• assisted reproductive techniques;
  • embryo transfer;
  • endometrial injury;
  • endometrial perturbation;
  • endometrium


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To investigate the effect of endometrial scratching, performed during oral contraceptive pill (OCP) pretreatment, on reproductive outcome and on ultrasound markers of endometrial receptivity, and to assess the pain involved in the procedure, in unselected women undergoing assisted reproductive techniques (ART).


Women undergoing ART were randomly allocated to undergo either endometrial scratching with a pipelle de Cornier or a sham procedure, 7–14 days before starting controlled ovarian stimulation (COS). We evaluated subsequent rates of clinical pregnancy, live birth, implantation, miscarriage and multiple pregnancy. Pain during the procedure was evaluated using a 10-cm visual analog scale. Endometrial thickness and volume and three-dimensional power Doppler (3D-PD) indices (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) were assessed during COS when there was at least one follicle ≥ 17 mm in diameter.


We included 158 women. Endometrial scratching was associated with higher rates of live birth (41.8% vs 22.8%, P = 0.01) and clinical pregnancy (49.4% vs 29.1%, P = 0.01) and higher pain score (6.42 ± 2.35 cm vs 1.82 ± 1.52 cm, P < 0.001), endometrial VI (3.71 ± 1.77 vs 2.95 ± 1.56, P < 0.01) and VFI (0.97 ± 0.51 vs 0.76 ± 0.40, P < 0.01). There was no significant effect of endometrial scratching on rate of miscarriage (15.4% vs 21.7%, P = 0.53) or multiple pregnancy (22.5% vs 25.0%, P = 0.79), or on endometrial thickness (10.12 ± 1.55 mm vs 9.98 ± 1.62 mm, P = 0.59), endometrial volume (6.18 ± 1.63 cm3 vs 6.01 ± 1.48 cm3, P = 0.51) or FI (26.12 ± 2.82 vs 25.91 ± 2.72, P = 0.65).


Endometrial scratching performed once, during OCP pretreatment 7–14 days before starting COS, increases the chance of live birth and clinical pregnancy, but might cause considerable pain. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.


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Assisted reproductive techniques (ART) are used widely to treat fertility problems, which affect approximately 7–15% of women of reproductive age[1]. Although there have been several improvements in techniques during the last three decades[2, 3], clinical pregnancy and live-birth rates remain at approximately 30–40% and 20–30%, respectively[4, 5]. Increasing these rates is desirable for couples undergoing ART, as treatment failure is a source of psychological distress[6], and the most common cause of drop-out before achieving pregnancy[7]. The most common interventions to improve ART outcome are the use of maximized controlled ovarian stimulation (COS), transference of multiple embryos into the uterus and cryopreservation of surplus oocytes/embryos. However, the first two of these interventions might increase the risk of ovarian hyperstimulation syndrome and multiple pregnancy[8, 9], and there are ethical and financial concerns regarding oocyte/embryo cryopreservation[10, 11].

Endometrial scratching (or injury) is defined as intentional damage to the endometrium, such as by biopsy or curettage[12]. A link between endometrial scratching and increased chance of pregnancy in subsequent ART procedures was first described a decade ago[13]. Although the underlying mechanism remains unknown, hypotheses include: (1) that endometrial scratching during the previous cycle might induce decidualization, increasing the chance of implantation[14, 15]; (2) that it induces a significant increase in the secretion of cytokines, interleukins, growth factors, macrophages and dendritic cells, all of which might be beneficial to embryo implantation[16]; and (3) that endometrial scratching might lead to better synchronicity between the endometrium and the transferred embryo[14].

In order to evaluate properly the effect of endometrial scratching, one should compare the main reproductive outcomes (live birth, clinical pregnancy, miscarriage) in women who received this intervention before undergoing ART with those in women who did not. This comparison was performed in previous studies[17-20], which observed that endometrial scratching improved the main reproductive outcomes[21]. However, these previous studies did not assess the side effects, the most important of these being pain during the procedure: information that is important for infertile couples and their care providers. Another interesting point is that all of the previous trials performed endometrial scratching in women who were not using oral contraceptive pills (OCP). OCPs are a frequently used pretreatment in fertility centers as this allows greater flexibility to start COS, and can be used to optimize oocyte retrieval during weekdays[22]. Additionally, performing endometrial scratching during OCP pretreatment might be considered safer, as it reduces the risk of damaging an early pregnancy. Lastly, it would be interesting to provide further insight into the biological mechanism of action of this intervention by assessing the results of ultrasound evaluation of endometrial receptivity, particularly three-dimensional power Doppler (3D-PD) evaluation of the endometrium, which is considered as a non-invasive marker of endometrial receptivity[23-25].

Our objectives were to investigate the effect of endometrial scratching, performed once during OCP pre-treatment, on reproductive outcome, pain and ultrasound markers of endometrial receptivity, in unselected women undergoing ART procedures.


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Study design and participants

This was a parallel randomized controlled trial (RCT), in a 1:1 ratio, approved by the local institutional ethics committee. We assessed all women undergoing ART at the fertility clinic of the university hospital of the Medical School of Ribeirao Preto, University of Sao Paulo, Brazil. Women aged < 38 years who would be submitted to COS, oocyte retrieval and embryo transfer were considered eligible. Those who agreed to participate and gave written informed consent were included. We tried to follow the intention-to-treat (ITT) principle as far as possible.


For each woman an appointment was scheduled 7–14 days before the planned start of COS. All women had been using the OCP (ethinyl estradiol 30 mcg + levonorgestrel 150 mcg) since their last menstruation, for at least 10 days before the appointment. On the scheduled day, the participants were prepared for a gynecological examination and the uterine cervix was identified using a vaginal speculum. Only then was the sealed allocation envelope opened.

In the intervention group, endometrial biopsy was performed once with a pipelle de Cornier® (Laboratoires Prodimed, Neully-En-Thelle, France). The pipelle was introduced gently through the cervix up to the uterine fundus. The piston was then drawn back to the end of the biopsy cannula until it self-locked, creating a negative pressure. Aiming to cover the entire endometrium, the examiner applied regular back-and-forth movements (2–4 cm) while rotating the sampler, over the whole uterine cavity, during a period of 30 s. In those cases in which the pipelle suction orifice was clogged before the 30-s period had ended, we restarted the procedure using another pipelle and counted another 30 s. The obtained specimens were discarded. The control group was submitted to a sham procedure comprising drying of the cervix with gauze for 30 s. All procedures were performed by the same physician (W.P.M.). Thus, all women, regardless of intervention, underwent a gynecological examination comprising speculum examination and manipulation of the cervix for 30 s. The difference was only in the type of uterine manipulation: endometrial biopsy in the intervention group, and drying of the cervix with gauze in the control group. In both groups a visual analog scale (a 10-cm horizontal line anchored at one end with the words ‘no pain’ and at the other end with the words ‘worst pain imaginable’[26]) was given to participants just after the procedure. They were asked to mark a point on this scale that would represent the pain associated with the procedure. The marked point was measured using a ruler by another researcher (C.O.N.).

On the planned COS start day (day 2–3 of the menstrual cycle), women underwent transvaginal ultrasound examination; COS was started only if no follicle ≥ 10 mm in diameter was observed or if estradiol levels were < 50 pg/mL in the presence of a follicle ≥ 10 mm. At the discretion of the physicians and participants, one of three different regimens was selected to induce COS: a) clomiphene citrate (CC) (Indux™, EMS, Hortolandia, Brazil, 100 mg/day for 5 days) + human menopausal gonadotropin (hMG) (Menopur™, Laboratórios Ferring Ltda, São Paulo, Brazil, 150 IU/day, every other day when using CC, and every day after CC was stopped) + gonadotropin-releasing hormone (GnRH) antagonists (Ganirelix (Orgalutran™), MSD Brasil, Sao Paulo, Brazil, 0.25 mg/day, started when a follicle ≥ 14 mm was observed); b) recombinant FSH (Puregon™, MSD Brasil, Sao Paulo, Brazil or Gonal™, Serono Produtos Farmaceuticos Ltda, São Paulo, Brazil, 150–300 IU/day) + GnRH antagonist (Ganirelix, 0.25 mg/day, started when a follicle ≥ 14 mm was observed); or c) recombinant FSH (150–300 IU/day) + GnRH agonist (leuprolide acetate (Lupron™), Abbott Laboratórios do Brasil Ltda, Rio de Janeiro, Brazil, 0.5 mg/day, started 5 days before stopping OCP).

Transvaginal ultrasound monitoring of follicle development was scheduled to start after 5 days of COS, repeating every other day. 3D-PD ultrasound examination was performed when we observed at least one follicle ≥ 17 mm. Final follicular maturation was triggered on this day or 1 day later, using recombinant human chorionic gonadotropin (hCG, 0.25 mg, single injection) between 22:00 and 23:00 hours. Oocyte retrieval was performed 34–36 h after the recombinant hCG injection.

All 3D-PD ultrasound examinations were performed using either a Voluson 730 or a Voluson E8 (GE Healthcare Austria GmbH & Co, Zipf, Austria) ultrasound machine equipped with a vaginal probe. They were conducted by a single observer (W.P.M.), using a standardized technique: briefly, the uterus was located and power Doppler ultrasound was applied using predetermined settings which were kept constant throughout the study (two-dimensional settings: THI, CRI and SRI, turned off; main power Doppler settings: Filter, low1; PRF, 0.6KHz; gain, 0.0; Quality, normal; Sub power Doppler settings: Freq, mid; Flow res, mid1; Smooth, 5/6; Ensemble, 12; Line Den, 7; PD map, 5 (Gently Color, on); Balance, G > 200; Artifact, on; L. Filter, 2). The resulting truncated sector was adjusted and moved to cover the endometrium in the longitudinal plane of the uterus. The woman was asked to breathe gently and to remain as still as possible and every effort was made by the observer to limit inappropriate movements of the transducer. A 3D-PD dataset of the uterus was then acquired using a sweep angle of 90° (‘high 1’ sweep mode) in order to acquire the entire endometrium[24]. The 3D-PD datasets were saved to the hard drive of the ultrasound machine and were analyzed by the same observer (W.P.M.) using 4D View and Virtual Organ Computer-aided AnaLysis (VOCAL, GE Medical Systems, Zipf, Austria). Endometrial thickness was measured after the dataset had been manipulated to produce a standardized multiplanar view of the uterus[27]. The endometrium was then defined using a 15° rotation step in this view, and its volume was calculated by the software. The volume was analyzed using the ‘color-off’ mode, which facilitates morphological visualization by removing Doppler signals from the display[28]. 3D-PD data within the endometrium were quantified using the histogram facility to generate values for the vascularization index (VI), flow index (FI) and vascularization flow index (VFI).

One to three embryos were transferred 48–72 h after oocyte retrieval. The luteal phase was supported by the administration of micronized progesterone (600 mg/day), which was stopped if the pregnancy test (serum β-hCG test performed 14 days after embryo transfer) was negative or after week 12 of pregnancy.


The main outcome was clinical pregnancy per allocated woman, defined as the presence of at least one fetus with heart beat. Secondary outcomes were live birth (at least one liveborn baby) per allocated woman; multiple pregnancy (presence of more than one fetus with heart beat) per clinical pregnancy; spontaneous miscarriage (loss of a clinical pregnancy before 20 completed weeks of gestation) per clinical pregnancy; and pain during the procedure. Additionally, we examined the endometrial thickness, volume and 3D-PD indices VI, FI and VFI in the next cycle, during COS. Although implantation rate might not be considered a ‘proper’ outcome because the denominator was not actually randomized, we include this outcome for completeness. All reproductive outcomes were defined as described previously[29]; endometrial measurements were performed during COS when at least one follicle ≥ 17 mm was observed; pain during the procedure was evaluated using a 10-cm visual analog scale within 5 min after the procedure.

Sample size

We estimated a clinical pregnancy rate in the control group of 30%[30, 31]. To have an 80% power to detect a relative increase of 50% (intervention group ≥ 45%), with a significance level of 5%, we would need 162 subjects per group, i.e. a total of 324 participants. Initially we planned to include 400 participants, because we intended to exclude women who had their treatment cycle canceled for any reason (estimating that about 20% of participants would be excluded). However, after starting the study we realized that this would lead to an unacceptable risk of bias (e.g. if women submitted to endometrial scratching have more chance of cycle cancelation, this would go unnoticed), and we changed the analyses in order to respect the ITT principle. Thus, we reduced our total sample to 324, which was the planned number without exclusions.

One of the investigators (C.O.N.) performed the planned interim analyses after inclusion of 60 participants, and then after each inclusion of 30 participants. We planned these interim analyses in order to discontinue the study when a significant difference in clinical pregnancy rate between groups was observed; this was with the aim of reducing the number of women submitted to uncomfortable sham procedures. However, this strategy is acknowledged as being the main limitation of our study, since stopping a trial early causes an increased risk of overestimating the treatment effect[32].

Randomization and blinding

For allocation of the participants we used a computer-generated random sequence of numbers in blocks of 30 (each block having 15 numbers assigned to intervention and 15 to control). The allocation was sealed in consecutively numbered opaque envelopes and an envelope was assigned as the participant entered the study; however, sealed envelopes were only opened just before the procedure, to ensure allocation concealment.

One researcher (W.P.M.) was responsible for enrolling the participants, and for performing the endometrial scratching and sham procedures and 3D-PD evaluation. Another researcher (C.O.N.) made the random allocation list, and put the papers with the assigned group inside the opaque numbered envelopes, sealing them to conceal allocation. Participants, care providers and other outcome assessors were blinded; only one researcher (W.P.M.) was aware of the allocation.


Statistical analysis was performed by one of the investigators (C.O.N.). Demographic and baseline data were compared between the two groups using the chi-square test. For the dichotomous outcomes (e.g. live birth and clinical pregnancy) we determined risk ratios, their respective 95% CIs, and P-values. For the continuous outcomes (e.g. pain and endometrial thickness), we estimated the mean differences between groups, their respective 95% CIs, and P-values by unpaired t-tests. No ancillary analysis was performed.


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A total of 372 women undergoing ART were assessed for eligibility. Of these, 158 women met our inclusion criteria and consented to participate: 79 women were allocated to the intervention group and 79 to the control group. Among the 79 women allocated to the intervention group, 77 women were submitted to endometrial scratching and two women were not because the researcher was unable to insert the pipelle through the cervix. In five women the pipelle orifice became clogged before 30 s (the estimated duration of the procedure) had elapsed, so the researcher immediately repeated the procedure. We performed the sham procedure in all 79 women allocated to the control group. All 158 women were considered in the final analysis to preserve the ITT principle as far as possible. A flow chart of participants is shown in Figure 1.


Figure 1. Flow diagram of participants. ICSI, intracytoplasmic sperm injection; IVF, in-vitro fertilization.

Download figure to PowerPoint


Participants were included from June 2010 to March 2012. Women were followed up until either a negative pregnancy test or resolution of pregnancy. After the fourth interim analysis the study was stopped because a significant difference in clinical pregnancy rate was observed, the rate being higher in women who underwent endometrial scratching; at this point 158 participants had been included.

Baseline data

Among the 158 women included, COS was initiated in 74 women in the endometrial scratch group and in 75 women in the control group. The distributions of the COS regimens were not significantly different between the groups (P = 0.92). The mean ± SD age of women in the endometrial scratch group was 32.4 ± 3.2 years and in the control group it was 32.1 ± 3.1 years (P = 0.55). All baseline data are presented in Table 1.

Table 1. Demographic and baseline data for women undergoing assisted reproduction allocated to endometrial scratching (n = 79) or sham procedure (n = 79) prior to controlled ovarian stimulation (COS)
ParameterEndometrial scratching (n (%))Sham procedure (n (%))Pa
  1. a

    Chi-square test. CC, clomiphene citrate; FSHr, recombinant follicle stimulating hormone; hMG, human menopausal gonadotropin.

Initiated COS74/79 (93.67)75/79 (94.94)0.73
Ovarian stimulation protocol  0.92
  CC+hMG+antagonist21/74 (28.38)19/75 (25.33) 
  FSHr+agonist20/74 (27.03)21/75 (28.00) 
  FSHr+antagonist33/74 (44.59)35/75 (46.67) 
Oocyte retrieval72/79 (91.14)74/79 (93.67)0.55
Embryo transfer67/79 (84.81)69/79 (87.34)0.65
Number of embryos transferred  0.88
  14/67 (5.97)5/69 (7.25) 
  259/67 (88.06)61/69 (88.41) 
  34/67 (5.97)3/69 (4.35) 
Number of previous unsuccessful embryo transfers  0.72
  08/79 (10.13)10/79 (12.66) 
  127/79 (34.18)22/79 (27.85) 
  232/79 (40.51)31/79 (39.24) 
  ≥ 312/79 (15.19)16/79 (20.25) 

Numbers analyzed

Although not all women actually underwent COS, oocyte retrieval and embryo transfer (Table 1), we analyzed live birth, clinical pregnancy and pain using all women randomized as the denominator (79 women in each group), to follow the ITT principle. Miscarriage and multiple pregnancy were evaluated using clinical pregnancy as the denominator because these are events that can occur only in pregnant women. There were 39 clinical pregnancies in the endometrial scratch group and 23 in the control group. Ultrasound examinations were only performed in those women who underwent COS and had at least one follicle ≥ 17 mm. Thus, for endometrial thickness and volume and the 3D-PD indices, we only analyzed data for 72 women in the scratch group and 74 in the control group. All analyses were performed according to original allocation: in order to follow the ITT principle we also included in the analysis those participants in whom we were unable to perform the intervention.

Outcomes and estimation

Endometrial scratching was associated with increased live birth and clinical pregnancy rates (Table 2). There was no evidence of effect on either miscarriage or multiple pregnancy rates (Table 2), but the confidence intervals were wide, preventing any meaningful conclusion. Endometrial scratching was associated with considerable pain (Table 3). We did not observe any difference in endometrial thickness or volume. Regarding the 3D-PD indices, VI and VFI were increased in the endometrial scratch group, whilst no significant difference was observed in FI (Table 3). Additionally, the implantation rate was significantly higher in women submitted to endometrial scratching: 48/134 (35.82%) vs 29/136 (21.32%) for endometrial scratch vs control groups (P = 0.01).

Table 2. Reproductive outcomes in women undergoing assisted reproduction allocated to endometrial scratching (n = 79) or sham procedure (n = 79) prior to controlled ovarian stimulation
OutcomeEndometrial scratching (n (%))Sham procedure (n (%))RR (95% CI)Pa
  1. a

    Mantel–Haenszel test. RR, risk ratio.

Live birth33/79 (41.77)18/79 (22.78)1.83 (1.13–2.97)0.01
Clinical pregnancy39/79 (49.37)23/79 (29.11)1.70 (1.13–2.56)0.01
Miscarriage6/39 (15.38)5/23 (21.74)0.71 (0.24–2.06)0.53
Multiple pregnancy9/39 (23.08)6/23 (26.09)0.88 (0.26–2.17)0.79
Table 3. Pain and sonographic outcomes in women undergoing assisted reproduction allocated to endometrial scratching (n = 79) or sham procedure (n = 79) prior to controlled ovarian stimulation
OutcomeEndometrial scratchingSham procedureMean difference (95% CI)Pa
nMean ± SDnMean ± SD
  1. a

    Unpaired t-test. 3D-PD, three-dimensional power Doppler; FI, flow index; VAS, visual analog scale; VI, vascularization index; VFI, vascularization flow index.

Pain VAS (cm)796.42 ± 2.35791.82 ± 1.524.60 (3.98 to 5.22)< 0.001
Endometrial thickness (mm)7210.12 ± 1.55749.98 ± 1.620.14 (−0.37 to 0.65)0.59
Endometrial volume (cm3)726.18 ± 1.63746.01 ± 1.480.17 (−0.34 to 0.68)0.51
Endometrial 3D-PD      
  VI723.71 ± 1.77742.95 ± 1.560.76 (0.22 to 1.30)< 0.01
  FI7226.12 ± 2.827425.91 ± 2.720.21 (−0.69 to 1.11)0.65
  VFI720.97 ± 0.51740.76 ± 0.400.21 (0.06 to 0.36)< 0.01

Adverse events

Pain and a small amount of bleeding during the procedure occurred in most participants in the intervention group. However, no women complained of bleeding on the days following the procedure when questioned at the next appointment, 7–14 days later. No fetal major malformation was reported by the participants.


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We observed a significant benefit of endometrial scratching, performed once, during OCP pretreatment, 7–14 days before starting COS. The intervention was associated with increased live birth and clinical pregnancy rates without evidence of effect on miscarriage and multiple pregnancy rates. However, women also reported substantial pain during the procedure. Endometrial scratching was also associated with an increase in endometrial vascularization, reflected in an increase in the 3D-PD indices VI and VFI. These findings might help us to understand the mechanisms underlying the role of endometrial scratching in improving reproductive outcome.


This study was stopped before including all the participants we had planned because the safety interim analysis showed a significant benefit of intervention; at this point 158 participants had been included. Although we were aware of the increased risk of overestimating a treatment effect when a trial is stopped early[32] and of the increased risk of type 1 error due to the multiple analyses, the decision to do so was made before starting the study. This was mainly because we agreed that it would not be proper to continue submitting women to sham procedures, particularly considering the large body of evidence[12, 18-21, 31, 33, 34]: several recently published studies also observed that endometrial scratching performed in the cycle before COS resulted in a beneficial effect on reproductive outcome. We acknowledge the following additional limitations. (1) Although we aimed to evaluate the effect of endometrial scratching in an unselected population of women undergoing in-vitro fertilization (IVF), the majority of participants had had at least two previous, unsuccessful embryo transfers, and the results cannot be generalized to all women undergoing ART, particularly those at the first attempt. (2) The COS regimen was not standardized (three different regimens), which can be considered as a potential source of bias. (3) The pain related to the intervention might have jeopardized our efforts to blind the women undergoing intervention. (4) 3D-PD quantification, used as a non-invasive marker of endometrial receptivity, is currently considered as a limited tool, mainly because of its high dependency on machine settings and attenuation[28, 35-37].


This is the first study to evaluate the effect of endometrial scratching performed in women using OCP pretreatment; pretreatment OCP is used frequently by women undergoing ART, and performing endometrial scratching in women using OCP reduces the risk of damaging a spontaneous implantation. We also performed the procedure just once whilst in some other studies endometrial scratching was repeated[19]; besides simplifying the treatment, this is important because the procedure causes considerable pain. As a consequence of the characteristics of the women who consented to participate, the findings of this study should be generalizable only to women with previous unsuccessful embryo transfers.


The observed effect is consistent with current evidence[12],[38]. Three non-randomized trials[13, 31, 33] agreed with our findings, observing a beneficial effect of the intervention, and five RCTs that performed endometrial scratching compared with no scratching within 30 days before initiating COS observed a beneficial effect of a magnitude similar to our findings[17-20, 39]. However, two RCTs observed different results: in one of these RCTs[34], endometrial scratching was compared with no intervention, but scratching was performed on the day of oocyte retrieval using a Novak curette; in this study the authors observed a marked detrimental effect on clinical and ongoing pregnancy. In the other discordant RCT[40], the intervention (endometrial scratching using a pipelle de Cornier) was compared with inserting the same pipelle through the cervix, and no significant difference was observed.

Based on our results and considering the whole body of evidence, we believe that endometrial scratching is a reasonable procedure to improve reproductive outcome for women undergoing ART (IVF/intracytoplasmic sperm injection (ICSI)), particularly for women with previous unsuccessful embryo transfers. However, we still need to examine the effect of the intervention in women undergoing the first IVF/ICSI attempt, and in non-IVF/ICSI situations, such as frozen/thawed embryo transfer, embryo or gamete donation and intrauterine insemination. Further research is also needed to elucidate the mechanisms underlying the benefit of endometrial scratching on reproductive outcome.


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This study was funded by two Brazilian official government research foundations: CNPq (direct funding (process number 473475/2010-3) and research scholarship) and CAPES (PhD scholarship).


The trial protocol was registered at under the ID ‘NCT01132144’(

Interim analyses

Two interim analyses with partial results were published as conference abstracts[12, 41].


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