UOG Journal Club: October 2013
Endometrial scratching performed in the
non-transfer cycle and outcome of assisted
reproduction: a randomized controlled trial
CO Nastri, RA Ferriani, N Raine-Fenning, WP Martins
Volume 42, Issue 4, Date: October 2013, pages 375–382
Journal Club slides prepared by Dr Ligita Jokubkiene
(UOG Editor for Trainees)
• 7–15% women of reproductive age encounter
fertility problems
• Live birth rate in those using assisted reproductive
techniques (ART) are 20–30%
• ART outcome can be improved by:
• Controlled ovarian stimulation (COS)
• Multiple embryo transfer
• Cryopreservation of oocytes/embryos
Thoma et al., Fertil Steril 2013; Sunkara et al., 2011; Gunby et al., Fertil Steril 2011
Hypotheses
• Endometrial scratching (ES) induces decidualization,
improving the chances of embryonic implantation
• ES induces the secretion of cytokines, interleukins,
growth factors, macrophages and dendritic cells, all
potentially beneficial to embryonic implantation
• ES may lead to better synchronicity between
endometrium and the transferred embryo
Barash et al., Fertil Steril 2003;
Li R and Hao G, Curr Opin Obstet Gynecol 2009;
Garris DR and Garris BL, Tissue Cell 2003; Gnainsky Y et al., Fertil Steril 2010
Reproductive outcomes of ART compared in
women with and without endometrial scratching
The main reproductive outcomes that were
shown to be improved by ES were:
• Miscarriage
• Clinical pregnancy
• Live birth
Karimzadeh et al., Aust N Z J Obstet Gynaecol 2009; Nastri et al., Gynecol Endocrinol 2013
Endometrial scratching performed in the non-transfer cycle and
outcome of assisted reproduction: a randomized controlled trial
Nastri et al, UOG, 2013
Objective:
To investigate the effect of endometrial scratching on
reproductive outcome, pain and three-dimensional power
Doppler (3D-PD) vascular indices in women undergoing ART
with combined oral contraceptive pre-treatment
Randomized controlled trial
Eligibility criteria:
• Age < 38 years
• Submitted for ART with controlled
ovarian stimulation, oocyte retrieval
and embryo transfer
Pre-treatment:
Combined oral contraceptives with:
• 30mcg ethinyl estradiol
• 150mcg levonorgestrel (for at least
10 days prior to randomization)
Inclusion criteria:
• Agreement to participate
• Written informed consent
Randomized controlled trial
Endometrial biopsy
with Pipelle de
Cornier
•
•
•
OR
A sham procedure
(drying cervix with a
gauze )
Randomization 7–14 days prior to planned COS
Manipulation according to randomization for 30
seconds
Evaluation of pain on visual analog scale (VAS)
within 5 minutes after procedure
Methodology
•
Tranvaginal ultrasound examination at day 2–3 of
menstrual cycle
• COS proceeded if no follicle ≥10mm in diameter was observed or
if estradiol levels were <50pg/ml in the presence of a follicle
≥10mm
•
Transvaginal ultrasound monitoring of follicle
development started 5 days after COS, and was
repeated every other day
•
3D-PD ultrasound examination was performed
when at least one follicle ≥17mm was observed
Methodology
Ultrasound variables at 3D-PD examination:
• Endometrial thickness
• Endometrial volume
• Vascularization index (VI)
• Flow index (FI)
• Vascularization flow index (VFI)
VOCAL™ software analyzed the results, 15° rotation steps
helped define the endometrium and a histogram facility for
the calculation of PD vascular indices was used
Outcomes
Primary outcome: Clinical pregnancy per woman*
Secondary outcomes:
• Live birth per woman
• Multiple pregnancy per woman
• Spontaneous miscarriage per clinical pregnancy
• Pain during procedure
• Ultrasound variables
*at least one fetus with heart beat
Flow chart of patients
The study stopped
after 158 patients
had been included
The study was stopped after fourth interim analysis because a
signficant difference in clinical pregnancy was observed
IVF = in-vitro fertilization, ICSI = intracytoplasmic sperm injection
Results on reproductive outcomes
Outcome
Endometrial scratching
Sham procedure
P-value*
Live birth
33/79 (42%)
18/79 (23%)
0.01
Clinical
pregnancy
39/79 (49%)
23/79 (29%)
0.01
Multiple
pregnancy
9/39 (23%)
6/23 (26%)
0.79
Miscarriage
6/39 (15%)
5/23 (22%)
0.53
Pain VAS, cm
(mean (SD))
6.4 (2.35)
1.8 (1.52)
<0.001†
*Mantel-Haenszel test, †unpaired t-test
Results
•
Endometrial scratching was associated with increased
live birth and clinical pregnancy rates (P=0.01 for both)
•
Endometrial scratching was associated with
considerable pain (P<0.001)
•
No difference was observed in endometrial thickness
or volume (P=0.59 and P=0.51, respectively)
•
VI and VFI were increased in endometrial scratch
group but no difference in FI observed (P<0.01, P<0.01
& P=0.65, respectively)
Limitations
The study was stopped after interim analysis – risk of
overestimating treatment effect
•
Selected population - majority of women had at least 2
unsuccessful embryo transfers prior to this trial
•
The COS regimen was not standardized – choice of 3
regimens may introduce bias
•
Intervention pain - might have affected blind
randomization
•
3D-PD quantification lacked standardization dependent on machine settings and attenuation
Endometrial scratching performed in the non-transfer cycle and
outcome of assisted reproduction: a randomized controlled trial
Nastri et al, UOG, 2013
Conclusions
1. Endometrial scratching is a reasonable procedure to
improve reproductive outcome for women undergoing
ART, particularly those with previous unsuccessful
transfers
2. Further research is needed to elucidate the
mechanisms of the benefit of endometrial scratching
on reproductive outcome
Endometrial scratching performed in the non-transfer cycle and
outcome of assisted reproduction: a randomized controlled trial
Nastri et al, UOG, 2013
Discussion Points
• What are reproductive outcomes and how can we improve
them?
• Does endometrial scratching affect outcome of ART?
• What are the underlying mechanisms between endometrial
scratching and improved ART outcomes?
• Can these results be applied to clinical practice?
• What happens if a study is interrupted when a significant
difference in study results is observed?
• What are the limitations of this study?