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Human Reproduction Update, Vol.20, No.2 pp.

262–278, 2014
Advanced Access publication on September 29, 2013 doi:10.1093/humupd/dmt045

Systematic review and meta-analysis


of intrauterine adhesions after
miscarriage: prevalence,
risk factors and long-term
reproductive outcome
Angelo B. Hooker1,2,3,*, Marike Lemmers4, Andreas L. Thurkow2,
Martijn W. Heymans 5, Brent C. Opmeer 6, Hans A.M. Brölmann 3,
Ben W. Mol4, and Judith A.F. Huirne 3
1
Department of Obstetrics and Gynaecology, Zaans Medical Center, Zaandam, The Netherlands 2Department of Obstetrics and Gynaecology,
Sint Lucas Andreas Hospital, Amsterdam, The Netherlands 3Department of Obstetrics and Gynaecology, VU University Medical Center,
Amsterdam, The Netherlands 4Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands
5
Department of Epidemiology and Biostatics, VU University Medical Center, Amsterdam, The Netherlands and 6Clinical Research Unit,
Academic Medical Center, Amsterdam, The Netherlands

Correspondence address. Departement of Obstetrics and Gynaecology, Zaans Medical Center (ZMC), Koningin julianaplein 58, PO Box 210,
1500 EE Zaandam, The Netherlands. Tel: +31-75-6502615; Fax: +31-75-6502758; E-mail: hooker.a@zaansmc.nl; a.b.hooker@hotmail.com

Submitted on April 27, 2013; resubmitted on July 8, 2013; accepted on August 1, 2013

table of contents
...........................................................................................................................
† Introduction
† Methods
Systematic searches
Paper selection procedure
Eligibility criteria
Nomenclature
Outcome measures
Extent and degree of intrauterine adhesions
Classification of intrauterine abnormalities
Data extraction and assessment of methodological quality
Data analysis
† Results
Prevalence of post-miscarriage intrauterine adhesions
Description and quality of included studies assessing post-miscarriage intrauterine adhesions
Intrauterine adhesions
Numbers of miscarriages
Type of miscarriage and numbers of D&C procedures
Intrauterine abnormalities
Long-term fertility and reproductive outcome
Description and quality of included studies assessing long-term reproductive outcome
Reproductive outcome following intrauterine adhesions
Reproductive outcome following miscarriage

& The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Intrauterine adhesions after miscarriage 263

† Discussion
Summary of the evidence
Strengths and limitations of the review
Comparison with previous research
Implications for clinical practice
Implications for further research
† Conclusions

background: Approximately 15– 20% of all clinically confirmed pregnancies end in a miscarriage. Intrauterine adhesions (IUAs) are a pos-
sible complication after miscarriage, but their prevalence and the contribution of possible risk factors have not been elucidated yet. In addition, the
long-term reproductive outcome in relation to IUAs has to be elucidated.
methods: We systematically searched the literature for studies that prospectively assessed the prevalence and extent of IUAs in women who
suffered a miscarriage. To be included, women diagnosed with a current miscarriage had to be systematically evaluated within 12 months by
hysteroscopy after either spontaneous expulsion or medical or surgical treatment. Studies that included women with a history of recurrent
miscarriage only or that evaluated the IUAs after elective abortion or beyond 12 months after the last miscarriage were not included. Subsequently,
long-term reproductive outcomes after expectant (conservative), medical or surgical management were assessed in women with and without
post-miscarriage IUAs.
results: We included 10 prospective studies reporting on 912 women with hysteroscopic evaluation within 12 months of miscarriage and 8
prospective studies, including 1770 women, reporting long-term reproductive outcome. IUAs were detected in 183 women, resulting in a pooled
prevalence of 19.1% [95% confidence interval (CI): 12.8 –27.5%]. The extent of IUAs was reported in 124 women (67.8%) and was mild, mod-
erate and severe respectively in 58.1, 28.2 and 13.7% of cases. Relative to women with one miscarriage, women with two or three or more mis-
carriages showed an increased risk of IUAs by a pooled OR of 1.41 and 2.1, respectively. The number of dilatation and curettage (D&C)
procedures seemed to be the main driver behind these associations. A total of 150 congenital and acquired intrauterine abnormalities were
encountered in 675 women, resulting in a pooled prevalence of 22.4% (95% CI: 16.3 –29.9%). Similar reproductive outcomes were reported
subsequent to conservative, medical or surgical management for miscarriage, although the numbers of studies and of included women were
limited. No studies reported long-term reproductive outcomes following post-miscarriage IUAs.
conclusions: IUAs are frequently encountered, in one in five women after miscarriage. In more than half of these, the severity and extent of
the adhesions was mild, with unknown clinical relevance. Recurrent miscarriages and D&C procedures were identified as risk factors for adhesion
formation. Congenital and acquired intrauterine abnormalities such as polyps or fibroids were frequently identified. There were no studies report-
ing on the link between IUAs and long-term reproductive outcome after miscarriage, while similar pregnancy outcomes were reported subse-
quent to conservative, medical or surgical management. Although this review does not allow strong clinical conclusions on treatment
management, it signals an important clinical problem. Treatment strategies are proposed to minimize the number of D&C in an attempt to
reduce IUAs.

Key words: adhesions / infertility / miscarriage / reproductive outcome / systematic review

has proven to be cost-effective (You and Chung, 2005; Niinimäki et al.,


Introduction 2009). However, even after medical evacuation, 30 –50% of women
The term miscarriage is used to describe a pregnancy that fails to pro- undergo a surgical procedure because of the suspicion of incomplete
gress before the middle of the second trimester (24 weeks of gestation), evacuation (Creinin et al., 2004; Graziosi et al., 2004, Davis et al., 2007).
resulting in the death, and often expulsion, of the embryo or fetus Post-traumatic intrauterine adhesions (IUAs) were first described by
(Christiansen et al., 2005). Approximately 15 –20% of all clinically Heinrich Fritsch in 1894 (Fritsch, 1894). In 1948, Joseph Asherman was
recognized pregnancies will end in a miscarriage (Ballagh et al., 1998; the first to describe the etiology and frequency of this syndrome, ever
Hemminki, 1998; Wang et al., 2003). Some women will experience re- since known as the Asherman syndrome (Asherman, 1948a, b). Since
current miscarriage but these are estimated to be a small proportion then, multiple reports addressing the cause, diagnosis and treatment of
of all women experiencing a miscarriage. IUAs have been published. Although IUAs have been described after
Miscarriage can be managed expectantly (i.e. conservatively), aiming spontaneous miscarriage, it is mainly reported as a complication after
at spontaneous resolution, or medically or surgically with dilatation intrauterine surgery (Schenker and Margalioth, 1982).
and curettage (D&C). D&C has been the cornerstone in the treatment IUAs are thought to develop following the destruction of the basal
of women with a miscarriage for many years, based on the assumption layer of the endometrium. In the healing process, opposing walls of the
that retained trophoblastic tissue increases the risk of infection and hem- uterus adhere together causing minimal, marginal or complete obliter-
orrhage (Tam et al., 2005). Over the last decade, medical treatment, pri- ation of the uterine cavity (Schenker and Margalioth, 1982; Schenker,
marily with mifepristone and misoprostol, has been introduced as a 1996). IUA formation is multifactorial with multiple predisposing and
non-surgical alternative for women with early pregnancy failure and causal factors; the specific role of factors like intrauterine trauma,

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264 Hooker et al.

technique of curettage, infection, inflammation and retention of tropho- ‘Asherman syndrome’, ‘traumatic amenorrhea’, ‘endometrial sclerosis’, ‘ad-
blastic tissue has not been established yet (Schenker and Margalioth, hesive endometriosis’, ‘post-traumatic intrauterine synechiae’, ‘uterine syne-
1982; Al-Inany, 2001). IUAs can be asymptomatic and remain undiscov- chiae’ and ‘uterine atresia’. The latter terms have been used in the past for
ered but often result in menstrual and fertility disorders. Menstrual intrauterine adhesions and were therefore included in the search.
To be able to compare the long-term reproductive outcomes, a second
disturbances like amenorrhea, hypomenorrhoea, menorrhagia, metror-
search was performed for published papers in which key reproductive indi-
rhagia, dysmenorrhea and pelvic pain can be present.
cators (conception rate, pregnancy rate and miscarriage rate) in women
Although subsequent fertility is a key issue for women, little has been
following a miscarriage, in particular women with post-miscarriage IUAs,
published and reported about the long-term implications of a miscar- were reported. The following terms were used in title or abstract searches
riage, in particular in patients with post-miscarriage IUAs. The category or as MESH terms: ‘abortion’, ‘miscarriage’, ‘curettage’, ‘fertility’, ‘infertility’,
of possible fertility symptoms in patients with IUAs includes secondary ‘pregnancy rate’, ‘human’ and ‘reproductive outcome’.
infertility and recurrent miscarriages (Schenker and Margalioth, 1982). The following electronic databases were searched: MEDLINE (1966 to
Other reported complications in patients with IUAs are miscarriage, January 2013), EMBASE (1974 to January 2013), Cochrane Central Register
ectopic pregnancy, abnormal placentation, fetal growth restriction, of Controlled Trials (CENTRAL). The search terms were modified according
fetal anomalies, premature delivery and post-partum hemorrhage to database requirements. The reference lists of the included studies were
(Schenker and Margalioth, 1982; Valle and Sciarra, 1988; Capella-Allouc also hand-searched for additional relevant studies.
et al., 1999).
Because of the possible implications of IUAs, some investigators have Paper selection procedure
advocated to perform a hysteroscopy after every miscarriage (Salzani
All prospective cohort, cross-sectional studies or randomized controlled
et al., 2007). Early IUA detection is claimed to be important because trials (RCTs) reporting on prevalence, risk factors and/or symptoms of
early treatment can prevent further complications (Valle and Sciarra, IUAs in women diagnosed with a current miscarriage (first search) and key
1988; Goldenberg et al., 1995; Katz et al., 1996). Treatment aims to reproductive indicators following a miscarriage (second search) were consid-
restore the normal size and shape of the uterine cavity, normal endomet- ered for inclusion. Original articles had to be published as full papers in peer-
rium function and to increase the chance of becoming pregnant (Proto- reviewed journals while language restrictions were not applied. Case reports
papas et al., 1998). However, the effect of treatment of IUAs on and small case series with ,30 patients were not included.
improvements in reproductive outcome has not been established. Studies were selected independently in a two-stage process by two
Hysteroscopy is considered to be the most reliable technique for IUA researchers; the first search was by A.B.H. and J.A.F.H. and the second
detection; direct vision of the uterine cavity enables accurate identifica- search was by A.B.H. and M.L. First, eligibility was assessed based on the
title and abstract. Full manuscripts were obtained for all studies that were
tion of their presence, localization and extent (Goldenberg et al., 1997;
selected. In the second step, examination of the full manuscript was
Cohen et al., 2001). Although heavy bleeding might impair the visualiza-
carried out to study the eligibility of the study. Additional information was
tion and therefore limit this utility shortly after the miscarriage or in the sought from authors if papers contained insufficient information.
case of symptomatic pregnancy remnants, hysteroscopy generally has
the advantage of enabling immediate treatment following the diagnostic
procedure. Furthermore, both congenital and acquired intrauterine ab- Eligibility criteria
normalities can be detected. Studies reporting the prevalence of post-miscarriage IUAs had to include
The reported prevalence of post-miscarriage IUAs varies consider- women with a previous miscarriage, in whom within 12 months after spon-
ably, depending on different parameters including the population taneous expulsion or medical or surgical treatment a hysteroscopy was per-
studied, the diagnostic method applied and the classification system formed to study the presence of IUAs.
used (Shaffer, 1986). Subsequently, the effect of number of miscarriages Studies reporting on women after elective abortion were excluded; elect-
and D&C procedures on the rate of IUAs has not been established. We ive abortion is considered a different clinical condition, implicating the possi-
bility of a difference in adhesion formation. Studies mainly evaluating women
present a systematic review of the literature to evaluate adhesion forma-
because of a history of recurrent miscarriage, without a recent miscarriage
tion after miscarriage and to identify potential risk factors. We also
within 12 months, were also excluded. These articles evaluated a selective
assessed long-term reproductive outcome following a miscarriage, par- group, women with a history of recurrent miscarriage who did not achieve
ticularly in women with post-miscarriage IUAs. a new pregnancy, to elucidate possible causal factors. We excluded these
studies since we consider them to evaluate a group with a potentially
higher prevalence of intrauterine abnormalities, causing the risk of overesti-
Methods mation of IUAs due to selection bias.
This systematic review and meta-analysis was conducted in accordance The presence of IUAs had to be studied as a primary or secondary
with PRISMA (Preferred Reporting Items for Systematic Reviews and outcome parameter. A hysteroscopic evaluation of the uterine cavity after
Meta-Analyses) guidelines. miscarriage for the presence of adhesions was obligatory; studies in which
Institutional review board approval was not sought since all data were other diagnostic methods were used for evaluation were not included.
extracted from previously published data. In the second search, studies had to report time to conception, conception
rate, pregnancy rates and/or miscarriage rates by natural conception in
women with post-miscarriage IUAs and/or women following conservative,
Systematic searches medical or surgical management of miscarriage. Studies reporting reproduct-
We searched the literature for published papers reporting on women who ive outcomes of subfertile couples or after assisted reproductive treatment
were systematically evaluated by hysteroscopy after miscarriage. The follow- (ART) were excluded. Papers describing obstetric complications, apart
ing terms were used in title or abstract searches or as MESH terms: ‘abortion’, from miscarriage, in the pregnancy subsequent to miscarriage were also
‘miscarriage’, ‘curettage’, ‘intrauterine adhesions’, ‘uterine adhesions’, excluded.

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Intrauterine adhesions after miscarriage 265

Women with a history of recurrent miscarriage were excluded. The preva- (1988) classification of IUAs is based on the extent of cavity involvement, type
lence of other factors affecting long-term reproductive outcome, such as sub- of adhesions and menstrual pattern. Cumulative scores determine the sever-
sequent miscarriage, is expected to be increased in this selected population. ity ranging from stage I to III. The ESGE emerged from the ESH; both classi-
By including this group, the relationship between adhesions and subsequent fications are based on a combination of the type of adhesions, site and extent
pregnancy outcome is affected and cannot be interpreted because of selec- of cavity involvement and the presence of amenorrhea or pronounced hypo-
tion bias. menorrhoea (Wamsteker, 1990; Wamsteker and de Blok, 1995). The sever-
Overall, women had to be included consecutively and independent of their ity of the adhesion is classified in seven grades.
symptoms. In order to allow eventual meta-analyses, we re-categorized the severity of
adhesions in three categories, based on data extracted from the reported
Nomenclature classification system. The categories were defined as mild, moderate
The nomenclature used to describe clinical events in early pregnancy in this or severe depending on the scale of the different classification systems
paper was according to the revised terminology by the ESHRE Special Inter- (Table I).
est Group for Early Pregnancy (SIGEP) (Farquharson et al., 2005). A miscar-
riage was defined as the spontaneous expulsion of products of conception or Classification of intrauterine abnormalities
the disappearance of fetal heart activity on ultrasound or a gestational sac that
Intrauterine malformations found by hysteroscopy can be divided into con-
did not grow in consecutive ultrasound examinations during the first 20
genital and acquired abnormalities. Congenital uterine abnormalities may
weeks of gestation. A delayed miscarriage, previously named missed abor-
arise from malformation at any step of the Müllerian developmental
tion, was defined as an anembryonic pregnancy without blood loss or expul-
process and are classified in different groups, some with further division in
sion of products of conception. Women were divided into conservative,
subtypes (Grimbizis et al., 2013). Acquired intrauterine abnormalities
medical or surgical treatment groups depending on the treatment received.
include uterine polyps, leiomyoma, retained products of conception and
endometritis. The prevalence of intrauterine abnormalities was calculated
Outcome measures for the entire group and furthermore, according to the number of
The primary outcome measure was the presence and degree of the reported miscarriages.
IUAs. Secondary meta-analyses were performed to estimate the associations
between prevalence of IUAs and type of miscarriage, number of miscarriages
or number of curettage procedures. Furthermore, the frequencies of both Data extraction and assessment of
congenital and acquired abnormalities, such as polyps and fibroids, were methodological quality
assessed if reported. The following information was extracted from the included studies: publica-
Subsequently, in the second analysis, conception, live birth and miscarriage tion year, study design, inclusion and exclusion criteria, patients’ characteris-
rates and time to conception in women diagnosed with IUAs following a mis- tics, treatment received, duration of follow-up, evaluation after miscarriage,
carriage were assessed and compared for women after conservative, medical congenital and acquired intrauterine abnormalities, evaluation of adhesions
or surgical management of a miscarriage. and IUA occurrence rate. If available, the degree and extent of IUAs were
also extracted. Potential prognostic factors such as infection or inflammation
Extent and degree of intrauterine adhesions contributing to adhesion formation were analyzed if systematically registered
To enable evaluation of the extent and degree of IUAs and outline prognosis in the paper. Data on the long-term reproductive outcomes (cumulative con-
and results of treatment, a classification system is essential. Over time a ception, live birth, miscarriage rates and time to conception) in women fol-
variety of updated classifications systems have been used, based on different lowing miscarriage, in particular women with post-miscarriage IUAs, were
diagnostic tools, clinical presentation and past reproductive performance. assessed.
Unfortunately the classification systems are not uniformly used and none The methodological quality of the selected papers was evaluated inde-
have been validated by clinical studies (Yu et al., 2008). The most used IUA pendently by two reviewers (A.B.H. and J.A.F.H.) using the Strengthening
classification systems are the classification of March et al., the American Fer- the Reporting of Observational Studies in Epidemiology (STROBE)
tility Society (AFS) classification, the European Society of Hysteroscopy statement-Checklist (von Elm et al., 2007). The checklist consists of key ele-
(ESH) classification and the European Society of Gynecological Endoscopy ments that should be transparently addressed and reported concerning
(ESGE) classification. objectives, study design, patient selection, verification, statistical method,
In the classification system of March et al. (1978), the adhesions are cate- outcome data and main results, limitation and generalizability. During evalu-
gorized in minimal, moderate and severe groups based on a combination of ation, items are ‘rated ‘1’ if the content is transparently and adequately
the type of adhesions and cavity involvement. The American Fertility Society described, ‘0’ if items are inadequately or insufficiently reported and ‘NA’

Table I Defined clinical categories to describe the extent and degree of intrauterine adhesions (IUAs) after miscarriage.

Classification systems
......................................................................................................................................................................
Clinical American Fertility Society European Society of European Society of Gynecological March,
category (AFS), 1988 Hysteroscopy (ESH), 1989a Endoscopy (ESGE), 1995 1978
.............................................................................................................................................................................................
Mild Stage I Stage I Stage I Mild
Moderate Stage II Stage II, IIa or III Stage II, IIa or III Moderate
Severe Stage III Stage IIIa, IIIb or IV Stage IV, Va or Vb Severe
a
The European Society of Hysteroscopy (ESH) was adopted by the European Society of Gynecological Endoscopy (ESGE) in 1995.

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266 Hooker et al.

if not applicable. The final score is the number of items scored ‘1’, with a Description and quality of included studies
maximum of 34. Discordant ratings of the two researchers were adjusted
through consultation with a third author (H.A.M.B.).
assessing post-miscarriage intrauterine
adhesions
One RCT (Yasar et al., 2004), eight prospective cohort studies (Golan
et al., 1992; Friedler et al., 1993; Römer, 1994; Römer et al., 1996;
Data analysis Tam et al., 2002; Congendez et al., 2011; Kuzel et al., 2011; Wang
Statistical analyses were conducted using the Review Manager (RevMan) et al., 2011) and one prospective cross-sectional study (Salzani et al.,
version 5.0 software (Cochrane Collaboration) and SAS 9.3 (SAS Institute, 2007) met the inclusions criteria. The characteristics of the included
Cary, NC, USA). For each study separately, the odds ratio (OR) with 95% studies are presented in Table II. In the only RCT (Yasar et al., 2004),
confidence interval (CI) was calculated for dichotomous variables. The pres- women with a miscarriage were randomized to receive prophylactic
ence of statistical heterogeneity was determined using the I 2 statistics. Het- doxycycline, prophylactic doxycycline plus conjugated equine estrogen
erogeneity was considered substantial when I 2 was .50% (Higgins and
or no treatment for prevention of IUAs following D&C. The prospective
Thompson, 2002; Higgins et al., 2003).
cohort study of Tam et al. (2002) was a follow-up study of women en-
In order to compare the overall prevalence of IUAs in women following
miscarriage and in women with one versus more than one miscarriage, in-
rolled in a previous RCT. In the initial study (Chung et al., 1999),
complete versus delayed miscarriage or one D&C versus more than one women diagnosed with a complete spontaneous miscarriage were
D&C, pooled ORs and 95% confidence intervals (CI) were calculated. Differ- managed conservatively; otherwise women were randomly allocated
ences in the incidence of IUAs in women with one, two, three or more mis- to either D&C or treatment with misoprostol. In one study, women
carriages were tested using meta-regression. after IVF-embryo transfer with early pregnancy failure were analyzed,
Depending on the presence of statistical heterogeneity, the data of studies but the method of treatment was not stated (Wang et al., 2011). In
were pooled on the basis of a fixed effects model or a random effects model. the remaining seven studies (Table II), six prospective cohort studies
Cumulative conception, live birth and miscarriage rates were calculated for and one cross-sectional study, women diagnosed with a current miscar-
women with IUAs after miscarriage and compared for women after conser- riage were subjected to D&C and evaluated after surgery for the pres-
vative, medical or surgical management of the miscarriage. For all tests per-
ence of IUAs.
formed, statistical significance was determined at P , 0.05.
A total of 912 women evaluated by post-miscarriage hysteroscopy
were included in the studies, ranging from 53 to 151 women per study,
with a mean of 91. The hysteroscopy was performed between 1 and
12 months following the miscarriage. The majority of the 781 patients
Results (86%) were treated by curettage whereas only 22 patients (2.4%) had
been treated medically while 25 (2.7%) were evaluated after a spontan-
Prevalence of post-miscarriage intrauterine eous miscarriage without any intervention. For the remaining 84 women
adhesions (9.2%), the treatment method was not stated.
Using the limitations ‘human only’ and ‘clinical trial’, the first search strat- In three studies (Römer et al., 1996; Tam et al., 2002; Salzani et al.,
egy yielded 804 citations including 201 duplicates. The quorum flow 2007), .30% of women were lost to follow-up, as shown in Table II.
diagram illustrating the selection procedure is shown in Fig. 1. Of the Given the substantial proportion of women not revised, inducing
603 remaining articles, 503 were excluded after title and abstract selec- some kind of verification bias, a separate analysis was performed
tion as they did not study IUAs in relation to miscarriages. One potential excluding these studies.
eligible article was not available for full manuscript reviewing even after The results of the assessment of the methodological quality of the
contacting the author and publisher (Santangelo, 1996). After reviewing included studies using the STROBE checklist are reported in Supplemen-
full manuscripts of the remaining 99 articles, 63 papers were excluded; tary data, Table SI. The included studies had a mean item score of 17.5
the reason for exclusion was lack of uterine evaluation after miscarriage. (from 31 relevant items), ranging between 14 and 25.
Five articles that used hysterosalpingography for uterine evaluation
(Adoni et al., 1982; Harger et al., 1983; Stray-Pedersen and Stray-
Pedersen, 1984; Stephenson, 1996; Tsapanos et al., 2002) were also Intrauterine adhesions
excluded. Additionally, 19 papers were excluded from analysis; 17 arti- Overall, IUAs were detected in 183 of the 912 women, resulting in a
cles reported on women evaluated because of recurrent miscarriages pooled prevalence of 19.1% (95% CI: 12.8 –27.5%), I 2 ¼ 86%, P ,
in their reproductive history, without a recent miscarriage within 12 0.001. When the studies with significant numbers lost to follow-up
months (Shiotsuka et al., 1980; Feng et al., 1989; Wang et al., 1992; Tulp- were excluded, the result did not change significantly; the pooled preva-
pala et al., 1993; Raziel et al., 1994; Fedele et al., 1996; Ebrashi et al., 1998; lence was 19.7% (95% CI: 12.0 –29.7%).
Valli et al., 2001; Badawy et al., 2002; Ballester et al., 2004; Ventolini et al., In one study, some of the women were treated by expectant
2004; Weiss et al., 2005; Guimarães Filho et al., 2006; Dendrinos et al., management (n ¼ 25) or medically (n ¼ 22), and no IUAs were
2008; Bohlmann et al., 2010; Jaslow et al., 2010; Souza et al., 2011), one reported in these women. In nine studies women were treated by
reported on infertile women with a history of curettage (Taylor et al., D&C, and IUAs were identified in 151 of the 781 patients, with a
1981) and one reported on women after elective induced abortion pooled prevalence of 18.5% (95% CI: 12.6 –26.4%), I 2 ¼ 82.5%, P ,
(Salat-Baroux et al., 1984). Two case series with respectively 3 and 10 0.001, while the pooled prevalence did not change significantly when
women were also excluded (Westendorp et al., 1998; Dalton et al., studies with significant numbers lost to follow-up were excluded;
2006). 16.3% (95% CI: 11.2 –23.1%). In the 10th study (Wang et al., 2011),

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Intrauterine adhesions after miscarriage 267

Figure 1 Flow diagram illustrating the selection procedure of relevant articles reporting on IUA post miscarriage. HSG, hysterosalpingography.

the treatment method was not mentioned and IUAs were detected in 32 1.25 –3.48). Women with more than one miscarriage had statistically sig-
of the 84 patients (38.1%; 95% CI: 28.4 –48.8%). nificantly more IUAs compared with women with one miscarriage. The
The extent and degree of the adhesions were reported in seven vast majority of the patients were managed surgically.
studies accounting for 124 women with adhesions, 67.8% of all IUAs were detected in 17 of 77 women with three or more miscar-
women with adhesions. The adhesions were classified according to riages compared with 21 cases among 111 women with two miscarriages
the ESH/ESGE, AFS and March systems in four, one and one studies, re- (Fig. 2B), OR 1.52 (95% CI: 0.68– 3.38), I 2 ¼ 0%, P ¼ 0.30. Excluding
spectively, while in one study the classification system was not stated one study with significant loss to follow-up resulted in an OR 1.38
(Table II). In one article (Römer et al., 1996), the moderate and severe (95% CI: 0.57– 3.31). No significant differences in IUAs were found
adhesions of seven patients were not separately reported; we consid- between women with two or three miscarriages. Relative to women
ered these patients to have moderate adhesions. The extent of the with one miscarriage, women with two miscarriages showed no statistic-
reported IUAs is reported in Table III; in 72 patients (58.1%) mild adhe- al significant risk OR 1.41 (95% CI: 0.78 –2.5) but women with three or
sions were reported, in 35 (28.2%) the adhesions were moderate and in more miscarriages showed a statistically significantly increased risk of
17 (13.7%) the adhesions were severe. IUAs OR 2.1 (95% CI: 1.09 –4.1). Figure 2E shows the reported preva-
lence of IUAs per study as well as the pooled estimates across the three
groups.
Numbers of miscarriages
Results of the meta-analysis are summarized in Fig. 2. The data of seven
prospective studies were pooled to compare the prevalence of IUAs in
Type of miscarriage and numbers
women with more than one versus one miscarriage (Fig. 2A). There were of D&C procedures
63 cases of IUAs among 270 women with more than one miscarriage In four studies, there were 68 cases of IUAs among 234 women with an
compared with 69 cases among 430 women with one miscarriage, OR incomplete miscarriage compared with 37 cases of IUAs among 155
1.99 (95% CI: 1.32– 3.00), I 2 ¼ 0%, P ¼ 0.001. Excluding two studies women with a delayed miscarriage (Fig. 2C), with an OR of 1.22 (95%
with significant loss to follow-up resulted in an OR 2.08 (95% CI: CI: 0.76 –1.96), I 2 ¼ 21%, P ¼ 0.41. Excluding two studies with

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268
Table II Characteristics of the included studies reporting the prevalence of post-miscarriage intrauterine adhesions (IUAs).

Study Design Period Characteristics of the Treatment n Mean age Systema Follow-up Lost to IUAs (%) Other
patients (range) hysteroscopy follow-up abnormalities
(%) (%)
.........................................................................................................................................................................................................................................................
Congendez PCS 2005–2007 Women with a miscarriage D&C 151 28.6 (18– 42) AFS End of first 0 14 (9.3%) 45 (29.8%)
et al. (2011) during the first 20 weeks of menstruation
gestation
Wang et al. PCS NR Women with early pregnancy NR 84 NR NR Prior to next 0 32 (38.1%) 26 (31.0%)
(2011) loss after IVF-ET. treatment
Kuzel et al. PCS NR Women with a delayed D&C 100 32 (21– 43) ESH 4– 12 weeks 0 7 (7%) 18 (18%)
(2011) miscarriage
Salzani et al. CSS NR Women with a miscarriage D&C 109 28.4 (18– 45) ESH 3– 12 months 169 (60.8%) 41 (37.6%) NR
(2007)
Yasar et al. RCT NR Women with a delayed D&C 58 NR NR 8 weeks 0 13 (22.4%) NR
(2004) miscarriage
Tam et al. PCS 1995–1998 Women with a miscarriage Exp, D&C, 70 29 (15– 44) AFS 6 months 56 (44.4%) 2 (2.9%) NR
(2002) MIS
Römer et al. PCS 1991–1995 Women with an incomplete or D&C 80 27.7, SD 5.4 ESH 8– 12 weeks 43 (35.0%) 20 (25%) 20 (25%)
(1996) delayed miscarriage and who
had a desire of further
pregnancy
Römer (1994) PCS 1991–1993 Women with an incomplete or D&C 53 27.5, SD 5.4 ESH 6– 12 weeks 0 16 (30.2%) 14 (26.4%)
delayed miscarriage with desire
of further pregnancy
Friedler et al. PCS 1990 Women with an incomplete or D&C 147 34 (19– 41) March After first 10 (6.4%) 28 (19.0%) 10 (6.8%)
(1993) delayed miscarriage between menstruation
the 7th and 12th week of
pregnancy
Golan et al. PCS NR Women with a delayed D&C 60 30 (19– 41) NR 8– 12 weeks 0 10 (16.7%) 15 (25%)
(1992) miscarriage

PCS, prospective cohort study; CSS, cross-sectional study; RCT, randomized controlled trial; NR, not reported; Exp, expectant management; D&C, dilation and curettage; MIS, misoprostol treatment.
a
AFS, American Fertility Society; ESH, European Society of Hysteroscopy.

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Intrauterine adhesions after miscarriage 269

potentially relevant citations were identified, including 715 duplicates.


Table III Extent of reported intrauterine adhesions After title and abstract selection 3694 citations were excluded,
(IUAs) after miscarriage.
because it was clear that they did not fulfill the inclusion criteria.
Extent of IUAs Cases % After reviewing the full manuscripts of the remaining 144 articles, 100
........................................................................................ were excluded from analysis: 71 articles did not report on follow-up after
Stated 124 67% miscarriage, while 29 articles reported long-term reproductive out-
Mild 72 58.1 comes in subfertile couples or after assisted conception. Subsequently,
Moderate 35 28.2 36 articles were excluded including 12 articles reporting on symptomatic
Severe 17 13.7 women with IUAs, i.e. women with menstrual disturbances and/or infer-
Not stated 59 32% tility (Caspi and Perpinial, 1975; Bergquist et al., 1981; Fedele et al., 1986;
Total 183 100% Valle and Sciarra, 1988; Katz et al., 1996; Pabuçcu et al., 1997;
Capella-Allouc et al., 1999; Fernandez et al., 2006; Adesiyun et al.,
2010; March et al., 2010; Roy, 2010; Roy et al., 2010). Eleven studies
examined the associations between pregnancy and obstetric complica-
significant loss to follow-up resulted in OR 1.59 (95% CI: 0.82 –3.10). No
tions and past reproductive performance in population-based cohorts
significant differences were found in IUAs in the women with incomplete
and were excluded (David and Smith, 1980; Rachootin and Olsen,
and delayed miscarriage.
1982; Regan et al., 1989; Knudsen et al., 1991; Thom et al., 1992; Joffe
In seven studies, after more than one D&C, 59 cases of IUAs were
and Li, 1994; Taskinen et al., 1999; Gray and Wu, 2000; Maconochie
detected among 253 women compared with 70 cases in 443 women
et al., 2007; Bhattacharya et al., 2008; Hure et al., 2012). Seven articles
after one D&C (Fig. 2D), OR 2.05 (95% CI: 1.35 –3.12), I 2 ¼ 0%,
evaluating women with recurrent pregnancy loss (Cowchock and
P , 0.001. Excluding two studies with significant loss to follow-up
Smith, 1995; Ruiz et al., 1996; Saitoh et al., 1998; Sheiner et al., 2005;
resulted in an OR 2.06 (95% CI: 1.23 –3.46). Women with more than
Prakash et al., 2006; Rai and Regan, 2006; Stephenson and Kutteh,
one D&C had statistically significantly more IUAs compared with
2007), three case reports (Kobayashi et al., 1996; Raziel et al., 2000;
women with one D&C.
Sills et al., 2004) and one article (Creinin, 1999) reporting unplanned con-
ceptions following miscarriage were excluded. Furthermore, two retro-
Intrauterine abnormalities spective articles reporting on reproductive outcomes following a
Seven studies reported on the prevalence of intrauterine abnormalities, miscarriage were excluded (Levin et al., 1979; Hassan and Killick, 2005).
other than adhesions, assessed by hysteroscopy. Overall, 150 cases of
intrauterine abnormalities were detected in 675 women, resulting in
a pooled prevalence of 22.4% (95% CI: 16.3–29.9%), I 2 ¼ 68.5%,
Description and quality of included studies
P ¼ 0.001. When the studies with significant loss to follow-up were assessing long-term reproductive outcome
excluded, the pooled prevalence did not change significantly, 22.0% Finally, eight prospective studies (Table IV) were identified, in which
(95% CI: 15.3–30.6%). The prevalence of intrauterine abnormalities key reproductive indicators following a miscarriage were reported
was 12.5% (34/271) after one miscarriage and 29.4% (55/187) after (Ben-Baruch et al., 1991; Kaplan et al., 1996; Blohm et al., 1997;
more than one miscarriage, and the difference was statistically significant, Adelusi et al., 1998; Graziosi et al., 2005; Tam et al., 2005; Fontanarosa
P , 0.0001. et al., 2007; Smith et al., 2009). A total of 1770 women who had suffered a
Congenital abnormalities were reported in 92 women, accounting for miscarriage were included in the eight studies.
61.3% of all encountered abnormalities. The most reported anomaly was The results of the assessment of the methodological quality of the
the septate uterus or bicornual uterus in 69 of the 92 women (75.0%), eight included prospective studies using the STROBE checklist are
followed by the arcuate uterus (19.6%), hypoplastic uterus (3.3%) and reported in Supplementary data, Table SII. The included studies had a
uni-cornuate uterus in respectively three (3.3%) and two (2.2%) mean item score of 14.4 (from 31 relevant items), ranging between 11
women. The most reported acquired uterine abnormality was uterine and 29.
polyps in 28 of 58 women (48.3%) with an acquired abnormality, fol-
lowed by leiomyoma, endometritis and retained products of conception Reproductive outcome following intrauterine
in 15 (25.9%), 10 (17.2%) and 5 (8.6%) women, respectively.
adhesions
The influence of infection or inflammation on the formation of IUAs
could not be examined due to insufficient reports of this event while The relationship between IUAs following a miscarriage and subsequent
the use of antibiotics was not stated. The effect of estradiol application fertility and reproductive outcome could not be assessed, as the pres-
was studied in three studies, but was insufficient for analysis. Information ence of IUAs was not studied in the included eight studies.
concerning the indication for, and the method of, performing D&C was
not stated. As such, these possible risk factors could not be examined. Reproductive outcome following miscarriage
In three studies, key reproductive indicators were reported for 430
Long-term fertility and reproductive outcome women after medical management with misoprostol. Cumulative con-
A second literature search was performed for relevant articles reporting ception rates ranged between 94 and 98% and live birth rates ranged
on long-term reproductive outcomes in women following a miscarriage, between 79 and 87% (Graziosi et al., 2005; Tam et al., 2005; Smith
especially in women with post-miscarriage IUAs. The study selection and et al., 2009). A live birth rate of 87% was reported by Graziosi et al.
number of included studies are reported in Fig. 3. In summary, 4553 (2005) after medical evacuation and Tam et al. (2005) reported a

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270 Hooker et al.

Figure 2 Summary of meta-analysis presenting odds ratio (OR) with 95% confidence interval (CI) for number (A and B) or type (C) of miscarriage and
number of D&C procedures (D). (E) The reported prevalence per study as well as the pooled estimates across women with one, two and three or more
miscarriages. Abbreviations: D&C, dilatation and curettage, IUAs, intrauterine adhesions, Mis, miscarriage.

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Intrauterine adhesions after miscarriage 271

Figure 3 Flow diagram illustrating the selection procedure of relevant articles reporting long-term reproductive outcome following miscarriage. ART,
assisted reproductive technique.

miscarriage rate of 13%. The percentage of women who received add- to 67% and 58%, respectively (Smith et al., 2009). There were more
itional surgical treatment was not reported in all studies. viable pregnancies among women who have no previous miscarriages,
A total of 511 women were evaluated in five studies after surgical while the number of pregnancies decreases with an increase in the
treatment. Cumulative conception rates ranged between 75 and 98%, number of previous miscarriages (Kaplan et al., 1996).
ongoing pregnancy rates ranged between 72 and 87%, live birth rates Time to conception was not uniformly defined in the included studies
ranged between 82 and 88% and miscarriage rates ranged between 11 and could not be assessed. Furthermore, the conception rates were
and 28% (Ben-Baruch et al., 1991; Blohm et al., 1997; Graziosi et al., reported over different time scales, which made it impossible to
2005; Tam et al., 2005; Smith et al., 2009). compare the results of the different studies.
In 6 studies, 829 women were evaluated after conservative manage-
ment. Subsequent conception rates between 73 and 91%, live birth
rates between 64 and 79% and miscarriage rates between 26 and 30%
Discussion
were reported (Ben-Baruch et al., 1991; Kaplan et al., 1996; Blohm To our knowledge, this is the first published systematic review and
et al., 1997; Adelusi et al., 1998; Fontanarosa et al., 2007; Smith et al., meta-analysis reporting the prevalence of IUAs after miscarriage and po-
2009). The proportion of women who received additional medical or tential risk factors, and long-term reproductive outcome following a mis-
surgical treatment could not be reported, as it was not reported in all carriage was also assessed.
studies. Hysteroscopy was considered the gold standard for IUA detection;
The number of previous miscarriages seems predictive of subsequent the uterine cavity can be visualized and the extent, localization and
reproductive outcome. Even when adjusted for age, the live birth rate degree of IUAs can be accurately determined, while other intrauterine
declined following one, two or three or more miscarriages from 74%, abnormalities can also be detected (Goldenberg et al., 1997; Cohen

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272
Table IV Characteristics of the prospective studies reporting long-term reproductive outcome after miscarriage.

Study Design Period Characteristics of the women Follow-up Treatment n Conception Live birth Miscarriage
(m) rate (%) rate (%) rate (%)
..........................................................................................................................................................................................................................................................
Smith et al. (2009) PCS 2005– 2007 Women with a miscarriage (,13 weeks) enrolled in a previous 70 EXP 224 NR 177/224 (79) NR
RCT comparing expectant, surgical and medical evacuations were MED 230 181/230 (79)
followed up by questionnaires. D&C 235 192/235 (82)
Fontanarosa et al. PCS NR Women with a symptomatic early miscarriage managed 12 EXP 60 18/60 (81) NR NR
(2007) conservatively followed up by telephone survey.
Tam et al. (2005) PCS 1995– 1998 Women enrolled in a previous RCT comparing medical and 48– 108 MED 131 128/131 (98) 109/128 (85) 17/128 (13)
surgical evacuation were followed up by telephone survey. D&C 130 127/130 (98) 112/127 (88%) 14/127 (11)
Graziosi et al. (2004) PCS 2001– 2003 Women with a miscarriage (,14 weeks) enrolled in a previous 12 MED 69 65/69 (94) 60/69a (87) NR
RCT, comparing surgical and medical evacuation, were followed D&C 57 54/57 (95) 50/57a (87)
up by a telephone survey.
Adelusi et al. (1998) PCS 1992 Women, who spontaneously aborted after suffering a 6– 48 EXP 273 222/273 (81) NR NR
spontaneous miscarriage in an obstetric clinic, were followed.
Blohm et al. (1997) PCS 1993– 1994 Women with a miscarriage enrolled in a previous RCT comparing 24 D&C 37 33/37 (89) NR NR
expectant and surgical management were followed up by EXP 76 69/76 (91)
questionnaires.
Kaplan et al. (1996) PCS NR Women with first trimester miscarriage (,8 weeks) managed 18 EXP 161 118/161 (73) 75/118a (64) 35/118 (30)
conservatively were followed up on future fertility.
Ben-Baruch et al. (1991) PCS 1983– 1988 Women with a miscarriage (,10 weeks) managed conservatively 12– 72 EXP 35 27/35 (77) 19/27 (70)b 7/27 (26)
or surgically were followed up to compare long-term fertility. 12– 68 D&C 52 39/52 (75) 28/39 (72)b 11/39 (28)

PCS, prospective cohort study; NR, not reported; EXP, expectant management; D&C, dilation and curettage; MED, medical treatment; RCT, randomized control trial.
a
Ongoing pregnancy rate is reported.
b
Reported rate is a combination of live birth rate and ongoing pregnancies.

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Intrauterine adhesions after miscarriage 273

et al., 2001). Because of the high frequency of false positive and diagnostic The number of previous miscarriages seems to predict subsequent re-
errors, hysterosalpingography, ultrasonography and sonohysterography productive performance; the live birth rate declines and the risk of mis-
are less suitable for accurate detection of IUAs (Valle, 1980; Raziel et al., carriage increases (Knudsen et al., 1991; Kaplan et al., 1996; Smith et al.,
1994; Soares et al., 2000). 2009). As shown by Hure et al. (2012), different groups of women ex-
perience different miscarriage rates; factors such as smoking status and
fertility problems have great impact on the miscarriage rate, with an
8-fold difference in the group with the lowest versus the highest calcul-
Summary of the evidence able rate of miscarriage.
The prevalence of IUAs in women treated for a current miscarriage varied
between 3 and 38%, with a pooled prevalence of 19%. The majority of
women were treated by D&C and women with more than one miscarriage Strengths and limitations of the review
had a significantly higher incidence of IUAs than women with only one mis- Our study has several points to be highlighted. We performed a system-
carriage (P ¼ 0.001). The prevalence of IUAs was not different in women atic review of the literature to determine the prevalence of IUAs and to
with two compared with three or more miscarriages or in women with in- identify risk factors. Furthermore, long-term reproductive outcome in
complete versus delayed miscarriage, although the small number of women after miscarriage was assessed. The strength of this report is
included women may have played an important role in this finding; the that the methodology and quality of included studies were individually
studies were underpowered to detect a significant difference between analyzed and only studies in peer-reviewed journals were included.
the groups. Exclusion of the studies with a substantial number lost to Only studies in which participants were included prospectively and con-
follow-up (.30%), did not influence the results of the meta-analysis. secutively were eligible for inclusion. Studies were included if in all the en-
Recurrent curettage procedures were identified as the most import- rolled patients a validated method for IUA ascertainment was used and
ant risk factor for IUA formation. Our results are in agreement with IUAs were clearly defined or if key reproductive indicators were used to
earlier observations; Westendorp et al. (1998) and Tsapanos et al. establish long-term reproductive outcome.
(2002) studied the presence of IUAs in women undergoing a second cur- We applied this protocol in order to minimize verification bias. For this
ettage and reported a prevalence of IUAs of 50%. In our study, no adhe- reason, studies including only symptomatic women after miscarriage were
sions were encountered in women after a spontaneous miscarriage excluded. In addition, we did not include studies reporting the prevalence
without any intervention and in women treated medically, although of IUAs or key reproductive indicators with a retrospective design, or
they were a minority (5.1%). The time between treatment and hystero- studies in which women were evaluated by hysteroscopy beyond 12
scopic evaluation for IUAs ranged between 1 and 12 months. In 42% of months after miscarriage, given the higher risk of selection bias.
the reviewed patients, moderate to severe IUAs were encountered and This study has also several weaknesses. Unfortunately, only one ran-
these are of concern as they may have serious reproductive implications. domized controlled trail was available to be included in this systematic
Besides IUAs, other abnormalities were frequently encountered in review; cohort studies are less reliable especially to determine
women undergoing hysteroscopy after miscarriage, with an overall treatment-associated factors. Only ten prospective cohort studies
prevalence of 22.4%. Congenital abnormalities accounted for 61.3% of with IUAs as end-point in women diagnosed with a current miscarriage
all encountered intrauterine abnormalities, especially uterine septum were encountered. The individual studies with a limited number of
or bi-cornuate uterus. Uterine polyps were the most reported acquired patients, a maximum 151, are underpowered to evaluate risk and prog-
abnormality. The prevalence of intrauterine abnormalities was signifi- nostic factors. Despite meta-analysis, the sample sizes in subgroups
cantly increased in women with more than one miscarriage compared remained small.
with women with only one miscarriage. The methodological quality of the studies included in this review is
After extensive review of the literature, only eight prospective studies considered poor to average. The studies reporting on IUAs, assessed
were identified in which key reproductive indicators were reported after by the STROBE statement checklist, resulted in an average score of
conservative, medical or surgical treatment for a miscarriage. Despite the 17.5 (ranging 14–25), of a maximum of 34. Although all patients had
extensive literature search, we were unable to find any study that had experienced a miscarriage and had a hysteroscopic evaluation within
specifically looked at reproductive outcome or long-term fertility in 12 months after miscarriage, eligibility criteria, sources and methods of
women with post-miscarriage IUAs. Only symptomatic women with selection of participant were barely described. There was insufficient in-
IUAs of different cause were reported in the available studies on this formation in most studies regarding the number of patients who met all
subject. inclusion criteria and the reason for received treatment and there were
Similar pregnancy outcomes were reported subsequent to conserva- no explanations of how the study sizes were determined.
tive, medical and surgical management of miscarriage, although the In three studies .30% of women were lost to follow-up and these
number of studies evaluating the long-term reproductive outcome was were the studies with the longest period between miscarriage and hys-
limited and different time scales were used. The limited number of teroscopic evaluation. This could be a relevant source of bias, as
studies and small sample size of the treatment groups obviously limit women achieving early pregnancy are excluded. A separate analysis, ex-
the statistical power to detect any difference in reproductive outcomes cluding these studies, did not influence the results significantly. Another
between the treatment regimes. Due to a large variation in primary out- noticeable point is that only 5.1% of the women were evaluated after a
comes, methodology and populations, we were not able to perform spontaneous miscarriage and expectant management or after medical
meta-analyses on reproductive outcome after miscarriage. The relation- evacuation.
ship and impact of IUAs on long-term reproductive outcomes remain un- Variations in different potential influencing factors including maternal
determined. age, chromosomal abnormalities, endocrine diseases, mode of

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274 Hooker et al.

conception and term of pregnancy failure (early and/or late) could not be reproductive outcomes in women with after miscarriage IUAs. The
ruled out. The majority of patients received surgical treatment and no largest study that classified IUAs following different antecedent endo-
distinction could be made between patients with and without D&C in metrial trauma, including incomplete or elective abortion and post-
the subgroups. The indication to perform a surgical treatment (D&C) partum curettage, showed that the subsequent reproductive outcome
was not reported. Women requiring surgical treatment (D&C) may after hysteroscopic treatment depends on the extent of IUAs. The preg-
differ from those who would be amenable to medical treatment or re- nancy rate declined from 93% in women with mild to 57% in women with
quiring no treatment at all. severe IUAs while the term pregnancy rate declined from 88 to 57%
Furthermore, there was lack of information concerning the D&C tech- (Valle and Sciarra, 1988). Schenker (1996) reported a pregnancy rate
nique (sharp, blunt, suction or combinations), cervical ripening, skills of of 95% in the mild IUA group compared with 60% in the severe group
the surgeons, indication, signs of infection or inflammation, the use of after hysteroscopic treatment.
antibiotics and treatment with estradiol. Because different classification In general, hysteroscopic adhesiolysis is advised when IUAs are
systems were used, the scoring of the adhesions was not uniform detected (Valle and Sciarra, 1988; Katz et al., 1996). Schenker and Mar-
while the presence of pre-existing adhesions was not assessed. These galioth (1982) reported poor reproductive outcome in a cohort of 292
factors may have biased the results in an unknown way. women with IUAs, who did not receive treatment before attempting
The methodological quality of the included studies reporting on long- to conceive. Pregnancy was reported in only 45%, while 40% ended
term reproductive outcome was poor. The average STROBE statement in a spontaneous miscarriage and another 23% were pre-term deliveries.
score was 14.4, ranging between 11 and 29. A substantial percentage of Even after hysteroscopic treatment, the reproductive outcome remains
patients treated medically or conservatively received additional surgical unsatisfactory; the post-operative pregnancy rate varies between 60 and
treatment because of incomplete management. Furthermore, no adjust- 75% (March, 1995).
ments were made in the studies for confounding variables such as parity, Subsequently, miscarriage rates of 15 –50% and pre-term delivery
gravidity, infertility, or number of prior induced abortions and miscar- rates of 10 –23% are reported in patients with IUAs while in 12% obstet-
riages. The studies did not report on the prevalence of other pathologies; ric complications, especially related to abnormal placentation, are
no adjustments were made for intrauterine abnormalities, although they encountered (Schenker and Margalioth, 1982; Friedman et al., 1986).
can be detected frequently and contribute to the incidence of miscar- In our study the extent of the reported IUAs was mild in 58% of the
riage. In this regard, the result of this review should be interpreted reviewed patients. The clinical implications and significance of mild
with caution as the overall quality of the included studies reporting on IUAs are still under debate, but it is likely that they are of minor import-
both post-miscarriage IUAs and in particular on the related long-term re- ance for fertility and symptomatology (Westendorp et al., 1998). There
productive outcomes needs to be considered as poor to average. are no studies comparing expectant management and hysteroscopic
The long-term reproductive outcome could not be reported in adhesiolysis in patients with mild IUAs. Whether hysteroscopic treat-
women with post-miscarriage IUAs due to a lack of studies reporting ment of mild adhesions is beneficial remains unclear, particularly in
on key reproductive indicators in these women. A total of 1770 case of asymptomatic patients.
women were included in eight cohort studies, reporting on one or A high overall prevalence (22.4%) of congenital and acquired uterine
more long-term reproductive indicators in women following a miscar- abnormalities was encountered in this study. The most reported con-
riage, was a limited number and a small overall sample size. Similar out- genital abnormality was the septate or bi-cornuate uterus. A septate
comes were reported over different time scales in the different treatment uterus results from incomplete resorption of the utero-vaginal septum
groups, while no adjustment was made in the studies for important con- and is frequently quoted as the most common congenital anomaly, asso-
founding factors. So, on the basis of the current literature no solid con- ciated with a high rate (.60%) of spontaneous miscarriage (Homer et al.,
clusions can be drawn on the link between treatment modality and 2000). This can be explained by the inability of the relative avascular
adhesion formation. The issue of possible impairment of future fertility septum, with an abnormal overlying endometrium, to provide an ad-
after miscarriage remains inconclusive on basis of the current literature. equate blood supply to the developing embryo (Burchell et al., 1978).
Systematic reviews and meta-analyses rely on aggregated published An arcuate uterus is considered a normal variant although the associ-
data to provide estimates of treatment effects or diagnostic tests. It is ation of an arcuate uterus with reproductive failure remains controversial
not possible to perform detailed analyses that take into account (Salim et al., 2003). The relationship between acquired intrauterine ab-
patient covariates or other features. A potentially more coherent ap- normalities and miscarriage remains unclear. The presence of intrauter-
proach to summarize the evidence is to acquire the original data from ine polyps and leiomyoma can interfere with implantation and fertility,
the included studies. Meta-analysis based on individual patient data pre- creating a hostile environment to embryo implantation (Somigliana
vents drawbacks and biases compared with conventional review, allow- et al., 2007; Pritts et al., 2009; Sunkara et al., 2010).
ing the possibility of investigating effectiveness in patients with different
profiles and offering a more valid outcome (Broeze et al., 2010).
However, to do so, access to original data sets is imperative, which Implications for clinical practice
can be a problem in older studies, while authors need to be willing to This meta-analysis shows that recurrent miscarriages and D&C proce-
share their data. dures should be considered as an important risk factor in IUA formation.
Although considerable advances have been made in the treatment of
IUAs, the results are still not satisfactory. This has implications for clinical
Comparison with previous research practice, as D&C should be prevented as much as possible and adhesion
This systematic review and meta-analysis reports the prevalence of IUAs formation should be taken into account when treatment options for mis-
after miscarriage, while no studies were found to report on long-term carriage are discussed.

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Intrauterine adhesions after miscarriage 275

In order to minimize the numbers of D&C, and probably IUAs in conservative, medical and surgical management, although the number of
patients after miscarriage, we propose the following strategy. First, studies and sample size are limited. Furthermore, the quality of the
expectative management could be emphasized as treatment option in studies was poor to average.
patients diagnosed with a miscarriage. Wieringa et al. (2002) reported To date, D&C is often performed in clinical practice in women diag-
that 50% of the patients with a miscarriage evacuated spontaneously nosed with a miscarriage despite the possibility of expectant manage-
and completely within 2 weeks without a significant increase in morbidity, ment and medical treatment and this may account for unnecessary
making this an attractive management option. Secondly, medical evacu- curettages and related IUAs. Further research is urgently needed to
ation should be considered as a serious alternative. Treatment with mife- analyze treatment modalities in women with a miscarriage in relation
pristone and misoprostol is equally as effective as surgery in achieving to IUAs and to identify risk factors. Subsequently, long-term fertility
complete evacuation with a RR of 0.96 (95% CI: 0.92 –1.0), and a and preventive measures to avoid adhesion formation following miscar-
success rate of .80% in both treatment groups (Neilson et al., 2010). riage can be identified.
There was a large and statistically significant reduction in surgical treat-
ment when patients were treated with misoprostol compared with im-
mediate D&C, RR 0.07 (95% CI: 0.03 –0.18), without differences in Supplementary data
blood transfusion, anemia, pelvic infection or use of pain relief. More- Supplementary data are available at http://humupd.oxfordjournals.org/.
over, women were satisfied with the treatment they received (Neilson
et al., 2010).
When there is a necessity, D&C should be performed in the gentlest Acknowledgements
manner avoiding unnecessary trauma. Application of materials for the
The authors thank Linda Kos (medical librarian) for her contribution in
prevention or reduction of adhesion may be effective in the prevention
developing search strategy and running searches on a periodic basis.
of IUAs, although the evidence is limited and only a minority have been
studied in women after miscarriage.
Authors’ roles
Implications for further research
A.B.H. was responsible for designing the study. M.L., A.L.T., H.A.M.B,
To accurately define the prevalence of IUAs, a systematic and prospect- B.W.M. and J.A.F.H. participated in study design and provided knowl-
ive evaluation is required after spontaneous miscarriage and expectant edge during the analysis and writing of the paper. A.B.H., ML and
management, medical evacuation and surgical treatment (D&C). After J.A.F.H. performed data abstraction and analyzed the data. A.B.H.
reviewing the literature, no study was encountered in which this was drafted the first manuscript. M.W.H. and B.C.O. performed the statistic-
studied. Several randomized studies have been performed comparing al analysis; B.C.O. performed the meta-analysis. All the authors critically
treatment strategies for miscarriage, but without systematic follow-up revised the manuscript, contributed to the final draft of the manuscript
with IUAs as end-point of interest. and approved the version to be published.
IUAs is a surrogate indicator: long-term fertility, reproductive
outcome and obstetric complications are clinically relevant. There is an
association between the presence and extent of IUAs and long-term Funding
complications but studies addressing the link, especially in women with
No external funding was used for this study.
after miscarriage IUAs, are lacking. Only symptomatic women with
IUAs of different causes are reported in the studies available on this
subject. Conflict of interest
To accurately define the prevalence of IUAs, pregnancy, obstetric and
fertility complications, one needs to prospectively follow a large cohort None declared.
of women after miscarriage for a long period. Subsequently, structural
follow-up is necessary to examine cumulative pregnancy, birth and mis-
carriage rates after conservative, medical and surgical treatment for mis-
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