Eight chromosomes were chosen in this study because this is about the limit that can be tested at one time with current technology (called FISH or Fluorescent In-Situ Hybridization). However, human beings have 23 pairs of chromosomes. So when these investigators found that between 40-60% of the embryos were abnormal, they were testing only 1/3 of the chromosomes! Using a newer investigational technique (CGH or comparative genomic hybridization) that allows for testing of all the chromosomes, a recent study identified an abnormality rate of 75% in young patients. There may be other factors besides age that predispose some women toward a higher probability of producing chromosomally abnormal embryos. Consider the following cases: 1)
A 37 year old patient came to see me with 7 years of
infertility. She responded well to stimulation and produced
30 mature eggs, 23 fertilized normally. Upon PGD for
only 5 chromosomes, 21 of 23 were abnormal (91.3% normal). In these examples, the abnormality rate of 90% seems far higher than would be expected based on the age of the patient. At a presentation at the American Society for Reproductive Medicine, a California group performed PGD on four egg donors aged 20 to 27. The percentage of abnormal embryos ranged from (33% to 91%) There may be two explanations for this phenomenon: 1)
Each case represented a random event and the patients
were just unlucky. One patient told me that her doctor said that they could identify abnormal embryos by looking at their development under the microscope and grading the embryos. Unfortunately, chromosomally abnormal embryos can look perfectly normal under the microscope. In many instances, the use of PGD has resulted in the transfer of embryos that would not otherwise have been chosen for transfer based on their microscopic appearance. It turns out, that we are truly not very good at assessing embryos simply by looking at them under a microscope. I recently had a patient who presented to me with a history of infertility but also had given birth to and lost a baby with a chromosomal abnormality in which the baby had three copies of a single chromosome (similar to Down's Syndrome). With IVF, she produced 10 embryos of which six were normal for the five chromosomes we studied. Her best looking embryo under the microscope was a beautiful blastocyst that had the same abnormality as the baby she lost. We ended up transferring an embryo of seemingly poorer quality instead that had not even reached blastocyst stage. We would not have transferred that embryo had we not performed PGD. She conceived and delivered a healthy baby. Had we transferred the affected blastocyst, she may have had a baby with the same problem as the one she lost. Incidentally, in this example we used blastocyst transfer. PGD results can be obtained to allow a cleavage stage (day 3) embryo transfer is some cases but more chromosomes can be tested by waiting until the blastocyst stage (Day 5 or 6). Confirmation of uncertain results can also be accomplished by waiting until blastocyst. I feel there is an additional advantage to waiting until the blastocyst stage. Since embryo development can be more accurately assessed, it further allows for embryo selection in the event that there are multiple chromosomally normal embryos. Will
performing PGD on all IVF patients result in an improvement
in pregnancy rates? Of those who do have an embryo transfer, we only expect to see an improvement in pregnancy rates if the patient has more embryos than she is willing to transfer. Another example will help illustrate this point. Consider two identical twins going through an IVF cycle at the same time at the same program. Both twins are able to produce seven apparently normal looking embryos. However, only one embryo out of seven is chromosomally normal for each. Twin A and her partner are uncomfortable transferring more than two embryos. They have PGD performed, find the normal embryo, and complete the transfer. Twin B and her partner don't have PGD performed but decide to transfer all seven embryos. Since the "good" embryo was included in the group of seven, she has the same chance of becoming pregnant as Twin A. If B had decided to transfer only two embryos, the "good" embryo has only about a (30%) chance of being selected for transfer. Let us look at another example. The same twins both produce seven apparently normal embryos. This time however, there are four normal embryos in each group. Twin A again has PGD performed, finds the four normal embryos, decides to transfer only two of the "normals" and has a twin pregnancy. Twin B again transfers all seven embryos without PGD and has a quadruplet pregnancy. Last example. The same twins again with the same embryos. Only one embryo in each group of seven is normal. Twin A again has PGD, finds the normal embryo, transfers it gets pregnant and delivers. Twin B now has a new doctor who recommends transferring only two embryos. The two chosen are both abnormal. Twin B gets pregnant but then miscarries. The point to all these examples is that PGD is a means to improve the selection of embryos for transfer. This selection allows for potential advantages:
Will women who have all abnormal embryos in one cycle have all embryos abnormal in every future cycle? The answer is most likely not, but we have no way to predict. Consider a patient who came to me from Seattle to have PGD. She is 41 years old:
This patient had anywhere from 0 to 50% of her available embryos with normal chromosomes. The failure of pregnancy to occur highlights the deficiencies associated with testing for only 1/3 of the chromosomes and the fact that other abnormalities in an embryo may still play a role in determining viability. A final word about miscarriage and recurrent pregnancy loss. The majority of miscarriages, whether a woman has had one or several in a row, are due to chromosomal abnormalities in the embryos. This is true even in the presence of other factors known or thought to increase the risk of miscarriage. There is no way to prevent these conceptions from occurring and no way to prevent their loss. Heparin won't do it, IVIG won't do it, prednisone or baby aspirin or progesterone won't do it. The only way to reduce the risk of chromosomal miscarriage is to generate a number of embryos during IVF, perform PGD, hope that there are at least some embryos that have normal chromosomes, and transfer those embryos to the uterus. Remember, until we have the ability to test all chromosomes routinely, there is still the possibility that an embryo which seems normal based on nine chromosomes, may still have abnormalities in one of the other 14. In an Italian PGD study, the risk of miscarriage in women over 36 years old having PGD was 4% whereas the risk of the same aged women having IVF without PGD was 20% Conclusions The vast majority of in-vitro fertilization failures result from the transfer of abnormal embryos that have limited or no potential to produce a viable baby. These abnormalities cannot be corrected or treated in any way. The only way to address these problems is by enhanced embryo selection. Currently, preimplantation genetic diagnosis can improve the likelihood of selecting the correct embryos for transfer but is not yet 100% accurate. Assessment of the embryos under a microscope is incapable of detecting chromosomal abnormalities. Couples who wish to improve the odds of pregnancy during IVF and reduce the risk of miscarriage can be offered PGD today. In the future, with further refinements in technology probably all in-vitro fertilization cycles will be performed with preimplantation genetic diagnosis. Additional Links |
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