Hysteroscopic Management of Asherman's Syndrome

Accepted Manuscript Title: Hysteroscopic Management of Asherman's Syndrome: Special Issue Report on Uterine Surgery in the Journal of Minimally Invasive Gynecology Author: Zaraq Khan, Jeffrey M. Goldberg PII: DOI: Reference:

S1553-4650(17)31201-3 https://doi.org/doi:10.1016/j.jmig.2017.09.020 JMIG 3289

To appear in:

The Journal of Minimally Invasive Gynecology

Received date: Revised date: Accepted date:

16-6-2017 25-9-2017 26-9-2017

Please cite this article as: Zaraq Khan, Jeffrey M. Goldberg, Hysteroscopic Management of Asherman's Syndrome: Special Issue Report on Uterine Surgery in the Journal of Minimally Invasive Gynecology, The Journal of Minimally Invasive Gynecology (2017), https://doi.org/doi:10.1016/j.jmig.2017.09.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Hysteroscopic Management of Asherman’s Syndrome: Special issue report on

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Uterine Surgery in the Journal of Minimally Invasive Gynecology

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Zaraq Khan MBBS1 and Jeffrey M. Goldberg MD2 1

Assistant Professor of Obstetrics & Gynecology, Divisions of Reproductive

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Endocrinology & Infertility and Minimally Invasive Gynecologic Surgery, Mayo Clinic,

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Rochester, U.S.A.

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Comment [A1]: AUTHOR: Two different versions of Article Title were provided and the one in the manuscript has been used. Please check and confirm that it is correct

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Professor of Obstetrics & Gynecology, Division of Reproductive Endocrinology &

Infertility, Cleveland Clinic Foundation, Cleveland, U.S.A.

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Abstract

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In developed countries, Asherman’s Syndrome is almost always the result of a prior

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intrauterine operative trauma. This is often asymptomatic but may result in hypo- or

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amenorrhea and can contribute to infertility and pregnancy complications. We will

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review their etiology, clinical implications, and the systems which have been proposed

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to classify their extent. The numerous methods reported for performing lysis of

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intrauterine adhesions will be summarized along with the clinical results. Current

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strategies to prevent recurrence of intrauterine adhesions have not been conclusively

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shown to be clinically effective but the potential for endometrial regeneration using stem

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cells is an exciting modality under investigation.

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Key words: intrauterine adhesions, Asherman's syndrome, hysteroscopy, lysis

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of adhesions, adhesion reformation, menstrual abnormalities, infertility,

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pregnancy complications

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The formation of adhesions in an organ that routinely undergoes cyclical change

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with growth and sloughing is not well understood. (1) Intrauterine adhesions have been

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described as early as the end of the 19th century. (2) The term “Asherman’s Syndrome”

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became popularized after Joseph Asherman, described the condition in 29 patients after

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pregnancy. (3, 4) The terms “intrauterine adhesions” and “Asherman’s Syndrome” are

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often used interchangeably, though the syndrome requires signs and symptoms like

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pain, menstrual disturbances, subfertility etc. in the presence of intrauterine adhesions.

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(4)

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I.

Epidemiology & Etiology The true prevalence of intrauterine adhesions is difficult to establish, as a large

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number of patients will have no symptoms. (4) Prevalence ranges from 0.3% as an

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incidental finding in women undergoing IUD placement to 21.5% in women with a

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history of postpartum curettage. (5) The number of cases reported has been

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increasing with more than 2500 cases reported from 1982 to 2008. (6). The widespread

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use of hysteroscopy and improvement in imaging modalities concentrating on

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intrauterine pathology leading to more disease detection may be an important reason

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for the increasing prevalence.

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Traumatic denudation of the endometrial basalis layer to raw myometrium may

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result in permanent scar. This is the most common reason for intrauterine adhesions in

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the industrialized world. An older review of 1856 women with intrauterine adhesions

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demonstrated that 67% had curettage because of first trimester losses and 22%

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because of postpartum bleeding. (7)

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In a clinical trial that assessed the risk of uterine instrumention after incomplete

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abortion, 82 women were randomized to either a non-surgical treatment or dilation and

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curettage (D&C). (8) 7.7% of women who underwent D&C had some form of

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intrauterine adhesions compared to no adhesions in the non-surgical group. (8).

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Another review included 10 retrospective studies (n=912 women) and 8 prospective

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studies (n=1770 women) to assess the prevalence and risk factors for intrauterine

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adhesions after a first trimester loss. (9) An overall prevalence of intrauterine adhesions

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after a first trimester miscarriage was 19.1%. D&C appeared to be the major driver

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behind development of intrauterine adhesions and the number of losses was also a

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significant factor. (9)

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The risk of developing intrauterine adhesions, especially more severe adhesions,

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after postpartum cavity instrumentation is particularly high. The D&C for postpartum

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hemorrhage may be overly aggressive in a desperate attempt to halt the bleeding. In

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addition, the hypoestrogenic state impedes endometrial regeneration. This risk is

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highest if instrumentation is performed between 2nd and 4th week postpartum for the

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above reasons, as well as potential infection of the retained placental fragments. (7)

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Surprisingly, curettage in the first 48 hours postpartum seems to cause fewer

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adhesions. (10) Additionally uterine compression sutures used to treat severe

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postpartum hemorrhage have also been associated with the development of adhesions.

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In four retrospective reviews the prevalence of adhesions was 19% to 27%. (11-14).

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Finally, any procedure other than a D&C which includes uterine cavity

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instrumentation, can lead to development of uterine synechiae. For example the rate of

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adhesions formation was 6.7% after uterine septum takedown, 31.3% after single

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myoma resection and 45.5% after multiple myoma resections in one report. (15) Others

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have reported presence of adhesion after diagnostic hysteroscopy (1.6%), full thickness

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abdominal myomectomy (1.3%), cesarean delivery (2%) and IUD insertion (0.2%). (7)

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Infection of the endometrium is an important cause of uterine synechiae.

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Mycobacterium tuberculi- an obligate bacterial species - is commonly linked to

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development of intrauterine adhesions and cavity scarring. Two to 25% of infertile

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women can have genital tuberculosis in certain areas of the world. The threat of genital

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tuberculosis cannot be ignored especially in the era of the Human Immunodeficiency

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Virus-Acquired Immune Deficiency Syndrome (HIV-AIDS) epidemic. (16, 17)

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II.

Clinical Symptoms and Diagnosis Intrauterine adhesions can present with no symptoms at all or a variety of

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menstrual disorders including infrequent, light or absent bleeding, shortened days of

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flow, painful and very rarely heavy menstrual bleeding. (7) Light menstrual bleeding is

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correlated with severity and location of the adhesions. (18) Secondary infertility as an

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initial symptom has been reported in as high as 43% of women with intrauterine

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adhesions. (7) Defective vascularization at the level of the endometrium leading to

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ineffective implantation is hypothesized as a major reason for sub/infertility. (19, 20)

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Physical examination on its own frequently fails to reveal abnormalities in women

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with adhesive cavitary disease. (21) A detailed history accompanied by some form of

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uterine cavity imaging is the most helpful in making a diagnosis (Figure 1). Diagnostic

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hysteroscopy is considered the gold standard for diagnosis of intrauterine adhesions.

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(22) It provides a real-time view of the cavity that can aid in classifying the location and

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extent of the disease. (23) Additionally, it can be performed in the office with the ability

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to treat minimal disease at the same time. (24, 25)

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Hysterosalpingography (HSG) is the historical method of diagnosing intrauterine

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adhesions. (23) The filling defects with homogenous opacity and sharp contours make

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a classic appearance that is reproducible (26) and provides an imaging modality with a

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detection capacity comparable to hysteroscopy. (27-29)(Figure 1)

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Transvaginal ultrasound by itself has poor diagnostic ability, (30) however, when

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a distension media is used for the cavity (saline or gel; also called saline

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sonohysterogram [SIS] or gel infusion sonography [GIS]) the diagnostic ability is

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comparable to HSG. (27, 30) Three dimensional (3D) ultrasound may be more helpful

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in detecting intrauterine adhesions. (31, 32) The addition of power doppler sonography

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has shown promise in not only diagnosis, but also in determining prognosis for patients

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with Asherman’s syndrome. (33, 34)(Figure 1)

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Finally, magnetic resonance imaging (MRI) has also been evaluated for

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diagnosing intrauterine adhesions, but it is an expensive modality with limited availability

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and unknown diagnostic ability. (35, 36)(Figure 1) A comparison of most used

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diagnostic modalities can be seen in Figure 2a-e.

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III.

Classification of Intrauterine Adhesions Hysteroscopy is typically required to classify the location and severity of

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intrauterine adhesions. Classifying the disease process can be important as the

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severity dictated prognosis after treatment. (23, 37) There are seven reported

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classification systems. (5, 22, 38-43) A summary of these classifications systems can

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be seen in table 1. The lack of a standard scoring system makes it difficult to compare

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treatment outcomes between studies using different classifications.

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IV.

Disease Management After diagnosis of intrauterine adhesions, treatment is considered in cases where

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the patient has symptoms from the disease process. These symptoms can include

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hypo- or amenorrhea, pain, or more commonly, infertility or recurrent pregnancy loss.

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(23, 44) Surgery is considered the main therapy with no role for medical management.

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(5) There is however, a lack of level I evidence for comparing expectant management

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to surgery and for comparing the different methods of surgical interventions for

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intrauterine adhesions to each other. The ultimate goal of surgery is to have an

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anatomically restored and physiologically functional uterine cavity.

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i-

Expectant Management

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There are limited data that evaluate the role of expectant management in women

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with intrauterine adhesions. Expectant management in women has led to resumption of

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regular menses in 1 to 7 years in up to 78% (18/23 women) in one report. (45) Return

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of fertility was observed in 45.5% (133/292 women) who were observed expectantly.

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(45) It is important to note that these old data did not use any of the classification

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systems described previously. Moreover, many of these women had only cervical

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obstruction with expected reasonable obstetric outcomes.

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ii- Cervical Probing

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Cervical probing was one of the original interventions described for women with

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intrauterine adhesions. The report describes return of menses within a month in all 29

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patients. (3) However, it is likely that most women in the series only has cervical canal

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scarring with a healthy endometrial cavity. This technique currently has a limited role.

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iii- Dilation and Curettage (D&C) Before widespread use of operative hysteroscopy, blind D&C followed by oral

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estrogen therapy and placement of an intrauterine device (IUD) was used as one of the

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mainstays of treatment. Schenker and colleagues reported an 84% (1049/1250

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women) rate of resumption of normal menses after D&C. Conception was noted in 51%

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(540/1052 women) and 55% had term deliveries. (7) It is again likely that most of these

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women had mild disease, and the more severe cases were treated with a laparotomy

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and hysterotomy with lysis of adhesions. Blind D&C is associated with high risk of

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uterine rupture perforation and a low success rate and therefore, has a very limited role

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as well. (4)

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iv- Operative Hysteroscopy

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Lysis of intrauterine adhesions under direct hysteroscopic visualization is

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considered the treatment of choice for Asherman’s syndrome. Hysteroscopic guidance

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aids surgery by the following principles:

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a) Hysteroscopy enables lysis of adhesions under direct visualization and magnification. b) Cavity distension and separation of the uterine walls may place bands of fibrosis under tension, which can facilitate lysis of adhesions. c) Filmy adhesions (especially central cavity lesions) can be bluntly lysed with cavity distension and the tip of the hysteroscope. (46) (Figure 3a-b) d) Operating channels of hysteroscopes can allow various instruments to be used

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for lysis of adhesions including hysteroscopic scissors (22, 37, 39), monopolar

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energy systems (39, 47), bipolar energy systems (48, 49), or Neodymium-doped

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Yttrium Aluminium Garnet [Nd-YAG] laser(39, 50, 51)

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e) Surgical treatment may be performed in an office or outpatient setting with

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outcomes similar to those in an inpatient setting. (52)

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The basic principle involves beginning adhesiolysis in a caudad to cephalad

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manner. The filmy and central cavity adhesions are taken down first to enable cavity

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distension. The dissection is continued cephalad towards the uterine fundus. Lateral or

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extremely dense adhesions are taken down last, as they are technically harder to resect

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and can result in a higher chance of uterine perforations. (4)

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1. Instruments for Operative hysteroscopy and lysis of intrauterine adhesions

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A surgeon has a choice of several modalities for lysis of adhesions at the time of hysteroscopy. These include the following: a) Hysteroscopic Scissors:

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Semi-rigid 5 French (F) or 7F scissors through a 6.5 mm operating hysteroscope

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is the preferred method for resection of intrauterine adhesions. (22, 37, 39)(Figure4)

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Using sharp dissection gives an advantage of minimizing destruction of healthy

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endometrium. (4) This can decrease the risk for further damage and reduce the risk of

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recurrence. (53) Additionally the lack of coagulation while dissecting with scissors can

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be used to the surgeon’s advantage while determining when to stop resection at the

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uterine fundus. Slight bleeding at the fundus indicates entry into myometrium - and

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adequate adhesiolysis- a phenomenon that is masked if instruments with coagulation

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capacity are used.

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b) Monopolar Electrosurgery Instruments: Monopolar electrosurgery instruments have been described for resection of

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intrauterine adhesions with noted success. (39, 54) The main advantage of this

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modality is precise and hemostatic resection of disease. Monopolar instruments require

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non-electrolyte distending media like glycine and sorbitol. (55) These solutions are

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however hypotonic and excessive absorption can lead to hypo-osmolality and

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hyponatremia, and in extreme cases, potentially fatal cerebral edema with brain stem

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herniation. (56) A 1000 mL hypotonic fluid deficit can lead to a significant drop in serum

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sodium. (56)

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Furthermore, there is an increased risk of visceral damage if uterine perforation occurs

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while using monopolar instruments. (23) Additionally, endometrial damage from these

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instruments may predispose to recurrence of intrauterine adhesions. (57) The

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procedure is hence best performed under experienced hands where time management

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and efficiency of movement in the surgical field is of paramount importance.

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c) Bipolar Electrosurgery Instruments: Bipolar vaporization of adhesive disease in the uterine cavity using the

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Versapoint instrument (Versapoint Electro-Surgical System, Gynecare, Inc., Menlo

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Park, CA) has been described. (48, 49) The advantage over monopolar instruments is

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the fact that these instruments use normal saline (an isotonic solution) as the uterine

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distension medium. Even though excessive fluid deficit with normal saline can result in

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hypervolemia, pulmonary edema and congestive heart failure, these complications are

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typically seen at fluid deficit of >2500 mL and, most can be reversed by Lasix induced

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diuresis. (55)

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d) Neodymium-doped Yttrium Aluminum Garnet (Nd-YAG) laser: Nd-YAG laser is another modality that can be used to assist with hysteroscopic

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lysis of intrauterine adhesions. (39, 50, 51) The use of the laser allows for precise

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resection, however, there stands a significant risk for injury, if a uterine perforation were

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to occur. (37)

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2. Additional techniques for guidance during hysteroscopy

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Several ancillary techniques have been described to improve the performance

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and safety in difficult cases of hysteroscopic adhesiolysis (typically with severe

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occlusive disease)

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a) Installation of Methylene Blue Dye: Installation of methylene blue dye to stain the endometrium can guide the surgeon into pockets of island of endometrium in between areas of fibrosis. The dye

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stains endometrium well but uptake into myometrium is not seen. (39) This technique

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is best used in treatment of mild and marginal disease.

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b) Ultrasound guided resection: Transabdominal ultrasound guidance can help to delineate the location and

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extent of the adhesions and reduce the risk of uterine perforation. (4, 58) The

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availability and familiarity of sonography to gynecologists makes this option easy to

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implement. Still, uterine perforations in as many as 5% of cases have been reported.

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(58) The use of transrectal ultrasound and laparoscopic intracorporal ultrasound to

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guide hysteroscopic adhesiolysis have recently been described but needs further study.

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(59)

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c) Fluoroscopic guided resection:

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Fluoroscopic guidance allows the surgeon to view islands of endometrium behind

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scar tissue in an obliterated uterine cavity. The use of a Touhy needle as an instrument

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that is used in parallel to hysteroscopy has been described. (60, 61) Radiopaque dye is

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injected into an area of dense scar at the point where the cavity is obliterated. Any

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pockets of endometrium beyond the adhesive area, can then be identified using

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fluoroscopy and this area can be opened up by sharp dissection under hysteroscopic

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view. (60) This technique has also been described as an outpatient procedure, though

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further study is needed. (62)

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d) Laparoscopic guided resection:

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Laparoscopic guidance for severe cases of intrauterine adhesiolysis has been

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advocated for immediate recognition and treatment of uterine perforation and

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minimizing extrauterine trauma. (49, 63, 64) However, it will not decrease the

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occurrence of uterine perforation.

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3. Unique hysteroscopic techniques for severe cases of intrauterine adhesions

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There are a few techniques described in the literature almost exclusive to

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women with severe occlusive cavitary disease. These techniques are yet to be studied

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in detail and their use should be reserved to experienced surgeons, as they may result

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in serious complications.

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a) Myometrial Scoring

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In patients with severe disease a myometrial scoring technique has been

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described. (63, 65) A Collins knife electrode is used to score 6-8, 4-mm deep incisions

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from the fundus to the cervix, and a transverse incision at the uterine fundus. The goal

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is for creation of a cavity with endometrium regenerating over the new exposed area.

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Restoration of the cavity was successful in 71% of patients (5/7 women), with

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42% (3/7 women) achieving a pregnancy in one report. (63) Another case series

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reported restoration of the cavity with at least one ostium visible in 100% of the patients

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(31/31 women) and a pregnancy rate of 42.8% (12/28), however, these pregnancies

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were at risk of hemorrhage with abnormal placentation. (65)

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b) Dense adhesions treated as a uterine septum

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In cases where the endometrial cavity is obliterated, a cervical dilator can be directed

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from the cervical canal towards each tubal ostium. This creates two 2 lateral landmarks

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and a fibrous septum in the middle which was resected transcervically under

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laparoscopic guidance in the one 1997 study of this technique. (64) Currently,

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hysteroscopic resection would be the preferred modality. Two out of 6 women in this

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report experienced a uterine perforation and an additional woman had a significant

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hemorrhage. (64) However, a normal cavity was restored in all cases and 5

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pregnancies were achieved in 4 women.

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v- Laparotomy

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The use of laparotomy followed by a hysterotomy and transfundal lysis of adhesions

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using a finger or curette has been the traditional treatment for severe cases of

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intrauterine adhesions in the era prior to hysteroscopy. (21, 49, 66) A review reported

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52% (16/31 women) conception rate and 36% (11/31 women) live birth rate after this

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procedure. (45) This technique is of historic interest only and should be reserved for the

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rare severe case where other techniques are not possible. (67)

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V.

Postoperative Management Postoperative management is focused on reducing the risk of reformation of

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adhesions, the rate of which can be up to 1/3 with mild to moderate adhesions, and 2/3

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with severe adhesions. (39, 44, 65, 68, 69) Table 2 summarizes the studies on the

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various methods which are described below. There is however, no consensus

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regarding the optimal methods to prevent intrauterine adhesions. In fact, two recent

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systematic reviews concluded that the limited studies had low/very low quality of

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evidence with underpowered sample sizes, significant heterogeneity and high risk of

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bias. There was insufficient evidence to support any treatment as being effective for

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preventing adhesions or improving clinical pregnancy or live birth rates. (70, 71)

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Studies not included in those reviews looked at medications to increase vascular flow to

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the endometrium and explored the role of human stem cells for regeneration of the

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endometrium.

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a) Solid Barriers IUD insertion after lysis of intrauterine adhesions is a time honored treatment.

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(22, 45) However, data to support its effectiveness is lacking. The type of IUD inserted

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may be important. Copper IUD for example can provoke inflammation and may be

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counter-productive. (72) Similarly the T-shaped IUDs have a small surface area limiting

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their ability to keep the walls of the endometrial cavity separated during healing. (73)

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There are a few studies comparing IUD use to intrauterine balloon, Foley catheter,

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hormone treatment and barriers like amniotic membranes with conflicting outcomes.

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(Table 2) (71, 74-77) The risk of infection after IUD insertion post-surgical resection of

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intrauterine adhesions is around 8%. (74)

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Use of a pediatric Foley catheter or intrauterine balloon has also been described

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after adhesiolysis. (22, 62, 66, 74) The use of postprocedure Foley catheter has been

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compared to other modalities with mixed outcome results. (Table 2) (74, 75, 78)

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b) Semi-Solid Barriers: Newer adhesions barriers include auto crosslinked hyaluronic acid gel and modified hyaluronic acid. While initial reports on their use have been encouraging,

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larger confirmatory studies are needed prior to incorporating them in clinical practice.

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(Table 2) (79-83)

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Fresh and dry amniotic membranes have been used as an adhesion barrier with

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fresh amnion showing better results.(78, 84) The complementary use of fresh amnion

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graft with a Foley catheter has been described in cases of severe Asherman’s

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syndrome. (84) Follow-up hysteroscopy in this study revealed postoperative formation

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of adhesions in only those that had severe disease before adhesiolysis. In all cases

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these new adhesions were classified as minimal. Patients who had moderate disease

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had no adhesion reformation. (84)

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c) Hormone therapy

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Postoperative estrogen treatment has not been standardized in terms of dosage,

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duration, administration route or combination with progesterone and data on its

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effectiveness is limited. (Table 2) (37, 60, 67, 76, 85)

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Techniques to increase vascular flow to the endometrium

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Medications like aspirin, sildenafil and nitroglycerine have been used to increase

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the endometrial blood flow in an attempt to encourage endometrial regeneration. (86-

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88) Successful pregnancies after their use have been reported (89), but given the

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limited data, more extensive study is required before their use can be recommended.

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d) Stem Cell Treatment The use of stem cell therapy to help regenerate the endometrium has recently shown promise. (90-94) In one report, all 16 women treated with uterine intravascular

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infusions of bone marrow derived stem cells (BDSC) had return of menses following

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adhesiolysis. (93) There were three spontaneous pregnancies and another seven

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pregnancies with in vitro fertilization. (93) Further study with larger randomized trials

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will help establish the role of BDSC in treatment of Asherman’s syndrome.

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e) Use of Antibiotics

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Studies are lacking regarding the risks and benefits of antibiotics before, during

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or after surgical lysis of intrauterine adhesions. The American Congress of Obstetrics

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and Gynecology (ACOG) does not recommend the routine use of antibiotics for this

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procedure. (95)

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VI.

Outcomes after Hysteroscopic Treatment

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There are several different outcomes that are important to assess after

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hysteroscopic treatment of intrauterine adhesions. These include: return of menses,

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improvement in postoperative adhesion scores, and pregnancy rates and outcomes.

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The primary difficulty with analyzing the outcome data after surgery arises from lack of a

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standard scoring system small case numbers, different follow-up intervals and lack of

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randomized controlled trials.

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In general most patients with absent menses will resume some form of a

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bleeding pattern after surgery, with a rate between 92%-96% reported in most studies.

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(49, 61, 96, 97) It is more difficult to report on postoperative adhesion scores and

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comment on fertility and pregnancy outcomes with accuracy.

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A systematic review has gathered information on 36 articles that reported fertility

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and obstetric outcomes after hysteroscopic surgery for intrauterine adhesions. (5) This

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report quotes a pregnancy rate of 63% (968 of 1542 women) and a live birth rate of 75%

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(696 of 930 women). (5) Major complications in pregnancy have been reported in women who have

347 348

undergone hysteroscopic adhesiolysis for Asherman’s syndrome. Abnormal

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placentation is the most commonly reported complication after hysteroscopic treatment

350

of intrauterine adhesions. (4, 39, 49, 63, 64) Of the 696 births reported after

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hysteroscopic treatment of Asherman’s syndrome, 17 pregnancies were reported to

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have placental abnormalities. (5) Seven peripartum hysterectomies, (39, 49, 61, 63, 98,

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99) and a single neonatal death have been reported in this group of patients.(100)

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Similarly, preterm labor after surgical treatment for intrauterine adhesions is noted to be

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as high as 40% to 50%. (49, 63-65)

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obstetrician for pregnancies after surgical treatment for Asherman’s syndrome.

These data emphasize the role of a high-risk

Our lack of understating of the molecular pathophysiology of benign uterine

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disease including intrauterine adhesions has caused a major hurdle in reaching a goal

359

of complete cure. While surgical management is gaining finesse, prevention of disease

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and its recurrence is of greater importance. As we begin to emphasize more on the

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molecular mechanisms behind these diseases, avenues to for innovative therapy will

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open.

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Yu D, Wong YM, Cheong Y, Xia E, Li TC. Asherman syndrome--one century later. Fertil Steril.

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Al-Inany H. Intrauterine adhesions. An update. Acta Obstet Gynecol Scand. 2001;80(11):986-93.

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Schenker JG, Margalioth EJ. Intrauterine adhesions: an updated appraisal. Fertil Steril.

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surgical management of spontaneous abortion. J Am Assoc Gynecol Laparosc. 2002;9(2):182-5.

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review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-

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term reproductive outcome. Hum Reprod Update. 2014;20(2):262-78.

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examination of 141 patients. Dan Med Bull. 1960;7:50-1.

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Figure 1: Flowsheet highlighting the diagnostic potential of various radiologic modalities

600

for intrauterine adhesions.

601

Figure 2: These images present a comparison between 2-dimensional (2D) ultrasound,

602

3-D ultrasound, Saline sonohysterography and diagnostic hysteroscopy in the same

603

patient who developed intrauterine adhesions after a D&C following a first trimester loss.

604

(a) On 2D ultrasound the trilaminar appearance of the endometrium is lost. (b) On 3D

605

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606

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607

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608

arrow). (d) Diagnostic hysteroscopy revealed an obstructed cavity with loss of

609

anatomical landmarks. (e) After extensive lysis of intrauterine adhesions, the uterine

610

cavity was successfully restored.

611

Figure 3: Postoperative flexible hysteroscopy images are shown. (a) A band of

612

adhesion that had reformed after initial surgery is noted at the uterine fundus. (b) The

613

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614

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615

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616

Figure 4: The image displays the use of a hysteroscopic scissors for resection of

617

intrauterine adhesions. This is typically the preferred method for resection of most

618

intrauterine adhesions.

619

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620

Table 1: Summary of Classification Systems for Intrauterine Adhesions Reference March et al 22

Year 1978

Determinants of Classification Degree of cavity involvement

Hamou et al 38 Valle et al 39

1983 1988

Location of disease Type of adhesion and Extent of occlusion

European 1989 Society for Hysteroscopy40

Type of adhesion, Tubal ostia involvement and Menstrual patterns

American Fertility Society 41

1988

Extent of cavity involvement, Type of adhesion and Menstrual patterns

Donnez et al 42

1994

Location of disease

Nasr et al 43

2000

Location of disease, Type of adhesion, Tubal ostia involvement, Menstrual patterns, Reproductive history

Summary of Classification Mild (<1/4th of cavity involved) vs. Moderate (1/4-3/4th cavity involved, No ostia involved) vs. Severe disease (>3/4th cavity involved, ostial involvement, upper cavity occluded) Isthmic vs. Marginal vs. Central disease Mild vs. moderate vs. severe type of adhesions, partial vs. complete involvement of cavity I: filmy adhesions, no ostial disease II: Firm adhesions, no ostial disease III: Multiple firm adhesions; either with ostial disease or menstrual abnormalities IV: Extensive firm adhesions with agglutination of uterine walls and both ostia occluded Scoring system taking into account: Extent of cavity involvement ( <1/3 vs. 1/31/2 vs. >2/3) Type of adhesions (Filmy vs. filmy and dense vs. dense) Menstrual pattern (normal vs. light vs. absent flow) Central disease (Class I) vs. Marginal disease (Type II) vs. Global disease (Type III) Scoring system taking into account: Location of disease (Isthmic disease yes/no) Type of adhesion (filmy vs. dense) Tubal Ostia involvement (none vs. single vs. both ostia involved) Menstrual pattern (normal vs. light vs. absent flow) Reproductive history (normal vs. recurrent pregnancy loss vs. infertility)

621 622

Page 29 of 45

623

Table 2: Summary of reports, comparing various modalities to reduce reformation of adhesions post resection Study Design

Comparison groups

Relevant Information

Outcomes

Solid Barriers Orhue et al.

Lin et al.

74

75

Prospective Cohort Study

IUD vs. Foley catheter

IUD arm: 51 women with Lippes loop IUD placed after surgery for 3 months Foley arm: 59 women with a Foley catheter placed postoperatively for 10 days

Absent menses: 19% in Foley group vs. 38% in IUD group (p<0.03) Pregnancy Rate: 34% in Foley group vs. 28% in IUD group (p=0.4656) Fewer infections and fewer recurrent adhesions in Foley Group.

Randomized trial

IUD vs. Intrauterine Balloon

IUD arm: 80 women for 1 week postsurgery Foley arm: 82 women for 1 week postsurgery

No difference in adhesion reformation (35% in IUD vs.30% in Foley group) No report on pregnancy outcomes

Randomized trial

Hyaluronic acid gel (Hyalobarrier gel; Baxter International Inc., Deerfield, IL) vs. No treatment

Hyalobarrier arm: 43 women No treatment arm: 41 women

2 look hysteroscopy 3 months after surgery for intrauterine adhesions 14% (6/43) in hyaluronic acid arm vs. 32% (13/41) in no treatment arm (p<0.05)

Randomized Trial

Auto-crosslinked Hyaluronic Acid gel (ACP) vs. No treatment

ACP arm: 67 women No treatment arm: 65 women

2 look hysteroscopy after surgery for intrauterine adhesions 10.4% with adhesions in theACP arm vs. 26.2% in the no treatment arm (p<0.05)

Randomized Trial

Modified Hyaluronic acid + carboxymethylcellulose (Seprafilm; Genzyme Corp., Cambridge, Massachusetts) vs. No treatment control

Seprafilm arm: 50 women Control arm: 100 women

Randomized Trial

Auto-crosslinked Hyaluronic Acid gel (ACP) vs. No treatment

ACP arm: 77 women Control arm: 72 women

8 months after surgery in Women who did not have a D&C: 100% (32/32) pregnant in Seprafilm arm vs. 54% (34/56) in the control arm (p<0.05) If no pregnancy after 8 months all got HSG: 10% (1/10) had intrauterine adhesions at HSG in Seprafilm arm vs. 50% (7/14) in the control arm nd 2 look hysteroscopy Intrauterine adhesions in ACP arm were seen in 13% (10/77) vs. 30.6% (22/72) in the control group (p= 0.013)

Randomized Trial

Hormones vs. No Hormones

Semi-Solid Barriers Acunzo et al.

Guida et al.

80

81

Tsapanos et al.

Hooker et al.

82

79

Data was stratified on whether or not a woman had a D&C prior to the surgery for removal of adhesions

nd

nd

Hormonal Treatments Farhi et al.

85

Hormone arm: 30 women (daily 2 mg estradiol valerate for 21 days + 0.5 mg norgestrel for 10

Hormone arm had greater endometrial thickness than control group (0.84 cm vs.

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Sanfilippo et al.

Amer et al.

Lin et al.

77

78

76

days) Control arm: 30 women Mixed Comparisons

0.67 cm) (p=0.02)

No difference in postoperative intrauterine adhesion reformation Pregnancy rate slightly higher in IUD + hormone group Diagnostic Hysteroscopy after 2-4 months Amnion grafts reduced reformation of adhesions (p= 0.003). Fresh Amnion were superior to dry Amnion (p= 0.01) Of the 10 patients who were pregnant 80% (8/10) had amnion graft 20% (2/10) had balloon placement nd At 2 look hysteroscopy: Balloon group had the lowest number of adhesions (p<0.001). IUD group had fewer adhesions than the gel and control group

Randomized Trial

IUD + hormones vs. Hormones only

IUD + Hormones arm: 26 women Hormones only arm: 9 women

3-arm pilot Randomized Trial

Fresh Amnion vs. Dry Amnion vs. Intrauterine balloon

Fresh Amnion arm: 15 women Dry Amnion arm: 15 women Intrauterine Balloon arm: 15 women

Retrospective cohort

Balloon catheter vs. IUD vs. Hyaluronic gel vs. Control

Balloon catheter arm: 20 women IUD arm: 28 women Hyaluronic Gel arm: 18 women Control arm: 41 women

624 625 626

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10. Figure 3a.jpg

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11. Figure 3b.jpg

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12. Figure 4.jpg

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5. Revised_Figure 2a_bestsetConverted.png

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6. Revised_Figure2b_bestsetConverted.png

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7. Figure2c_bestsetConverted.png

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8. Figure2d.jpg

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9. Figure2e.jpg

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5. Revised_Figure 2a.tif

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6. Revised_Figure2b.tif

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7. Figure2c.tif

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