Most people are aware of the fact that we all have genetic material that is used to construct a human. However, using the phrase “genetic testing” encompasses a number of different tests. A gene is a long string of chemicals that direct the construction of proteins. The body used proteins to function. So, if there is an error in the gene, the body may not function correctly.

Genes are organized in very long chains that shrink forming a sausage like structure called a chromosome. There are 23 different chromosomes.  Humans get one copy of their genetic code from each parent, so humans have 23 sets of chromosomes with two chromosomes in each set.

Genetic testing can be done for humans from the embryo stage to the adult human. Adults may have a genetic test called a karyotype which counts the number chromosomes and determines if there are very large rearrangements.

Another type of genetic test determines if a gene is normal or abnormal (gene mutation). Gene mutations may cause very severe and debilitating diseases such as Cystic Fibrosis or Tay-Sachs disease.  Remembering that there are two sets of genes, some disease will occur if the mutation occurs on just one set of genes. However, for many gene diseases, both genes need to be mutated. This causes a recessive genetic disease and the person with a single gene mutation is called a carrier.

People considering becoming pregnant can do prenatal genetic carrier screening where their genetic material can be tested to determine if they are carriers. Hundreds of possible deleterious gene mutations have been identified. If both the male and the female have a gene that has the same mutation, then one of four of the offspring will have the disease. Knowing this can help the people decide if they should test their embryos to see if the embryo has the disease.

Testing an embryo for a gene disease as another type of genetic testing which is done on embryos prior to their transfer. A common cause of miscarriage is pregnancies that have the wrong number of chromosomes. Pre-implantation embryos can be tested for chromosome numbers which is called karyotyping. Pregnant women can have their child tested while they are still pregnant. This has been done on amniotic fluid, placental cells from first trimester pregnancies, or from maternal blood. Lastly, miscarriages or stillborn children can be tested for genetic diseases especially karyotyping.

Preimplantation genetic testing of embryos:

IVF has unquestionably been a tremendous benefit in the treatment of infertility. Yet, internationally, the pregnancy rate per embryo transfer has remained lower than had been expected. A successful pregnancy requires a normal embryo (“euploid embryo”) and a normal lining of the uterus. The major reason the pregnancy rate remains lower than hoped is that the majority of human embryos are not normal (“aneuploid embryos”).

One explanation for this suggests that the successful evolution of the human species was possible due to the ability of humans to rapidly adapt to a number of different environments. A consequence of this adaptability is the creation of embryos that have the wrong number of chromosomes. Thus, the major reason that the success rate for lVF remains lower than hoped for is that most human embryos have the wrong number of chromosomes (aneuploid as opposed to euploid). Chromosomes are the structures within a cell that have the genetic information needed to reproduce. The information consists of long strings of the genetic code tightly wound to form chromosomes. There are 23 different chromosomes with one set contributed by the mother and one set contributed by the father. An egg (oocyte) contains one set of chromosomes and a sperm contains one set of chromosomes. When the sperm enters the egg, the chromosomes duplicate, and the job of the egg is to separate the chromosomes so that when the fertilized egg (embryo) divides, an equal number of chromosomes goes to each daughter cell. The process is very mechanical with structures resembling a rail system, energy generating areas in the embryo, and proteins used as ropes and facilitators. Many oocytes have broken rails or low energy or poorly functioning proteins. When the fertilized oocyte divides too many chromosomes may go to one daughter cell and too little may go to the other. The most common clinical example of this is a Down syndrome child who is born with three number 21 chromosomes.

Women actually have two different sets of oocytes at any given time: one group is normal, and one group has damaged eggs. Even young egg donors have groups of damaged eggs. This has been demonstrated by testing embryos created from donor oocytes where up to 30% of the embryos are aneuploid. Over time, all cells are damaged by the aging process – eggs are no different. As women age, more and more of the eggs become damaged, which increases the number of abnormal embryos. By age 42, as many as 90% of embryos are aneuploid. During an IVF cycle, it makes sense that abnormal embryos are not transferred. But it is not always that simple. Knowing normal vs. abnormal can be complicated. It’s not like the embryo has a sign saying ‘don’t transfer me.’ In fact, an embryo can have a bizarre set of chromosomes and still look like a beautifully normal embryo. So how does the embryologist pick the best embryo?

The initial method for determining which embryo to transfer was based upon how the embryo looked under the light microscope and “grading” it. This approach is very good in determining embryos that will not result in the birth of a child (non-viable). However, the various embryo grading systems, which are based upon how the embryo looks, all suffer from a high degree of inaccuracy…’looks’ aren’t everything. Advances in technology have increased the ability to choose the best embryo including: watching them grow while they are in the incubator, measuring substances in the fluids the embryos grow in, and actually studying the embryo’s cells by taking a biopsy of the embryo. In addition, methods for analyzing how many chromosomes in an embryo has also advanced. Now next-generation sequencing for a day 5 embryo (blastocyst) is being used to determine the chromosome number for an embryo. This process is called PGT-A (preimplantation embryo testing – aneuploid).

PGT-A is an evolving science which, predictably, has created complexity and controversy. One issue is that knowing if the embryo has the correct number of chromosomes does not allow the embryologist to fix the embryo. Either it is normal or it’s not. Thus, for any group of embryos created from an oocyte retrieval, the number of normal embryos remains constant. The argument then is that if this is true, there is no need to do testing because a patient can just keep transferring embryos until the normal embryo is transferred and is successful. This approach does not reduce the time to pregnancy or the miscarriage rate. Furthermore, there are circumstances where knowing the rate of normal embryo formation is valuable when the IVF cycle is unsuccessful because that knowledge may help formulate a successful approach for future treatment. A second issue concerns the safety of the procedure. It is always somewhat interesting to talk about safety in IVF since the oldest IVF person is just 42 years old. However, PGT-A seems safe given that the procedure as done today is only a few years old. A third issue is just how accurate is PGT-A.

PGT-A seems to be accurate but not perfect. This relates to how the procedure is actually done. Embryos are grown in culture for 5-6 days at which time the embryo is a blastocyst. A blastocyst looks like a basketball with a sticky mass of cells to one side. The sticky mass forms the baby, and the rind of the basketball forms the placenta. The PGT-A procedure creates a small hole in the shell of the embryo and allows the removal of 4-8 cells. The blastocyst has over 150 cells and the ones removed are not part of the sticky mass (more correctly termed the inner cell mass). This does create a safer way to assay the embryo. However, it raises the question of whether such a low number of cells taken from an area that does not form the baby is really an accurate reflection of the inner cell mass. If the error in separating the chromosomes occurs with the first cell division, then all cells will be the same and the results are accurate. However, what happens if the error occurs after the first cell division? Then some of the cells are normal and some are abnormal. This is called mosaicism. Under these conditions the test is less accurate because only a few cells are tested in a biopsy. This means an abnormal embryo could be transferred even though the test was normal, or an embryo that could have resulted in the birth of a child may not be transferred.

Currently, the problem of mosaicism is being debated and the American Society for Reproductive Medicine has issued guidelines for the transfer of mosaic embryos. Each patient with mosaic embryos will have a different set of circumstances and communication between the IVF team and the patient as to what to do with mosaic embryos is key.

PGT-A is a good tool and has added another technique to help people conceive. It is not perfect, but it is a step in the right direction. However, a pregnancy created from tested embryos will still need late first trimester or second trimester prenatal screening to determine whether the fetus is normal. Currently, most insurance policies do not cover PGT-A unless there are special circumstances, so cost becomes an issue for people trying to decide if they want to use this technology. In certain situation, however, PGT-A makes sense and will be well worth the cost.