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

Endometrial injury and non-IVF cycles

Article information

Korean J Fertil Steril. 2025;.cerm.2024.07612
Publication date (electronic) : 2025 July 10
doi : https://doi.org/10.5653/cerm.2024.07612
Nour A.M. El-Goly1orcid_icon, Ahmed M. Maged,2orcid_icon, 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 2024 October 17; Revised 2024 November 28; Accepted 2024 December 17.

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 We included all published and unpublished randomized controlled trials involving ESI in women undergoing either natural or IUI cycles.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.

Figure 1.

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

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.

Study characteristics

Figure 2.

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

GRADE quality of evidence

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).

Figure 3.

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

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).

Figure 4.

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

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).

Figure 5.

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

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.

Subgroup analysis of outcome parameters

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.

Notes

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

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43. Wadhwa L, Mishra M. Therapeutic efficacy of endometrial scratching in repeated controlled ovarian stimulation (COS) failure cycles. J Hum Reprod Sci 2018;11:59–71. 10.4103/jhrs.jhrs_130_17. 29681718.
44. Yavangi M, Varmaghani N, Pirdehghan A, Varmaghani M, Faryadras M. Comparison of pregnancy outcome in intrauterine insemination-candidate women with and without endometrial scratch injury: an RCT. Int J Reprod Biomed 2021;19:457–64. 10.18502/ijrm.v19i5.9255. 34278199.
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Article information Continued

© 2025. THE KOREAN SOCIETY FOR REPRODUCTIVE MEDICINE

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.

Figure 1.

Figure 1.

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

Figure 2.

Figure 2.

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

Figure 3.

Figure 3.

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

Figure 4.

Figure 4.

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

Figure 5.

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
Sample size Wide CI
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
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
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
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
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
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
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
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
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
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
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
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
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
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.