Whenever a patient fails to achieve a successful outcome following IVF, the question arises as to why. Clearly, if the embryos had appeared to be of poor quality microscopically, arrested in their development or failed to achieve appropriate developmental milestones over time, the answer would be clear. Similarly, if the uterine lining was thin, having failed to thicken appropriately in response to hormonal stimulation or there was an intractable immunologic implantation dysfunction, the cause of the failure would be clearly apparent. These are all examples of cause and effect relationships between response-to-treatment and outcome.

In the vast majority of cases – especially when the quality of the embryos transferred is deemed to be adequate, the uterine lining well developed, and the embryo transfer technique satisfactory – the reason for failure is not that cut and dried. In fact, in such cases the explanation given by the treating physician, albeit well intended, usually amounts to nothing more than educated speculation. The reason for this is that when it comes to evaluating embryo competence, microscopic assessment has significant limitations, as does the assessment of uterine receptivity. In addition, we have no control of what happens to embryos after they have been transferred to the uterus (albeit under ultrasound guidance).

While poor uterine receptivity and inadequate technique with regard to embryo transfer do indeed contribute to poor IVF outcome, there can be little doubt that in more than 70% of cases where IVF fails, it is due to the embryo being abnormal and thus incapable of propagating a viable pregnancy. Such embryo “incompetence” is almost invariably the consequence of there being an abnormal quota of chromosomes (aneuploidy) in its cells. Such aneuploid embryos will fail to develop normally, fail to gain attachment to the uterus, miscarry, or result in abnormal offspring (e.g., Down’s syndrome).

It is important to recognize that in spite of looking normal microscopically, an embryo can still be aneuploid. In fact, on average,under one half of normal looking embryos are chromosomally normal (euploid), even in younger women. In women in their early to mid 40’s, less than 1 in 10 are normal. It is thus “disingenuous” to discount poor embryo quality as the reason for failure simply because the embryos that were transferred appeared to have a “good” microscopic grade. The truth is that without a genetic assessment to confirm the presence of all 23 chromosome pairs, it is impossible to reliably affirm embryo “competence”.

We at SIRM were the first to introduce CGH embryo testing into the clinical IVF realm… a few years back. This method does permit relatively accurate assessment of embryo “ploidy”. We have reported on the fact that when a healthy euploid embryo (one that has the correct number of chromosomes in their respective places) is transferred, it affords about a 60-70% chance of a viable pregnancy (several times better than for an untested embryo).

The problem with CGH testing is that it takes so long to get the result back from the laboratory that it becomes necessary to vitrify (freeze and bank) the embryos while awaiting the results of the genetic evaluation, and then perform a subsequent frozen/thawed embryo transfer. While IVF outcome is unaffected by the process of vitrification, the delay in receiving the CGH report nevertheless introduces an additional waiting period which is inconvenient, and introduces an element of apprehension into what already represents a very stressful process.

Hitherto, the inability to reliably assess embryo “competence” through the use of microscopic evaluation led to uncertainty in being able to identify the cause of IVF failure. The fact that embryo aneuploidy (regardless of embryo microscopic appearance) is responsible for more than 70% of poor IVF outcomes, serves to explain why prior to the CGH era it was virtually impossible to reliably pinpoint the cause. It follows that the transfer of chromosomally normal (CGH tested) embryos to the uterus would permit the IVF physician to focus on the remaining 20-30% of causes (i.e., implantation failure and poor embryo transfer technique). This would vastly enhance the ability to define the exact cause of IVF failure and so modify future treatment.

About Hindsight CGH: Many couples, once made to understand the benefits associated with selectively transferring CGH normal embryos rapidly come to terms with the inconvenience and stress related to delaying their embryo transfers. What really discourages people from doing CGH is the cost, which can be $3000-$4000. This is where a new approach we have referred to as “Hindsight CGH” comes in. Here we perform an egg retrieval, fertilize the woman’s eggs and on the third day biopsy her embryos. The biopsied DNA specimens are frozen and stored rather than being sent off for CGH testing. The embryos are then transferred fresh to the uterus (without requiring vitrification and storage). Thereupon once the result of the IVF procedure is known, a decision can be made whether or not to dispatch the biopsied material for CGH analysis. If the woman/couple achieves a viable pregnancy following the fresh embryo transfer, she/they might decide to forgo CGH testing and so save the cost of the genetic analysis. On the other hand, if a viable pregnancy does not ensue, the decision might be made to perform CGH testing in the hope of reaching a diagnosis as to why the procedure had failed in the first place. The latter information might play a pivotal role in helping the patient(s) decide whether they wish to try again, how any future treatment cycle should be modified to address the underlying cause of failure, whether to disengage altogether or move on to third party parenting (egg donation or gestational surrogacy).

A large number of IVF patients who fail to conceive from a fresh cycle of treatment end up having several vitrified (cryostored) embryos remaining. Many of these patients would benefit from knowing whether those embryos are chromosomally normal before embarking on the frozen embryo transfer. The prior performance of embryo biopsy (during the fresh cycle) and storage of the DNA material would afford such couples the opportunity to gain insight into the quality of their remaining embryos. For this reason, it is probably advisable for most couples undergoing IVF to consider hindsight CGH as an approach that would leave them with options should their initial fresh cycle fail.

There is nothing worse for an IVF patient than to undergo repeated attempts and to fail and to not know why. “Hindsight CGH”,through its diagnostic benefits and through the opportunity it provides to modify future treatment in the hope of ultimately succeeding, is an invaluable addition to the IVF diagnostic and therapeutic armamentarium.