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Intrauterine adhesion prevention after hysteroscopy: a systematic review and meta-analysis Mae Wu Healy, DO; Brian Schexnayder, MD; Matthew T. Connell, DO; Nancy Terry; Alan H. DeCherney, MD; John M. Csokmay, MD; Belinda J. Yauger, MD; Micah J. Hill, DO

T

he development of intrauterine adhesions is a significant potential fertility complication resulting from operative hysteroscopy.1,2 Trauma to the basalis layer of the endometrium during hysteroscopy3 can result in infertility, recurrent miscarriages, abnormal uterine bleeding, amenorrhea, dysmenorrhea, or abnormal placentation.4-6 Furthermore, intrauterine adhesions can cause the obliteration of portions of the endometrial cavity, leading to hematometra and severe pelvic pain.7 Several measures have been proposed in an effort to decrease the formation of postsurgical intrauterine adhesions.

From the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Drs Healy, Connell, DeCherney, Csokmay, Yauger, and Hill), Uniformed Services University of Health Sciences (Dr Schexnayder), National Institutes of Health Library, National Institutes of Health (Ms Terry), and Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center (Drs Healy, Connell, Csokmay, Yauger, and Hill), Bethesda, MD. Received Feb. 22, 2016; revised April 22, 2016; accepted May 2, 2016. The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the US Government. This research was supported in part by the intramural research program of the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.

BACKGROUND: Despite years of studies evaluating prevention strategies for intrauterine

adhesion formation after operative hysteroscopy, it is still unclear which strategies are most effective. OBJECTIVE: The objective of the study was to perform a systematic review and meta-analysis to evaluate the effectiveness of postoperative prevention strategies on intrauterine adhesion formation following operative hysteroscopy. STUDY DESIGN: Literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases. Inclusion criteria were published randomized controlled clinical trials from 1989 to 2014 comparing any postoperative preventative measures of intrauterine adhesion after hysteroscopy. The main outcome measure was a reduction in postoperative intrauterine adhesion. Heterogeneity of the studies was evaluated using a Q test and an I2 index. Analyses were performed using a random-effects model with outcome data reported as relative risk with 95% confidence interval. RESULTS: Twelve studies were included in the systematic review. Eight studies compared similar treatment methods and were included in the meta-analysis. Three studies evaluated hyaluronic acid gel, of which 2 reported a significant decrease in intrauterine adhesion with treatment. The meta-analysis demonstrated a significant reduction of intrauterine adhesion when using hyaluronic acid gel. Two studies evaluated polyethylene oxide-sodium carboxymethylcellulose gel, 1 of which demonstrated a decrease in intrauterine adhesion with treatment. A meta-analysis showed a significant reduction of intrauterine adhesion with polyethylene oxide-sodium carboxymethyl cellulose gel. However, these 3 studies demonstrating a benefit of the gels in preventing adhesion formation were all conducted by the same research group. Other research groups have not confirmed these results. A sensitivity analysis excluding these trials from this single group demonstrated no benefit to adhesion prevention with either gel formation. Three studies investigated oral estrogen therapy after hysteroscopy and found no difference in intrauterine adhesion. A meta-analysis showed no decrease in intrauterine adhesion with estrogen therapy after hysteroscopy. Data were lacking to perform metaanalyses on the use of intrauterine balloon, intrauterine device, and other adhesion prevention barriers in preventing intrauterine adhesion. CONCLUSION: There was a lack of definitive evidence to conclude that any treatment is effective in preventing posthysteroscopy uterine adhesion formation. The available literature has significant heterogeneity and a high risk of bias, making any definitive conclusions difficult. Key words: intrauterine adhesion, meta-analysis, operative hysteroscopy, prevention strategy

The authors report no conflict of interest. Presented as an abstract presentation at the 2015 annual meeting of the American Society for Reproductive Medicine, Baltimore, MD. Corresponding author: Mae Wu Healy, DO. [email protected] 0002-9378/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ajog.2016.05.001

Intraoperative techniques include reducing the use of electrosurgery8 and minimizing trauma to the healthy endometrium and myometrium.9 Surgeons have placed intrauterine instillments of different agents such as polyethylene oxide-sodium

and carboxymethylcellulose gel10 11,12 to treat the hyaluronic acid uterine lining immediately after the disruption of the endometrium. Other strategies to prevent intrauterine adhesions include a course of postoperative conjugated estrogen,13

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Systematic Reviews gonadotropin-releasing hormone analogs,1 or antibiotics.5 Additionally, physical barriers such as balloon catheters or intrauterine devices have been used postoperatively in an attempt to decrease intrauterine adhesions.14-16 Despite the many proposed solutions, no particular method has proven to be the optimal measure in preventing adhesion formation. This systematic review and metaanalysis was performed to review data from published randomized controlled trials using any postoperative preventative measures of intrauterine adhesions after operative hysteroscopy.

Materials and Methods Sources Literature searches were conducted in databases to include MEDLINE, Embase, ClinicalTrials.gov, and the Cochrane Library to retrieve randomized controlled trials on any postoperative preventative measures on intrauterine adhesions formation after hysteroscopy. The searches were not limited by language, with dates included from 1990 to 2014 to give a broad review of 25 years of published literature and include studies that were likely to reflect relatively modern surgical techniques. One study from 1989 returned in the search and was included in the review28. Key words and search strategy are in the Supplemental Addendum. Study selection Inclusion criteria were established prior to performing the literature search, and the systematic review was not registered in PROSPERO, the international prospective register of systematic reviews. Inclusion criteria were published randomized controlled trials evaluating intrauterine adhesions prevention with any postoperative intervention. Postoperative hysteroscopic evaluation of adhesion formation was required for inclusion. There were no other inclusion criteria based on age, subject population, or surgical indication. Exclusion criteria included publications of abstracts only, nonrandomized controlled trials or failure to report randomization, duplicate

ajog.org publications, review articles, or book chapters. There were 2 authors (M.W.H. and M.J.H.) who independently screened the studies with 1 disagreement noted in the included studies. A third author (M.T.C.) assisted in the discrepancy decision for included studies, and the 1 study was ultimately excluded because it contained a preoperative and not a postoperative intervention for adhesion prevention.1 The search yielded 73 total publications. The 73 abstracts were reviewed and 54 were excluded based on clear failure to meet inclusion criteria. There were 19 full-text articles that were evaluated for inclusion and exclusion criteria. Of these, 7 full-text articles were further excluded for not meeting inclusion criteria. Furthermore, 12 studies were chosen for inclusion in the systematic review and 8 studies in the meta-analysis. Only studies that were similar in methodology or clinical outcomes were included in the metaanalysis. The 2 authors (M.W.H. and M.J.H.) also evaluated study quality as well as potential for bias. Specifically, attention was placed on randomization methods, concealment of allocation, double blinding of providers and patients, treatment, outcomes, data reporting, and declaration of conflicts of interest. Data collection Data were extrapolated separately by 2 authors (M.W.H. and M.T.C.) and further confirmed with a third author (B.S.). Data to include the type of surgical instruments used during the initial operative hysteroscopy, therapy type, and time to follow-up hysteroscopy to evaluate for formation of intrauterine adhesions were extracted from the source articles. Severity of adhesions was based on intrauterine adhesions staging, according to the American Fertility Society.17 Furthermore, data on fertility outcomes were extracted to include pregnancy rates and miscarriage. Data synthesis Outcomes were evaluated for the presence or absence of postoperative

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adhesion formation (dichotomous), postoperative adhesion scores based on the American Fertility Society scoring system (continuous), pregnancy, and miscarriage. Heterogeneity was evaluated for each outcome and reported as a P value using the Q test and as percentages using the I2 index values. Random-effects models were used for meta-analysis if the I2 index was >50% or if clinical heterogeneity was noted in patient indication for surgery or methodology between studies. Fixed-effects models were used for meta-analysis if the I2 index was <50% and studies had clinical homogeneity in patient indication for surgery or methodology between studies. The meta-analysis was not performed when study methodology or clinical outcomes demonstrated extreme heterogeneity because such studies likely represent data inappropriate for statistical synthesis. The risk of bias was evaluated using qualitative assessments of study quality. Dichotomous outcomes were reported as relative risks with 95% confidence intervals and continuous data reported as weighted means with 95% confidence intervals. Data collection was performed in Excel (Microsoft Office; Microsoft Inc, Richmond, WA) and statistical analysis was performed using Mix Pro 2.0. P values for dichotomous outcomes in the source studies were calculated using vassarstats.net when not provided in the original papers. This study was instituional review board exempt because of the systematic review and meta-analysis nature of the paper.

Results Selection of studies for meta-analysis Abstracts from 73 papers were reviewed, of which 19 papers were further evaluated in detail (Supplemental Figure 1). There were 7 studies that were excluded after review of the full text articles: 1 study evaluated adhesions with hysterosalpingogram only in patients not pregnant 8 months postoperatively,18 3 were not randomized controlled trials,19-21 1 was a duplicate from a prior publication included in the review,22

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TABLE 1

Summary of postoperative adhesion formation rates in control and treatment groups of the included studies Study Acunzo et al, 2003

11

29

Amer et al, 2010

Dabirashrafi et al, 199525

Therapy type

Control, n, % adhesions

Treatment, n, % adhesions

P value

Hyaluronic acid

41

31.7%

43

13.95%

< .05

Intrauterine balloon vs plus fresh amnion graft vs plus dry amnion graft

15

14.0%

Fresh amnion, 15 dry amnion, 5

10.7% 13.3%

.27

Conjugated estrogen

23

0%

23

0%

10

Oxiplex/AP gel

26

14.0%

26

4%

12

Guida et al, 2004

Hyaluronic acid

69

26.15%

69

10.44%

De Iaco et al, 200324

Hyaluronic acid

22

21.8%

18

17.8%

.78

Carboxymethylcellulose hyaluronic acid gel

95

17.9%

92

9.1

.18

Intrauterine device

35

82.8%

36

8.3%

Estradiol valerate

45

6.9%

45

0%

.24

6%

< .05

Fuchs et al, 2014

30

Kim et al, 2012

Pabuccu et al, 1997

16

26

Roy et al, 2014

Sardo et al, 2011

7

Oxiplex/AP gel

55

22.0%

Tonguc et al, 201027

Estrogen therapy intrauterine device

25

5.3%

Estrogen, 16 IUD, 19 Estrogen plus IUD, 25

55

Vercellini et al, 198928

Estrogen and intrauterine device

10

0%

10

0% 10.5% 12% 0%

NS .30 < .05

< .05

.50

1.0

Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

1 was published only as an abstract,23 and 1 study included a randomized and nonrandomized arm and evaluated presurgical danazole for adhesion prevention.1 Thus, 12 randomized controlled trials met inclusion criteria and were included in the systematic review. Furthermore, 8 studies compared similar preventative intrauterine adhesions methods and were included in the meta-analysis. There was a lack of similar trials comparing the use of an intrauterine balloon, an intrauterine device, or other adhesions prevention barriers. Thus, these therapies were included in the systematic review but were not included in the meta-analysis data synthesis. There were 3 studies that evaluated hyaluronic acid gel,11,12,24 3 studies that evaluated estradiol valerate,25-27 and 2 studies that evaluated polyethylene oxide-sodium carboxymethylcellulose gel.9,10 Assessment of bias Of all the studies, 5 failed to report on allocation concealment and may have been at risk for participation bias16,24,25,28 (Supplemental Table 1).

There were 8 studies that did not blind investigators to subject group assignment and may have been at risk for performance and ascertainment bias.7,10-12,16,24,25,28 Furthermore, 5 studies did not have complete data reporting of patient dropout or loss to follow-up.11,24-26,28 There were 2 trials that reported their outcomes on an intent-to-treat basis, and both had no patients lost to follow-up.7,16 There were 2 studies that had a 21% patient dropout and may have been at risk for attrition bias.10,27 Fuchs et al10 had a similar dropout between the groups, making it unlikely that retention bias affected the results. Tonguc et al27 had dropout rates from 0% to 44% in the various arms of the study, placing it at risk for retention bias. The remaining studies that had complete data reporting had between 0% and 9% subject dropout. The majority of subject dropout across all studies was due to failure to follow up for a second-look hysteroscopy. Hyaluronic acid gel There were 3 studies that evaluated hyaluronic acid gel for adhesion prevention (Supplemental Table 2). Guida et al12

evaluated the prevention after polypectomy, myomectomy, or septum resection; Acunzo et al11 evaluated the prevention after septum resection; and De Iaco et al24 incorporated all of these same procedures. The incidence of postoperative adhesion formation ranged from 22% to 32% in the control groups and from 10% to 18% in the treatment groups (Table 1). Of these studies, 2 reported a significant reduction in the presence of intrauterine adhesions with the intrauterine application of hyaluronic acid.11,12 Guida et al12 reported a 10% rate of intrauterine adhesions in the treatment group compared with 26% in the control group (P < .05). Acunzo et al11 reported a 14% rate of intrauterine adhesions in the treatment group compared with 32% in the control group. The reported P value was P < .05; however, with a 2 tail test, this comparison is not statistically significant (P ¼ .06).11 De Iaco et al24 reported similar rates of intrauterine adhesions in the control group (22%) compared with the hyaluronic treatment group (18%). A meta-analysis with a random-effects model demonstrated a significant

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Systematic Reviews decrease in intrauterine adhesions when using hyaluronic acid gel (relative risk, 0.44, 95% confidence interval, 0.22e0.77). Minimal heterogeneity was suggested by the result of the Q test (Q ¼ 1.3, P ¼ .52) and the I2 index (I2 value ¼ 0%, 95% confidence interval, 0e90%). In these studies looking at hyaluronic acid gel for adhesion prevention, 2 studies also evaluated postoperative adhesion scores.11,12 Guida et al12 reported a lower mean adhesion score of 2.4 in the hyaluronic acid group compared with a score of 3.8 in the treatment group (P < .05). Acunzo et al11 reported a lower mean adhesion score of 2.0 in the hyaluronic acid group compared with a score of 6.2 in the treatment group (P < .05). A meta-analysis was not performed in these studies because of the extremely high heterogeneity (I2 value ¼ 98%, 95% confidence interval, 0e100%). The 3 studies evaluating hyaluronic acid did not follow up patients for pregnancy or miscarriage outcomes. The 2 studies demonstrating benefit of hyaluronic acid gel for adhesion prevention were performed by the same investigator group of authors at the University of Naples (Naples, Italy).11,12 The study that showed no benefit was performed by a different research group at the University of Bologna (Bologna, Italy).24 A sensitivity analysis removing the studies from the Naples group leaves a single study that demonstrates no benefit of hyaluronic acid gel for adhesion prevention. There is a lack of reproducible evidence that hyaluronic acid may decrease the incidence and severity of postoperative intrauterine adhesions. The impact of its use on pregnancy outcomes has not been evaluated. The data are inconsistent across 3 studies including 252 subjects. All 3 studies were between unclear to high risk of bias because of the lack of outcomes blinding. There were no low-risk studies for bias stratification.

ajog.org Polyethylene oxide-sodium carboxymethylcellulose gel There were 2 studies that evaluated polyethylene oxide-sodium carboxymethylcellulose gel for adhesion prevention. Di Spiezio Sardo et al7 evaluated prevention in patients with polypectomy, myomectomy, septum resection, and endometrial ablation. Fuchs et al10 evaluated adhesion prevention in patients, with missed abortion being managed with hysteroscopic resection. Di Spiezio Sardo et al7 reported a significant reduction in the incidence of postoperative intrauterine adhesions with the treatment group with 6% postoperative intrauterine adhesions compared with 22% in the no treatment group (P < .05). However, Fuchs et al10 found no significant difference between the treatment group with 4% and the control group with 14% (P ¼ .80). A meta-analysis with a random-effects model demonstrated a significant reduction of intrauterine adhesions when polyethylene oxide-sodium carboxymethylcellulose was used as the primary preventative method in 2 studies (relative risk, 0.26, 95% confidence interval, 0.09e0.76). Minimal heterogeneity was suggested by the result of the Q test (Q ¼ 0.1, P ¼.89) and the I2 index (I2 value ¼ 0%, 95% confidence interval, 0e100%). Both studies reported the incidence of moderate to severe formation of intrauterine adhesions but did not report adhesion scores. Di Spiezio Sardo et al7 reported a significant reduction in the severity of postoperative intrauterine adhesions with the treatment group, with only 2% having moderate to severe adhesions compared with 20% in the control group (P < .001). However, Fuchs et al10 found no significant difference between their treatment group with 4% and the control group with 14% (P ¼ .80). Fuchs et al10 reported a 14% pregnancy rate in the control group and 27% in the treatment group (P ¼ .66) over a 20 month follow-up period (Table 2). Miscarriage rates were not reported in either study and Di Spiezio

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Sardo et al7 did not report pregnancy rates. The study demonstrating benefit of polyethylene oxide-sodium carboxymethylcellulose for adhesion prevention7 came from the same group at the University of Naples,11 who demonstrated the benefit of hyaluronic acid.11,12 The study that showed no benefit was performed by a different research group at Tel-Aviv University (Tel-Aviv, Israel).10 The sensitivity analysis removing the studies from the Naples group demonstrates no benefit of using polyethylene oxide-sodium carboxymethylcellulose gel for adhesion prevention. There is a lack of reproducible evidence that polyethylene oxidesodium carboxymethylcellulose gel may decrease the incidence and severity of postoperative intrauterine adhesions. There is no evidence that its use affects pregnancy outcomes. The data are inconsistent across 2 studies and is limited to 162 subjects. Both studies were between unclear to high risk of bias because of the lack of outcomes blinding (Supplemental Table 1). There were no low-risk studies for bias stratification. Comparison of estrogen therapy There were 3 studies that evaluated postoperative estrogen therapy for adhesion prevention, none of which demonstrated benefit. All 3 studies evaluated patients with septum resection. Postoperative adhesion rates were consistently low across the studies, ranging from 0% to 6.9%. Roy et al26 reported postoperative intrauterine adhesions in 6.9% of patients in the control group compared with 0% in the estrogen group (P ¼ .24). Tonguc et al27 found intrauterine adhesions in 5.3% in the control group compared with 0% in the estrogen group (P ¼ 1.0). Dabirashrafi et al25 found intrauterine adhesions in 0% in both the control group and estrogen group. A metaanalysis with a fixed-effects model demonstrated no reduction of adhesions with the use of oral estrogen (relative risk, 0.78, 95% confidence interval,

5.2% vs estrogen, 6.2% IUD, 10.5% Estrogen plus IUD, 12% .49 31.5% 31.6% 32.0% Estrogen, 16 IUD, 19 Estrogen plus IUD, 25 47.7% Tonguc et al, 2010

Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

25 Estrogen therapy Intrauterine device

.82 18.7% vs. 14.2% .82 36.6% 45 40.5% 45

— — .22 47.2% 36 30.0% 35 Intrauterine device

— — .66 27.0% 26 14.0% 26 Oxiplex/AP gel

Estradiol valerate

27

Roy et al, 2014

26

Pabuccu et al, 1997

16

Fuchs et al, 2013410

— — .95 28.6% 26.7% Fresh amnion, 15 dry amnion, 5 14.3% 15 Amer et al, 2010

29

Intrauterine balloon vs plus fresh amnion graft vs plus dry amnion graft

P value Miscarriage % control vs. treatment P value Treatment n % pregnancy Control, n, % pregnancy Therapy type Study

Summary of pregnancy and miscarriage rates in control and treatment groups of the included studies

TABLE 2

0.49e1.25) (Figure). Minimal heterogeneity was suggested by the result of the Q test (Q ¼ 0.2, P ¼.64) and the I2 index (I2 value ¼ 0%, 95% confidence interval, 0e89%). None of the estrogen treatment studies reported severity scores for postoperative adhesion formation. Dabirashrafi et al25 did not report pregnancy outcomes. The other 2 studies reported no difference in postoperative pregnancy rates between the treatment and control groups (Table 2). Roy et al26 reported pregnancy rates of 40.5% of patients in the control group compared with 36.6% in the estrogen group (P ¼ .82) over a 23 month follow-up period. Similarly, Tonguc et al27 reported pregnancy rates of 47.7% in the control group compared with 31.5% in the estrogen group (P ¼ .66) over a 1 month follow-up period. A meta-analysis with a fixed-effects model demonstrated no difference in pregnancy with the use of oral estrogen (relative risk, 0.78, 95% confidence interval, 0.28e1.25) (Supplemental Figure 2). Minimal heterogeneity was suggested by the result of the Q test (Q ¼ 0.2, P ¼ .62) and the I2 index (I2 value ¼ 0%, 95% confidence interval, 0e100%). Both studies reported no difference in postoperative miscarriage rates between the treatment and control groups. Roy et al26 reported miscarriage rates of 18.7% in the control group compared with 14.2% in the estrogen group (P ¼ .82). Similarly, Tonguc et al27 reported pregnancy rates of 5% in the control group compared with 6.2% in the estrogen group (P ¼ 1.0). A meta-analysis with a fixed-effects model demonstrated no difference in pregnancy with the use of oral estrogen (relative risk, 0.87, 95% confidence interval, 0.21e3.49). Minimal heterogeneity was suggested by the result of the Q test (Q ¼ 0.1, P ¼.77) and the I2 index (I2 value ¼ 0%, 95% confidence interval, 0-100%). There is no evidence that estrogen use decreases intrauterine adhesion formation or improves subsequent pregnancy outcomes. The data are consistent across 3 individual studies but is limited to 171 subjects. The study by Tonguc et al27 was

.76

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FIGURE

Forest plot comparing estrogen vs placebo for adhesion prevention

CI, confidence interval. Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

at low risk of bias and the other 2 studies at unclear risk of bias because of unclear allocation concealment (Supplemental Table 1). Bias stratification of only the low-risk trial did not change the outcome. Human amnion There was 1 study that evaluated fresh and dried human amnion for the prevention of intrauterine adhesions. Amer et al29 evaluated patients with severe synechiae and postoperative treatment with an intrauterine balloon, fresh amnion, and dried amnion. The amnion was applied into the uterus around an intrauterine balloon. Postoperative adhesion scores were similar in the 3 groups: 2 in the intrauterine balloon group, 1.5 in the fresh amnion group, and 2 in the dried amnion group (P ¼ .27). Although postoperative adhesion scores were similar between the groups, the authors reported that the

fresh amnion group had a great reduction in adhesion scores compared with the balloon only and the dried amnion groups. Pregnancy rates were similar in the 3 groups: 14.3% in the balloon group, 28.6 in the fresh amnion group, and 26.7% in the dried amnion group (P ¼ .95). The study did not report on the rate of adhesion reformation or miscarriage rates in the 3 groups. There is no evidence that human amnion is superior to placebo for the prevention of intrauterine adhesions. There is no evidence that the use of human amnion improves pregnancy outcomes. The data are limited to a single study with 43 subjects. Alginate carboxymethylcellulose hyaluronic acid gel and carboxymethylcellulose hyaluronic acid gel There was 1 study that evaluated alginate carboxymethylcellulose hyaluronic acid

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gel and carboxymethylcellulose hyaluronic acid gel for the prevention of intrauterine adhesions. Kim et al30 evaluated patients with hysteroscopy for polypectomy, myomectomy, septum resection, adhesion resection, and abnormal uterine bleeding treated with alginate carboxymethylcellulose hyaluronic acid gel or carboxymethylcellulose hyaluronic acid gel. The presence of postoperative adhesions was similar in the 2 groups: alginate carboxymethylcellulose hyaluronic acid gel, 9.1%, vs carboxymethylcellulose hyaluronic acid gel, 17.9% (P ¼ .21). Postoperative adhesion scores were similar in the 2 groups: alginate carboxymethylcellulose hyaluronic acid gel, 2.8, v carboxymethylcellulose hyaluronic acid gel, 1.9 (P ¼ .21). The study did not report on pregnancy or miscarriage outcomes. There is no evidence to support a difference between alginate carboxymethylcellulose hyaluronic acid gel and

Systematic Reviews

ajog.org carboxymethylcellulose hyaluronic acid gel. The data are limited to a single study with 187 subjects. Repeat hysteroscopy at 1 week Pabuccu et al16 evaluated the use of an intrauterine device and guided hysteroscopy 1 week after the initial surgery in patients treated for severe synechiae. Both groups received intrauterine device placement and 2 months of estrogen and progesterone treatment. The study divided the groups in which 1 group received a hysteroscopy 1 week after the initial surgery with further lysis of new adhesions, whereas the other group did not. The repeat hysteroscopy group had a lower rate of adhesions at 2 months compared with the control group (10.9% vs 82.9%, P < .05). Pregnancy rates were similar in the repeat hysteroscopy group (47.2%) and the control group (30%) (P ¼ .22). There is evidence to suggest repeat hysteroscopy at 1 week decreases intrauterine adhesion formation when combined with estrogen, progesterone, and intrauterine device use. However, there was no demonstrable effect on pregnancy outcomes. Additionally, the intervention (repeat operative hysteroscopy at 1 week) is the same ultimate intervention needed if adhesions form postoperatively. The data are limited to a single study of 71 subjects. Intrauterine device Tonguc et al27 had study arms comparing estrogen with a copper intrauterine device and an intrauterine device alone in addition to the control and estrogenonly arms already discussed. They demonstrated similar rates of postoperative intrauterine adhesions in all groups: control, 5.3%; intrauterine device, 10.5%; and intrauterine device with estrogen, 12% (P ¼ .50). The investigators did not evaluate the severity of the postoperative adhesions. They also demonstrated similar pregnancy rates in the study arms: control, 47.4%; intrauterine device, 31.6%; and intrauterine device with estrogen, 32% (P ¼ .49). Similarly, miscarriage rates were similar in the 3 arms: control, 5.2%; intrauterine device, 10.5%; and

intrauterine device with estrogen, 12% (P ¼ .76). Vercellini et al28 also evaluated a copper intrauterine device with estrogen vs no treatment. The study of 20 women had no postoperative intrauterine adhesions in either group. The study did not report on pregnancy outcomes following the treatment. These studies were not included in the meta-analysis because of the usage of different formulations of estrogen therapy in addition to small sample sizes with no difference in the results. There is no evidence to suggest that copper intrauterine device use prevents postoperative adhesions or improves pregnancy outcomes. The data are limited to 2 studies of only 83 subjects. The study by Tonguc et al27 was at low risk of bias and the study by Vercellini et al28 at unclear risk of bias because of unclear allocation concealment and blinding (Supplemental Table 1). Bias stratification of only the low-risk trial did not change the outcome.

Comment Operative hysteroscopy is the optimal treatment for normalizing the uterine cavity in patients with lesions associated with abnormal uterine bleeding or infertility. Unfortunately, it can also lead to complications such as the formation of intrauterine adhesions postoperatively. Postoperative intrauterine adhesions can occur in up to 88% of septum resections, 76% of synechiae resections, and 40% of myomectomies if no prophylaxis is given.31 Adhesion prevention methods studied in this meta-analysis included hyaluronic acid gel, polyethylene oxidesodium carboxymethylcellulose gel, oral estrogen, an intrauterine balloon, an intrauterine device, and human amnion. Unfortunately, the available data have significant limitations, which make it difficult to conclude that any treatment modality is effective at reducing adhesion formation. One challenge in interpreting the results of the studies in this systematic review is the small sample sizes. The use of underpowered studies makes it more likely to find no difference between the

treatment and control groups and increases the risk of a type II error.32 The 3 studies on estrogen had a combined sample size of 171 subjects with adhesion rates up to 7% in the control groups. Combined, these studies lacked the power to detect a difference in adhesion formation with estrogen, even if estrogen treatment resulted in a 0% adhesion formation rate, which was indeed the case. In other words, no matter what effect estrogen had on preventing adhesions, these studies combined could not find a difference based on the overall low adhesion formation rate in the control groups and the small sample sizes. The lack of blinding in the trials also places them at risk for several potential biases. When subjects are not blinded, they may be at increased risk of feeling either disappointed or relieved at not receiving the experimental treatment.33 This can lead to increased dropout in the experimental or control arms, either of which can affect results.33-35 In this review, 9 of the 12 studies did not blind the subjects and were at risk of this bias. This is exemplified by studies that had significant patient dropout and may have been at high risk for attrition bias.10,27 Five studies in this review did not have complete data reporting of patient dropout or loss to follow-up, making it difficult to assess for this bias.11,24-26,28 Another way to minimize bias based on the loss of subject recruitment recommended by the Consolidated Standards of Reporting Trials guidelines36 would be reporting on an intent-totreat basis. However, only 2 trials reported their outcomes with an intentto-treat basis.7,16 A potential greater source of bias is the lack of blinding of the assessment of adhesion outcomes in the studies.33 Studies in which the researchers are unblinded are at increased risk of ascertainment bias.34 Studies in which the outcome is a subject measurement, such as a visual assessment of adhesion severity, may be at even further risk of ascertainment bias.33 The well-designed controlled trials in this review blinded the assessment of outcomes by using a second-look hysteroscopy with a new surgeon that was blinded to the

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Systematic Reviews treatment the subject had received. However, 8 of the 12 studies failed to provide this study design. The 3 studies that showed benefit from hyaluronic acid gel or polyethylene oxide-sodium carboxymethylcellulose gel for adhesion prevention were at risk from a lack of blinding of both patients and the researchers.7,11,12 These studies also failed to report whether any conflict of interest was present and whether any industry support for the trials occurred. All 3 of these studies demonstrating benefit from gels came from the same investigator group. Other groups who repeated similar study designs were unable to demonstrate benefit from adhesion prevention gels.10,24 However, these studies also had similar bias risks in review of their study design and outcome reporting. When a sensitivity analysis was performed, removing the group from the University of Naples, there were no randomized studies showing benefit to the use of gels for adhesion prevention. This makes it difficult to interpret if there is a bias inherent in the large proportion of the literature originating from a single group or perhaps other research groups have undetected variables that make it difficult to replicate the same findings. These potential significant sources of bias and heterogeneity of results make us unable to conclude that gels are effective in the prevention of uterine adhesions. Four studies in the current metaanalysis failed to have a nonintervention control group16,28-30 but instead randomized patients to 2 or more treatment arms. This would be an effective study design if a new intervention was being compared with a gold standard for adhesion prevention. Given the lack of robust evidence that any treatment is effective in preventing adhesions, a welldesigned trial must contain a nonintervention control group. The conclusions from these studies that the interventions were similar does not help us determine whether any of those interventions were inferior, equivalent, or superior to no intervention at all. Three studies evaluated the ability of a copper intrauterine device to prevent uterine adhesions.16,27,28 The rationale

ajog.org behind this approach is to cause a physical barrier between the anterior and posterior walls of the uterus in a physical attempt to prevention adhesion formation. However, copper intrauterine devices increase local inflammation in the endometrium,37 which could be criticized for potentiating adhesion formation rather than preventing it. It is possible that the 83% adhesion rate in the intrauterine device group from Pabuccu et al16 was the result of an increase in this inflammatory process. Based on its inflammatory properties and small surface area, which is unlikely to cause adequate physical separation of the uterine walls, the American Association of Gynecologic Laparoscopists recommends that intrauterine devices not be utilized for postoperative adhesion prevention.17 There was a large amount of clinical heterogeneity in the studies included in this review. Adhesion formation may be affected by the use of cautery during surgery, the skill of the surgeon, and the surgery being performed.38 An observational study reported postoperative adhesions rates as low as 0% following polypectomy and as high as 88% following septum resection.31 Adhesion rates were highly heterogeneous in this review, ranging from 0% to 83%. The type of surgery performed was also highly heterogeneous in this review, including septum resection, myomectomy, polypectomy, adhesiolysis, removal of retained products of conception, and endometrial ablation. The 3 studies evaluating estrogen therapy were all performed in patients undergoing septum resection, making it the only comparison in this metaanalysis that included a group of studies performing a single type of surgical procedure. All other comparisons involved grouping multiple different types of surgical procedures. This clinical heterogeneity makes it more difficult to assess whether any of the interventions are effective in preventing adhesions after any specific individual type of surgical procedure. One way to account for heterogeneity in a meta-analysis is to utilize random-effects models. Random-effects models attempt

274 American Journal of Obstetrics & Gynecology SEPTEMBER 2016

to estimate the mean of a distribution of various effects and assumes some of the differences between studies are the result of heterogeneity.39,40 Conversely, fixed-effect models attempt to estimate a single true effect and assumes differences between studies are the result of random sampling.39,40 This makes random-effect models more appropriate for estimating the ability of an intervention to prevent adhesions in different types of surgeries with different surgical techniques. In conclusion, despite 12 randomized controlled trials evaluating the prevention of uterine adhesions after operative hysteroscopy, the available literature either lacks the statistical power to answer the question or suffers from potential sources of bias and heterogeneity, which makes interpretation of the results difficult. Many of the interventions described in this review have biological plausibility for benefit in adhesion prevention; however, patients should be counseled that there is a lack of definitive evidence for any benefit with treatment. Given the sequelae and prevalence of postoperative intrauterine adhesions, this is an area in need of well-designed, adequately powered controlled trials.17 REFERENCES 1. Taskin O, Sadik S, Onoglu A, et al. Role of endometrial suppression on the frequency of intrauterine adhesions after resectoscopic surgery. J Am Assoc Gynecol Laparoscop 2000;7: 351-4. 2. Touboul C, Fernandez H, Deffieux X, et al. Uterine synechiae after bipolar hysteroscopic resection of submucosal myomas in patients with infertility. Fertil Steril 2009;92:1690-3. 3. Klein SM, Garcia CR. Asherman’s syndrome: a critique and current review. Fertil Steril 1973;24:722-35. 4. Menzies D. Postoperative adhesions: their treatment and relevance in clinical practice. Ann R Coll Surg Engl 1993;75:147-53. 5. Schenker JG. Etiology of and therapeutic approach to synechia uteri. Eur J Obstet Gynecol Reprod Biol 1996;65:109-13. 6. Valle RF, Sciarra JJ. Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. Am J Obstet Gynecol 1988;158:1459-70. 7. Di Spiezio Sardo A, Spinelli M, Bramante S, et al. Efficacy of a polyethylene oxide-sodium carboxymethylcellulose gel in prevention of

Systematic Reviews

ajog.org intrauterine adhesions after hysteroscopic surgery. J Minim Invas Gynecol 2011;18:462-9. 8. Chen FP, Soong YK, Hui YL. Successful treatment of severe uterine synechiae with transcervical resectoscopy combined with laminaria tent. Hum Reprod 1997;12:943-7. 9. Di Spiezio Sardo A, Mazzon I, Bramante S, et al. Hysteroscopic myomectomy: a comprehensive review of surgical techniques. Hum Reprod Update 2008;14:101-19. 10. Fuchs N, Smorgick N, Ben Ami I, et al. Intercoat (Oxiplex/AP gel) for preventing intrauterine adhesions after operative hysteroscopy for suspected retained products of conception: double-blind, prospective, randomized pilot study. J Minim Invas Gynecol 2014;21:126-30. 11. Acunzo G, Guida M, Pellicano M, et al. Effectiveness of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic adhesiolysis: a prospective, randomized, controlled study. Hum Reprod 2003;18:1918-21. 12. Guida M, Acunzo G, Di Spiezio Sardo A, et al. Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod 2004;19:1461-4. 13. Roge P, D’Ercole C, Cravello L, et al. Hysteroscopic management of uterine synechiae: a series of 102 observations. Eur J Obstet Gynecol Reprod Biol 1996;65:189-93. 14. Comninos AC, Zourlas PA. Treatment of uterine adhesions (Asherman’s syndrome). Am J Obstet Gynecol 1969;105:862-8. 15. Orhue AA, Aziken ME, Igbefoh JO. A comparison of two adjunctive treatments for intrauterine adhesions following lysis. Int J Gynaecol Obstet 2003;82:49-56. 16. Pabuccu R, Atay V, Orhon E, et al. Hysteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation and fertility. Fertil Steril 1997;68: 1141-3. 17. American Fertility Society. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusions, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions. Fertil Steril 1988;49:944-55.

18. Tsapanos VS, Stathopoulou LP, Papathanassopoulou VS, Tzingounis VA. The role of Seprafilm bioresorbable membrane in the prevention and therapy of endometrial synechiae. J Biomed Mater Res 2002;63: 10-4. 19. Assaf A, Serour G, Elkady A, el Agizy H. Endoscopic management of the intrauterine septum. International J Gynaecol Obstet 1990; 32:43-51. 20. Ducarme G, Davitian C, Zarrouk S, Uzan M, Poncelet C. Interest of auto-cross-linked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a casecontrol study. J Gynecol Obstet Biol Reprod 2006;35:691-5. 21. Shawki O, Ebrashi A, Kandeel H. Evaluation of different approaches for prevention of intrauterine adhesions following hysteroscopic metroplasty for septate uterus. Middle East Fertil Soc J 1999;4:135-9. 22. Guida M, Acunzo G, Di Spiezio SA, et al. Auto-cross-linked hyaluronic acid gel after hysteroscopic surgery reduced formation of intrauterine adhesions. Gynecology 2004;7: 27-8. 23. Lin X, Wei ML. A prospective randomized control trial to compare the efficacy of intrauterine balloon and intrauterine contraceptive device in the prevention of adhesion reformation following hysteroscopic adhesiolysis. Gynecol Surg 2011;1:89-90. 24. De Iaco PA, Muzzupapa G, Bovicelli A, et al. Hyaluronan derivative gel in intrauterine adhesion (IUA) prevention after operative hysteroscopy. Ellipse 2003;19:15-8. 25. Dabirashrafi H, Mohammad K, MoghadamiTabrizi N, et al. Is estrogen necessary after hysteroscopic incision of the uterine septum? J Am Assoc Gynecol Laparoscop 1996;3: 623-5. 26. Roy KK, Negi N, Subbaiah M, et al. Effectiveness of estrogen in the prevention of intrauterine adhesions after hysteroscopic septal resection: a prospective, randomized study. J Obstet Gynaecol Res 2014;40:1085-8. 27. Tonguc EA, Var T, Yilmaz N, et al. Intrauterine device or estrogen treatment after hysteroscopic uterine septum resection. Int J Gynaecol Obstet 2010;109:226-9.

28. Vercellini P, Fedele L, Arcaini L, et al. Value of intrauterine device insertion and estrogen administration after hysteroscopic metroplasty. J Reprod Med 1989;34:447-50. 29. Amer MI, Abd-El-Maeboud KH, Abdelfatah IS, et al. Human amnion as a temporary biologic barrier after hysteroscopic lysis of severe intrauterine adhesions: pilot study. J Minim Invas Gynecol 2010;17:605-11. 30. Kim T, Ahn KH, Choi DS, et al. A randomized, multi-center, clinical trial to assess the efficacy and safety of alginate carboxymethylcellulose hyaluronic acid compared to carboxymethylcellulose hyaluronic acid to prevent postoperative intrauterine adhesion. J Minim Invas Gynecol 2012;19: 731-6. 31. Yang JH, Chen MJ, Chen CD, et al. Optimal waiting period for subsequent fertility treatment after various hysteroscopic surgeries. Fertil Steril 2013;99:2092-6. 32. Sedgwick P. Pitfalls of statistical hypothesis testing: type I and type II errors. Br Med J 2014;349. 33. Schultz KF, Grimes DA. Blinding randomised trials: hiding who got what. Lancet 2002;359:696-700. 34. Sedgwick P. Controlled trials: allocation concealment, random allocation, and blinding. BMJ 2015;350. 35. Sedgwick P. Bias in experimental study designs: randomised controlled trials with parallel groups. BMJ 2015;351. 36. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c869. 37. Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception 2007;75:S16-30. 38. Mazzon I, Favilli A, Cocco P, et al. Does cold loop hysteroscopic myomectomy reduce intrauterine adhesions? A retrospective study. Fertil Steril 2014;101:294-8. 39. Haidich AB. Meta-analysis in medical research. Hippokratia 2010;14:29-37. 40. Bernstein M. Introduction to meta-analyses. Chichester (United Kingdom): John Wiley & Sons; 2009.

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Systematic Reviews Supplemental Addendum Uterine adhesion prevention: systematic review literature search strategy/methods Literature searches were conducted to retrieve RCTs, retrospective studies, or prospective studies on the prevention of intrauterine adhesions after hysteroscopic surgery. Databases searched included PubMed, Embase, and the Cochrane Library. The searches were limited by date to papers published between 1990 and 2014. The searches were conducted in December 2014. References were exported into an EndNote bibliographic management database and duplicates were removed. Searches utilized key words and specific database indexing terminology where available. The following search strategies were used: MEDLINE

ajog.org Intrauterine adhesion [tiab] or uterine adhesion [tiab] or (tissue adhesions [mh] and uterine diseases [mh]) or (adhes [ti] and (uterine [ti] or uterus [ti] or intrauterin [tiab])) or synechia [tiab] or asherman [ti] and hysteroscopy [mh] or hysteroscop [tiab] and prevent [tiab] or reduc [tiab] or manage [tiab] or pc [sh] or (decreas [tiab] and recurr [tiab]) and (“study characteristics” [publication type] or “clinical trial” [ptyp] or “epidemiologic studies”[Mesh] or “support of research” [ptyp] or cohort [tiab] or retrospective [tiab] or prospective [tiab]), not (editorial [ptyp] or comment [ptyp] or news [ptyp] or letter [ptyp] or review [ptyp] or systematic [sb]). EMBASE “Uterus synechia”/exp or (“tissue adhesion”/exp and “uterus”/exp) or adhes NEAR/5 ([uterine or uterus]): ab,ti) and “hysteroscopy”/exp or hysteroscop: ab, ti, and “Prevention and

275.e1 American Journal of Obstetrics & Gynecology SEPTEMBER 2016

control”/exp or “prevention”/exp or “prevention study”/exp or reduc: ab, ti, or manage: ab, ti, or decreas: ab, ti, or recurr: ab, ti, and “Cohort analysis”/de or cohort: ab, ti, or “cross-sectional study”/de or “cross-sectional”: ab, ti, or longitudinal: ab, ti, or observational: ab, ti, or prospective: ab, ti, or “comparative study”/de or retrospective: ab, ti, or “randomized controlled trial”/exp or “crossover procedure”/exp or (controlled clinical trial)/lim or (randomized controlled trial)/lim or “placebo”/de or “clinical trial”/exp or “clinical trial (topic)”/exp or “controlled study”/exp or “controlled study”: ab or random: ab, ti, or trial: ab, ti or ([singl* or doubl* or trebl* or tripl*] NEAR/3 [blind or mask]): ab, ti RCT, randomized controlled trial. Healy et al. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

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SUPPLEMENTAL FIGURE 1

Evaluation of articles in analysis

Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

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275.e2

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Meta-analysis with a fixed-effects model

Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

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SUPPLEMENTAL TABLE 1

Summary of bias assessment of the included studies Conflicts Trial of interest registry

9%

Per protocol

Not stated

Not stated

4%

Per protocol

None

Not stated

Not stated Unclear

Not stated

Not stated

Yes

21%

Per protocol

None

Not stated

No

Yes

4%

Per protocol

Not stated

Not stated

Not stated

Not stated

No

Not stated

Not stated

Prospective randomized Software generated Blinded comparative randomization sequence

Not stated

Yes

Yes

3%

Per protocol

Not stated

Not stated

Pabuccu et al, 199716

Prospective randomized Not stated controlled

No

No

Yes

0%

Intent to treat Not stated

Not stated

Roy et al, 201426

Prospective randomized Software generated Not stated controlled randomization sequence

Yes

Yes

No

8%

Per protocol

Not stated

Sardo et al, 20117

Prospective randomized Software generated Blinded controlled randomization sequence

No

No

Yes

0%

Intent to treat None

Not stated

Tonguc et al, 201027

Prospective randomized Statistician-allocated controlled based on application number

Blinded

No

Yes

Yes

21%

Per protocol

None

Not stated

Not stated

Not stated

Not stated

Yes

Not stated Per protocol

Not stated

Not stated

Study design

Acunzo et al, 200311

Prospective randomized Software generated Blinded controlled randomization sequence

No

No

Yes

Amer et al, 201029

Prospective randomized Software generated Blinded comparative randomization sequence

No

Yes

Yes

Dabirashrafi et al, 199625

Prospective randomized Not stated controlled

Not stated

Not stated

Unclear

Fuchs et al, 201410

Prospective randomized Software generated Blinded controlled randomization sequence

Yes

Not stated

Guida et al, 200412

Prospective randomized Software generated Blinded controlled randomization sequence

No

De Iaco et al, 200324

Prospective randomized Software generated Not stated controlled randomization sequence

Kim et al, 201230

Vercellini et al, 198928 Prospective randomized Not stated controlled Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

Not stated

Not stated

Not Stated Unclear

Not stated

275.e4

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Analysis type

Randomization

Allocation Blinding of Blinding of Complete data Subject concealment participants outcomes reporting dropout

Authors

Summary of study characteristics included in the systematic review Time to follow-up hysteroscopy

Randomization groups

Intervention

Acunzo et al, 200311

Italy, Intrauterine adhesions United Kingdom

Age >50 y Weight >100kg Postmenopausal Pregnancy Uterovaginal prolapse Current illness Presence of other intrauterine lesions

Hyaluronic acid (n ¼ 43) vs no treatment (n ¼ 41)

Hyaluronic acid, 10 mL placed after surgery

Monopolar resectoscope

Amer et al, 201029

Egypt

Intrauterine adhesions

Diagnosis of any other cause of infertility Adhesions limited to lower uterine segment or upper cervical canal

Intrauterine balloon without amnion graft (n ¼ 15) vs Balloon plus fresh amnion graft (n ¼ 15) vs Balloon plus dried amnion graft (n ¼ 15)

Intrauterine balloon, removed Monopolar 2 wks postoperatively scissors/knife Human amnion graft (fresh vs dry) All groups, postoperative estrogen therapy for 50 d

2e4 mo

Dabirashrafi et al, 199625

Iran

Uterine septum Infertility

Diagnosis of any other cause of infertility

Conjugated estrogen (n ¼ 23) vs No treatment (n ¼ 23)

Conjugated estrogen 1.25 mg/d for 30 d Medroxy-progesterone acetate 10 mg/d added for last 7 d

Monopolar scissors/knife

1 mo

Fuchs et al, 201410

Israel

Suspected retained products of conception Age 18e50 y

Active bleeding or infection on admission

Oxiplex/AP gel (n ¼ 26) vs no treatment (n ¼ 26)

Oxiplex/AP gel, up to 10 mL, placed after surgery All groups, antibiotics and postoperative estrogen therapy for 11 d, estrogen plus norgestrel for next 10 d

Blunt dissection 7 wks with loop resectoscope

Guida et al, 200412

Italy

Submucosal myoma, polyp, or uterine septum

Age >50 y Weight >100 kg Postmenopausal Pregnancy Uterovaginal prolapse Current illness Presence of other intrauterine lesions

Hyaluronic acid (n ¼ 69) vs no treatment (n ¼ 69)

Hyaluronic acid, 10 mL placed after surgery

Bipolar loop resectoscope

3 mo

De Iaco et al, 200324

Italy

Intrauterine adhesions, submucosal myoma, polyp, or uterine septum Planned ablation Age 18e65 y

Not stated

Hyaluronic acid/ carboxy-methylcellulose (n ¼ 18) vs no treatment (n ¼ 22)

Hyaluronic acid/carboxy-methylcellulose, 10.5  5.5 mL, placed after surgery

Monopolar resectoscope

9 wks

Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

3 mo

(continued)

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Exclusion criteria

Surgical instrument

Authors

Country of study Inclusion criteria

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275.e5 American Journal of Obstetrics & Gynecology SEPTEMBER 2016

SUPPLEMENTAL TABLE 2

Summary of study characteristics included in the systematic review (continued) Authors

Country of study Inclusion criteria

Exclusion criteria

Randomization groups

Intervention

Surgical instrument

Time to follow-up hysteroscopy

Resectoscope

1 mo

Korea

Intrauterine adhesions, submucosal myoma, polyp, or uterine septum Dysfunctional uterine bleeding Age >20 y On contraception during study

Intrauterine device Postoperative hormone therapy Infection Cancer Heavy uterine bleeding Abnormal hepatic, renal, or hemostatic function Anticoagulant or steroid use within 1 wk preoperatively Immunosuppression or autoimmune disease Allergies to study materials Pregnancy

Alginate carboxymethylcellulose hyaluronic acid (n ¼ 92) vs carboxy-methylcellulose hyaluronic acid (n ¼ 95)

Alginate carboxy-methylcellulose hyaluronic acid, 10 mL, placed after surgery Carboxy-methylcellulose hyaluronic acid, 10 mL, placed after surgery

Pabuccu et al, 199716

Turkey

Intrauterine adhesions

Male factor infertility

Intrauterine device with early hysterosopic interventions (n ¼ 36) vs intrauterine device without early intervention (n ¼ 35)

Cooper intrauterine device Intrauterine Early intervention, device 1 wk postoperative hysteroscopic adhesiolysis All groups, postoperative estrogen and medroxy-progesterone acetate for 2 mo

Early intervention, 1 wk and 2 mo Without early intervention, 2 mo

Roy et al, 201426

India

Uterine septum Negative pregnancy test

Age >35 y Acute cervicitis Diagnosis of any other cause of infertility or abortion

Estradiol valerate (n ¼ 45) vs no treatment (n ¼ 45)

Estradiol valerate, 2 mg/d for 30 d Placebo, folic acid 5 mg/d for 30 d

Monopolar scissors/knife

2 mo

Sardo et al, 20117

Italy

Intrauterine lesions Dysfunctional uterine bleeding

BMI >30 kg/m2 Postmenopausal Pregnancy Uterovaginal prolapse Severe urinary symptoms Cancer Current illness

Oxiplex/AP gel (n ¼ 55) vs no treatment (n ¼ 55)

Oxiplex/AP gel, 10 mL placed after surgery

Bipolar loop resectoscope

1 mo

Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

(continued)

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Kim et al, 201230

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SUPPLEMENTAL TABLE 2

Summary of study characteristics included in the systematic review (continued) Authors Tonguc et al, 201027

Exclusion criteria

Randomization groups

Intervention

Turkey

Uterine septum

Not Stated

Estrogen therapy (n ¼ 16) vs estrogen plus intrauterine device (n ¼ 25) vs copper intrauterine device (n ¼ 19) vs no treatment (n ¼ 19)

Estradiol valerate 2 mg plus norgestrel 0.5 mg daily for 2 mo Intrauterine device Antibiotics for 2 wks

Monopolar resectoscope

2 mo

History of 2 or more spontaneous abortions Uterine septum

Not stated

Conjugated estrogen plus copper intrauterine device (n ¼ 10) vs no treatment (n ¼ 20)

Conjugated estrogen 1.25 mg twice daily for 30 d Medroxy-progesterone acetate 10 mg/d for last 5 d Intrauterine device

Microscissors

After IUD removal plus first withdrawal bleed or after first spontaneous menstrual cycle

Vercellini et al, Italy 198928

Surgical instrument

Time to follow-up hysteroscopy

Country of study Inclusion criteria

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SUPPLEMENTAL TABLE 2

BMI, body mass index. Healy. Preventing intrauterine adhesions. Am J Obstet Gynecol 2016.

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