Human Reproduction, Vol.34, No.1 pp.

92–99, 2019
Advanced Access publication on November 29, 2018 doi:10.1093/humrep/dey334

ORIGINAL ARTICLE Infertility

Decrease in pregnancy rate after

endometrial scratch in women
undergoing a first or second in vitro
fertilization. A multicenter

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randomized controlled trial
Sandrine Frantz1,*, Jean Parinaud2, Marion Kret3,
Gaelle Rocher-Escriva1, Aline Papaxanthos-Roche4, Hélène Creux1,
Lucie Chansel-Debordeaux4, Antoine Bénard3, and Claude Hocké1
1
CHU de Bordeaux, Endocrinology and Metabolism, Reproductive Medicine Unit, F-33000 Bordeaux, France 2CHU Toulouse, Department
of Reproductive Medicine, F-31059 Toulouse, France 3CHU de Bordeaux, Pôle de Santé Publique, Clinical Epidemiology Unit (USMR), F-
33000 Bordeaux, France 4CHU de Bordeaux, Biology of reproduction Unit-CECOS, F-33000 Bordeaux, France

*Correspondence address. Endocrinology and Metabolism, Reproductive Medicine Unit, Hôpital Pellegrin
CHU de Bordeaux, F-33000 Bordeaux, France. Tel: +33-5-56-79-58-35; Fax: +33-5-56-79-58-55; E-mail: sandrine.frantz@chu-bordeaux.fr

Submitted on May 9, 2018; resubmitted on September 30, 2018; accepted on October 22, 2018

STUDY QUESTION: Does endometrial scratch in women undergoing a first or second IVF/ICSI attempt improve the clinical pregnancy
rate (CPR)?
SUMMARY ANSWER: Endometrial scratch (ES) in women undergoing their first or second IVF/ICSI attempt does not enhance the CPR
under the technical conditions of our study.
WHAT IS KNOWN ALREADY: Several studies have suggested that physical scratch of the endometrium before an IVF attempt could
improve embryo implantation.
STUDY DESIGN, SIZE, DURATION: This was a randomized controlled multi-center, two-arm, parallel trial. Inclusions started in
February 2010 and stopped prematurely in July 2014 after an unplanned interim analysis. At the time of study closure, 191 of the planned 358
patients had been included.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients included in the study were randomly assigned to either the ES arm or
the non-ES arm. Local ES was performed between Day 20 and Day 24 of the cycle preceding ovarian stimulation using a device for endomet-
rial biopsy. Ovarian stimulation used a combination of recombinant FSH and either an GnRH agonist protocol or a GnRH antagonist protocol
without any estrogen pre-treatment. CPR was analyzed on an intent-to-treat basis. All comparisons between the two groups were done using
a logistic regression model adjusted for age, BMI and infertility etiology. Differences between the two arms were considered statistically signifi-
cant at P value of less than 0.0446 for the primary outcome only.
MAIN RESULTS AND THE ROLE OF CHANCE: Sixty-eight embryo transfers were performed in the ES arm and sixty-four in the non-
ES arm. CPR was 23.5% (16/68) in the ES arm and 35.9% (23/64) in the non-ES arm (hazard ratio (HR) = 0.43; 95% CI, 0.18–1.02; P =
0.0568). The implantation rate was 19.1% and 24.0% in the ES arm and in the non-ES arm, respectively. Two miscarriages and one ectopic
pregnancy were reported in each arm. The multiple pregnancy rate was higher in the scratch arm (50.0% vs 20.0%), but the difference was
not statistically significant (odds ratio (OR) = 4.54; 95% CI, 0.50–40.93; P = 0.1349). The endometrial biopsy procedure was well tolerated
in most women. Of 50 patients in the ES arm having received the embryo transfer, 40 (80.0%) patients reported having felt pain during the
procedure, the pain resolving quickly for 31 of them.

© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Endometrial scratch in women undergoing an IVF attempt 93

LIMITATIONS, REASONS FOR CAUTION: An interim analysis of the primary endpoint was conducted and an independent data moni-
toring committee agreed on stopping the inclusions. This analysis was prompted by the tendency towards lower pregnancy rates observed in
the ES arm. Consequently, the study suffered from a lower inclusion rate and failed to reach the planned sample size.
WIDER IMPLICATIONS OF THE FINDINGS: Under the technical condition employed in this study, ES in the luteal phase of the cycle
preceding the ovarian stimulation does not improve CPR in patients undergoing a first or second IVF/ICSI attempt.
STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from Ministère de la Santé Français (Programme
Hospitalier de Recherche Clinique 2009). There are no conflicts of interest.
TRIAL REGISTRATION NUMBER: NCT01064193
TRIAL REGISTRATION DATE: 08-Feb-2010
DATE OF FIRST PATIENT’S ENROLMENT: 08-Feb-2010

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Key words: assisted reproductive technologies / in-vitro fertilization / embryo implantation / endometrial scratch/RCT

presenting with primary or secondary infertility, undergoing a first or second

Introduction
Success of assisted reproductive technologies (ART) remains relatively low
with the European registers reporting a pregnancy rate per embryo transfer
of around 30% (European IVF-monitoring Consortium (EIM) et al., 2017).
The embryo implantation of in vitro fertilization (IVF) is the limiting step,
and its failure can be related to inappropriate ovarian stimulation, embryo
abnormalities, sub-optimal embryonic culture conditions, embryo transfer
process and/or a non-receptive endometrium (Karimzadeh et al., 2009).
Several studies have focused on endometrial receptivity at the time of
embryo transfer. Among the numerous medical approaches that have been
proposed to improve implantation (Khairy et al., 2007; Revelli et al., 2008;
Segev et al., 2010), endometrial scratch (ES) in the cycle preceding IVF may
be one of the most effective in improving endometrial receptivity (El-Toukhy
et al., 2012; Potdar et al., 2012; Nastri et al., 2014, 2015b). Barash et al. were
the first to report an increase in pregnancy rate in patients undergoing ES
before IVF. Later, Raziel et al. and Zhou et al. confirmed these results (Barash
et al., 2003; Raziel et al., 2007; Zhou et al., 2008). The mechanism underlying
this process remains unclear but several hypotheses have been suggested
(Zhou et al., 2008; Gnainsky et al., 2010; Dekel et al., 2014; Siristatidis et al.,
2014). Firstly, a local scratch in the endometrium might induce the endomet-
rium decidualization and thus increase its receptivity to the embryo
(Gnainsky et al., 2010). Secondly, it might provoke the wound healing, involv-
ing a mass secretion of different cytokines and growth factor, which are bene-
ficial for embryo implantation (Cakmak and Taylor, 2011). Lastly, it might
promote the maturation of the endometrium (Nastri et al., 2015b).
A recent systematic review reported that, even though endometrial
scratch is associated with improved reproductive outcomes, more evi-
dence is needed concerning the benefit in women undergoing their
first or second IVF cycle (Nastri et al., 2015b).
The aim of this study was to assess the impact of ES in the cycle pre-
ceding IVF on clinical pregnancy rate (CPR) in women undergoing their
first or second IVF attempt.
Materials and Methods
Patients
We included patients from three French reproductive centers (Gynecology
and obstetrics center in Pessac, Bordeaux University Hospital and Toulouse
University Hospital). The study included women aged 18–38 years old,
IVF attempt, with regular menstrual cycles (between 27 and 32 days) and FSH
levels ≤2IU/L. Patients were excluded from the study if they were enrolled or
had participated to in oocyte donation program, presented a BMI > 35, had
hydrosalpinx, uterine deformations, uterine fibroids (≥4 and the largest >
5 cm), abnormal gynecological bleeding of unknown origin, or ongoing vaginal
infection, had been pre-treated with estrogen–progesterone or estradiol pills,
or were participating in another medically assisted reproduction study.
The study was approved by local ethics committees and was carried out in
accordance with the principles of Good Clinical Practice and the Declaration
of Helsinki. Patients were required to sign a written informed consent form to
participate in the study (Clinical trial registration number: NCT01064193).
The study is reported according to CONSORT guidelines.
Study design
A randomized controlled multi-center, two-arm, parallel trial was con-
ducted. The randomization sequence was generated using SAS Software
(PLAN procedure, Copyright (c) 2002–2012 by SAS Institute Inc., Cary,
NC, USA) and was stratified by center with a 1:1 allocation using random
block sizes of 4 and 6. Patients included in the study were randomly
assigned by the investigator to one of the following arms: (i) the ES arm:
fresh IVF- or ICSI-embryo transfer after controlled ovarian hyperstimula-
tion plus local scratch to the endometrium on the cycle preceding IVF; (ii)
non-ES arm: fresh IVF- or ICSI-embryo transfer treated after controlled
ovarian stimulation alone. Randomization was stratified by site and was
performed using a centralized web-based service.
Local ES was performed between Day 20 and Day 24 of the cycle pre-
ceding ovarian stimulation using a device for endometrial biopsy (Pipelle de
Cornier, CCD international, PROMIDED, Neuilly-en Thelle, France). A
sample of uterine mucosa (representative of the whole uterus cavity) was
retrieved by suction and rotation. The sample was placed in a flask con-
taining formaldehyde. A piece of the biopsy was sent for anatomical and
-pathological examination. Patients started their IVF treatment in the sub-
sequent cycle. Ovarian stimulation used a combination of recombinant
FSH and gonadotrophin-releasing hormone (GnRH) agonist or GnRH
antagonist without prior estrogen administration. Oocyte retrieval, IVF
(with or without ICSI) and embryo transfer procedures were carried out
according to standard protocols, 2 or 3 days after fertilization (Terriou
et al., 2006). Embryo morphology was classified according to the Giorgetti
4-point score. In this classification embryos are assigned 1 point each if, on
Day 2, they (i) are cleaved, (ii) present no fragmentation, (iii) display no
irregularities and (iv) have four cells (Giorgetti et al., 1995).
94 Frantz et al.

Endpoints BMI, infertility etiology, quality of embryo and smoking status. These fac-
tors were considered, a priori, as being strong predictors of clinical preg-
The primary endpoint was clinical pregnancy rate (CPR), defined by the
nancy. Statistical analyses were carried out using SAS software (Version
presence of at least one intrauterine gestational sac with fetal heartbeat.
9.3).
Secondary endpoints were: rate of clinically ongoing pregnancy in the first
An unplanned interim analysis of the primary endpoint was carried out
trimester (defined as pregnancies ≥ 12 weeks), rate of embryo implant-
through both a futility analysis and a formal between-group comparison
ation, rate of miscarriage in the first trimester, rate of extrauterine preg-
with adjustment of the alpha risk. The futility analysis was performed using
nancy, rate of multiple pregnancy and tolerance of the intervention.
a Bayesian method to calculate the predicted power at the end of inclu-
Adverse events (infections, pain, bleeding) occurring during and after
sions considering the observations at the time of the interim analysis
scratching were collected after the intervention and at the end of the
(Dmitrienko and Wang, 2006). The adjustment of the alpha risk used the
study. Pain was assessed with a visual analog scale (VAS). Type of pain was
method proposed by O’Brien and Fleming (O’Brien and Fleming, 1979).
determined by means of a questionnaire administered by a nurse or phys-
Consequently, the final differences between the two arms were con-
ician by telephone or in consultation.
sidered statistically significant at a P value of less than 0.0446 for the pri-
mary outcome only.

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Statistical methods
The sample size was determined using the nQuery Advisor® 7.0 software
(Statistical Solutions, Saugus, MA, USA) based on the Chi squared test.
Assuming a CPR of 25% in the non-ES arm and a 40% increase in the CPR
in the ES arm, the required sample size to obtain 80% power at an alpha
risk of 5% was estimated at 152 patients for each study arm. In order to
take into consideration a 15% of patients without oocyte, embryo transfer
and/or patients stopping treatment, 179 patients had to be enrolled in
each arm, that is, 358 patients.
The analysis of the primary outcome was conducted on an intention-to-
treat (ITT) basis (analysis based on the initial treatment assignment and
not on the treatment eventually received) and was carried out in the popu-
lation comprising all-treated patients (patients having received an embryo
transfer). This analysis was also conducted on an as-treated principle (con-
sidering the treatment effectively received). It was assumed that missing
values represented a failure (no clinical pregnancy). A subgroup analysis
was performed comparing women undergoing the first attempt versus
those undergoing a second attempt. Secondary analyses were based on
the same principles, but on available data. All comparisons between the
two groups were done using a logistic regression model adjusted for age,
Results
Patients
Inclusions for this study started in February 2010 and stopped prema-
turely in July 2014 on the recommendation of an independent data
monitoring committee after an unplanned interim analysis. This ana-
lysis was prompted by the tendency towards lower pregnancy rates
observed in the ES arm. The futility analysis, using several hypotheses,
yielded a maximal predicted power of 22% to demonstrate a differ-
ence between ES and no ES.
At the time of study closure, 191 of the planned 358 patients had
been included in the study. Fig. 1 shows the CONSORT flow diagram.
Ninety-eight (51.3%) patients were assigned to the ES arm and 93
(48.7%) to the non-ES arm. One patient in the ES arm was wrongfully
included (presented a contra-indication) and was finally excluded from
the analyses.

Figure 1 CONSORT flow diagram. Abbreviations: ITT: intent-to-treat.

Endometrial scratch in women undergoing an IVF attempt 95

Patient baseline characteristics of ES and non-ES patients are pre- Pregnancies

sented in Table I for the included and for the treated population. Age,
BMI and infertility status were well balanced between the two arms.
For 63 (67.7%) patients in the non-ES arm this was the first IVF
attempt versus 75 (77.3%) in the ES arm. The rate of smokers in the
ES arm was greater than in the non-ES arm in both populations.
Characteristics of ART
ES was performed at cycle Day 20.6 (mean, standard deviation (SD) =
2.2 days) of the cycle preceding the IVF attempt. Of the 97 patients in
the intervention arm, only 80 (81.6%) presented to the scratch pro-
cedure. Sixteen patients did not attend the visit and the remaining
Five weeks after embryo transfer, the CPR was 35.9% (23/64) in the
non-ES arm versus 23.5% (16/68) in the ES arm (hazard ratio (HR) =
0.43; 95% CI, 0.18–1.02; P = 0.0568) (Fig. 2 and Table III). For women
undergoing their first IVF attempt, CPR was 34.1% (15/44) in the non-
ES arm and 21.2% (11/52) in the ES arm (odds ratio (OR) = 0.46;
95% CI, 0.17–1.29; P = 0.1403). For women undergoing their second
CPR was 40.0% (8/20) in the non-ES arm and 31.3% (5/16) in the ES
arm (OR = 0.45; 95% CI, 0.07–2.7; P = 0.3798). The as-treated ana-
lysis (considering the treatment effectively received) yielded clinical
pregnancy rates of 30.8% (24/78) in the non-ES arm, and 27.8% (15/
54) in the ES arm (HR = 0.84; 95% CI, 0.37–1.91; P = 0.6747). The

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patient encountered a randomization error. Eight (10%) of the 80
patients who attended the visit could not undergo the intervention:
local scratch could not be carried out for four patients, three patients
presented with a cervical stenosis and one patient presented no uter-
ine passage.
As shown in Table II, there was no clinically significant difference in
the ART characteristics between the two arms. In total, 132 transfer
cycles were performed, 68 in the ES arm and 64 in the non-ES arm.
The number of Grade 1 embryos transferred was greater in the non-
ES arm (23/64, 35.9%) than in the ES arm (19/68, 27.9%).
rate of ongoing pregnancy was 20.6% (14/68) in the ES and 31.7%
(20/63, 1 missing data) in the non-ES arm (OR = 0.45; 95% CI,
0.18–1.2 P = 0.0866) (Table III).
Of 50 patients in the ES arm having received the embryo transfer,
40 (80.0%) patients reported having felt pain during the procedure.
Pain resolved quickly for 31 women and the questionnaire was incom-
plete for the remaining 3. Among the six patients for whom pain did
not resolve quickly, three felt a contraction-like pain, one patient felt
period-like pain, one patient felt piercing pain and one patient stabbing
pain. Three patients also reported bleeding after the ES. All patients

Table I Patients’ characteristics.

Analysis per cycle Analysis per transfer

(All-included population (All-treated population
N = 190) N = 132)
............................................. ..............................................
Characteristics Non-ES arm ES arm Non-ES arm ES arm
N = 93 N = 97 N = 64 N = 68
.............................................................................................................................................................................................
Age, years mean (SD) 32.5 (3.8) 32.6 (3.8) 32.9 (3.4) 32.8 (4.0)
BMI mean (SD) 23.5 (4.3) 23.0 (4.1) 22.4 (3.0) 23.2 (4.3)
Current smokers n (%) 15 (16.1) 26 (26.8) 7 (10.9) 19 (27.9)
Duration of infertility, months mean (SD) 49.7 (27.8) 44.6 (24.2) 49.3 (26.9) 41.7 (22.6)
Infertility
Primary n (%) 76 (81.7) 81 (83.5) 51 (79.7) 56 (82.4)
Secondary n (%) 17 (18.3) 16 (16.5) 13 (20.3) 12 (17.6)
Infertility causes
Female n (%) 12 (12.9) 20 (20.6) 10 (15.6) 15 (22.1)
Male n (%) 52 (55.9) 53 (54.6) 32 (50.0) 34 (50.0)
Mixed n (%) 15 (16.1) 5 (5.2) 12 (18.8) 4 (5.9)
Idiopathic n (%) 14 (15.1) 19 (19.6) 10 (15.6) 15 (22.1)
Antral follicle counts mean (SD) 16.4 (8.0) 16.1 (7.6) 16.5 (8.3) 16.0 (7.5)
FSH, UI/ml mean (SD) 7.1 (1.8) 6.8 (2.0) 7.2 (1.6) 6.8 (2.1)
AMH, ng/ml mean (SD) 3.0 (1.6) 3.1 (1.7) 2.8 (1.6) 3.0 (1.6)
Number of previous IVF attempts mean (SD) 0.4 (0.7) 0.2 (0.5) 0.4 (0.7) 0.3 (0.5)
IVF attempt
First n (%) 63 (67.7) 75 (77.3) 44 (68.8) 52 (76.5)
Second or more n (%) 30 (32.3) 22 (22.7) 20 (31.3) 16 (23.5)

Abbreviations: ES = endometrial sratch; BMI = body mass index; FSH = follicle-stimulating hormone; AMH = anti-müllerian hormone; SD = standard deviation; IVF = in vitro
fecundation.
No clinically significant difference was found between the two randomized groups for any parameter.
96 Frantz et al.

Table II Stimulation characteristics.

Per cycle (N = 177a) Per transfer (all-treated

population N = 132)
............................................. ..............................................
Characteristics Non-ES arm ES arm Non-ES arm ES arm
N = 86 N = 91 N = 64 N = 68
.............................................................................................................................................................................................
Antagonist protocol n (%) 12 (14.0) 12 (13.2) 11 (17.2) 8 (11.8)
Long agonist in luteal phase n (%) 74 (86.0) 79 (86.8) 53 (82.8) 60 (88.2)
Duration of rFSH stimulation (days) mean (SD) 10.8 (1.6) 10.6 (2.2) 11.0 (1.3) 11.0 (1.9)
Total administrated FSH dose (IU) mean (SD) 1936 (764) 1906 (858) 1974 (716) 1980 (810)
Follicular punctures n (%) 69 (80.2) 72 (79.1) 64 (100) 68 (100)
Number of retrieved oocytes mean (SD) 8.0 (3.5) 7.6 (4.1) 8.2 (3.4) 7.8 (4.1)

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Number of inseminated oocytes mean (SD) 8.0 (3.4) 7.6 (4.2) 8.1 (3.3) 7.8 (4.1)
Number of obtained embryos mean (SD) 5.1 (3.3) 4.8 (3.4) 5.5 ± 3.1 5.1 ± 3.3
Embryo transfers mean (%) 64 (94.1) 68 (95.8)
Number of transferred embryos
1 n (%) 11 (17.2) 15 (22.1)
2 n (%) 50 (78.1) 48 (70.6)
3 n (%) 2 (3.1) 5 (7.4)
4 n (%) 1 (1.6) 0 (0.0)
Fertilization rate mean (SD) 54.2 (28.4) 59.8 (26.4) 58.4 (24.9) 61.8 (23.4)
a
13 patients did not attend the oocyte retrieval visit, and one patient did not fulfill all the eligibility criteria.
Abbreviations: ES = endometrial scratch; FSH = follicle-stimulating hormone.

Figure 2 Pregnancies in the endometrial scratch and the non-endometrial scratch arms.

reported no regrets for having undergone the scratch. Details on pain
scores and types are presented in Table IV.
Twenty-three (17.4%) of the 132 patients having undergone the
embryo transfer reported adverse events (AEs), 8/23 patients in the
ES arm versus 15/23 patients in the non-ES arm. Most common AEs in
the non-ES arm were ovarian hyperstimulation (4/15, 26.7%), pelvic
pain (2/15, 13.3%) and abdominal pain (2/15, 13.3%). Most com-
monly reported AEs in the ES arm were metrorrhagia (2/8, 25%) and
pelvic pain (2/8, 25%). One of the metrorrhagia cases was related to
the study intervention. Serious AEs occurred only in the non-ES group:
Endometrial scratch in women undergoing an IVF attempt 97

Table III Summary of outcomes in the non-ES and ES arms.

Outcome Non-ES arm ES arm P value Measure of risk 95% CI

N = 64 N = 68
.............................................................................................................................................................................................
Clinical pregnancy rate (ITT) n (%) 23 (35.9) 16 (23.5) 0.0568 HR=0.43 0.18–1.02
Filled 64 68
Missing data 0 0
Clinical pregnancy rate (as-treated$) n (%) 24 (30.8) 15 (27.8) 0.6747 HR=0.84 0.37–1.91
Filled 78 54
Missing data 0 0
Ongoing pregnancy n (%) 20 (31.7) 14 (20.6) 0.0866 OR=0.45 0.18–1.12

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Filled 63 68
Missing data 1 0
Implantation rate Mean (SD) 24 19.1 NA§ NA§ NA§
Filled 121 126
Missing data 0 2
Rate of miscarriage in the first trimester* n (%) 0 (0.0) 1 (1.5) NA§ NA§ NA§
Filled 63 68
Missing data 1 0
Rate of ectopic pregnancies n (%) 1 (1.6) 1 (1.5) NA§ NA§ NA§
Filled 63 68
Missing data 1 0
Rate of multiple pregnancies n (%) 4 (20.0) 7 (50.0) 0.1779 OR=4.54 0.50–40.93
Filled 20 14
Missing data 0 0
$
Considering the treatment effectively received.
*The rate of miscarriage was defined as the number of lost pregnancies between week 12 and week 20 divided by the number of ongoing pregnancies at week 12.
§
Measure of risk analyses could not be performed due to the small number of events.
NA = not applicable; ITT = intention-to-treat; ES = endometrial scratch; HR = hazard ratio; OR = odds ratio; CI = confidence interval.

two patients reported ovarian hyperstimulation and one an allergy to a
specific drug. None of the AEs were related to the study procedures
as assessed by the investigator.
Discussion
This study indicates that ES is of no benefit in patients undergoing their
first or second IVF/ICSI cycle: furthermore, the data suggest that ES
has a detrimental effect on pregnancy outcome. There is increasing
evidence in the literature about the beneficial effect of ES in women
after several failed IVF attempts (Raziel et al., 2007; Karimzadeh et al.,
2009; Narvekar et al., 2010; Öztürk İnal et al., 2012; Nastri et al.,
2014). A Cochrane systematic review published in 2015 concluded
that ES significantly improved clinical pregnancy rate (CPR) (RR =
1.34; 95% CI, 1.21–1.61; P = 0.002) and live birth (LBR) or ongoing
pregnancy rate (RR = 1.42; 95% CI, 1.08–1.85; P = 0.01) (Nastri et al.,
2015b). This review included 14 RCT’s with 2128 women; seven stud-
ies included women with previous IVF failures, five included women
regardless of the number of previous IVF cycles and one included only
women undergoing their first IVF cycle. In a recent retrospective study,
Reljic et al. reported that local ES is an independent prognostic factor
for pregnancy (OR = 1.73; 95% CI 1.02–2.92): they included women
with at least three previous failed ICSI/IVF cycles (Reljič et al., 2017).
These studies demonstrate that endometrial scratch may improve
reproductive outcomes in women undergoing ART by inducing
changes in the endometrium.
Conversely, Yeung et al. carried out an RCT with 300 infertile
women and reported no significant difference in the ongoing preg-
nancy (P = 0.375) or implantation (P = 0.120) rates between patients
in the ES group and the non-ES group (Yeung et al., 2014). Most
patients (>70%) were undergoing their first IVF/ICSI cycle and very
few had suffered repeated implantation failure (10%) following ≥3
IVF/ICSI cycles. A subgroup analysis in women with no previous IVF
attempts reported no benefits in the ongoing pregnancy rate between
the two groups. Nevertheless, the analysis did not have enough power
to detect any significant difference. Also, and as noted by Nastri et al.
in a recent editorial, all women in the series by Yeung et al. had under-
gone uterine procedures that may have caused previous injury to the
endometrium (hysterectomy or saline sonography) in the 3 months
prior to the IVF cycle (Nastri et al., 2015a). Tk et al. have recently pub-
lished their results from an RCT with 111 women with at least one
previous failed IVF (Tk et al., 2017). No significant difference in CPR
(per embryo transfer) was found between women undergoing ES in
the cycle preceding IVF and the control non-ES group (34.09% vs
27.65%; OR 1.35, 95% CI, 0.55–3.30, P = 0.5). Less than 10% of
women, however, had undergone ≥3 previous IVF/ICSI cycles. No
98 Frantz et al.

reported that performing ES in the transfer cycle on the day of oocyte

Table IV Pain assessment for endometrial scratch in retrieval had detrimental effects (Karimzade et al., 2010).
patients having undergone endometrial in patients
Mak et al. conducted a RCT to assess the impact of ES in women
having undergone embryo transfer.
using frozen embryos and found no difference in clinical pregnancy and
Variable Total implantation rates between the ES group and the non-ES group (Mak
........................................................................................ et al., 2017).
Pain during procedure n (%) 40/50 (80.0) In terms of safety, our study demonstrated that ES is a well-
If yes, VAS* score mean (SD) 4.6 (2.1) tolerated procedure; results are in good agreement with previous
If yes, type of pain reports. No cases of endometritis were reported in this study.
twinge, sharp pain n (%) 2/38 (5.3) One of the limitations of this study is that it failed to reach the
a type of contraction n (%) 5/38 (13.2) planned sample size. After an intermediate analysis of the primary end-
as with period n (%) 13/38 (34.2) point, an independent monitoring committee recommended terminat-
ing recruitment to the trial. However, given the lower CPR in the ES

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agonizing n (%) 3/38 (7.9)
group in our study, the superiority of ES compared to non-ES would
piercing n (%) 6/38 (15.8)
not have been shown even if we had reached the planned study size.
electrical discharges n (%) 2/38 (5.3)
Another limitation of this RCT is subject to performance bias; ES was
stabbing n (%) 5/38 (13.2)
performed by different persons meaning the results were operator
squeezing n (%) 1/38 (2.6)
dependent.
heaviness n (%) 1/38 (2.6) In conclusion, this study is an important contribution to the body of
If pain during procedure, pain after scratch n (%) 6/37 (16.2) evidence required for the use of ES in routine practice. Our results
Bleeding after scratch n (%) 22/47 (46.8) show that ES does not improve CPR in women with zero or one previ-
Fever after scratch n (%) 0/47 (0.0) ous failed IVF cycle under the technical conditions employed in this
Abnormal vaginal discharge n (%) 2/47 (4.3) study. Further research should focus on subgroup analyses in order to
Regret having had scratch done n (%) 0/47 (0.0) better define what population will benefit from the procedure.

All data were not available for all patients

*VAS score ranged from 0 to 10
Abbreviations: SD = standard deviation; VAS = visual analog scale.
analyses were carried out in the subgroup of women with <3 IVF
attempts due to the small sample size. Mahran et al. on the other
hand, randomized 400 patients undergoing their first IVF/ICSI cycle to
undergo either ES in luteal phase of the preceding cycle or no treat-
ment and found that outcomes (implantation, live birth, clinical preg-
nancy rates) were significantly higher in patients undergoing ES (P <
0.05). As in the study by Yeung et al. all women had undergone a hys-
teroscopic evaluation, which may have caused prior injury to the endo-
metrium (Mahran et al., 2016).
In addition to differences in the patients included (e.g. number of
previous failed attempts), discrepant results among studies may arise
from the heterogeneity in terms of the technique used for ES (Pipelle
versus aspiration (Yeung et al., 2014)), the degree of scratch (Pipelle vs
hysteroscopy (Shohayeb and El-Khayat, 2012)), the number of inter-
ventions (one procedure vs multiple procedures (Öztürk İnal et al.,
2012)) and the timing of the intervention. In our study, ES was per-
formed in the luteal phase (between Days 20 and 24). In 9 of the 14
RCTs included in the Cochrane review, ES was performed in the luteal
phase of the cycle preceding the IVF; in one study ES was performed in
the follicular phase; in two studies two ES were done – one in the
luteal phase and one in the follicular phase; and in two studies ES pro-
cedures were performed in the same cycle of IVF. Comparing out-
comes in these studies did not lead to a clear conclusion on the
optimal time to do the ES. Liu et al. recently carried out an RCT and
found that performing the ES in the proliferative phase versus the luteal
phase had no impact on outcomes (Liu et al., 2017). Karimzade et al.
Authors’ roles
SF: conception and design, acquisition of data, interpretation of data,
drafting the article, and final approval of the version to be published.
JP: conception and design, interpretation of data, drafting the article,
and final approval of the version to be published. MK: conception and
design, analysis and interpretation of data, drafting the article, and final
approval of the version to be published. GR-E: conception and design,
acquisition of data, interpretation of data, revising the draft critically
for important intellectual content, and final approval of the version to
be published. Aline P-R: conception and design, acquisition of data,
interpretation of data, revising the draft critically for important intellec-
tual content, and final approval of the version to be published. HC:
conception and design, acquisition of data, interpretation of data,
revising the draft critically for important intellectual content, and final
approval of the version to be published. LC-D: conception and design,
acquisition of data, interpretation of data, revising the draft critically
for important intellectual content. AB: conception and design, analysis
and interpretation of data, drafting the article, and final approval of the
version to be published. CH: conception and design, acquisition of
data, interpretation of data, revising the draft critically for important
intellectual content, and final approval of the version to be published.
Funding
This study was supported by a grant from Ministère de la Santé
Français (Programme Hospitalier de Recherche Clinique 2009).
Conflict of interest
There were no conflicts of interest.
Endometrial scratch in women undergoing an IVF attempt
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