Comparing Two Types of Endometrial Activation Prior to Embryo Transfer: A Pilot Study
Phase: NA
Conditions: Infertility, Endometrial Disorder
Sponsor: Wake Forest University Health Sciences

 
 
 
 
 
 
 
 
Title: Comparing Two Types of Endometrial Activation Prior to 
Embryo Transfer 
 
NCT04363879 
Protocol ID: 07-14-06B 
 
Date: 4/27/20 
 
 

Protocol – Comparing Two Types of Endometrial Activation Before Embryo Transfer: A 
Pilot Study 
 
Principle Investigator: Dr. Brad Hurst, Reproductive Endocrinology and Infertility 
 
 
 
   Carolinas Medical Center – Women’s Institute  
               1025 Morehead Medical Drive, Suite 500  
 
 
 
   Charlotte, NC 28204 
 
 
 
   704-355-3149 (P), 704-355-8798 (F) 
 
Co-Investigator: Katie Merriam, Medical Student  
 
                             Carolinas Medical Center – Women’s Institute 
     1025 Morehead Medical Drive, Suite 500  
 
 
     Charlotte, NC 28204 
 
 
     704-355-3149 (P), 980-442-2139 (F) 
 
Department Chair: Dr. Robert Higgins   
 
 
          Levine Cancer Institute, Suite 2100 
          1021 Morehead Medical Drive  
 
 
          Charlotte, NC 28204 
 
 
          704-355-3143 (P), 704-355-8798 (F) 
 
Purpose  
To determine if two types of endometrial activation (Pipelle curette or Shepard catheter) prior to 
embryo transfer result in similar live birth rates. Also to determine if patients experience similar 
pain from both types of endometrial activation.  
 
Hypothesis  
1. We predict that the Pipelle curette and Shepard catheter will have similar live birth rates when 
performed in the cycle before embryo transfer.  
2. We predict that endometrial activation with the Shepard catheter will be less painful than the 
Pipelle curette.   
 
Background and Significance  
Assisted reproductive technologies (ART), including in vitro fertilization (IVF), are methods 
used to treat infertility, which affects approximately 10% reproductive aged women (1). 
Physicians at the Women’s Institute perform over 300 embryo transfer procedures every year. 
Despite advances and improvements in ART over the past three decades, clinical pregnancy rate 
and live birth rate remain 30-40% and 20-30% (2). Implantation is essential for successful ART 
and IVF procedures, and many interventions have been studied to possibly improve implantation 
rates and thus pregnancy and live birth rates (3). 

 
Endometrial activation is one such intervention, sometimes referred to as endometrial 
“activation” or “scratch,” and it is defined by the Cochran Collaboration as “intentional 
endometrial injury, such as endometrial biopsy or curettage, in women undergoing ART” (4).  
 
In 2003, Barash et al. found that implantation rates, clinical pregnancy rates, and live birth rates 
were more than twofold higher in women who underwent endometrial biopsy in the cycle before 
subsequent IVF treatment (3). A Cochrane Review which examines endometrial activation prior 
to IVF similarly has concluded that endometrial activation prior to the embryo transfer cycle 
significantly improves clinical pregnancy rates and live birth rates in women undergoing ART. 
Although the type of endometrial procedure is not specified, the timing activation was found be 
most effective when performed in the cycle prior to the embryo transfer (4).  
 
The mechanism of increase endometrial receptivity is still unknown; however three proposed 
hypothesis exist. The first hypothesis proposes that local activation of the endometrium induces 
endometrial decidualization which increases the probability of embryo implantation. The second 
hypothesis is that endometrial healing following endometrial activation increases secreted 
cytokines, interleukins, growth factors, macrophages, and dendritic cells which are beneficial to 
embryo implantation. The final hypothesis suggests that endometrial maturation is abnormally 
advanced during ovarian stimulation, so endometrial activation may lead to better synchronicity 
between the endometrium and the embryo (4).  
 
Endometrial activation has been found to have clear benefit in pregnancy and live birth rates in a 
Cochrane Review (4), however no uniform technique has been determined. Our objective is to 
compare two types of endometrial disruption – a vigorous endometrial biopsy with a Pipelle 
curette and a four quadrant endometrial “scratch” using a Shepard insemination catheter – to 
determine if the live birth rates are equivalent for the two methods. We also will compare pain 
with the two types of endometrial activation. By comparing two distinct types of endometrial 
activation, we hope to determine which method is both effective and tolerable to patients.  
  
The Shepherd catheter is a 1.8 mm malleable insemination catheter that can be curved to traverse 
the cervix. It is also used by some physicians in the Women’s Institute to perform saline infusion 
sonography. When the catheter is inserted under ultrasound guidance, it is often placed in the 
subendometrial tissue, and causes deflection and disruption of the endometrium but is tolerated 
well. The Pipelle is a 3.1 mm semi-rigid catheter with an internal stylet plunger. A biopsy is 
performed by placing the catheter into the uterus, withdrawing the stylet to create suction, and 
aspirating endometrial tissue into the catheter. 
 

A study done by Leclair et al. found that the mean pain that women had when the Pipelle was 
used for an endometrial biopsy was 6.2±2.4 on a visual analog scale from 1-10 (5). Pain with the 
Shepard catheter has not been studied when it is used for endometrial biopsy.  
 
Type of Study  
This will be a non-blinded randomized control trial with parallel treatment arms.  
 
Study Population  
Female patients at the CMC Women’s Institute undergoing IVF with either a fresh or frozen 
embryo transfer. 
 
Inclusion Criteria:  
•! All patients undergoing embryo transfer who are in the cycle prior to their embryo 
transfer 
 
Exclusion Criteria:  
•! Patients not undergoing embryo transfer 
•! Known pregnancy 
•! Active pelvic infection   
•! Known endometrial hyperplasia or cancer  
•! Inability to tolerate endometrial  catheter placement  
•! Severe cervical stenosis  
•! Patients who will receive operative hysteroscopy in the cycle prior to embryo transfer  
 
Materials and Methods  
1)! After Institutional Review Board approval is obtained, patients will be consented in the 
cycle prior to their fresh or frozen embryo transfer.  
2)! Demographic data including age, gravity and parity, reason for infertility, BMI, fresh or 
frozen embryo transfer, prior IVF cycles and results, ovarian reserve (AMH), prior ART 
attempts, prior ART outcomes, embryo stage and quality at time of cryopreservation, 
technique of cryopreservation (slow-cooled for vitrified), own eggs or donor eggs, 
ovarian stimulation regimen, number of oocytes retrieved, number fertilized, number of 
embryos cryopreserved, whether or not preimplantation genetic testing (PGT) was 
performed, type of hormonal regimen for frozen embryo transfer, and endometrial 
thickness before transfer as measured by ultrasound, will be recorded on a data collection 
sheet.  
3)! Patients will be randomized by sealed envelopes containing randomized numbers (either 
1 or 2) which corresponds with the research group. 1 will be vigorous endometrial biopsy 
with a Pipelle curette. 2 will be 4 quadrant endometrial activation with a Shepard 
insemination catheter.  

4)! During the cycle prior to their embryo transfer, patients will come to the Women’s 
Institute between cycle days 21-27 for the endometrial activation procedure.  
5)! For patients in group 1, physicians will insert the Pipelle curette into the uterus and 
remove an adequate endometrial sample using vigorous motion.  
6)! For patients in group 2, physician will insert the Shepard insemination catheter into the 
uterus at 12:00 and then withdrawn. The catheter will be turned one-quarter turn and 
withdrawn. This will be repeated two more times so that 4 endometrial quadrants will 
have been touched by the catheter.  
7)! Immediately following the endometrial procedure, patients will be given a Numerical 
Rating Scale for pain, on which they will circle the number which best correlates with the 
patient they experienced during the procedure. This data will also be collected on the data 
collection sheet.  
8)! The rest of the IVF cycle and embryo transfer will proceed by standard protocol.  
9)! After the embryo transfer, additional data will be collected for the data collection sheet 
including number of embryos, grade and stage of the embryos, number of embryos 
transferred, pre-implantation genetic testing, type of freezing (slow freeze vs. 
vitrification), difficulty of the transfer procedure, implantation rate, positive pregnancy 
test, live birth rate. 
 
 
Independent Variables  
The independent variable is type of endometrial activation – vigorous Pipelle curette vs. four 
quadrant placement of the Shepard insemination catheter.  
 
Outcome Variables 
 Our primary outcome variable is live birth rate. Our secondary outcome variables are pain 
(using a numerical pain scale), implantation rate, and positive pregnancy tests, ultrasound 
evidence of pregnancy, implantation rate, birth rate, and incidence of multiple pregnancies (twins 
or more). 
 
Confounding Variables  
Variables which may confound the results are patient age, frozen or fresh embryo transfer, 
ovarian reserve, number of embryos, grade and stage of the embryos, number of embryos 
transferred, pre-implantation genetic testing, previous IVF, previous IVF failure, own eggs or 
donor eggs, type of freezing (slow freeze vs. vitrification), difficult transfer, ovarian stimulation 
regimen, type of hormonal regimen for frozen embryo transfer, uterine abnormalities.  
 
We plan to sub-stratify our randomization based on the most important confounding variables: 
fresh embryo transfer and frozen embryo transfer.  
 

Statistical Analysis  
Based on the distribution of the data results, we will plan to use means, standard deviations, and 
p-values by Chi-squared testing for normally distributed data or medians, interquartile ranges, 
and p-values by Mann-Whitney testing for non-normally distributed data.  
 
We plan to work with the statisticians from CMC’s Dickson Advanced Analytics who used DA2 
software.   
 
Sample Size  
Based on an 80% power calculation in which a 10% change in live birth rate was deemed to be 
clinically significant, the sample size needed to attain adequate power is 200 total patients.  
 
Duration  
We believe it will take approximately one year to enroll and complete all 200 patients.  
 
Budget  
This study does not have a budget. There will be no charge to the patient for the endometrial 
activation because the physicians have agreed to donate their time, and the procedures will be 
done in-office.  
 
References  
1)! Infertility. Center for Disease Control and Prevention: FastStats. 
http://www.cdc.gov/nchs/fastats/fertile.htm. Retrieved on April 4, 2014. 
2)! Nastri CO, Ferriani RA, Raine-Fenning N, Martins WP. Endometrial scrating performed 
in the non-transfer cycle and outcome of assisted reproduction: a randomized control 
trial. Ultrasound Obstet Gynecol 2013;42:375-82. 
3)! Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the 
endometrium doubles the incidence of successful pregnancies in patients undergoing in 
vitro fertilization. Fertil Steril 2003;79(6):1317-22. 
4)! Nastri CO, Gibreel A, Raine-Fenning N, Maheshwari A, Ferriani RA, Bhattacharya S, 
Martins WP. Endometrial injury in women undergoing assisted reproductive techniques 
(review). Cochrane Collaboration 2012;7:1-43.  
5)! Leclair CM, Zia JK, Doom CM, Morgan TK, Edelman AB. Pain experienced using two 
different methods of endometrial biopsy: a randomized control trial. Obstet Gynecol 
2011; 117(3):636-41.