Performing Personalized Embryo Transfer (Pet)
Using the Endometrial Receptivity Analysis (ERA)
Test in A Case With Recurrent Implantation Failure
Kaur Jasneet* and Mahajan N
Department of Reproductive Medicine. Mother and Child Hospital, Delhi, India
Submission: June 20,2018; Published: October 11, 2018
*Corresponding author: Kaur Jasneet, Mother and Child Hospital, Defence Colony, New Delhi, India.
How to cite this article: Kaur J, Mahajan N. Performing Personalized Embryo Transfer (Pet) Using the Endometrial Receptivity Analysis (ERA) Test in A
Case With Recurrent Implantation Failure. Anatomy Physiol Biochem Int J: 2018; 5(4): 555666. DOI: 10.19080/APBIJ.2018.05.555666.
Background: Recurrent implantation failure (RIF) is a major challenge to ART success. Despite extensive research a comprehensive understanding of the intricacies of the process of implantation remain elusive. Historically, it has been assumed that the window of implantation is always constant in all women. However, molecular analyses of endometrial receptivity demonstrate a personalized WOI (pWOI) that is displaced in one out of four patients with recurrent implantation failure. Here, we report a clinical case of successful pET after one fresh and three frozen embryo transfer failure
Case description:A 31-year-old women with primary infertility, grade 4 endometriosis and recurrent implantation failures underwent embryo transfer in the personalized window of implantation as guided by the ERA test and had a successful ART outcome.
Conclusion:In the era of personalized medicine, a “one size fits all” policy is no longer acceptable and performing a personalized embryo transfer in patients with RIF as guided by the ERA test maybe the way forward.
Clinical significance: Diagnosis of endometrial receptivity has posed a challenge because of the lack of accurate, non-invasive, and clinically applicable tests. However, performing the Endometrial Receptivity Analysis (ERA) test which is a customized array based on the transcriptomic signature of human endometrium helps to improve the reproductive outcomes in patients with RIF.
After four decades of IVF, implantation failure still remains a major challenge to ART success. Human implantation is a multifaceted, finely orchestrated event requiring the presence of a healthy embryo, a receptive endometrium, successful embryo-endometrial cross talk and maternal immune protection of the allograft . The most important causes of implantation failure include embryo aneuploidy, altered endometrial receptivity and immune dysregulation. Modern tools like genomics and bioinformatics help us in determining the personalized WOI. Our case report shows how performing an embryo transfer in the pWOI can make a difference after several previous IVF attempts.
Mrs S.B. 31-year-old presented to us as a case of primary infertility with grade 4 endometriosis and recurrent implantation failure. She had a married life of 4 years, regular menstrual cycles with previous h/o congestive dysmenorrhea and dyspareunia. She had undergone a laparoscopic ovarian cystectomy along with adhesiolysis in view of chronic pelvic pain three years back. Post her surgery for endometriosis she underwent 4 cycles of ovulation
augmentation with both oral ovulogens and gonadotropins followed by 3 cycles of IUI. She underwent two consecutive IVF attempts two years back. In her first cycle she had a fresh embryo transfer in which 2 d3 embryos were transferred followed by a frozen embryo transfer in which two good quality blastocysts were transferred. In her second IVF cycle a freeze all strategy was employed, and she underwent two frozen embryo transfers, each involving transfer of two good quality blastocysts. However, her urine pregnancy test was however negative.
We planned on another cycle of IVF followed by a frozen embryo transfer (in the pWOI as guided by the ERA test).We followed the flexible antagonist protocol and ovarian stimulation was started with 300 IU recombinant follicle-stimulating hormone (follitropin-alfa Gonal-f®, EMD Serono, Inc.,) guided by her age 31 years ,AMH-1.9ng/ml ,AFC 5/6 and BMI 24.5kg/m2 for first 5 days followed by Menopur (highly purified HMG-Ferring Pharmaceutical Ltd.) 300 iu for another 4 days. GnRH antagonist (Cetrolix, Intas Pharmaceuticals Ltd.) was started according to the flexible protocol. On day 9 of her stimulation her estradiol levels were 2357pg/ml and progesterone level were 0.87ng/ml with an endometrial thickness of 7.4mm. Inj human chorionic
gonadotropin (hCG) 5000 IU with triptorelin 0.2mg s/c was given
as the trigger. Oocyte retrieval was performed 35 hours later
under general anesthesia, using transvaginal ultrasound guidance.
We retrieved 11 oocytes out of which 9 fertilized and we had 6d3
good quality embryos that were cryopreserved.
We performed the endometrial receptivity analysis in the next
cycle to determine the personalized window of implantation. ERA
was performed in an HRT cycle in which estradiol valerate was
started in a dose of 2 mg (after performing a tvs on day 2); was
increased to 6 mg till an appropriate endometrial thickness of 7.8
mm was achieved. This was followed by administration of vaginal
progesterone suppository 400 mg twice a day for 5 days starting
from day 12 of HRT after ensuring that the serum progesterone
was less than 0.9ng/ml. An endometrial biopsy was performed
using the pipelle catheter from Gynetics and the endometrial
tissue was transferred to a cryotube containing 1.5 mL RNA
stabilizing agent (Qiagen), vigorously shaken for a few seconds,
and kept at 4°C in refrigerator for 4 h which was later transported
to the Igenomix lab. ERA result came as post receptive (p+4.5
receptive) and it was recommended to perform the blastocyst
transfer 12 hours prior to the scheduled time. A downregulated
frozen embryo transfer was performed in which two good quality
blastocysts were transferred a traumatically under ultrasound
guidance as suggested by the ERA test. Luteal phase support in
the form of Inj uterine 50 mg daily along with vaginal micronized
progesterone 400mg bd was given. Her urine pregnancy test was
positive after 14 days. An ultrasound performed one week later
showed a single intrauterine pregnancy with a gestational sac
diameter corresponding to 5w2d.
Recurrent implantation failure remains a major challenge
even after four decades of ART. Approximately 10% of couples
undergoing IVF are faced with the issue of RIF. Polanski et al in
2014  suggested that RIF should be defined as the absence of
implantation after two consecutive cycles of IVF, ICSI or frozen
embryo replacement cycles where the cumulative number of
transferred embryos was no less than four for cleavage-stage
embryos and no less than two for blastocysts, with all embryos
being of good quality and of appropriate developmental stage
.Important causes of implantation failure include embryo
aneuploidy,, altered endometrial receptivity and a dysregulation
of the immune system.
Diagnosis of endometrial receptivity has posed a challenge
because of the lack of accurate, non-invasive, and clinically
applicable tests. Histological, biochemical, and ultrasound markers
of ER have been proposed for use to improve implantation rates
(IRs) in IVF. Unfortunately, most of these methods are unreliable
and do not have any predictive value. However, with the coming
up of the ERA test we can have a better insight of the endometrial
receptivity. It is a customized array based on the transcriptomic
signature of human endometrium and analyzes the expression
levels of 248 genes linked to the status of endometrial receptivity,
using RNA sequencing with the help of NGS . It involves use
of an informatic predictor that analyzes the gene expression data
and classifies the endometrium as “Receptive” or “Non-Receptive”
with a sensitivity of 0.997 and a specificity of 0.885 and helps us
to determine the pWOI .
Studies have shown that in patients with endometriosis there
is a dysregulation of selected genes in the endometrium leading
to impaired embryonic attachment, embryotoxicity and apoptosis
during the window of implantation. Several molecules involved
in implantation have been shown to be differently expressed
in patients with endometriosis including reduced expression
of the cellular adhesion molecule αvβ3 integrin and altered
expression of methylation of HOXA10, a potent stimulator of αvβ3
expression. However, there is still a lack of conclusive evidence
to prove the role of endometriosis in altering the endometrial
receptivity . ERA is a step forward in improving ART outcomes
by personalizing embryo transfers in patients with RIF. It is the
most objective and accurate test available today for diagnosing
endometrial receptivity and is extremely beneficial in patients
with RIF. Studies have shown that in about 25 percent of patients
with RIF there is a displacement in the WOI which could be caused
by some intrinsic genomic alterations and so personalizing
our embryo transfers might help to improve the reproductive
performance in these patients .
In the era of personalized medicine, a “one size fits all”
policy is no longer acceptable and performing an embryo
transfer in patients with RIF as guided by the ERA test which
allows synchronization between the blastocyst and a receptive
endometrium—a key factor in promoting implantation; is the way