The ERA explained.
Doctors love to share clinical anecdotes. I am no exception:
The year was 2014, and I was treating a young and healthy woman whose only reason for IVF was because her partner’s sperm count was low. She wanted to make sure we were picking the best embryos, so we took the extra step of PGT-A (back when it was still called CCS, or comprehensive chromosomal screening). Six of her embryos were found to be normal, an outstanding result we were all very excited about! A sure thing, I thought, given that the implantation rate for chromosomally normal embryos is typically 75% in our clinic.
In preparation for her embryo transfer, everything looked great: the endometrium was more than 8mm thick with a trilaminar pattern. Her transfer procedure was simple, but alas it failed. Disappointed, but still encouraged by how many embryos she still had left, we just tried again. Unfortunately, the second transfer failed too. Let’s add some extra treatments, I suggested, such as aspirin, heparin, prednisone, and intralipid. These are controversial, but sometimes seem to help patients with unexplained implantation failure. Yet her third cycle also failed despite “the kitchen sink” approach.
This lovely patient had done everything I counseled her to do, spent thousands upon thousands of dollars, and suffered immense heartache, especially since little hope was apparent going forward. By far, the most common reason for implantation failure can be ascribed to unhealthy embryos, but hers were highly graded and chromosomally normal. We had also added all the “extras” too, and still no avail. I was at wits end to the say the least.
It was at that time I learned about a test called the Endometrial Receptivity Array (now the A stands for Assay), or ERA for short. This was the first time we tried it at Olive (and perhaps one of the first in Canada). The ERA requires a dress rehearsal of sorts: a mock cycle is performed to prepare the endometrium for an embryo transfer. However, instead of the transfer, an endometrial biopsy taken, and the tissue sample is sent to a company called iGenomix where the RNA is extracted and an expression profile is performed for 238 genes that are known to be important for implantation.
The rationale for the test is based on the fact that the endometrium will only allow the implantation during a finite time frame known as the window of implantation (WOI). If the embryo is delivered to the uterus too early or too late, when the window is closed, implantation cannot occur. The concept of the WOI has been recognized for decades. However, until the ERA test was developed, there was no meaningful way to measure it in any given individual. More importantly, the ERA was actionable: if the endometrium was found to be non-receptive a plan to optimize receptivity was provided. I was not convinced by the data I had read at the time but given that we had exhausted all our traditional options we decided to give it a try.
Sure enough, the ERA showed that her WOI was shifted 24 hours later than we thought, a diagnosis we would have never made otherwise. We made the suggested adjustments, and low and behold, she conceived with her subsequent transfer, had a successful pregnancy and a beautiful baby, then two more over the next few years!
In 2018 we published a review of our data with the ERA for patients who had previously experienced implantation failure with chromosomally normal embryos. We found that if the ERA results were non-receptive, and we made the appropriate adjustments, patients were more likely to conceive with the next transfer. (If you would like a copy of the paper, email me: email@example.com).
We have used the ERA hundreds of times over the years for patients with a history of implantation failure, but a question that has always lingered: should we be using the ERA for all patients? Why wait until implantation failure has already occurred and precious embryos have been wasted?
The bottom line is that ERA test was designed specifically for those with a history of implantation failure, not all comers. Most patients will have the typical WOI, thus for the majority the ERA won’t offer any actionable results. Some would suggest that normal results would at least offer reassurance even if they don’t change the treatment which may be true, but it is also important to consider what is involved in the ERA: 1) it requires a dedicated month which delays the transfer cycle, 2) an endometrial biopsy needs to be performed, which is usually quick, but can be uncomfortable for many patients, and 3) there are financial costs involved.
A recently published study did in fact suggest that the ERA may add value for patients from the get-go. The designs and conclusions of the study are not perfect for many reasons, but at least it offers some evidence that the usefulness of the ERA may extend beyond implantation failure. We are also participating in an ongoing clinical trial further investigating the value of the ERA for patients who have had PGT-A. (If you are an Olive patient who has had IVF with PGT-A, ask your care team about the “PEAR study” if you are interested).
(As a newish twist, we can also perform 2 more tests at the same time as the ERA, called the EMMA and ALICE, which analyze the microbiome and chronic endometritis, respectively. I will discuss these in a future post.)
If you have the ERA, we find the problem and fix it, is implantation guaranteed to happen with the next transfer? Unfortunately, no. The ERA doesn’t give us all the answers. However, in our experience, it can be a helpful tool for many patients. Talk to your Olive team to determine if the ERA is right for you.