The value of endometrial scratch injury in infertile women trying to conceive through non-<i>in vitro</i> fertilization cycles: A systematic review and meta-analysis

Nour A.M. El-Goly; Ahmed M. Maged; Nehal Bassiouny; Safaa I. Mahmoud; Amira Shoab

doi:10.5653/cerm.2024.07612

Clin Exp Reprod Med > Volume 52(4); 2025 > Article

El-Goly, Maged, Bassiouny, Mahmoud, and Shoab: The value of endometrial scratch injury in infertile women trying to conceive through non-in vitro fertilization cycles: A systematic review and meta-analysis

Review Article

Clinical and Experimental Reproductive Medicine 2025;52(4):310-333.

Published online: July 10, 2025

DOI: https://doi.org/10.5653/cerm.2024.07612

The value of endometrial scratch injury in infertile women trying to conceive through non-in vitro fertilization cycles: A systematic review and meta-analysis

Nour A.M. El-Goly¹

, Ahmed M. Maged²

, Nehal Bassiouny², Safaa I. Mahmoud², Amira Shoab²

¹Faculty of Medicine, Cairo University, Cairo, Egypt

²Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt

Corresponding author: Ahmed M. Maged Department of Obstetrics and Gynecology, Cairo University, Kasr Alainy St., Cairo, Egypt
Tel: +20-1005227404 Fax: +20-235693055 E-mail: prof.ahmedmaged@gmail.com

Received October 17, 2024 Revised November 28, 2024 Accepted December 17, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

To assess the effects of endometrial scratch injury (ESI) in infertile couples seeking fertility through non-in vitro fertilization (IVF) cycles. We conducted a comprehensive search of MEDLINE, EMBASE, Web of Science, Scopus, the Cochrane Library, and Google Scholar from their inception through August 2023. The search terms included ‘endometrial scratch,’ ‘infertility,’ ‘implantation,’ ‘intrauterine insemination (IUI),’ and their corresponding MeSH terms. We included all published and unpublished randomized controlled trials involving ESI in women undergoing either natural or IUI cycles. The ESIs varied in severity and were performed during either the follicular or luteal phase of the same or preceding cycle. Our review encompassed 32 studies, totaling 5,897 participants. Of these, seven studies with 1,094 participants assessed ESI in natural cycles, while 25 studies with 4,803 participants evaluated it in IUI cycles. The data extracted included trial location, number of participants, inclusion and exclusion criteria for participants, details of the ESI, and outcome parameters (trial registration: CRD42023434127). ESI significantly increased the clinical pregnancy rate (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.72 to 2.47; p<0.001), ongoing pregnancy/live birth rate (OR, 1.68; 95% CI, 1.32 to 2.13; p<0.001), and chemical pregnancy rate (OR, 2.32; 95% CI, 1.79 to 3.00; p<0.001). However, it had no significant effect on the rates of multiple pregnancy, miscarriage, and ectopic pregnancy (p>0.05). ESI improved the clinical pregnancy rate, ongoing pregnancy/live birth rate, and chemical pregnancy rate in both natural and IUI cycles.

Keywords: Endometrial injury; Endometrial scratch; Endometrial trauma; Infertility; Intrauterine insemination; Natural cycles; Pregnancy rate

Introduction

Infertility is defined as failure to attain a clinical pregnancy after 1 or more years of regular unprotected sexual intercourse [1]. Approximately one in six couples, or 17.5% of the adult population, experience infertility. The prevalence of this condition shows only slight variation between different regions, ranging from 17.8% in high-income areas to 16.5% in low- to middle-income regions [2]. Infertility can result from male factors, female factors, a combination of both, or unknown causes. Female-related causes of infertility may involve issues with the fallopian tubes, ovulation, the uterus, or endometriosis [3].

Although assisted reproductive technology (ART) plays a crucial role in managing infertility, its availability and quality vary significantly across different regions [4]. ART is an expensive, time-consuming, and stressful procedure with uncertain outcomes [5]. In women who have patent tubes and male partners with satisfactory semen analysis, attempts to achieve pregnancy can be made through natural cycles, with or without ovulation induction, or through straightforward procedures such as intrauterine insemination (IUI) [6]. Successful pregnancy hinges on successful implantation. Implantation begins with the developing embryo approaching the uterine wall, followed by invasion and permeation of maternal sinusoids to establish the future placental circulation [7]. The success of implantation relies on precise synchronization between endometrial and embryological developments [8].

Endometrial development encompasses cellular, immunological, and vascular modifications. These modifications depend on ovarian steroids [9]. The value of endometrial scratch injury (ESI) was first documented in 2003 [10]. ESI refers to a deliberate injury to the endometrium intended to improve its receptivity [11] by altering various cytokines and growth factors, which attract leukocytes and promote vascularity at the implantation site [12]. ESI may also exert its effects through immunological mediation by modulating endometrial genes [13]. A recent meta-analysis assessing the efficacy of ESI in in vitro fertilization (IVF) cycles demonstrated its positive impact on clinical pregnancy rates (CPRs), ongoing pregnancy rates (OPRs), live birth rates (LBRs), and implantation rates in couples undergoing IVF/intracytoplasmic sperm injection (ICSI) cycles [14]. The efficacy of ESI in women undergoing IVF remains uncertain, and even more so for those attempting to conceive through natural cycles or IUI.

This review assessed the evidence regarding the benefits and risks of ESI in infertile couples attempting conception through spontaneous, induction, or IUI cycles.

Methods

The review protocol was prospectively registered with International Prospective Register of Systematic Reviews (PROSPERO) and adheres to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for meta-analyses of randomized controlled trials (RCTs), under registration number CRD42023434127. Every participant provided their permission to be published.

1. Search strategy

Two authors independently conducted searches on MEDLINE, EMBASE, Web of Science, Scopus, the Cochrane Library, and Google Scholar from inception to August 2023. The search terms included ‘endometrial scratch injury,’ ‘implantation,’ ‘infertility,’ ‘natural cycles,’ ‘intrauterine insemination,’ and their corresponding MeSH terms. Additionally, the references cited in all related studies, trial registration sites, theses on related subjects, and presentations (both poster and oral) from major gynecological and reproductive conferences were also reviewed.

2. Study selection

The included studies were RCTs that involved ESI in women seeking conception through non-IVF cycles, whether natural, spontaneous, or following ovulation induction or insemination. All types and intensities of ESI administered at various times during the cycle were considered. Studies excluded from this review were nonrandomized trials, as well as narrative and systematic reviews and trials that included IVF treatment.

3. Data extraction

Data from the included studies were individually extracted by two authors, and any unclear or incomplete data were clarified by contacting the authors directly. The extracted data encompassed the trial location, the number of participants randomized and analyzed, the type of cycle, inclusion and exclusion criteria for participants, details of ESI and its comparator, outcome parameters, and registration details. Specific details about ESI included its timing and intensity. Outcome parameters covered clinical pregnancy, ongoing pregnancy/live birth, multiple pregnancy, ectopic pregnancy, miscarriage rates, and complications such as bleeding and pain.

Clinical pregnancy was defined as the detection of fetal cardiac activity within a gestational sac during an ultrasonography examination 4 weeks after embryo transfer. The OPR was defined as the number of pregnancies exceeding 12 weeks of gestational age. The LBR was defined as the number of live-born fetuses. The multiple pregnancy rate (MPR) was defined as the number of patients with a multifetal pregnancy divided by the total number of clinical pregnancies 4 weeks after embryo transfer. The miscarriage rate was defined as the number of patients who experienced a spontaneous abortion before 12 weeks of pregnancy, divided by the total number of clinical pregnancies.

4. Assessment of risk of bias

The Cochrane recommendations for assessing systematic reviews were employed to evaluate the risk in the included studies. These recommendations include random sequence generation, allocation concealment, blinding of participants and outcome assessors, addressing incomplete outcome data, selective reporting, and other potential biases.

5. Statistical analysis

The effect estimate for dichotomous outcomes was calculated using the odds ratio (OR) and 95% confidence interval (CI), while the effect estimate for continuous data utilized the mean difference and 95% CI. The Mantel-Haenszel method with a random effects model was employed to analyze the effect size. The heterogeneity (I²) of the studies was assessed using the I² statistic. Significant differences were established when the p-value was less than 0.05 or the I² value exceeded 40%. Statistical analyses were performed using Review Manager (RevMan) version 5.4.1 (The Nordic Cochrane Center, Cochrane Collaboration, 2020).

Results

The PRISMA flow chart depicting the search process is illustrated in Figure 1.

1. Study selection and characteristics

The characteristics of the studies included are presented in Table 1. Thirty-two studies (5,897 participants) were included in our systematic review [15-46]. Of these, seven studies (1,094 participants) evaluated ESI in natural cycles [15-21], while 25 studies (4,803 participants) assessed it in IUI cycles [22-46]. Three studies were conducted across two centers [15,24,37], one across six centers [17], one across nine centers [21], and one was a multicenter study [35]; the remaining 26 were single-center studies. Four studies included three arms [22,28,39,42], while the other 28 had only two arms. Thirteen studies were conducted in Egypt [15,16,18,20,25-28,33,37,38,41,45], eight in Iran [19,24,30,32,34,39,44,46], five in India [29,31,36,42,43], two each in three countries (New Zealand, United Kingdom, and Brazil) [17,21], and one study each in Iraq [23], Turkey [40], United Arab Emirates [22], and the United Kingdom [35]. In terms of procedure intensity, ESI was performed with high intensity using a curette or brush in eight trials [16,20,22,26,27,40,45,46], and with mild or moderate intensity using a pipelle or cannula in the remaining 24 trials. The timing of ESI varied: in 14 studies, it was during the follicular phase of the same natural/IUI cycle; in nine studies, during the follicular phase of the preceding cycle; and in 13 studies, during the luteal phase of the preceding cycle. Regarding study registration, only seven studies were prospectively registered, 12 were retrospectively registered, and 13 were not registered at all. The risk of bias is described in Figure 2, and the quality of evidence is presented in Table 2.

2. Synthesis of results

The CPR was evaluated in 32 studies with 5,897 participants (seven natural cycles [1,094 participants] and 25 IUI cycles [4,803 participants]). The results indicated an OR of 2.06, with 1.75 in natural cycles and 2.14 in IUI cycles. The 95% CI ranged from 1.72 to 2.47 overall, with 1.17 to 2.63 in natural cycles and 1.75 to 2.62 in IUI cycles. The p-values were <0.001 overall, 0.007 in natural cycles, and <0.001 in IUI cycles. Study I² was 34% overall, with 32% in natural cycles and 34% in IUI cycles (Figure 3).

The OPR/LBR was assessed in 17 studies involving 3,134 participants. These studies included seven natural cycles with 1,094 participants and 10 IUI cycles with 2,040 participants. The overall OR was 1.80: 2.30 in natural cycles and 1.66 in IUI cycles. The 95% CI ranged from 1.41 to 2.32 overall (1.37–3.87 in natural cycles and 1.25–2.21 in IUI cycles). The p-values were <0.001 overall, 0.002 for natural cycles, and <0.001 for IUI cycles. Study I² was 29% overall, 45% in natural cycles, and 20% in IUI cycles (Figure 4).

The chemical pregnancy rate was evaluated in 16 studies involving 2,854 participants, with four natural cycle groups (537 participants) and 12 IUI groups (2,317 participants). The results indicated an OR of 2.32 (1.91 in natural cycles and 2.48 in IUI cycles). The 95% CI ranged from 1.79 to 3.00 overall (0.98–3.73 in natural cycles and 1.91–3.23 in IUI cycles). The p-values were <0.001 overall, 0.06 in natural cycles, and <0.001 in IUI cycles. Study I² was 40% overall, with 62% in natural cycles and 24% in IUI cycles (Figure 5).

The MPR was evaluated in 13 studies involving 2,456 participants, divided into four natural cycle groups (547 participants) and nine IUI groups (1,909 participants). The analysis revealed an OR of 1.53, with ORs of 2.53 for natural cycles and 1.40 for IUI cycles. The 95% CI ranged from 0.79 to 2.99 overall (0.48–13.73 for natural cycles and 0.67–2.89 for IUI cycles). The p-values were 0.21 overall, 0.27 for natural cycles, and 0.37 for IUI cycles. Study I² was 0% for both natural cycles and IUI cycles (Supplementary Figure 1).

The miscarriage rate was evaluated in 25 trials involving 4,695 participants, including seven trials with natural cycles (1,094 participants) and 18 trials with IUI groups (3,601 participants). The analysis revealed an OR of 1.35 (1.33 in natural cycles and 1.35 in IUI cycles). The 95% CI ranged from 0.96 to 1.88 overall (0.58–3.03 in natural cycles and 0.94–1.94 in IUI cycles). The p-value was 0.08 overall, with values of 0.49 in natural cycles and 0.11 in IUI. Study I² was 0% across all groups (Supplementary Figure 2).

The ectopic pregnancy rate was reported in seven studies involving 999 participants. The results indicated an OR of 2.01 with a 95% CI of 0.58 to 6.90, a p-value of 0.77, and no study I² (0%), as shown in Supplementary Figure 3.

The incidence of bleeding within 24 hours following ESI was assessed in four studies involving 525 participants. The results indicated an OR of 6.84 with a 95% CI ranging from 2.39 to 19.60. The p-value was <0.001, and the study I² was 78% (Supplementary Figure 4).

Pain associated with the procedure was documented in two studies involving 337 participants. The results indicated a mean difference of 2.42, with a 95% CI of 1.25 to 3.60. The p-value was <0.001, and the study I² was 86% (Supplementary Figure 5).

A subgroup analysis of all measured outcomes was conducted based on the type of cycle (natural or IUI), the intensity of ESI (low or high), and the timing of ESI (administered during the follicular phase of the same cycle, during the follicular phase of the preceding cycle, or during the luteal phase of the preceding cycle). The results are presented in Table 3.

Discussion

Numerous systematic reviews have been conducted to assess the value of endometrial scratching before IVF/ICSI cycles. However, only a limited number of reviews have evaluated the value of this procedure in non-IVF cycles.

The pooled evidence from 32 RCTs included in our systematic review indicated that ESI improved the CPR (high evidence), OPR/LBR (moderate evidence), and chemical pregnancy rate (high evidence). ESI was also associated with an increased number of women experiencing bleeding (moderate evidence) and pain (low evidence) within the first 24 hours following the procedure. Overall, the evidence demonstrated that ESI was not linked to significant changes in the rates of multiple pregnancies (high evidence), miscarriages (moderate evidence), or ectopic pregnancies (moderate evidence). The improvement in CPRs was apparent in both natural and IUI cycles, regardless of whether the ESI was mild or intense, and irrespective of the timing of the procedure (during the follicular phase of the same or preceding cycle, or the luteal phase of the preceding cycle). However, the improvement in OPR/LBR was less pronounced with intense ESI and when the procedure was performed during the follicular phase of the same cycle. Additionally, the impact of ESI on chemical pregnancy rates was less noticeable when performed during the follicular phase of the preceding cycle.

Several mechanisms have been proposed to explain the impact of ESI on the endometrium. These mechanisms include differential expression of endometrial genes, recruitment of immune cells to the scratch site, increased expression of co-act proteins involved in endometrial differentiation, and enhanced local endometrial vascularization [12]. The mechanical theory posits that ESI induces a delay in endometrial development, which allows for better synchronization between embryological and endometrial development [47]. According to the wound healing theory, ESI optimizes the decidual environment for embryo implantation [48]. The inflammatory mechanism is supported by a strong correlation between the implantation process and elevated levels of endometrial inflammatory cells and cytokines [49].

This meta-analysis represents the most comprehensive evidence currently available on the efficacy and safety of ESI in infertile women pursuing fertility through non-IVF cycles. We systematically searched for, screened, and selected both published and unpublished RCTs that involved either spontaneous cycles or ovulation induction cycles with timed intercourse or IUI. Each study underwent thorough risk evaluation, data extraction, and risk of bias assessment. We conducted both quantitative and qualitative analyses for all included studies. Additionally, we performed detailed subgroup analyses based on the type of cycles, the intensity of ESI, and the timing of its administration.

The main limitation of this systematic review is the I² of the included studies, particularly in terms of participant and intervention characteristics. Many studies failed to distinguish between OPR and LBR. To address this I², we employed the random effects model and conducted thorough subgroup analyses.

Few reviews have assessed ESI in non-IVF cycles. In 2018, Vitagliano et al. [11] reported that ESI improved both CPR and OPR. However, their review was limited to only eight RCTs and did not evaluate the quality of evidence or conduct a comprehensive subgroup analysis.

In conclusion, we concluded that ESI significantly improves the CPR (high evidence), OPR/LBR (moderate evidence), and chemical pregnancy rate (high evidence). However, the performance of ESI was also associated with a higher incidence of women experiencing bleeding (moderate evidence) and pain (low evidence) within the first 24 hours post-procedure. This procedure offers a cost-effective and relatively safe alternative that should be considered for all women with patent tubes and normal or mild male factors before advancing to more expensive and stressful IVF programs. ESI provides infertile couples, particularly those facing unexplained infertility and limited financial resources, with greater hope compared to repeating natural or IUI cycles.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Author contributions

Conceptualization: NAE, AMM, NB, SIM, AS. Methodology: NAE, AMM. Formal analysis: AMM, AS. Data curation: SIM, AS. Funding acquisition: NAE, AMM, NB, SIM, AS. Project administration: NAE, AMM, NB, SIM, AS. Visualization: NB, SIM. Software: NAE, AMM. Validation: NAE, AMM, NB, SIM, AS. Investigation: NAE, AS. Writing-original draft: NAE, AMM. Writing-review & editing: NAE, AMM, NB, SIM, AS. Approval of final manuscript: NAMEG, AMM, NB, SIM, AS.

Supplementary material

Supplementary material can be found via https://doi.org/10.5653/cerm.2024.07612.

Supplementary Figure 1.

Multiple pregnancy rate. M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

cerm-2024-07612-Supplementary-Fig-1.pdf

Supplementary Figure 2.

Miscarriage rate. M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

cerm-2024-07612-Supplementary-Fig-2.pdf

Supplementary Figure 3.

Ectopic pregnancy rate. M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

cerm-2024-07612-Supplementary-Fig-3.pdf

Supplementary Figure 4.

Bleeding. M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

cerm-2024-07612-Supplementary-Fig-4.pdf

Supplementary Figure 5.

Pain. SD, standard deviation; IV, interval variable; CI, confidence interval.

cerm-2024-07612-Supplementary-Fig-5.pdf

Figure 1.

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram. IUI, intrauterine insemination.

Figure 2.

Risk of bias (A) summary and (B) graph.

Figure 3.

Clinical pregnancy rate. M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

Figure 4.

Ongoing pregnancy and live birth rates. ESI, endometrial scratch injury; M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

Figure 5.

Chemical pregnancy rate. M-H, Mantel-Haenszel; CI, confidence interval; IUI, intrauterine insemination.

Table 1.

Study characteristics

Study	Location	No. of participants	Participants’ characteristics	Intervention	Outcome	Registration
Abdelhamid et al. (2013) [22]	1 Center	150 Randomized	Inclusion criteria:	Intervention group I: preceding cycle day 8–9 endometrial scratch using a Tao brush	CPR	No
	UAE	150 Analyzed	Women with unexplained Infertility between 22 and 35 years of age with adequate ovarian function and fertile semen	Intervention group II: same cycle day 8–9 endometrial scratch using a Tao brush	ChPR
			Exclusion criteria:	Control group: no intervention	MPR
			Women with endometriosis, tubal obstruction (unilateral or bilateral), PID or intracavitary lesion as polyp, synechia or submucous leiomyoma	Ovulation induction by letrozole and α-follitropin and triggering by rhCG, then IUI once followed by luteal phase support with dydrogesterone
Al-Tamemi (2014) [23]	1 Center	73 Analyzed	Inclusion criteria:	Intervention group: pipelle ESI at day 21 of preceding cycle	CPR	No
	Iraq		Age 20–35 years	Control group: no ESI	MPR
			BMI 20–35 kg/m²	COH with CC and/or gonadotropins followed by single IUI
			Unexplained or mild male factor infertility
			Exclusion criteria:
			Indication for IVF
			PID or active vaginal/cervical infection
Ashrafi et al. (2017) [24]	2 Centers	167 Randomized 150 Analyzed	Inclusion criteria:	Intervention group: sterile pipelle ESI was at day 8 or 9	ChPR	Retrospective IRCT201507271141N19
	Iran		Women with unexplained infertility, mild male factor or PCOS, mild male factor, and ≥2 previous IUI failures	Control group B: no intervention.	CPR
			Normal tubes	COH with 50 mg CC twice daily from day 3 to 7 or letrozole 2.5 mg/day, and then 1–2 ampoules of HMG from day 6 to 8. Triggering by hCG when follicle size reached 18 mm; IUI was carried out 36 hours after hCG. 400 mg of natural progesterone daily was given as a luteal phase support	Miscarriage rate
			Exclusion criteria:
			Age >40 years
			BMI 35 kg/m² or more
			Intracavitary lesions
			as submucosal myoma
			Moderate to severe pelvic endometriosis
			Severe male factor infertility, smoking, and/or alcoholism
Bahaa Eldin et al. (2016) [25]	1 Center	349 Randomized	Inclusion criteria:	Intervention group: pipelle catheter ESI on day 5–7 of the same induction cycle followed by single IUI once 34–36 hours after triggering	CPR	Retrospective NCT02542280
	Egypt	344 Analyzed	Women with unexplained or mild male factor infertility underwent IUI, between 20 and 35 years of age and with patent fallopian tubes	Control group: COH cycle followed by IUI once 34–36 hours after triggering without another intervention	ChPR
			Exclusion criteria:	COH with CC and HMG: triggering by 10,000 units of hCG when the leading follicle reached 18 mm
			PID
			Bilateral tubal disease
			Poor ovarian responders
			Severe male factor infertility
			Intracavitary lesion (polyp, synechia, or submucous myoma)
Elkhateeb et al. (2021) [26]	1 Center	136 Randomized	Inclusion criteria	Intervention group: anterior and posterior wall gentle endometrial curettage with sharp curette for 1 minute during luteal phase	Primary:	Prospective PACTR201604001405465
	Egypt	136 Analyzed	Women with unexplained infertility younger than 35 years of age with infertility less than 3 years duration	Control group: no intervention beside the usual laparoscopic procedure	6 months cumulative pregnancy rate
			Investigations revealed semen parameters compatible with fertility, normal hormonal assay, normal pelvic ultrasonography and patent tubes on laparoscopy	All participants were monitored for 3 months.	Secondary:
			Exclusion criteria:		Intervention to pregnancy duration and intervention complications as infection and bleeding)
			Previous trial of ART
El-Khayat et al. (2015) [27]	1 Center	332 Randomized	Inclusion criteria:	Intervention group: grasping forceps with teeth ESI done during office hysteroscopy once in the follicular phase at day 4–7 in the cycle preceding the IUI	Primary:	Retrospective NCT01544426
	Egypt	332 Analyzed	Age younger than 39 years	Control group: office hysteroscopy without ESI	CPR
			BMI <32 kg/m²	Mild COH using oral CC 100 mg/day from cycle day 3 to 7 and intramuscular HMG 75 IU/day from cycle day 6 to 8. When 2–3 follicles reached 18 mm or more, 10,000 IU of intramuscular hCG was used to trigger ovulation. A single IUI was performed 36 hours after triggering, and 30 mg/day of oral dydrogesterone was administered for luteal phase support.	Secondary:
			Infertility unexplained, mild male factor		MPR
			Regular menstrual cycles		Miscarriage rate MPR
			Normal uterine cavity with Bilateral patent tubes		LBR
			Normal basal hormones
			Exclusion criteria: significant neurological, cardiovascular, lung, liver or kidney diseases
			Ovarian cyst of 2 or more cm
			Intracavitary lesion as polyp, submucous fibroid, septum, bicornuate uterus or intrauterine synechia.
Gad (2018) [28]	1 Center	60 Randomized 60 Analyzed	Inclusion criteria:	Intervention group I: preceding cycle day 21 pipelle ESI	CPR	No
	Egypt		Unexplained infertility undergoing IUI	Intervention group II: same cycle day 7 pipelle ESI		Conference abstract
				Control group: no ESI
Ghuman et al. (2020) [30]	1 Center	150 Randomized 150 Analyzed	Inclusion criteria:	Intervention group: same cycle day 6–7 pipelle ESI	Primary:	Prospective CTRI/2018/04/013501
	India		Women with unexplained infertility between 18 and 35 years of age and a BMI less than 30 kg/m²	Control group: no ESI	CPR
			Bilateral patent tubes	COH with CC from cycle day 2 for 5 days. When the antral follicle reached 18 mm or triggering with a 5,000 IU intramuscular HCG injection, then IUI was done after 36–38 hours.	Secondary:
			Normal pelvis evaluated by ultrasound		Endometrial: thickness
			Normal semen analysis		ChPR
			Exclusion criteria:		Miscarriage rate pain score
			Intrauterine procedures within 3 months (endometrial biopsy, curettage, and hysteroscopy) or other treatment for infertility
Gibreel et al. (2013) [15]	2 Centers	105 Randomized	Inclusion criteria:	Intervention group: pipelle ESI on days 21–26 of the spontaneous menstrual cycle	Primary:	Retrospective NCT01412606
	Egypt	105 Analyzed	Women with unexplained infertility of 1 year or more between 20 and 39 years of age	Control group: sham procedure with uterine sound at same time	CPR
			Regular-length (22–34 days) menstrual cycle	All women received oral or rectal 75 mg of diclofenac 30 minutes before the procedure and 100 mg of oral doxycycline twice daily for 5 days after the procedure.	Secondary:
			Ovulation confirmed	Non-hormonal contraception in ESI or sham cycle	MPR
			Normal semen	Couples were advised to have sexual intercourse according to their convenience for the next 6 months.	Miscarriage rate
			Bilateral patent tubes
Gibreel et al. (2020) [16]	1 Center	210 Randomized	Inclusion criteria:	Intervention group: 4 punctures laparoscopic ovarian drilling and sharp endometrial curette was used for ESI	Primary:	Prospective NCT02140398
	Egypt	210 Analyzed	Women with PCOS between 20 and 39 years of age with bilateral patent tubes	Control group same laparoscopic ovarian drilling without ESI	LBR
			Exclusion criteria:	Women with regular cycles and oligomenorrhoea underwent folliculometry and ovulation induction (with CC, tamoxifen, letrozole or gonadotropins) after 3 months respectively. Sexual intercourse either timed or at the couple convenience was tried for 9 months.	Secondary:
			Endometriosis		CPR
			Abnormal uterine cavity		MPR
			Male factor infertility		Miscarriage rate
			Endocrinal disorders as thyroid abnormalities		Time to pregnancy
			Endometrial curettage within 6 months of enrollment
Glanville et al. (2022) [17]	6 Centers New Zealand, UK, and Brazil	117 Randomized 117 Analyzed	Inclusion criteria:	Intervention group A: pipelle endometrial biopsy catheter between cycle days 1 and 12	Primary:	Prospective ACTRN12614000657628
			PCOS	Control group: pipelle endometrial biopsy catheter placed in the posterior fornix without passing through the external os.	LBR
			Age ≤42 years	Couples were instructed to practice regular unprotected intercourse for 3 study cycles.	Secondary:
			BMI ≤35 kg/m²	Ovulation induction medication including letrozole, clomiphene, recombinant FSH, metformin or metformin combinations was permitted.	CPR
			Regular unprotected sexual intercourse and able to have regular sexual intercourse for 3 cycles including procedure one		Ectopic pregnancy
			Normal semen analysis		OPR
			Has 2 ovaries		MPR
			Bilateral patent tubes		Miscarriage rate
			Planning to undergo at least 3 consecutive ovulation induction cycles		Neonatal outcome
			Exclusion criteria		Placental characteristics
			Any uterine instrumentation within 3 months or planned during the study duration		Pain during procedure
			Grade III or IV endometriosis couple planning to have further fertility treatment in following 3 months (e.g., IUI)		Bleeding day after procedure
			Previously enrolled into this study or in another trial within the preceding 30 days
			Contraindication to endometrial biopsy or pregnancy.
			Miscarriage within 12 months
			Recurrent miscarriage
Goel et al. (2017) [29]	1 Center	144 Randomized	Inclusion criteria:	Intervention group: same IUI cycle day 8 Karman’s cannula no. 4 ESI	Primary:	Retrospective CTRI/2015/12/006419
	India	144 Analyzed	Age 21–35 years	Control group: no ESI	CPR
			BMI 18.5–29.9 kg/m²	COH with 50 mg/day CC from cycle day 2 for 5 days and 75 IU HMG on cycle days 6 and 7. Triggering with 5,000 IU hCG when the lading follicle reached 18 mm. IUI was performed after 36 to 38 hours of triggering for 3 cycles along with intercourse at participants' convenience.	Secondary:
			Infertility primary or secondary unexplained or mild male factor	200 mg of micronized progesterone twice daily per vagina was used for luteal phase support with vaginal 200 mg twice a day for 15 days.	Overall conception rate
			Normal baseline hormones (FSH <10 mIU/mL) and thyroid and prolactin hormones		OPR
			Bilateral patent tubes		Miscarriage rate
			No adnexal mass		Ectopic pregnancy
			Exclusion criteria:
			Severe male factor infertility
			Severe endometriosis (stage III/IV)
			Uterine fibroid
			Systematic disease
Gupta et al. (2018) [31]	1 Center	240 Randomized	Inclusion criteria:	Intervention group: pipelle ESI on cycle day 20 to 22 (in 28–30 length cycles) or on postovulatory day 6 to 8 (in prolonged cycles)	Primary:	No
	India	205 Analyzed	Unexplained or mild male factor infertility with previous failed IUI	Control group: no ESI	CPR
			Documented ovulation	COH with gonadotropins then IUI was done. Micronized progesterone was used for luteal support with for 15 days	ChPR
			Minimal endometriosis with patent tubes		Secondary:
			At least one patent tubes		Luteal phase endometrial E-cadherin
			Exclusion criteria:		Luteal phase endometrial IL-6
			Acute PID and/or vaginal infection		Miscarriage rate
			Uterine cavitary lesion as submucous myomas or endometrial polyps		Ectopic pregnancy
Hamdi et al. (2019) [32]	1 Center	150 Randomized	Inclusion criteria:	Intervention group: same cycle day 1–5 pipelle biopsy catheter ESI	CPR	Retrospective IRCT2016110213566N7
	Iran	150 Analyzed	Age less than 35 years	Control group: no ESI	Miscarriage rate
			BMI ≤35 kg/m²	COH with combined CC (100 mg/day) for 5 days and 75 IU FSH for 3 to 5 days, triggering with hCG when the leading follicle reached 18–20 mm. IUI was done 36 hours after triggering followed by 10 mg dydrogesterone for 14 days as luteal phase support.
			Infertility
			Unexplained, mild anovulation, mild male factor, or mild endometriosis
			Exclusion criteria:
			Uterine masses as submucous fibroid
			Endometriosis stage III/IV
			Unilateral blocked tubes
			Severe semen abnormalities
Hamza et al. (2016) [33]	1 Center	150 Randomized 146 Analyzed	Inclusion criteria	Intervention group: 1 minutes pipelle ESI	Primary:	Prospective PACTR201509001264171
	Egypt		Unexplained infertility undergoing IUI	Control group: pressing a piece of gauze on the cervix as a sham procedure.	HS-CRP	Conference abstract
			Exclusion criteria:	IUI once in the following cycle	Endometrial thickness
			Autoimmune diseases		Endometrial-subendometrial vascularization
			Endocrinal disorders		Secondary:
			Hirsutism		CPR
			Endometriosis		Cumulative pregnancy rate
			OHSS
Helmy et al. (2017) [18]	1 Center	110 Randomized	Inclusion criteria:	Intervention group: pipelle catheter ESI on days 15–24 of a spontaneous cycle	Primary:	Retrospective NCT02345837
	Egypt	105 Analyzed	Age 20–35 years	Control group: sham procedure (drying the cervix with gauze for 30 seconds) on same days	CPR
			BMI 19–30 kg/m²	COH with clomiphene citrate from days 3–5 of next cycle for 5 days. Triggering with 10,000 IU hCG when at least one follicle reached 18 mm or more.	MPR
			Unexplained primary or secondary infertility	36 hours after hCG, timed intercourse was tried.	Miscarriage rate
			Day 2 FSH <12 IU/L		Secondary:
			Normal thyroid and prolactin hormones		ChPR
			Normal uterine cavity		OPR
			Unilateral or bilateral patent tube		LBR
			Normal semen analysis		Ectopic pregnancy
			Exclusion criteria:
			Hypogonadism secondary to low gonadotropins
			CC resistance for 3 cycles
			Intracavitary uterine lesions as (fibroid, polyp, or synechia)
			Previous IUI and/or IVF failure
Jafarabad et al. (2020) [34]	1 Center	120 Randomized	Inclusion criteria:	Intervention group: a vaginal cannula no. 4, ESI on cycle day 3	Primary:	Retrospective IRCT20180624040214N1
	Iran	118 Analyzed	Women with primary or secondary unexplained infertility between 21 and 35 years of age with a BMI between 18 and 30 kg/m²; normal basal hormones (FSH <10 IU/L), prolactin, and thyroid hormones	Control group: no ESI	CPR
			Normal menstrual cycle between 25 and 31 days	COH with 2.5 mg letrozole twice daily from cycle day 3 for 5 days. hCG triggering ovulation was performed when at least 1 follicle reached 18 mm. IUI was done once 36 to 38 hours after triggering.	ChPR
			Exclusion criteria:	400 mg of vaginal progesterone every 12 hours was used as a luteal phase support sexual intercourse was allowed.	Secondary:
			Adnexal masses		Miscarriage rate
			Uterine fibroid		Ectopic pregnancy
			Systemic disease
Kandavel et al. (2018) [35]	Multicenter UK	109 Randomized 109 Analyzed	Inclusion criteria:	Intervention group: Wallace catheter, luteal phase endometrial scratch	Primary:	Retrospective NCT02681627
			Age 18–40 years	Control group: saline moist cotton swab cleaning of the cervix	LBR
			Women trying to conceive who signed an informed written consent	A self-assessment questionnaire was supplied to all participants at the day of randomization to be returned after completion within 4 weeks.	Secondary:
			Exclusion criteria:	This questionnaire included a quantitative assessment of pain and bleeding with empty space to provide any special comments.	Miscarriage rate
			Medical disorders as hypertension, diabetes, thyroid diseases, or thrombophilia		Pregnancy complications
			Intolerant to internal pelvic examinations		Acceptability of the intervention
			Uterine abnormalities
			Previous enrollment in the study
Madhuri et al. (2022) [36]	1 center India	168 Randomized	Inclusion criteria:	Intervention group: day 8, 9 pipelle scratch through a cannula	Primary:	Prospective
		162 Analyzed	Women with unexplained or mild male factor infertility between 25 and 35 years of age	Control group: no intervention	CPR	CTRI/2017/10/010056
			Exclusion criteria:	COH by combined CC and gonadotropins and IUI for 3 cycles	Secondary:
			Bilateral tubal block.		Size of dominant follicle
			Unruptured follicle syndrome		Endometrial thickness at triggering
			Endometriosis		LBR
			Donor sperm cycles		Pain
			Improper semen preparation		Bleeding
			Allergy to the used drugs
Maged et al. (2016) [37]	2 Centers	154 Randomized	Inclusion criteria:	Intervention group: neonatal feeding tube no. 8 ESI on the day of triggering during first IUI cycle	Primary:	Retrospective NCT02349750
	Egypt	154 Analyzed	Age less than 40 years	Control group: no ESI	CPR
			BMI <35 kg/m²	COH with 100 mg of CC from day 3 of spontaneous cycle for 5 days, followed by 150 IU of HMG daily till 2 follicles reached 17 mm when triggering with 5,000 of IU hCG followed by IUI 24 to 36 hours after triggering for 3 cycles.	Secondary:
			Unexplained infertility		MPR
			Normal semen		Miscarriage rate
			One or 2 patent tubes		Ectopic pregnancy
			Normal FSH (<12 mIU/mL)
			Exclusion criteria:
			Intracavitary uterine lesions
			Pelvic abnormalities
			Ovarian cyst
			Grade III/IV endometriosis
			PCOS
			Ovulatory disorders
			Hyperandrogenism
Mahran et al. (2015) [38]	1 Center Egypt	200 Randomized 200 Analyzed	Inclusion criteria:	Intervention group: pipelle endometrial endosampler injury done once on day 21 of the preceding cycle.	CPR	No
			Unexplained infertility	Control group: no intervention
			Planned to have IUI
Mardanian et al. (2018) [39]	1 Center	180 Randomized 178 Analyzed	Inclusion criteria:	Intervention group I: day 8 preceding cycle tube feeding ESI	ChPR	No
	Iran		Age between 18 and 40 years;	Intervention group II: day 8 or 9 same cycle tube feeding ESI	Miscarriage rate
			unexplained infertility (primary: or secondary)	Control group: no ESI
			Presence of 1 to 3 follicles (18–20 mm) during IUI injection	COH with 100 mg/day of CC from cycle day 5 for 5 days and 100 IU of HMG from cycle day 8. Triggering of ovulation with 10,000 IU of hCG when the leading follicles reached >18 mm. IUI was done 36 hours after triggering once.
			Normal hormones (FSH, LH, prolactin, and TSH)
			Normal semen
			Normal patent tubes
			Exclusion criteria:
			Autoimmune or endocrinal disorders
			Liver or blood diseases
			PID
			Hirsutism
			Alcohol abuse or smoking
			PID
			Endometriosis
			Pelvic adhesion
			Uterine fibroid
Parsanezhad et al. (2013) [19]	1 Center	234 Randomized	Inclusion criteria:	Intervention group: pipelle ESI with endometrial sampling in the posterior uterine wall on the preovulatory day.	CPR	Retrospective IRCT2012082510657N1
	Iran	217 Analyzed	Age between 23 and 35 years	Control group: a mock pipelle catheter without passing through inner cervical os or uterine manipulation.	Miscarriage rate
			BMI 18–25 kg/m² unexplained infertility for 2–5 years	COH by 100 mg/day of oral CC from cycle day 3 for 5 days and 75 IU/day of intramuscular HMG from cycle day 6 to 8. The LH surge was checked twice daily when the dominant follicles reached 18 mm.	OPR
			Normal ovarian reserve (antral follicle count 10–12 follicles, anti-Müllerian hormone >1 ng/L; FSH <10 lU/L)	Three cycles of timed intercourse every other day after the LH surge for 8 days.
			Normal semen
			Used only CC for the past 3 months
			Exclusion criteria:
			Painters or factory workers males
			Smoking/alcohol abuse
Senocak et al. (2017) [40]	1 Center	80 Randomized	Inclusion criteria:	Intervention group: posterior wall Novak curette ESI on cycle days 21–25 of the preceding cycle	CPR	No
	Turkey	80 Analyzed	Age between 19 and 35 years	Control group: no ESI	ChPR
			Unexplained infertility	COH with gonadotropins. When a dominant follicle reached >18 mm triggering with hCG and IUI was performed once after 36 hours.
			Normal BMI
			Normal pelvic ultrasound
			Normal hormones (basal FSH <10 IU/L, LH, prolactin, estradiol, and TSH)
			Patent tubes
			Normal semen analysis
			Exclusion criteria:
			Endocrinal or systemic disorders
			Uterine abnormalities as submucous fibroid, endometrial polyp, septate uterus or uterine anomalies
Shokeir et al. (2016) [20]	1 Center	122 Randomized	Inclusion criteria	Intervention group: a claw forceps was used to induce a single site-specific (midline upper posterior endometrium) ESI during office hysteroscopy between cycle days 4 and 7.	Primary:	No
	Egypt	120 Analyzed	Age between 18 and 39 years	Control group: no ESI	CPR
			Unexplained infertility	Three cycles of natural cycle with folliculometry. When the leading follicle reached 16 mm or more, triggering of ovulation with 10,000 IU of hCG was done and timed sexual intercourse was carried out for 3 cycles.	Secondary:
			Patent tubes		Miscarriage rate
			Fertile semen
			Regularly ovulating
			Normal pelvic anatomy
			Exclusion criteria:
			Irregular menstrual cycles
			Ovarian cyst
			Pelvic endometriosis
			Uterine myoma
			Participants were asked to stop any ovarian stimulation drugs before enrollment.
Soliman et al. (2017) [41]	1 Center	226 Randomized	Inclusion criteria:	Intervention group: an embryo mucus aspiration catheter ESI on day 7 of IUI cycle	ChPR	No
	Egypt	212 Analyzed	Women with unexplained or mild male factor infertility between 19 and 37 years of age	Control group: no ESI	CPR
			Normal baseline hormones (FSH and LH 3–10 and 1.8–8.5 mIU/mL, respectively)	COH with CC 100 mg/day from cycle day 2 to 7 and 75 IU/day HMG from cycle day 7 until the dominant follicle reached 17 mm or more and the endometrial thickness reached at least 8 mm with tripleline appearance then triggering of ovulation by 10,000 IU hCG.	Miscarriage rate
			Normal uterine cavity	Single IUI was done 36 hours after triggering.	OPR
			Normal ovulation	400 mg vaginal progesterone was administered as a luteal phase support for 14 days.
			Bilateral patent tubes
			Exclusion criteria:
			Unilateral tubal block
			Previous OHSS
			Poor ovarian responders
			Endometriosis
			Multifactorial infertility
Wadhwa et al. (2015) [42]	1 Center	251 Analyzed	Inclusion criteria:	Intervention group A: endometrial aspiration cannula ESI between day 19 and day 24 of the spontaneous preceding cycle	Primary:	Retrospective CTRI/2012/12/004356
	India		Age between 18 and 38 years	Intervention group B: endometrial aspiration cannula ESI before day 6 of the IUI cycle	CPR
			Primary: or secondary infertility planning for COH and IUI	Control group: no ESI.	Secondary:
			Unilateral or bilateral patent tubes	IUI was done once after 36 hours after hCG triggering or 24 hours after LH surge and sexual intercourse	MPR
			Exclusion criteria:		Miscarriage rate
			PID or acute vaginal/cervical infection
			Severe male factor with Intracavitary lesion (submucosal myoma, polyp, or adhesions)
Wadhwa et al. (2018) [43]	1 Center	165 Randomized	Inclusion criteria:	Intervention group I: same cycle early follicular (between days 2 and 4) endometrial aspiration cannula ESI.	Primary:	Retrospective CTRI/2017/09/009649
	India	165 analyzed	Age between 20 and 38 years	Intervention group II: same cycle late follicular (between days 7 and 9) endometrial aspiration cannula ESI	CPR
			Primary: or secondary infertility	Control group: no ESI	Secondary:
			≥2 failed cycles of COH	Ovulation triggering after the leading follicle reached between 18 and 20 mm followed by IUI and luteal phase support for 3 cycles.	Miscarriage rate
			Unilateral or bilateral patent tubes		MPR
			No ESI during the previous 3 COH cycles		Pain
			Exclusion criteria:
			PID or acute vaginal/cervical infection
			Bilateral tubal block
			Uterine abnormalities as submucosal myoma, endometrial polyp, intrauterine adhesions, bicornuate, and septate uterus)
			Endometriosis
			Hydrosalpinx
Wong et al. (2022) [21]	9 Centers New Zealand, UK, and Brazil	220 Randomized	Inclusion criteria:	Intervention group A: pipelle endometrial biopsy catheter between cycle days 1 and 12	Primary:	ACTRN12614000656639
		220 Analyzed	Age ≤42 years	Control group: pipelle endometrial biopsy catheter placed in the posterior fornix without passing through the external os.	LBR
			BMI ≤35 kg/m²	Regular unprotected sexual intercourse for 3 cycles	Secondary:
			Unexplained infertility despite regular unprotected sexual intercourse, and sexual intercourse is feasible for 3 cycles including the one during the procedure.		CPR
			Has 2 ovaries		Ectopic pregnancy
			Bilateral patent tubes		OPR
			Exclusion criteria:		MPR
			Any uterine		Miscarriage rate
			Instrumentation within 3 months		Neonatal outcome
			Previously enrolled in this study or in another trial within the last month		Placental characteristics
			Pregnancy or other contraindication to endometrial biopsy		Pain during procedure
			Grade III or IV endometriosis miscarriage within 12 months		Bleeding day after procedure
			Recurrent miscarriage
			Women taking or planning any fertility treatment during the study cycles
Yavangi et al. (2021) [44]	1 Center Iran	150 Randomized 150 Analyzed	Inclusion criteria:	Intervention group: pipelle endometrial biopsy catheter between cycle days 19 and 21 in four directions (12–6–9–12 hours)	ChPR	Not found; the authors mentioned registration by searching the site the trial was not found
			Age between 18 and 40 years	Control group: no intervention	CPR
			Infertile couples	CC and HMG were used for ovulation induction before IUI.	Endometrial thickness
			BMI 18–30 kg/m²
			Normal menstrual pattern
			Normal fallopian tube
			Exclusion criteria:
			Hirsutism
			Autoimmune disorders
			Endocrine diseases
			Smoking and alcohol intake
Zakaria et al. (2018) [45]	1 Center Egypt	200 Randomized 200 Analyzed	Inclusion criteria:	Intervention group: ESI was done by using grasping forceps with teeth through hysteroscopy at cycle days 21–26 using	CPR	No
			Mild male factor infertility.	Control group: hysteroscopy without ESI	ChPR
			Unexplained infertility.	Mild controlled ovarian stimulation protocol.
			Age <39 years	IUI was done 36 hours after hCG triggering.
			BMI less than 32 kg/m²
			Regular menstrual cycles
			Normal thin endometrium without intracavitary lesion
			Normal fallopian tubes
			Normal hormonal profile
			Abnormal semen parameters
			Exclusion criteria:
			Other causes of infertility
			Significant medical disorders as cardiovascular, neurologic, pulmonary, hepatic, or renal diseases
			Ovarian cyst larger than 2 cm before COH
Zarei et al. (2013) [46]	1 Center	146 Randomized	Inclusion criteria:	Intervention group: preceding cycle day 6–8 Novak curette biopsy catheter ESI	CPR	Retrospective IRCT2012070810210N1
	Iran	144 Analyzed	Women with unexplained, mild male factor, or mild endometriosis-linked infertility between 18 and 40 years of age	Control group: no ESI	Miscarriage rate
			Normal basal hormones (D3, FSH, and LH)	COH with 100 mg of CC daily from cycle day 5 for 5 days and 100 IU of recombinant FSH daily from day 8. Triggering with 10,000 IU of hCG when the leading follicle reached 18 mm.	MPR
			Normal liver, kidney and blood picture tests	IUI was done 36 hours after triggering for 3 cycles	OPR
			Patent tubes		Endometrial thickness
			Non-pregnant		No. of follicles >18 mm
			Exclusion criteria:
			Hirsutism
			Autoimmune and endocrinal abnormalities
			OHSS
			Smokers or alcohol abuser (either partner)

PID, pelvic inflammatory disease; rhCG, recombinant human chorionic gonadotropin; IUI, intrauterine insemination; CPR, clinical pregnancy rate; ChPR, chemical pregnancy rate; MPR, multiple pregnancy rate; BMI, body mass index; IVF, in vitro fertilization; ESI, endometrial scratching injury; COH, controlled ovarian hyperstimulation; CC, clomiphene citrate; PCOS, polycystic ovarian syndrome; HMG, human menopausal gonadotropin; hCG, human chorionic gonadotropin; ART, assisted reproductive technology; LBR, live birth rate; os, ostium; OPR, ongoing pregnancy rate; FSH, follicle-stimulating hormone; IL-6, interleukin-6; OHSS, ovarian hyperstimulation syndrome; HS-CRP, high-sensitivity C-reactive protein; LH, luteinizing hormone; TSH, thyroid-stimulating hormone;.

Table 2.

GRADE 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	32	N	N	N	5,897	N	N	High
Ongoing pregnancy/live birth rate	17	N	S	N	3,134	N	N	Moderate
Chemical pregnancy rate	16	N	N	N	2,854	N	N	High
Multiple pregnancy rate	13	N	N	N	2,456	N	N	High
Miscarriage rate	25	N	N	N	4,695	S	N	Moderate
Ectopic pregnancy rate	7	N	N	N	999	S	N	Moderate
Bleeding	4	N	N	N	525	S	N	Moderate
Pain	2	N	N	N	337	N	N	Low

GRADE, Grading of Recommendations Assessment, Development and Evaluation; CI, confidence interval; N, not serious; S, serious.

Table 3.

Subgroup analysis of outcome parameters

	Outcome	Subgroup	No. of studies	No. of participants	Effect estimate OR (95% CI)	p-value	Heterogeneity I², %
Clinical pregnancy rate		Total	32	5,897	2.06 (1.72–2.47)	<0.001	34
	Type of cycle	Natural	7	1,094	1.75 (1.17–2.63)	0.007	32
	Type of cycle	IUI	25	4,803	2.14 (1.75–2.62)	<0.001	34
	Intensity of scratch	Mild/moderate	24	4,388	2.13 (1.74–2.60)	<0.001	26
	Intensity of scratch	Hard	8	1,509	1.96 (1.31–2.94)	0.001	52
	Time of scratch	Follicular phase of same cycle	14	2,231	2.19 (1.73–2.78)	<0.001	0
		Follicular phase of preceding cycle	9	1,665	1.38 (1.06–1.80)	0.02	0
		Luteal phase of preceding cycle	13	2,001	2.67 (1.92–3.71)	<0.001	44
Ongoing pregnancy rate/live birth rate		Total	17	3,134	1.80 (1.41–2.32)	<0.001	29
	Type of cycle	Natural	7	1,094	2.30 (1.37–3.87)	0.002	45
	Type of cycle	IUI	10	2,040	1.66 (1.25–2.21)	<0.001	20
	Intensity of scratch	Mild/moderate	13	2,241	1.80 (1.33–2.44)	<0.001	37
	Intensity of scratch	Hard	4	893	1.33 (0.92–1.93)	0.13	0
	Time of scratch	Follicular phase of same cycle	8	1,327	1.83 (1.26–2.64)	0.001	28
		Follicular phase of preceding cycle	5	1,096	1.29 (0.92–1.82)	0.14	2
		Luteal phase of preceding cycle	4	480	2.21 (1.12–4.37)	0.02	49
Chemical pregnancy rate		Total	16	2,854	2.32 (1.79–3.00)	<0.001	40
	Type of cycle	Natural	4	537	1.91 (0.98–3.73)	0.06	62
	Type of cycle	IUI	12	2,317	2.48 (1.91–3.23)	<0.001	24
	Intensity of scratch	Mild/moderate	12	2,164	2.35 (1.72–3.22)	<0.001	40
	Intensity of scratch	Hard	4	690	2.27 (1.37–3.78)	0.002	49
	Time of scratch	Follicular phase of same cycle	6	1,100	2.63 (1.60–4.33)	<0.001	49
		Follicular phase of preceding cycle	4	545	1.38 (0.94–2.02)	0.10	3
		Luteal phase of preceding cycle	7	1,209	2.82 (2.06–3.85)	<0.001	0
Multiple pregnancy rate		Total	13	2,456	1.53 (0.79–2.99)	0.21	0
	Type of cycle	Natural	4	547	2.53 (0.48–13.32)	0.27	0
	Type of cycle	IUI	9	1,909	1.40 (0.67–2.89)	0.37	0
	Intensity of scratch	Mild/moderate	10	1,693	1.81 (0.78–4.16)	0.16	0
	Intensity of scratch	Hard	3	763	1.15 (0.38–3.48)	0.80	0
	Time of scratch	Follicular phase of same cycle	5	789	1.52 (0.39–5.98)	0.55	0
		Follicular phase of preceding cycle	5	1,000	1.15 (0.36–3.66)	0.81	0
		Luteal phase of preceding cycle	5	667	1.92 (0.70–5.29)	0.21	0
Miscarriage rate		Total	25	4,695	1.35 (0.96–1.88)	0.08	0
	Type of cycle	Natural	7	1,094	1.33 (0.58–3.03)	0.49	0
	Type of cycle	IUI	18	3,601	1.35 (0.94–1.94)	0.11	0
	Intensity of scratch	Mild/moderate	19	3,578	1.57 (1.08–2.30)	0.02	0
	Intensity of scratch	Hard	5	973	0.74 (0.36–1.51)	0.41	0
	Time of scratch	Follicular phase of same cycle	12	2,091	1.84 (1.06–3.20)	0.03	0
		Follicular phase of preceding cycle	8	1,565	0.87 (0.44–1.72)	0.69	0
		Luteal phase of preceding cycle	7	1,039	1.31 (0.77–2.23)	0.33	0
Ectopic pregnancy		Total	7	999	2.01 (0.58–6.90)	0.77	0
	Type of cycle	Natural	3	442	3.10 (0.12–77.78)	0.49	NA
	Type of cycle	IUI	4	557	1.86 (0.49–7.09)	0.36	0
	Time of scratch	Follicular phase of same cycle	3	448	1.68 (0.39–7.33)	0.49	0
		Follicular phase of preceding cycle	2	337	3.10 (0.12–77.78)	0.69	NA
		Luteal phase of preceding cycle	2	214	3.00 (0.12–75.28)	0.67	NA
Bleeding		Total	4	525	6.84 (2.39–19.60)	<0.001	78
	Type of cycle	Natural	2	337	4.68 (1.46–15.01)	0.01	81
	Type of cycle	IUI	2	188	18.90 (5.49–65.06)	<0.001	NA
	Time of scratch	Follicular phase of preceding cycle	3	457	4.68 (1.46–15.01)	0.010	81
	Time of scratch	Luteal phase of preceding cycle	1	68	18.90 (5.49–65.06)	<0.001	NA

Natural cycles depend on regular intercourse with or without ovulation induction. IUI cycles involved semen processing, followed by intrauterine injection of the processed semen through a cannula passing through the cervix. Mild/moderate intensity involved scratching using a pipelle or cannula. High intensity involved using a curette or brush.

OR, odds ratio; CI, confidence interval; IUI, intrauterine insemination; NA, not applicable.

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