Hysteroscopic Metroplasty for the Septate Uterus: Review and Meta-Analysis

Review Article Hysteroscopic Metroplasty for the Septate Uterus: Review and Meta-Analysis Rafael F. Valle, MD*, and Geraldine E. Ekpo, MD From the Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (both authors). ABSTRACT Keywords: The introduction of hysteroscopy to diagnose and treat intrauterine conditions, specifically to divide the uterine septum, or metroplasty, has replaced the traditional laparotomy approach, and objective results demonstrate its salutary effects in women treated. Hysteroscopic metroplasty averts the implications of major invasive abdominal surgery, with good and satisfactory results in pregnancy and live-birth rates, despite the lack of prospective, randomized, controlled studies. A careful review of the published results supports this type of treatment when the uterine septum adversely affects normal reproductive function. Journal of Minimally Invasive Gynecology (2013) 20, 22 42 Ó 2013 AAGL. All rights reserved. Uterine anomalies; Uterine septum; Pregnancy wastage; Hysteroscopy; Hysteroscopic metroplasty DISCUSS You can discuss this article with its authors and with other AAGL members at http://www.aagl.org/jmig-20-1-12-00451 Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for QR scanner in your smartphone s app store or app marketplace. Errors of arrest in the development of the embryologic m ullerian ducts are conducive to uterine anomalies. The lack of fusion of the original ducts or lack of reabsorption of the embryologic septum can result in a bicornuate or a septate uterus. While not all uterine anomalies may impair normal uterine reproductive function, some do, and may require surgical treatment. One common uterine anomaly that benefits from treatment by metroplasty is the septate uterus. Congenital Uterine Malformations Incidence It is difficult to determine the incidence of congenital uterine malformations in the general population because most affected women do not experience reproductive problems. The incidence has been calculated to be 1 or 2 per The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding author: Rafael F. Valle, MD, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, 880 N Lake Shore Dr, Ste 20-C, Chicago, IL 60611-5715. E-mail: rafaelvalle1@aol.com Submitted September 18, 2012. Accepted for publication September 22, 2012. Available at www.sciencedirect.com and www.jmig.org 1000 women and as high as 15 per 1000 women. Some studies have reported a 12% incidence [1 5]. Genetic Factors The occurrence of congenital uterine malformations seems to be influenced by a genetic heterogeneity and/or polygenic multifactorial inheritance. Inasmuch as these anomalies develop early in embryonic life, a short review of this crucial period is appropriate [6]. The m ullerian ducts arise from the urogenital ridge of the embryo as an invagination of the celomic epithelium at about 5 to 6 weeks of embryonic life. The ducts grow downward immediately to fuse in the midline at about 9 weeks and then are united with the endodermal bulbs of the urogenital sinus to form the remainder of the vagina. This process is completed by 12 to 14 weeks of gestation, and reabsorption of the septum is completed by week 19 to 20 embryonic life. In the absence of m ullerian inhibiting factor produced by the testes, the paramesonephric m ullerian ducts progress to normal female development. The different stages of arrest in m ullerian ducts differentiation are manifested in various clinical entities. Unilateral absence of a m ullerian duct results in a unicornuate uterus, and medial absence of the ducts results in absence of the uterus. Lack of fusion at various stages results in a didelphic 1553-4650/$ - see front matter Ó 2013 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2012.09.010

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 23 Fig. 1 Septate uterus: partial (1 and 2), complete (3), complete with septate cervix (4), and complete with cervical and vaginal septation (5). uterus with a double cervix and septate vagina. Failure of reabsorption of the medial septum in the uterus results in a septate uterus [7 10] (Fig. 1). Classification of Uterine Anomalies There are many classifications of developmental anomalies of the uterus. In 1979, Buttram and Gibbons [11] proposed a classification that was further revised in 1988 by the American Society of Reproductive Medicine, then known as the American Fertility Society [12] (Fig. 2). This classification groups anomalies in categories on the basis of similarities in clinical features, obstetric outcome, and treatment options [12]. While the American Society of Reproductive Medicine classification has gained widespread acceptance, subclassifications have been proposed to further differentiate uterine anomalies previously classified as class V (septate) and class VI (arcuate) [13]. Alternative grouping systems include vaginal anomalies and separate uterovaginal anomalies in 3 separate groups on the basis of embryonic developmental defects and clinical features. Such is the classification proposed by Jones and Rock [14] and Jones [15], which is based on lateral or vertical defects of fusion, both with or without obstruction. However, a simpler, easy to remember, and clinically useful classification of uterine anomalies is that proposed in 1966 by Strassman [3], based on the various stages of embryologic developmental arrest that occur during embryogenesis, and that by Lindeman et al [16]. These classifications are given in Table 1. Because of the close relationship and common embryologic origins of the genital tract and urinary systems, with both developing from the mesonephric system, m ullerian anomalies are frequently associated with urologic malformations. Various urinary tract anomalies have been described in patients with septate uterus and other m ullerian anomalies including unilateral renal agenesis, unilateral or bilateral pelvic kidneys, malrotation of the kidney, and duplication of the collecting system, hydroureter, or extrophy of the bladder. Conventional management of any uterine anomaly should therefore include imaging to rule out renal and urinary tract malformations. In addition, anomalies of the spine and skeletal system have been reported in patients with m ullerian anomalies independently or as part of a syndrome [17]. Vascularization and Muscular Components of the Uterine Septum Few histologic evaluations of the uterine septum have been performed. It is clear that the composition of the septum varies according to site and level at which the tissue samples are obtained for study. In addition, the width of the septum is important inasmuch as some are very thin and others very thick; thus, the results obtained from studies vary considerably. The uterine septum, in general, is

24 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 Fig. 2 American Fertility Society classification of m ullerian anomalies. composed of fibromuscular tissue and may borrow vascularization from the adjacent uterine walls. When hysteroscopic metroplasty is performed, the uterine cavity is distended, and the septum becomes apparent as it stretches away from the uterine walls. This effect enables the medial portion of the septum to be practically free of vascularization, except with a thick septum, thus enabling its division in the middle without substantial bleeding. Studies in which samples were obtained at hysteroscopy or laparotomy (Tompkins procedure) to evaluate the components of the uterine septum have challenged the concept of poor vascularization of the septum; however, the evaluations were performed using resected portions of the septum or hysteroscopic selected biopsy samples, which do not represent the totality of the septum [18,19]. Further and more systematic evaluations of different types of septum will be valuable to better elicit the true composition of the different septae. Kupesic and Kurjak [20] have used transvaginal color and pulsed Doppler sonography and 3-dimensional (3-D) sonography in the evaluation of the uterine septum, showing septal vascularity in 71% of patients studied, which suggests that most uterine septae carry myometrial vessels. They also concluded that most obstetric problems could be due to higher and uncoordinated activity of the septum muscular tissue [20]. In addition, magnetic resonance imaging (MRI) is a useful and accurate method for evaluating the muscular and vascular components of the uterine septum. It is not clear the role uterine motility has, if any, in septate uterus as a cause of pregnancy loss, although motility has been studied in the bicornuate uterus and showed dissimilar responses when the 2 uterine horns were asymmetric. No such studies have been performed on the septate uterus [21]. Diagnosis and Evaluation Although the diagnosis of a malformed uterus can be made during physical examination when obvious anomalies of the vagina and cervix are present, the subtlest uterine anomalies can be discovered and confirmed only by other methods of evaluation such as hysterosalpingography, sonography in all its modes, and hysteroscopy (Figs. 3 and 4). Differentiation of a bicornuate from a septate uterusmay require additional evaluation via ultrasonography and/ or laparoscopy. Imaging techniques are discussed later in this review (see Preoperative Evaluation and Diagnosis. ). Reproductive Problems Caused by Uterine Septum Most women with m ullerian anomalies, specifically of the septum, have efficient reproductive function; only about 20% to 25% may experience recurrent spontaneous abortions [22,23]. Of all of the uterine anomalies encountered, septate uterus is most often associated with reproductive wastage. The classic clinical finding is of repeated early mid-trimester pregnancy wastage with obvious signs of labor, including bleeding. Infertility rarely results from a uterine anomaly alone. Therefore, the mere recognition of a uterine anomaly does not dictate surgical therapy. Furthermore, in patients who have demonstrated pregnancy wastage, a complete workup is necessary to rule out other possible extrauterine causes of the reproductive failures [23].

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 25 Table 1 Classifications of uterine anomalies Strassman Classification [3] Symmetric With external division of uterus (2 cavities) Complete Incomplete Without external division but with midline septum Complete Incomplete Asymmetric With rudimentary horn Communicating Noncommunicating Jones Classification [14,15] Agenesis Problems of vertical fusion Obstructive Nonobstructive Problems of lateral fusion Obstructive Nonobstructive Buttram and Gibbons Classification [11] Segmental m ullerian agenesis/hypoplasia Vaginal Cervical Fundal Tubal Combined anomalies Unicornuate With rudimentary horn With endometrial cavity Communicating Noncommunicating Without endometrial cavity Without rudimentary horn Didelphys Bicornuate Complete (division down to internal os) Partial Arcuate Septate Complete (septum to internal os) Partial Diethylstilbestrol related Fig. 3 Hysteroscopic view of septate uterus. Obstetric problems associated with uterine anomalies include breech presentation (25% 30%), oblique and transverse positions (5%), and premature labor (20%). In the postpartum period, retained placenta can occur in 5% to 10% of patients [24]. In recent studies by Hua et al [24] and Agostini et al [25], the presence of a uterine anomaly was associated with a 6-fold increased risk of preterm birth, 3-fold preterm premature rupture of the membranes, breech presentation, and cesarean section performed in the presence of a fetus not in the breech position. In some patients, a uterine anomaly is diagnosed if there is incomplete uterine evacuation in association with voluntary pregnancy interruption. Because of the significant association of urinary tract anomalies with uterine anomalies (30% 40%), in particular in the asymmetric forms, evaluation of renal function via sonography and intravenous pyelography should be performed routinely [5,11]. Why Do Some Women With Uterine Septum Abort? Several theories have been offered to explain why repetitive abortions occur in women with uterine septum. These include decreased luminal space, impaired development of the endometrium such that it cannot support the pregnancy, decreased steroid estrogens receptors, decreased serum cystine aminopeptidase, and decreasing neutralization of circulating oxytocin [26]. Other theories include an alteration in cervical fibromuscular/connective tissue ratios. The Fig. 4 Sonographic view of septate uterus.

26 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 hypermuscular cervix, with increased cervical fibromuscular tissue and decreased connective tissue, results in less resistance to cervical dilation, leading to pregnancy wastage [27]. A decrease in growth factors such as vascular endothelial growth factor has been noted in women with septate uterus and repeated abortions as compared with women without reproductive problems [28]. Although all of these factors may have a synergistic role, the most generally accepted cause has been decreased vascularization of the septal area, as demonstrated during surgical division of the septum when the uterus is distended, therefore affecting blastocyst implantation and nutrition of the implanted embryo. Fedele et al [29] conducted serial sonographic studies of implanted embryos in patients with known septate uterus and found that when implantation in the septum occurred, most of these patients aborted as compared with those with implantation occurring in the lateral uterine walls. Endometrial biopsy samples obtained at hysteroscopy in the preovulatory phase of the cycle from uterine septal areas and evaluated via scanning electron microscopy have demonstrated decreased sensitivity of this endometrium to preovulatory hormonal changes as compared with biopsy samples obtained from the lateral walls of the uterus, which suggests a possible role in and pregnancy wastage [30]. Indications for Metroplasty Most women with septate uterus reproduce successfully; only 20% to 25% may have pregnancy wastage, late firsttrimester abortion, or early second-trimester abortion initiated with mini-labor and bleeding. This problem seems to correlate with the length of the septum, with longer septae posing the greatest risk. The most genuine indication for treatment is repeated abortion. However, with the advances in minimally invasive procedures such as hysteroscopy, other relative indications include requiring special treatment for induction of ovulation, insemination, or other assisted-reproduction technologies. The role of metroplasty in patients with primary continues to be controversial, and although some patients have been treated solely for this reason, with subsequent postoperative pregnancies, the pregnancy rate in general has been much lower than when the indication for metroplasty is pregnancy wastage. Because the septate uterus seldom causes, other uterine and extrauterine causes of the should be ruled out before metroplasty is performed [31]. A rough pregnancy rate of 48% was obtained after metroplasty in 84 infertile patients gathered from 7 reports [32]. In a study by Shokeir et al [33], the pregnancy rate after hysteroscopic metroplasty in 88 patients with primary unexplained was 40.7%, with 80% of patients conceiving spontaneously. Of 44 pregnancies in 42 women, 36 live newborns were delivered [33]. Pabuccu and Gomel [34] reported on the reproductive outcomes after hysteroscopic metroplasty in women with septate uterus and unexplained. Of 61 women who underwent hysteroscopic metroplasty, 25 (41%) conceived after metroplasty. Of the 25 patients who conceived, 18 (29.5% of the total group) delivered live infants and 7 (11.5% of the total group) had spontaneous abortions. The authors concluded that hysteroscopic metroplasty had a beneficial effect in these women [34]. In a similar study, which was retrospective and controlled, 127 women with septate uterus and unexplained were evaluated, 102 after metroplasty (group 1) and 25 before metroplasty (group 2). Forty-four patients (43.1%) achieved pregnancy in group 1, compared with only 5 (20%) in group 2. The abortion rate was 11.4% in group 1, and 60% in group 2. It was concluded that hysteroscopic metroplasty improved reproductive outcome in patients with septate uterus and unexplained [35,36]. Other observational studies have reported similar findings [37]. To evaluate the role of septate uterus in the reproductive performance of patients requiring in vitro fertilization (IVF), a retrospective, matched, controlled study was performed that evaluated 2481 embryo transfers in stimulated IVF/intracytoplasmic sperm injection cycles in women with known septate uterus. Two hundred eighty-nine embryo transfers were performed before metroplasty, and 538 after metroplasty, and were compared with 2 consecutive embryo transfers in the control group. The pregnancy rate before metroplasty was lower than after metroplasty, and the abortion rate was higher. These results show that the presence of septate uterus decreases the pregnancy rate and may increase the abortion rate after embryo transfers for IVF/intracytoplasmatic sperm injection [38]. Preoperative Evaluation and Diagnosis Multiple imaging methods have been used to delineate uterine anomalies. Because most women with uterine anomalies have normal external genitalia, most uterine anomalies are not apparent until the time of expected menarche or at work-up because of or pregnancy loss. Laparoscopy and Hysteroscopy Evaluation of the septate uterus is frequently performed via laparoscopy or hysteroscopy, in particular when the laparoscope is used to monitor the hysteroscopic performance of the metroplasty. This approach also enables evaluation of the adnexae and pelvic cavity for possible pelvic adhesions, tubal or ovarian distortions, and endometriosis that could be treated during the same session. The accuracy of these methods has been reported as 100%, and they have been the criterion standard in the evaluation of the septate and bicornuate uterus before and during metroplasty. Hysterosalpingography and Virtual Hysterosalpingography Hysterosalpingography (HSG) is the most accurate method of diagnosing a division of the uterine cavity.

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 27 Table 2 Outcome after abdominal metroplasty Source, year No. of patients Method Rock and Jones [62], 1977 Musich and Behrman [67], 1978 Mercer et al [68], 1981 Kessler et al [69], 1986 Candiani et al [70], 1990 Ayhan et al [71], 1992 Kirk et al [72], 1993 43 Bicornuate, septate, didelphys 21 12 Septate, 6 bicornuate, 3 arcuate 17 15 Septate, 1 bicornuate, 1 didelphys 17 4 Septate, 12 bicornuate, 1 didelphys 144 73 Septate, 2 bicornuate 89 49 Septate, 40 bicornuate 22 Patients, 44 Pregnancies Jones Tompkins, Jones, Strassman 15 Jones, 2 Strassman 13 Strassman, 3 Tompkins, 1 Jones 55 Tompkins, 6 Jones, 5 Te Linde, 5 Strassman 44 Jones, 40 Strassman, 5 Tompkins 18 Tompkins, 5 Jones, 3 Strassman Postoperative outcome a Complications 1 Intrauterine synechiae Pregnancy rate/no. of pregnancies 37/39 (58 pregnancies) Live-birth rate Term Preterm Abortion 41/58 42/58 4/58 12/58 NR 16/21 12/16 12/16 NA 14/16 NR 12/16 14/15 14/15 NA 1/15 NR 4 2/4 2/4 NA 2/4 NR 56 45/56 45/56 NR 11/56 NR 46 30/46 16/30 22/30 8/30 NR 44 33/44 31/44 4/44 9/44 NA 5 not applicable; NR 5 none reported. a When provided, listed outcomes are only for metroplasty to treat septate uterus. However, to avoid confusing the anomaly with a bicornuate uterus, laparoscopy or sonography is added to determine the external uterine configuration and to evaluate other tuboperitoneal factors. Diagnostic accuracy of HSG in differentiating septate from bicornuate uterus has been reported to be as low as 55%. Limitations of HSG also include exposure to ionizing radiation, postprocedural pain, and risk of pelvic inflammatory disease [39]. Virtual HSG is another imaging method that enables visualization of the uterine cavity, cervix, and fallopian tubes, and has several advantages over standard HSG. It seems to be better tolerated by patients, with less discomfort; offers minimal radiation exposure; and takes less time to complete. Furthermore, it provides a variety of visual findings such as coronal and sagittal multiplanar reconstruction. In addition, it gives a 3-D volume rendering and virtual endoscopic images, showing an inner view of the lumen of the uterine cavity, cervix, and fallopian tubes. It can accurately differentiate bicornuate uterus from septate uterus [40]. Ultrasonography Two-dimensional (2-D) ultrasonography is an excellent noninvasive method of evaluation of the uterine cavity and surrounding uterine walls. It has several advantages over HSG because no radiation is used, the procedure is not uncomfortable for the patient, it is quick, and it is relatively inexpensive. It can be used as the first line for evaluating the uterus. The sensitivity of 2-D ultrasonography in detecting uterine malformations ranges from 88% to 93% in some studies, and the specificity from 94% to 99%. The positive predictive value ranges from 50% to 55%, and the negative predictive value from 88% to 100%. For detection of the septate uterus, sensitivity has been reported as 81%. With the instillation of saline solution, the sensitivity of transabdominal ultrasonography increases to 56% to 92%, and specificity from 56% to 100% [41 44]. Three-dimensional ultrasonography can provide a coronal view of the uterine surface and contour, therefore adding

28 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 precision in the diagnosis and differentiation of bicornuate and septate uterus. Furthermore, the images obtained can be stored and evaluated later. Three-dimensional ultrasonography has been evaluated and proved reproducible for the diagnosis of uterine anomalies including uterine cavity measurements in all 3 dimensions. The accuracy of 3-D ultrasonography for detection of septate uterus has been reported as 92% and 100% for bicornuate uterus, with positive and negative predictive values of 100%. The combined use of hysteroscopic evaluation and 3-D ultrasonography seem to be a reliable and simple strategy to determine septate uterus for performance of metroplasty without laparoscopic investigation of the uterine fundus. Threedimensional ultrasonography may become the only method needed for assessment of the uterine cavity in patients with a suspected septate or bicornuate uterus before performing surgical correction [45 47]. The diagnostic value of 3-D sonohysterography (SHG) is comparable to hysteroscopy for detecting intrauterine lesions, and both are superior to 2-D SHG [48]. Sonohysterography By infusing saline solution into the uterine cavity as a contrast medium, excellent appraisal of the uterine cavity can be obtained, most useful in delineating uterine anomalies with sensitivity of 97% and specificity of 11%. When saline solution is infused into the uterine cavity, sensitivity increases to 98%, and specificity to 100%. Three-dimensional SHG is perhaps the most accurate imaging method for evaluation of septate uterus. In one study, compared with hysteroscopy, 3-D SHG had a sensitivity of 100% and a positive predictive value of 92% in diagnosing intrauterine lesions [48 52]. Magnetic Resonance Imaging Although MRI is not frequently used for evaluation of uterine anomalies because of its cost, its accuracy and lack of ionizing radiation make this method invaluable, in particular in difficult and complex situations and when HSG or sonography fail to provide the proper and precise diagnosis. Some septate uterus may not be well delineated via HSG or sonography or even via laparoscopy or hysteroscopy because one of the chambers of the divided cavity may not be enlarged and the entrance to the hemi-cavity may be obscured at hysteroscopy. In such situations, MRI becomes invaluable in establishing the diagnosis before metroplasty. In one report, MRI to detect intrauterine lesions had sensitivity of 100% and specificity of 79% [53 55]. It is important to evaluate other factors that may cause pregnancy wastage before surgically correcting septate uterus. A karyotype of both partners should be obtained, and normal maturation of the endometrium should be evaluated during the late luteal phase (days 21 23 of the cycle) via serum progesterone and transvaginal ultrasound to measure endometrial thickness in lieu of endometrial biopsy in the middle or late luteal phase, which has not proved reliable in predicting fertility [56]. Endocrine conditions such as hypothyroidism should be evaluated via a thyroid-stimulating hormone assay. Autoimmune conditions must be ruled out via a lupus anticoagulant factor study, partial thromboplastin time, and anti-cardiolipin antibodies. Alloimmune conditions should be evaluated only in selected individuals via tissue typing for histocompatibility leukocyte antigens. Chronic endometritis should be ruled out via endometrial biopsy [57 61]. Treatment of Uterine Septum Because the original metroplastic procedures via laparotomy paved the way to the modern approach via hysteroscopy, a brief review of those methods is in order. Abdominal Metroplasty The original surgical treatments of the septate uterus were all via laparotomy and hysterotomy and were performed only in habitual aborters. Noninvasive methods such as cerclage, bed rest, and tocolytic agents were frequently used to preserve the ongoing pregnancy before any surgical procedure was undertaken. Abdominal metroplasty procedures performed were of the Jones type, involving transfundal uterine excision of the septate uterus by removing a cuneiform portion of the fundal myometrium and septum with subsequent repair [62]. The other method used was the Bret-Tomkins metroplasty with division of the uterus in the anteroposterior plane and transverse division of the septum in the middle without excision of myometrial tissue. Both methods achieved 70% to 80% rate of viable pregnancies [63,64]. Nonetheless, because they required laparotomy and hysterotomy, abdominal metroplasty exposed the patient to formation of postoperative adhesions, prolonged recovery, and longer waiting time before attempting conception (3 6 months), with a mandatory cesarean section as the route of delivery in subsequent pregnancies [65]. In 1976, El Magoub [66] introduced another approach using small fundal, transverse incisions in the uterus along the septum and removal of the uterus transfundally using long scissors. However, this method did not gain much acceptance. Experience with and outcomes of abdominal metroplasty are given in Table 2. Hysteroscopic Metroplasty In 1884, Ruge [73] attempted transcervical division of septate uterus blindly; however, this technique did not gain clinical acceptance because of its blind approach. In 1974, Edstrom [74] attempted removal of a uterine septum using a biopsy forceps guided by hysteroscopy; in the following years, hysteroscopic scissors were introduced and markedly facilitated the procedure. The generally avascular central portion of the fibrotic septum, enhanced by uterine distention, facilitates its central division without substantial

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 29 Fig. 5 Hysteroscopic division of septum with semi-rigid scissors. bleeding. Furthermore, the hysteroscopic approach reduces the adverse effects and morbidity of the procedure, enabling prompt resumption of patient activities and earlier possibility of conception (4 5 weeks) after the procedure. Patients who conceive do not require mandatory cesarean section [75]. Hysteroscopic metroplasty can be accomplished via several methods including use of mechanical scissors; electrosurgery with specially designed electrodes fitted to the hysteroscope or resectoscope; vaporizing or bipolar electrodes; lasers of the fiber type such as the neodymium- YAG, the KTP-532, and the argon laser with extruded tips; and mechanical morcellators [76 83] (Figs. 5 7). The most commonly used instruments are the hysteroscopic scissors and the resectoscope fitted with an appropriately designed electrode. All require experience and knowledge of their properties and specific requirements in the use of uterine distending fluids and energies. Although the best time for performance of these procedures is in the early follicular phase when the endometrium is thin, alternatively they can be performed after hormone therapy Fig. 6 Resectoscopic division of uterine septum with knife-electrode. to artificially thin the endometrium, as with the use of gonadotropin-releasing hormone analogues. Concomitant laparoscopic or ultrasonic monitoring of the procedure is an option to increase safety and security during septal division. Other approaches to septal division have been described including use of fluoroscopy, sonographically guided septal division, and even tactile sensation guidance of a thin scissors [84 90]. However, these methods are less effective and precise, and because the uterus is not distended, it exposes the patient to significant intraoperative bleeding, which may be difficult to control except with tamponade and may prohibit completion of the treatment in one setting or stage. The results achieved with hysteroscopic metroplasty not only compare well with those of abdominal metroplasty, they seem to surpass them with an 80% to 90% rate of viable pregnancies in patients treated because of repeated abortion and no sequelae of secondary due to subsequent pelvic adhesions, as with laparotomy. Furthermore, the patient is spared the inconveniences of hospitalization, laparotomy and hysterotomy, mandatory cesarean section in future pregnancies, and cost [91,92]. It has been proposed that performance of hysteroscopic metroplasty be moved to the office setting to make it more acceptable to the patient and less invasive [93 95]. Nonetheless, although division of a uterine septum via hysteroscopy or resectoscopy is easy, in particular if it is partial and thin and the procedure can be performed in an ambulatory surgical center, certain precautions and availability of additional instrumentation are important such as those required for laparoscopy and supportive anesthesia personnel, should the need arise. These are important aspects of safety and supportive team measures that should be available to approach the procedure with Fig. 7 Hysteroscopic view of unified uterine cavity after hysteroscopic laser metroplasty.

30 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 Table 3 Adjunctive therapy and complications of hysteroscopic metroplasty Source, year No. of patients Technique Routine preoperative or postoperative therapy Danazol/ GnRH) Estrogen Progesterone IUD/Foley catheter Antibiotics Complications Valle and Sciarra 12 Flexible, semi-rigid 2 1 1 2 2 None [104], 1986 or rigid scissors Fayez [92], 1986 19 Rigid scissors 2 2 2 1 1 2 Perforations Corson and Batzer [105], 1986 18 Resectosocope 2 2 2 2 2 1 Perforation, 1 delayed postoperative bleed DeCherney et al 72 Resectoscope 1 2 2 1 2 1 Perforation [80], 1986 March and Israel [77], 1987 66 Flexible scissors 2 1 1 1 2 1 Perforation, 3 postoperative significant bleeding Perino et al 24 Semi-rigid scissors 2 1 1 1 2 None [106], 1989 Daly et al 51 Flexible scissors 2 1 1 2 2 None [107], 1989 Guarino et al 29 Semi-rigid scissors 2 2 2 1 2 None [108], 1989 Choe and Baggish [82], 1992 14 Nd:YAG laser 1 1 1 1 2 1 Perforation, 1 postoperative uterine synechiae Fedele et al 102 80 Semi-rigid scissors, 1 1 1 1 2 NR [110], 1993 10 argon laser, 12 resectoscope Marabini et al [111], 1994 26 Resectoscope 1 1 1 2 1 None Cararach et al [90], 1994 70 17 Hysteroscopic scissors, 53 resectoscope 1 2 2 2 2 3 Perforations, 1 pulmonary edema Colacurci et al 69 Resectoscope 1 2 2 2 2 None [112], 1996 Valle [109], 1996 124 98 Semi-rigid scissors, 20 resectoscope, 6 Nd: YAG laser 2 1 1 2 1 1 Admission because of possible pulmonary aspiration Romer and Lober 6 Resectoscope 2 1 2 2 2 1 Perforation [113], 1997 Jourdain et al 15 Nd:YAG laser with 2 2 2 2 1 None [114], 1998 flexible hysteroscopy Grimbizis et al 42 Resectoscope 1 1 1 2 2 2 Perforations [115], 1998 Porcu et al [116], 2000 56 55 Resectoscope, 5 Nd:YAG laser, 2 2 2 2 2 1 Perforation 1 abnormal bleeding 3 endoscopic scissors Venturoli et al 141 Resectoscope 1 2 2 2 2 None [117], 2002 Saygiili-Yilmaz 361 Resectoscope 2 2 2 2 2 None et al [118], 2002 Jakiel et al 31 Resectoscope 2 1 2 2 1 None [119], 2004 Pabuccu and Gomel 61 Resectoscope 2 2 2 2 2 None [34], 2004 Pace et al [120], 2006 40 Resectoscope, rigid scissors 1 2 2 2 1 None Hollett-Caines et al [121], 2006 Yang et al [122], 2006 26 6 Versapoint bipolar needle, 20 resectoscope 2 1 1 1 1 None 28 Nd:YAG laser 2 1 1 1 1 None (Continued)

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 31 Table 3 Continued Source, year Zlopasa et al [123], 2006 Colacurci et al [124], 2007 Litta et al [125], 2008 Mollo et al [126], 2009 Wang et al [127], 2009 Pai et al [128], 2009 Roy et al [129], 2009 Nouri et al [130], 2010 Sendag et al [131], 2010 Tonguc et al [35], 2011 No. of patients Technique Routine preoperative or postoperative therapy Danazol/ GnRH) Estrogen Progesterone IUD/Foley catheter Antibiotics 25 Resectoscope 2 2 2 2 2 None 135 70 Resectoscope, 65 Versapoint bipolar system 45 21 Resectoscope, 42 Versapoint bipolar system Complications 2 2 2 2 2 2 Significant intraoperative blood loss 2 2 2 2 2 2 Cervical lacerations 44 Resectoscope 2 2 2 2 2 None 18 Resectoscope 2 1 1 1 1 None 64 Resectoscope, Versapoint bipolar system 152 Hysteroscopic monopolar knife 2 1 1 2 2 None 2 1 2 2 1 2 Perforations, 1 cervical injury, 2 excessive bleeding 2 2 2 2 2 2 Uterine perforations 49 Monopolar electrosurgery 30 Resectoscope 2 1 2 2 2 None 102 Resectoscope 2 2 2 2 1 None GnRH 5 gonadotropin-releasing hormone; IUD 5 intrauterine device; Nd:YAG 5 neodynium:yttrium-aluminum-garnet; NR 5 none reported; 1 5 yes; 2 5 no. safety and efficiency. Although in some selected cases, hysteroscopic metroplasty may be performed in the office setting, the unpredictable nature of this type of procedure demands caution and selection to avoid failure, frustration, and possible complications. Furthermore, health regulations at local, state, and national levels for performance of surgical procedures in the office setting should be respected and followed. Role of Various Adjuncts Before and After Metroplasty Prophylactic Antibiotic Therapy Although various antibiotic regimens are used perioperatively with hysteroscopic metroplasty, no prospective randomized studies have been performed to demonstrate their efficacy. Hormone Therapy Because hysteroscopic metroplasty is ideally performed in the early follicular phase of the menstrual cycle, when the endometrium is thin, occasionally hormone therapy may be required, and among the various options, gonadotropin-releasing hormone analogues are well suited for this task [96,97]. Postoperative hormone therapy using estrogen and terminal progesterone is controversial because their efficacy has not been demonstrated in well-designed, prospective, randomized studies. Nonetheless, artificial stimulation of endometrial growth postoperatively may assist in the overall healing process by artificially enhancing endometrial growth by use of estrogen and subsequent shedding by use of terminal progesterone, paving the way to normal endometrial growth and subsequent spontaneous ovulation. Once withdrawal bleeding occurs, the uterine cavity is evaluated at HSG, hysteroscopy, or ultrasonography to assess its symmetry and normality [98]. The HSG has the advantage of enabling inspection of the uterine cavity in a perpendicular axis and direction, as compared with hysteroscopy, which evaluates the uterine cavity from a cervical axis, therefore better appraising symmetry of the uterine cavity. However, ultrasonography is gaining in acceptance because it enables evaluation not only of the uterine cavity but also the entire uterine body. Stents The use of stents postoperatively to prevent formation of adhesions was an adaptation of the treatment used for intrauterine adhesions. However, being of different pathophysiology and manner of healing, stents never were adopted as

32 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 Table 4 Uterine rupture after hysteroscopic metroplasty Source, year Patient age, yr Method of metroplasty Uterine perforation recognized Time from metroplasty to pregnancy Gestational age at rupture, wk Israel and March [156], 1984 25 Scissors No 2 Mo 39 a Creinin and Chen [157], 1992 36 Resectoscope Yes 5 Mo 37 (twin gestation) Howe [158], 1993 29 Rigid scissors Yes 12 Mo 33 Halvorson et al [159], 1993 29 Scissors Yes 1 Mo 19 Lobaugh et al [160], 1994 29 KTP laser No 1.6 Yr 32 Tannous et al [161], 1996 36 Resectoscope Yes 2 Mo 39 Alatas et al [162], 1998 27 Resectoscope No 18 Wk 33 (placenta accreta) Gabriele et al [163], 1999 31 Scissors with electrosurgery Yes 11 Mo 37 (rupture during induction of labor) Chokri et al [164], 2000 38 Resectoscope No 2 Yr 35 b Angell et al [165], 2002 NR Rigid scissors No NR 37 Kerimis et al [166], 2002 37 Scissors with No 3 Mo 41 (spontaneous labor) electrosurgery Conturso et al [167], 2003 28 Resectoscope Yes 12 Mo 28 Ducarme et al [168], 2003 22 Resectoscope No 1 Yr 32 Kucera et al [169], 2005 20 Resectoscope Yes 14 Mo 40 (rupture during labor) Sanchez et al [170], 2005 32 Resectoscope Yes 17 Mo 37 Satiroglu et al [171], 2009 30 Resectoscope No 2 Mo 29 Gultekin et al [172], 2012 26 Resectoscope No 8 Mo 37 (cesarean section, fetus alive) 26 Resectoscope No 11 Mo 34 (cesarean section, fetus dead) NR 5 not reported. a At 18 months after uterine rupture and repair, the patient became pregnant, and delivered at term via elective cesarean section. b At 7 months after uterine rupture and repair, the patient became pregnant; however, at 27 weeks, uterine rupture occurred again. a standard treatment after metroplasty. The postoperative use of intrauterine devices, catheters, inflated balloons, and such has been found to be unnecessary because division of the uterine septum does not lead to formation of adhesions. When fundal defects are discovered postoperatively, they usually are due to remnants of septal tissue left behind [99 102]. Anti-adhesive Agents Many attempts have been made to place gels and other anti-adhesive substances in the uterine cavity after metroplasty; nonetheless, contrary to intrauterine adhesions, their use seems unnecessary because of the high potential for regeneration innate in normal endometrium [103]. Experience with adjunctive therapy with metroplasty are given in Table 3. Healing of the Uterus After Hysteroscopic Metroplasty The high regenerative capacity of the normal endometrium helps in the healing process of the defect from septal division. Fedele et al [132] demonstrated the centripetal and centrifugal directions of the endometrial repair that occurs after division of the uterine septum. At 13 days after the procedure, they studied, via light microscopy and scanning electron microscopy, the histologic changes of the defect left after resection of the septum. Re-epithelialization of the defect proceeded centripetally via proliferation of the surrounding endometrium and centrifugally from the bottom of the glands present at the center, therefore expediting repair [132]. Candiani et al [133] further studied healing of the uterus after hysteroscopic metroplasty via multiple biopsy samples obtained after surgery in 19 women. Complete healing occurred within 8 weeks after metroplasty [133]. Treatment of Complete Septate Uterus With Septate Cervix Treatment of complete septate uterus with septate cervix may be somewhat more challenging than treatment of the corporeal septum alone [109,113,134 137]. With the background of the embryologic origin of the uterus and arrest of reabsorption of the medial septum, the complete septum is thinner in the lower segment, close to the internal cervical os, where the original reabsorption begins. Therefore, by inserting a probe or indwelling catheter through one of the cervical openings and just above the internal cervical os, the area is made to slightly bulge into the opposite uterine chamber of the divided cavity, and fenestration is performed using either a hysteroscopic scissors or an electrode guided by the resectoscope introduced in the opposite chamber of the

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 33 divided cavity. The indwelling catheter is slightly deflated and pulled down to occlude the hemi-cavity, or if a probe has been used, the probe is removed after fenestration, and the cervix on that side is occluded using a tenaculum to enable better uterine distention without reflux of the distention medium. The reminder of the corporeal septal division is then completed. An alternative treatment of a complete septate uterus with septate cervix is to remove the cervical septum first, using a straight scissors and with division of the corporeal septum using a resectoscope [138]. The results obtained using this method apparently have been satisfactory, with no untoward sequelae such as bleeding or incompetent cervix. However, experience and follow-up are limited, and more experience is needed before accepting routine use of this method, in particular with a thick septum. Nonetheless, this method is a good alternative when preservation of the cervical septum is difficult or fenestration of the corporeal septum fails, rather than proceeding with abdominal metroplasty. Vercellini et al [139] proposed resecting initially the cervical portion of the septum using a straight scissors and then proceeding with division of the corporeal septum via endoscopy. Although the results of this method have been satisfactory, it should be approached with caution, in particular when the cervical septum is thick, because bleeding may occur, and the possibility of an incompetent cervix should also be kept in mind [140,141]. Endoscopic Treatment of Bicornuate Uterus or Strassman Metroplasty Bicornuate uterus is a defect that results from lack of fusion of the m ullerian ducts and can be the cause of pregnancy wastage. The original treatment proposed by Strassman was laparotomy and hysterotomy. A transverse uterine fundal incision between the round ligaments is made to divide the uterine fundus until the uterine cavity is entered; then the incision is closed anteroposteriorly. Attempts have been made to perform this operation less invasively by using endoscopes. The methods used are laparoscopy alone or laparoscopy and hysteroscopy with or without the aid of minilaparotomy for closure of the defect. With the laparoscope in place and using the resectoscope, the uterine nadir of the defect is divided transversally until the serosal layer is observed; then the transverse incision is performed laparoscopically until the uterine cavity is reached. The repair anteroposteriorly is then completed via laparoscopy. Because of the difficulty of achieving a secure closure at laparoscopy, mini-laparotomy can be performed and the uterine repair completed through this small incision. However, these techniques have not been used frequently, and experience with their use is limited [142 145]. Occasionally, bicornuate uterus is combined with the septum, and the treatment, if required, does not vary from that of the septum alone; however, it benefits from concomitant laparoscopic or ultrasonographic monitoring to prevent inadvertently entering the muscular layer of the uterine wall [146]. Early and Late Complications of Hysteroscopic Metroplasty As with any surgical procedure, hysteroscopic metroplasty may have its complications. These include bleeding, fluid overload, uterine perforation, formation of adhesions, and uterine rupture in subsequent pregnancy. Bleeding Bleeding during hysteroscopic metroplasty can occur, in particular if uterine distention is insufficient to adequately visualize the septum and enable the accompanying vessels from the uterine wall to be deflected from the central portion of the uterine septum. In addition, risk of bleeding is increased if the operator drifts close to the uterine wall rather than keeping the division in the midline portion of the septum. Postoperative bleeding may occur when the procedure is performed in the luteal phase of the menstrual cycle rather than in the early follicular phase, sometimes mixing with impending menstruation [147,148]. Fluid Overload Excessive fluid absorption may occur if the duration of the operation is prolonged and intake and output of the fluids used is not closely monitored. This is especially important during monopolar electrosurgery because the fluids used are devoid of electrolytes, potentially triggering hyponatremia [149 151]. Uterine Perforation Division of the uterine septum requires awareness of the uterine anatomy, and some type of monitoring of the procedure is advantageous to prevent uterine perforations, if not totally, at least substantially decreased. Laparoscopy will help to assess the diaphanoscopy or translucency of the hysteroscopic/resectoscopic light through the uterine wall and will also aid in evaluation of the adnexae and pelvic cavity for additional deleterious factors such as adhesions and endometriosis that can be treated concomitantly. In addition, it can warn the hysteroscopist early of possible perforation [152]. An alternative to laparoscopy is sonography, which can warn of deep penetration of the dissection into the myometrium and possible perforation [153]. Postoperative Intrauterine Adhesions Postoperative intrauterine adhesions have not been a problem with hysteroscopic metroplasty when the procedure is performed systematically and completely without leaving untreated septal remnants that can be confused with adhesions at subsequent examinations.

Table 5 Reproductive outcome after hysteroscopic metroplasty Source, year Valle and Sciarra [104], 1986 Canadian task force classification No. of patients Technique Indication Pregnancy rate II-3 12 Flexible, semi-rigid and rigid scissors Fayez [92], 1986 II-1 19 Rigid scissors primary Corson and Batzer [105], 1986 DeCherney et al [80], 1986 March and Israel [77], 1987 Perino et al [106], 1987 III 18 Resectoscope DES-related malformation Recurrent miscarriage 10/12 7/12 (3 ongoing) Live-birth rate Term Preterm Abortion 5/10 2/10 2/10 16/19 14/19 14/16 NA 2/16 13/18 (17 pregnancies) II-3 72 Resectoscope Recurrent miscarriage 67/72 58/72 (5 ongoing) III 79 (66 Flexible scissors III 24 Semi-rigid scissors Daly et al [107], 1989 III 70 (60 Guarino et al [108], 1989 Choe and Baggish [82], 1992 II-3 35 (29 III 19 (14 Flexible scissors Semi-rigid scissors Nd:YAG laser with bare or sculpted fibers Fedele et al [110], 1993 III 102 80 Semi-rigid scissors, 10 argon laser, 12 resectoscope Marabini et al [111], 1994 III 40 (26 Resectoscope Cararach et al [90], 1994 II-1 81 (70 Colacurci et al [112], 1996 17 Hysteroscopic scissors, 53 resectoscope primary primary, dysmenorrhea III 69 Resectoscope primary Valle [109], 1996 III 124 98 Semi-rigid scissors, 20 resectoscope, 6 Nd:YAG laser Romer and Lober [113], 1997 Kupesic and Kurjak [175], 1998 III 6 Resectoscope III 116 Operative hysteroscopy, secondary, spontaneous abortion, preterm delivery Jourdain et al [114], 1998 III 17 (15 Nd:YAG laser with flexible hysteroscopy 57/66 (63 pregnancies) 11/18 10/13 1/13 2/13 48/63 (7 ongoing) 16/24 14/24 (1 lost to follow-up) 47/51 (79 pregnancies) 58/79 (4 ongoing) 22/29 13/29 (4 ongoing) 13/15 10/15 (3 ongoing) 58/67 NA 4/67 44/63 4/63 8/63 14/16 NA 1/16 55/79 5/79 15/79 13/22 1/22 4/22 10/15 1/15 1/15 66/102 55/102 45/66 10/66 11/66 19/26 13/26 (4 ongoing) 13/15 13/15 0/15 51/70 29/70 29/51 29/51 NA (10 ongoing) 46/69 36/69 31/46 31/46 5/46 (4 ongoing) 101/124 91/124 84/101 84/101 7/101 3/6 3/6 3/3 3/3 NA 59/116 48/116 44/59 44/59 4/59 12/15 10/15 10/12 10/12 NA 34 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013

Grimbizis et al [115], 1998 III 57 (42 Resectoscope Porcu et al [116], 2000 III 56 55 Resectoscope, 5 Nd:YAG laser, 3 endoscopic scissors Preutthipan and Linasmita [176], 2001 Venturoli et al [117], 2002 Saygiili-Yilmaz et al [118], 2002 III 28 (19 7 Scissors, 10 Versapoint system, 11 resectoscope Infertility, spontaneous abortion II-3 141 Resectoscope II-3 361 Resectoscope Recurrent miscarriage 19 patients (20 pregnancies) 30/42 (44 pregnancies) 30/42 28/44 28/44 2/44 45/56 28/56 26/43 26/43 2/43 (2 ongoing) 15/20 (2 ongoing) 15/20 15/20 0/20 92/141 57/141 45/92 45/92 12/92 (14 ongoing) 180/361 135/361 117/180 117/180 34/180 Jakiel et al [119], 2004 III 26 Resectoscope Infertility 18/31 10/31 7/18 7/18 4/18 Pabuccu and Gomel III 61 Resectoscope Primary 25/61 18/61 13/25 13/25 5/25 [34], 2004 Pace et al [120], 2006 III 75 (40 Resectoscope, semi-rigid scissors, preterm delivery 30/40 27/40 22/30 22/30 5/30 Hollett-Caines et al [121], 2006 III 26 6 Versapoint bipolar, 19 resectoscope, 1 Nd: YAG laser Yang et al [122], 2006 III 45 (28 Zlopasa et al [123], 2007 Colacurci et al [124], 2007 Nd:YAG laser, preterm delivery III 25 Resectoscope Recurrent miscarriage 25 patients (52 pregnancies) I 180 (135 Litta et al [125], 2008 II-1 63 (45 followed up) Mollo et al [126], 2009 Wang et al [127], 2009 70 Resectoscope, 65 Versapoint bipolar 21 Resectoscope, 42 Versapoint bipolar primary 21/26 15/26 12/21 12/21 3/21 20/28 16/28 16/20 16/20 NR 32/52 23/52 23/52 9/52 99/135 82/135 66/99 66/99 16/99 Spontaneous abortion 36/45 27/45 22/36 22/36 5/36 II-1 44 Resectoscope Infertility 17/44 15/44 12/17 12/17 3/17 III 25 (18 Resectoscope Paietal[128], 2009 III 64 Resectoscope, Versapoint bipolar Roy et al [129], 2009 III 152 Hysteroscopic monopolar knife Nouri et al [130], 2010 Sendag et al [131], 2010 Tonguc et al [35], 2011 III 64 (49 Monopolar electrosurgery 15/18 6/18 (7 ongoing) 5/15 5/15 1/15 Infertility 33/64 29/64 24/33 24/33 5/33, preterm delivery 142/152 (186 pregnancies) 162/186 148/186 148/186 14/186 34/49 24/49 15/34 15/34 9/34 III 30 Resectoscope Spontaneous abortion, 20/30 13/30 11/20 11/20 2/20 preterm delivery II-1 102 Resectoscope Infertility 44/102 36/102 31/44 31/44 8/44 DES 5 diethylstilbestrol; NA 5 not available; Nd:YAG 5 neodynium:yttrium-aluminum-garnet; NR 5 not reported. Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 35

36 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 Fig. 8 Pregnancy rate after hysteroscopic metroplasty. Initial meta-analysis was performed on all studies (groups 1 and 2) with pregnancy rate reported as percentage. After excluding studies with inconsistent definition of pregnancy rate (i.e., all post-metroplasty pregnancies reported, not just index pregnancy) and studies with a substantial number of subjects lost to follow-up or with ongoing pregnancies, a second analysis was performed on the clean studies (group 1). Statistics for each study Source, Year Event 95% CI Z Value p Value Rate (%) Group 1 Fayez, 1966 8.42 6.08 9.48 2.67.008 Fedele et al, 1993 6.47 5.50 7.33 2.93.003 Valle, 1996 8.15 7.36 8.74 6.40 0 Romer and Loper, 1997 5.00 1.68 8.32 0.00 0 Kupesic and Kurjak, 1998 5.09 4.18 5.98 0.19 8.5 Jourdain et al, 1998 8.00 5.30 9.34 2.15.03 Saygiili-Yilmaz et al, 2002 4.99 4.47 5.50 0.05.96 Jakiel et al, 2004 5.81 4.04 7.39 0.89.37 Pabuccu and Gomel, 2004 4.10 2.94 5.36 1.40.16 Pace et al, 2006 7.50 5.95 8.60 3.10.003 Hollet-Caines et al, 2006 8.08 6.13 9.18 2.88.004 Yang et al, 2006 7.14 5.24 8.50 2.19.03 Colacurci et al, 2007 7.33 6.53 8.01 5.20 0 Litta et al, 2008 8.00 6.58 8.93 3.72 0 Mollo et al, 2009 3.86 2.56 5.36 1.50.14 Pai et al, 2009 5.16 3.95 6.35 0.25.80 Nouri et al, 2010 6.94 5.53 8.06 2.64.008 Sendag et al, 2010 6.67 4.84 8.10 1.79.07 Tonguc et al, 2011 4.31 3.39 5.29 1.38.17 6.35 5.66 6.99 3.78 0 Group 2 Valle, 1986 8.33 5.23 9.58 2.08.04 Decherney et al, 1986 9.31 8.44 97.1 5.60 0 Perino et al, 1987 6.67 4.61 8.24 1.60.11 Guarino et al, 1989 7.59 5.73 8.80 2.64.008 Choe and Baggish, 1992 8.67 5.95 9.66 2.46.01 Marabini et al, 1994 7.31 5.33 8.66 2.26.02 Cararach et al, 1994 7.29 6.13 8.20 3.67 0 Colacurci et al, 1996 6.67 5.48 7.67 2.71.007 Porcu et al, 2000 8.04 6.79 8.88 4.19 0 Venturoli et al, 2002 6.52 5.70 7.26 3.56 0 7.61 6.77 8.29 5.41 0 Overall 6.78 6.25 7.28 6.17 0 Event Rate and 95% CI -1.00-0.50 0.00 0.50 1.00 Favors A Favors B Uterine Rupture With Subsequent Pregnancy The literature includes 18 confirmed reports of uterine rupture during pregnancy or delivery after hysteroscopic metroplasty (Table 4). All describe some complication during the procedure such as excessive or overzealous excision, with substantial penetration of the myometrium and even perforation of the uterine wall, and excessive use of electrosurgical or laser energy [154 172]. Therefore, regardless of the treatment method used, meticulous attention to technique should always be exercised. Published Surgical Results of Hysteroscopic Metroplasty and Their Level of Evidence Many reports in the literature have detailed the salutary effects of treatment of septate uterus on subsequent reproduction[173,174]. However, all have uniformly used the patients as their own control, without prospective randomization or sufficient number of patients for comparison of treatment vs no treatment. Nonetheless, the accumulated experience and favorable results indicate the beneficial effect of surgery. Thus, perhaps a prospective randomized study comparing treatment vs no treatment becomes moot or even unnecessary because it would be difficult to perform due to the ethical implications and willingness of patients to participate in a randomized trial because of the urgency sometimes associated with childbearing. The overall rate of pregnancy and viable pregnancies after surgery is 80% to 90% (Table 5). Meta-analysis of Reproductive Outcomes After Hysteroscopic Metroplasty We identified studies that reported outcomes after hysteroscopic metroplasty from 1986 to 2011 by performing an extensive search of Medline and by hand searching cross-references and review articles. Keywords used in the

Valle and Ekpo. Hysteroscopic Metroplasty for Septate Uterus 37 Fig. 9 Live-birth rate after hysteroscopic metroplasty. Initial meta-analysis was performed on all studies (groups 1 and 2) with live-birth rate reported as percentage. After excluding studies with inconsistent definition of pregnancy rate (i.e., all post-metroplasty pregnancies reported, not just index pregnancy) and studies with a substantial number of subjects lost to follow-up or with ongoing pregnancies, a second analysis was performed on the clean studies (group 1). Statistics for each study Source, Year Event 95% CI Z Value p Value Rate (%) Group 1 Fayez, 1966 7.37 5.02 8.86 1.98.048 Fedele etal, 1993 5.39 4.42 6.33.79.43 Valle, 1996 7.34 6.49 8.04 4.50 0 Romer and Loper, 1997 5.00 1.68 8.32 0 1.00 Kupesic and Kurjak, 1998 4.14 3.28 5.05 1.85.07 Jourdain et al, 1998 6.67 4.06 8.54 1.27.21 Saygiili-Yilmaz et al, 2002 3.74 3.26 4.25 4.74 0 Jakiel et al, 2004 3.23 1.83 5.03 1.93.49 Pabuccu and Gomel, 2004 2.95 1.94 4.21 3.10.002 Pace et al, 2006 6.75 5.17 8.01 2.17.03 Hollet-Caines et al, 2006 5.77 3.85 7.48.78.44 Yang et al, 2006 5.71 3.87 7.38.75.45 Colacurci et al, 2007 6.07 5.23 6.86 2.48.01 Litta et al, 2008 6.00 4.52 7.31 1.33.18 Mollo et al, 2009 3.41 2.17 4.91 2.07.04 Pai et al, 2009 4.53 3.36 5.75 7.49.45 Nouri et al, 2010 4.90 3.54 6.27 0.14.89 Sendag et al, 2010 4.33 2.71 6.12 0.73.47 Tonguc et al, 2011 3.53 2.67 4.50 2.93.003 5.02 4.34 5.71 0.07.95 Group 2 Valle, 1986 7.78 4.21 9.44 1.56.12 Decherney et al, 1986 8.66 7.62 9.29 5.20 0 Perino et al, 1987 6.09 4.02 7.82 1.03.30 Guarino et al, 1989 5.20 3.31 7.04 2.00.84 Choe and Baggish, 1992 8.33 5.23 9.58 2.08.04 Marabini et al, 1994 5.91 3.82 7.72 0.85.40 Cararach et al, 1994 4.83 3.61 6.08 0.26.80 Colacurci et al, 1996 5.54 4.32 6.69 0.87.39 Porcu et al, 2000 5.19 3.87 6.47 0.27.79 Venturoli et al, 2002 4.49 3.65 5.36 1.15.25 6.03 5.03 6.94 2.02.04 Overall 5.35 4.78 5.91 1.20.23 Event Rate and 95% CI -1.00-0.50 0.00 0.50 1.00 Favors A Favors B search included hysteroscopy, metroplasty, uterine septum, recurrent miscarriage,, and uterine anomalies. No randomized controlled trials were identified; thus, all included studies in the meta-analysis were categorized as Canadian Task Force classification II or III. The outcome measures of interest were pregnancy rate and live-birth rate after hysteroscopic metroplasty. Studies were excluded if both outcome measures were not reported or if full article text could not be obtained. To avoid duplication, studies describing the same study population were included only once. We did not include studies of hysteroscopic metroplasty in patients undergoing IVF. Data were extracted by one of us (G.E.E.) with population information including number of patients, indication, and interventional technique (Table 5). The data were then analyzed using Comprehensive Metaanalysis software (version 2; Biostat, Inc., Englewood, NJ). After eliminating studies using exclusion criteria as described above, 29 studies remained and were used for initial meta-analysis (groups 1 and 2). Given the substantially different populations, a random-effects model was used for the calculations. The calculated overall pregnancy rate was 67.8% (95% confidence interval [CI], 62.5 72.8), and live birth rate was 53.5% (95% CI, 47.8 59.1) (Figs. 8 and 9). There was significant heterogeneity between studies (p,.01). Significant within study variability was also noted. After eliminating 10 studies in which the reported pregnancy rate included more than 1 pregnancy per patient and/or unreliable live-birth rates as a result of patients being lost to follow-up before giving birth, a second analysis was performed of the remaining 19 clean studies (group 1), which showed a lower overall pregnancy rate of 63.5% (95% CI, 56.6 69.9) and live-birth rate of 50.2% (95% CI, 43.4 57.1) (Figs. 8 and 9). This difference is not surprising inasmuch as some studies in the larger group likely reported falsely elevated pregnancy rates because subsequent pregnancies in the same subject were included in the pregnancy

38 Journal of Minimally Invasive Gynecology, Vol 20, No 1, January/February 2013 rate and also because the live-birth rate was reported as the number of births divided by this exaggerated number of pregnancies. The test of heterogeneity using subgroup analysis was significant when calculating the pregnancy rate (p 5.02); thus, the reported event rates (63.5% pregnancy rate and 50.2% live-birth rate) from group 1 are more reliable. In a review of 12 published retrospective studies, Homer et al [32] compared reproductive outcome before and after hysteroscopic surgery. Such comparison is less than ideal, but showed a pooled postoperative pregnancy rate of 80% in women with miscarriage or. In addition, the term birth rate increased from 0% to 7% to 73% to 100% after the operation. In another systematic review and pooled analysis of 1501 women in 18 studies, Nouri et al [130] reported an overall pregnancy rate of 60.1% and a live-birth rate of 45% after hysteroscopic metroplasty, which is similar to findings from our meta-analysis. The present meta-analysis is limited by predominantly observational studies because there are no published prospective randomized trials that compared metroplasty with no intervention, which could provide the highest level of evidence. The realities of performing a randomized controlled trial and the possible ethical implications leave only observational studies for analysis and interpretation. Methods were quite varied in the selected studies despite an attempt to define clear inclusion criteria, and indications also varied. Some studies contained inconsistent follow-up data, with findings published before reaching the outcome of live birth in some individuals, which could be a source of confounding bias. No comparisons of pregnancy and live birth rates before metroplasty were made. Perhaps the most important inference from this metaanalysis is the clinical heterogeneity within and between studies. This reflects the controversy in the indications for performing hysteroscopic metroplasty, with current indications ranging from history of R1 pregnancy loss to preterm labor, unexplained, and even removal of identified septum in the absence of any adverse pregnancy outcomes. A random-effects model was used for the calculations to adjust for this heterogeneity, and perhaps inclusion of different populations enables generalization to a broader range of patients. On the basis of data from the current literature, findings from our descriptive meta-analysis show a 63.5% pregnancy rate and a 50.2% live-birth rate after hysteroscopic metroplasty of septate uterus. These rates may certainly be higher in subjects with exclusively recurrent miscarriages in whom their septum has been removed, and lower in those with other causes of. The focus of further research studies should be on specific populations with clear indications, to draw reasonable and meaningful conclusions about the outcomes of hysteroscopic metroplasty. Adequate time after the procedure should be allowed so that subjects have ample time to attempt conception and also to give birth, to allow for accurate live-birth rate calculations. Future of Hysteroscopic Metroplasty Innovations in instrumentation and safe energy sources will continue to improve the safety and simplicity of hysteroscopic metroplasty. The hysteroscopic scissors should be made sturdier without compromising diameter and semirigidity. They also should maintain their ability to cut after several uses. On the horizon is the introduction of endoscopes that are also capable of sonographic evaluation with sufficient resolution and penetration to aid in the safe, precise, and efficient division of the uterine septum, eventually simplifying the procedure and adding precision to its performance. These and other advances may eventually become reality, even further simplifying hysteroscopic metroplasty. Summary and Conclusions Septate uterus resulting from failure of reabsorption of the embryologic original fusion of the m ullerian ducts may impair reproductive function in 20% to 25% of women with this anomaly. When this occurs, the septum may be amenable to surgical correction now performed via hysteroscopic or resectoscopic division. The limitations and inconveniences of laparotomy and hysterotomy are thus averted, and preservation of the integrity of the uterine walls does not require cesarean section in subsequent viable pregnancies. Hysteroscopic treatment of a symptomatic septate uterus can be accomplished via various methods including scissors, electrosurgical electrodes guided through the hysteroscope, or resectoscopy, which are the most commonly used methods. Fiber lasers have been used, although their use has markedly decreased because of cost and the simplification of electrosurgery using vaporizing and bipolar electrodes. Mechanical morcellators have also been tried, although the shape of the morcellators does not seem to surpass the available electrosurgical electrodes and the mechanical hysteroscopic scissors. In patients with a history of reproductive failure manifested by repeated abortions, it is important to rule out other potential causes such as genetic, metabolic, and endocrine abnormalities before proceeding with surgical treatment. The results achieved with hysteroscopic metroplasty surpass those of previous invasive abdominal metroplasty procedures, with a rate of viable pregnancies.80% in patients with a history of repeated abortion. It is expected that in the future, research will focus on specific populations with clear indications, to draw meaningful conclusions on the outcomes of hysteroscopic metroplasty. Although no prospective randomized studies have been performed with an adequate number of patients to demonstrate the efficacy of treatment vs no treatment, the overall success reported indicates its efficacy and reaffirms the place of minimally invasive treatment such as hysteroscopic metroplasty as the criterion standard and method of choice for treatment of this septate uterus.

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