Wednesday, March 18, 2015

Endometrial receptivity assay and other endometrial function tests - are they of any use ?

Failed implantation is one of the most frustrating problems IVF doctors and patients need to deal with. We are good at making gorgeous looking embryos in the lab , but most of them never become babies ! Why is this ? Is the problem with the embryo ? or with the uterine lining ?

In order to improve the chances of transferring healthy embryos, IVF labs now use  advanced genetic technology ( such as CCS and NGS for PGD) , to select the chromosomally normal embryos. However, not all of these embryos  implant either ! Doesn't it then logically follow that if a normal embryo does not implant, this means the problem is with the uterine lining ?

This is why so much research has been done on developing endometrial  function tests, to optimise endometrial receptivity, and improve the chances of IVF success.

Thus, Yale has  developed the EFT ( endometrial function test) ; IVIomics has developed the ERA
( endometrial receptivity array) ; and CCRM does a test called Beta Integrin 3 which tests for the missing protein that is the "glue" for implantation.

All these tests harp on the importance of the "soil" in facilitating embryo implantation, and because there is so much competition, they are being hyped and marked as "breakthrough tests" to improve IVF success rates.

The problem is that no one really knows whether these tests are helpful or not. However, because infertile women are so desperate , they are happy to serve as guinea pigs . To add insult to injury, they have to fork out huge sums of money for the privilege of getting these tests done ( even though they are research tests only, and not of proven clinical value).

For example, even if the test picks up a problem, does this mean that the "abnormality" is consistent  and occurs cycle after cycle ? After all, we all know that there's lots of biological variation and we should not jump to conclusions based on just one abnormal result. Ideally,  the test should be repeated in the next cycle, to see if the result is persistently abnormal , but because the tests are so expensive, this is hard to do in real life. Also, both doctor and patient are so happy that they've finally pinpointed the reason for the failure, that they are happy to go ahead with the "treatment". Yes, some women will get pregnant after the treatment, and both the patient and their doctor will be happy to give credit to the test for the success, but who knows whether the "treatment" really helped or not ?

The problem is that the concept of an "unripe soil" makes biological sense , and because we have so little to offer, doctors are happy to proceed along the lines of "Well, in theory this should help, so let's try it and see ! "? The tests are promoted with lots of clever marketing, by using emotionally evocative terms, such as " personalised embryo transfer ". This means makes intuitive sense - after all, isn't every patient different ?

The problem is that all these tests are patented  to protect "intellectual property" , which means there's  no external independent validation. It's hard to blindly believe what the manufacturer says.  They claim that the tests are backed by "10 years of research and published medical journal articles " - but this doesn't mean anything. In fact, because they have invested so much time and money on this research, they are compelled to show a return on their investment for financial reasons !

In fact, the very fact that there are so many tests is testimony to the fact that we don't know how well any of them work. So how do we know whether to do something ? or nothing? “When many cures are offered for a disease,” wrote Anton Chekhov, “it means the disease is not curable.” If past experience or data suggests that multiple solutions are possible but none are reliably successful, nothing may be the best strategy.

There is no way to properly validate these tests, and each RE and researcher has their own beliefs. In fact, many of these beliefs are very deeply held, because they are based on "intuition " rather than evidence . Doctors are not always objective, and get wedded to their beliefs very easily.  We need to remember Mark Twain's words of wisdom , "It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so."

The common justification for these tests are - " Infertility testing is not a perfect science, and will improve as more becomes known.  Infertility, is a multifactorial pathology. Scientists' progress is a never-ending story, and if we wait until all is clear, we will never test and never treat. Infertility patients cannot wait for that. They should and ought to be given the benefit of less-than-perfect studies, if it's helpful even for 1 in ten patients." This sounds very benign, but is a dangerous and unscientific attitude to take. It will just promote quackery , because the hidden sub-text is - So what if it's not been proven to help - let's try it and see if it works !

In 1949, Georgeanna Jones, MD, first described luteal phase deficiency (LPD). It was believed that this condition explained why the endometrium was unreceptive to the embryo, and prevented it from implanting. In fact, this was a condition which REs treated "routinely" for many years. However, data today show that 6-10% of women who are fertile demonstrate an inadequate luteal phase, which is why the ASRM published an opinion in 2012, The clinical relevance of luteal phase deficiency: a committee opinion, which states that "LPD as an independent entity causing infertility has not been proven".

I think we need to be honest with our patients. Let's tell them we don't know why embryos don't always implant - and that just because a test comes from Yale or Iviomics , or uses a lot of genetic jargon, doesn't mean it's reliable !

Confused and don't know what to do next after a failed IVF cycle ? Please send me your medical details by filling in the form at so that I can guide you better !

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