Intrauterine adhesions: Clinical manifestation and diagnosis

INTRODUCTION — Intrauterine adhesions (IUAs) are bands of fibrous tissue that form in the endometrial cavity, often in response to a uterine procedure. Disease severity can range from thin strings of tissue to complete obliteration of the cavity. Clinical sequelae include infertility, recurrent pregnancy loss, menstrual abnormalities, and pain. Clinical challenges include primary prevention of adhesions and prevention of recurrent adhesions after surgical treatment.

This topic will discuss the etiology, pathogenesis, clinical presentation, diagnosis, and management of IUA. Related topics on dilation and curettage and postpartum hemorrhage as well as general principles of the evaluation of amenorrhea, infertility, or recurrent pregnancy loss are discussed separately.

●(See "Dilation and curettage".)

●(See "Overview of postpartum hemorrhage".)

●(See "Evaluation and management of secondary amenorrhea".)

●(See "Female infertility: Evaluation".)

●(See "Recurrent pregnancy loss: Evaluation".)

DEFINITION AND TERMINOLOGY — IUAs, or intrauterine synechiae, is a condition in which scar tissue develops within the uterine cavity. IUAs that are accompanied by symptoms (eg, infertility, amenorrhea) are referred to as Asherman syndrome [1-3]. The terms are often used interchangeably. The degree of adhesion formation and the impact of the adhesions on the contour of uterine cavity vary greatly. Minimal disease is characterized by thin strands of tissue stretched across the uterine cavity while severe disease is characterized by complete obliteration of the cavity, with the anterior wall of the uterus densely adherent to the posterior wall.

EPIDEMIOLOGY — The true prevalence of IUAs is difficult to establish, in part because the condition is uncommon in the general population, often asymptomatic, and requires an invasive procedure for diagnosis. In addition, few studies prospectively evaluate for postprocedure adhesions [4]. Estimates of the prevalence range from 1.5 percent as an incidental finding at hysterosalpingogram to 21.5 percent of women with a history of postpartum uterine curettage [3]. In a meta-analysis that included over 900 women evaluated with hysteroscopy within 12 months following a spontaneous abortion (86 percent underwent curettage), the prevalence of IUAs was 19.1 percent [5]. Even relatively minor surgeries can be complicated by IUAs (table 1) [6].

ETIOLOGY AND RISK FACTORS — IUAs appear to result from trauma to the basalis layer of the endometrium (figure 1). The basalis layer appears to be most susceptible to damage in the first four postpartum or postabortal weeks. Emerging data suggest that angiogenic factors such as vascular endothelial growth factor (VEGF) are important modulators of endometrial stromal fibrosis [7]. VEGF is downregulated in the endometrial tissue of women with Asherman's syndrome. Subsequent tissue healing on opposing surfaces of the uterus may eventually fuse to produce tissue bridges. These IUAs range from filmy adhesions composed of endometrial tissue to dense adhesions consisting entirely of connective tissue. The resulting adherence of the uterine walls may result in partial or complete obliteration of the uterine cavity. In addition, vascularization may be compromised due to endometrial damage and scarring [8]. These changes account for menstrual abnormalities, frequent dysmenorrhea, infertility, and recurrent pregnancy loss.

Risk factors include intrauterine processes that have the potential to damage the basalis layer, including:

●Pregnancy – While it is impossible to separate the impact of pregnancy-related changes from the risk of an intrauterine procedure on the development of subsequent IUAs, pregnancy appears to be an independent risk factor distinct from intrauterine surgery. In a study of 85 women who underwent operative resection of IUAs, 65 percent (n = 55) had a previously undergone a pregnancy-related intrauterine procedure while 12 percent (n = 10 women) had undergone a procedure on a nongravid uterus, most commonly hysteroscopic surgery [9]. A comparison of the reported incidence of IUAs following procedures in both gravid and nongravid uteri is presented in the table (table 2) [5,10-17].

In addition, the duration of pregnancy and the timing of pregnancy relative to the procedure appear to impact the risk of IUA formation. At least one study has reported an increased prevalence of IUAs among patients who underwent curettage after a pregnancy loss at a more advanced gestational age compared with earlier pregnancy loss [18]. A different study reported a higher risk of adhesion formation in women who underwent postpartum curettage two to four weeks after delivery compared with early in the postpartum period [19].

Repeated curettage following pregnancy loss also increases the risk of developing adhesions, but again it is unclear how much of the risk is related to the gravid state versus repetitive intrauterine trauma. In a meta-analysis of 10 prospective studies including 912 women who underwent hysteroscopic evaluation within 12 months of miscarriage, the pooled prevalence of IUAs was nearly 20 percent [5]. Women who had >1 miscarriage had nearly double the odds of IUAs compared with women who had one miscarriage, which was similar to the odds of IUAs for women who had >1 or 1 curettage procedure. Of the 47 women who had expectant or medical management (ie, no intrauterine manipulation), no IUAs were noted. However, the possibility of forming IUAs after expectant or medical management cannot be excluded based on the small number of women studied and lack of randomly assigned study design.

Possible explanations for uterine susceptibility to IUA formation following pregnancy include the low-estrogen state associated with the postpartum or postabortion time period, antagonistic effects from elevated prolactin levels associated with breastfeeding, or postpregnancy physiologic changes that make the basalis layer more susceptible to injury [9,20].

●Intrauterine procedures – Intrauterine manipulation, separate from pregnancy, is associated with the development of IUAs as demonstrated by the formation of adhesions after procedures such as myomectomy or curettage in nongravid uteri [10,11,17,21-25]. Some studies suggest that removal of multiple fibroids at the time of hysteroscopic myomectomy is associated with higher risk of IUAs than removal of one fibroid [23,24], while other studies report no differences in the risk of adhesions with a single or multiple hysteroscopic myomectomy [25].

While intrauterine device (IUD) use has been associated with adhesion formation, the data are mainly limited to case reports and IUD use does not appear to be a major cause of IUAs [26]. As discussed below, IUDs can be used to prevent adhesion reformation after surgical resection.

●Inflammation or infection – In a study assessing chronic endometritis in women with known IUAs, 35 percent of women (29 of 82) had chronic endometritis confirmed by histology [27]. However, it is not known if the chronic endometritis was the cause or the sequelae of the adhesions. The role of postpartum or postabortal infection in adhesion formation is also unclear as data are limited. A study that evaluated 28 women with significant postcesarean delivery endometritis by hysteroscopy reported the frequency of adhesions in these women was similar to that in controls without postcesarean infection [28]. Another study reported a nonsignificant increase in adhesion formation when dilation and curettage was performed in the presence of concurrent infection [29].

In contrast, genital tuberculosis is associated with IUAs, which are often severe, with complete obliteration of the uterine cavity [30,31]. These patients typically present with amenorrhea and cyclic pelvic pain. The adhesions are believed to form secondary to chronic inflammation of the endometrium. (See "Endometritis unrelated to pregnancy", section on 'Tuberculous endometritis'.)

●Uterine compression sutures – Uterine compression sutures (eg, B-Lynch suture) used to treat severe postpartum hemorrhage have been associated with the development of IUAs. In four retrospective reviews, IUAs were diagnosed in 19 to 27 percent of women who received uterine compression sutures to treat postpartum hemorrhage [32-35]. (See "Postpartum hemorrhage: Management approaches requiring laparotomy", section on 'B-Lynch suture' and "Postpartum hemorrhage: Management approaches requiring laparotomy", section on 'Atony' and "Postpartum hemorrhage: Use of an intrauterine hemorrhage-control device".)

CLINICAL PRESENTATION — The classic clinical presentation of IUAs is of an ovulatory woman who develops secondary amenorrhea or hypomenorrhea after an intrauterine procedure, particularly if the procedure was performed on a gravid uterus [4]. Pregnancy-related intrauterine procedures occurring prior to symptom onset have been reported in 91 to 99.8 percent of women treated for Asherman syndrome [36,37]. Alternately, some women are identified as likely having IUAs by imaging studies ordered for the evaluation of infertility (eg, saline infusion sonohysterogram [SIS] (image 1) or hysterosalpingogram [HSG] (image 2)). (See 'Imaging studies' below.)

Typical symptoms associated with IUAs include:

●Abnormal uterine bleeding – Abnormal, or changed, menstrual bleeding patterns are reported by 70 to 95 percent of women with IUAs [3,36]. In a literature review of over 2900 patients with IUAs, the abnormal uterine bleeding patterns were the following: amenorrhea (37 percent), light bleeding (31 percent), normal menses (5 percent), and menorrhagia (1 percent) [3]. Patients are more likely to present with secondary amenorrhea than with primary amenorrhea, since endometrial damage is rare prior to menarche. While hypomenorrhea is a poorly defined term, we define it here as menstrual flow that is light (<5 mL) or shortened (<5 days) [38]. However, volume of uterine bleeding is difficult to measure and the interpretation of light menses is typically based on the patient's report of a noticeable decrease in volume or a volume that requires fewer or lighter tampons or pads.

Of note, adhesions can also be asymptomatic. In one report, up to three percent of women with severe adhesions noted cyclic, pain-free menses of normal volume and duration [20].

●Infertility – Infertility has been reported in 7 to 40 percent of women with IUAs [3,36]. IUAs are one of the differential diagnoses for the etiology of female infertility, and may be discovered when a HSG or hysteroscopy is performed as part of the standard infertility evaluation. Possible mechanisms by which IUAs could contribute to infertility include blockage of sperm [3] or injury/destruction of the endometrium that prevents implantation of the blastocyst [9]. (See "Female infertility: Evaluation", section on 'Assessment of the uterine cavity'.)

●Cyclic pelvic pain or dysmenorrhea – Cyclic pelvic pain, which has been reported by 3.5 percent of women with IUAs, is likely due to obstruction of menstrual flow and/or hematometra [39]. Thus, pain is typically associated with amenorrhea or hypomenorrhea. These symptoms are similar to those in women who undergo endometrial ablation and who have both intrauterine scar tissue induced by the procedure and residual functional endometrium. (See "Overview of endometrial ablation", section on 'Complications'.)

●Recurrent pregnancy loss – Recurrent pregnancy loss may occur in women with IUAs due to abnormalities of implantation in areas of denuded endometrium or insufficient vascularization. In one study of 85 women who underwent hysteroscopic lysis of IUAs, 13 percent had recurrent pregnancy loss (defined as ≥3 losses) [9]. (See "Recurrent pregnancy loss: Definition and etiology", section on 'Intrauterine adhesions'.)

●Incidental finding – IUAs may be found as an incidental finding in a woman who undergoes a pelvic ultrasound, saline infusion SIS, HSG, or hysteroscopy for another indication (eg, infertility, abnormal uterine bleeding). As asymptomatic women do not routinely undergo hysteroscopy or pelvic imaging, the prevalence of asymptomatic IUAs is not known. (See 'Hysteroscopy' below and 'Imaging studies' below.)

DIAGNOSTIC EVALUATION

Our approach — The main components of the diagnostic evaluation for IUAs are the medical history and uterine cavity evaluation. We take the following approach:

●The assessment begins with a history. We pay particular attention to menstrual symptoms and any pregnancies or intrauterine procedures that occurred prior to the onset of symptoms.

●Physical examination is performed next, which is typically normal. Some patients may have undergone a prior pelvic ultrasound as part of their evaluation for infertility or menstrual dysfunction. In some cases, a pelvic ultrasound may demonstrate an unusually thin endometrial lining, in the peri- or postovulatory phase. A pelvic ultrasound is not required for the diagnosis of IUAs.

●The next steps are determined by the likelihood of adhesive disease:

•Women with a high suspicion of IUAs go directly to endometrial evaluation, typically with hysteroscopy. While hysteroscopy is the gold standard, a saline infusion sonohysterogram (SIS) can also be used to evaluate the uterine cavity [4,40].

•Women with a low risk of IUA ultimately often undergo hysteroscopy, but may have additional testing prior. As an example, for women with a primary complaint of oligomenorrhea or amenorrhea and suspicion of IUAs, we first perform SIS or office ultrasound to assess the endometrial thickness. A thin endometrial lining (<4 mm) can be suggestive of IUAs.

History — The key components of the medical history include ascertainment of symptoms (menstrual change, infertility, or dysmenorrhea), history of prior pregnancies, and history of prior uterine procedures. For asymptomatic women, we focus on IUA risk factors such as uterine instrumentation and pelvic infection (eg, endometritis). (See 'Clinical presentation' above and 'Etiology and risk factors' above.)

In addition, in women from regions with endemic tuberculosis, we advise evaluating for pelvic tuberculosis. Some clinicians propose screening at-risk patients for tuberculosis. For those who screen positive, endometrial biopsy is advised [41]. (See "Endometritis unrelated to pregnancy", section on 'Tuberculous endometritis'.)

Physical examination — Bimanual pelvic examination will not reveal IUAs. We do not routinely probe the cervix at the time of physical examination. However, if cervical dilation is required for another indication during evaluation (eg, endometrial biopsy), practitioners may note difficulty passing a dilator during the procedure due to obstructive adhesions.

Ultrasound — Ultrasound is a very useful adjunct during the early evaluation of patients with amenorrhea and/or a history suggestive of IUAs. A very thin endometrium following amenorrhea and/or endometrial irregularity with hyperechoic regions may be suggestive of IUAs. However, while ultrasound findings can be suggestive of IUAs, this study is not definitive.

Estrogen/progestin withdrawal test — We do not routinely perform an estrogen/progestin withdrawal test for women suspected of having IUAs because the test takes additional time and only further delays the diagnosis. An estrogen-progestin withdrawal test is a two-month process during which the patient receives progestin alone followed by estrogen and progestin. The test is appropriate for some women being evaluated for amenorrhea. (See "Evaluation and management of secondary amenorrhea", section on 'Normal laboratory results and history of uterine instrumentation'.)

Hysteroscopy — Hysteroscopy allows direct visualization of the presence, extent, and morphologic characteristics of IUAs (image 3). In addition, the uterine cavity can be assessed to determine how much of the endometrial surface appears viable. Hysteroscopy also allows for simultaneous diagnosis and treatment. Hysteroscopic findings are the basis for most classification systems [29,42-47]. (See 'Classification' below.)

Adhesions may arise from the endometrium, myometrium, or connective tissue. They vary in size from thin and fragile to thick and dense, with the ends broader than the middle. They may occur at the margins of the endometrial cavity or diffusely; in severe cases, they completely obliterate the cavity. Marginal adhesions may appear crescent-shaped or like a curtain. Mucosal adhesions are the same color as the endometrium and fragile, whereas fibrous adhesions are pale and strong. IUAs due to tuberculosis tend to give the endometrial cavity a honeycomb appearance.

Hysteroscopy, with lysis of adhesions as indicated, can be performed in an office or operating room setting [48]. This allows diagnosis and treatment in a single procedure and decreases the probability of trauma to the surrounding endometrium. (See "Overview of hysteroscopy".)

Classification — Hysteroscopic findings are the basis for most classification systems [29,42-47]. While several societies endorse using a classification system because the prognosis is correlated with disease severity, at least one review concluded that the lack of trials comparing the various systems prevents the endorsement of any one system [48]. A summary of the various systems is presented in the table (table 3).

Two of the more commonly used systems are from the American Society for Reproductive Medicine (ASRM, previously the American Fertility Society) and the European Society for Hysteroscopy. [3,29]. The ASRM system consists of three stages of disease, based upon the extent of cavity involvement of the uterine cavity (<1/3, 1/3 to 2/3, >2/3), the type of adhesion seen at the time of hysteroscopy (filmy, filmy and dense, dense), and the patient's menstrual pattern (normal, hypomenorrhea, amenorrhea) (figure 2) [29]. The European Society for Hysteroscopy system grades adhesions based on the operator's ability to disrupt them with the hysteroscope and visualize the tubal ostia as well as the amount of scarring of the uterine cavity (table 4) [3].

Imaging studies — SIS (image 1), hysterosalpingogram (HSG) (image 2), and magnetic resonance imaging (MRI) have limited roles in the diagnosis of IUAs [49]. While these imaging studies can detect adhesions, they do not provide complete information about the extent and appearance of adhesions or the condition of the endometrium compared with hysteroscopy [4]. These studies may help the practitioner decide whether or not to perform hysteroscopy and, based on the surgeon's skill and available equipment, the appropriate setting in which to perform hysteroscopy with surgical correction (ie, office setting, outpatient operating room, or hospital-based operating room). (See 'Hysteroscopy' above.)

Studies of the performance of these tests for detecting IUAs include:

●In a systematic review of 20 studies comparing SIS with hysteroscopy for the detection of IUAs, the pooled sensitivity and specificity of SIS were 0.82 and 0.99 (95% CIs 0.65-0.93 and 0.98-1.00, respectively) [40]. The positive and negative likelihood ratios were 34.58 (95% CI 16.68-71.70) and 0.36 (95% CI 0.22-0.58).

●In a prospective study of 65 infertile women that compared HSG, SIS, and transvaginal ultrasonography (TVUS) with hysteroscopy, HSG and SIS were equally sensitive for diagnosing IUAs (both detected 3 of 4 cases, sensitivity 75 percent) [50]. TVUS alone appeared to have limited usefulness in this series (detected 0 of 4 cases).

●A retrospective study of 78 women that used hysteroscopy as the reference standard reported that HSG had a sensitivity of 81.2 percent and specificity of 80.4 percent for detecting IUAs [51].

Advantages of SIS compared with HSG are that it does not involve radiation and some clinicians are able to perform the study in an office setting. HSG, on the other hand, must be performed in a radiology suite. The advantage of HSG is the ability to evaluate tubal patency, if this is indicated, although newer techniques for SIS that involve infusion of a water/air combination may improve assessment of tubal patency with SIS [52].

Pelvic ultrasound alone is not generally a useful test to assess this condition, although adhesions may be detected by highly experienced ultrasonographers [53,54]. A thin and irregular endometrium (sometimes referred to as "skip lesions") may represent IUAs [55]. MRI has been used for women with cervical stenosis that prevents hysteroscopy, HSG, or SIS, but data on this technique are mainly limited to case studies [39,56-58].

DIAGNOSIS — Direct visualization of IUAs with hysteroscopy is the gold standard for the diagnosis [42,43,48,50]. While imaging studies such as hysterosalpingography (HSG) and saline infusion sonohysterography (SIS) can detect adhesions, the sensitivity is lower compared with hysteroscopy, and therefore negative imaging studies cannot exclude adhesions [50]. In a prospective study of 65 infertile women comparing different imaging techniques with hysteroscopy as the standard, both HSG and SIS had a 75 percent sensitivity for the detection of IUAs and positive predictive values of 50 and 43 percent, respectively [50]. (See 'Imaging studies' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of IUAs depends upon the presenting symptoms.

For women with amenorrhea or hypomenorrhea, the patient should be evaluated for an endocrine etiology. However, as part of this evaluation, if an estrogen/progestin withdrawal test does not result in bleeding, then IUAs, a cervical or uterine anomaly, or cervical stenosis are the likely etiologies. Even in the setting of a positive withdrawal test, IUAs should be considered in the differential diagnosis of hypomenorrhea, especially in women with infertility. (See 'Estrogen/progestin withdrawal test' above and "Congenital uterine anomalies: Clinical manifestations and diagnosis" and "Benign cervical lesions and congenital anomalies of the cervix" and "Evaluation and management of secondary amenorrhea", section on 'Normal laboratory results and history of uterine instrumentation'.)

Cervical stenosis can frequently be differentiated from IUA by history, as cervical stenosis is often associated with cyclic pain that results from obstructed menstrual flow. As noted above, a failed attempt to pass an instrument (eg, cervical dilator or hysteroscope) through the external or internal cervical os may indicate cervical stenosis, but blind exploration of the cervical canal is not recommended in the office. Ultrasound guidance during cervical dilation or hysteroscopy with a 3 or 5 mm hysteroscopy without any prior dilation can directly visualize cervical stenosis and, once through the stenotic cervix, also evaluate the endometrial cavity.

Uterine anomalies, such as a uterine septum, may also result in abnormal uterine bleeding, infertility, or recurrent pregnancy loss. However, the hysteroscopic appearance is significantly different. A uterine septum is located in the midline fundus and retracts with incision, while adhesions are rarely symmetrical and do not retract with incision, and thus require excision for complete removal. (See "Congenital uterine anomalies: Clinical manifestations and diagnosis", section on 'Septate or subseptate uterus'.)

For women with infertility or recurrent pregnancy loss, there are many potential etiologies. The evaluation for these conditions typically includes hysteroscopy, which would identify IUAs. (See "Female infertility: Evaluation" and "Recurrent pregnancy loss: Evaluation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hysteroscopy".)

SUMMARY AND RECOMMENDATIONS

●Intrauterine adhesions (IUAs), or intrauterine synechiae, is a condition in which scar tissue develops within the uterine cavity. IUAs accompanied by symptoms (eg, infertility, amenorrhea) is also referred to as Asherman syndrome. (See 'Definition and terminology' above.)

●The prevalence of IUAs is difficult to establish because the condition is rare, can be asymptomatic, and is not typically assessed for in a prospective fashion. Estimates of the prevalence range from 1.5 percent as an incidental finding at hysterosalpingogram (HSG) to 21.5 percent of women with a history of postpartum uterine curettage. (See 'Epidemiology' above.)

●IUAs appear to result from trauma to the basalis layer of the endometrium (figure 1). The basalis layer appears to be most susceptible to damage in the first four postpartum or postabortal weeks. Trauma typically results from intrauterine procedures such as dilation and curettage, although inflammation, infection, and uterine compression sutures can play a role. (See 'Etiology and risk factors' above.)

●Clinical manifestations of severe intrauterine adhesive disease include menstrual irregularities (amenorrhea, hypomenorrhea), infertility, cyclic pain, recurrent pregnancy loss, and abnormal placentation. IUAs can also be an incidental finding in an otherwise asymptomatic women. (See 'Clinical presentation' above.)

●The diagnosis of IUAs is based upon visualization of IUAs directly by hysteroscopy. Imaging studies such as HSG or saline infusion sonohysterogram can detect adhesions, but the sensitivity is lower compared with hysteroscopy and therefore a negative imaging study does not exclude adhesions. (See 'Diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Yanett Anaya, MD, who contributed to an earlier version of this topic review.