG has been reported to have a low specifity, a false positive rate of 15.6% and a false negative rate of 35.4% (Golan et al., 1992; Shamma et al., 1992; Golan et al., 1996; Wang et al., 1996; Keltz et al., 1997; Cunha-Filho et al., 2001). Therefore, it appears that in more than one-third of the cases where the HSG is interpreted as normal, it may cause a false reassurance. Since it enables direct visualization of the endometrium, hysteroscopy is the gold standard for the evaluation of the endometrial cavity. Intrauterine pathologies and structural uterine abnormalities which may be responsible for embryo implantation failure (such as adhesions, polyps, uterine septum or submucous myomas) can be detected and treated hysteroscopically resulting in improved pregnancy rates. In addition to this, it has been shown that HSG is insufficient for predicting tubal potency for some patients with risk of pelvic adhesions, with a sensitivity between 0.0% and 83% and specificity between 50% and 90% (Montoya et al., 2002). Office hysteroscopy can be performed without general anaesthesia in an ambulatory setting with low cost, minimal morbidity and inconvenience to the patients (Betocchi, 1996; Betocchi et al., 2002, 2003; Nagele et al., 1996; Vercellini et al., 1997; Ruach et al., 1998; Valle, 1999), and some lesions diagnosed can be operated easily using different equipment introduced through the operative channel of the hysteroscopy. The aim of this study was to determine if the diagnosis and treatment of intrauterine lesions with office hysteroscopy is of value in improving the pregnancy outcome in patients with recurrent IVF failure. Materials and methods Four hundred and twenty-one patients who had undergone two or more failed IVF cycles, in which two or more good quality embryos transferred, participated prospectively in the study. The study was performed between May 2000 and February All the participants had normal HSG (normal intrauterine cavity and bilaterally patent tubes). Informed consent was obtained before entry into the study. The patients ages ranged from 24 to 40 years (mean 32 years), the duration of infertility ranged from 2 to 14 years (mean 6.5 years), and all of the patients had primary infertility. Patients were randomized into two groups using computergenerated random numbers. Those in Group I (n = 211) did not have office hysteroscopic evaluation of the uterine cavity and cervix before commencing controlled ovarian stimulation for IVF treatment, whereas patients in Group II (n = 210) had office hysteroscopy. The patients who had normal hysteroscopic findings were included in Group IIa (n = 154) and patients who had abnormal hysteroscopic findings were included in Group IIb (n = 56). Intrauterine lesions diagnosed were operated during the office procedure. All office hysteroscopies were performed 2 to 6 months after the last failed IVF cycles by the same physician. The hysteroscopy was performed in the early proliferative phase using saline distention medium and a 5 mm continuous flow office hysteroscope (Bettocchi office hysteroscope, size 5; Karl Storz GmbH and Co., Tuttlingen, Germany). The scope is based on a rod lens system with a diameter of 2.9 mm and 30 view. The continuous flow sheath has an oval profile and maximum 5 mm diameter with an incorporated 5Fr working channel; the mechanical instruments used were grasping forceps with teeth and scissors (Karl Storz GmbH and Co.). Intrauterine pressure was maintained at a constant 25/235 mmhg using an electronic pump for irrigation and aspiration (Endomat; Karl Storz GmbH and Co.) Semi-rigid operative hysteroscopic instruments such as scissors, grasping forceps, and biopsy forceps were used for the treatment of small intrauterine lesions such as polyps and focal adhesions. Polyps and other suspicious hysteroscopic lesions were biopsied for pathological examination. The procedures were carried out at the IVF centre on outpatient basis and without anaesthesia. Sedation was induced by midazolam (Dormicum; Roche; F Hoffmann-La Roche Ltd, Basel, France) 0.1 mg/kg given intravenously when needed. Patients and their partners who wanted to be in the operative room observed the procedures and necessary information was given to them during the course of operation. The patients were discharged after min and no complications occurred. All IVF treatments were carried out on the menstrual cycles after office hysteroscopies. Patients were placed on an ovarian stimulation protocol that began with daily subcutaneous injections of leuprolide acetate (Lucrin; Abbott, Silic, France) 1 mg on day 21 of that cycle and continued until day 3 of the next menstrual cycle. If ovarian supression was achieved (oestradiol < 40 pg/ml) 225 IU/day of gonadotrophin (recombinant FSH, Gonal-F; Serono Laboratories, Geneva, Switzerland) was started on day 3 or 4 and the dose arrangement was performed on the basis of individual response. Ovulatory dose of 10,000 IU human chorionic gonadotrophin (HCG, Profasi; Serono Laboratories) were given when at least two follicles of 18 mm diameter or more were observed. Transvaginal ultrasonography (TVS)-guided oocyte retrieval was performed, embryo transfer was performed on day 3 and a maximum of four embryos, selected according to their quality, were transferred. Luteal support was given by progesterone vaginal suppositories (Progestan, Koçak, Turkey). Clinical pregnancies were confirmed by TVS at 6 7 weeks of gestation. 591

3 592 Results There was no difference in the mean age, duration of infertility, number of failed cycles and causes of infertility in either group (P > 0.05) (Table 1). Among the 210 patients (Group II) who had office hysteroscopy, 56 (26%) had intrauterine pathologies. Table 2 summarizes the hysteroscopic findings diagnosed and treated during office hysteroscopy. The duration of the procedures was mostly less than 10 min. In all cases, diagnostic hysteroscopy and operative procedures when needed were carried out without any particular difficulty and with success. Most of the patients experienced mild pain resembling menstrual cramps, especially during the passage of the tip of the hysteroscope through the internal cervical ostium. Six patients had repeat office hysteroscopy due to unsatisfactory distention of uterine walls and all of these attempts were successful. Thirty-three patients (15.7%) had endometrial polyps ranging in size from 0.9 to 2 cm. Of these, 11 patients had multiple polyps (five patients had three polyps and six patients had two polyps). All polyps were excised with forceps and confirmed with histological examination. Filmy or mild intrauterine adhesions involving the uterine cavity were diagnosed and operated in 18 patients. Five patients had cervical adhesions, which were easily lysed using scissors. There was no difference in the mean number of oocytes retrieved, fertilization rate or number of embryos transferred among the patients in different groups (Table 3). Of the 421 patients, three were not included in the analysis secondary to failed embryo transfer, poor ovarian response or availability of only poorly graded embryos (two in Group I and one in Group IIB). Clinical pregnancy rates in Group I, Group IIa and Group IIb were 21.6%, 32.5% and 30.4% respectively. There was a statistically significant difference in the clinical pregnancy rates between patients in Group I and Group IIa (21.6% and 32.5%, P = 0.044, respectively) and Group I and Group IIb (21.6% and 30.4%, P = 0.044, respectively). There was no significant difference in the clinical pregnancy rates in patients in groups IIa and IIb (Table 3). There were no significant differences in terms of first trimester abortions in all groups. Discussion Four hundred and twenty-one patients participated prospectively in this study to evaluate the impact of detected and treated uterine and cervical abnormalities on the success rate of ICSI-embryo transfer treatment of patients who had had two previous failed IVF or ICSI-embryo transfer cycles, despite the fact that at least two good quality embryos had been transferred. Poor embryo quality, difficult embryo transfer technique and intrauterine abnormalities are three important factors that may be responsible for failure of the IVF-embryo transfer cycles. In the treatment of infertility, HSG is being used as the firstline approach because of its low costs, and low risk. Actually, this test should be used to prove tubal potency in very young patients where there is no suspicion of tubal pathology (Montoya et al., 2002). HSG has a low sensitivity and specifity for pelvic or tubal adhesions (Swart et al., 1995). Saline infusion hysterosonography (SIS) is an another outpatient technique for the evaluation of the intrauterine cavity. There are conflicting results about the accuracy of this technique (Brown et al., 2000; Rogerson et al., 2002). SIS is a diagnostic technique, not therapeutic, and in some cases may have a high failure rate. Hysterosalpingo-contrast sonography (HyCoSy) is an advanced SIS technique where tubal patency can be evaluated in addition to the intrauterine cavity. HyCoSy offered some benefits over HSG in some studies (Dietrich et al., 1996; Ayida et al., 1997; Exacoustos et al., 2003), but this technique is only diagnostic too. SIS and HyCoSy are acceptable first-line screening procedures but office hysteroscopy offers diagnosis and treatment at the same time with a simple procedure. This option is important especially for patients who have some risks of intrauterine pathology like recurrent IVF failure patients. In most IVF programmes, HSG is only a diagnostic tool suggested for evaluation of the uterine cavity before undergoing IVF treatment (Rowe et al., 1993). On the other hand, hysteroscopy is the most accurate method for assessing intrauterine anomalies such as endometrial polyps, adhesions, malformations or uterine fibroids and these pathologies can be treated at the same time. Some reports have shown that approximately 35% of the patients who have these lesions have normal HSG findings (Wang et al., 1996). Hysteroscopic treatments may be performed easily with new instruments like Versapoint (coaxial bipolar electrode surgical system, Gynecare; Issy-les-Moulineaux, France) nowadays. In a study performed by Zikopoulos et al. (2003) it has been shown that hysteroscopic septum resection using the Versapoint system in subfertile patients improved the reproductive outcome. The present study demonstrates that 26% of patients with normal HSG had abnormal hysteroscopic findings. Previously undiagnosed or subtle newly added intrauterine abnormalities may be a significant cause of IVF-embryo transfer failure. It has been postulated that the process of ovulation induction may adversely affect the endometrium, inducing endometrial hyperplasia, endometrial polyps and small submucous myomas to proliferate and interfere with embryo implantation. Furthermore traumatic factors during the embryo transfer procedure can cause bleeding, inflammatory processes and adhesion formations, and can prevent successful nidation of the blastocyts by creating an unfavourable environment for its development. Hysteroscopic assessment of transfer catheter effects on the endometrium was performed in a recent study (Murray et al., 2003). There was no clear association between the perceived difficulty of transfer and amount of endometrial damage, and clinical perception of ease of transfer did not relate well to the degree of endometrial disruption (Murray et al., 2003). Patients with recurrent IVF failure may have some intrauterine disruption because of the treatment cycles and embryo transfer. It has been shown that repeat hysteroscopic evaluation in recurrent failure of IVF-embryo transfer patients, in spite of an initial normal hysteroscopy, permits diagnosis of these newly added lesions (Dicker et al., 1992).

4 The impact of missing or newly developed intrauterine or cervical pathology on the success of IVF treatment has not been prospectively evaluated. It was only shown that the patients with abnormal hysteroscopic findings had lower clinical pregnancy rates after IVF treatment when compared with those with no intrauterine or cervical lesions (Shamma et al., 1992; Balmaceda and Ciuffardi, 1995). In this study, 56 patients in Group II had abnormal hysteroscopic findings including endometrial polyps and intrauterine and cervical adhesions. Although no difference in patients or cycle characteristics was present, there was a significant difference in the clinical PR among the patients in Groups I, IIa and IIb (Table 3). Interestingly there was no difference in abortion rates between the groups. This prospective randomized study showed that the clinical PR could be improved significantly after treatment of mild intrauterine and cervical abnormalities by office hysteroscopy. It is possible that these mild abnormalities are altering the uterine environment and hence negatively affecting uterine receptivity and ultimately pregnancy outcome. In conclusion, patients with normal HSG but recurrent IVFembryo transfer failure should be evaluated prior commencing IVF-embryo transfer cycles, to improve the clinical PR. Table 1. Mean age, duration of infertility, number of failed transfer cycles and cause of infertility among the groups. Parameter Group I Group IIa Group IIb P-value (n = 211) (n = 154) (n = 56) Mean age (years) 34.3 ± ± ± 0.1 NS Mean duration of 6.2 ± ± ± 0.5 NS infertility (years) Mean number of failed 2.8 ± ± ± 0.1 NS transfer cycles Cause of infertility (%) Ovulatory 74 (35) 50 (33) 16 (29) NS Male 50 (24) 47 (31) 15 (27) NS Idiopathic 87 (41) 57 (36) 25 (44) NS NS = not significant. Table 2. Results of office hysteroscopy. Result Number of patients (%) Normal 154 (73.3) Endometrial polyp 33 (15.7) Filmy and mild endometrial adhesions 18 (8.5) Cervical adhesion 5 (2.3) Table 3. Results of IVF outcome in patients. Variable Group I Group IIa Group IIb P-value (n = 211) (n = 154) (n = 56) Mean number of NS mature oocytes Fertilization rate (%) NS Number of clinical 45 (21.6) 50 (32.5) 17 (30.4) <0.05 pregnancies (%) Number of first 9 (4.2) 5 (3.2) 2 (3.5) NS trimester abortions (%) NS = not significant. 593

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