Sometimes, there will be clear-cut reason but often there is no answer. The recommendation will be to try another cycle of IVF and if that fails, try another and so on until out of sheer exhaustion- physical and mentally- a person stops doing IVF. In this physician’s experience, it is critical when faced with multiple cycles of IVF, to try and determine when enough is enough. Approaching the answer to this question requires evaluating various aspects of the IVF process in an attempt to define why multiple attempts at IVF have failed. Dividing the world of IVF into the world of the embryo and the world of the uterus offers a starting point for this investigation.
The world of the embryo requires a normal sperm and a normal egg (oocyte) to join, for the egg to mix and then equally separate the genetic material (chromosomes) and then divide into two reproductively competent daughter cells. If either the male or the female have abnormal chromosomes, then the embryo is more likely to also have abnormal chromosomes. A test which may be of use is to obtain a karyotype on both the male and the female. It is possible that there may be a male component to poor embryo formation beyond the obvious chromosomal abnormality but the frequency of the happening, the extent to which it is a factor, and the best method to detect this problem have yet to be scientifically proven. Thus there may be a problem caused by male facto that remains undetectable and thus undefined. Fortunately, this is a rare situation.
The egg (oocyte) is the most frequent cause of abnormal embryo formation and remains the leading cause of failure in IVF. The most common embryo abnormality is an embryo that forms with the wrong number of chromosomes. Many IVF programs are culturing embryos for 5-6 days so that nature can select (by elimination) only those embryos meeting certain criteria for transfer. But that means that a person could have one or two embryos transferred on day five or six and still not get pregnant and have a child. The embryos looked perfectly normal…again, WHY didn’t it work? Many human embryos can appear perfectly normal under the light microscope on day five and yet have the wrong number of chromosomes. For example, in embryos created from donor eggs (oocytes), up to 30% will have the wrong number of chromosomes. These are the best embryos possible since the eggs are from young, reproductively capable women. As many as 90% of all normal looking embryos from a women in her 40s will have the wrong number of chromosomes. If the embryo implants and a pregnancy starts but ends in a miscarriage, the most common cause is that the fetus had the wrong number of chromosomes. And, the most common cause of this problem is age. Clinically, a poor response, reduced ovarian reserve (demonstrated through clinical tests), age, length of infertility and the number of attempts at IVF, are all indicators that the failed IVF is due to poor egg quality, and consequently, poor pregnancy potential.
Repeated attempts at IVF will not correct this problem. Treatment options, historically, include doing nothing, adoption or the use of donor eggs. Fortunately, recent advances in technology can be used to reduce the number of embryos transferred with the wrong number of chromosomes. The use of preimplantation genetic screening allows us to determine the actual chromosome number of an embryo which has developed to day 5/6.
Using data from the literature, we see that transferring an embryo with the correct number of chromosomes result in delivery rates as high as 50-60%, and may actually go higher. However, not all transfers result in the birth of a child so the question still remains- why?
It is possible that there are genetic problems with the embryo that are not detected by counting chromosomes, and for the time being, these problems will remain undetectable. People experiencing this will be encouraged to try more cycles of IVF. Many will conceive on a subsequent cycle but some will not. At that point, consideration must be given to the fact that the uterus may not be functioning properly and even though the embryos could implant, it will not be able to implant in that specific uterus.
If the problem is that pregnancies occur but end in miscarriage, then after two pregnancy losses, we recommend an evaluation for recurrent pregnancy loss. Many times, a cause can be determined. Based upon the findings, recommendations can be made as to how best approach the diagnosed problem.
That leaves a very small number of people who have undergone multiple cycles of IVF with embryo transfers and yet are not pregnant. The technical term for this is recurrent implantation failure (RIF), a diagnosis only possible since IVF became a form of treatment. Two critical issues with RIF are how it is defined and what to do about it. Defining RIF uses a statistical approach and starts by counting how many embryos needed to be transferred to result in a delivery of a child. Some people may get pregnant with their first cycle of IVF with only one embryo being transferred. Some people will get pregnant on their third try after six embryos have been transferred. Collecting this information for a large number of successful IVF cycles permits the construction of a bell-shaped curve plotting the number of embryos transferred for successful IVF cycles base upon how many embryos were transferred in total, not the number of IVF cycles performed.
The definition of RIF can then be assigned as the number of embryos that needs to be transferred for either 80% or 95% of the pregnancies to be achieved. Thus if 95% of the women became pregnant with having had 5 or fewer embryos transferred, then if a patient has had 7 embryos transferred but is not pregnant she has RIF. Twenty years ago the number required for 95% level of confidence was 12 embryos. Today that number is closer to 4-5. But utilizing Preimplantation Genetic Screening (PGS), that number will probably diminish to as few as 2-4.
Once RIF has been established, then testing can be done in an attempt to determine a diagnosable problem. Based upon that, treatment options can be defined. However, the current testing approach is based upon these patients having recurrent pregnancy loss and not RIF. Until more research has been done specifically on RIF, the diagnosis and treatment will remain sub-optimal. Although less than satisfactory and extremely expensive, a person with RIF and embryos with the correct number of chromosomes can utilize gestation hosts with a high degree of success, ideally closing the gap on the issues that stand in the way of achieving a healthy pregnancy and ‘take home baby’.