An endometrial receptivity analysis (ERA) has the goal of identifying the perfect time, or window of implantation, to transfer an embryo for better live birth rates. ERA was initially developed for patients with recurrent implantation failure and then became available for all IVF patients. But as this test evolved into an optional add-on for all IVF patients, we stopped and asked ourselves: Who benefits from ERA testing?
The test’s manufacturer, Igenomix, recently worked with Nicole Doyle, M.D., Ph.D., and a team of SGF researchers to conduct the largest randomized trial of its kind to better understand the effectiveness of ERA within the entire IVF patient population.
Given the study’s new findings, which were presented at the 2021 ASRM Scientific Congress and Expo, let’s evaluate what ERA testing is, live birth success rates, and who might benefit most from ERA testing.
How does ERA testing work?
Let’s first examine why ERA was created. In unassisted reproductive physiology, an embryo does not implant into the uterine lining right away. After fertilization, it spends about three days in the Fallopian tube, where it then travels to the uterus and takes a few more days before it implants.
“With fertility treatment, we try to mimic the concept of natural physiology and transfer the embryo after it has developed for about a week in the embryology lab,” explains Dr. Doyle. “However, the optimal time for transfer is still unknown. When we transfer a genetically normal embryo at the ‘perfect time,’ the chance for live birth is about 60-65%, so there’s definitely room for improvement.”
The embryo transfer is performed at the same time for all women. However, it has been suggested that a proportion of women are not receptive to an embryo that is trying to implant at standard transfer timing. These women may benefit from a more targeted transfer at an earlier or later time.
ERA is a diagnostic test that seeks to identify the ideal time for embryo transfer. The introduction of next-generation gene sequencing allowed researchers to characterize the endometrium, or tissue lining of the uterus, based on what genes are expressed throughout each phase of the menstrual cycle.
ERA classifies the menstrual cycle into five phases:
- Pre-receptive phase: Before the window of implantation
- Early receptive phase: Nearing the ideal window of implantation
- Receptive phase: Ideal window of implantation
- Late receptive phase: Window of implantation is closing
- Post receptive phase: The window of implantation has closed
The goal of ERA is to determine an individual’s personal window of implantation. With ERA, physicians can isolate a patient’s unique receptive phase down to a specific, six-hour window.
How to prepare for an ERA
The ERA cycle takes about four weeks to complete from initial testing to when results are available. The cycle itself takes about 16 days, then allow an additional 14 days to receive results.
An ERA cycle is performed the same way a patient prepares for a frozen embryo transfer (FET). However, rather than performing an actual embryo transfer, an endometrial biopsy is performed. The biopsy assesses whether the uterine lining would have been receptive if an embryo transfer was performed.
What can patients expect during the ERA testing process?
- Estrogen) pills are taken for 10 days, or until the lining measures at least 7mm and Estrogen levels are adequate.
- Progesterone is then prescribed for 6 days. Receptivity to implantation depends on the length of time exposed to progesterone.
- A subset of patients may benefit from longer or shorter timelines of progesterone exposure.
- An endometrial biopsy is performed, and the lab then analyzes tissue samples for more than 200 genes to predict the best time to transfer the embryo into the uterus.
- The FET protocol and length of progesterone exposure is then adjusted to align with the most optimal time to transfer an embryo.
Study findings on live birth rates with ERA testing
Our recent in-house study was designed to investigate whether or not fertility specialists should individualize embryo transfer windows for all IVF patients. For standard embryo transfers at SGF, our doctors transfer an embryo after 123 +/- 3 hours of progesterone. It’s important to note that embryo transfer protocols between practices and even physicians can vary.
“For this study, we randomized 767 good prognosis patients into a study group and control group*,” explains Dr. Doyle. “The study group included patients who underwent ERA testing and transferred an embryo according to the ERA recommendation. The control group also underwent ERA testing, but then followed SGF’s standard embryo transfer protocol.”
SGF’s findings revealed that in a population of good prognosis IVF patients, ERA appears to have no superiority over standard frozen embryo transfer and does not result in improved transfer outcomes:
- Study group: 58%
- Control group: 62%
“We had hoped for better results, but from a cost-benefit, ERA testing is not worth it,” Dr. Doyle reported to the New York Times in a December 2021 article on ERA study findings for good prognosis IVF patients without a history of recurrent implantation failure.
When is ERA testing recommended?
ERA could be beneficial for patients with recurrent implantation failure with high-quality embryos, but the data to confirm this is lacking.
“It is important to emphasize that we cannot assess the benefit of ERA for patients with recurrent implantation failure,” explains Dr. Doyle. “We still need a clinical trial to evaluate if ERA is a beneficial adjunct for this particular patient population. When it comes to counseling patients, we are discussing the data from our clinical trial and will ultimately respect the patient’s wishes.”
Ultimately, since no universal recommendation criteria exist, the decision to proceed with an ERA cycle will be one made by the physician and the patient after thorough counseling.
Medical contribution by Nicole P. Doyle, M.D., Ph.D.
Nicole P. Doyle, M.D., Ph.D., FACOG, is board certified in obstetrics and gynecology and reproductive endocrinology and infertility. Dr. Doyle’s clinical interests include diminished ovarian reserve, in vitro fertilization, oocyte donation, and fertility preservation. She sees SGF patients in the Fairfax, Virginia office.