Submucous myomas and their implications in the pregnancy rates of patients with otherwise unexplained primary infertility undergoing hysteroscopic myomectomy: a randomized matched control study Tarek Shokeir, M.D., Muhammed El-Shafei, M.D., Hamed Yousef, M.D., Abdel-Fattah Allam, M.D., and Ehab Sadek, M.D. Department of Obstetrics and Gynecology, Fertility Care Unit, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt Objective: To determine whether hysteroscopic myomectomy for submucous fibroids in women with unexplained primary infertility achieved better pregnancy rates than no intervention. Design: Prospective randomized matched control trial. Setting: Tertiary university fertility care unit. Patient(s): From January 1999 to February 2006, a total of 215 women with unexplained primary infertility and with ultrasonographically diagnosed submucous myomas as the sole cause for fertility failure were recruited. Intervention(s): Women were randomly allocated to one of two pretreatment groups matched by age. Hysteroscopic myomectomy was performed in the study group (n ¼ 101). Diagnostic hysteroscopy and myoma biopsy was performed in the control group (n ¼ 103). No fertility therapy was given for either group. Main Outcome Measure(s): Clinical pregnancy rates according to patient and myoma characteristics. Result(s): The baseline characteristics of both patients and submucous myomas were comparable. Among patients with complete follow-up, a total of 93 (45.6%) pregnancies occured 64 (63.4%) in the study group and 29 (28.2%) in the control group. Women in the study group had a better possibility of becoming pregnant after hysteroscopic myomectomy with a relative risk of 2.1 (95% confidence interval, 1.5 2.9). No difference in pregnancy rates was observed according to size, number, and location of myomas in both groups. However, fertility rates appeared to increase after hysteroscopic myomectomy of type 0 and type I myomas (P < 0.05). In contrast, for the subgroup of patients with type II myomas, no difference in fertility rates were noted. Conclusion(s): Hysteroscopic myomectomy for submucous fibroids in women with unexplained primary infertility is effective in achieving a better pregnancy rate. We think that a multicenter study should be conducted before evaluating the impact of submucous myoma characteristics on fertility outcome. (Fertil Steril Ò 2010;94:724 9. Ó2010 by American Society for Reproductive Medicine.) Key Words: Submucous myoma, hysteroscopic myomectomy, infertility There are many reports in the literature concerning infertility and submucous fibroids, and none of them contain a confirmed conclusion. Physicians who have female patients with uterine submucous myomas who want to become pregnant face a clinical quandary regarding the best management of such fibroids. The main argument against conservative hysteroscopic myomectomy is the lack of definite evidence of a causal association between submucous fibroids and infertility (1 3). Concerns remain about potential adverse consequences, such as morbidity, complications, and intrauterine adhesion formations in some cases. However, indirect evidence suggests that the pregnancy rate in women with otherwise unexplained primary infertility is fairly good, and more than half of patients become pregnant after hysteroscopic surgery (4). Most publications addressing submucous myomas report a high pregnancy wastage rate, frequently exceeding 70%. However, the role of the submucous myoma in this regard and indications for myomectomy remain controversial (5, 6). We have recently published an observational prospective study of 26 women 11 with primary infertility and 15 with recurrent pregnancy loss, with a submucous myoma as the only explanation for the diagnosis and reported improved reproductive outcomes after hysteroscopic myomectomy. After a mean postoperative follow-up period of 40 months, 81% of women with unexplained primary infertility and 63% of those with recurrent pregnancy loss achieved a live birth (7). Received December 9, 2008; revised March 16, 2009; accepted March 19, 2009; published online May 5, 2009. T.S. has nothing to disclose. M.E-S. has nothing to disclose. H.Y. has nothing to disclose. A-F.A. has nothing to disclose. E.S. has nothing to disclose. Reprint requests: Tarek A. Shokeir, M.D., Department of Obstetrics and Gynecology, Fertility Care Unit, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt (TEL: þ 20 50 2331118; FAX: þ 20 50 2319922; E-mail: tarekshokeir@hotmail.com). Hysteroscopic removal of such myomas is now the accepted treatment, despite the lack of good prospective, 724 Fertility and Sterility â Vol. 94, No. 2, July 2010 0015-0282/$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2009.03.075
randomized control trials and the small size of many reported series. A majority of these trials are retrospective or case control studies that compare the reproductive outcome before and after hysteroscopic myomectomy (1 4). Furthermore, to our knowledge, no prospective controlled data exist regarding fertility outcome after hysteroscopic myomectomy among this select patient group, according to the characteristics of the submucous myomas. Because of the considerable controversy that surrounds the topic of submucous myomas and unexplained primary infertility, we designed this prospective, randomized, agematched control trial to discover whether hysteroscopic myomectomy in women with otherwise unexplained infertility affects pregnancy rates. MATERIALS AND METHODS From January 1999 to February 2006, 352 patients fulfilling the inclusion criteria of unexplained primary infertility with submucous myoma discovered on initial pelvic sonographic studies as the sole cause for a diagnosis were selected. Patients (aged 21 35 years) were informed of the study design and were recruited for the trial. Two hundred and fifteen (61%) of them agreed to participate and informed consent was obtained. The study was approved by the hospital s ethics committee. The sonographic diagnosis of submucous myomas has been described elsewhere (8). In all patients, a baseline diagnosis was made using ultrasonography performed with a multifrequency endovaginal transducer (Sonace Medical Corporation, Seoul, Korea). The size, number (single or multiple), and location of the fibroid in the uterus was recorded based on height (fundus, corpus, lower segment, or cervical). If >3 months elapsed between the initial baseline sonogram and the occurrence of pregnancy, the myoma was reevaluated every 3 months to determine any significant changes in the myoma characteristics. Inclusion criteria were women with R12 months of primary infertility (duration of infertility ranged 12 120 months), regular menstruation, a sonographic diagnosis of submucous myoma, and candidacy for hysteroscopic myomectomy. The indication for myomectomy was a submucous myoma in combination with a history of unexplained primary infertility if the lesion was thought to be the only contributing factor to infertility. No patients were experiencing menorrhagia in our study. Women older than 35 years were excluded from the study to avoid the inclusion of subjects with age-related subfertility. Also excluded from the study were women with pelvic lesions, such as endometriosis, that could adversely affect fertility. Cases with associated interstitial fibroids, submucous myomas >5 cm in diameter and/or a uterine cavity >10 cm in length were also excluded. All patients had never had previous surgery for leiomyomata or other uterine surgery, and no other uterine cavity abnormalities existed (e.g., uterine septum or endometrial polyps). After a detailed history and thorough clinical examination, all of the patients received a complete infertility workup including semen analysis, assessment of ovulation by midluteal serum progesterone level, assessment of ovarian reserve by cycle day 3 serum FSH level, postcoital test (PCT), and hysterosalpingography (HSG). The initial suggestion of diagnosing submucous myoma was made by HSG for most of the cases within 1 year. Laparoscopy was performed primarly for all patients to assess the pelvis for causes of infertility. Those with pelvic lesions were excluded from the study. In those with a healthy pelvis, hysteroscopic examination was performed to assess the uterine cavity, confirm the diagnosis, and assess the characteristics of the myoma including its size, number, location, and type. The classification proposed by the European Society of Hysteroscopy (9) was used in our study for identifying the type of leiomyoma by the degree of intramural development. Accordingly, type 0 was defined as the myoma with development limited to the uterine cavity (pedunculated myoma), type I was defined as the myoma with partial intramural development (endocavitary component >50%), and type II was defined as the myoma with predominantly intramural development (endocavitary component <50%). Idiopathic primary infertility was diagnosed in patients with normal ovulatory cycles, semen analysis, HSG, and PCT in infertile couples for >24 months. Except for submucous fibroids, no concurrent causes of infertility were identified in any patient. The study group was composed of 107 women in whom a myoma was extracted during hysteroscopy in the early proliferative phase of the menstrual cycle. Alternatively, the control group was composed of 108 women in whom submucous myomas were not extracted during diagnostic hysteroscopy and myoma biopsy only was performed. Randomization When a patient with a submucous myoma was selected for myomectomy, she was matched with the next case in which the other patient was nearly of the same age (within 2 years) and scheduled for no myomectomy. Patients matched by age were randomized into two groups with the use of an envelope technique, with assignment determined by a computer-generated random number table. Operative Procedure The myomectomy was performed by means of a 5.5-mm Karl-Storz (Tuttlingen, Germany) continuous flow office hysteroscope under local anesthesia using a paracervical block. The formations were resected by means of a rigid scissors and forceps and submitted for histopathologic examination. When resection was not possible during the diagnostic hysteroscopy, in cases with multiple myomas, and in those with residual lesions or myomas >3 cm in diameter, the patient was scheduled for operative hysteroscopic examination under general anesthesia. Electrosurgical resection was done during the early proliferative phase of the subsequent menstrual cycle Fertility and Sterility â 725
by using a 26-Fr resectoscope with a cutting knife electrode (Karl-Storz, Tuttlingen, Germany). Glycine 1.5% was used to distend the uterine cavity. All hysteroscopic examinations were performed by the same surgeon. No hormonal or antihormonal treatment was given before and after the resection until complete healing had been proven by a second-look hysteroscopic examination at the clinician s office. For type I and II myomas, the intracavitary dome of the myoma was resected to a flat surface that was even with intrauterine cavity. Next, prostaglandin F2 alpha was intraoperatively injected into the uterine body when concomitant laparoscopy was performed (10) or into the uterine cervix transvaginally. The remnant part of the myoma was then compressed by uterine contractions. Finally, the newly raised myomal dome in the uterine cavity was resected electrosurgically. Electrosurgical manipulation was never performed deeply into the intramural remnant myoma or into the intramyometrial space. In the case of this procedure failing, a second resection was planned. Follow-up Patients in the study group were seen on the first postoperative day and returned for a follow-up visit approximately 1 month later for assessment and to evaluate the configuration of the uterine cavity. This was accomplished with follow-up outpatient hysteroscopic examination under local anesthesia. The criteria for a second procedure were the presence of a partially resected myoma and/or regrowth of the excised one. Women in both groups were advised to engage in natural intercourse. No fertility therapy was given for either group. Following hysteroscopic resection and to assess fertility outcome, women were asked by telephone or regular visits to complete a health questionnaire. This questionnaire concerned pregnancy data including date of last normal menstrual period, serum hcg titre, and ultrasound confirmation of a viable clinical pregnancy. Any postoperative complications were also recorded. For outcome analysis, only women with a follow-up of 12 months in both groups were included in the present study. For women requiring a second resection, follow-up dates were derived from the time of the second procedure. Serum hcg level was determined in absence of menstruation for diagnosis of pregnancy. Outcome Measures Clinical pregnancy was the main outcome measure analyzed to determine the effectiveness of treatment. We studied the first normally intrauterine pregnancy after the surgical procedure rather than its outcome. The secondary outcome was to determine whether the different characteristics of the fibroid influenced the pregnancy rate. Statistical Analysis Subjects were randomized into one of two groups in a 1:1 ratio and matched by age using a restricted randomization. A descriptive analysis was performed for each variable of the study, as well as a bivariate analysis between the dependent and each of the independent variables with contingency tables, with c 2 -test for categorical variables and Student s t test for continuous variables. The relative risk (RR) of achieving pregnancy was calculated along with 95% confidence intervals (CIs). With the report of the pathologist, myomas in the study group were subdivided into four groups based on their quartiles (<5 mm, 5 10 mm, 11 20 mm, 21 50 mm), and pregnancy rates were compared between groups. Furthermore, the type, site, and number of the myomas were determined and pregnancy rates were compared between groups accordingly. Significance was defined as P < 0.05. RESULTS In-office hysteroscopic examination was not possible with seven patients (3.2%), so they were performed in the operating room under general anesthesia. The cause for the failures was severe pain because of cervical conditions in all cases. Concomitant laparoscopic and hysteroscopic examinations were performed in approximately 50 (50%) cases. Eleven patients were lost from the study, six from the study group (three lost to follow-up, two pathologic reports of endometrial polyps, and one patient in whom the myoma was not confirmed), and five from the control group (one lost to follow-up, two patients in whom the myoma was not confirmed, and two pathologic reports of endometrial polyps). These 11 cases were excluded from the study, leaving 101 patients in the study group and 103 in the control group. Of 101 infertile patients in the study group, 99 had a complete resection in one surgical setting and two patients (2%) needed a second resection procedure. For these two patients, the reasons for needing a second resection were intraoperative complication (uterine perforation treated conservatively) and incomplete resection of large fundal myoma. The mean number of myomas removed was 1.4 (range, 1 4). The mean diameter of the largest extracted myoma was 20 mm (range, 10 50 mm). No postoperative complication was noted. After resection, all 101 infertile women had a second-look office hysteroscopic examination result that confirmed the healthiness of the cavity. Table 1 summarizes the characteristics of the patients and submucous fibroids in both groups. The mean time of followup and the duration of infertility were comparable. Regarding the myoma characteristics, there were no statistically significant differences between groups, including the size, number, type, and location of the myomas. Furthermore, no significant changes in the myoma characteristics were noted at followup transvaginal sonography (TVS) among the control group. Overall, among patients with complete follow-up, a total of 93 (45.6%) pregnancies occured 64 (63.4%) in the study group and 29 (28.2%) in the control. Women in the study group had a better possibility of becoming pregnant after 726 Shokeir et al. Hysteroscopic myomectomy in unexplained infertility Vol. 94, No. 2, July 2010
TABLE 1 Baseline patients and submucous myoma characteristics (n [ 204). Myomectomy myomectomy with an RR of 2.1 (95% CI, 1.5 2.9). The mean delay (SD) between myomectomy and the conception was 3.8 2.1 months among the study group compared with 7.5 2.6 months in the control (P < 0.05). Nearly 80% of the women conceived spontaneously after 6 months of unprotected intercourse. Fertility outcome according to myoma characteristics in women undergoing myomectomy for whom follow-up was complete compared with the control group is shown in Table 2. Pregnancy rates did not differ significantly according to the size, number, and location of the myoma (P > 0.05). However, according to the type of the fibroid, the myomectomy group was associated with significantly higher pregnancy rates in patients with type 0 and type I myomas compared with controls (P < 0.001). Alternatively, no statistically significant difference in pregnancy rate was observed with type II myomas (P > 0.05; Table 2). DISCUSSION To our knowledge there are no randomized, control trials examining fertility outcome after hysteroscopic myomectomy in patients with unexplained primary infertility. Retrospective and case control studies demonstrated that submucous myomas are associated with decreased pregnancy and No myomectomy Study (n [ 101) Control (n [ 103) P value Age (y), mean SD 30.8 4.1 30.9 4.4 Follow-up (mo), mean SD 9.4 2.5 8.8 2.4 Duration of infertility (y), % R3 15.0 14.0 <3 27.7 31.0 Myoma size (mm), % <5 24.8 32.0 5 10 31.7 29.1 11 20 25.7 22.1 >20 17.8 20.4 Myoma number, % 1 89.1 90.3 R2 10.9 9.7 Myoma type, % 0 56.4 58.2 I 27.7 28.2 II 15.8 13.4 Myoma location, % Fundal 59.4 63.1 Lower uterine segment 41.0 36.9 Cervical 0.0 0.0 Note: ¼ not significant. Shokeir. Hysteroscopic myomectomy in unexplained infertility. Fertil Steril 2010. implantation rates in patients who attempt to conceive spontaneously or who are undergoing IVF (4 6, 11). Our data support these findings; the pregnancy rate was relatively high in women with prolonged duration of infertility (63.4%). Pregnancies were achieved after a relatively short delay in conception (3.8 2.1 months [mean SD]), and the rate of spontaneous conception was remarkably high (81.8%) after 6 months of unprotected intercourse. The proportion of pregnant patients in the study group was nearly twice that of the control. Literature data suggest that an improved uterine contour may result in an improved pregnancy rate in women with unexplained infertility (1 4). Varasteh et al. (12) reported a correlation of 65.2% between hysteroscopic myomectomy and the accumulated rate of pregnancies, but polyps and submucous myomas were mixed and the study was retrospective and not randomized, so their conclusions raise some questions. In another retrospective series, 11 of 31 infertile women (35.5%) in whom hysteroscopic myomectomy was performed conceived within a 12-month period (13). No prospective data exist regarding fertility outcome after hysteroscopic myomectomy according to the characteristics of submucous myomas. To our knowledge, only Bernard et al. (14) have reported retrospectively on subsequent fertility and outcome of pregnancies after hysteroscopic Fertility and Sterility â 727
TABLE 2 Pregnancy rates according to the characteristics of submucous myomas. Myomectomy myomectomy according to the characteristics of the submucous myomas and also the association with intramural fibroids. They found no difference in pregnancy and delivery rates according to the size and location of submucous myomas. The authors suggest that fertility after hysteroscopic myomectomy depends mainly on the number of submucous myomas resected and the association with intramural fibroids. However, their analyses included mixed patients of variable age groups and different types of infertility. In the present prospective study, the data suggest that restoration of reproductive ability among patients with unexplained primary infertility is found to be unrelated to myoma size, number, and location, although it is well-known that such morphologic factors of submucous myomas are important for the occurrence of repeated pregnancy losses (15 19). In contrast, Varasteh et al. (12) in his retrospective study included a control group of infertile women with a normal uterine cavity at hysteroscopy, and showed a significant benefit of removing submucous myomas of >2 cm in size. Fernandez et al. (13), again using a retrospective series, also described better pregnancy rates after removal of larger myomas, although the difference was not statistically significant, suggesting a space-occupying lesion mechanism for infertility. Pregnancy rates No myomectomy Myoma characteristic Study (n [ 101) Control (n [ 103) P value Size (mm), % <5 68.0 69.6 5 10 56.2 53.3 11 20 61.5 58.3 >20 61.1 61.5 Number, % 1 44.4 40.9 R2 36.4 30.0 Type, % 0 57.9 33.3 <0.001 I 35.7 17.2 <0.001 II 31.3 29.0 Location, % Fundal 50.0 53.8 Lower uterine segment 41.5 42.1 Note: ¼ not significant. Shokeir. Hysteroscopic myomectomy in unexplained infertility. Fertil Steril 2010. In the current study, submucous myoma type in relation to pregnancy rate has been evaluated. In this trial, fertility rates appear to increase after hysteroscopic myomectomy of type 0 and type I myomas (P < 0.05). However, for the subgroup of patients with type II myomas, no difference in fertility was observed compared with controls. These results are in accordance with those published by Ioannis et al. (20), who reported that hysteroscopic myomectomy was associated with an increase in pregnancy rate in patients with type 0 and type I myomas, whereas in patients with type II fertility rates did not increase in contrast with those with type II myomas who received expectant management. Actually, the interpretation of these data concerning the submucous myoma type in relation to pregnancy rate is difficult. The difference cannot be due simply to uterine cavity abnormality. In our series, the absence of cavity distortion was systematically verified by a hysteroscopic examination performed in the clinician s office 1 month after resection. Therefore, these results possibly reinforce the hypothesis that other mechanisms associated with leiomyomas might contribute to the infertility (1 3). The implications of different submucous myoma characteristics in the pregnancy rates in patients with unexplained infertility are difficult to be organized. Possibly, in another study we should eliminate women whose fibroids are beyond a certain character. For example, the mean size for the study presented here was 20 mm. If we kept the sizes the same, for our fertility care unit to have approximately the right number of patients to show any significant differences it would take about 6 more years. Hopefully this study will encourage a multicenter cooperative study to evaluate sooner than this whether submucous myomas of a certain character negatively affect pregnancy rates. Our results suggest that in addition to the presence of submucous myomas in women with otherwise unexplained primary infertility, other physiopathologic pathways might 728 Shokeir et al. Hysteroscopic myomectomy in unexplained infertility Vol. 94, No. 2, July 2010
be involved, such as an impairment of implantation subsequent to endometrial alterations. We think that the extent of endometrial alterations subsequent to the resection depends on the size, number, type and location of submucous myomas resected. This suggestion is supported with evidence from several studies evaluating the effect of myoma uteri on the pregnancy rate after assisted reproductive technique (ART). Use of ART provides a unique setting because factors such as mechanical factors, greater distance for the gametes to travel, position of the cervix, or menometrorrhagia can be excluded as possible causes for infertility associated with this condition. Stovall et al. (19) showed that even after patients with submucosal fibroids are excluded, the presence of fibroids reduces the efficacy of ART. Eldar-Geva et al. (18) compared 106 ART cycles in patients with uterine fibroids with 318 ART cycles in age-matched patients without uterine fibroids and concluded that implantation and pregnancy rates were significantly lower in patients with intramural or submucosal myomas, even in those with no deformation of the uterine cavity. Therefore, if women with unexplained primary infertility have a better chance of conception after hysteroscopic myomectomy and if the main factors in treatment success are patient age and duration of infertility as stated by other authors (1 6), this conservative surgery should not be postponed for too long. A recent systematic review and metaanalysis (4) has been suggested that different types of fibroids may affect reproductive outcome to a different extent, and removal of submucous fibroids may be indicated in infertile women in whom no other factor has been identified. Our prospective data support these guidelines and provide some information on the reproductive potentials of selected women who have undergone hysteroscopic myomectomy for submucous myomas. If we combine the data from our first prospective control study with data from previously published ones, we then consider it worthwhile to perform a hysteroscopic myomectomy in an infertile woman with otherwise unexplained infertility whose only known problem is the presence of a submucous myoma. Although vaginal delivery can be safe after hysteroscopic myomectomy, and uterine rupture has never been reported following this procedure, the obstetric management should be extremely careful (2). Many investigators believe that cesarean section as a mode of delivery is the best whenever managing type I or type II submucous myomas hysteroscopically (12, 16). In conclusion, pregnancy rates seem to be relatively good after hysteroscopic myomectomy in women with otherwise unexplained primary infertility. 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