Review of Intrauterine Adhesions

Transcription

1 Review Article Review of Intrauterine Adhesions Rebecca Deans, MBBS, MRANZCOG, and Jason Abbott, B MED (Hons), MRCOG, FRANZCOG, PhD* From the Department of Gynaecology, Royal Hospital for Women, and School of Women s and Children s Health, University of New South Wales, Randwick, New South Wales, Australia. ABSTRACT Keywords: This article has been produced to review the literature on symptomatic and asymptomatic intrauterine adhesions. Electronic resources including Medline, PubMed, CINAHL, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Current Contents, and EMBASE were searched using the Medical Subject Headings (MeSH), including all subheadings, and the keywords Asherman syndrome, Hysteroscopic lysis of adhesions, Hysteroscopic synechiolysis, Hysteroscopy and adhesion, Intrauterine adhesions, Intrauterine septum and synechiae, and Obstetric outcomes after intrauterine surgery. The vast majority of evidence in the literature consists of uncontrolled case series, with only intrauterine adhesion barriers being assessed in a randomized controlled format. This article reviews epidemiology, pathologic features, classification systems, and treatments. Seven classification systems are described, with no universal acceptance of any one system and no validation of any of them. Hysteroscopy is the mainstay of both diagnosis and treatment, with medical treatments having no role in management. There is a wide range of treatment techniques with no controlled comparative studies, and assessments are descriptive and report fertility and menstrual outcomes, with more severe adhesions having the worst clinical outcomes. One of the most important features of treatment is prevention of recurrence, with the best available evidence demonstrating that newly developed adhesion barriers such as hyaluronic acid show promise for preventing new adhesions. Journal of Minimally Invasive Gynecology (2010) 17, Crown Copyright Ó 2010 Published by Elsevier Inc. on behalf of the AAGL. All rights reserved. Asherman syndrome; Hysteroscopic treatment of adhesions; Hysteroscopic synechiolysis; Hysteroscopy; Intrauterine adhesions Recognition that organic intrauterine adhesions can lead to secondary amenorrhea has been demonstrated since the end of the 19th century [1], although not until 1948, when Joseph Asherman described the eponymous condition in 29 patients, did the syndrome became popularized and treatment described. Asherman s original description related to postpregnancy intrauterine adhesions in all cases, and such adhesions remain the commonest cause of this syndrome. Asherman expanded his original thoughts, and related endometrial trauma and adhesion formation to menstrual disturbance, cyclical pelvic pain, and subfertility including recurrent pregnancy loss [2]. Important in his description was that the adhesions seemed to have an inherent effect on the endometrium, The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. Corresponding author: Jason Abbott, MB, BS, Royal Hospital for Women, University of New South Wales, Barker St, Randwick, 2031 New South Wales, Australia. j.abbott@unsw.edu.au Submitted December 18, Accepted for publication April 30, Available at and causing it to be quiescent, rather than the adhesions causing clinical effect merely by obstruction. The terms Asherman syndrome and intrauterine adhesions are often used interchangeably, although the syndrome requires the constellation of signs and symptoms (e.g., pain and menstrual disturbance) in the presence of intrauterine adhesions. When the signs and symptoms are present in women with intrauterine adhesions not caused by pregnancy, the term Asherman syndrome should be applied, despite this being outside of the original description [3]. Given these conditions, the diagnosis of Asherman syndrome can be made in women with a uterus during their reproductive lifetime, whereas the diagnosis of intrauterine adhesions can be made in women with a uterus at any time during their life. It is important to differentiate intentional intrauterine adhesions such as those produced from endometrial ablation in any of its various forms as treatment of dysfunctional uterine bleeding to intrauterine adhesions that come to clinical attention because of symptoms. Intentionally induced intrauterine adhesions and asymptomatic intrauterine adhesions do not require any treatment and are not considered further in this review except when comparative data may be necessary /$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Inc. on behalf of the AAGL. All rights reserved. doi: /j.jmig

2 556 Journal of Minimally Invasive Gynecology, Vol 17, No 5, September/October 2010 Data Sources This review was produced by searching electronic resources including Medline, PubMed, CINAHL, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Current Contents, and EMBASE. The Medical Subject Headings (MeSH) included all subheadings, and keywords included Asherman syndrome, Hysteroscopic lysis of adhesions, Hysteroscopic synechiolysis, Hysteroscopy and adhesions, Intrauterine adhesions, Intrauterine septum and synechiae, and Obstetric outcomes after intrauterine surgery. Epidemiology The true incidence of intrauterine adhesions is unknown because a large number of patients with intrauterine adhesions have no symptoms [3]. The prevalence varies with geographic location, the population being studied, and the availability of investigations for diagnosis. Most early reports were summarized in a 1982 review by Schenker and Margalioth [4], and suggested geographic variations in intrauterine adhesions, with increased awareness, differences in instrumentation (sharp, blunt, or suction curettage), presence of genital tuberculosis, and availability of therapeutic termination of pregnancy cited as possible causes [3]. Such variations have not been reported in the last 20 years, with prevalence varying between 0.3% as an incidental finding in women undergoing intrauterine device placement without gynecologic symptoms to 21.5% in women who have undergone postpartum curettage [4]. It is possible that greater recognition of the condition and the more widespread use of hysteroscopy and noninvasive means of diagnosis such as sonography have caused an increase in the diagnosis of intrauterine adhesions [5]. From 1894 to 1982, there were 1250 cases reported for treatment of intrauterine adhesions, and from 1982 to 2008, more than 2500 cases have been reported in the literature. Performance of both a greater number and increasingly complex uterine surgical procedures in an expanding world population may be contributing to a higher number of reported cases, which may not necessarily represent a true increase in prevalence. Histopathologic Features Asherman syndrome causes endometrial fibrosis in which the stroma is largely replaced with fibrous tissue and the glands are replaced by inactive cubocolumnar endometrial epithelium. The functional and basal layers are indistinguishable, with the functional layer replaced by an epithelial monolayer unresponsive to hormonal stimulation, and fibrotic synechiae forming across the cavity [6]. The tissue is usually avascular, although thin-walled telangiectatic vessels can be observed. Calcification or ossification can occur in the stroma, and the glands may be sparse and inactive or cystically dilated [6]. The resulting intrauterine adhesions may involve different layers of the endometrium, myometrium, or connective tissue. When full thickness, adhesions may be composed of collagen bundles, fibrous strips, or muscle with the same characteristics as normal myometrium [6]. Biopsy specimens from patients with intrauterine adhesions compared with patients without intrauterine adhesions contain 50% to 80% of fibrous tissue compared with 13% to 20% in the uterine wall [7]. Samples of endometrium from women with Asherman syndrome are similar in appearance to those after induced intrauterine adhesions, such as after transcervical resection of the endometrium [8]. Histologically, the endometrium appears atrophic with increased connective tissue despite being in a nonaffected part of the uterus. This explains in part the apparent lack of hematometra found clinically despite the apparent blockage to the cervical os. These pathologic findings are different from Asherman s initial proposal of a neurovascular reflex between the cervical os and the endometrial lining leading to amenorrhea. However, Asherman did recognize a relative lack of hematometra despite obstruction of the cervical os. The mechanism may be different, but the result is the same: an atrophic and inert endometrial lining. Etiology Any event that causes damage to the endometrium may lead to development of intrauterine adhesions. There is often a definable causative event on an unknown predisposing background. The major cause of intrauterine adhesions is damage to the basilar layer of the endometrium after curettage. Pregnancy is certainly important; a review of 1856 women with intrauterine adhesions demonstrated that 67% had undergone curettage because of induced or spontaneous abortion, and 22% because of postpartum hemorrhage [4]. In the only class I study to examine the etiology of intrauterine adhesions, 82 women were randomized to undergo either surgical or nonsurgical management of incomplete miscarriage [9]. At hysteroscopy 6 months after treatment, no intrauterine adhesions were observed in women treated conservatively or medically; however, 2 of 26 of women in the surgical group (7.7%) had intrauterine adhesions. This is the first methodologically sound evidence suggesting that uterine instrumentation is likely a predisposing factor in intrauterine adhesions. While trauma to the nonpregnant uterus can also cause intrauterine adhesions, the risk is lower, with rates of intrauterine adhesions estimated to be 1.6% after diagnostic curettage, 1.3% after abdominal myomectomy, 0.5% after cervical biopsy or polypectomy, and 0.2% after insertion of and intrauterine device (IUD) [4]. It is possible that newer endometrial biopsy methods and hysteroscopic and laparoscopic myomectomy may have reduced these rates further, although data are not available. Recurrent miscarriage is often associated with intrauterine adhesions, with adhesions reported in 5% to 39% of women with this problem [10 14]. It is uncertain whether these intrauterine adhesions are a cause or consequence of the recurrent abortions. Changes to the vascularization of the endometrium have been demonstrated using pelvic

3 Deans and Abbott. Review of Intrauterine Adhesions 557 angiography, with a marked reduction in myometrial vascular flow and even vascular occlusion in patients with hypomenorrhea and amenorrhea [15]. Such changes may have an effect on implantation, with a hypotrophic endometrium being unreceptive to an embryo, and the same conditions may predispose to development of intrauterine adhesions. Postpartum curettage resulted in the first reported case of secondary amenorrhea due to intrauterine adhesions [1]. Instrumental interventions performed between the 2nd and 4th postpartum weeks seem to result in more frequent and severe intrauterine adhesions [4]. The risk of developing intrauterine adhesions postpartum is high, affecting 21.5% to 40.0% of women requiring uterine instrumentation [4,16 18]. Curettage in the first 48 hours postpartum seems to be less conducive to adhesion formation [19] suggesting that endoganous estrogen levels have a major role. Postpartum hemorrhage is a risk factor for intrauterine adhesions, with an early report noting an incidence of intrauterine adhesions of 9% [20]. Contributing factors include postpartum uterine instrumentation or fibrosed retained products of conception that may have caused the postpartum hemorrhage. Surgical treatment of a silent miscarriage (missed abortion) has been reported to lead to 31% of intrauterine adhesions compared to an incomplete miscarriage, in which only about 6.4% of women are likely to develop intrauterine adhesions [4]. This difference is likely due to the retained products in a silent miscarriage causing greater fibroblastic effect before endometrial regeneration can occur. Curettage after evacuation of a hydatidiform mole is an uncommon cause of intrauterine adhesions, with an incidence of 0.6% to 3% [4,21]. Possible reasons for the lower rate may include underreporting, molar tissue being less adhesiogenic or fibroblastic than placental tissue, or the elevated estradiol or b-human chorionic gonadotropin in molar pregnancy being protective against the development of intrauterine adhesions. Patients undergoing repeat curettage because of miscarriage have an increased incidence of intrauterine adhesions, as high as 39% [10,13]. The number of procedures performed seems proportional to the frequency and severity of the intrauterine adhesions. In 1993, Friedler et al [22] reported a 16% incidence of intrauterine adhesions found at diagnostic hysteroscopy after curettage after a single miscarriage, with adhesions being thin and filmy and occupying less than a third of the uterine cavity, whereas after 2 or 3 surgical terminations of pregnancy, the incidence was 14% and 32%, respectively, and the area of cavity affected increased to 58%. A single class II study indicated that resective hysteroscopic surgery predisposes to intrauterine adhesions. In that study, the frequency of postsurgical intrauterine adhesions was 6.7% after resection of uterine septa, 31.3% after resection of a single myoma, and 45.5% after resection of multiple myomas [23]. Abdominal surgery involving the uterus has also been implicated in the formation of intrauterine adhesions. The risk of intrauterine adhesions after cesarean delivery is estimated to be 2% [4], and after laparotomy and full-thickness myomectomy is 1.3% [4]. Rare causes of intrauterine adhesions include genital tuberculosis, with the condition first described in 1956 [24]. Tuberculous adhesions characteristically respond poorly to intervention, with a poor prognosis for future fertility [3,4]. Pelvic irradiation is thought to be responsible for 0.05% of cases in a large series [4]; however, this figure may be increasing because of more widespread used of radiotherapy to treat malignant disease of the pelvis. To date, there has been only 1 reported case of Asherman syndrome after bilateral uterine artery embolization [25], and another case has been described after severe postpartum hemorrhage [26]. The contribution of infection to the development of intrauterine adhesions is controversial [11,21]. Some authors have stated that the findings of peritubal adhesions, histologically evident endometritis, and bacterial isolation in cases of Asherman syndrome support the role of infection as a predisposing factor [12]. Opposing views have suggested that bacterial pathogens are rarely isolated, and the finding of inflammatory cells, degenerative products, and tissue edema at histologic analysis of endometrial cells in patients with intrauterine adhesions are not different compared with patients without intrauterine adhesions [27]. Endometritis after caesarean section is not reported to increase the risk of intrauterine adhesions compared with cesarean delivery without infection [28], and the American Fertility Society states that dilation and curettage in the setting of endometritis has a nonsignificant effect on adhesion formation [29]. While the evidence for infection contributing to the condition is limited, it seems reasonable that the postinfectious inflammatory process could exacerbate traumatic endometrial damage [30,31] and should be considered in the pathogenesis and subsequent treatment of Asherman syndrome. Clinical Manifestations Menstrual abnormalities are the most common symptom in patients with Asherman syndrome. Of 2981 patients with intrauterine adhesions, 1102 (37%) reported amenorrhea, 924 (31%) reported hypomenorrhea, only 30 (1%) reported menorrhagia, and 179 (5%) reported normal menses [4]. The original theory from Asherman for altered menses with cervical adhesions was a neurovascular reflex that inhibited the endometrium from normal hormonal response [2]. Subsequently, cases with cervical obstruction, hematometra, and hematosalpinx were reported [24], and it is apparent that there is a variance in manifestation of Asherman syndrome. Hypomenorrhea is likely due to endometrial damage, with the severity and location of adhesions correlated with the degree of hypomenorrhea [13]. The residual endometrium may become atrophic due to decreased uterine perfusion and limited hormonal circulation locally [11], causing myometrial fibrosis, which is significantly increased in women with intrauterine adhesions [7]. Pelvic pain from intrauterine adhesions is commonly cyclic and associated with menstrual dysfunction. Pain is usually associated with decreased or absent menstrual flow. The

4 558 Journal of Minimally Invasive Gynecology, Vol 17, No 5, September/October 2010 mechanism may be due to outflow obstruction with backflow into the fallopian tubes, creating hematosalpinx and retrograde menstruation, or as a result of pockets of residual endometrium responding to hormonal stimuli, with no route for egress [11]. Secondary infertility is a common initial symptom, with 1 large-scale review reporting this in 922 of 2151 patients with intrauterine adhesions (43%) [4]. Subfertility may be due to obstruction of sperm into the cervix or prevention of embryo migration within the uterine cavity. Endometrial insufficiency may prevent implantation of the blastocyst [32]. As with menstrual disturbance, the degree of symptoms does not necessarily relate to the intrauterine disease, and it is reported that women with eumenorrhea with subfertility are more likely to have Asherman syndrome compared with their fertile counterparts [33]. There is a high incidence of recurrent miscarriage, and its presence should alert the clinician to consider the diagnosis of intrauterine adhesions. Defective vascularization at the level of the denuded endometrium inhibits effective implantation, leading to an occlusion of blood supply to the uterus and early fetus [28]. Diagnosis Because clinical examination usually fails to reveal abnormalities [20,24], other methods of investigation are necessary for diagnosis. Sounding the uterus may reveal cervical obstruction [24]. Hysteroscopy Hysteroscopy is now established as the criterion standard for diagnosis of intrauterine adhesions [34]. Compared with radiologic investigations, hysteroscopy more accurately confirms the presence, extent, and degree of adhesions and the quality of the endometrium. It provides a real-time view of the cavity, enabling accurate description of the location and degree of adhesions, classification, and concurrent treatment of intrauterine adhesions [35]. At hysteroscopy, superficial adhesions may have the same appearance as the adjacent endometrium, fibrous or myometrial bands appear white and are dense, and endometrial fibrosis appears as pale patches. Fig. 1 shows the appearance of an intrauterine adhesion as seen at hysteroscopy. Office hysteroscopy is useful for both diagnosis and second-look follow-up after treatment of intrauterine adhesions. It is a well tolerated, less expensive, and convenient alternative to inpatient hysteroscopy [36], although dense adhesions may not be amenable to in-office treatment. Office hysteroscopy and treatment of mild adhesions have been reported to increase clinical pregnancy rates in women with recurrent failure of in vitro fertilization [37]. Hysterosalpingography Hysterosalpingography (HSG) is the historical method of diagnosis of intrauterine adhesions [35]. It requires no anesthesia, can be performed in an ambulatory setting, and Fig. 1. Note thick intrauterine adhesion (arrow) from front to back uterine walls in the mid-cavity. can enable diagnosis of tubal patency [3]. Filling defects can be characterized by an irregular and angulated form with sharp contours and homogeneous opacity, and are reproducible [38]. In the case of severe and extensive lesions, intravascular and intralymphatic extravasations may also be observed. When complete occlusion occurs, HSG will fail to show any contrast medium filling of the uterine cavity [3]. Compared with hysteroscopy for diagnosis of intrauterine adhesions, sensitivity of HSG is 75% to 81%; specificity, 80%; and positive predictive value, 50% [39,40]. The high false-positive rate (%38%) [41] is a limiting factor. Transvaginal Ultrasound Transvaginal ultrasound (US) is inexpensive, noninvasive, and a readily available procedure that can aid in the diagnosis of intrauterine adhesions [42,43]. Hyperechoic areas within the endometrium are characteristic. In widespread endometrial destruction from intrauterine adhesions, the endometrial echo may be difficult to visualize, with irregular thickness or interruptions in the lining at the sites of fibrosis. Echolucent areas with interruption of the endometrium (skip lesions) may represent localized menstrual blood in areas in which functional endometrium is preserved [3]. Overall, the diagnostic ability of transvaginal US alone is poor, with sensitivity of 52% and specificity of 11% compared with sonohystography and hysteroscopy [44]. The preoperative endometrial thickness observed at transvaginal US may provide information for posttreatment prognosis. Patients with thin preoperative endometrium are reported to have a poorer response to surgical treatment than those with normal appearing endometrium above an obstruction. This reflects severity of intrauterine adhesions, and is in accord with surgical outcomes [3,43]. Three-dimensional US may be more helpful in evaluation of intrauterine adhesions, with sensitivity

5 Deans and Abbott. Review of Intrauterine Adhesions 559 reported to be 87%, and specificity of 45% compared with 3-dimensional sonohystography [45]. Sonohysterography or saline solution infusion sonohysterography (SHG/SIS) may be used to diagnose intrauterine adhesions if there is at least 1 echogenic area between the anterior and posterior walls or if cavity distention is impeded from tethering of the uterine walls by synechiae. This method was as effective as HSG in a number of studies, with both reported to have a sensitivity of 75%; positive predictive value was 43% for SHG/SIS, and 50% for HSG, compared with hysteroscopy [40,44]. Similar to HSG, SHG/SIS has a high false-positive rate, and is best used as a screening test for intrauterine adhesions, but can be used to assess tubal patency. Three-dimensional sonohysterography has the added advantage of estimating the volume of the endometrial cavity, which is decreased in the presence of intrauterine adhesions [46,47]. Magnetic Resonance Imaging Magnetic resonance imaging has been reported in the diagnosis of intrauterine adhesions [48,49], although its expense, limited availability, and unknown sensitivity as a diagnostic method should necessarily limit its use to research at this time. It may be useful in diagnosing cervical adhesions causing obstruction when the upper uterus, including endometrial remnants, can be assessed [50]. At this time, intrauterine adhesion signal characteristics have not been examined in detail, and it is anticipated that adhesions would produce low signal intensity on T2-weighted images [50]. Classification Hysteroscopy is required for accurate classification of Asherman syndrome [11]. Radiography and HSG have been used to classify intrauterine adhesions [34], although not considered standard practice. Classification of intrauterine adhesions is useful because the prognosis is related to the severity of disease [35]. The 7 reported systems proposed for classification of Asherman syndrome are as follows. 1. March et al [34] were the first group to attempt to classify intrauterine adhesions. Hysteroscopy was used to classify intrauterine adhesions based on the degree of uterine cavity involvement (Table 1). 2. Another system described adhesions in terms of their location [51]. Adhesions were classified as isthmic, marginal, central, and severe. 3. Valle and Sciarra [52] described a classification system to incorporate type of adhesion (mild, moderate, or severe) and the extent of occlusion (partial or total) (Table 2). 4. A European classification system was devised in 1984 and refined 1989 as the European Society for Hysteroscopy classification [53]. This system classifies intrauterine adhesions as grade I through IV, and incorporates a combination of hysteroscopic and HSG findings, as well as clinical Table 1 Hysteroscopic classification of intrauterine adhesions a Classification Minimal Moderate Severe Involvement Less than one-fourth of uterine cavity; thin or filmy adhesions; ostial areas, and upper fundus minimally involved or clear One-fourth to three-fourths of uterine cavity; no agglutination of walls; ostial areas and upper fundus only partially occluded More than three-fourths of uterine cavity; agglutination of walls or thick bands; ostial area and upper cavity occluded a Adapted with permission from [34]. symptoms (Table 3). Fig. 2 demonstrates an illustrated guide to classification using this system. Although both more precise and prognostic than earlier classification systems, it is criticized for being difficult to use in clinical practice [54], especially in differentiating grades III, IIIa, and IIIb. 5. The American Fertility Society classification is based on extent of endometrial obliteration, hysteroscopic appearance of adhesions, and menstrual characteristics of the patient. Menstrual characteristics are also included because of the perceived effect on fertility [29]. The classification system can be undertaken with direct (hysteroscopy) or indirect (HSG) assessment (Table 4). Stage of disease is calculated from the Table 4, with stage 1 (mild) score of 1d4, stage 2 (moderate) score of 5d8, and stage 3 (severe) score of 9d12. The physician predicts prognosis as excellent, good, fair, or poor based on stage, tubal patency, and clinical judgment. 6. More recent classification systems have considered location of intrauterine adhesions to be the most important prognostic factor in determining postoperative pregnancy rate [55]. In one of these classification systems, adhesions are divided into degrees, with each degree containing 2 subtypes (Table 5). This system has been criticized because category IIIa (inability to perform HSG because of obstruction of the cervical canal) generally has a good prognosis for subsequent fertility after treatment, Table 2 Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome a Classification Mild adhesions Moderate adhesions Severe adhesions Involvement/Extent a Adapted with permission from [52]. Filmy adhesions composed of basal endometrium producing partial or complete uterine cavity occlusion Fibromuscular adhesions that are characteristically thick; still covered with endometrium that may bleed when divided; partial or total occlusion of the uterine cavity Composed of connective tissue; lacking any endometrial lining, and likely to bleed when divided; partial or total occlusion of the uterine cavity

6 560 Journal of Minimally Invasive Gynecology, Vol 17, No 5, September/October 2010 Table 3 European Society for Hysteroscopy classification of intrauterine adhesions a Grade I II IIa III IIIa IIIb IV Extent of intrauterine adhesions Thin or filmy adhesions easily ruptured by hysteroscope sheath alone. Cornual areas normal. Singular filmy adhesions connecting separate parts of the uterine cavity. Visualization of both tubal ostea possible. Cannot be ruptured by hysteroscope sheath. Occluding adhesions only in the region of the internal cervical os. Upper uterine cavity normal. Multiple firm adhesions connecting separate parts of the uterine cavity. Unilateral obliteration of ostial areas of the tubes. Extensive scarring of the uterine cavity wall with amenorrhea or hypomenorrhea Combination of III and IIIa Extensive firm adhesions with agglutination of uterine walls. Both tubal ostial areas occluded. a From Wamsteker K. European Society for Hysteroscopy (ESH) classification of IUA and this is reflected in most other classification systems, in which these adhesions are given a relatively lower stage or score. 7. The most recent classification system incorporates menstrual and obstetric history, and intrauterine adhesion findings (Table 6) [54]. In this classification system, a score of 0d4 (grade 1, mild) reflects a good prognosis, a score of 5d10 (grade 2, moderate) reflects a fair prognosis, and a score of 11d22 (grade 3, severe) reflects a poor prognosis. This classification system has been compared with previous systems [34,53] assessing correlations with the result that the new classification system correlated well with grades 1 and 3; however, there was much overlap in grade II, which the investigators attribute to the differences in the inclusion of menstrual and reproductive performance in assessment of these patients. The limitation of this new system is that it is not yet validated, and it is based on a relatively small number of patients. In summary, a number of reported classification systems have been published that can make comparison between studies difficult to interpret. Classification systems that incorporate clinical history may provide better prognostic information. However, to date, no classification or grading system has been validated or received universal endorsement, which may reflect inherent deficiencies in all of these proposed systems. Management After diagnosis of intrauterine adhesions, treatment is considered when there are symptoms of pain or menstrual dysfunction that are unacceptable to the patient, or more commonly when there is a history of infertility or recurrent pregnancy loss and the patient wishes to conceive [35]. Itis important to remember that intrauterine adhesions (and Asherman syndrome) are not life-threatening, and patients Fig. 2. Schematic representation of one type of classification system demonstrating the variation in adhesion location and severity, and depicting one of the problems with classification systems when cervical obstruction may prevent further evaluation of the uterine cavity. may have no symptoms. Treatment should, therefore, be reserved for patients with Asherman syndrome. There is almost universal support that surgical treatment is the criterion standard in management of Asherman syndrome, and there is no role for medical treatments. There is no consensus as to the optimal technique of division of adhesions. Equally, there is a lack of prospective randomized controlled trials on the treatment of Asherman syndrome. The primary objective of intervention is to restore normal volume and shape of the uterine cavity. Secondary goals include treating associated symptoms (including infertility) and preventing recurrence of adhesions. Table 4 American Fertility Society classification a Extent of cavity involved,1/3 1/3-1/2.2/3 Score Type of adhesions Filmy Filmy and dense Dense Score Menstrual pattern Normal Hypomenorrhea Amenorrhea Score a Adapted with permission from [29].

7 Deans and Abbott. Review of Intrauterine Adhesions 561 Table 5 Degree and location of intrauterine adhesions a Degree Location I Central adhesions (bridgelike adhesions) IIa Thin or filmy adhesions (endometrial adhesions) IIb Myofibrous or connective adhesions II Marginal adhesions (always myofibrous or connective) IIa Ledgelike projections IIb Obliteration of 1 horn III Uterine cavity absent at hysterosalpingography IIIa Occlusion of internal os (upper cavity normal) (pseudo Asherman syndrome) IIIb Extensive coaptation of uterine walls (absence of uterine cavity) (true Asherman syndrome) a Adapted with permission from [55]. Expectant Management There is a role for expectant management, with an early report of 23 women with amenorrhea with Asherman syndrome observed expectantly. Of these, 18 (78%) began having regular menses after 1 to 7 years [4]. Fertility is also reported to have returned in 133 of 292 women (45.5%) observed expectantly who desired fertility, who conceived within the same follow-up period [4]. These 25-year-old data are not classified by any of the 7 systems described. Although based on descriptions alone, many of these women had cervical obstruction only and, therefore, intrauterine adhesions would be considered minimal, with an expected good obstetric outcome. Cervical Probing This is the original surgical intervention described for Asherman syndrome in women with cervical stenosis without damage to the uterine cavity or endometrium [56]. Table 6 Clinicohysteroscopic scoring system of intrauterine adhesions a Hysteroscopic findings Score Isthmic adhesions 2 Filmy adhesions Few 1 Excessive (.50% of cavity) 2 Dense adhesions Single band 2 Multiple bands (.50% of cavity) 4 Tubal ostia Both visualized 0 Only 1 visualized 2 Neither visualized 4 Tubular cavity (sounds,6) 10 Menstrual pattern Normal 0 Hypomenorrhea 4 Amenorrhea 8 Reproduction Good obstetric history 0 Recurrent pregnancy loss 2 Infertility 4 a Adapted with permission from [54]. Although Asherman described a return to menstruation in all 29 patients within 1 month after treatment, our current understanding of the pathophysiologic findings makes it likely that many of these women had minimal intrauterine adhesions with localized obstruction. This technique currently has a limited role, and uterine perforation could still be an outcome of blind cervical probing. Dilation and Curettage Before hysteroscopy, blind dilation and curettage followed by oral estrogen therapy and placement of an IUD was advocated for treatment of Asherman syndrome [4]. In a review of women treated in this manner, 1049 of 1250 (84%) reported return of normal menses, 540 of 1052 (51%) conceived, 142 of 559 (25%) miscarried, and 306 of 559 (55%) delivered at term. Fifty of 559 (9%) delivered prematurely, and in 42 of 559 (9%), pregnancy was complicated by placenta accreta. Because hysteroscopy was not in widespread use, many patients in this review had mild adhesions, and more severe cases were treated using open hysterotomy and lysis. Inasmuch as blind dilation and curettage is associated with a high risk of uterine perforation and a low success rate [3], it should now be considered obsolete. Hysteroscopy Hysteroscopic treatment enables lysis of intrauterine adhesions under direct vision and with magnification. Uterine distention has the dual role of providing visualization and separating the uterine walls, providing direct breakdown of adhesions and acting to increase tension at the point of adhesion, making division easier. Mild adhesions may simply be divided using fluid distention of the cavity or blunt dissection with the tip of the hysteroscope [57]. Fig. 3 shows mild adhesions before and after fluid distention. Division of moderate to severe adhesions is more technically challenging and requires greater surgical skill and more advanced instrumentation. In general, adhesiolysis begins caudally, with filmy or central adhesions divided first to increase cavity size, and then advanced cephalad until the uterine architecture has been restored. Lateral or dense adhesions should be divided last because they are associated with a higher risk of uterine perforation [3]. Instruments for Adhesiolysis Mechanical instruments such as semirigid 5F to 7F scissors through a 6.5-mm operating hysteroscope [11] can be used to divide adhesions under direct vision [34,52]. Sharp dissection may, in theory, minimize destruction of the endometrium [3]. An 18-gauge, 80-mm Tuohy needle mayalso be usedas a sharp instrument alongside a 2.5-mm hysteroscope [58,59]. Advantages include low cost and, should perforation occur, decreased risk of visceral injury (compared with use of energy sources), and a disadvantage is that they are less

8 562 Journal of Minimally Invasive Gynecology, Vol 17, No 5, September/October 2010 Fig. 3. A, Hysteroscopic view of minor adhesion is seen in the central portion of the cavity (arrow). B, With hydrostatic pressure alone, the adhesion is divided. hemostatic. Fig. 4 shows adhesions being lysed using hysteroscopic scissors. Monopolar electrosurgery with a knife electrode has been described as an adhesiloytic instrument [52,60 63]. Advantages include precise hemostatic cutting, although there is an increased risk of visceral damage if uterine perforation occurs [35], and additional endometrial damage may predispose to recurrence of intrauterine adhesions [64,65]. Bipolar vaporization using the Versaport instrument (Versapoint Electro-Surgical System, Gynecare, Inc., Menlo Park, CA) to divide intrauterine adhesions has been described [66,67], and uses saline solution as a distention medium, decreasing the risk of electrolyte disturbance compared with glycine. Use of the Nd-YAG laser has also been reported [52,62,68], although with all energy modalities, there is risk of significant visceral injury should perforation occur [11]. Techniques for Intrauterine Adhesiolysis Insertion of a Laminara tent (Shivata Medical Products Co., Nagoya, Japan) into the cervix preoperatively may assist in placement of the hysteroscope and aid in the dissection of Fig. 4. Hysteroscopic scissors are used to mechanically divide dense adhesions in the uterus. difficult dense cervical adhesions [69]. Pressure lavage under US guidance is based on sonohysterography, in which a continuous infusion of saline solution leads to mechanical disruption of intrauterine adhesions. This technique is likely to be successful only in patients with mild adhesions [70]. Hysteroscopy and Associated Techniques Instillation of methylene blue dye to stain the endometrium and guide the hysteroscopist to pockets of normal endometrium is described as helpful because the endometrium stains well but connective tissue and myometrium do not [52]. This technique is not helpful in instances of complete uterine obliteration, and is best suited to treatment of mild and marginal adhesions. An entirely different technique of dissection, myometrial scoring, has been described [71], in which six to eight 4-mm deep incisions are created in the myometrium using a resectoscope and Collins knife electrode from the fundus to the cervix. These incisions enable widening of the uterine cavity. In a similar technique, a transverse incision is added at the uterine fundus [61]. These techniques create a cavity, and it is hypothesised that the endometrium may regenerate over this new exposed surface area. All treated women had severe intrauterine adhesions, and results of these techniques demonstrated restoration of the cavity in 71.0% [71] and 51.6% [61], respectively. Pregnancy was achieved in 3 of 7 women (2.9%) [71] and 12 of 31 (38.7%) women [61]. Use of physical landmarks is described in cases of an obliterated endometrial cavity in which the dense adhesions are treated as a uterine septum. A cervical dilator is directed from the cervical canal toward the 2 ostia, which creates 2 lateral landmarks, leaving a fibrous septum, which is divided transcervically under laparoscopic guidance. This technique is not without risk: 2 of 6 women in the only reported series experienced uterine perforation, and 1 had substantial hemorrhage [72]. The clinical results were encouraging, with cavity restoration in all cases, and 5 pregnancies achieved in 4 women, resulting in 4 live births. The 50% major complication rate is of substantial concern, and the technique should be performed only by expert hysteroscopists.

9 Deans and Abbott. Review of Intrauterine Adhesions 563 Fig. 5. Left, Using an image intensifier, an obliterated cavity demonstrates an intravascular flow pattern (arrow), indicating incorrect placement of the needle into the myometrium. Right, After sharp dissection using this technique, the cavity is seen to be reconstructed (arrow), with flow demonstrated in the right tube. Fluoroscopic guidance enables a radiologic view of pockets of endometrium behind an otherwise blind-ending hysteroscopic view. Using a Tuohy needle as an instrument in parallel with a small-diameter hysteroscope, radiopaque dye (Ultravist 76.9%; Iopromide; Scherring AG, Pharmaceutical Division, Berlin Germany) can be injected into an area of dense adhesions at the point of obliteration of the cavity. Under image intensifier control, views can be obtained of normal areas of endometrium and direct sharp synechiolysis under hysteroscopic vision [58]. Fig. 5 demonstrates the radiologic findings before and after this technique was performed. This technique requires a substantial amount of equipment, exposes the patient (and staff) to ionizing radiation, and is technically challenging. Fluoroscopic guidance to divide intrauterine adhesions has also been described in an outpatient setting using a specialized balloon-tipped catheter inserted through the cervix [73]. This treatment seems to be limited to patients with mild adhesions only, and there are no longterm data for this technique. Transabdominal US has been advocated as a technique to guide hysteroscopic division of intrauterine adhesions [3,65,71,74,75], with a reported reduced risk of uterine perforation [75]. Ultrasound is readily available and familiar to gynecologists; however, total reported numbers in these studies are small, and success and perforation prevention is both surgeon- and sonographer-dependent. Perforations in as many as 5% of cases have been reported with use of this technique [67,71,72]. More recently, the use of transrectal US has been used to guide hysteroscopic synechiolysis, with reported success in 1 patient [76]. There is also a single case report of intracorporeal US control to guide adhesiolysis [77] that requires 3 modalities: hysteroscopy, laparoscopy, and US. Its use cannot be recommended without further research. The use of laparoscopic guidance is controversial because, although advocates suggest its use in division of severe intrauterine adhesions [67,71,72], perforations have been reported, and perhaps its primary use is best considered for immediate recognition and treatment with minimal extrauterine trauma [3,67,71,72]. Laparotomy, hysterotomy, and blunt dissection through adhesions using a finger or curette are the traditional treatment for severe intrauterine adhesions [2,24,78]. A review of 31 cases in which this approach was used revealed that 16 of 31 women (52%) achieved conception, with 11 (38%) live births and 8 (26%) term deliveries. Five of 16 pregnancies (31%) were complicated by placenta accreta [4]. In contemporary practice, this technique is rarely used, and is reserved only for severe cases in which other techniques are not practical or possible [21]. Risks and Complications of Hysteroscopic Synechiolysis Perforation of the uterus is more likely with severe adhesions, and is technique-dependent, generally ranging from 2% to 5% [3]. Hemorrhage can occur in 6% to 27% of cases [3]. Injury to myometrial blood vessels may obstruct the surgeon s view and enable rapid absorption of distention medium, which can lead to significant electrolyte disturbances including hyponatremia. Repeated cervical dilation increases the risk of cervical incompetence and complications such as mid-trimester loss [61]. Because of the high risk of recurrence of adhesions, patients should be counselled about repeat surgery [3], particularly in severe cases [52]. Genital Tuberculosis Genital tuberculosis is described here separately because there are few reported cases of lysis of intrauterine adhesions due to this infection, although outcomes are particularly poor, with recurrence reported in all patients in 3 separate studies [63,78 80]. Ancillary Treatments Physical Barriers Insertion of an IUD provides a physical barrier between the uterine walls, separating the endometrial layers after lysis of intrauterine adhesions [4,34,81]. The Dalcon shield was the first described IUD to be used, in 1966, with moderate success but significant associated problems. Since then, it

10 564 Journal of Minimally Invasive Gynecology, Vol 17, No 5, September/October 2010 has been reported as an adjunctive treatment in many studies [14,34,51,52,57,60,62,67,75,82 85]. The type of IUD is reported to be important. Copper-containing IUDs provoke an inflammatory reaction [86], and T shaped IUDs are thought to have too small a surface area to be truly effective in providing a physical barrier [87]. The loop IUD (e.g., Lippes loop) is considered the IUD of choice when treating intrauterine adhesions [3], although it is no longer available in many geographic areas. In a small nonrandomized study, postoperative IUD plus hormone therapy was compared with hormone therapy alone, and no significant difference was found in the re-formation of adhesions [88]. Because of the suppressive effect on the endometrium, progesterone loaded IUDs should not be used postoperatively. To date, there have been no class I studies investigating the use of IUDs after hysteroscopic lysis of intrauterine adhesions. There is a risk of infection when an IUD is introduced into the uterus immediately after adhesiolysis, quantified as 8% in 1 series [85], and perforation of the uterus during IUD insertion is a further risk. Use of a Foley catheter for 3 to 10 days is similarly reported to act as a physical intrauterine barrier after surgical lysis of intrauterine adhesions [2,34,73,79,84,85,89,90]. In a nonrandomized study, a pediatric Foley catheter was inflated and placed in the uterus for 10 days in 59 patients postoperatively in a 4-year study and compared with use of an IUD postoperatively for 3 months in 51 women treated in the next 4 years. Most striking was that amenorrhea continued in 19% of the Foley group and 38% of the IUD group, with poor fertility rates in the IUD group (20 of 59 [34%]) and Foley group (14 of 51 [28%]). There were fewer infections in the Foley group, and a lower recurrence rate of intrauterine adhesions as assessed at HSG [85]. Use of a fresh amnion graft over an inflated Foley catheter to prevent recurrence of intrauterine adhesions after hysteroscopic lysis in 25 women with moderate to severe Asherman syndrome has been reported, demonstrating minimal adhesion reformation in 48% of patients with severe adhesions [90]. However, no fertility data for this technique have been reported. Newer adhesion barriers include modified hyaluronic acid, and have been reported to be successful after treatment of intrauterine adhesions [91 93]. Hyaluronic acid has been used as a barrier agent to prevent adhesion formation after abdominal or pelvic surgery [94], with the antiadhesive effects depending on the preparation s molecular weight and concentration [95]. In a prospective, single-blind, randomized, controlled study of 150 women undergoing suction curettage after incomplete, missed, or recurrent miscarriage, 50 were randomized to receive Seprafilm (Genzyme Corp., Cambridge, Massachusetts), and 100 patients served as a control group [92]. There was stratification depending on the performance of previous curettage. In 32 women who received Seprafilm who had not undergone a previous curettage procedure, all became pregnant in the 8 months after the procedure. In the control group, 34 of 56 patients (54%) who had never undergone a previous curettage procedure conceived. If patients had not become pregnant 8 months after the intervention, HSG was performed to review the endometrial cavity. In the treatment group (women who had previously undergone at least 1 curettage procedure), adhesion formation reoccurred in 1 of 10 patients (10%); however, intrauterine adhesions were observed in 7 of 14 (50%) of the untreated group. There were no reported adverse reactions using Seprafilm in the endometrial cavity, and US examination did not demonstrate any abnormal echoes at follow-up of the patients receiving treatment. Auto-cross-linked hyaluronic acid gel may be more suitable for preventing intrauterine adhesions because of higher sensitivity and prolonged residency time on the injured surface compared with unmodified hyaluronic acid [96]. In a prospective randomized controlled trial of 84 women, auto-cross-linked hyaluronic acid gel (Hyalobarrier gel; Baxter International Inc., Deerfield, IL) was compared with no therapy after surgical treatment of Asherman syndrome. Postoperative US studies showed that the walls of the uterine cavity remained separated for at least 72 hours. At secondlook hysteroscopy 3 months after the procedure, intrauterine adhesions were significantly reduced in patients receiving the adhesion barrier (6 of 43 [14%]) compared with the control group (13 of 41 [32%]) (p,.05) [91]. These newer adhesion barrier studies provide encouraging results with more methodologically sound studies than traditional barriers such as IUDs or Foley catheters. Further studies are essential before these barriers are used in routine practice. Hormone Therapy In 1964, Wood and Pena [97] described estrogen therapy to stimulate regeneration of the endometrium and promote reepithelization of the endometrium after surgical treatment of intrauterine adhesions. Various regimens have been described for postoperative treatment with estrogens (e.g., a daily dose of 2.5 mg of conjugated equine estrogen) with or without opposing progesterone for 2 to 3 cycles [11,21,58,59]. No comparative studies have been performed on dosage, administration, or combination of hormones. In a related study, 60 women undergoing dilation and curettage during the first trimester of pregnancy were randomized to receive estrogen and progestin or no treatment [98]. Women in the combined hormone group had a significantly thicker endometrium (0.84 cm vs 0.67 cm) and endometrial volume (3.85 cm 2 vs 1.97 cm 2 ) compared with the control group [99]. This suggests that there may be a benefit to postoperative treatment of intrauterine adhesions; however, no data are available at this time on pregnancy or intrauterine adhesion recurrence. Adverse effects of estrogen or estrogen plus progesterone must be evaluated in the absence of evidence, with nausea, headache, and the risk of thromboembolic disease considered if using this treatment. Preoperative estrogen therapy has also been suggested to be of potential benefit in increasing endometrial thickness before any surgical intervention, although data are limited [35].