Endometrial scratch injury in infertile women undergoing in vitro fertilization cycles: a systematic review and meta-analysis

Abstract

Objective

This study aimed to evaluate the effect of endometrial scratch injury (ESI) in infertile women undergoing in vitro fertilization (IVF).

Methods

We screened MEDLINE, CENTRAL, EMBASE, Web of Science, and the Cochrane Central Register from inception to April 2023 using keywords related to endometrial scratch, implantation, infertility, and IVF. We included 41 randomized, controlled trials of ESI in IVF cycles (9084 women). The primary outcomes were the clinical pregnancy, ongoing pregnancy, and live birth rates.

Results

The clinical pregnancy rate was reported in all 41 studies. The odds ratio (OR) for the clinical pregnancy rate had an effect estimate of 1.34 with a 95% confidence interval (CI) of 1.14 to 1.58. The live birth rate was reported in 32 studies with 8129 participants. The OR for the live birth rate had an effect estimate of 1.30 with a 95% CI of 1.06 to 1.60. The multiple pregnancy rate was reported in 21 studies with 5736 participants. The OR for the multiple pregnancy rate had an effect estimate of 1.35 with a 95% CI of 1.07 to 1.71.

Conclusion

ESI increases the clinical pregnancy, ongoing pregnancy, live birth, multiple pregnancy, and implantation rates in women undergoing IVF cycles.

Keywords

Clinical pregnancy rate endometrial injury endometrial scratch infertility implantation

Introduction

The success of in vitro fertilization (IVF) is related to several factors. Unfortunately, many of these factors are not known until the treatment cycle is well underway (response to stimulation) or even nearing completion (number and quality of embryos).¹ Despite the fast development of IVF and its related procedures, implantation failure still occurs in 60% to 70% of IVF cycles.² Abnormality in endometrial receptivity is responsible for two thirds of implantation failures.³

Implantation starts by attachment of the growing embryo to the uterine wall and is completed by invasion of the maternal sinusoids and establishment of the maternal–fetal circulation.¹ Successful implantation requires a precise developmental synchronization of the endometrium and blastocyst.⁴ Ovarian steroids are responsible for endometrial preparation for implantation, including cellular, vascular, and immunological changes.⁵

Endometrial scratch injury (ESI) is intentional endometrial injury to improve its receptivity.⁶ ESI delays endometrial development owing to the wound repair process and subsequently synchronizes the development of the endometrium and embryo.⁷ ESI enhances endometrial gene modulation and increases the receptivity of the endometrium.⁸ The ESI effect may be mediated through immunological factors.⁹ The changes in growth factors and cytokine release lead to attraction of leucocytes to the implantation site and improvement in endometrial vascularity.¹⁰ Although the first study of the effect of ESI on IVF was published in 2003,¹¹ its usefulness is still questionable. There is no agreement regarding the proper timing, ideal intensity, or best number of injuries to achieve the best outcome. Therefore, this meta-analysis was conducted to evaluate the usefulness of ESI before or during the stimulation cycle in women undergoing IVF/intracytoplasmic sperm injection (ICSI) cycles.

Methods

Ethics

A protocol that followed the PRISMA guidelines for a meta-analysis of randomized, controlled trials (RCTs) was prepared prospectively. The registration number is CRD42020151590. Consent was not required for this meta-analysis.

Eligibility criteria, information sources, and search strategy

The electronic databases MEDLINE, CENTRAL, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched by two authors (AM and AE) from inception to April 2023 using the keywords related to endometrial scratching, implantation, IVF, and their MeSH terms. Additionally, trial registration sites, Google Scholar, reference lists of related studies, and abstracts of international gynecology and infertility conferences were searched. Contacting authors via emails was performed for any missing information or the requirement for clarification.

Study selection

Our systematic review included all RCTs (published and unpublished) that involved ESI at different timings, preceding or at the same stimulation cycle, and of different intensities in different participants. All RCTs with single or double ESI compared with no intervention, cervical manipulations, or sham procedures were included.

Clinical pregnancy, ongoing pregnancy, and live birth rates were the primary outcome parameters. Secondary outcomes were miscarriage, multiple pregnancy, and implantation rates. The authors were contacted for any non-reported or unclear data, such as the unpublished data of Polanski and colleagues.

Data extraction

Assessment of all studies and extraction of data were performed by two investigators (AM and AE) independently, and disagreements were discussed with other investigators. The extracted data included the location, the number of participants and their characteristics, ESI (timing, intensity, and number), and primary and secondary outcomes.

Assessment of risk of bias

The Cochrane Handbook of Systematic reviews recommendations was followed in quality assessment of the included RCTs. Quality assessment was performed by two investigators (AM and YL) independently, and disagreements were discussed with other investigators. Items included random sequence generation, allocation concealment, blinding of the participants and outcome assessors, incomplete outcome data, selective reporting, and other bias. Absent and unclear data were checked by contacting the authors.

Statistical analysis

The effect estimate of outcomes was reported as the odds ratio (OR) and its 95% confidence interval (CI) for all dichotomous data. A subgroup analysis was performed according to the timing (follicular phase of the preceding cycle of stimulation, follicular phase of the same cycle of stimulation, luteal phase of the preceding cycle of stimulation, both follicular and luteal phases, or unspecified timing), the number of previous IVF cycles (first IVF cycle, one previous IVF failure, two or more previous IVF failures, or without including previous IVF failures in the selection criteria), the number of ESIs (single or double), and the intensity of ESI (mild to moderate or high). Analyses were performed with Review Manager (RevMan) version 5.1.7 (The Nordic Cochrane Centre, Copenhagen, Denmark).

Results

Our search yielded 1055 studies through databases, and 5 records were identified through other resources. A total of 681 studies were screened after the removal of duplicates, and 70 were screened for the full text (Figure 1).

Figure 1.

PRISMA flow chart.

Study selection and characteristics

We finally included 41 studies with 9084 women who fulfilled the inclusion criteria. All studies were in the English language. Eleven RCTs were multicenter studies (1/32 centers,¹² 1/16 centers,¹³ 1/13 centers,¹⁴ 1/4 centers,¹⁵ 3/3 centers,^16–18 and 4/2 centers^19–22), while the remaining 30 studies were in a single center. One study was conducted in five countries,¹⁴ and another study was conducted in two countries.²⁰ The remaining 39 studies were conducted in one country (7 in Iran,^21,23–28 5 in Egypt,^{4,16,19,29,30} 4 in China,^22,31–33 3 in India,^34–36 3 in Turkey,^37–39 2 in the United kingdom,^13,40 2 in Hong Kong,^41,42 2 in Denmark,^15,43 2 in the USA,^44,45 and 1 each in Brazil,⁴⁶ Belgium,⁴⁷ France,¹⁷ Israel,⁴⁸ Italy,⁴⁹ The Netherlands,¹² Poland,⁵⁰ and Spain).⁵¹ The timing of ESI was not the same in all studies. In five studies, ESI was performed in the same follicular phase of stimulation.^{28,33,36,41,51} In four studies, ESI was performed in the follicular phase of the preceding cycle.^20,22,38,43 In four studies, ESI was performed in both the follicular and luteal phases.^33,36,45,48 In two studies, the timing of ESI was not specified.^14,31 In the remaining 21 studies, ESI was performed in the luteal phase in the preceding cycles. The usefulness of ESI was tested in women undergoing their first IVF cycle in eight studies,^{7,18,23,24,28,37,44,46} in those with one previous IVF failure in one study,¹² and in those with two or more IVF failures in nine studies.^{20–22,24,26,34,42,48,49} In 23 studies, the number of previous IVF failures was not included in the selection criteria. In the included studies, ESI was performed twice in 8 studies^{16,23,28,35,36,39,45,48} and once in the remaining 33 studies. The intensity of ESI was high in only 6 studies^{20,23,26,34,38,43} and was mild to moderate in 34 studies. Among the 41 studies, only 11 were prospectively registered. Eighteen trials were retrospectively registered, and 11 trials were not registered. Women in the control group were subjected to the sham procedure in 8 studies,^{16,33,41,44–46,48,49} to hysteroscopy in 2 studies,^20,36 to granulocyte colony-stimulating factor administration in 1 study,³² and to no intervention in the remaining 29 studies. Table 1 summarizes the main characteristics of the included studies.

Table 1.

Characteristics of the included studies.

Study	Setting	Sample size	Participants	Interventions	Outcomes	Registration and funding
²⁵Aflatoonian, 2016	One center,Iran	Randomized: 100Analyzed: 93	Inclusion criteria:Age <40 yearsFrozen ET (≥1) Normal endometrial cavityExclusion criteria:Endocrinal disorders such as diabetes mellitus or hypothyroidism Intracavitary lesions such as uterine polypi, submucous myoma, and intrauterine synechia Endometrioma and/or severe endometriosis	Protocol: endometrial preparation 6 mg estradiol valerate daily from cycle day 2 until ≥8-mm triple-line endometrial thickness and then 800 mg vaginal progesterone daily ET of 6–8-cell frozen-thawed embryos after 3 days using a Cook catheterIntervention group: a Pipelle catheter was used in the proceeding luteal phase Control: none	IRCPROPRMRMPRChPR	Retrospective (IRCT2015101324512N1)Funding: Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
³⁵Aleyamma, 2017	One center,India	Randomized: 111Analyzed: 91	Inclusion criteria:Age < 38 years≥1 previous failed IVF cycle with ≥2 good quality embryos transferred. BMI < 29 kg/m²FSH concentrations <10 mIU/mLExclusion criteria:Previous poor response of <3 oocytes retrieved in a previous cycleLocal endometrial pathologyUterine malformations Severe endometriosisGross adenomyosis Systemic disease such as autoimmune disorders	Protocol: 43 long, 11 short, 3 ultralong, 54 antagonistIntervention group: 2 Pipelle biopsies were performed in the preceding luteal phase within 48 hours Control: none	CPRLBRMRMPRIRPreterm delivery rate	Retrospective (CTRI/2013/003564)No funding
⁴⁸Baum, 2012	One center,Israel	Randomized: 36Analyzed: 32	Inclusion criteria:Age of 18–41 yearsFresh ET ≥3 failed previous IVF cycles despite an adequate ovarian responseExclusion criteria:Uterine abnormality, endometrioma, and hydrosalpinx	Protocol: long, short, or antagonist Intervention group: 2 Pipelle biopsies were performed on days 9–12 and 21–24 of the preceding spontaneous cycleControl: a cervical Pipelle was introduced into the cervix without scraping or taking a biopsy	CPRLBRMRIR	Retrospective (NCT00411021)No funding
⁴³Berntsen, 2020	Two centers (all data were from 1 center),Denmark	Randomized: 229Analyzed: 184	Inclusion criteria:Age of 18–40 years≥1 previous failed cycle Fresh FTBMI < 35 kg/m²Exclusion criteria:Freeze-all cycles, intrauterine abnormalities or pathology, systemic diseases, and active local or systemic infections	Protocol: 63 long and 121 shortIntervention group: hysteroscopy and biopsy using 7 F forceps were performed in the preceding follicular phase of the cycleControl: none	CPROPRLBRMR	Prospective (NCT01743391)No funding
⁴⁴Eskew, 2019	One center,USA	Randomized: 100Analyzed: 100	Inclusion criteria:Age of 18–43 yearsFresh or frozen ETExclusion criteria:Uterine cavity abnormalities and cycles including a third party	Protocol: not describedIntervention group: a Pipelle catheter was used in the preceding luteal phase Control: a sham biopsy	CPROPRLBRMR	Not registeredFunding: NIH (5T32HD055172-09, UL1 TR002345)
¹⁷Frantz, 2018	Three centers,France	Randomized: 191Analyzed: 190	Inclusion criteria:Age of 18–38 years1ry or 2ry primary infertility First or second IVF cycle27–32 days of regular cycles (between)FSH concentrations ≤2 IU/LBMI < 35 kg/m²Exclusion criteria:Oocyte donation, hydrosalpinx, uterine abnormalities, ≥4 uterine myomas (largest > 5 cm), undiagnosed vaginal bleeding or active vaginal infection, pretreatment with estrogen and or progesterone, and women involved in another ART trial	Protocol: 153 long and 24 antagonistIntervention group: a Pipelle was used in the preceding luteal phaseControl none	CPROPRLBRMRMPRIRPain/bleeding	Prospective (NCT01064193)Funding: Ministère de la Santé Français
¹⁶Gibreel, 2015	Three centers,Egypt	Randomized: 387Analyzed: 387	Inclusion criteria:Age < 40 years≥1 previous failed IVF cycleExclusion criteria:Poor ovarian responder, endocrinological abnormality, women with hydrosalpinx and tubal disconnection, previous endometrial curettage in the last 3 months, and uterine abnormalities, such as polyps and fibroids or synechia	Protocol: longIntervention group: a Pipelle biopsy was performed twice on day 21 of the preceding cycle, and then after 2–3 days Control: a placebo procedure using uterine sounding of the cervix that stopped just before the internal OS was performed	CPROPRLBRMRMPRFertilization rateIR	Prospective (NCT01245309)No funding
Gürgan, 2019	One center,Turkey	Randomized: 305Analyzed: 239	Inclusion criteria:Age < 40 years≥3 failed fresh or frozen IVF cycles after transfer of ≥4 good-quality embryosFSH concentrations ≤15 IU/mLBMI of 18.5–29.9 kg/m²Exclusion criteria:Congenital uterine abnormalities and uterine cavity distortion by polypi, myomas, or synechia. Thin endometrium < 7 mm in the preceding cycleEndometriosis and/or endometrioma	Intervention group: scissors injury was introduced through office hysteroscopy on days 10–12 (late follicular phase in the preceding cycle) Control: none	CPROPRLBRMRMPR	Retrospective (NCT03748238)No funding
³⁷Guven, 2014	One center,Turkey	Randomized: 124Analyzed: 118	Inclusion criteria:Age < 35 years1ry infertilityNormal ovarian responder (AFC of 5–10 in 1 ovary) ET of grade I or II embryos and consent for an endometrial biopsyExclusion criteria:Endocrinological abnormalities, such as diabetes mellitus, high prolactin concentrations, and adrenal abnormalities Systemic disorders, such as sickle cell anemia, high cholesterol concentrations, and collagen disordersPrevious neoplastic disordersPrevious or high risk for OHSS Use of drugs such as insulin sensitizers, and GnRH antagonists Failed ovum pick-upSevere male factor requiring testicular manipulations, congenital genital anomalies, endometrial manipulations in the past 30 days, and an abnormal uterine cavity, such as polypi, myomas, and synechia	Protocol: long agonist Intervention group: a Pipelle biopsy catheter was used on cycle day 3 after leuprolide acetate downregulation Control: none	CPROPRLBRMRFertilization rate IR	Retrospective (NCT01851876)No funding
¹⁸Hilton, 2019	Three centers,Canada	Randomized: 51Analyzed: 51	Inclusion criteria:Age of 18–39 yearsFirst or second IVF/ICSI cycleBMI of 18–35 kg/m²Exclusion criteria:FSH concentrations ≥12 IU/L Poor responders (previous IVF cycle canceled with ≤4 oocytes retrieved), PGD or preservation of fertility, endocrinal disorders, such as diabetes mellitus or thyroid abnormalities, an abnormal endometrial cavity, hydrosalpinx, contraindication to endometrial sampling, and previous uterine manipulations during the preceding cycleSurgically retrieved sperm	Intervention group: Pipelle injury 5–10 days before gonadotropin inductionControl: none	CPRLBRMRIR	Retrospective (NCT01983423)Funding: Unrestricted Educational Grant from Ferring Inc. (Canada)
³⁹Inal, 2012	One center,Turkey	Randomized: 100Analyzed: 100	Inclusion criteria:Age unknownGood ovarian response ≥1 failed IVF cycle after ETExclusion criteria:HydrosalpinxCoagulation defects such as thrombophiliaIntrauterine lesions such as submucous fibroid	Protocol: long agonistIntervention group: a Pipelle was used twice with a 1-week interval during the luteal phase of the preceding cycleControl: none	CPRLBRMRIR	Retrospective (NCT01340560)No funding
Karim Zadeh Meybodi, 2008	One center,Iran	Randomized: 160Analyzed: 1160	Inclusion criteria:Age unknownTwo or more previous implantation failuresExclusion criteria unknown	Protocol: unknownIntervention group: Novak suction curettage was used during the luteal phase of the preceding cycleControl: none	CPRIR	Not registeredNo funding
²⁴Karimzadeh, 2009	One center,Iran	Randomized: 115Analyzed: 93	Inclusion criteria:Age of 20–40 yearsRIF (2–6 failed IVF cycles with transfer of ≥10 high grade embryos per patient Exclusion criteria:Poor responders in previous cycles (day 3 FSH concentrations > 10 IU⁄mL or < 4 follicles at the day of triggering), blood diseases, uterine abnormalities, endometrioma, and hydrosalpinx.	Protocol: long agonistIntervention group: a Pipelle was used at the luteal phase of the preceding spontaneous menstrual cycle on days 21–26Control: none	CPR IR	Not registered Funding: Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences
²³Karimzade, 2010	One center,Iran	Randomized: 156Analyzed: 152	Inclusion criteria:Age < 38 yearsFirst IVF cycleDay 3 FSH concentrations < 12 mIU/mL Endometrium triple layer > 8 mm and prostaglandin E2 concentrations of 500–3000 pg/mL on the day of triggeringNormal responders (4–14 retrieved oocytes)BMI of 19–30 kg/m²Exclusion criteria:Uterine intrauterine lesions such as myoma or polypsEndometrioma (> 3 cm)Hydrosalpinx	Protocol: long agonistIntervention group: anterior and posterior wall small biopsies were performed using a Novak curette on the day of ovum pick-up Control: none	CPROPRMRIR	Retrospective (NCT00846183)No funding
¹⁴Lensen 2019	Thirteen centers in 5 countries (New Zealand, Australia, UK, Belgium, and Sweden)	Randomized: 1364Analyzed: 1364	Inclusion criteria:Age unknownFresh or frozen ET using the participant’s own oocytesExclusion criteria:Freeze-all cycles and preservation of fertilityContraindication to a Pipelle such as vaginismus)Intrauterine procedures, such as hysteroscopy, a sonohysterogram, a hysterosalpingogram, laparoscopy, and surgical treatment of miscarriage or endometrial biopsy within 3 months of the procedure	Protocol: 354 long, 50 short, 462 antagonist, 8 ultralong, and 4 unknownIntervention group: a Pipelle biopsy was performed once between the 3rd day of the preceding menstrual cycle and the 3rd day of the IVF cycleControl: none	CPROPRLBRMRMPRIRPain/bleeding	Prospective (ACTRN12614000626662)Funding: University of Auckland; the A+ Trust, Auckland District Health Board; the Nurture Foundation; and the Maurice & Phyllis Paykel Trust, New Zealand
³³Liu, 2017	One center,China	Randomized: 142Analyzed: 142	Inclusion criteria:Age ≤40 yearsFirst IVF cycleNormal endometrial cavity assessed by a sonohysterogram Basal FSH concentrations < 12 IU/L Exclusion criteria: Intracavitary fibroids or polyps, hydrosalpinx, and endometriosis	Protocol: 91 long, 15 short, and 35 antagonistIntervention group: a Pipelle catheter was used between cycle days 10–12Intervention group: a Pipelle catheter was used 7–9 days after ovulationControl: a Pipelle was introduced through the cervix on cycle days 10–12	CPRLBRMRMPRIR	Retrospective (ChiCTR-IOR-17011506)Funding: the National Natural Science Foundation of China (81471520), Beijing Natural Science Foundation Project (5122015), and Project Training High-Level Medical Technical Personnel in the Health System in Beijing (2014–3-075)
⁴⁷Mackens, 2020	One center,Belgium	Randomized: 200Analyzed: 199	Inclusion criteria:Age of 18–40 yearsFresh ETBMI of 18–35 kg/m²Exclusion criteria:HydrosalpinxIntracavitary lesions such as fibroids and synechiaGenital tuberculosisThrombophilia Oocyte donation cyclesFrozen ETPlanned embryo biopsyInvolvement in another ART trialPrevious involvement in a trialInability to follow the required investigation	Protocol: antagonistIntervention group: a Pipelle was used on days 6–8 of ovarian stimulationControl: none	CPROPRLBRMRMPR IRPain/bleeding	Prospective (NCT02061228)Funding: Fonds Wetenschappelijk Onderzoek (FWO, Flanders, Belgium; 11M9415N, 1524417N)
⁴Maged, 2018	One center,Egypt	Randomized: 300Analyzed: 300	Inclusion criteria:Age < 40 yearsFirst ICSI cycleDay 3 FSH concentrations < 10 IU/LNormal endometrial cavityExclusion criteriaEndocrinal abnormalities such as thyroid, adrenal, and prolactin abnormalitiesOvarian cystHydrosalpinxAzoospermic male partnerEndometrial cavity lesions such as polyps and PGD cycles	Protocol: 166 long, 16 short, and 118 antagonistIntervention group: midluteal phase endometrial aspiration of the preceding cycle was performed Control: none	CPR OPRMRMPRIR	Prospective (NCT02660125)No funding
¹⁹Mahran, 2016	Two centers,Egypt	Randomized: 418Analyzed: 400	Inclusion criteria:Age of 20–40 years FSH concentrations ≤12 IU/LNormal endometrial cavity evaluated by hysteroscopyTransfer of ≥2 good quality embryosExclusion criteria:Intracavitary lesions such as fibroids, polypi, and synechiaCongenital uterine anomalies	Protocol: long and short antagonistIntervention group: a Pipelle endosampler was used once between days 21 and 24 of the nontransfer cycleControl: none	CPROPRLBRMRMPRIRPain/bleeding	Retrospective (ISRCTN61316186)No funding
⁴¹Mak, 2017	One center,Hong Kong	Randomized: 229Analyzed: 186	Inclusion criteria:Age unknownNormal ovulatory women Natural-cycle FETExclusion criteria:Uterine abnormality such as endometrial polypsEndometriomas > 4 cmHydrosalpinx	Protocol: natural cycleIntervention group: a Pipelle was used in the mid-luteal phase of the preceding cycleControl: a sterile cotton wool stick was used for endocervical manipulation	CPROPRMRMPRIR	Prospective (ChiCTRTRC-12002389)No funding
¹³Metwally, 2020	16 centers,UK	Randomized: 1048Analyzed: 1048	Inclusion criteria:Age of 18–37 yearsBMI > 35 kg/m²First IVF cycle Long agonist or antagonist protocolFresh ETNormal ovarian responderNormal uterine cavityExclusion criteria:Previous uterine instrumentation, resection of intrauterine synechia, submucous myoma, and endometrial injury or biopsySevere endometriosisCurrent involvement in any other ART trialFormerly randomized into this study	Protocol: long and antagonistIntervention group: a Pipelle or similar catheter was used in the mid-luteal phase of the preceding cycleControl: none	CPRLBRMR	Prospective (ISRCTN23800982)Funding: NIHR (UK)Abstract only
³⁶Narvekar, 2010	One center,India	Randomized: 100Analyzed: 100	Inclusion criteria:Age ≤37 years≥1 previous failed IVF/ICSI cycle Fresh autologous ETNormal ovarian responseExclusion criteria:Previous endometrial tuberculosis and whether antituberculous treatment was receivedIntracavitary lesions such as fibroids and synechiaHydrosalpinx	Protocol: 48 long, 12 short, and 40 antagonistIntervention group: two Pipelle samplings were performed on the first day of hysteroscopy, and between days 24 and 25 days of the nontransfer cycleControl: hysteroscopy on days 7–10 of the preceding cycle	CPRLBRMRIR	Not registeredNo funding
⁴⁶Nastri, 2013	One center,Brazil	Randomized: 158Analyzed: 158	Inclusion criteria:Age < 38 yearsFresh ETExclusion criteria: not clear	Protocol: long or antagonistIntervention group: the Pipelle procedure was performed once 7–14 days before ovarian stimulationControl: a sham procedure was performed at the same time. This procedure comprised drying of the cervix with no insertion of any instrument into the cervix or womb.	CPRLBRMRMPRIRPain/bleeding	Prospective (NCT01132144)Funding: CNPq ((473475/2010-3) and CAPES (PhD scholarship)
²⁸Noori, 2022	One center,Iran	Randomized: 110Analyzed: 100	Inclusion criteria:Age of 20–40 yearsBMI ≤35 kg/m²1ry infertility and undergoing the first IVF cycleNormal uterine cavityFSH concentrations ≤12 IU/LFrozen ETExclusion criteria: Moderate or severe endometriosisModerate to severe male factorHistory of alcohol or tobacco useLack of proper embryos	Protocol: antagonistIntervention group: the Pipelle procedure was performed once between days 18 and 24Control: none	CPRChemical PRIRMR	Prospective (IRCT20180425039418N8)Funding: Research Department of Zahedan University of Medical Sciences
¹⁵Olesen, 2019	Four centers,Denmark	Randomized: 304Analyzed: 304	Inclusion criteria:Age of 18–40 yearsBMI of 18–32 kg/m²IVF/ICSI cycle≥1 previous implantation failures, despite good quality ETRegular 28–32 days of the menstrual cycleExclusion criteria:Congenital uterine anomaliesUterine lesions such as fibroids or polyps and hydrosalpinxAdenomyosis	Protocol: antagonistIntervention group: a Pipelle de Cornier was used in the luteal phase (days 18–22) of the preceding cycleControl: none	CPROPRLBRMRMPRIR	Prospective (NCT01963819)Funding: Health Research Fund of Central Denmark
⁴⁹Pecorino, 2018	One center,Italy	Randomized: 80Analyzed: 80	Inclusion criteria:Age of 25–37 years1ry or 2ry infertility ≥2 previous failed ICSIs Normal endometrial thickness and patternGood quality semen Exclusion criteria: Severe deep endometriosis Considerable genetic, metabolic, or systemic diseases or infections Abnormal endometrial cavity such as fibroids and polyps	Intervention group: luteal phase Pipelle scratching was performed by 2 operators of a dedicated team 5 and 10 days before menstruationControl group: a uterine cavity sham procedure was performed using an ET catheter	CPRPain/bleeding	No registeredNo funding
⁴⁰Polanski, 2015	One centerUK	Randomized: 160Analyzed: 160	Inclusion criteria:Age < 40 years1ry or 2ry infertility undergoing fresh or frozen ETExclusion criteria:Non-ovulatory cycleUterine aplasiaUterine manipulation in the preceding 3 cyclesOvum donation	Intervention group: a Pipelle or Wallace/Wallach endometrial sampler endometrial biopsy was performed on days 7–9 after the luteinizing hormone surge Control: none	CPRMR	Retrospective (NCT01882842)Funding: the University of Nottingham and Nurture Fertility
⁵¹Rodriguez, 2020	One center,Spain	Randomized: 352Analyzed: 352	Inclusion criteria:Age of 18–50 yearsBMI < 35 kg/m²Ovum donation cycles Normal uterine cavityExclusion criteria:Severe male factor (< 2 ×10⁶ sperm/mLMullerian duct anomaliesUterine cavity abnormalities such as fibroids class 0–2 Severe adenomyosisHydrosalpinx regardless of whether it was uni- or bilateralEndometrial manipulations, such as scratching and hysteroscopy, within the preceding month before the randomization	Intervention group: a luteal phase Pipelle endometrial catheter was used 5–10 days before menstruationControl: none	CPROPRLBRMRMPR	Retrospective (NCT03108157)Funding: ProcreaTec Fertility Center (no specific grant)
²⁷Safdarian, 2011	One center,Iran	Randomized: 100Analyzed: 74	Inclusion criteria:Age of 20–39 yearsExclusion criteria:FSH concentrations > 11 IU/LAzoospermic partner EndometriosisHypothalamic amenorrhea	Protocol: longIntervention group: a Pipelle was used on day 21 of the preceding cycle with contraceptive pill administrationControl: none	CPRIR	Retrospective (IRCT201008154572N1)Funding: Shariati Hospital Infertility Center, University of Medical Sciences
²¹Shahrokh, 2016	Two centers,Iran	Randomized: 120Analyzed: 120	Inclusion criteria:Age < 40 yearsBMI < 30 kg/m²≥2 previous IVF/ICSI failures after ET of ≥4 good quality embryosNormal uterine cavity (evaluated by hysterosalpingography, sonohysterography, or hysteroscopyEndometrial thickness ≥7 mm on the day of progesterone administrationExclusion criteria:Fibroids > 5 cmEndometrioma ≥3 cmHydrosalpinxBilateral tubal obstruction<3–4 embryos for transfer Endometrial tuberculosis or a history of tuberculosis treatment, Intrauterine synechiaActive infection (vaginal and/or cervical)Systemic diseases such as diabetes and SLE	Protocol: antagonistIntervention group: Pipelle endometrial scratching was performed in all 4 uterine walls on day 21 of the preceding cycleControl: none	CPRLBRMR	Retrospective (IRCT 201311065181N12R2)No funding
²⁹Sherif, 2018	One center,Egypt	Randomized: 60Analyzed: 60	Inclusion criteria:Age of 25–30 yearsBMI of 20–30 kg/m²Infertility resulting from tubal or ovulatory factors, or unexplainedExclusion criteria:EndometriosisMale infertilityEndometrial cavity abnormalities evaluated by HSG or ultrasound Previous IVF failure Hydrosalpinx or pyosalpinx	Protocol: longIntervention group: one posterior wall (1–2 cm from the fundus) injury using a modified Cook catheter on day 6 of the ICSI cycleControl: none	CPR	Retrospective (PACTR201701001968212)No funding
²⁰Shohayeb, 2012	Two centers in 2 countries (Egypt and KSA)	Randomized: 210Analyzed: 200	Inclusion criteria:Age < 39 yearsDay 4 endometrial thickness <5 mm ≤2 previous IVF failuresExclusion criteria:Abnormal uterine cavity, such as submucous fibroids, polyps, intrauterine adhesions, and aseptate or bicornuate uterus diagnosed by HSG or ultrasound	Protocol: long or shortIntervention group: hysteroscopy and endometrial scraping using a Novak curette were performed during the follicular phase (days 4–7) in the preceding cycleControl: hysteroscopy only	CPRLBRMRIR	Not registeredNo funding
³⁴Singh, 2015	One center,India	Randomized: 60Analyzed: 60	Inclusion criteria:Age < 35 years>1 previous IVF failure despite an adequate ovarian reserve (FSH concentrations < 8 IU/L, AMH concentrations of 2–6 ng/mL, and an AFC > 8Normal uterine cavityConsent for participationExclusion criteria:Uterine instrumentation, such as hysteroscopy, septum resection, and adhesiolysis in the preceding 3 monthsEndometriosis grade III or IVSystemic diseases such as diabetes, hypertension, and autoimmune diseases	Protocol: longIntervention group: anterior and posterior wall endometrial scratching was performed using a 4-mm disposable Karman’s cannula once between days 14 and 21 of the preceding cycleControl: none	CPROPRLBRMRIR	Not registered No funding
²²Tang, 2020	Two centers,China	Randomized: 220Analyzed: 200	Inclusion criteria:Age < 40 yearsBMI < 27 kg/m²Frozen–thawed ETDay 3 progesterone concentrations <1.2 ng/mL≥2 previous implantation failuresNormal endometrial cavityExclusion criteria:Previous pelvic surgeryHistory of difficult ET Intracavitary lesions such as submucous fibroids, polyps, and adhesionsHydrosalpinxEndometriosis Recent administration of oral contraceptives	Intervention group: a Pipelle catheter with soft endometrial scratching was used on day 3 of the preceding cycle Control: none	CPRLBRMRMPR	Retrospective (ChiCTR-IPR-17014013)Funding: HeFei Municipal Health Planning Commission (hwk2017yb009), AnHui Project Key Research and Development Province (1701a0802171), Key Talents of Maternal and Child Health in Jiangsu Province (FRC201715), and Science Technology Innovation Project of Suzhou (SS201702)
¹²Van Hoogenhuijze, 2017	Multicenter,The Netherlands	Randomized: 946Analyzed: 946	Inclusion criteria:Age of 18–44 yearsPrevious 1 failed IVF cycle after ≥1 ETFresh ET1ry or 2ry infertilityNormal transvaginal ultrasoundExclusion criteria: Endometriosis grade III or IV, uni- or bilateral hydrosalpinx, or previous endometrial scratch injuryUntreated endocrinal disorders Intermenstrual bleedingNiche and intracavitary fluid from a prior cesarean deliveryOvum donationPGDHigh risk of intra-abdominal infection	Protocol: long, short, and antagonistIntervention group: one mid-luteal endometrial scratch using an endometrial biopsy catheter in the preceding cycle (natural or hormonally prepared).Control: none	CPRLBRMR	Prospective (NTR 5342)Funding: Dutch organization for funding of healthcare research ZonMW
³⁰Wafa, 2021	One center,Egypt	Randomized: 150Analyzed: 150	Inclusion criteria:Age of 20–43 years≥1 prior failed ICSI attempt with an adequate ovarian response and good quality ETExclusion criteria:Fibroids and previous endometrial operations	Protocol: longIntervention group: endometrial scratch injury occurred on the 21st day of the spontaneous cycle before ICSI-ET treatment using a Pipelle endometrial samplerControl: sildenafil citrate 25 mg tablets for 3 times daily intravaginally starting from the first day of FSH stimulation	CPR	Not registeredNo funding
⁴⁵Wolff, 2018	One center,USA	Randomized: 19Analyzed: 19	Inclusion criteria:Age of 18–37 yearsBMI of 18–30 kg/m²≥1 prior implantation failure with fresh or frozen blastocyst transferFresh ET cycleNormal uterine cavity≥1 good quality blastocyst available for ETWilling and understanding the aim and nature of the studyExclusion criteria:PregnancySystemic disorders EndometriosisHydrosalpinxUterine cavity anomalies or lesions such as fibroids, polyps, and synechiaPoor responders (day 3 FSH concentrations >12 IU/L or <4 follicles in a previous cycle)Hematological or genetic factors of infertility	Protocol: longIntervention group: Pipelle endometrial scratching was performed twice on days 4–7 after starting the pill and at an evaluation visit for the Lupron in the preceding cycleControl group: cervical placement of a small cotton swab	CPRLBRMRMPR	Retrospective (NCT01800513)Funding: NIH and Shady Grove
³²Xu, 2015	One center,China	Randomized: 79Analyzed: 79	Inclusion criteria:Age < 40 yearsFSH concentrations <10 mIU/mLThin endometrium <7 mm (measurements were obtained using regular methods)Exclusion criteria: Uterine cavity lesions such as fibroids, polyps, and synechia Uterine malformationsSystemic diseases that can affect endometrial growthContraindications for granulocyte colony-stimulating factor such as previous malignancy, sickle cell disease, chronic neutropenia, and kidney disease	Intervention group: Pipelle scratching and granulocyte colony-stimulating factor administration were performed before ovulation (dominant follicle = 12 mm)Control: only granulocyte colony-stimulating factor administration was performed at the same time as that in the intervention group	CPRLBRMR	Not registered No funding
⁴²Yeung, 2014	One center,Hong Kong	Randomized: 300Analyzed: 300	Inclusion criteria:Tubal, unexplained, or male factors of infertilityNormal uterine cavity assessed by hysteroscopy or sonohysterographyExclusion criteria:Ovum donationHydrosalpinxEndometrial cavity lesions such as polyps or fibroids PGD	Intervention group: Pipelle endometrial aspiration was performed 7 days after the luteiniozing hormone surge in the preceding cycle Control: none	CPROPRLBRMRMPR IRPain/bleeding	Retrospective (NCT01977976)Funding: Small Project Funding 201309176012 of the Committee on Research and Conference Grants, University of Hong Kong
³¹Zhou, 2008	One center,China	Randomized: 121Analyzed: 121	Inclusion criteria:Age unknownFresh ET cycles Normal menstrual cycle (26–34 days)Good ovarian responders to hormonal stimulationIrregular endometrial echo (strong or inhomogeneous) diagnosed by ultrasoundExclusion criteria not clear	Protocol: longIntervention group: a no. 5 biopsy catheter was used between cycle days 5 and 22 of the controlled ovarian hyperstimulation cycleControl: none	CPROPRLBRMRMPRFertilization rate IR	Not registered No funding
⁵⁰Zygula, 2016	One center,Poland	Randomized: 120Analyzed: 120	Inclusion criteria: Age <40 yearsWomen with prior IVF failureExclusion criteria not clear	Intervention group: Pipelle endometrial scratching was performed during the luteal phase of the preceding cycleControl: none	CPRIR	Not registered No funding

ET, embryo transfer; IR, implantation rate; CPR, clinical pregnancy rate; OPR, ongoing pregnancy rate; MR, miscarriage rate; MPR, multiple pregnancy rate; ChPR, chemical pregnancy rate; IVF, in vitro fertilization; BMI, body mass index; FSH, follicle-stimulating hormone; LBR, live birth rate; AFC, antral follicular count; OHSS, ovarian hyperstimulation syndrome; GnRH, gonadotropin-releasing hormone; PGD, preimplantation genetic diagnosis; RIF, recurrent implantation failure; ART, assisted reproductive technique; ICSI, intracytoplasmic sperm injection; SLE, systemic lupus erythematosus; HSG, hysterosalpingography; AMH, anti-Mullerian hormone.

Synthesis of results

The clinical pregnancy rate was reported in all 41 studies. The OR was 1.34 with a 95% CI of 1.14 to 1.58 and a P value of 0.0005 (Figure 2). The subgroup analysis of the clinical pregnancy rate is shown in Figure 2 and Table 2.

Figure 2.

Clinical pregnancy rate according to (a) the time of endometrial scratch injury, (b) the number of previous IVF cycles, (c) the number of endometrial scratch injuries, and (d) the intensity of endometrial scratch injury.

Table 2.

Subgroup analysis of outcome parameters

Outcome	Subgroup	No. of studies	No. of participants	Effect estimate OR [95% CI]	P value	Heterogeneity
Clinical pregnancy rate
Timing	Preceding follicular phase	4	823	1.87 [1.37, 2.57]	<0.001	I² = 0%P = 0.93
	Same follicular phase	5	562	1.17 [0.55, 2.48]	0.68	I² = 73%P = 0.005
	Luteal phase	26	6023	1.30 [1.06, 1.60]	0.01	I² = 65%P < 0.001
	Follicular and luteal phases	4	297	1.19 [0.46, 3.08]	0.73	I² = 56%P = 0.08
	Unspecified timing	2	1485	1.45 [0.63, 3.36]	0.39	I² = 79%P = 0.03
I VF failure	First IVF cycle	9	2541	1.33 [1.12, 1.56]	0.30	I² = 85%P < 0.001
	One previous IVF failure	1	946	1.29 [0.80, 2.08]	0.25	NA
	Two or more IVF failures	9	1032	1.19 [0.89, 1.60]	0.38	I² = 58%P = 0.01
	Unspecified IVF failures	23	4661	1.24 [0.77, 2.02]	0.002	I² = 37%P = 0.04
Number	Single scratch	34	8285	1.36 [1.15, 1.61]	<0.001	I² =61%P < 0.001
Number	Double scratch	7	905	1.17 [0.59, 2.30]	0.65	I² = 73%P < 0.001
Intensity	Mild to moderate	35	8196	1.35 [1.13, 1.60]	<0.001	I² = 63%P < 0.001
Intensity	High	6	995	1.27 [0.73, 2.23]	0.40	I² = 70%P = 0.005
Ongoing pregnancy rate
Timing	Preceding follicular phase	4	823	1.85 [1.33, 2.58]	<0.001	I² = 0%P = 0.82
	Same follicular phase	4	502	0.87 [0.36, 2.08]	0.75	I² = 73%P = 0.01
	Luteal phase	19	5288	1.36 [1.07, 1.75]	0.01	I² = 72%P < 0.001
	Follicular and luteal phases	4	297	1.07 [0.32, 3.51]	0.92	I² = 61%P = 0.08
	Unspecified timing	1	1364	0.98 [0.77, 1.24]	0.84	NA
IVF failure	First IVF cycle	8	435	1.37 [0.80, 2.32]	0.25	I² = 87%P < 0.001
	One previous IVF failure	1	946	1.26 [0.92, 1.71]	0.15	NA
	Two or more IVF failures	6	707	1.17 [0.61, 2.25]	0.64	I² = 63%P = 0.02
	Unspecified IVF failures	18	4186	1.25 [1.01, 1.54]	0.04	I² = 45%P = 0.02
Number	Single scratch	25	7369	1.35 [1.10, 1.66]	0.004	I² = 69%P < 0.001
Number	Double scratch	7	905	1.10 [0.53, 2.27]	0.80	I² = 74%P = 0.002
Intensity	Mild to moderate	27	7439	1.32 [1.08, 1.62]	0.007	I² = 69%P < 0.001
Intensity	High	5	835	1.29 [0.59, 2.79]	0.52	I² = 76%P = 0.003
Live birth rate
Timing	Preceding follicular phase	4	823	1.96 [1.40, 2.74]	<0.001	I² = 0%P = 0.92
	Same follicular phase	4	509	0.84 [0.34, 2.04]	0.70	I² = 74%P = 0.009
	Luteal phase	8	5015	1.30 [0.99, 1.70]	0.06	I² = 75%P < 0.001
	Follicular and luteal phases	4	297	1.08 [0.41, 2.83]	0.87	I² = 49%P = 0.12
	Unspecified timing	2	1485	1.42 [0.61, 3.31]	0.41	I² = 77%P = 0.04
IVF failure	First IVF cycle	7	2166	1.23 [0.64, 2.37]	0.53	I² =90%P< 0.001
	One previous IVF failure	1	946	1.33 [0.97, 1.83]	0.07	NA
	Two or more IVF failures	6	707	0.95 [0.44, 2.01]	0.88	I² = 68%P = 0.007
	Unspecified IVF failures	19	4310	1.30 [1.06, 1.59]	0.01	I² = 42%P = 0.03
Number	Single scratch	25	7220	1.33 [1.07, 1.65]	0.01	I² = 72%P < 0.001
Number	Double scratch	7	909	1.12 [0.57, 2.21]	0.75	I² =70%P = 0.003
Intensity	Mild to moderate	27	7290	1.32 [1.07, 1.63]	0.009	I² = 70%P < 0.001
Intensity	High	5	839	1.08 [0.45, 2.60]	0.87	I² = 79%P < 0.001
Miscarriage rate
Timing	Preceding follicular phase	4	823	1.39 [0.75, 2.61]	0.30	I² = 0%P = 0.96
	Same follicular phase	4	505	1.52 [0.73, 3.17]	0.26	I² = 4%P = 0.37
	Luteal phase	20	4978	0.83 [0.66, 1.04]	0.11	I² =0%P =0.65
	Follicular and luteal phases	4	307	1.39 [0.45, 4.33]	0.57	I² = 0%P = 0.54
	Unspecified timing	1	1364	1.18 [0.72, 1.94]	0.51	NA
IVF failure	First IVF cycle	9	2166	0.77 [0.51, 1.17]	0.22	I² = 0%P = 0.93
	One previous IVF failure	1	946	0.82 [0.40, 1.69]	0.59	NA
	Two or more IVF failures	6	647	1.28 [0.69, 2.37]	0.44	I² = 0%P = 0.79
	Unspecified IVF failures	18	4208	1.17 [0.89, 1.54]	0.26	I² = 0%P = 0.89
Number	Single scratch	26	7155	0.95 [0.78, 1.16]	0.62	I² = 0%P = 0.55
Number	Double scratch	7	822	1.18 [0.60, 2.31]	0.63	I² = 0%P = 0.78
Intensity	Mild to moderate	28	7142	0.94 [0.78, 1.15]	0.57	I² = 0%P = 0.55
Intensity	High	5	835	1.29 [0.67, 2.50]	0.45	I² = 0%P = 0.88
Multiple pregnancy rate
Timing	Preceding follicular phase	3	705	2.73 [1.33, 5.58]	0.006	I² = 0%P = 0.74
	Luteal phase	14	3406	1.26 [0.95, 1.67]	0.11	I² = 0%P = 0.45
	Follicular and luteal phases	3	261	1.13 [0.52, 2.46]	0.77	I² = 0%P = 0.81
	Unspecified timing	1	1364	1.23 [0.57, 2.64]	0.60	NA
IVF failure	First IVF cycle	5	900	1.48 [1.01, 2.15]	0.04	I² = 0%P = 0.96
	One previous IVF failure	1	946	0.50 [0.12, 2.01]	0.33	NA
	Two or more IVF failures	4	508	2.88 [1.46, 5.67]	0.002	I² = 0%P = 0.87
	Unspecified IVF failures	12	3382	1.09 [0.77, 1.54]	0.62	I² = 0%P = 0.65
Number	Single scratch	17	5202	1.41 [1.10, 1.82]	0.008	I² = 0%P = 0.59
Number	Double scratch	4	534	0.99 [0.50, 1.97]	0.98	I² = 8%P = 0.35
Intensity	Mild to moderate	19	5231	1.34 [1.06, 1.71]	0.02	I² = 1% P = 0.45
Intensity	High	2	505	1.67 [0.39, 7.13]	0.49	I² = 0%P = 0.86
Implantation rate
Timing	Preceding follicular phase	3	1066	1.90 [1.38, 2.63]	<0.001	I² = 0%P =0.89
	Same follicular phase	1	54	0.94 [0.30, 2.96]	0.91	NA
	Luteal phase	7	1978	1.28 [1.05, 1.57]	0.02	I² = 0%P = 0.64
	Follicular and luteal phases	1	293	1.03 [0.61, 1.72]	0.92	NA
IVF failure	First IVF cycle	3	797	1.40 [1.02, 1.93]	0.04	I² = 9%P = 0.34
	Two or more IVF failures	3	881	1.68 [1.25, 2.27]	<0.001	I² = 0%P = 0.40
	Unspecified IVF failures	6	1713	1.18 [0.92, 1.51]	0.19	I² = 0%P = 0.65
Number	Single scratch	11	3168	1.41 [1.19, 1.66]	<0.001	I² = 0%P = 0.52
Number	Double scratch	1	223	0.92 [0.47, 1.80]	0.81	NA
Intensity	Mild to moderate	10	2695	1.33 [1.11, 1.59]	0.002	I² = 6%P = 0.39
Intensity	High	2	696	1.74 [1.07, 2.84]	0.03	I² = 0%P = 0.93

OR, odds ratio, CI, confidence interval; IVF, in vitro fertilization; NA, not applicable.

The ongoing pregnancy rate was reported in 32 studies that included 8274 participants. The OR was 1.32 with a 95% CI of 1.09 to 1.61 and a P value of 0.005. The subgroup analysis according to the timing of ESI, number of previous IVF cycles, number of ESIs, and intensity of ESI is shown in Figure 3 and Table 2.

Figure 3.

Ongoing pregnancy rate according to (a) the time of endometrial scratch injury, (b) the number of previous IVF cycles, (c) the number of endometrial scratch injuries, and (d) the intensity of endometrial scratch injury.

The live birth rate was reported in 32 studies with 8129 participants. The OR was 1.30 with a 95% CI of 1.06 to 1.60 and a P value of 0.01. The subgroup analysis according to the timing of ESI, number of previous IVF cycles, number of ESIs, and intensity of ESI is shown in Figure 4 and Table 2.

Figure 4.

Live birth rate according to (a) the time of endometrial scratch injury, (b) the number of previous IVF cycles, (c) the number of endometrial scratch injuries, and (d) the intensity of endometrial scratch injury.

The miscarriage rate was reported in 32 studies that included 7939 participants. The OR was 0.98 with a 95% CI of 0.81 to 1.19 and a P value of 0.86. The subgroup analysis according to the timing of ESI, number of previous IVF cycles, number of ESIs, and intensity of ESI is shown in Figure 5 and Table 2.

Figure 5.

Miscarriage rate according to (a) the time of endometrial scratch injury, (b) the number of previous IVF cycles, (c) the number of endometrial scratch injuries, and (d) the intensity of endometrial scratch injury.

The multiple pregnancy rate was reported in 21 studies that included 5736 participants. The OR was 1.35 with a 95% CI of 1.07 to 1.71 and a P value of 0.01. The subgroup analysis according to the timing of ESI, number of previous IVF cycles, number of ESIs, and intensity of ESI is shown in Figure 6 and Table 2.

Figure 6.

Multiple pregnancy rate according to (a) the time of endometrial scratch injury, (b) the number of previous IVF cycles, (c) the number of endometrial scratch injuries, and (d) the intensity of endometrial scratch injury.

The implantation rate was reported in 12 studies with 3391 participants. The OR was 1.38 with a 95% CI of 1.17 to 1.61 and a P value of <0.0001. The subgroup analysis according to the timing of ESI, number of previous IVF cycles, number of ESIs, and intensity of ESI is shown in Figure 7 and Table 2.

Figure 7.

Implantation rate according to (a) the time of endometrial scratch injury, (b) the number of previous IVF cycles, (c) the number of endometrial scratch injuries, and (d) the intensity of endometrial scratch injury.

Risk of bias of included studies

Figure 8 shows the risk of bias assessment of the included studies. An adequate computer-generated random sequence was described in 35 studies, 19 had a proper allocation concealment, 8 showed appropriate blinding of both participants and personnel, 30 showed appropriate blinding of outcome assessors, 32 had no incomplete data reporting, 19 had no reporting bias, and 28 had bias related to registration.

Figure 8.

Risk of bias summary and graph.

The quality of the evidence was evaluated using the grading of recommendations, assessment, development, and evaluations (GRADE) system and is shown in Table 3. GRADE includes publication bias, inconsistency, indirectness, imprecision, and the risk of bias in the included research. Each item reduces the evidence if there are substantial concerns about it by one level, and if there are serious issues, by two levels. The quality of evidence varied from high (if we were confident that the true effect was near to the effect estimate), moderate (if we were somewhat convinced that the true effect was close to the effect estimate, but there was the potential fora significant difference), and low (if there was no certainty that the true effect was close to the effect estimate).

Table 3.

Grading of recommendations, assessment, development, and evaluations quality of evidence.

Outcome	No. of studies	Risk of bias	Inconsistency	Indirectness	Imprecision		Publication bias	Quality
Outcome	No. of studies	Risk of bias	Inconsistency	Indirectness	Sample size	Wide CI	Publication bias	Quality
Clinical pregnancy rate	41	N	S	N	9190	N	N	Moderate
Ongoing pregnancy rate	32	N	S	N	8274	N	N	Moderate
Live birth rate	32	N	S	N	8129	N	N	Moderate
Miscarriage rate	33	N	S	N	7977	S	N	Low
Multiple pregnancy rate	21	N	S	N	5736	N	N	Moderate
Implantation rate	12	N	N	N	3391	N	N	High

N, not serious; S, serious; CI, confidence interval.

Discussion

Principal findings

In this study, ESI increased the clinical pregnancy, ongoing pregnancy, live birth, multiple pregnancy, and implantation rates in women undergoing IVF/ICSI cycles. The miscarriage rate was similar in women who underwent ESI and in those who did not undergo ESI.

There was a significant improvement in the clinical pregnancy, ongoing pregnancy, and live birth rates when ESI was performed during the follicular or luteal phase of the cycle preceding the stimulation cycle. This improvement was not significant in those who underwent ESI during the follicular phase of the same stimulation cycle or during both follicular and luteal phases. Although the clinical pregnancy rate was improved in women without specific selection criteria related to previous IVF failure, the pooled evidence of studies in women who underwent their first IVF cycle and in those with one or more IVF failures failed to show this beneficial effect. With regard to the number and intensity of ESI, the pooled evidence showed an improved clinical pregnancy rate in women who underwent a single scratch and in those who had a mild to moderate intensity scratch, but not in women with a double or high intensity scratch.

The miscarriage rate was not affected by the performance of ESI in women who underwent IVF cycles. This finding was observed in women who underwent ESI during any phase of the cycle, in all women with different numbers of previous IVF failures, and with all intensities of ESI, and regardless of whether ESI was performed once or twice.

An increase in the multiple pregnancy rate was observed when ESI was performed during the follicular phase of the cycle preceding the stimulation cycle, but this was not found if ESI was performed during the follicular phase of the same cycle of stimulation, the luteal phase, or both follicular and luteal phases. When the multiple pregnancy rate was evaluated according to the number of previous IVF failures, it was increased in women who underwent their first IVF cycle and in those with two or more previous IVF failures, but not in women with one previous IVF failure or in women with an unspecified number of IVF failures. The multiple pregnancy rate was increased in women who underwent a single ESI and mild to moderate intensity injury, but not in those with double or high intensity ESI.

There was a significant improvement in the implantation rate when injury was performed during the follicular or luteal phase of the cycle preceding the stimulation cycle. This improvement was not significant in those who underwent ESI during the follicular phase of the same stimulation cycle or during both follicular and luteal phases. The implantation rate was significantly improved in women who underwent their first IVF cycle and in those with history of two or more previous IVF failures. This beneficial effect was not observed in women without specific selection criteria related to a previous IVF failure. Data from pooled evidence confirmed an increase in the implantation rate in women who underwent single, mild to moderate intensity, or high intensity ESI, but not in those who underwent double injury.

Many theories have been suggested to explain the beneficial effects of ESI on implantation. A mechanical theory states that ESI results in a delay in endometrial maturation and subsequent enhancement of synchronicity between the endometrium and the embryo.³¹ An inflammatory theory depends on the association between implantation and high levels of endometrial cytokines, chemokines, and leukocytes.⁵² The wound healing process following ESI creates an optimal environment in the decidua for implantation.⁵³ Other theories include differential gene expression in the endometrium, recruitment of uterine immune cells to the injury site, enhancement of an angiogenic environment, and expression of a variety of proteins that co-act in the differentiation of the human endometrium.¹⁰

Our findings suggest that ESI of mild to moderate intensity that is not performed at the time of implantation is effective in improving implantation. Mild intensity and single ESI causes a mild inflammatory reaction with ideal outcomes. However, high intensity and double scratch ESI may be associated with excessive tissue damage and an intense inflammatory reaction, which may not enhance the implantation process. Our findings also showed that ESI in the preceding cycle for implantation yielded a better implantation rate because it provided more time for starting the healing process with its beneficial effects. These effects were not evident when ESI was performed during the follicular phase in the same cycle of stimulation because it did not allow sufficient time to achieve healing of the endometrium.

Strengths and limitations

To the best of our knowledge, this is the largest systematic review to evaluate the effect of ESI in infertile couples seeking fertility through IVF cycles. We included all reliable RCTs in all available languages without restrictions. All available studies were screened and evaluated properly, and selected studies were subjected to quantitative and qualitative methodological assessment.

The main limitation is the substantial methodological heterogeneity in the inclusion and exclusion criteria among the different studies, especially regarding the previous failed IVF cycles and their numbers. We attempted to account for these effects by performing a subgroup analysis according to previous IVF failure. There was high heterogeneity regarding the timing, number, and intensity of ESI among the studies. We also attempted to control for these effects by performing a subgroup analysis according to different characteristics of ESI. We performed a meta-analysis using random effects to incorporate and examine any possible heterogenicity of the included studies. The second limitation is not reporting pain and bleeding following ESI because they were not completely reported in most studies.

Comparison of our study with existing literature

One systematic review assessed the effect of ESI on women with one or more previous failed embryo transfers⁵⁴ and another systematic review assessed the effect of ESI on women who underwent their first embryo transfer.⁶ These studies focused on one category in infertile couples. We believe that studying the effect of ESI on all participants with subgroup analysis for each type of participant would provide higher evidence of the effects of ESI. These systematic reviews included 10⁵⁴ and 7⁶ studies. However, we analyzed 41 studies, which provides stronger evidence of the effects of ESI than previous reviews. More conclusive evidence of the effects of ESI is required for practitioners who treat all types of patients undergoing IVF.

Metwally et al.⁵⁵ conducted a systematic review in 2022 that included the effect of scratching in women undergoing their first IVF cycle. Their review included 12 studies. A full subgroup analysis was performed because of the small number of studies.

A recent, lengthy (125 pages) Cochrane review⁵⁶ included only 37 studies. No GRADE evaluation for the quality of evidence was performed. A subgroup analysis of the timing of ESI included only the follicular and luteal phases and no recurrent, recurrent, or unclear previous failures. In our systematic review, we performed a subgroup analysis of five different timings of ESI and four groups of previous failures.

Conclusions and implications

According to our findings, we recommend the performance of ESI in all couples undergoing IVF cycles before proceeding to IVF. Practicing ESI in the preceding cycle to stimulation (at the follicular or luteal phase) leads to a better result than that in the same cycle. We recommend that mild to moderate intensity scratching should be performed once without any need to repeat it or to perform high-intensity injury. However, the evidence supporting the findings of the effects of ESI is not high, and more randomized, high-quality studies are still required.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231175365 - Supplemental material for Endometrial scratch injury in infertile women undergoing in vitro fertilization cycles: a systematic review and meta-analysis

Supplemental material, sj-pdf-1-imr-10.1177_03000605231175365 for Endometrial scratch injury in infertile women undergoing in vitro fertilization cycles: a systematic review and meta-analysis by Ahmed M Maged, Akmal El-Mazny, Yossra Lasheen and Noura El-Nassery in Journal of International Medical Research

Footnotes

Author contributions

AMM: Literature search, assessment, writing, and revision.

AE: Data extraction, writing, and revision.

YL: Data analysis, writing, and revision.

NE: Data extraction, writing, and revision.

All authors have read and approved the manuscript.

Synopsis

ESI increased clinical pregnancy, ongoing pregnancy, live birth, multiple pregnancy, and implantation rates in women undergoing IVF/ICSI cycles.

Summary of the study: [Database]

Why was this study conducted?

To evaluate the safety and efficacy of endometrial scratching performed before or during the stimulation cycle in women undergoing IVF/ICSI cycles.

What are the key findings?

ESI improved the clinical pregnancy, ongoing pregnancy, live birth, multiple pregnancy, and implantation rates in women undergoing IVF/ICSI cycles.

ESI had no significant effect on the miscarriage rate.

What does this study add to what is already known?

This study confirms the benefits of ESI in infertile women undergoing IVF/ICSI cycles.

The beneficial effects of ESI are more evident when it is performed during the preceding cycle (during the follicular or luteal phase) than when it is performed in the same IVF cycle.

Mild to moderate intensity injury is more beneficial than high intensity injury, and a single scratch is more effective than double injury.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iD

Akmal El-Mazny

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