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Meta-Analysis
. 2017 Nov 27;11(11):CD011110.
doi: 10.1002/14651858.CD011110.pub3.

Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility

Jan Bosteels  1 , Steven Weyers, Thomas M D'Hooghe, Helen Torrance, Frank J Broekmans, Su Jen Chua, Ben Willem J Mol
Affiliations
Meta-Analysis

Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility

Jan Bosteels et al. Cochrane Database Syst Rev. .

Abstract

Background: Observational evidence suggests a potential benefit with several anti-adhesion therapies in women undergoing operative hysteroscopy (e.g. insertion of an intrauterine device or balloon, hormonal treatment, barrier gels or human amniotic membrane grafting) for decreasing intrauterine adhesions (IUAs).

Objectives: To assess the effectiveness of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy, following operative hysteroscopy for treatment of female subfertility.

Search methods: We searched the following databases from inception to June 2017: the Cochrane Gynaecology and Fertility Group Specialised Register; the Cochrane Central Register of Studies (CRSO); MEDLINE; Embase; CINAHL and other electronic sources of trials, including trial registers, sources of unpublished literature and reference lists. We handsearched the Journal of Minimally Invasive Gynecology, and we contacted experts in the field. We also searched reference lists of appropriate papers.

Selection criteria: Randomised controlled trials (RCTs) of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy in subfertile women. The primary outcome was live birth. Secondary outcomes were clinical pregnancy, miscarriage and IUAs present at second-look hysteroscopy, along with mean adhesion scores and severity of IUAs.

Data collection and analysis: Two review authors independently selected studies, assessed risk of bias, extracted data and evaluated quality of evidence using the GRADE method.

Main results: The overall quality of the evidence was low to very low. The main limitations were serious risk of bias related to blinding of participants and personnel, indirectness and imprecision. We identified 16 RCTs comparing a device versus no treatment (two studies; 90 women), hormonal treatment versus no treatment or placebo (two studies; 136 women), device combined with hormonal treatment versus no treatment (one study; 20 women), barrier gel versus no treatment (five studies; 464 women), device with graft versus device without graft (three studies; 190 women), one type of device versus another device (one study; 201 women), gel combined with hormonal treatment and antibiotics versus hormonal treatment with antibiotics (one study; 52 women) and device combined with gel versus device (one study; 120 women). The total number of participants was 1273, but data on 1133 women were available for analysis. Only two of 16 studies included 100% infertile women; in all other studies, the proportion was variable or unknown.No study reported live birth, but some (five studies) reported outcomes that were used as surrogate outcomes for live birth (term delivery or ongoing pregnancy). Anti-adhesion therapy versus placebo or no treatment following operative hysteroscopy.There was insufficient evidence to determine whether there was a difference between the use of a device or hormonal treatment compared to no treatment or placebo with respect to term delivery or ongoing pregnancy rates (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.42 to 2.12; 107 women; 2 studies; I² = 0%; very-low-quality evidence).There were fewer IUAs at second-look hysteroscopy using a device with or without hormonal treatment or hormonal treatment or barrier gels compared with no treatment or placebo (OR 0.35, 95% CI 0.21 to 0.60; 560 women; 8 studies; I² = 0%; low-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 5 to 17). Comparisons of different anti-adhesion therapies following operative hysteroscopyIt was unclear whether there was a difference between the use of a device combined with graft versus device only for the outcome of ongoing pregnancy (OR 1.48, 95% CI 0.57 to 3.83; 180 women; 3 studies; I² = 0%; low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without graft/gel or gel combined with hormonal treatment and antibiotics compared with using a device only or hormonal treatment combined with antibiotics, but the findings of this meta-analysis were affected by evidence quality (OR 0.55, 95% CI 0.36 to 0.83; 451 women; 5 studies; I² = 0%; low-quality evidence).

Authors' conclusions: Implications for clinical practiceThe quality of the evidence ranged from very low to low. The effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for researchMore research is needed to assess the comparative safety and (cost-)effectiveness of different anti-adhesion treatments compared to no treatment or other interventions for improving key reproductive outcomes in subfertile women.

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Conflict of interest statement

JB: no conflicts of interest.

SW: no conflicts of interest.

TD is a Professor in Reproductive Medicine, Department of Development and Regeneration, University of Leuven (KU Leuven), Belgium, and Professor Adjunct, Department of Obstetrics and Gynecology, Yale University, New Haven, USA. Since October 2015, he has been appointed as Vice‐President and Head of Global Medical Affairs Fertility, Merck KGaA, Darmstadt, Germany. His participation in this publication is part of his academic work. Merck KGaA is not involved in the development or marketing of products related to hysteroscopy. Professor D'Hooghe's employment by Merck is not in breach of Cochrane's Commercial Sponsorship Policy (clause 2) as he does not have a real or potential financial interest in the outcome of this review. This matter was referred to Cochrane's Funding Arbiter for advice.

HT has received conference travel assistance from Merck.

FJB has received monetary compensation for the following: member of the external advisory board for Merck Serono and Ferring, the Netherlands; educational activities for Ferring BV, the Netherlands; consultancy work for Gedeon Richter, Belgium; strategic co‐operation with Roche on automated anti‐Müllerian hormone (AMH) assay development; and research co‐operation with Ansh Labs.

SJC: no conflicts of interest.

BWM has received consultancy from ObsEva Geneva, Guerbet, and Merck; payment for review preparation from European Journal of Obstetrics and Gynecology and Reproductive Biology; and travel/accommodation/meeting expenses for various non‐commercial scientific meetings.

Figures

1
1
Study flow diagram: summary of searches since 2015. PICO: population, intervention, comparator, outcome; RCT: randomised controlled trial.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, outcome: 1.1 Live birth.
5
5
Forest plot of comparison: 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, outcome: 1.4 Presence of intrauterine adhesions at second‐look hysteroscopy.
6
6
Cates' plot of numbers needed to treat for an additional beneficial outcome (NNTB) for Analysis 1.4 assuming medium risk of 545 women per 1000 with intrauterine adhesions at second‐look hysteroscopy in the control group (no treatment or placebo). Randomly compared to control, the use of device with or without hormonal treatment or hormonal treatment or barrier gels (intervention) decreased the number of women with intrauterine adhesions at second‐look hysteroscopy to 234 women per 1000 (95% confidence interval 153 to 365 women per 1000). Figure drawn using www.nntonline.net.
1.1
1.1. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 1 Live birth.
1.2
1.2. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 2 Clinical pregnancy.
1.3
1.3. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 3 Miscarriage.
1.4
1.4. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 4 Presence of intrauterine adhesions at second‐look hysteroscopy.
1.5
1.5. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 5 Mean adhesion scores at second‐look hysteroscopy in women not treated for intrauterine adhesions.
1.6
1.6. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 6 Mean adhesion scores at second‐look hysteroscopy in women treated for intrauterine adhesions.
1.7
1.7. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 7 Mild adhesions at second‐look hysteroscopy.
1.8
1.8. Analysis
Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 8 Moderate or severe adhesions at second‐look hysteroscopy.
2.1
2.1. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 1 Live birth.
2.2
2.2. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 2 Clinical pregnancy.
2.3
2.3. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 3 Miscarriage.
2.4
2.4. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 4 Presence of intrauterine adhesions at second‐look hysteroscopy.
2.5
2.5. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 5 Mean adhesion scores in women treated for intrauterine adhesions.
2.6
2.6. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 6 Mild adhesions at second‐look hysteroscopy.
2.7
2.7. Analysis
Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 7 Moderate or severe adhesions at second‐look hysteroscopy.
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