#NIAW Judging a book by its cover?

As part of the National Infertility Awareness Week (#NIAW#flipthescript) John S. Rinehart MD, PhD, Reproductive Medicine Institute (www.teamrmi.com) talks about Selecting embryos for Invitro Fertilization A constant challenge for patients using Invitro Fertilization (IVF) for fertility treatment is deciding which embryo to transfer and how many to transfer.  In a perfect world, the embryo with the best chance of producing a normal, healthy singleton child would be selected for transfer.  But, as with all things, medicine does not rely on ‘perfection’.   Currently, most clinics report that one third of the embryos transferred result in a child.  These estimates vary depending upon how the data was used, but honest reporting backs up these results. So why does only one out of three embryos implant?   The answer could be the embryo or it could be the uterus, but both causes are ‘not created equal’.   There certainly are reasons that are related to the uterus which may reduce the pregnancy rates but for the most part, the embryo is the problem. HOW DO WE KNOW? One criteria used to predict which embryo will be successful is the appearance of the embryo under the light microscope. While many patients become fixated on the score of their embryo, practically however, this method of embryo selection leaves a lot to be desired. In fact, the appearance of the embryo can only be accurately used to identify those embryos that are non- viable (will not produce a child). Once the embryologist has determined that the embryo may have a chance, the ability of the appearance of the embryo to predict a successful outcome becomes clinically irrelevant. If this were not true, then why transfer embryos that have a lower score? IT’S IN THE NUMBERS So, what is the problem with the embryo? One major problem is that many, if not most, human embryos do not have the correct number of chromosomes. Embryos with the wrong number of chromosomes are called aneuploid embryos. Formation of aneuploid embryos is the major factor associated with the age- related decline in fertility.   Some studies suggest that for women over the age of 40, more than 90% of the embryos are aneuploid. However, an embryo with the correct number of chromosomes from a woman over the age of 40 seems to have the same chance of success as a similar embryo from a woman in her 20s. Why does the oocyte produce aneuploid embryos? Formation of a normal embryo is a mechanical process. Human genetic material is organized into long strands called chromosomes. There are 23 sets of these strands of DNA, with one set coming from the mother and one from the father. The job of the egg is to mix these chromosomes and then separate them equally into the first two cells of life. The oocyte does this mechanically through a rail system in the oocyte where the chromosomes attach. The oocyte has energy generating structures called mitochondria. Finally, the oocyte uses proteins to perform the task of proper division. But imagine that one of the rails is broken and instead of separating the chromosome equally, one cell gets an extra chromosome and the other cell gets one too few. As woman age, more and more of the remaining oocytes have broken structures or failing mitochondria, accounting for the increase in aneuploidy with age. There is currently no way to correct for this and IVF does not fix this problem. Recent advances in technology have permitted the determination of the number of chromosome in an embryo. This has resulted in a significant increase in the chance of an embryo resulting in the birth of a child. Many centers are honesty reporting a 50-60% delivery rate per embryo for embryos that have been tested and are known to have the correct number of chromosomes. Interestingly, many embryos that have a lower morphological score have the correct number of chromosomes and thus have a higher chance of resulting in the birth of a child than would have been precited from the morphology score. WORKING ON THE  QUESTION OF WHY But what about the other 40% of embryos that are transferred which do have the correct number of chromosomes and appear normal under the light microscope? Why don’t they work? Currently, science is seeking answers to these questions. Two areas of research that are trying to help decide which embryo to transfer are a uterine focused technique and an embryo focused technique. The lining of the uterus undergoes many changes during an IVF cycle. The estrogen causes it to grow thicker and the progesterone matures the lining so that the embryo can implant. It turns out that the lining has a somewhat narrow timeframe when an embryo can implant, which is called the implantation window. The ability of the embryo to implant and the window of implantation must coincide or else the embryo will not implant.  One proposed reason why the embryo may not implant is that the window and embryo are out of sync. A technique has been developed to estimate when is the proper time for the window of implantation which is determined from a biopsy of the lining of the uterus during what should be the optimal time for implantation. One suggested approach for the use of this assay is when the embryos have been assayed and are known to be euploid. The suggestion is to transfer a single embryo and then if there is no pregnancy, perform a biopsy before doing a second frozen embryo transfer. Preliminary data from one center demonstrated a significant proportion of those failing their first embryo transfer with tested embryos had an implantation window out of the normal range. Adjusting the timing of these second transfer results in a very high success rate. A second method to improve success rates measures the DNA content from the energy generating mitochondria. If there was too much mitochondrial DNA, then the implantation rates were very low. This technique is still only available from a limited number of research labs but may become more widely available if it can be proven to be useful.  One major problem with these techniques is cost. They are not cheap and insurance does not cover their cost. However, under certain circumstances, the cost may be worth the information gained. Science continues to make advances so that the chance of having a child keeps increasing. However, a cautionary note is that the success of these techniques is dependent upon three factors, the technology, the technician, and the disease causing the infertility. Both the technology and the technicians are highly standardized in today’s medical community. But, the disease process remains a major limitation. IVF was not designed to treat many causes of infertility, and in these cases, does not offer a person an increased chance of success over the treatment independent pregnancy rate i.e. doing nothing gives the same chance as doing something.  Why is everything.