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Implantation Failure and The Endometrial Receptivity ERA: Important Points To Know

For several decades we in the reproductive medical field have been trying to identify reasons that apparently normal embryos fail to implant. That is once transferred in the context of in vitro fertilization (IVF), the embryo fails to result in a positive pregnancy test.  Certainly, we know that certain uterine abnormalities can contribute to the failure.  These are typically easily identified (things like polyps, etc.) and corrected prior to the process of embryo transfer.  No one believes that all failures of implantation can be the result of a specific pathologic abnormality such as polyps in the context of IVF and embryo transfer.  Clearly, there are other issues at play that are above and beyond structural abnormalities of the uterine environment.

The Endometrial Receptivity Array (ERA) test is a molecular diagnostic test that assesses the activity of roughly 240 genes that are implicated in the function of the endometrium and confer upon it this concept of “receptivity”.  This test is coupled with a bioinformatics assessment to subsequently define the endometrium as “proliferative, pre-receptive, receptive or post-receptive”.  This is an attempt to define the so-called “window of receptivity, WOI”.  It has demonstrated superior accuracy and consistency to previous methods of trying to date the endometrium.

The question really has been whether a given patient’s endometrium is “pathologic or abnormal” or whether there is a desynchrony. Obviously, the development of the endometrium and the development of the embryo are regulated independently, and they may not occur at the same time during a cycle of IVF.  If this timing is off, then the otherwise normal embryo will fail.  Again to reiterate, this is not a pathologic problem, per se, of the endometrium but simply a personal difference that some patients may have that their endometrium develops at a different rate than the embryo.  This personal differential development may indeed be due to inherent factors of that given person’s endometrium or hormonal factors.  This has led to the development of theERA test.

The ERA has attempted to identify personal differences that a patient may have in the way their endometrium develops and thus allow the clinician/physician to alter the administration of progesterone in the context of an embryo transfer accordingly.  Thus, improving the synchronicity between the embryo development and the endometrium development.

Studies have demonstrated that there may be up to 25% of individuals with recurrent implantation failure (RIF) than indeed were demonstrated to show non-receptivity during the timing of the previously failed cycle.  This appears reproducible, also, in any given patient over repeated cycles.  The key point here is that these were patients with “recurrent” implantation failure, not a single implantation failure, that is not a single failed IVF transfer.  The average number of failed cycles in these patients that were studied was about 4.  However, the study also suggested that in patients without a history of recurrent failure, that as many as 1 in 8 showed a displaced window, that is roughly 12% of individuals failing for the first time will have abnormal ERA findings.  Again, these patients do not have a disorder or pathology, per se, but simply that they may require a “personalized” administration of medications to obtain receptivity in their endometrium.  The problems with this particular situation include:

  1. Various costs associated with the test, approximately $600 to $800.  This may be changing over time, lower perhaps.
  2. The test cycle wherein the ERA is obtained requires that the frozen embryo transfer in the future be delayed by perhaps 2 months.  This can be a problem for some patients and their interests.
  3. These studies did not utilize PGS testing of the embryos prior to the transfer, thus abnormal embryos leading to implantation failure may be the cause of many of these issues and not the endometrium itself.
  4. Question remain on whether a patient should endure multiple cycles of implantation failure before performing the test. In other words, does it benefit patients to do this before the first embryo transfer or indeed should you wait for at least 1 failure?  This is a tough question, obviously, that time will tell with further studies.

So, it appears that the endometrium of a certain individual may vary under different circumstances.  Such circumstances as the hormone treatment received during an IVF/embryo transfer cycle and the so-called window of implantation (WOI) may be different from other patients.  The ERA test is designed to try to identify these differences and thus allow personal alterations for the individual, utilizing different hormonal administration methods to synchronize the WOI with the embryo.

Peter Ahlering, M.D.

Medical Director