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Meta-Analysis
. 2021 Jun 10;6(6):CD009517.
doi: 10.1002/14651858.CD009517.pub4.

Endometrial injury in women undergoing in vitro fertilisation (IVF)

Sarah F Lensen  1 , Sarah Armstrong  2 , Ahmed Gibreel  3 , Carolina O Nastri  4 , Nick Raine-Fenning  5 , Wellington P Martins  4
Affiliations
Meta-Analysis

Endometrial injury in women undergoing in vitro fertilisation (IVF)

Sarah F Lensen et al. Cochrane Database Syst Rev. .

Abstract

Background: Implantation of an embryo within the endometrial cavity is a critical step in the process of in vitro fertilisation (IVF). Previous research has suggested that endometrial injury (also known as endometrial scratching), defined as intentional damage to the endometrium, can increase the chance of pregnancy in women undergoing IVF.

Objectives: To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing in vitro fertilisation (IVF) including intracytoplasmic sperm injection (ICSI) and frozen embryo transfer.

Search methods: In June 2020 we searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE and two trial registries. We also checked the reference sections of relevant studies and contacted experts in the field for any additional trials.

Selection criteria: Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing IVF, versus no intervention or a sham procedure.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Two independent review authors screened studies, evaluated risk of bias and assessed the certainty of the evidence by using GRADE (Grading of Recommendation, Assessment, Development and Evaluation) criteria. We contacted and corresponded with study investigators as required. Due to the high risk of bias associated with many of the studies, the primary analyses of all review outcomes were restricted to studies at a low risk of bias for selection bias and other bias. Sensitivity analysis was then performed including all studies. The primary review outcomes were live birth and miscarriage.

Main results: Endometrial injury versus control (no procedure or a sham procedure) A total of 37 studies (8786 women) were included in this comparison. Most studies performed endometrial injury by pipelle biopsy in the luteal phase of the cycle before the IVF cycle. The primary analysis was restricted to studies at low risk of bias, and included eight studies. The effect of endometrial injury on live birth is unclear as the result is consistent with no effect, or a small reduction, or an improvement (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.98 to 1.28; participants = 4402; studies = 8; I2 = 15%, moderate-certainty evidence). This suggests that if the chance of live birth with IVF is usually 27%, then the chance when using endometrial injury would be somewhere between < 27% and 32%. Similarly, the effect of endometrial injury on clinical pregnancy is unclear (OR 1.08, 95% CI 0.95 to 1.23; participants = 4402; studies = 8; I2 = 0%, moderate-certainty evidence). This suggests that if the chance of clinical pregnancy from IVF is normally 32%, then the chance when using endometrial injury before IVF is between 31% and 37%. When all studies were included in the sensitivity analysis, we were unable to conduct meta-analysis for the outcomes of live birth and clinical pregnancy due to high risk of bias and statistical heterogeneity. Endometrial injury probably results in little to no difference in chance of miscarriage (OR 0.88, 95% CI 0.68 to 1.13; participants = 4402; studies = 8; I2 = 0%, moderate-certainty evidence), and this result was similar in the sensitivity analysis that included all studies. The result suggests that if the chance of miscarriage with IVF is usually 6.0%, then when using endometrial injury it would be somewhere between 4.2% and 6.8%. Endometrial injury was associated with mild to moderate pain (approximately 4 out of 10), and was generally associated with some minimal bleeding. The evidence was downgraded for imprecision due to wide confidence intervals and therefore all primary analyses were graded as moderate certainty. Higher versus lower degree of injury Only one small study was included in this comparison (participants = 129), which compared endometrial injury using two different instruments in the cycle prior to the IVF cycle: a pipelle catheter and a Shepard catheter. This trial was excluded from the primary analysis due to risk of bias. In the sensitivity analysis, all outcomes reported for this study were graded as very-low certainty due to risk of bias, and as such we were not able to interpret the study results.

Authors' conclusions: The effect of endometrial injury on live birth and clinical pregnancy among women undergoing IVF is unclear. The results of the meta-analyses are consistent with an increased chance, no effect and a small reduction in these outcomes. We are therefore uncertain whether endometrial injury improves the chance of live birth or clinical pregnancy in women undergoing IVF. Endometrial injury does not appear to affect the chance of miscarriage. It is a somewhat painful procedure associated with a small amount of bleeding. In conclusion, current evidence does not support the routine use of endometrial injury for women undergoing IVF.

Trial registration: ClinicalTrials.gov NCT01340560 NCT00846183 NCT00837733 NCT00796341 NCT01132144 NCT01882842.

PubMed Disclaimer

Conflict of interest statement

All review authors are investigators or otherwise closely associated with trials included in this review.

Sarah F Lensen is an investigator of one included study (Lensen 2019)

Sarah Armstrong is an investigator of one included study (Lensen 2019)

Ahmed Gibreel is an investigator of one included study (Gibreel 2015)

Carolina O Nastri is an investigator of one included study (Nastri 2013) and two excluded studies (NCT02093442; NCT02180256)

Nick Raine‐Fenning is an investigator of one included study (Polanski 2015). He has received lecture payments from GE Healthcare and is a minority share holder in an IVF unit (Nurture)

Wellington P Martins is an investigator of one included study (Nastri 2013) and two excluded studies (NCT02093442; NCT02180256)

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Endometrial injury vs control, outcome: 1.1 Live birth per woman randomised (studies at low risk of selection bias and other bias).
4
4
Forest plot of comparison: 1 Endometrial injury vs control, outcome: 1.9 Miscarriage per woman randomised (studies at low risk of selection bias and other bias).
5
5
Forest plot of comparison: 1 Endometrial injury vs control, outcome: 1.12 Clinical pregnancy per woman randomised (studies at low risk of selection bias and other bias).
1.1
1.1. Analysis
Comparison 1: Endometrial injury versus control, Outcome 1: Live birth per woman randomised (studies at low risk of selection bias and other bias)
1.2
1.2. Analysis
Comparison 1: Endometrial injury versus control, Outcome 2: Live birth per woman randomised: sensitivity analysis (no high risk)
1.3
1.3. Analysis
Comparison 1: Endometrial injury versus control, Outcome 3: Live birth per woman randomised: sensitivity analysis (including all studies)
1.4
1.4. Analysis
Comparison 1: Endometrial injury versus control, Outcome 4: Live birth per woman randomised: subgrouping by control exposure to endometrial manipulation
1.5
1.5. Analysis
Comparison 1: Endometrial injury versus control, Outcome 5: Live birth per woman randomised: subgrouping by RIF
1.6
1.6. Analysis
Comparison 1: Endometrial injury versus control, Outcome 6: Live birth per woman randomised: subgrouping by timing of endometrial injury
1.7
1.7. Analysis
Comparison 1: Endometrial injury versus control, Outcome 7: Live birth per woman randomised: subgrouping by intensity of endometrial injury
1.8
1.8. Analysis
Comparison 1: Endometrial injury versus control, Outcome 8: Live birth per woman randomised: subgrouping by timing and intensity
1.9
1.9. Analysis
Comparison 1: Endometrial injury versus control, Outcome 9: Miscarriage per woman randomised (studies at low risk of selection bias and other bias)
1.10
1.10. Analysis
Comparison 1: Endometrial injury versus control, Outcome 10: Miscarriage per woman randomised: sensitivity analysis (no high‐risk)
1.11
1.11. Analysis
Comparison 1: Endometrial injury versus control, Outcome 11: Miscarriage per woman randomised: sensitivity analysis (including all studies)
1.12
1.12. Analysis
Comparison 1: Endometrial injury versus control, Outcome 12: Clinical pregnancy per woman randomised (studies at low risk of selection bias and other bias)
1.13
1.13. Analysis
Comparison 1: Endometrial injury versus control, Outcome 13: Clinical pregnancy per woman randomised: sensitivity analysis (no high‐risk)
1.14
1.14. Analysis
Comparison 1: Endometrial injury versus control, Outcome 14: Clinical pregnancy per woman randomised: sensitivity analysis (including all studies)
1.15
1.15. Analysis
Comparison 1: Endometrial injury versus control, Outcome 15: Clinical pregnancy per woman randomised:subgrouping by control exposure to endometrial manipulation
1.16
1.16. Analysis
Comparison 1: Endometrial injury versus control, Outcome 16: Clinical pregnancy per woman randomised:subgrouping by RIF
1.17
1.17. Analysis
Comparison 1: Endometrial injury versus control, Outcome 17: Clinical pregnancy per woman randomised:subgrouping by timing of endometrial injury
1.18
1.18. Analysis
Comparison 1: Endometrial injury versus control, Outcome 18: Clinical pregnancy per woman randomised:subgrouping by intensity of endometrial injury
1.19
1.19. Analysis
Comparison 1: Endometrial injury versus control, Outcome 19: Clinical pregnancy per woman randomised:subgrouping by timing and intensity
1.20
1.20. Analysis
Comparison 1: Endometrial injury versus control, Outcome 20: Multiple pregnancy per woman randomised (studies at low risk of selection bias and other bias)
1.21
1.21. Analysis
Comparison 1: Endometrial injury versus control, Outcome 21: Multiple pregnancy per woman randomised: sensitivity analysis (no high risk)
1.22
1.22. Analysis
Comparison 1: Endometrial injury versus control, Outcome 22: Multiple pregnancy per woman randomised: sensitivity analysis (including all studies)
1.23
1.23. Analysis
Comparison 1: Endometrial injury versus control, Outcome 23: Pain (visual analogue scale): sensitivity analysis (including all studies)
2.1
2.1. Analysis
Comparison 2: Higher versus lower degree of injury, Outcome 1: Live birth rate per woman randomised: sensitivity analysis (including all studies)
2.2
2.2. Analysis
Comparison 2: Higher versus lower degree of injury, Outcome 2: Miscarriage: sensitivity analysis (including all studies)
2.3
2.3. Analysis
Comparison 2: Higher versus lower degree of injury, Outcome 3: Clinical pregnancy per woman randomised: sensitivity analysis (including all studies)
2.4
2.4. Analysis
Comparison 2: Higher versus lower degree of injury, Outcome 4: Pain (visual analogue scale): sensitivity analysis (including all studies)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Liu 2017 {published data only}
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Mackens 2020 {unpublished data only}
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Metwally 2020 {published data only}
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References to studies excluded from this review

ACTRN12611001222932 {unpublished data only}
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Alalfy 2019 {published data only}
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NCT01798862 {unpublished data only}
    1. Kreatsa M, Siristatidis C. Endometrial injury and IVF outcome parameters in patients with failed IVF cycles. https://clinicaltrials.gov/ct2/show/NCT01798862 (first received 26-02-2013).
NCT01842178 {unpublished data only}
    1. Checa MA. Endometrial Scratching in in vitro fertilization cycles with oocyte donation. https://clinicaltrials.gov/ct2/show/NCT01842178 (first received 29-04-2013).
NCT01844453 {unpublished data only}
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NCT02093442 {published data only}
    1. Martins, WP. Endometrial Scratching for cryopreserved embryo transfer. https://clinicaltrials.gov/ct2/show/NCT02093442 (first received 21-03-2014).
NCT02180256 {published data only}
    1. Martins WP. Effect of Endometrial Scratching on assisted reproduction outcomes: a randomized controlled trial. https://clinicaltrials.gov/ct2/show/NCT02180256 (first received 02-07-2014).
NCT02197832 {published data only}
    1. Lee VC. A RCT on the effect of endometrial injury on improving ongoing pregnancy rate in subfertile women undergoing FET cycles. https://clinicaltrials.gov/ct2/show/NCT02197832 (first received 23-07-2014). - PubMed
NCT03157765 {published data only}
    1. Rose B, Opdycke E. Trial of Endometrial Scratch prior to frozen embryo transfer in patients with recurrent implantation failure. https://clinicaltrials.gov/ct2/show/NCT03157765 (first received 17-05-2017).
NCT04240860 {published data only}
    1. Aboelnasr MM. Autologous intrauterine platelet-rich plasma instillation and Endometrial Scratching for thinned endometrium. https://clinicaltrials.gov/ct2/show/NCT04240860 (first received 27-01-2020).
Rigos 2019 {published data only}
    1. Rigos I, Basios G, Salamalekis G, Vrantza T, Siristatidis C, Despotidi A. Combination of endometrial injury and freeze all strategy in women with repeated implantation failures: recent data from a pilot study. In: European Journal of Obstetrics & Gynecology and Reproductive Biology. Vol. 234. 2019:e127.
Salehpour 2016 {published data only}
    1. Salehpour S, Zamaniyan M, Saharkhiz N, Zadehmodares S, Hosieni S, Seif S, et al. Doesintrauterine saline infusion by intrauterine insemination (IUI) catheter as endometrial injury duringIVF cycles improve pregnancy outcomes among patients with recurrent implantation failure?: An RCT. International Journal of Reproductive BioMedicine 2016;49(9):583-8. - PMC - PubMed
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    1. Yoldemir T, Erenus M. Does the timing of mock embryo transfer trial improve implantation in intracytoplasmic sperm injection cycles? Gynecological Endocrinology 2011;27(6):396-400. - PubMed
Zhou 2008 {published data only (unpublished sought but not used)}
    1. Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertility and Sterility 2008;89(5):1166-76. [PMID: ] - PubMed

References to studies awaiting assessment

Aghajanpour 2017 {published data only}
    1. Aghajanpour S, Amirchaghmaghi E, Yahyaei A, Ashrafi M, Aflatoonian R. The effect of endometrial injury on VEGF expression in patients with repeated implantation failure:a randomized control trial. In: Human Reproduction. Vol. 32 (Supplement 1). 2017:i349.
Deepika 2016 {published data only}
    1. Deepika K, Pranesh G, Vinaykumar M, Garg N, Navya V, Ksheerasagar S, et al. Follicular phase endometrial stimulation (FES) in the transfer cycle in RIF cases: A Randomized control trial. In: Human Reproduction. Vol. 31 (Supplement 1). 2016:i266.
Hebeihsa 2018 {published data only}
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Mahran 2016 {published data only}
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Shawki 2018 {unpublished data only}
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Singh 2015 {unpublished data only}CTRI/2013/12/004206CTRI/2014/01/004307
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Vidal 2019 {published data only}
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References to ongoing studies

ChiCTR1800015943 {published data only}
    1. Xiaokui Y. Effect of Endometrial Scratching on IVF/ICSI-ET outcomes of women with repeated implantation failure: a randomized controlled trial. https://apps.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR1800015943 (first received 01-05-2018).
IRCT20110731007165N4 {published data only}
    1. Parsaeian, Z. Comparison of local endometrial injury efficacy in follicular versus luteal phases on the success rate of frozen embryo transfer cycle. https://en.irct.ir/trial/7605 (first received 31-08-2018).
IRCT201302091141N13 {published data only}
    1. Kiani K. Evaluating the effect of endometrial local injury in increasing pregnancy rate in patients undergoing ART (IVF/ICSI). https://en.irct.ir/trial/206 (first received 03-07-2013).
IRCT201604261556N89 {published data only}
    1. Akhondzadeh S. Effect of local endometrial injury in women with one and two failure history in IVF cycle on success rate of embryo implantation and pregnancy. http://en.irct.ir/trial/938 (first received 28-12-2016).
IRCT201708081306N9 {published data only}
    1. Zahiri Z. Investigating the success rate of hysteroscopy and Endometrial Scratching for intra vitro fertilization in recurrent Implantation failure case. http://en.irct.ir/trial/545 (first received 12-09-2017).
IRCT20180425039418N8 {published data only}
    1. Sanani MG. Assessment the effect of endometrial scratch on fertility rate in infertile women undergoing IVF. https://www.irct.ir/trial/40463 (first received 27-10-2019).
IRCT20191031045292N1 {published data only}
    1. Pilehvar S. Comparing the effect of endometrial scratch with luteal phase versus follicular phase in FET women candidates outcome. https://www.irct.ir/trial/43433 (first received 16-12-2019).
ISRCTN09447850 {published data only}
    1. Srivastava G. Pre In vitro fertilisation (IVF) pipelle biopsy following a previous unsuccessful IVF cycle. http://www.isrctn.com/ISRCTN09447850 (first received 26-04-2012).
ISRCTN24605402 {published data only}
    1. Zhang S. Effect of endometrial scratch on repeat implantation failure following in vitro fertilization embryo transfer or frozen embryo transfer. http://www.isrctn.com/ISRCTN24605402 (first received 16-01-2013).
ISRCTN63112626 {unpublished data only}ISRCTN63112626
    1. Ma C. Effect of endometrial injury on repeat implantation failure following in vitro fertilization embryo transfer or frozen embryo transfer: a randomized controlled study. http://www.isrctn.com/ISRCTN63112626 (first received 11-01-2012).
NCT00367367 {published data only}
    1. Weiss A. Endometrial curettage before embryo transfer. https://clinicaltrials.gov/ct2/show/NCT00367367 (first received 22 August 2006).
NCT02153814 {published data only}
    1. Mendoza G. Endometrial injury and in vitro fertilization outcomes. https://clinicaltrials.gov/ct2/show/NCT02153814 (first received 03-06-2014).
NCT02245750 {published data only}
    1. Mohammed AM, Gomaa MF. Value of routine hysteroscopy prior to IVF/ICSI cycles. https://clinicaltrials.gov/ct2/show/NCT02245750 (first received 22-09-2014).
NCT02306395 {published data only}
    1. Chuai H, Wang A. Endometrial local injury to improve the outcome of embryo transfer. https://clinicaltrials.gov/ct2/show/NCT02306395 (first received 03-12-2014).
NCT02409745 {published data only}
    1. Sun Y, Hu L. The effectiveness of endometrial injury in IVF. https://clinicaltrials.gov/ct2/show/NCT02409745 (first received 07-04-2015).
NCT02522806 {published data only}
    1. Genod A, Werlen S. Endometrial local Injury before first IVF: evaluation of pregnancy rate (BEONE). https://clinicaltrials.gov/ct2/show/NCT02522806 (first received 13-08-2015).
NCT02752568 {published data only}
    1. Abdelhamid SA. Assisted Hatching Versus Endometrial Scratch in recurrent implantation failure. https://clinicaltrials.gov/ct2/show/NCT02752568 (first received 27-04-2016).
NCT03220503 {published data only}
    1. Sherbiny Y. Effect of endometrial injury before frozen embryo transfer on pregnancy rate. https://clinicaltrials.gov/ct2/show/NCT03220503 (first received 18-07-2017).
NCT03470298 {published data only}
    1. Zayed AE. Retrieval versus mid-luteal Endometrial Scratching (ES) for Intra Cytoplasmic Sperm Injection (ICSI) (ICSI). https://clinicaltrials.gov/ct2/show/NCT03470298 (first received 19-03-2018).

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References to other published versions of this review

Nastri 2011
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Publication types

Associated data