Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

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Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review Rea Konci, BSc;1 Natasha Caminsky, MDCM, MSc;1 Togas Tulandi, MD, MHCM;1,2 Michael H. Dahan, MD1,2
al, QC Faculty of Medicine, McGill University, Montre

1


al, QC Department of Obstetrics and Gynecology, McGill University Health Centre, Montre

2

R. Konci

Abstract Intrauterine adhesions (IUAs) are a result of trauma to the basalis layer of the endometrium and may lead to clinical sequelae such as miscarriage, infertility, and menstrual irregularities. Hysteroscopy is recognized as the gold standard in diagnosis and management, although the optimal treatment after surgical intervention remains unclear. This review aimed to provide an update on the treatment options available after hysteroscopic adhesiolysis and to facilitate clinical management of patients with IUAs. To avoid duplicating previous work, the review focused on studies that compared various adjunctive postoperative treatments in patients receiving hormone therapy. Of 548 studies, 15 papers fit our criteria that compared postresection treatment options in women with IUAs. Meta-analysis of the use of Foley catheter or amnion graft as an adjunctive therapy after adhesiolysis failed to show a statistical difference (Odds Ratio 1.55; 95% confidence interval 0.60−3.99). Meta-analysis could not be done for the 13 remaining studies as a result of extensive heterogeneity, bias, or non-comparable end points. The lack of a universal classification system for IUAs and the use of variable outcomes to measure the success of adjunctive treatment pose challenges in generating standard treatment recommendations. This review calls for the development of a universal classification system and studies with consistent parameters and end points to allow for the generation of standard treatment guidelines. On the basis of the available evidence, recommendation of specific adjunctive treatments after hysteroscopic adhesiolysis is unjustified. Key Words: Intrauterine adhesions, hysteroscopy, infertility, miscarriage, treatment Corresponding author: Dr. Togas Tulandi, Faculty of Medicine, McGill University; Department of Obstetrics and Gynecology, McGill
al, QC. [email protected] University Health Centre. Montre

Résumé
rences intra-ute
rines (AIU) sont le re
sultat d’un traumatisme Les adhe  la couche basale de l’endome tre; elles peuvent entra^ıner des a
quelles cliniques telles que l’avortement spontane
, l’infertilite
et se
gularite
menstruelle. L’hyste
roscopie est reconnue comme la l’irre
thode par excellence en matie  re de diagnostic et de traitement, me s l’intervention chirurgicale quoique le traitement optimal apre  fournir une mise a  jour sur demeure incertain. Cette analyse visait a
rapeutiques possibles apre  s le de
bridement les options the
roscopique et a  faciliter la prise en charge clinique des patientes hyste
viter de reproduire les travaux existants, ayant des AIU. Pour e
sur des e
tudes qui comparaient les traitements l’analyse a porte
ratoires chez les patientes qui suivent une d’appoint postope
rapie. Des 548 e
tudes re
pertorie
es, 15 articles hormonothe re de se
lection, a  savoir la comparaison des correspondaient au crite
section chez les femmes ayant des
rapeutiques postre options the
ta-analyse n’a pas e
te
en mesure de faire ressortir une AIU. Une me
rence statistique relativement a  l’utilisation de la sonde de Foley diffe ou la greffe de membrane amniotique comme traitement d’appoint s un de
bridement (OD : 1,55; intervalle de confiance a  95 % : apre
te
possible de re
aliser une me
ta-analyse pour 0,60-3,99). Il n’a pas e
tudes en raison de l’he
te
roge
ne
ite
importante, des les 13 autres e  res de jugement non comparables. En raison de biais ou des crite me de classification universel des AIU et de l’absence d’un syste
sultats variables pour e
valuer l’efficacite
des l’utilisation de re traitements d’appoint, il est difficile de produire des recommandations
rapeutiques standards. Cette analyse pre
conise la cre
ation d’un the tres et de me de classification universel et l’utilisation de parame syste res de jugement cohe
rents dans les e
tudes afin de permettre la crite s les production de directives sur les traitements standards. D’apre
es probantes disponibles, il n’est pas justifie
de recommander donne s un de
bridement des traitements d’appoint en particulier apre
roscopique. hyste

Competing interests: See Acknowledgements.

© 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.

Each author has indicated that they meet the journal’s requirements for authorship.

J Obstet Gynaecol Can 2019;000(000):1−17

Received on January 6, 2019

https://doi.org/10.1016/j.jogc.2019.09.008

Accepted on September 10, 2019

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INTRODUCTION

ntrauterine adhesions (IUAs) were first reported by Heinrich Fritsch, a German gynaecologist in 1894. However, the clinical picture of cyclical pelvic pain, menstrual disturbance, and subfertility in addition to the presence of IUAs was only recognized 50 years later, when it was named Asherman’s syndrome or intrauterine synechiae. IUAs cause either partial or complete obliteration of the uterine cavity and sometimes lead to infertility or miscarriage.

I

IUAs develop when the basal layer of the endometrium undergoes trauma, usually surgical, including the performance of curettage, particularly when infection is present. This trauma can occur after curettage for retained placentas or postpartum hemorrhage, myomectomy, or any other injury to the endometrium. The traumainduced granulation tissue forms bridges with tissue adjacent to either side of the endometrial cavity. Endometrial glands are usually replaced by inactive cuboidal or columnar epithelium, typically unresponsive to hormonal stimulation. The symptoms associated with IUAs vary depending on the location and extent of the adhesions. Patients can experience hypomenorrhea (32.1%), amenorrhea (9.0%), or infertility (55.1%).1 Should a patient with untreated IUAs achieve pregnancy, there is a risk of abnormal placentation. Pregnancy complications may include (1) spontaneous abortion, (2) preterm delivery, (3) placenta accreta, and (4) ectopic pregnancy.2 The diagnosis of IUAs requires a combination of clinical and imaging findings. Hysteroscopy is the gold standard for the diagnosis of IUAs because it allows for both the visualization and treatment of adhesions. Other imaging

techniques include hysterosalpingography, saline infusion sonography, three-dimensional ultrasound, and magnetic resonance imaging. Once diagnosed, IUAs can be graded (Table 1). Al-Inany provided a comprehensive summary of the six classification systems.3 However, there is still no consensus on the best classification system, thus making comparison of studies difficult. The best treatment of IUAs, especially postoperative management, remains unclear. In general, treatment consists of removal of the adhesions and prevention of recurrent adhesion formation, the rates of which may be as high as 62.5% in patients with severe adhesions and 22% in moderate cases.2,4 The current treatment is hysteroscopic adhesiolysis, which is intended to restore the normal uterine architecture. In severe cases, a concomitant ultrasound examination can be performed to guide the surgeon in where to cut and to prevent uterine perforation. Laparoscopy is rarely needed. Several comprehensive reviews describing the various detection, lysis, and post-lysis treatment options exist; however, there is minimal consensus on the evidence supporting their uses.5 The challenge of interpreting the data is compounded by the various non-equivalent classification systems (Table 1), thereby making the comparison of results among studies challenging and the selection of a treatment regimen complicated. Although there are articles supporting different treatment options, the best treatments remain unclear.1,6 The purpose of our review was to summarize available data on post-hysteroscopic adhesiolysis treatment systematically to facilitate physicians’ informed and evidence-based decision-making process, to critically assess the findings to date, to perform meta-analyses where appropriate, and to propose future investigations.

Table 1. Classification systems for intrauterine adhesions Classification system March Classification (March et al., 1978)

Grading scale

Parameters

Mild, moderate, severe

Proportion of cavity occupied by adhesions Areas of uterus occupied/occluded by adhesions

American Fertility Society (American Fertility Society, 1988)

Mild, moderate, severe (score 1−12)

Extent of cavity involved Type of adhesions (filmy, dense, filmy and dense) Menstrual pattern (normal, hypomenorrhea, amenorrhea)

European Society for Hysteroscopy (Deans and Abbott, 2010)

I−IV

Areas of uterus occupied/occluded by adhesions Type of adhesions Clinical symptoms

Mild, moderate, severe

Extent of occlusion (partial or total) at hysterosalpingography

6 grades

LocationPostoperative pregnancy rate

Valle and Sciarra (1988) Donnez and Nisolle (1994) Nasr et al. (2000)

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Prognostic score

Menstrual and obstetric history Intrauterine adhesion findings at hysteroscopic assessment

Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

Figure 1. Selection of articles used for review and meta-analysis.

IUD: intrauterine device.

METHODS Search Strategy

We performed an electronic-based search using PubMed, EMBASE, Ovid Medline, Google Scholar, ClinicalTrials. gov, and Cochrane Central Register of Controlled Trials. The following medical subject headings (MeSH) term combinations were used: gynatresia, Asherman, intrauterine synechiae, intrauterine adhesion, uterine synechiae, postoperative period, postoperative, post-operation, post-surgery, post-surgical, therapy, treatment, therapeutics, prevention. The search was limited to trials in humans, published in English or French up to April 2, 2018. We manually searched the reference lists of identified studies. Initial abstract screening and subsequent manuscript review were performed by two independent reviewers (R. K., N.G.C.). The third and fourth authors (T.T. and M.D.) resolved any discrepancy. Only articles related to post-hysteroscopic adhesiolysis were evaluated. Randomized controlled trials (RCTs) and cohort studies were included in the review. Review articles and case reports were excluded.

The review was made following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (Figure 1). Articles and published abstracts were analyzed, and the following characteristics were obtained: study design, year of publication, number of patients, patient profile, details of treatment measurements, complementary hormone treatment and its duration, severity of adhesions, the classification system used, and outcomes. Methodological quality assessment of non-randomized studies for potential risk of bias was evaluated using the Newcastle-Ottawa Scale for observational studies (Table 2). RCTs were assessed by the Cochrane Collaboration’s tool for assessment of risk of bias (Figure 2). The main outcomes included were adhesion recurrence, menstrual status and endometrial thickness, fertility (pregnancy and/or live birth), and adhesion category. RESULTS

Our search initially retrieved 548 articles. After screening of the titles and abstracts, 492 articles did not fulfill the selection criteria. An additional 41 studies were excluded for the following reasons: the full text was not

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Table 2. Newcastle-Ottawa assessment of non-randomized studies Amer et al. Chen et al. Lin et al. Liu et al. Liu et al. Orhue et al. Peng et al. (2006) (2017) (2013) (2016) (2018) (2003) (2017) Selection

Compatibility

Outcome

Total number of stars

1. Representativeness of the exposed cohort: (a) truly representative of the average population in the community*; (b) somewhat representative of the average population in the community*; (c) selected group of users (e.g., nurses, volunteers); d) no description of the derivation of the cohort

C

A*

B*

D

D

D

D

2. Selection of the non-exposed cohort: (a) drawn from the same community as the exposed cohort*; (b) drawn from a different source; (c) no description of the derivation of the non-exposed cohort

—

A*

A*

A*

A*

C

A*

3. Ascertainment of exposure: (a) secure record (e.g., surgical records)*; (b) structured interview*; (c) written self-report; (d) no description

A*

A*

A*

A*

A*

A*

A*

4. Demonstration that outcome of interest was not present at start of study: (a) Yes*; (b) No

A*

A*

A*

B

A*

A*

A*

(a) study controls for age, no. pregnancies, deliveries, miscarriages, D&Cs*

—

*

*

—

*

*

*

(b) study controls for any additional factor* (concomitant laparoscopy, tubal patency*)

—

*

—

—

—

*

*

1. Assessment of outcome (a) independent blind assessment*; (b) record linkage*; (c) self-report and (d) no description

B*

A*

B*

B*

A*

B*

B*

2. Was follow-up long enough for outcomes to occur? (a) Yes (define an adequate follow-up period for the outcome of interest)*; (b) No

*

*

*

*

*

—

*

3. Adequacy of follow-up of cohorts: (a) complete follow-up - all subjects accounted for*; (b) subjects lost to follow-up unlikely to introduce bias - less than 20% or equal of the description of those lost suggested no difference from those followed*; (c) followup rate less than 80% and no description of those lost;(d) no statement

A*

B*

A*

D

B*

B*

A*

5

9

8

4

7

6

8

Good

Good

Poor

Good

Fair

Good

1. Comparability of cohorts on the basis of the design or analysis:

Quality rating Poor according to guideline D&C: dilatation and curettage.

Thresholds for converting the NOS (number of stars) rating to Agency for Healthcare Research and Quality standards (good, fair, and poor): Good quality: 3 or 4 stars in Selection domain AND 1 or 2 stars in Comparability domain AND 2 or 3 stars in Outcome domain Fair quality: 2 stars in Selection domain AND 1 or 2 stars in Comparability domain AND 2 or 3 stars in Outcome domain Poor quality: 0 or 1 star in Selection domain OR 0 stars in Comparability domain OR 0 or 1 stars in Outcome domain Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability.

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Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

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Pabuccu, R., et al. (2008).

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Zhou, Q., et al. (2018).

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Amer, M. I., et al. (2010) Chi, Y., et al. (2018) Gan, L., et al. (2017). Guo, J., et al. (2017) Lin, X. N., et al. (2015)

Selecve Reporng

Other Sources of Bias

Blinding of Outcome Assessment (detecon bias)

?

Acunzo, G., et al. (2003

Incomplete Outcome Data

Blinding of Parcipants and personnel (performance bias)

+

Random Sequence Generaon (Selecon Bias)

Allocaon Concealment (Selecon Bias)

Figure 2. Risk of bias using the Cochrane risk of bias assessment tool.

Green (+) refers to a low risk, yellow (?) refers to an unclear risk, and red ( ) refers to a high risk of bias. This tool has been used from “The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials” by Julian P T Higgins, €ni, David Moher, Andrew D Oxman, Jelena Savovi
Douglas G Altman, Peter C Gøtzsche, Peter Ju c, Kenneth F Schulz, Laura Weeks, Jonathan A C Sterne, Cochrane Bias Methods Group. Retrieved from https://doi-org.proxy3.library.mcgill.ca/10.1136/bmj.d5928.

accessible, the full paper was not written in either English or French, or the study was not controlled. Two of the studies were RCTs that met all other criteria, but both had to be excluded because the full articles were not available in English or French.7,8 Other-language (non-English, non-French) studies that were not included in the systematic review also failed to meet the selection criteria. Finally, 15 studies were included in our review (Figure 1). The study characteristics and risk of bias of those studies are shown in Tables 2 to 4. Of the total 15 remaining controlled studies, eight studies were RCTs and seven were cohort studies (prospective or retrospective). The severity of adhesions included in the studies was mainly moderate to severe, with one study including mild

adhesions. Several classification systems were used: the American Fertility Society, March Classification, and the European Society for Gynecological Endoscopy. All studies included in this review, with the exception of one, used complementary cyclical hormone therapy.9 However, the duration and dose of hormone therapy, as well as the mean follow-up period, were not uniform. Reported Interventions

Of eight RCTs consisting of 720 women with IUAs, the patients’ mean age varied from 27.0 to 33.7. Of the seven cohort studies (755 women), the mean age was between 20.2 and 35.6. Hysteroscopic adhesiolysis was the first step in the treatment of IUAs in all studies, whereas primary and secondary outcome measures and adjuvant therapy use varied among studies (Tables 3 and 4).

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Study

Type of study

Study size (age)

Treatment

Details of HT

Severity of adhesions (classification system)

Length of F/U

Primary outcome measures

Secondary outcome measures

Summary

Acunzo, et al. (2003)

Prospective RCT

92 (30.1) 46 control, 46 treatment

10 mL Hyalobarrier gel

N/A

N/A (AFS)

3 months

Adhesion recurrence

Adhesion category

Adhesion recurrence rate was significantly lower in the treatment group. After intervention, the treatment group had 100% stage I, mild adhesions. Control group had 25% stage I, mild adhesions; and 75% stage II, moderate adhesions.

Amer et al. (2010)

Pilot prospective randomized comparative study

45 (30.4) 15/group

Foley (2 weeks) Foley + fresh amnion Foley + dried amnion

Ethinyl estradiol (50 mg/day)

Severe (March)

6 60 months

Menstrual status, fertility outcome

Adhesion category, uterine length, complications

Both grafts were significantly better than balloon alone in reducing adhesion score. Fresh was significantly better than dried for adhesion score reduction, and better also for menstruation and uterine length, but this was not significant. Pregnancy rate for graft was also twice that of balloon only, but not significantly different.

Chi et al. (2018)

RCT

38 (29) 18 control 20 treatment

Intrauterine balloon Intrauterine balloon + aspirin

5 g/day transdermal estrogen gel (2 months)

Moderate or severe (AFS)

1 § 0.2 years

Menstrual status, fertility outcome

Adhesion category, endometrial thickness, uterine length, endometrial volume

Patients with a combined therapy of transdermal estrogen gel and oral aspirin had significant improvements in average AFS-score, with an absence of adhesions recorded in 8 out of 18 cases (44.44%) in group A and 15 out of 20 cases (75.00%) in group B. Patients with combination therapy had a relatively higher rate of pregnancy compared with patients with estrogen-alone therapy.

Gan et al., (2017)

Prospective RCT

Control: 40 (30.8) Amnion: 40 (29.6)

Control: no Foley or amnion Amnion: 2 sterilized freeze-dried amnion grafts on 20F Foley (removed after 7 days)

4 mg of oral estradiol valerate daily (day 1 21) + 20 mg of oral dydrogesterone daily from days 12 21)

Severe (AFS)

6 12 months

Adhesion recurrence, menstrual cycle, fertility outcome

Adhesion category

Amnion group had lower AFS score (2 vs 4), which was statistically significantly different. There was a statistically significant improvement in menstruation scores. Adhesion reformation rate was not significantly different. The pregnancy rates between the group were not statistically significant.

Guo et al. (2017)

Prospective RCT

Group A N = 59 (31.9) Group B N = 62 (32.3)

Group A: Foley catheter + 2 mg E Group B: Foley catheter + 6 mg E

21 days estrogen + progesterone in the last 10 days (3 cycles)

Moderate to severe (AFS)

3 months

Menstrual status

Adhesion category

The mean AFS scores at the second- and third-look hysteroscopy were found to be significantly lower than the scores before the surgery in both groups. There was no significant difference in the AFS adhesion scores between the second- and third-look hysteroscopy in both groups. This study does not support the use of high-dose estrogen therapy after hysteroscopic adhesiolysis. (continued on next page)

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Table 3. Randomized controlled trials included in the review

Table 3. (Continued)

Type of study

Treatment

Details of HT

Length of F/U

Primary outcome measures

Secondary outcome measures

Summary

Lin et al. (2015)

RCT

Balloon 82 (29.7) IUD 80 (30.1)

Cook Medical balloon (7 days) Heart-shaped copper IUD (7 days)

Estradiol valerate 6 mg/day £ 21 days + medroxyprogesterone acetate 6 mg/day for the last 7 days of the estrogen therapy £ 3 cycles

Moderate to severe (AFS)

2 months

Adhesion recurrence

Adhesion category

The rate of adhesion reformation in the balloon group (30%) was not significantly different from the rate (35%) in the IUD group. The median reduction in adhesion score was also not significantly different between the two groups. Subgroup analysis was also completed (moderate group vs. severe group). The median reduction of AFS in the moderate groups were balloon group 7, IUD group 6. The median reduction of AFS in the severe group were balloon group 10, IUD group 10.

Pabuccu et al. (2008)

Prospective RCT

A: 36 (33.2) B: 35 (32.6)

Group A: first-look hysteroscopic lysis + Lippes Loop, second-look hysteroscopic lysis (POD7), 2M PO E + P, IUD removed, third-look (1 week after IUD removal) Group B: first-look hysteroscopic lysis + Lippes Loop, 2M PO E + P, IUD removed, secondlook hysteroscopic lysis (1 week after IUD removal)

Conjugated equine estrogen (Premarin) 5 mg daily + medroxyprogesterone acetate (Farlutal) 10 mg for last 10 days

Severe (AFS)

38 months

Adhesion recurrence, fertility outcome

N/A

Group 1 had significantly lower rates of adhesion reformation (89.1% none, 2.7% filmy, 2.7% moderate, 2.7% severe). Spontaneous pregnancy rates: 17/36 in group 1 and 1/35 in group 2. Live births: 10/36 group 1 and 7/35 in group 2. IVF pregnancy rates and live births were 45% and 27% in group 1 and 30% and 15% in group 2.

Zhou et al. (2018)

RCT

39 (27)

Group 1: 4 mg EV Group 2: 9 mg EV

21 days of estradiol valerate + dydrogesterone last 10 days, 3 cycles

Mild, moderate, severe (AFS)

3 months

Menstrual status, fertility outcome

Protein levels

No significant difference observed in menstruation quantity between the 4-mg EV group and the 9-mg group. No significant difference in the rate of pregnancy was observed.

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AFS: American Fertility Society; E: estrogen; EV: estradiol valerate; F/U: follow-up; HT: hormone therapy; IUD: intrauterine device; IVF: in vitro fertilization; N/A: not applicable; PO: orally; POD: postoperative day; RCT: randomized controlled trial.



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Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

Study

Study size (age)

Severity of adhesions (classification system)



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Study

Type of study

Study size (age)

Treatment

Details of HT

Severity of adhesions (classification system)

Length of F/U

Primary outcome measures

Secondary outcome measures

Summary Group A: normal flow in 84.3%, no adhesion reformation Group B: normal flow in 77.9% and 93.3% had adhesion reformation (only mild, except for moderate in 2 cases of previous tuberculous endometriosis). 7/13 only required one procedure, 3/13 needed two.

Amer and Abd-ElMaeboud (2006)

Pilot nonrandomized comparative study

Group A 12 (30.75) Group B 13 (28.85)

Group A: moderate adhesions Conjugated estrogens Moderate vs. severe (Premarin) 0.625mg (March) Group B: severe adhesions Foley catheter + amnion graft (2 QID days 1 30 a medroxyprogesterone weeks) acetate (Provera) 5 mg BID days 24 30 (7 days)

3 months

Adhesion recurrence, Adhesion category, menstrual status uterine length

Chen et al. (2017)

Prospective cohort study

Group A 30 (30.77) Group B 32 (31.44) Group C 35 (30.94)

Group A: IUD + low-dose aspi- estradiol valerate Severe (AFS) rin + estrogen 3 mg/day TID & Group B: IUD + low-dose aspimedroxyprogesterrin + estrogen + aspirin one 10 mg/day Group C: IUD + low-dose aspirin + uterus-shaped balloon + estrogen + aspirin

3 months

Menstrual status, fertil- Endometrial thickness Aspirin is helpful for postoperative ity outcome increase in endometrial thickness, but the effect of balloon increasing endometrial thickness is required to be further confirmed. The reduction in AFS score in group C was higher than that in group B and group A. The increase in menstrual score after surgery in group C was significantly higher than that in group B and group A. The pregnancy rate and live birth rate were comparable among the three groups.

Lin et al. (2013)

Retrospective cohort study

107 (30.4)

Group 1: IUD 6 mg estrogen Mild, moderate, or Group 2: fitted intrauterine balvalerate + 6 mg severe (AFS) loon medroxyprogesterGroup 3: hyaluronic acid gel one acetate (2 Group 4: hysteroscopic lysis cycles) estrogen for 21 28 days; progesterone for the last 7-10 days

2 months

N/A

Liu et al., (2016)

Retrospective cohort study

120 (31.2)

Group 1: 3 mg estrogen + TCRAa Group 2: 9 mg estrogen + TCRA Group 3: TCRA

10 mg estradiol valerate + 8 mg Provera 21 days estrogen + Provera last 10 days (3 cycles)

Liu et al. (2018)

Retrospective cohort study

Group A N = 91 (31.7) Group B N = 85 (31.4)

Group A: 10 mg E Group B: 4 mg E

10 mg or 4 mg estra- Moderate to severe diol valerate for (AFS) 21 28 days; 10 mg dydrogesterone last 10 days

Severe (European 6 12 months Society for Gynecological Endoscopy)

Adhesion category

Reduction in adhesion score appeared greatest in the balloon group, followed by the IUD, then gel, then control. The reduction in the balloon group was significantly greater than all the other three groups. The reduction in the IUD group was greater than those of the gel group and control group; the reduction in the gel group was no different than the control group.

Menstrual cycle, fertil- Endometrial thickness, 66.7 % of women achieved a sucity outcome uterine cavity and cessful pregnancy (71% in 9-mg volume group, 64.1 % in 3-mg group, 65.5% in control group).

4 6 weeks; 18 months Adhesion recurrence, N/A (pregnancy menstrual status, outcomes) fertility outcome

No significant difference in AFS scores in the two groups before and after surgery. The proportion of women with no recurrence of adhesions in the 10 mg estrogen group (76.9%) was not significantly different from that in the 4 mg group (85.9%). The proportion of women in whom menstruation had improved or returned to normal in the 10-mg group (93.4%) was significantly higher than that of the subjects in the 4mg group (78.8%). Conception rate was not significantly different.

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Table 4. Non-randomized controlled studies included in the review

Table 4. (Continued) Study

Study size (age)

Treatment

Details of HT

Severity of adhesions (classification system)

Orhue et al. (2003)

Non-randomized, comparative

110 (26.9)

Blind adhesiolysis + IUD £3 months Blind adhesiolysis + Foley £ 10 days Repeat adhesiolysis at followup if adhesion recurrent

Peng et al. (2017)

Retrospective matched cohort study

A: 40 (30.7) B: 80 (30.4)

Group A: Foley balloon + fresh 8 mg/day of estradiol Severe (AFS) amnion graft valerate 21 Group B: Foley balloon days + 20 mg/day of dydrogesterone last 10 days (2 cycles)

Estradiol valerate 4 mg TID days 1 28, norethisterone acetate 10 mg TID days 29 32

Length of F/U

Primary outcome measures

Secondary outcome measures

Summary

Until no adhesion recurrence

Adhesion recurrence, Need for repeat menstrual status, adhesiolysis conception, live birth

Restoration of normal menses higher in Foley group (81.4% vs. 62.7%). Higher pregnancy rates in the Foley group (33.9% vs. 27.5%) higher number of pregnancies achieved term delivery (20.3% vs. 11.8%), though these were not statistically significant.

62 months

Adhesion recurrence, Adhesion category menstrual status, fertility outcome

The adhesion scores were not significantly different between the two groups at initial hysteroscopy and second-look. The median adhesion scores in the treatment group at third-look hysteroscopy were significantly lower than the comparison group. The rate of adhesion recurrence at the secondlook hysteroscopy was not significantly different between the two groups. At third-look hysteroscopy, the rate of adhesion recurrence in the treatment group was significantly lower than the control group. The menstrual pattern improvement rate in the treatment group was significantly better than the control group.

Transcervical resection of uterine adhesions.

AFS: American Fertility Society; BID: twice daily; F/U: follow-up; HT: hormone therapy; IUD: intrauterine device; QID: four times daily; TID: three times daily; TURA: transcervical resection of uterine adhesions.

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Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

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Figure 3. A comparison of the clinical pregnancy rate in the control group (hysteroscopic adhesiolysis and Foley catheter) versus the intervention group (hysteroscopic adhesiolysis and Foley catheter and amnion graft).

The types of adjuvant therapy used included hyaluronic acid gel, Foley catheter with or without amnion graft, intrauterine balloon (Foley, Cook, heart shaped), heart-shaped copper intrauterine device (IUD), regular IUD, a combination of IUD with low-dose aspirin, estrogen and aspirin, and a combination of Foley balloon with hyaluronic gel. Amer et al. compared outcomes between groups that received a Foley catheter with or without amnion graft, as well as the use of different types of amnion graft: fresh versus dried frozen.10 Guo et al. reported differences in outcomes between groups that received Foley catheters and different doses of adjuvant estrogen (2 mg vs. 6 mg).11 Chi et al. used aspirin as an adjuvant therapy to adhesiolysis, an intrauterine balloon, and transdermal estrogen therapy and found that the combination-therapy group had higher pregnancy rates than the no-aspirin group.12 Two studies including 109 women evaluated fertility outcomes after hysteroscopic adhesiolysis, placement of a Foley catheter, and the use of amnion graft as an adjunctive therapy.10,13 The results of meta-analysis of these two studies showed that, compared with the use of a Foley catheter alone, the addition of a dried amnion graft resulted in a non-significant increase in clinical pregnancy rates (Odds Ratio 1.55; 95% confidence interval 0.60−3.99) (Figure 3). Additional meta-analysis could not be performed because of the wide variety of treatment methods used and the lack

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of standardization in outcomes chosen to measure the impact of the treatment. Adhesion Recurrence

The rate of adhesion recurrence was evaluated at the second or third hysteroscopy in seven of the studies. Two studies used similar intervention methods (Foley catheter in combination with amnion graft vs. Foley catheter alone), included only patients with severe adhesions, and followed the American Fertility Society classification system. Peng et al. found that the rate of recurrent adhesions at the second-look hysteroscopy was not significantly different between the two groups.14 At the third-look hysteroscopy, the rate of recurrent adhesions in the treatment group (with amnion graft) was 30%, and in the control group it was 48.7%. This was not statistically different. In the second study by Gan et al., these investigators reported that women who received the freeze-dried amnion graft after lysis of adhesions had reductions in recurrent adhesion formation (11% vs. 16%).13 Amer and Abd-El-Maeboud used the same intervention method for two groups (Foley catheter and amnion graft) but divided the patients into subgroups according to the degree of IUA severity before the intervention: moderate (group A) and severe (group B).15 Group A experienced no adhesion recurrence, whereas group B had a recurrence rate of 93.3%. The recurrences were mild, with the exception of two cases that were moderate, possibly because of a history of tuberculous

Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

endometriosis. Lin et al. compared adhesion recurrence rates with the use of a heart-shaped balloon (30%) and a heart-shaped IUD (35%) and found no difference between groups.16 Menstrual Status and Endometrial Thickness

Chen et al. found a significant increase in menstrual score for group C (aspirin and uterus-shaped balloon as adjuvants) compared with group B (aspirin) and group A (no adjuvant treatment).17 The menstrual score was graded using a visual analogue scale from 0 (amenorrhea) to 100 (normal) before and after intervention. Group A had a difference in scores of 22.50 § 24.52, group B a difference of 38.91 § 28.70, and group C had a difference of 55.37 § 25.11. The increase in score in group C was statistically significant compared with both group B and group A (P = 0.035 and P < 0.0001, respectively). In addition, groups B and C had a thicker endometrium compared with group A (P = 0.030 and P = 0.022, respectively), but there was no significant difference between groups B and C (P > 0.05). Chi et al. compared the use of aspirin as an adjuvant to adhesiolysis, insertion of an intrauterine balloon, and transdermal estrogen gel therapy.12 These investigators found that the combination-therapy group had longer and heavier menstrual flows and thicker endometrium compared with the group that did not receive aspirin as an adjuvant. It seems that combination therapy facilitates endometrium rehabilitation after adhesiolysis as measured by mRNA and protein expression levels of anb3 and laminin (LAM), two endometrial receptivity markers.18 Menstrual status was also evaluated as an outcome by Gan et al.13 These investigators found that the group with an amnion graft as an adjuvant therapy to adhesiolysis and Foley catheter insertion had a higher mean pictorial blood loss assessment chart (PBAC) score, although both groups improved their scores overall.13 Fertility Outcome: Pregnancy and Live Births

Nine studies used pregnancy as an outcome when assessing the most appropriate adjuvant therapy for the treatment of IUAs. Chi et al. found that the aspirin combination therapy group had higher pregnancy rates than the control group (lysis, intrauterine balloon, estrogen therapy) at the 1-year follow-up (13.3% vs. 30%).12 Gan et al. compared pregnancy rates in groups that received an amnion graft versus the control group (lysis and Foley catheter) and did not find any difference in pregnancy rates: 23% and 18% in amnion and control groups, respectively.13 Pabuccu et al. studied the impact of IUD guidance

during hysteroscopic adhesiolysis in patients with severe IUAs.19 These investigators found that conducting a second adhesiolysis with an IUD in place and a third hysteroscopy after IUD removal resulted in higher pregnancy rates and live births than conducting a second adhesiolysis only after IUD removal.19 The spontaneous pregnancy rates after treatment were 17 of 36 (47.2%) and 11 of 35 (30%) after the third and second adhesiolysis, respectively. However, these differences were not statistically significant (P > 0.05). The remaining studies that evaluated pregnancy rates and fertility outcomes did not find any statistically significant differences between groups. Grade of Adhesions After Adhesiolysis

Acunzo et al. reported that the use of hyaluronic acid gel as an adjuvant to hysteroscopic adhesiolysis leads to a significant decrease in the severity of adhesions at the 3-month follow-up period (P < 0.001).9 The treatment group had 100% stage I (mild) adhesions at repeat hysteroscopy, whereas the control group had 25% stage I and 75% stage II (moderate) adhesions. Lin et al. evaluated the use of an IUD, a fitted intrauterine balloon, and hyaluronic acid gel as adjuvant therapies after hysteroscopic adhesiolysis.20 These investigators found that reduction in adhesion score was greatest in the intrauterine balloon group, followed by the IUD group and, finally, the hyaluronic acid group.20 The reduction in adhesion score for the balloon group was significantly greater than in the remaining three groups (P < 0.001). The reduction in the IUD group was greater than that in the gel group (P < 0.001) and the control group (P = 0.001). The reduction in the gel group was no different from that in the control group. DISCUSSION

The purpose of this review was to provide a summary of current management options available for women with intrauterine adhesions after hysteroscopic adhesiolysis. The success of those treatments was measured by a combination of the following outcomes: adhesion recurrence, adhesion grade, menstrual status, endometrial thickness, and fertility (pregnancy and/or live birth). Although there is a marked variability between treatment methods and outcomes of interest, rendering it difficult to recommend concrete guidelines, some treatment methods appear to be promising. For instance, the use of aspirin as an adjunctive therapy showed improved pregnancy rates, reduced adhesion score, increased endometrial thickness, and improved menstruation outcomes. These results, along with the

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treatment’s feasible use and low cost, could allow aspirin to become a common adjunctive treatment. Intrauterine balloons (Cook, Foley, heart-shaped balloon) as physical barriers showed promising results, with improved menstruation and reduction in adhesion grade. The most compelling adjunctive treatment modality was the use of amnion grafts in conjunction with an intrauterine balloon to facilitate the introduction of the graft into the cavity. Significant improvement in adhesion scores, adhesion recurrence, and menstruation were noted, along with non-significant improvement in pregnancy rates. Finally, the use of hyaluronic acid gel demonstrated mixed results. We classified various adjunctive treatments found in the literature into two categories: modalities that optimize endometrial proliferation and physical barriers. Optimization of Endometrial Proliferation Hormone Monotherapy or Combination Therapy

The endometrium cycles through stages of proliferation, shedding, and monthly renewal, regulated by the endogenous hormones: estrogen and progesterone. These steroids act on receptors of connective tissue stromal cells that direct the growth and differentiation of overlying epithelial cells.21 Estrogen also promotes vascular endothelial growth factor (VEGF) expression and microvessel density.22 Estrogen therapy with or without progesterone appears to be accepted as the mainstay treatment after hysteroscopic adhesiolysis (14 of the 15 studies used hormone supplementation) to promote endometrial growth.23 To the best of our knowledge, no studies have compared outcomes of adjunctive use of estrogen with or without progesterone. Combination therapy may have a role in restoration of menses and endometrial thickness, thus highlighting this as an area of future research. Among the studies included in our review, only two used estrogen without progesterone therapy. The duration and dose of postoperative estrogen also vary. In this review, treatment ranged from no postoperative hormone treatment to three cycles of 28 days, with doses ranging from 2 to 10 mg of estradiol valerate or conjugated estrogen daily. Two studies compared the use of different doses of estrogen (2 mg vs. 6 mg and 4 mg vs. 10 mg), and they showed no significant differences in rates of adhesion reformation or changes in adhesion grade at second-look hysteroscopy.11,24 In a non-randomized retrospective analysis of 120 cases of severe IUAs, one group studied the administration of estrogen before and after adhesiolysis and simultaneously examined whether the dose of estrogen altered the outcome of

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the treatment.25 The study showed that the use of estrogen before adhesiolysis could be an effective adjunctive method of treatment, and the most optimal dose would be 9 mg/day orally. These investigators reported significantly better rates of uterine shape and volume restoration, menses recovery, and successful term pregnancy. Endometrial Trauma as a Means of Promoting Proliferation

In a randomized study, Pabuccu et al. evaluated 36 women who underwent three rounds of adhesiolysis (the second of which was under IUD guidance) and 35 others who received only two rounds and no IUD guidance.19 The IUD served as a tool to achieve better visualization of the right pathway to the fundus and tubal orifices. Both groups received 2 months of estrogen and progesterone therapy. These investigators found no significant differences in pregnancy rates between the groups (47.2% vs. 30%).19 They recommended repeat adhesiolysis under IUD guidance as early as possible after the initial surgery to optimize the success of the treatment and possibly lead to higher pregnancy rates. Enhancing Endometrial Receptivity as a Means of Improving Pregnancy Outcomes

Endometrial receptivity is defined as a temporally unique state in which the endometrium is capable of accepting embryo implantation, and it is closely related to a successful pregnancy.26 A low dose of aspirin has been reported to improve implantation and pregnancy rates for patients undergoing in vitro fertilization, presumably through a positive effect on endometrial receptivity or through alterations in vascular flow, although this remains controversial.27 In an RCT, Chi et al. compared the use of combined therapy after adhesiolysis of moderate to severe adhesions (5 mg/day of transdermal estrogen and 100 mg/day of aspirin) with estrogen use alone.12 These investigators found that combination therapy improved endometrial receptivity and postoperative prognosis and resulted in an increased rate of pregnancy in patients with IUAs. Similarly, Chen et al. studied the role of aspirin after lysis of adhesions. All three groups in the study received the same baseline treatment (adhesiolysis, IUD, low-dose aspirin, and estrogen).17 An additional higher dose of aspirin was studied as an adjuvant therapy in one group, and a combination of intrauterine balloon and aspirin was used in the third group. These investigators reported that the additional dose of aspirin reduced adhesion score, increased endometrial thickness, and improved menstruation outcomes.17 It appears that aspirin could be useful in improving reproductive prognosis. It should be noted that the

Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

effect of aspirin on endometrial thickness in non−adhesion-related thin linings is very controversial, and aspirin use in this context has mostly fallen out of favour. Postoperative Separation of the Endometrial Surfaces

Optimization of endometrial regeneration is the first general approach to the treatment of IUAs. It is thought that to prevent adhesion reformation, the raw endometrial surfaces should be separated for at least 7 days after adhesiolysis.28,29 The basis of 7 days is unclear. In fact, no studies have compared separation of the uterine walls for different time periods. Many approaches have been used to achieve this goal, including balloon catheter, IUD, amnion graft, and hyaluronic acid gel. Intrauterine Device

The first method used for maintaining separation of the uterine walls was the IUD. Early reports showed a high pregnancy rate (90%) and subsequent successful delivery (85%) in patients with mild and moderate adhesions.30 Its use declined when non-medicated and non-copper IUDs (such as Lippes Loop) were removed from the market. Progesterone-containing IUDs are not desirable because they prevent endometrial proliferation, and copper IUDs induce an inflammatory response. The only controlled study was published by Lin et al., who found that the adhesion recurrence rate was significantly reduced in the IUD group compared with control subjects (balloon catheter placement) (P < 0.001).16 Unfortunately, these investigators did not report on pregnancy or live birth rates. The results in the literature with respect to IUD use as an adjunctive treatment in patients with IUAs are inconsistent and may require further study. IUD use is made difficult by the fact that non-copper, non-progesterone versions are no longer available in the market.31 Because of the lack of good prospective evidence, we do not recommend the use of IUD after hysteroscopic adhesiolysis. Balloon Catheter

Because of the difficulties associated with currently available IUDs, use of a balloon catheter for maintenance of the uterine cavity is an option that is often used. The advantages include increased surface area contact, which may induce better separation of the uterine walls. There have also been reports suggesting a lower infection rate when compared with IUD use.29 Chen et al. found that the combined use of a round IUD and concomitant balloon performed well in improving

uterine morphology, restoring menstruation, and reducing adhesion scores compared with IUD alone.17 The balloon was left in place for 2 weeks, compared with the 3- to 5day period of other studies. However, these investigators reported no change in rates of pregnancy or miscarriage. When directly compared with IUD, these results are conflicting. None of the studies reported that the balloon catheter is less effective than IUD. Two studies found the balloon to be significantly better than the IUD, whereas one found no difference (Table 3). Orhue et al. treated 110 patients with IUAs after adhesiolysis with either a Foley balloon or an IUD. Rates of restoration of menses, conception, and live birth were significantly better in the Foley group compared with the IUD group.29 One complication was reported in the Foley group (urinary tract infection) versus four in the IUD group (two cases of genital sepsis and two uterine perforations). Lin et al. performed a comparative study of 107 IUAs patients with mild, moderate, or severe adhesions who were receiving an IUD (copper coil for 1−2 months), an intrauterine balloon (Cook Medical for 10 days), hyaluronic acid gel, or no treatment as an adjunct to hysteroscopic adhesiolysis and cyclical hormone treatment.20 Patients receiving the balloon had significantly lower rates of adhesion recurrence compared with all other groups (P < 0.001), and adhesion scores were also significantly improved (P < 0.001).20 The IUD group fared significantly better than the hyaluronic acid and control groups; the hyaluronic acid did not provide a significant benefit when compared with the control subjects. Currently, there is no good evidence to suggest that Foley catheter use results in improvement of results over no mechanical barrier at all. If a mechanical barrier is to be placed, a balloon catheter should be considered for its relatively low complication rate, decreased duration within the uterine cavity, and lack of negative association for subfertile patients. It is important to exercise precaution when inflating the balloon because overinflation risks decreased blood flow, which would be counterproductive to supporting tissue regeneration.32 The duration of treatment is also important given that keeping the Foley catheter in place for a prolonged period predisposes patients to infection, thus increasing the risk of adhesion re-formation. The opposite is also true: not leaving it in long enough is ineffective at preventing recurrent adhesion formation. Howes and Harvey33 defined a 5-day “lag period” during which adhesions can form, such that any mechanical barrier to adhesion formation should stay in place for at least 5 days; this was confirmed by Kodaman and Arici.34

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Hyaluronic Acid Gel

Hyaluronic acid is a natural component of vitreous, extracellular matrix, cartilage, synovial fluid, skin, and the umbilical cord. Its main advantage is that it is safe and relatively inexpensive. Its use was inspired by a study in which a bioresorbable membrane derived from hyaluronic acid and carboxymethylcellulose (Sepra-film, Genzyme, Naarden, the Netherlands) was used postoperatively in patients undergoing dilation and curettage.35 In an RCT, the investigators evaluated 92 patients with IUAs and menstrual disturbances who underwent hysteroscopic adhesiolysis with or without postoperative hyaluronic acid (10 mL) application.9 The treatment group appeared to have significant reductions in adhesions and overall adhesion scores compared with control subjects. In contrast, Lin et al. found that the use of intrauterine hyaluronic acid was significantly inferior to both IUD and Foley catheter use and was not significantly better than results in the control group.20 This discrepancy may be related to the differences between the two studies in the grade of adhesion. Amnion Graft

Amnion graft is another method to separate raw uterine surfaces. This biological divider can suppress recurrent adhesion formation and can promote healing of the epithelial layer by promoting epithelial cell migration, thus reinforcing adhesion of epithelial cells to the basal layer, promoting differentiation, and preventing apoptosis.15 It has been used in the repair of surface epithelium of the eye, abdominal wall, and peritoneum. The amniotic membrane has antiadhesive effects and eliminates dead space where exudates could accumulate, which is thought to increase the risk of infection. Finally, it also obviates the risk of immunologic reaction because it does not express human leukocyte antigen (HLA) A, B, C, D, or DR, and therefore immunosuppression is not necessary. Amer and Abd-El-Maeboud conducted a pilot study in which women with moderate or severe adhesions underwent hysteroscopic adhesiolysis followed by insertion of a Foley catheter covered by an amnion graft, which was removed after 2 weeks (Table 3).15 There was a spontaneous expulsion of the Foley catheter in three of 25 cases, but no infections were reported. Normal menstrual flow was restored in 84.3% of women with moderate adhesion and in 77.9% of women with severe cases. However, approximately 93.0% of women had recurrent adhesion formation, albeit of a milder level of adhesions. An RCT followed using a set of 45 women with severe IUAs.10 Patients were divided into three groups: Foley catheter alone, Foley catheter and fresh amnion graft, or Foley catheter and dried amnion graft.

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Both study groups had significant reduction in adhesion score after adhesiolysis compared with the control group, especially with the use of fresh graft. The pregnancy rate for both graft groups, although not significant, was twice that of the control group. Gan et al. performed a prospective RCT comparing a Foley catheter with an amnion graft versus a Foley catheter with no amnion graft in 80 patients with severe IUAs.13 Their results showed a statistically significant improvement in both post-treatment IUAs and bleeding scores.13 The study was underpowered to determine whether the use of freezedried amnion graft could produce a substantial improvement in clinical pregnancy rates, which is the most relevant end point among the target population. In a retrospective matched cohort study, Peng et al. studied 120 patients who were treated with a Foley catheter with and without fresh amnion graft after adhesiolysis.14 The amnion graft group exhibited significantly higher menstruation scores and significantly lower adhesion scores at the end of the 62-month study period, with hysteroscopic assessments conducted twice (4 weeks, 12 weeks) following the initial intervention. This finding differs from those of most previous studies, which included only one hysteroscopic assessment. The additional intervention allows an opportunity to evaluate and liberate recurrent adhesion formation, if any, at an early stage. Other Adhesion Barriers

Several other substances are used to separate the raw endometrial surfaces after lysis of adhesions (Table 5). Cai et al. used Interceed (TC7) (Johnson & Johnson Patient Care Inc., New Brunswick, NJ), an oxidized regenerated cellulose (ORC) adhesion barrier, in a retrospective study of 76 women with moderate to severe IUAs.36 ORC is absorbed within 2 to 3 weeks and must be applied over a circular IUD. ORC has been used to reduce adhesion formation after abdominal surgery. Although it did not significantly improve menstrual function, pregnancy, or live birth when compared with the use of IUD alone, its use significantly reduced the time to conception and the number of treatments needed to be adhesion-free (menstruation improvement,P = 0.764; pregnancy rate, P = 0.310; live birth rate, P = 0.068; time to conception, P < 0.001; number of treatments, P = 0.001).36 Another substance is Intercoat (Oxiplex/AP) Gel (FzioMed, Inc., San Luis Obispo, CA), a viscoelastic gel composed of polyethylene oxide and carboxymethylcellulose stabilized by calcium chloride. Polyethylene oxide serves to repel precursors of fibrin bridges (which lead to

Study

Type of study

Study size (age)

Treatment

Details of HT

Cai et al. (2017)

Retrospective

76 (31.6)

IUD only, £ 3 months IUD + 7.6 cm £ 10.2 cm Interceed (1/2 around IUD and 1/2 in central bare region of uterine cavity) £ 3 months Repeat treatment if adhesion recurrence

Di Spiezio Sardo et al. (2011)

RCT

110 (37)

Hysteroscopic adhesioly- None sis + Intercoat (10 mL) Hysteroscopic adhesiolysis only

Kim et al. (2012)

Randomized, 187 (40) multicenter, single-blind, clinical trial

Hysteroscopic adhesiolysis + ACH or CH

Severity of adhesions (classification system)

3 cycles Moderate (≥5 − AFS) Days 1 28 estradiol valerate (2 £ 5 mg) Days 18 28 medroxyprogesterone acetate 10 mg

None

Length of F/U

Primary outcome measures

Secondary outcome measures

Outcome

Adhesion category, perioe- No significant difference in prative and postoperative improvement of menstrual complications, number of function between groups or in post-operative infections. operations required, coagulation function, liver IUD + Interceed significantly reduced time to conception enzyme levels compared with IUD alone.

Minimum 6 months

Menstrual status,

Mild, moderate, severe (AFS)

1 month

Adhesion category Adhesion recurrence, menstrual status

Significantly lower rate of postsurgical IUAs was observed in group 1 (3 of 55) compared with group 2 (12 of 55) (6% vs. 22%; P <0.05) Severity was lower in group 1 compared with group 2. The rate of moderate and severe IUAs was lower in group 1 (1 of 3) compared with group 2 (11 of 12) (33% vs. 92%).

N/S

4 weeks

Adhesion recurrence

At 4 weeks: no significant difference in measures. Adhesion formation rate for patients with preoperative adhesions was 43.8% and 42.1% for ACH and CH, respectively. ACH and CH were more effective in all other subgroups.

Adhesion category

ACH: alginate carboxymethylcellulose; AFS: American Fertility Society; CH: carboxymethylcellulose hyaluronic acid; F/U: follow-up; HT: hormone therapy; IUA: intrauterine adhesion; IUD: intrauterine device; NS: Not Stated; RCT: randomized controlled trial.

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Supplements to Conventional Treatment After Hysteroscopic Lysis of Intrauterine Adhesions: A Systematic Review

Table 5. Other methods for mechanical separation of the uterine walls for the treatment of intrauterine adhesions

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adhesions), and carboxymethylcellulose is thought to decrease injured tissue apposition, which is a requirement for adhesion formation. Di Spiezio Sardo et al. (2011) performed an RCT in which 110 patients with IUAs underwent hysteroscopic adhesiolysis with or without postoperative intrauterine Intercoat gel (10 mL).37 The treatment group was found to have a significantly lower rate of recurrent adhesion formation, and a lower severity score was noted in women with recurrent adhesions.37 In addition, most patients treated with Intercoat gel presented with an improvement in the integrity of tubal ostia, whereas the control group had a significantly higher incidence of ostial scarring. In an RCT, Kim et al. concluded that neither alginate carboxymethylcellulose nor alginate carboxymethylcellulose hyaluronic acid was effective in minimizing the rate of recurrent adhesion formation or adhesion severity in patients with IUAs.38

most common cause of IUAs is intrauterine injury, we call for clinicians to be mindful of methods to reduce the risk of formation of adhesions in patients undergoing uterine procedures. Future studies on adjunctive treatment should take into account the cause of IUAs. Our review revealed that no standardized guidelines currently exist for the postoperative management of women with IUAs. There is an overall lack of evidence to allow for the definition of standard treatment guidelines. On the basis of the available evidence, recommendation of specific adjunctive treatments after hysteroscopic adhesiolysis is unjustified. Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that they have no competing interests.

CONCLUSION

Estrogen treatment has been accepted as an adjunctive postoperative treatment after hysteroscopic lysis of adhesions. However, to date there has not been a standard treatment protocol after lysis of intrauterine adhesions. It seems that postoperative estrogen therapy is beneficial, but it must be combined with other treatments to achieve the best outcome, although estrogen therapy as a sole adjunctive treatment after adhesiolysis has been shown to yield better outcomes than the use of adhesiolysis alone.24 Other postoperative treatments are even less standardized. In support of a previous review, we found that there is still a paucity of evidence on adjunctive postoperative treatment in women with IUAs.39 RECOMMENDATIONS

Patients are usually looking for one of two outcomes: return to normal menses (with or without conception) and live birth. However, resumption of menses is not a direct measure of fertility because it does not rule out the presence of adhesions, which can negatively affect conception and time to pregnancy. We therefore recommend that future studies use endometrial thickness, resumption of normal menses, conception, and live birth as the primary outcome measures, with all other measures being secondary. One of the major factors preventing the development of a standardized approach to the prevention of IUAs is the existence of many classification systems. Development of a universal classification of IUAs is needed. Because the

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