Preimplantation genetic diagnosis (PGD) is being used increasingly at the Fertility Institutes to dramatically improve the chance of a successful IVF pregnancy in couples where prior IVF failures have remained unexplained. It has been estimated that over half of all IVF failures are not able to be explained by an apparent problem with embryo "quality". For many couples however, this statistic is quite misleading. Most IVF centers look very closely at the appearance of embryos under the microscope as they attempt to determine a "good" or "high quality" embryo from those of lesser quality.
Generally, embryos are given "good" marks when they demonstrate an appropriate number of cell divisions at a given time in their growth cycle, when the individual cells of the embryo appear to have a uniform size and when there is an absence of cellular "fragments" that may or may not represent problems in the growth progress of the embryo.
Recent advances however, have shown that even embryos receiving the highest ratings from scientists based on their "normal" or "excellent" appearance under the microscope may, in fact be highly abnormal and totally incapable of ever producing a pregnancy. This discovery was brought about by the addition of preimplantation genetic diagnosis (PGD) to the tools available to scientists in the IVF laboratory. PGD has offered physicians and scientists, for the first time ever, the ability to examine far beyond the superficial appearance of an embryo.
We are now able to examine the most important internal genetic code of the embryo as well. And with these new genetic tools, we have come to learn that some embryos that appear on the surface to be of the highest quality may carry a genetic code that makes them poor choices for attempting to establish a healthy pregnancy. We have also now learned that other embryos that might have been classified as less than optimal based on their appearance, and may not have been selected for return to the mother may in fact be of the finest quality and have ten or twenty times more chance of producing a healthy pregnancy than those that would have been selected without the use of the remarkable new PGD tools.
That beauty in an embryo is more than skin deep has now been confirmed by science. The technique has also allowed confirmation, for the first time, of the suspicions of our IVF scientists that simply observing and grading the appearance of an embryo may fall far short of being able to provide reliable information to patients who have failed IVF. The good news is that PGD is now available at the Fertility Institutes for couples who have been met with failure in a prior IVF cycle or cycles.
IVF Success Following PGD
Single cycle IVF success rates (the chance of becoming pregnant)in our program can be raised significantly* when 2 or 3 embryos known to be chromosomally normal are transferred. The chance of healthy pregnancy may double when known genetically normal embryos are utilized. Implantation rates (the chance of each single embryo becoming a gestation) can also be raised greatly with PGD. To determine whether these embryos are chromosomally normal, a PGD analysis is carried out by our scientists prior to their selection for transfer to the mother. In an genetically normal embryo, there should be 2 (and only 2) chromosomes of each of 22 chromosome types in addition to one set of XX female or one set of the XY male chromosomes.
Any more or less than 2 will result in defective embryos. This condition is called "aneuploidy" and will result in an embryo that will fail to develop and implant or will miscarry or may even produce a defective baby. When assisting couples that have failed IVF in other programs, PGD allows us to go an important step beyond what has been done in the past, and identify and separate the chromosomally normal embryos from those "abnormals" that have no chance of leading to healthy pregnancy. Armed with this crucial genetic information, we can assure with quite reasonable certainty that those embryos that truly provide a chance of healthy pregnancy are the ones returned to the uterus.
By employing PGD analysis of embryos, we have been able to provide dramatic improvements in IVF success to patients with prior IVF failures that have come to see us from all 50 United States as well as from every continent worldwide. These patients had failed prior IVF attempts prior to becoming pregnant with our PGD process. Our PGD program has been featured on national television news programs as well as in leading newspapers worldwide.
The Successful Use of PGD for Recurrent IVF Failure
Most couples presenting to us for consideration of PGD have one of the following conditions : -
Prior unexplained IVF failure
Recurrent miscarriages
Maternal age over 38
Conception of a chromosomally abnormal child or fetus
Polycystic ovary syndrome
History of ovarian hyperstimulation syndrome
Heritable medical condition in either the patient or in a prior child (such as hemophilia)
Two or more children of the same gender (sex selection for family balancing)
Multiple birth with desire to transfer just one embryo or a need for donor oocytes due to Turner's syndrome
Premature ovarian failure or premature menopause
The Accuracy Of PGD In "Genetic" IVF Failure
The accuracy of PGD in determining genetic abnormalities exceeds 98%. Once we have the genetic information about each embryo available, we are able to sit down with each couple prior to the embryo transfer, discuss the genetic health of each embryo, explain how the genetic information has improved the chances for pregnancy success compared to their prior unsuccessful attempts at IVF elsewhere, and make a determination about the return of the now "known to be normal" embryos to the mother to be.
Because PGD so improves the success of IVF, many couples elect, in consultation with us to decrease the total number of embryos placed back in the womb. This also decreases the chance of multiple birth and the chance of prematurity. It also allows for the cryopreservation of extra "normal" embryos for future pregnancies. Our experience has shown that even when far fewer embryos are returned to the uterus, pregnancy success increases following PGD.
The Success Of PGD In Improving Recurrent IVF Failure
Using PGD to select the best embryos is clearly superior to traditional methods of selection. Miscarriage rates following PGD are far less than with standard IVF. Currently more than half of couples with two or more normal embryos and maternal age under 41 will take home a baby on a first IVF-PGD attempt in our program. And these are in couples who have failed multiple prior IVF attempts elsewhere!
Twins occur in about 24% of these cases. Even couples with only one embryo to transfer achieve a 37% ongoing pregnancy rate past twelve weeks and a 35.5% delivery rate.
Seven per cent of couples presenting having failed multiple IVF attempts at other programs had no normal embryos to transfer after PGD analysis in our program.
This clearly indicates that, in spite of the best intentions of many IVF centers, without the genetic tools to evaluate embryos, there may have been no hope for a small percentage of patients that undertook repeated IVF cycles in the pursuit of pregnancy.
When PGD indicates that all of the embryos are abnormal on our standard genetic screen, we can immediately carry out a second, "double check" of those embryos using a completely different set of chromosome specific gene probes which attach to the tips of the chromosomes rather than to their centers (telomeric probes). This highly advance method allows us to provide definitive information to couples about their prospects for ever achieving a pregnancy with the females own eggs.
If the genetics demonstrate that the couple are unable to produce embryos able to lead to a healthy baby, it allows the couple to face this outcome secure in the knowledge that they have tried everything possible and allows them to consider alternative methods to parenthood including our highly successful and affordable egg donation program.
In our experience, most of the women who had no normal embryos for transfer even after the most advanced analysis of their chromosomes were over 40 years of age, though such findings were occasionally seen in women as young as 30. We carried out personal genetic studies on many of these couples and found that 12% of the couples carried slight chromosome abnormalities that did not effect their own health but that when passed to an embryo made it impossible for that embryo to continue on to produce a healthy pregnancy.
Most of these couples switched to donor egg IVF and some, as patients active in our program, were able to take advantage of our frozen (cryopreserved) donor egg program which makes donor eggs available to selected couples at no charge to the couple for the cryopreserved eggs.
What about the couple who has transferred more than one PGD normal embryo and does not deliver a baby? This is clearly an emotionally painful occurrence. However, these couples tend to reconsider, with our guidance, examining other, less obvious and often overlooked medical factors affecting pregnancy chances. We look closely at the maternal/uterine contribution to ongoing pregnancy. In many of these instances, we are able to step back from the IVF pursuit, and consider additional diagnostic studies looking at factors OTHER than the embryos that may be causing difficulties with conception.
Couples may rethink previous decisions regarding reparative surgery for the uterus (such as myomectomy or hysteroscopy) or medication options which they might have declined due to fears about side effects (such as depot GnRH agonist treatment). They often are more strongly motivated to stop smoking, increase exercise or diet. We have no information yet about the impact of these changes on the chromosomal balance of embryos. Some couples will overcome their reluctance to consider gestational surrogacy. The Fertility Institutes operate one of the largest, most successful and affordable gestational surrogacy programs in the world. When we have learned that the embryos returned to the mother are NORMAL, and pregnancy fails to occur within two attempts, gestational surrogacy the "borrowed womb", can provide pregnancy rates among the highest seen with any fertility treatment.
PGD and Amniocentesis
Because the most vital, but not all chromosomes have been tested, PGD cannot substitute for mid-trimester genetic ultrasound evaluation and amniocentesis or chorionic villi sampling. We encourage additional genetic testing once a successful pregnancy has been established to confirm the total genetic health of the resulting pregnancy.
PGD to Determine Sperm or "Both Partner" Infertility Issues
Another very important issue learned from PGD is the fact that sperm, while much less often involved in IVF failure, clearly have the potential to, in selected instances, cause repeated IVF failure. Although many sperm defects will lead to failure to fertilize or arrest of development before blastocyst formation by the embryo, more subtle microdeletions and sperm chromatin fragmentation may explain why some IVF cycles fail despite several PGD normal embryos to choose from. In response to this new information, we have begun considering sperm chromatin fragmentation and microdeletion testing in select IVF cycles to eliminate the potential for unrecognized sperm defects leading to repeated IVF failure.
Sometimes the couple's notion of which partner is "at fault" is reversed when the sperm alone or sperm and egg are found together to be contributing to the infertility or the repeated IVF failure. Advances in preimplantation genetic testing and its wider application will strengthen our understanding of human embryonic development and provide us the opportunity to assist even more couples.
PGD provides a true scientific basis for selecting embryos for use in IVF as well as for understanding how and why IVF fails repeatedly in some couples. When we uncover that no chromosomally normal embryos are being produced, there is little likelihood of success and we can direct our efforts toward alternate methods of assisting with the pursuit of pregnancy. Overall any procedure that enhances success rates will save time and money in the long run as well as reduce the emotional drain of dealing with infertility. Aneuploidy screening with PGD is neither simple nor inexpensive, but its benefits clearly outweigh its cost for many couples.
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