Systematic Reviews
org
Postsurgical barrier strategies to avoid the
recurrence of intrauterine adhesion formation
after hysteroscopic adhesiolysis: a network
meta-analysis of randomized controlled trials
Salvatore Giovanni Vitale, MD, PhD; Gaetano Riemma, MD; Jose Carugno, MD, FACOG;
Tirso Perez-Medina, MD, PhD; Luis Alonso Pacheco, MD; Sergio Haimovich, MD, PhD;
John Preston Parry, MD, MPH; Attilio Di Spiezio Sardo, MD, PhD;
Pasquale De Franciscis, MD, PhD
Introduction
Intrauterine adhesions (IUA) are condi-
tions where intracavitary granulation
From the Obstetrics and Gynecology Unit,
Department of General Surgery and Medical
Surgical Specialties, University of Catania,
Catania, Italy (Dr Vitale); Department of Woman,
Child and General and Specialized Surgery,
Obstetrics and Gynecology Unit, University of
Campania “Luigi Vanvitelli,” Naples, Italy (Dr
Riemma and Dr Franciscis); Division of Minimally
Invasive Gynecology, Department of Obstetrics
and Gynecology, University of Miami Miller
School of Medicine, Miami, FL (Dr Carugno);
Department of Obstetrics and Gynecology,
University Hospital Puerta de Hierro-
Majadahonda, Autonomous University of
Madrid, Madrid, Spain (Dr Perez-Medina);
Unidad de Endoscopia Ginecológica, Centro
Gutenberg, Hospital Xanit Internacional, Málaga,
Spain (Dr Alonso Pacheco); Department of
Obstetrics and Gynecology, Hillel Yaffe Medical
Center, The Ruth and Bruce Rappaport Faculty
of Medicine, Technion-Israel Institute of
Technology, Israel (Dr Haimovich); Parryscope
and Positive Steps Fertility, Madison, MS (Dr
Parry); Department of Obstetrics and
Gynecology, The University of Mississippi
Medical Center, Jackson, MS (Dr Parry); and
Department of Public Health, School of
Medicine, University of Naples Federico II,
Naples, Italy (Dr Di Spiezio Sardo).
Received April 19, 2021; revised Sept. 7, 2021;
accepted Sept. 12, 2021.
The authors report no conflict of interest.
This work did not receive any grant or funding.
PROSPERO registration date: October
27, 2020.
PROSPERO registration number:
CRD42020211276.
Corresponding author: Salvatore Giovanni
Vitale, MD, PhD. sgvitale@unict.it or
vitalesalvatore@hotmail.com
0002-9378/$36.00
ª 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2021.09.015
ajog.
OBJECTIVE: To assess the efficacy of mechanical strategies to avoid the recurrence of
intrauterine adhesions, to evaluate the impact on subsequent fertility after hysteroscopic
adhesiolysis and to rank the available antiadhesive options.
DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, CINAHL, Scielo, EMBASE,
PROSPERO, Cochrane Library, conference proceedings, and international controlled
trials registries were searched without temporal, geographic, and language restrictions.
STUDY ELIGIBILITY CRITERIA: Randomized trials that analyzed the recurrence, repro-
ductive outcomes, or both in women undergoing hysteroscopic adhesiolysis followed by
mechanical prevention of intrauterine adhesions were included. The exclusion criteria
included the following: quasi-randomized trials and trials without randomization and
studies including patients undergoing hysteroscopic surgery that was different from
adhesiolysis.
STUDY APPRAISAL AND SYNTHESIS METHODS: The Preferred Reporting Items for
Systematic reviews and Meta-Analyses extension statement for network meta-analyses
guidelines were followed. We performed a network meta-analysis based on the random
effects model for mixed multiple treatment comparisons to rank the antiadhesive stra-
tegies by surface under the cumulative ranking curve area. Quality assessment was
performed using the criteria outlined in the Cochrane Handbook for Systematic Reviews
of Interventions. The primary outcome was the recurrent presence of intrauterine
adhesions.
RESULTS: Eleven studies with data for 1596 women were identified as applicable. A
copper intrauterine device together with an intrauterine balloon (surface under the
cumulative ranking curve area¼46.4%) or with cross-linked hyaluronic acid gel
(surface under the cumulative ranking curve area¼21.3%) seemed effective in pre-
venting adhesions recurrence. Regarding the fecundity, hyaluronic acid gel demon-
strated the highest pregnancy rates (surface under the cumulative ranking curve
area¼79.8%). The greatest degrees of change in the mean adhesions scores were
found with the use of hyaluronic acid gel plus an intrauterine device (surface under the
cumulative ranking curve area¼38.9%). For postsurgical adhesion severity, hyaluronic
acid gel plus intrauterine device (surface under the cumulative ranking curve
area¼49.9%) followed by intrauterine device alone (surface under the cumulative
ranking curve area¼30.8%) was ranked the highest. Dried amnion graft (surface
under the cumulative ranking curve area¼53.8%) and uterine balloon (surface under
the cumulative ranking curve area¼45%) showed the greatest menstrual pattern
improvement.
CONCLUSION: Cross-linked hyaluronic acid gel, with or without insertion of a copper
intrauterine device, seems to be the most effective approach. However, the lack of a clear
best therapy suggests the need for further studies to draw firm conclusions.
Key words: adhesion recurrence, Asherman syndrome, hysteroscopy, intrauterine
adhesions, reproductive outcomes
APRIL 2022 American Journal of Obstetrics & Gynecology 487
Systematic Reviews ajog.org

the current evidence on the post-

AJOG at a Glance hysteroscopic prevention of IUA forma-
Why was this study conducted? tion and its effect on subsequent
To evaluate whether available mechanical strategies are effective in reducing reproductive outcomes using direct or
recurrent intrauterine adhesion formation and to evaluate their impact on sub- indirect comparisons of the available
sequent fertility after hysteroscopic adhesiolysis strategies.

Key findings Methods

Using mechanical antiadhesive strategies is an effective approach to decrease
postsurgical intrauterine adhesion formation and to improve reproductive out-
comes after hysteroscopic adhesiolysis
What does this add to what is known?
A variety of approaches aiming to reduce intrauterine adhesion formation have
been studied and compared with a placebo or other treatments. However, the
available evidence is still limited.
tissue is formed because of injury to the
basalis layer of the endometrium,
creating fibrous tissue bridges inside the
uterine cavity.1,2 In the most severe cases,
the uterine cavity may be completely
obliterated, without any evidence of a
healthy endometrium.3 Though Asher-
man syndrome4 is often used inter-
changeably with IUA as a term, the
syndrome overlaps hypomenorrhea and
amenorrhea with pain from hema-
tometra. Conversely, IUA is a broader
term addressing the spectrum of the
disease, including adhesions without
pain.
The most common causes of endo-
metrial damage relate to dilatation and
curettage after postpartum hemorrhage,
pregnancy loss, or induced abortion.5,6
Severe IUA is frequently associated
with menstrual pattern alterations
(hypomenorrhea, amenorrhea), chronic
pelvic pain, and dysmenorrhea.7
Importantly, the presence of IUA nega-
tively affects fertility and the subsequent
reproductive outcomes, with a reported
pregnancy loss rate of up to 90%.3,8
Obstetrical complications such as
placenta accreta and other placentation
abnormalities and preterm delivery are
also commonly reported in women with
IUA.9
Currently, hysteroscopy is considered
as the gold standard for both the diag-
nosis and treatment of the patient with
IUA.1,3 Direct visualization of the uterine
cavity allows the lysis of adhesions
through mechanical or electrosurgical
energy, occasionally without the need for
anesthesia when performed in an office
setting.10,11
A challenging issue that arises when
treating patients with moderate or severe
IUA is the recurrence of the adhesion
formation, which is typically estimated
as occurring in 3%e25% of cases but has
been reported in up to 60%.1,3 The
common mechanical strategies to pre-
vent IUA formation include the insertion
of a copper intrauterine device (IUD)12
and the placement of a balloon catheter
inside the uterine cavity to mechanically
separate the uterine walls.13; this latter
approach has been supplemented
through the concurrent use of amnion
grafts covering the balloon.14 Moreover,
the intrauterine instillation of anti-
adhesive gels that are mainly constituted
of auto-cross-linked hyaluronic acid
(HAG) are frequently used to protect the
endometrium and avoid synechiae
formation.15,16
Over the last 20 years, several studies
have been conducted to evaluate the ef-
ficacy of different strategies in prevent-
ing IUA recurrence and enhancing
fertility after the hysteroscopic lysis of
adhesions. A variety of approaches aim-
ing to reduce IUA formation have been
studied and compared with placebo or
other treatments. However, the available
evidence is still limited.
Objective
The aim of this systematic review and
network meta-analysis is to summarize
This network meta-analysis was con-
ducted in accordance with the Cochrane
Handbook for Systematic Reviews of In-
terventions17 and the methods outlined
in Mbuagbaw et al.18 It followed the
Preferred Reporting Items for Systematic
reviews and Meta-Analyses (PRISMA)
extension statement for network meta-
analyses (PRISMA-NMA) (Supplement
P1).19 The research protocol was regis-
tered in the International Prospective
Register of Systematic Reviews (PROS-
PERO) database (CRD42020211276) on
October 27, 2020.
Data sources and search strategy
Electronic databases including MED-
LINE (accessed through PubMed), Sco-
pus, EMBASE, Scielo.br, and
PROSPERO were searched with the use
of the following keywords and Medical
Subject Heading (MeSH) terms: “hys-
teroscopy,” “hysteroscopic adhesiolysis,”
“intrauterine adhesions,” “Asherman
syndrome” without any date restriction.
A filter for randomized controlled trials
only was applied to the search results.
Searches were also conducted on
CINAHL, PsycINFO, and AMED to seek
for other relevant papers and reduce
publication bias. To capture additional
randomized controlled trials,
Clinicaltrials.gov, Cochrane Central
Register of Controlled Trials, and World
Health Organization International
Clinical Trials Registry Platform
(ICTRP) were also searched. Moreover,
the gray literature (NTIS, PsycEXTRA)
was screened to search for the abstracts
of international and national confer-
ences. We also reviewed the references of
the included studies and the related re-
views for additional papers not captured
during the original search.
No language or geographic location
restriction was applied. Commentaries,
letters to the editors, editorials, and re-
views were excluded from the search.

488 American Journal of Obstetrics & Gynecology APRIL 2022

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Study selection criteria and data
extraction
The inclusion criteria included any ran-
domized clinical trial that included
women diagnosed with moderate-to-
severe intrauterine adhesions, described
as a score of at least 5 points according to
the American Fertility Society (AFS)
classification system. This score was
assigned by the authors of the original
research to the women who underwent
hysteroscopic adhesiolysis followed by
the application of at least one mechanical
antiadhesion treatment to prevent the
recurrence of intrauterine adhesion for-
mation. The exclusion criteria included
the following: quasi-randomized trials
and trials without randomization and
studies including patients undergoing
intrauterine surgery that was different
from adhesiolysis.
The abstraction forms were designed
specifically for the meta-analysis of this
network. The key characteristics that
were recorded included the following:
the patient descriptors, study duration,
setting, details of hysteroscopic surgery,
features of the treatment, outcomes
evaluated, mean follow-up length, re-
sults, and quality elements.
All the abstracts were reviewed and
classified by 2 authors (G.R., S.G.V.)
independently. The agreement for
possible relevance was accomplished by
consensus; the same 2 authors per-
formed a full text assessment of the
selected studies and independently
extracted significant data about the study
characteristics and the outcomes of in-
terest. All the inconsistencies were dis-
cussed by the reviewers and a consensus
was reached by consulting a third author
(P.D.F.). If necessary, unpublished data
were obtained by direct contact with the
authors of the original studies whenever
the study methodology indicated that
other outcome data were recorded.
Assessment of risk of bias
The risk of bias in each of the included
studies was evaluated using the criteria
outlined in the Cochrane Handbook for
Systematic Reviews of Interventions.20
Seven domains were critically investi-
gated in each included trial, because it
was evident that these issues were related
to biased estimates of the effects of
treatments as follows: (1) random
sequence generation; (2) allocation
concealment; (3) blinding of partici-
pants and personnel; (4) blinding of
outcome assessment; (5) incomplete
outcome data; (6) selective reporting,
and (7) other bias. The review of the
authors’ judgments was categorized as
“low risk,” “high risk,” or “unclear risk”
of bias.20
The risk of bias assessment was inde-
pendently judged by 3 authors (J.C.,
J.P.P., A.D.S.S.). The disagreement was
resolved by discussion with a fourth
reviewer (P.D.F.).
Primary and secondary outcomes
The primary outcome of this network
meta-analysis was IUA recurrence inci-
dence, defined for the included studies as
the number of patients who were diag-
nosed with IUA at a follow-up diagnostic
hysteroscopy. The secondary outcomes
were the mean adhesion score at follow-
up, defined according to the AFS classi-
fication and the IUA severity rate,
defined as the number of women who
were diagnosed with severe adhesions
(AFS score 5)21 during follow-up.
Other secondary outcomes included
the evaluation of the Pictorial Blood Loss
Assessment Chart score for assessing the
menstrual pattern changes after the in-
terventions; the clinical pregnancy rate
(CPR), defined as ultrasonographic
visualization of one or more intrauterine
gestational sacs in any women who un-
derwent IUA treatment; and live birth
rate, defined as the birth of a living fetus
after 24 weeks of gestational age.
Data extraction and statistical analysis
All the data analysis and the graphical
renderings were carried out using STATA
version 14.1 (StataCorp, College Station,
TX). For each outcome of interest, the
command <network meta incon-
sistency> was used to statistically
confirm the overall consistency
assumption among the networks. Sub-
sequently, for the local test on loop
inconsistency, the Separating Indirect
from Direct Evidence (SIDE)-splitting
method, using the command <network
sidesplit all> was used. When
APRIL 2022 American Journal of Obstetrics & Gynecology
Systematic Reviews
inconsistency was found to be absent in
both global and local tests, the consis-
tency assumption was accepted. In this
case, the consistency model suggested
that the direct and indirect comparisons
guaranteed significant results, and the
differences between the results were
related only to the effects of the inter-
vention and random errors.
The summary measures were re-
ported as relative risks (RR) or odds ratio
(OR) for the categorical variables and
mean difference (MD) for the contin-
uous variables, with 95% confidence
interval (CI) using the random effects
model of Der Simonian and Laird. Hig-
gins I-squared (I2) index higher than 0%
was used to target potential heterogene-
ity. In the cases of significant heteroge-
neity, sensitivity analyses were ruled out
to understand the relevant sources of
heterogeneity.
The potential publication bias was
analyzed by evaluating the symmetry of
the funnel plot. However, as different
observers may have drawn different
conclusions from the same funnel plot,
the Egger test was used to quantify the
publication bias. A forest plot and pre-
diction interval plot were then built for
each evaluated outcome to compare the
effectiveness of the different antiadhesive
strategies and to rank the treatments to
define superiority by means of a ranking
plot (Surface Under the Cumulative
Ranking curve Area [SUCRA]).
Results
Study selection
Four hundred and 10 studies were origi-
nally identified through database
searches. Of those, 164 were removed as
duplicates. After title and abstract
screening, 228 studies were subsequently
removed (Figure 1). Eighteen studies
were assessed for full text, of which 1 was
removed for being quasi-randomized, 5
of them were removed for including
other intrauterine pathologies along with
the lysis of IUA, and 1 trial was excluded
because the intervention and control
groups had the same adjuvant mechani-
cal barrier. Eleven studies,12e15,22e28
including 1596 participants, were
included in the quantitative synthesis and
network meta-analysis (Figure 1).
489
Systematic Reviews
FIGURE 1
Flow-diagram of the included studies in systematic review and network
meta-analysis
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.
Study characteristics
The studies were conducted between
2003 and 2020. All studies included
women diagnosed with moderate or se-
vere intrauterine adhesions, as measured
by an AFS score of at least 5 (Table 1).
The inclusion and exclusion criteria
provided by the studies included in the
network meta-analysis are reported in
Table 2.
Hysteroscopic adhesiolysis was car-
ried out with an 8 mm rigid hysteroscope
in 6 studies,14,15,22,24e26 whereas a 4 mm
office hysteroscope was used in the rest
of the trials12,23,27,28 (Table 1).
Out of 11 studies, monopolar energy
was used for adhesiolysis in 3
studies,12,15,22 4 trials13,14,26,28 adopted
the bipolar energy resection, and me-
chanical resection with scissors was uti-
lized in 2 trials.23,27 Two trials24,25 did
490 American Journal of Obstetrics & Gynecology APRIL 2022
not report the type of hysteroscopic
surgical approach (Table 1).
The types of strategies used to prevent
IUA formation after the hysteroscopic
lysis of adhesions included the use of
HAG, intrauterine balloon, fresh or
dried amnion graft, copper (IUD), or the
combination of IUD or HAG plus in-
trauterine balloon (Table 1). A placebo
(no treatment) was assumed as a refer-
ence for direct and indirect comparisons.
Postoperative hormonal treatment
was administered in 7 out of 11 studies.
Four studies used a combined estrogen
plus progesterone treatment (estradiol
valerate 4 mg plus medroxyprogesterone
acetate 6 mg12 or dydrogesterone 20
mg13,14,26) for 2 or 3 cycles. Three trials
adopted an estrogen-only postoperative
regimen (estradiol valerate 4 mg27,28 or
ethynyl estradiol 50 mg22) for 2 cycles.
ajog.org
Four studies did not report on using
postoperative hormonal therapy.15,23e25
The follow-up duration ranged from 30
days to 28 months.
Risk of bias of included studies
The quality of the methodology used for
each trial is shown in Supplemental
Figure 1, A, and a summary of the
quality of methodology expressed in
percentages across all trials is repre-
sented in Supplemental Figure 1, B. Most
of the included studies were considered
to have a low risk of bias. Data about
allocation concealment and random
sequence generation were reported by 10
out of 11 trials. All the included trials
were registered in authorized prospec-
tive registers before the enrolment of
participants.
Synthesis of results
Intrauterine adhesions recurrence.
All 11 studies analyzed the rate of IUA
recurrence after hysteroscopic adhesiol-
ysis. HAG, intrauterine balloon, dried
amnion graft, copper IUD with and
without balloon, and HAG plus intra-
uterine balloon and no treatment was
used as adjuvant therapy.12e15,22e28 IUA
recurrence was evaluated by means of
second-look hysteroscopy one,12,28
two27, or three13e15,22e24,26 months
after the application of the barrier
method.
Figure 2, A shows the frequency of the
studied interventions and the most ac-
curate direct comparisons. Inconsis-
tency analysis showed that global
inconsistency was not found (P¼.416).
The SIDE-analysis revealed that there
were no differences between direct and
indirect estimates in the closed loops
considered for the network (local
inconsistency) (Supplemental Tables
1e3) and no difference between the
consistency and inconsistency model
(P¼.416).
For this primary outcome, the sym-
metrical funnel plot (Supplemental
Figure 2) and Egger test (P¼.289) indi-
cated no significant publication bias in
this network meta-analysis.
The forest plot (Figure 2, B) and pre-
dictive interval plot (Figure 2, C) revealed
the influence on the reduction of
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TABLE 1
Main characteristics of trials included in the network meta-analysis
IUA recurrence
Intervention Intervention Type of Primary Secondary in no treatment
Study Design Location 1 2 Intervention 3 Hysteroscope surgery Age Follow-up outcome outcome arm (%)
15
Acunzo RCT single Italy Auto-cross- No treatment - 26Fr rigid IUA 30.5 3 months IUA Mean adhesion 13/42 (30.9)
linked resectoscope recurrence score; severe IUA
Hyaluronic rate rate
acid
Amer22 RCT Egypt Intrauterine Fresh amnion Dried 5Fr rigid IUA 30.4 28 months Mean IUA recurrence -
double balloon amnion hysteroscope adhesion rate; severe IUA
score rate; CPR
Gan14 RCT China Dried Amnion Intrauterine - 26Fr rigid IUA 30.2 3 months Mean Changes in 16/40 (40.0)
double balloon resectoscope adhesion menstrual
score pattern; IUA
recurrence rate;
CPR; severe IUA
rate
Lin12 RCT single China Intrauterine Copper IUD - 5Fr rigid IUA 29.9 1 month IUA Mean adhesion -
balloon hysteroscope recurrence score; severe IUA
rate rate
Mao23 RCT China Auto-cross- No treatment - 5Fr rigid IUA 36.3 6 months Mean CPR; IUA 3/32 (9.3)
double linked hysteroscope adhesion recurrence rate;
hyaluronic score severe IUA rate
acid
Shi13 RCT single China Intrauterine No treatment - 26Fr rigid IUA 32.0 12 months IUA Severe IUA rate; 39/97 (40.2)
APRIL 2022 American Journal of Obstetrics & Gynecology

balloon resectoscope recurrence changes in

rate menstrual pattern
Zhou26 RCT China Auto-cross- Intrauterine - 26Fr rigid IUA 31.9 3 months IUA Mean adhesion -
double linked balloon resectoscope recurrence score; severe IUA
hyaluronic rate rate
acid
Wang24

Systematic Reviews
RCT China Dried Amnion Intrauterine - 26Fr rigid IUA 31.1 3 months IUA Mean adhesion -
double balloon resectoscope recurrence score; severe IUA
rate rate; changes in
menstrual pattern
Xiao25 RCT China Auto-cross- Intrauterine - 26Fr rigid IUA 30.9 3 months IUA Mean adhesion -
double linked balloon resectoscope recurrence score; severe IUA
hyaluronic rate rate
acid
(continued)
491
Systematic Reviews ajog.org

postoperative adhesion recurrence with

respect to different strategies.12e15,22e28
in no treatment
IUA recurrence
The use of HAG was more effective in
reducing IUA recurrence than using a
arm (%)

balloon (RR, 0.29 [95% CI, 0.13e0.65]),

although balloon use seemed more
-

-
effective than no treatment (RR, 3.71
score; severe IUA

[95% CI, 1.39e9.90]), whereas IUD plus

Mean adhesion

IUA recurrence
balloon was more effective than balloon
Secondary

alone (RR, 2.10 [95% CI, 1.13e3.93]).

rate; CPR
outcome

These findings could be related to a long-

rate

lasting antiadhesive effect on the endo-

metrium mediated by HAG or IUD
application. On the other hand, the
recurrence
Age Follow-up outcome

adhesion
Primary

intermittency of the balloon treatment

Mean

score

might not give substantial adjuvant ben-

rate
IUA

efits to the uterine cavity.

Comparing IUA recurrence among
31.7 2 months
32.1 1 month

the other postsurgical methods did not

demonstrate statistically significant dif-
ferences. According to the SUCRA
analysis, the insertion of a copper IUD
together with an intrauterine balloon
(46.4%) or HAG (21.3%) were likely the
surgery
Type of

best methods for avoiding IUA recur-

IUA

IUA

rence after the hysteroscopic lysis of ad-

hesions (Figure 2, D).
Main characteristics of trials included in the network meta-analysis (continued)

Intervention 3 Hysteroscope

Mean adhesion score changes.

hysteroscope

hysteroscope

The mean adhesion score was evaluated

CPR, clinical pregnancy rate; Fr, French; IUA, intrauterine adhesions; IUD, intrauterine device; RCT, randomized controlled trials.
5Fr rigid

5Fr rigid

by 10 studies.12,14,15,22e28 HAG with or

without a copper IUD, fresh or dried
amnion, copper IUD alone, intrauterine
balloon combined with either a copper
IUD or amnion, and nonintervention,
were all compared. The network map in
IUD

Supplemental Figure 3, A shows that

-

HAG, balloon, dried amnion, and no

balloon + IUD
Intervention

Intrauterine

treatment were the most studied post-

AC+IUD

surgical adhesion prevention strategies.

The inconsistency analysis did not detect
2

inconsistencies (P¼.595). Adopting the

SIDE-analysis for closed inconsistency
Intervention

Auto-cross-

Intrauterine
hyaluronic

showed no inconsistency between loops

balloon

(Supplemental Table 1). For these rea-

linked

acid

sons, the consistency model was chosen

Location 1

for treatment analysis.

Forest plot and prediction interval
China

China

plot analysis (Figures 3, B and C)

demonstrated that there were no sta-
tistical differences between the treat-
Design

double

double

ments in changing the mean adhesion

RCT

RCT

score at follow-up hysteroscopy. Ac-

cording to the SUCRA ranking
TABLE 1

Huang27
28

(Figure 3, D), there were no substantial

Study
Wang

differences among the strategies, with

HAG plus IUD (38.9%) and dried

492 American Journal of Obstetrics & Gynecology APRIL 2022

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TABLE 2
Inclusion and exclusion criteria of included studies
Study Inclusion criteria
15
Acunzo Hysteroscopic diagnosis of intrauterine
adhesions
Amer22 Women with severe IUAs diagnosed at office
hysteroscopy
Gan14 Age <40 years; hypomenorrhea or
amenorrhea; infertility or at least one
pregnancy loss; AFS IUA score of at least eight.
Lin12 Age between 18e40 years; moderate to severe
intrauterine adhesion (AFS score over 5); no
history of hysteroscopic adhesiolysis; written
consent obtained; agreement to have second-
look hysteroscopy.
Mao23 Moderate to severe IUA (AFS score 5)
infertility for at least 1 year; expected to
undergo IVF/ICSI and FET; and had at least one
good quality embryo left
Shi13 Women aged 18e40 years with moderate to
severe intrauterine adhesion
Zhou26 Women aged 20e40 years; moderate to severe
IUAs (AFS score 5); written informed consent
obtained;
Wang24 Infertile women with moderate and severe IUA
(AFS score 5);
Xiao25 Patients with moderate to severe IUA (AFS
score 5);
Wang28 Infertile women aged 20e44 with mild-to-
severe IUA
Huang27 Age between 18e45 years, no previous
hysteroscopic adhesiolysis, willingness to
undergo a second-look hysteroscopy, moderate
to severe IUA according to the AFS scoring
system (AFS score 5)
AFS, American Fertility Society; FET, frozen embryo transfer; ICSI, intra-cytoplasmatic sperm inhection; IUA, intrauterine adhesions; IVF, in-vitro fertilization; NA: not available.
(20.7%) and fresh (20.6%) amnion
grafts being the most likely best treat-
ment choices.
Intrauterine adhesions severity.
The incidence of severe IUA after HAG
with or without IUD, intrauterine
balloon, fresh or dried amnion graft,
IUD alone, and no treatment were
analyzed and compared in 10
studies.12e15,22e26,28 Direct comparisons
Systematic Reviews
Exclusion criteria Surgical approach
Age over 50 years, weight over 100 kg, Monopolar resection
menopause or pregnancy, uterovaginal through hook knife
prolapse and severe urinary symptoms,
malignancy, severe intercurrent pathology,
presence of other intrauterine lesions (ie,
polyps, myomas, septa).
NA Monopolar resection
through hook knife
Premature menopause; presence of other Bipolar resection
intrauterine lesions (eg, polyps, myoma, or through cutting loop
septa); and severe intercurrent pathology
Minimal adhesion (AFS score <5) and previous Monopolar resection
hysteroscopic adhesiolysis. through hook knife
Uterine malformations, endometrial diseases, Mechanical removal
endometriosis, and adenomyosis using 5Fr blunt
scissors
Minimal intrauterine adhesions Bipolar energy
adhesiolysis
Previous history of endometrial tuberculosis; Bipolar energy
previous history of uterine artery embolization; adhesiolysis
patients with significant medical illness.
NA NA
NA NA
Surgical contraindications, patients with Bipolar
contraindications for postoperative hormone electrosurgical
replacement therapy, patients with fibroids and removal of adhesions
uterus anomalies, or patients who were allergic
to treatment
Presence of other intrauterine pathology (ie, Mechanical removal
myoma or septum); premature menopause and using 5Fr blunt
severe intercurrent disease, scissors
among the postsurgical strategies and use of an intrauterine balloon rather
their contribution to the network anal- than a dried amnion balloon graft (RR,
ysis are shown in the network map 2.57 [95% CI, 1.24e5.33]). Comparing
(Figure 4, A). There was nonsignificant severe IUA incidence after treatment
inconsistency in the overall analysis (P¼. among other postsurgical methods did
847). Local inconsistency between the not demonstrate statistically significant
closed loops evaluated for this outcome findings. According to the SUCRA
was not found (Supplemental Table 3). ranking (Figure 4, D), the combination
Analyzing the forest and prediction of HAG and IUD (49.9%) followed by
interval plots, (Figures 4, B and C), the the IUD alone (30.8%) were the most
risk for severe IUA was greater with the effective strategies.
APRIL 2022 American Journal of Obstetrics & Gynecology 493
Systematic Reviews ajog.org

FIGURE 2
Intrauterine adhesion recurrence

A, Network of comparisons of interventions analyzed in included studies. B, Forest plot for the outcome. C, Prediction interval plot. D, Ranking plot
according to SUCRA analysis.
IUD, intrauterine device; SUCRA, surface under the cumulative ranking curve area.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

Changes in menstrual pattern.
Analyses of the menstrual changes in
women affected by the IUA syndrome
were included in 3 studies.13,14,24 Adju-
vant strategies for preventing IUA
included the intrauterine balloon, dried
amnion graft, and no treatment.
Supplemental Figure 3, A depicts the
architecture of the network.
Network analysis showed no sources
of inconsistency among treatments. Ac-
cording to the forest and prediction in-
terval plot evaluation (Supplemental
Figures 3, B and C), no significant dif-
ferences among the treatments were
revealed. The SUCRA ranking showed
that both balloon (45%) and dried
amnion graft (53.8%) had similar
chances to be ranked as first choice
(Supplemental Figure 3, D).
Postsurgical fertility.
Four studies14,22,23,27 evaluated the CPR
among women who tried to conceive
after the treatment of IUA. HAG, intra-
uterine balloon with and without IUD,
fresh or dried amnion graft, and no
treatments were compared
(Supplemental Figure 4, A). CPR was
significantly higher in the women who
had HAG than those with an intrauterine
balloon (OR, 4.73 [95% CI, 2.43e9.22]).
Moreover, a significantly decreased CPR
was obtained with the combination of a
balloon plus IUD when compared with
dried amnion (OR, 0.39 [95% CI,
0.17e0.90]). No other statistically sig-
nificant differences were found among
the different postsurgical strategies
(Supplemental Figures 4, B and C).
According to the SUCRA ranking plot
(Supplemental Figure 4, D), the intra-
uterine instillation of HAG after the
hysteroscopic lysis of adhesions had the
highest chances of being ranked first
(79.8%).
Four studies13,22,23,27 comparing in-
trauterine balloon use with and without

494 American Journal of Obstetrics & Gynecology APRIL 2022

ajog.org Systematic Reviews

FIGURE 3
Mean adhesion score change (AFS adhesion score)

A, Network of comparisons of interventions analyzed in the included studies. B, Forest plot for the outcome. C, Prediction interval plot. D, Ranking plot
according to SUCRA analysis.
IUD, intrauterine device; SUCRA, surface under the cumulative ranking curve area.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

an IUD, HAG, fresh or dried amnion
graft, and no treatment (Supplemental
Figure 5, A) calculated the live birth
rate among the women who conceived
after hysteroscopic adhesiolysis. As
depicted by the forest and prediction
interval plots (Supplemental Figures 5, B
and C), there were no significant changes
when comparing treatments with no
treatment. The SUCRA analysis showed
no significant differences, with the use of
intrauterine balloon with IUD (32.1%)
and dried amnion (27.6%) having
similar chances of being ranked compa-
rably to no treatment (30.0%)
(Supplemental Figure 5, D).
Comment
Principal findings
This systematic review and network
meta-analysis of randomized controlled
trials showed that mechanical barriers
reduce the recurrence and severity of
IUA reformation, improve menstrual
patterns, and enhance subsequent
fertility in women diagnosed with in-
trauterine adhesions who are treated
with hysteroscopic lysis of adhesions.
Comparison with existing literature
IUA often occurs following blind
curettage for retained products of
conception (RPOC), where damage to
the stratum basale of the endometrium
and postoperative infection can occur
promoting intrauterine fibrosis.5 Hys-
teroscopic removal of RPOC has the
potential to replace blind curettage in
cases of RPOC, which can decrease the
risk of IUA formation.29 However, blind
curettage is still frequently performed
in clinical practice.30 Hysteroscopy is an
effective technique for the lysis of in-
trauterine adhesions.31 However, the
recurrence of adhesions is a concern.
The rationale of using an adjuvant
therapy to prevent IUA recurrence after
the hysteroscopic lysis of adhesions is
based on the following 2 core

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Systematic Reviews ajog.org

FIGURE 4
Intrauterine adhesion severity rate

A, Network of comparisons of interventions analyzed in included studies. B, Forest plot for the outcome. C, Prediction interval plot. D, Ranking plot
according to SUCRA analysis.
IUD, intrauterine device; SUCRA, surface under the cumulative ranking curve area.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

principles: biologically promoting the
regeneration of a healthy endometrium
and mechanically separating the uterine
walls to reduce the risk of adhesion
recurrence.14,22
Historically, HAG has been used in
endoscopic surgery to avoid adhesion
formation. It is a water-soluble poly-
mer that serves to physically separate
the uterine walls after intrauterine
surgery. Its safety for human use has
been established over time. Notably,
relative to the HAG used in the early
2000s, molecular modifications have
led to a cross-linked structure that re-
duces leakage and expulsion from the
uterine cavity.15 In this systematic re-
view, only 1 study15 reported the use of
a first-generation HAG (Hyalobarrier
gel; Baxter, Pisa, Italy), whereas in the
other 4 studies in which HAG was
compared with other strate-
gies,23,25,26,28 a new cross-linked poly-
mer (MateRegen gel; BioRegen
Biomedical Ltd, Inc, Changzhou,
China) was utilized.
Another IUA mechanical prevention
strategy is to place a copper IUD inside
the uterine cavity, which acts as a me-
chanical barrier to adhesion forma-
tion.12 A similar approach is to place a
Foley catheter or a Cook balloon into
the uterine cavity after the hystero-
scopic procedure; the balloon is subse-
quently inflated with a normal saline
solution and left inside the uterine
cavity.12 After 3 to 5 days, the balloon is
removed. A Foley catheter is also used to
deliver a dried or fresh amnion graft
inside the uterine cavity.14 With the
distal tip of the balloon cutoff, the
balloon portion of the catheter is
covered with sterilized, freeze-dried
amnion graft. Dried or fresh amnion
grafts are used to cover the upper sur-
face of the Foley catheter with the
epithelial amnion membrane portion
facing outward.

496 American Journal of Obstetrics & Gynecology APRIL 2022

ajog.org
Strengths and limitations
Considering all the above-described
available options, our main objective
was to determine the best strategy for
preventing the recurrence of intrauterine
adhesions after hysteroscopic adhesiol-
ysis. Several limitations could be
accounted for in this meta-analysis.
First, the effect of adjuvant therapies on
fertility outcomes was evaluated only in
3 different strategies owing to a paucity
of studies. Second, for each surgical
outcome evaluated, there were 2 treat-
ments that had similar SUCRA scores for
ranking first, not leading to a single
clearly superior treatment strategy.
Third, the presence of a postoperative
hormone therapy, administered in 7 out
of 11 studies, could influence the direct
estimate of the efficacy of the barrier
methods. In addition, the findings
related to changes in the menstrual
pattern and postsurgical fecundity
should be considered with caution
because of a paucity of studies and
comparisons available for these out-
comes. It should also be acknowledged
that having a follow-up at upto 6
months after the initial surgery differs
from the 6 to 8 weeks more typically
practiced. Though variability in the in-
terval follow-up adds heterogeneity, this
greater duration theoretically should
add sensitivity to detection, potentially
contributing to greater accuracy. In
addition, only 4 studies compared a
second-look hysteroscopy without the
administration of a mechanical barrier
to an antiadhesive strategy. This addi-
tional limitation for our study and the
literature is partially overcome by per-
forming indirect comparisons among
trials.
For certain approaches, multiple trials
came from single centers. Though in-
dependent participants were included,
there is greater risk for selection, per-
formance, detection, and reporting bia-
ses relative to multiple centers having
independent findings. It should also be
noted that HAG is not commercially
available in the United States, and with
most of the studies carried out in China,
this geographic limitation may reduce
the generalizability for this network
meta-analysis.
A strength of our study is the quality
of the selected studies, because only
randomized trials, with an overall low
risk of bias, were included in the quan-
titative analysis. Neither quasi-
randomized nor open trials or observa-
tional studies were selected.
The European Society of Gynecologi-
cal Endoscopy and the American Asso-
ciation of Gynecologic Laparoscopists
joint practice guidelines state that the use
of semisolid antiadhesive barriers (ie,
HAG intracavitary gel) is recommended
(evidence level A) to reduce IUA recur-
rence.32 However, there were not enough
data discussing postoperative fertility.
Our network analysis showed that HAG
might be considered the best choice for
improving fecundity. It is also noticeable
that other antiadhesive strategies have
shown interesting and even improved
efficacy on the IUA recurrence, men-
strual pattern improvement, and reduc-
tion of IUA severity.
Our findings suggest that multiple
strategies are effective in preventing IUA
formation. However, the lack of a clear
superior approach is a call to further
research.
Conclusions and implications
Applying antiadhesive barriers is effective
in preventing recurrent IUA formation. It
improves menstrual disorders and en-
hances the subsequent fertility. According
to this network analysis, the placement of
an IUD together with an intrauterine
balloon is the best choice to avoid IUA
recurrence. When copper IUDs and HAG
are simultaneously used, the IUA severity
is significantly reduced. Intrauterine
placement of an intrauterine balloon with
or without a frozen amnion graft might
be considered as the first choice for
improving menstrual patterns, whereas
hysteroscopic administration of HAG is
associated with higher postprocedural
pregnancy rates. -
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ajog.org
Appendix
MEDLINE (accessed through PubMed)
((“hysteroscopy”[MeSH Terms] OR
“hysteroscopy”[All Fields] OR “hyster-
oscopies”[All Fields] OR ((“hyster-
oscopes”[MeSH Terms] OR
“hysteroscopes”[All Fields] OR “hyster-
oscope”[All Fields] OR “hysteroscopi-
c”[All Fields] OR “hysteroscopical”[All
Fields] OR “hysteroscopically”[All
Fields]) AND “adhesiolysis”[All
Fields])) AND (((“intrauterin”[All
Fields] OR “intrauterine”[All Fields])
AND (“adhese”[All Fields] OR “adhe-
sion”[All Fields] OR “adhesions”[All
Fields] OR “adhesive s”[All Fields] OR
“adhesively”[All Fields] OR “adhesive-
ness”[MeSH Terms] OR “adhesive-
ness”[All Fields] OR
“adhesivenesses”[All Fields] OR “adhe-
sives”[Pharmacological Action] OR
“adhesives”[MeSH Terms] OR “adhesi-
ves”[All Fields] OR “adhesive”[All
Fields] OR “adhesivities”[All Fields] OR
“adhesivity”[All Fields])) OR (“gyna-
tresia”[MeSH Terms] OR “gyna-
tresia”[All Fields] OR (“asherman”[All
Fields] AND “syndrome”[All Fields])
OR “asherman syndrome”[All Fields])))
AND (randomizedcontrolledtrial
[Filter])
EMBASE
/exp OR hysteroscopy OR ’hysteroscopic
adhesiolysis’/exp OR ’hysteroscopic
adhesiolysis’ OR (hysteroscopic AND
(’adhesiolysis’/exp OR adhesiolysis)))
AND (’intrauterine adhesions’ OR (in-
trauterine AND (’adhesions’/exp OR
adhesions)) OR ’asherman syndrome’/
exp OR ’asherman syndrome’ OR
(asherman AND (’syndrome’/exp OR
syndrome))) AND (’clinical trial’/de
OR ’controlled clinical trial’/de OR
’randomized controlled trial’/de OR
’randomized controlled trial topic’/de)
Cochrane at CENTRAL
((hysteroscopy OR hysteroscopic adhe-
siolysis) AND (intrauterine adhesions
OR Asherman syndrome)):ti,ab,kw
AND (“randomized controlled trial”):pt
Scopus
TITLE-ABS-KEY ( {Clinical-trial} OR
{controlled-trial} OR randomi* OR
randomly OR ( random W/4 ( allocat*
OR distribut* OR assign* ) ) OR
APRIL 2022 American Journal of Obstetrics & Gynecology
Systematic Reviews
{placebo} OR {trial} OR {groups} OR
{subgroups} ) OR TITLE ( rct ) AND (
hysteroscopy OR hysteroscopic AND
adhesiolysis ) AND ( intrauterine
AND adhesions OR asherman AND
syndrome)
CINAHL / PsycINFO / AMED /
PsycExtra (accessed through EBSCO e
IDEM for Italian Universities)
“(hysteroscopy or hysteroscopic adhe-
siolysis) and (intrauterine adhesions or
Asherman syndrome) Prove controllate
randomizzate AND Cerca anche nel
testo completo degli articoli; Applica
argomenti equivalenti
Scielo.br
(hysteroscopy or hysteroscopic adhe-
siolysis) and (intrauterine adhesions or
Asherman syndrome)
Clinicaltrials.gov / ICTRP (accessed
through CENTRAL)
((hysteroscopy OR hysteroscopic
adhesiolysis) AND (intrauterine adhe-
sions OR Asherman syndrome)):-
ti,ab,kw AND (“randomized controlled
trial”):pt
498.e1
Systematic Reviews ajog.org

SUPPLEMENTAL FIGURE 1
Assessment of the risk of bias

A, Summary of the risk of bias for every trial; plus sign: low risk of bias; minus sign: high risk of bias;
question mark: unclear risk of bias. B, Risk of bias graph about each risk of bias item presented as
percentages across all included studies.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

498.e2 American Journal of Obstetrics & Gynecology APRIL 2022

ajog.org Systematic Reviews

SUPPLEMENTAL FIGURE 2
Symmetrical funnel plot for the primary outcome

Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

APRIL 2022 American Journal of Obstetrics & Gynecology 498.e3

Systematic Reviews ajog.org

SUPPLEMENTAL FIGURE 3
Changes in menstrual pattern (according to PBAC score)

A, Network of comparisons of interventions analyzed in included studies. B, Forest plot for the outcome. C, Prediction interval plot. D, Ranking plot
according to SUCRA analysis.
PBAC, pictorial blood loss assessment chart; SUCRA, surface under the cumulative ranking curve area.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

498.e4 American Journal of Obstetrics & Gynecology APRIL 2022

ajog.org Systematic Reviews

SUPPLEMENTAL FIGURE 4
Clinical pregnancy rate

A, Network of comparisons of interventions analyzed in included studies. B, Forest plot for the outcome. C, Prediction interval plot. D, Ranking plot
according to SUCRA analysis.
SUCRA, surface under the cumulative ranking curve area.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

APRIL 2022 American Journal of Obstetrics & Gynecology 498.e5

Systematic Reviews ajog.org

SUPPLEMENTAL FIGURE 5
Live birth rate

A, Network of comparisons of interventions analyzed in included studies. B, Forest plot for the outcome. C, Prediction interval plot. D, Ranking plot
according to SUCRA analysis.
SUCRA, surface under the cumulative ranking curve area.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

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SUPPLEMENTAL TABLE 1
Separating Indirect from Direct Evidence -analysis for mean adhesion score
Direct Indirect Difference
Side Coef. Std. Err. Coef. Std. Err. Coef. Std. Err. P>jzj
AB .7818593 1.158193 2.490522 1.644446 1.708663 2.011284 .396
AFa .0000001 1.655396 3.705915 4.969546 3.705915 5.237992 .479
a
AG 2.900000 1.731205 1.047042 1.96522 1.852958 2.619000 .479
AH 1.710324 1.233231 .8096342 2.416882 .9006898 2.713305 .740
BC a
.5000000 1.599253 2.666557 977.0582 3.166557 977.0595 .997
BDa 1.640112 1.245442 .7399047 2.410916 .900207 2.713407 .740
BE a
.5000000 1.587961 4.517823 3.803699 4.017823 4.120408 .330
BG 0.000001 1.656376 1.852679 2.028794 1.852679 2.619081 .479
DE a
.2500003 1.589894 3.767763 3.801981 4.017763 4.121022 .330
DH 1.250000 1.747406 2.150684 2.075800 .9006837 2.713370 .740
FGa 2.900000 1.731231 .8059153 4.891432 3.705915 5.238007 .479
Coef., coefficient; Std. Err., standard error.
a
All the evidence about these contrasts comes from the trials which directly compare them.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

SUPPLEMENTAL TABLE 2
Separating Indirect from Direct Evidence -analysis for intrauterine adhesions recurrence rate
Direct Indirect Difference
Side Coef. Std. Err. Coef. Std. Err. Coef. Std. Err. P>z
AH .8262797 .5909506 1.662228 .6061971 .8359482 .8493776 .325
AB .8493776 .4387385 .7499463 .6355191 .0067881 .7736662 .993
AF a
.984499 .7807111 1.501071 1.615823 2.48557 1.842269 .177
a
AG .984499 .7231644 .8008765 .5705584 1.242776 .9211426 .177
BH .984499 .4982943 .0017446 .5291968 .9744232 .7268745 .180
BCa .9492349 .5936123 .8406545 1461.386 1.789889 1461.386 .999
BD a
.4500391 .7000583 .0017653 .8019645 .4482738 1.079224 .678
BE a
1.165304 1.728075 1.944218 2.735807 3.109522 3.623348 .391
BG .2051362 .4815148 1.447923 .7852592 1.242786 .9211343 .177
DH .5639354 .6577172 1.012208 .855636 .4482727 1.079215 .678
DEa 0.000001 1.287385 3.109522 3.386927 3.109522 3.623345 .391
FGa 1.059153 .6604392 1.426419 1.769427 2.485573 1.842269 .177
Coef., coefficient; Std. Err., standard error.
a
All the evidence about these contrasts comes from the trials which directly compare them.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

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SUPPLEMENTAL TABLE 3
Separating Indirect from Direct Evidence -analysis for intrauterine adhesion severity
Direct Indirect Difference
Side Coef. Std. Err. Coef. Std. Err. Coef. Std. Err. P>jzj
AG .2646694 .8017456 .9496781 1.588132 .6850088 1.779033 .700
AB 1.039964 .3855823 .3806672 1.429308 1.420632 1.480404 .337
AE a
1.394327 1.525694 4.181935 5.165828 5.576262 5.082225 .273
AF a
1.75897 1.529694 1.029165 2.029114 2.788135 2.541115 .273
BG .0310906 1.994811 .6286765 .8338064 .5975859 2.16206 .782
BCa .0168266 1.397029 .5980752 2.146858 .5812485 2.561385 .820
BDa .0000001 1.968502 .5872712 4.484700 .5872712 4.897707 .905
BF .0243915 1.993892 2.763743 1.575329 2.788135 2.541115 .273
CG .0000001 1.987767 .5812478 1.615386 .5812478 2.561385 .820
CD a
.0000001 1.968502 .5872713 4.484701 .5872713 4.897708 .905
EFa .3646431 1.982983 5.211626 4.676794 5.576269 5.082231 .273
Coef., coefficient; Std. Err., standard error.
a
All the evidence about these contrasts comes from the trials which directly compare them.
Vitale. Hysteroscopic adhesiolysis and intrauterine adhesion. Am J Obstet Gynecol 2022.

498.e8 American Journal of Obstetrics & Gynecology APRIL 2022