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Do ERA Tests for IVF Work? What is an Endometrial Receptivity Analysis

Why do I keep hearing about ERA tests? Do they work? The answer? No.

Most women pursuing In Vitro Fertilization (IVF) are curious about additional tests or procedures that could increase their chances of a successful treatment. One such test that has been widely available is called an ERA test, or an Endometrial Receptivity Analysis.

Until recently, the value of an ERA test was debated – although it helped some women conceive and have an ongoing pregnancy, there was very little scientific research on whether it worked.

At the American Society for Reproductive Medicine (ASRM) 2021 congress, there was a Randomized Controlled Trial (RCT) – the highest standard of scientific study – showing the test did not improve outcomes in an unselected patient population. In other words, the ERA test doesn’t work for women in the general population pursuing IVF.

But more on that later. First, let’s dig into what the test is all about.

What is an ERA test?

An ERA Test or Endometrial Receptivity Analysis claims to help women pursuing In Vitro Fertilization (IVF) determine whether their endometrium is receiving an embryo at the right time in an attempt to maximize their chances of a successful pregnancy and live birth.

Even outside of a fertility clinic, getting pregnant is a delicate science. It involves all the right pieces being in the right place at the right time.

One of the most important pieces in this reproductive orchestra is the relationship between a woman’s endometrium (uterine lining) and the embryo that is about to implant inside it.

Both in the bedroom and the fertility doctor’s office, the meeting of the embryo and the endometrium has to happen at just the right time for implantation, and pregnancy, to occur.

If the meeting doesn’t happen when it needs to, like ships in the night, the embryo and endometrium will just miss each other, and pregnancy will not occur.

This concept is known as ‘the window of receptivity,’ or ‘the window of implantation.’ An ERA claims to help women determine this window during an IVF treatment cycle.

What is the window of receptivity, exactly?

The window of receptivity is a short amount of time when your uterus is ready to receive an embryo at the proper stage of development necessary for implantation, and therefore pregnancy, to occur.

In the case of the uterus, it’s the lining inside the uterus, the endometrium, that plays a major role.

In addition to being a certain thickness, the endometrium must be expressing the correct genes that tell a potential embryo it is ready for implantation, a process largely driven by the hormone progesterone.

As for the embryo, it must be mature enough to successfully implant (it must have reached the blastocyst stage, which is day 5 or 6 of growth).

In addition, the embryo should be chromosomally normal so that it can implant and lead to an ongoing pregnancy (abnormal embryos will usually fail to implant or result in a miscarriage.)

If both the embryo and uterus are ready at the same time, implantation and pregnancy can occur; if the window is missed, however, and the embryo is not at the right developmental stage by the time it reaches the uterus, it doesn’t contain the right number of chromosomes or the endometrium is not expressing the correct genes, implantation and pregnancy will not occur.

This ‘window of receptivity’ exists in both natural conception and in IVF.

Is every woman’s window of receptivity the same?

Though doctors used to believe that this window existed sometime between 8 and 10 days following ovulation for all women, it is now understood that this window is not universal for all women, and can vary depending on the woman’s level of progesterone and the genes being expressed by her endometrium.

Do I need to worry about my window of receptivity?

Many women who pursue IVF don’t need to worry about their window of receptivity because they do indeed get pregnant, meaning successful implantation has occurred.

In fact, RMA research has shown that women with three normal embryos have a 95% of pregnancy.

In other words, almost all women will have success on their third IVF cycle with a normal, or euploid, or embryo, meaning the window of implantation was met. (Women who test their embryos with Pre-implantation Genetic Testing, or PGT-A, will know whether their embryos are normal or abnormal).

For the small percentage of women who do not get pregnant after multiple attempts with normal embryos, fertility doctors may investigate whether the reason for their Recurrent Implantation Failure (RIF) – characterized as the inability to achieve pregnancy after the transfer of three or more normal embryos – is related to missing the window of receptivity.

So what is the ERA testing, exactly?

The ERA test claims to analyze whether a woman’s uterus is in, is about to be, or has passed its window of receptivity.

Many fertility clinics will offer the test, although RMA, for example, will not routinely offer the test after recent findings showed it is not effective in unselected patient populations.

The test aims to tell the IVF patient and her doctor whether their existing protocol (and embryo transfer timing) should remain as is, or be pushed forward or back.

This is known as a ‘personalized embryo transfer.’

How does the ERA test work?

The test consists of two parts:

  • Taking a sample of a woman’s endometrium (a biopsy)
  • Having that sample tested for its gene expression

Based on what genes are being expressed in the biopsy, the test claims to give clinicians information on whether the endometrium is receptive or non-receptive to an embryo at the time of the biopsy.

How is the ERA biopsy performed on a patient?

The biopsy is usually performed at the exact moment when doctors would transfer an embryo into a patient’s uterus.

This means that patients will undergo a transfer cycle but not actually have the embryo transferred. This is because the objective is to test the endometrium for its gene expression right before a transfer.

This ‘prep’ cycle involves the same steps as a ‘real’ transfer cycle. – taking oral medications and self-injected medications to stimulate your uterine lining.

This prep cycle will require transvaginal ultrasounds and bloodwork visits to monitor response to the medications.

At the end of the prep cycle, a doctor will perform the biopsy. The biopsy is a two-minute procedure that may be slightly uncomfortable. The procedure does not require sedation.

The biopsy involves placing a flexible plastic tube into the woman’s uterus (with the help of a vaginal speculum) and moving it back and forth to collect tissue from the lining of the uterus.

Afterward, a doctor will send this sample for processing to a third party who will test the sample for the expressions of hundreds of genes and deliver a result to the doctor and her patient.

Depending on the result, a doctor may move the patient’s transfer timing (by modifying the patient’s exposure to progesterone) forward or back so the patient can try to meet her window of receptivity during her next cycle.

So patients who get an ERA will delay their fertility treatment?

Yes. Because no embryo will be transferred during the prep cycle when the test is performed, a patient will be delaying treatment (in the form of a real transfer).

The delay will likely be about a month for those who have embryos to transfer. It can take up to two months for those who must undergo an egg retrieval cycle to make embryos prior to transfer.

Why doesn’t the test work?

While some women have seen success with the ERA test, an RCT presented at the ASRM 2021 Congress showed the test did not improve ongoing pregnancy rates in an unselected patient population.

Specifically, in this trial, a large group of women pursuing IVF with PGT-A had all undergone an ERA prep cycle before they were randomly split into two groups – the control group and the study group. From the study group, 375 women had a euploid Frozen Embryo Transfer (FET) based on the results and recommendation of the ERA, while 380 in the control group had their euploid FET based on the standard protocol. Then researchers waited to see the clinical outcomes between the two groups, specifically in relation to ongoing pregnancy rates, defined as having a heartbeat at 8-10 weeks and no subsequent miscarriage. Women who had recurrent pregnancy loss and recurrent implantation failure were excluded.

The results were undeniable – of all the women who had a non-receptive ERA result, meaning the test deemed their uterus not ready to receive an embryo, 62.5% of women in the control group, and 55.5% in the study group, had an ongoing pregnancy. Additionally, for those who the ERA test recommended a change in transfer timing, 63.3% in the control group had an ongoing pregnancy compared with 54.5% in the study group. Plus, the authors were able to get live birth data from women in both groups, finding the live birth rate was 61.9% in the control group and 58.3% in the study group.

These findings are significant because they show that an altered protocol based on the ERA test did not result in a higher ongoing pregnancy or live birth rate for women in this study.

In fact, the women who the ERA test deemed “non-receptive,” and those for who it recommended a change in transfer timing yet were in the control group and did not change their protocol, had higher pregnancy rates – although did not reach as statistical difference – than the women who adhered to the ERA recommendation.

The authors concluded: “Patients and physicians hold great hope that personalized medicine will improve [assisted reproductive technology] outcomes; however, ERA does not improve [ongoing pregnancy] from [frozen blastocyst transfer] of a single euploid blastocyst.”

One important caveat to these findings is that this study did not focus on women with RIF. The authors note that an additional RCT is necessary to test whether the ERA is beneficial for women with RIF.

So should anyone get an ERA?

The group with the best chance of success from an ERA is women with RIF. But again, because the recent RCT showed the test is not effective for women in the general IVF population, and the test has not been studied on women with RIF, the benefit of the test for these women is unknown.

Does RMA offer the ERA test?

Following the publication of the recent RCT showing the test does not work in unselected patients, RMA began phasing out the test at all its locations, and will not be offering it in the future. Despite this, your RMA doctor will be happy to talk with you in-depth about the test and the most recent findings, as well as to reassure you that RMA’s evidence-based medical protocols are positioned to give you the best chance of success.

Is the DEFENTS study at RMA still going on?

As a research clinic, RMA is currently conducting much-needed research on endometrial gene expression. Our current research is looking at the window of receptivity, which is related to, but different from, the ERA test.

Our research study, which is called DEFENTS and is currently enrolling patients, will help RMA clinicians understand the differences in gene expression between fertile, infertile and recurrent pregnancy loss patient populations, a critical step in understanding differences in the window of receptivity among women.

It will also help shed more light on the efficacy of commercially-available ERA tests, which, as stated above, RMA will no longer offer due to ineffectiveness in unselected patients.

Is the ERA test covered by insurance? If not, how much does it cost?

An ERA test may or may not be covered by insurance. The test usually costs around $1,000 out of pocket.

What’s the bottom line?

Recent data has shown that the ERA test does not stand to benefit women in the general IVF population, although a rigorous study looking at the test’s efficacy in women with RIF is still needed. Due to the recent findings, some clinics, like RMA, may no longer offer the test. If you want to know more about this research, the ERA test or RIF, talk to your fertility doctor.

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