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

Jan Bosteels; Steven Weyers; Thomas M D'Hooghe; Helen Torrance; Frank J Broekmans; Su Jen Chua; Ben Willem J Mol

doi:10.1002/14651858.CD011110.pub3

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Figure 1

Study flow diagram: summary of searches since 2015. PICO: population, intervention, comparator, outcome; RCT: randomised controlled trial.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, outcome: 1.1 Live birth.

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Figure 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.

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Figure 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.

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Analysis 1.1

Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 1 Live birth.

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Analysis 1.2

Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 2 Clinical pregnancy.

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Analysis 1.3

Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 3 Miscarriage.

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Analysis 1.4

Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 4 Presence of intrauterine adhesions at second‐look hysteroscopy.

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Analysis 1.5

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.

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Analysis 1.6

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.

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Analysis 1.7

Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 7 Mild adhesions at second‐look hysteroscopy.

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Analysis 1.8

Comparison 1 Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy, Outcome 8 Moderate or severe adhesions at second‐look hysteroscopy.

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Analysis 2.1

Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 1 Live birth.

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Analysis 2.2

Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 2 Clinical pregnancy.

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Analysis 2.3

Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 3 Miscarriage.

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Analysis 2.4

Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 4 Presence of intrauterine adhesions at second‐look hysteroscopy.

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Analysis 2.5

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.

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Analysis 2.6

Comparison 2 Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy, Outcome 6 Mild adhesions at second‐look hysteroscopy.

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Analysis 2.7

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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Summary of findings for the main comparison. Any anti‐adhesion therapy versus placebo or no treatment following operative hysteroscopy

Any anti‐adhesion therapy versus placebo or no treatment following operative hysteroscopy
Patient or population: women treated by operative hysteroscopy for uterine pathology associated with subfertility or adverse pregnancy outcome Settings: single centre, Hysteroscopy Unit or Department of Obstetrics and Gynaecology of a university or non‐university tertiary care hospital Intervention: any anti‐adhesion therapy Comparison: no treatment or placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment or placebo	Anti‐adhesion therapy
Live birth ^a	No treatment or placebo	Device or hormonal treatment	OR 0.94 (0.42 to 2.12)	107 (2 RCTs)	⊕⊝⊝⊝ Very low ^c,d,e	‐
	Mean‐risk population^b
	407 per 1000	399 per 1000 (261 to 603)
Presence of intrauterine adhesions at second‐look hysteroscopy (second‐look hysteroscopy at 4‐12 weeks after operative hysteroscopy)	No treatment or placebo	Device ± hormonal treatment or hormonal treatment or barrier gel	OR 0.35 ^g (0.21 to 0.60)	560 (8 RCTs)	⊕⊕⊝⊝ Low ^h,i	‐
	Low‐risk population^f
	0 per 1000	0 per 1000
	Medium‐risk population ^f
	545 per 1000	234 per 1000 (153 to 365)
	High‐risk population ^f
	875 per 1000	376 per 1000 (245 to 586)
The basis for the assumed risk* is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^a The two included studies reported term delivery (Abu Rafea 2013) or ongoing pregnancy (Roy 2014), which we used as a surrogate outcome for live birth. ^b The assumed risk for the mean‐risk population was the pooled risk of all live births in control groups of the two included studies. ^c Downgraded one level for serious risk of bias: one study was at high risk of bias in several domains, including allocation concealment. ^d Downgraded one level for serious imprecision; only 43 events in total. ^e Downgraded one level for serious indirectness, because only 30% (35/118) of all randomised women in this analysis were subfertile. ^f The assumed risk for low‐, medium‐ and high‐risk population based on presence of intrauterine adhesions following hysteroscopic removal of endometrial polyps/following removal of submucous fibroids and intrauterine adhesions (mean of both)/removal of uterine septum, respectively, based on findings of a prospective cohort study (Yang 2013). ^G Two studies reported no events (Lin 2015a; Vercellini 1989). ^h Downgraded one level for serious risk of bias: all eight studies had several limitations but none was at high risk for selection bias related to random sequence generation or allocation concealment. ⁱ Downgraded one level for serious indirectness, because in four of eight studies less than 50% of participants were subfertile and in four of eight studies it was unclear whether subfertile women were included.

Summary of findings for the main comparison. Any anti‐adhesion therapy versus placebo or no treatment following operative hysteroscopy

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Summary of findings 2. Any anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy

Any anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy
Patient or population: women treated by operative hysteroscopy for uterine pathology Settings: multicentric, Hysteroscopy Unit of Department of Obstetrics and Gynaecology of a university, university‐affiliated or non‐university tertiary care hospital Intervention: anti‐adhesion therapy A Comparison: anti‐adhesion therapy B
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Anti‐adhesion therapy B	Anti‐adhesion therapy A
Live birth ^a	Device	Device + graft	OR 1.48 (0.57 to 3.83)	180 (3 RCTs)	⊕⊕⊝⊝ Low ^c,d	‐
	98 per 1000 ^b	138 per 1000 (60 to 315)
Presence of intrauterine adhesions at second‐look hysteroscopy (6‐12 weeks)	Device or hormonal treatment with antibiotics	Device ± graft/gel or gel + hormonal treatment + and antibiotics	OR 0.55 (0.36 to 0.83)	451 (5 RCTs)	⊕⊕⊝⊝ Low ^f,g	‐
	Low‐risk population ^e
	0 per 1000	0 per 1000
	Medium‐risk population ^e
	545 per 1000	403 per 1000 (327 to 496)
	High‐risk population ^e
	875 per 1000	647 per 1000 (525 to 796)
The basis for the assumed risk* is provided in the footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio; RCT: randomised controlled trial.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
^a The three included studies reported term delivery (Wang 2016) or ongoing pregnancy (Amer 2010; Gan 2017; Wang 2016), which we used as a surrogate outcome for live birth. ^b The assumed risk for the average‐risk population is the pooled risk of all the live births in the control groups of the three included studies. ^c Downgraded one level for serious risk of bias: despite several limitations none of the studies was at high risk for selection bias related to random sequence generation or allocation concealment. ^d Downgraded one level for serious imprecision‐ only 21 events in total. ^e The assumed risk for low/medium/high‐risk population is based on the presence of intrauterine adhesions following hysteroscopic removal of endometrial polyps/following removal of submucous fibroids and IUAs (mean of both)/removal of uterine septum, respectively, based on findings of a prospective cohort study (Yang 2013). ^f Downgraded one level for serious risk of bias: despite several limitations none of the studies was at high risk for selection bias related to random sequence generation or allocation concealment. ^g Downgraded one level for serious indirectness because, in two of five studies, less than 50% of participants were subfertile; in one of five studies, it was unclear if subfertile women were included and in two of five studies, the proportion of infertile women was not reported.

Summary of findings 2. Any anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy

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Table 1. Median American Fertility Society (AFS) scores Lin 2015b

Outcome	Balloon group (intervention: n = 82)	IUD group (control: n = 80)	P value
AFS score before surgery (median, 95% CI)	8 (5 to 12)	8 (5 to 12)	1.00
Median reduction in AFS score	7 (2 to 12)	7 (0 to 12)	1.00
IUD: intrauterine device; n: number of participants.

Table 1. Median American Fertility Society (AFS) scores Lin 2015b

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Table 2. Median American Fertility Society (AFS) scores Amer 2010

Statistic	Fresh amnion graft (group 2: n = 14)	Dried amnion graft (group 3: n = 15)	No amnion graft (group 1: n = 14)	P value
Median	1.5	2	2	‐
IQR	1 to 2	1 to 2	1 to 2	0.27
IQR: interquartile range; n: number of participants.

Table 2. Median American Fertility Society (AFS) scores Amer 2010

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Table 3. Median American Fertility Society (AFS) scores Gan 2017

Statistic	Amnion graft (intervention: n = 40)	No graft (control: n = 40)	P value
Median	2	4	‐
IQR	2 to 5	2 to 6	0.03
IQR: interquartile range; n: number of participants.

Table 3. Median American Fertility Society (AFS) scores Gan 2017

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Comparison 1. Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth Show forest plot	2	107	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.42, 2.12]

1.1 Device vs no tx	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.18, 5.46]
1.2 Hormonal tx vs placebo/no tx	1	83	Odds Ratio (M‐H, Fixed, 95% CI)	0.93 [0.37, 2.33]
2 Clinical pregnancy Show forest plot	2	107	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.37, 2.01]

2.1 Device vs no tx	1	24	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 18.08]
2.2 Hormonal tx vs placebo	1	83	Odds Ratio (M‐H, Fixed, 95% CI)	0.85 [0.35, 2.06]
3 Miscarriage Show forest plot	2	54	Odds Ratio (M‐H, Fixed, 95% CI)	0.68 [0.18, 2.57]

3.1 Device vs no tx	1	22	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.11, 4.00]
3.2 Hormonal tx vs placebo	1	32	Odds Ratio (M‐H, Fixed, 95% CI)	0.72 [0.10, 5.01]
4 Presence of intrauterine adhesions at second‐look hysteroscopy Show forest plot	8	560	Odds Ratio (M‐H, Fixed, 95% CI)	0.35 [0.21, 0.60]

4.1 Device vs no tx	1	60	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Device + hormonal tx vs placebo/no tx	1	11	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Hormonal tx vs placebo	1	85	Odds Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.72]
4.4 Gel vs no tx	5	404	Odds Ratio (M‐H, Fixed, 95% CI)	0.37 [0.21, 0.64]
5 Mean adhesion scores at second‐look hysteroscopy in women not treated for intrauterine adhesions Show forest plot	1	132	Mean Difference (IV, Fixed, 95% CI)	‐1.46 [‐1.64, ‐1.29]

5.1 Gel vs no tx	1	132	Mean Difference (IV, Fixed, 95% CI)	‐1.46 [‐1.64, ‐1.29]
6 Mean adhesion scores at second‐look hysteroscopy in women treated for intrauterine adhesions Show forest plot	1	84	Mean Difference (IV, Fixed, 95% CI)	‐3.3 [‐3.37, ‐3.23]

6.1 Gel vs no tx	1	84	Mean Difference (IV, Fixed, 95% CI)	‐3.3 [‐3.37, ‐3.23]
7 Mild adhesions at second‐look hysteroscopy Show forest plot	6	494	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [0.68, 2.61]

7.1 Hormonal tx vs placebo/no tx	1	90	Odds Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 4.10]
7.2 Gel vs no tx	5	404	Odds Ratio (M‐H, Fixed, 95% CI)	1.56 [0.77, 3.18]
8 Moderate or severe adhesions at second‐look hysteroscopy Show forest plot	6	494	Odds Ratio (M‐H, Fixed, 95% CI)	0.08 [0.03, 0.24]

8.1 Hormonal tx vs placebo/no tx	1	90	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.22]
8.2 Gel vs placebo/no tx	5	404	Odds Ratio (M‐H, Fixed, 95% CI)	0.07 [0.02, 0.23]

Comparison 1. Anti‐adhesion therapy versus placebo or no treatment (tx) following operative hysteroscopy

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Comparison 2. Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth Show forest plot	3	180	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.57, 3.83]

1.1 Device + graft vs device	3	180	Odds Ratio (M‐H, Fixed, 95% CI)	1.48 [0.57, 3.83]
2 Clinical pregnancy Show forest plot	4	221	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [0.89, 3.33]

2.1 Device + graft vs device	3	180	Odds Ratio (M‐H, Fixed, 95% CI)	1.53 [0.74, 3.18]
2.2 Gel + hormone tx (HT) + antibiotics vs HT + antibiotics	1	41	Odds Ratio (M‐H, Fixed, 95% CI)	2.83 [0.62, 13.04]
3 Miscarriage Show forest plot	3	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.20, 3.19]

3.1 Device + graft vs device	3	40	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.20, 3.19]
4 Presence of intrauterine adhesions at second‐look hysteroscopy Show forest plot	5	451	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.36, 0.83]

4.1 Device vs device	1	162	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.42, 1.57]
4.2 Device + graft vs device	2	137	Odds Ratio (M‐H, Fixed, 95% CI)	0.53 [0.25, 1.10]
4.3 Device + gel vs device	1	111	Odds Ratio (M‐H, Fixed, 95% CI)	0.31 [0.13, 0.76]
4.4 Gel + HT + antibiotics vs HT + antibiotics	1	41	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.98]
5 Mean adhesion scores in women treated for intrauterine adhesions Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 Device vs device	1	162	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.68, 0.68]
5.2 Device + graft vs device	1	57	Mean Difference (IV, Random, 95% CI)	‐3.10 [‐4.17, ‐2.03]
5.3 Device + gel vs device	1	111	Mean Difference (IV, Random, 95% CI)	‐1.6 [‐2.32, ‐0.88]
6 Mild adhesions at second‐look hysteroscopy Show forest plot	1	111	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.53, 2.34]

6.1 Device + gel vs device	1	111	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.53, 2.34]
7 Moderate or severe adhesions at second‐look hysteroscopy Show forest plot	2	152	Odds Ratio (M‐H, Fixed, 95% CI)	0.25 [0.10, 0.61]

7.1 Device + gel vs device	1	111	Odds Ratio (M‐H, Fixed, 95% CI)	0.24 [0.09, 0.63]
7.2 Gel + HT + antibiotics vs HT + antibiotics	1	41	Odds Ratio (M‐H, Fixed, 95% CI)	0.28 [0.03, 2.98]

Comparison 2. Anti‐adhesion therapy A versus anti‐adhesion therapy B following operative hysteroscopy

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