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Pgd Or Array Cgh For Fresh Transfer


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#1 Choice4

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Posted 17 September 2008 - 11:33 AM

Dear Dr
I know CGH is the best for competent embryo but it involves a staggered IVF
If one would like a fresh transfer, which would you recommend PGD or Array CGH.
I know they both have their flaws, but which one is better, I would only want a fresh transfer.
Or is it better to transfer blast with none of the above test

#2 Geoffrey Sher, MD

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Posted 17 September 2008 - 03:06 PM

We can do PGD for you. Presently I do not have cofidence in the platform available for aCGH.

SIRM is the only IVF group in the world that has extensive experience with metaphase CGH (mCGH) .No one else to my knowledge has reported any births except us. We in fact introduced  mCGH embryo selection in to the IVF arena. Scores of babies born from this process with a birth rate of >60% per ET, attests to this approach. Array-CGH (aCGH) is a more rapid method than mCGH but it has as yet not reached the level of reliability needed. It is also is much more expensive than mCGH and aside from speed of performance has no real advantage over mCGH.

We are currently working with a group in Europe in testing an enhanced aneuploidy platform by which to improve the sensitivity and specificity of aCGH performed on single DNA. But, it will probably take a year or so before the reliability of aCGH might allow it to safely replace mCGH for single cell DNA analysis.

Geoff Sher.



#3 Barbara

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Posted 17 September 2008 - 03:14 PM

CCRM in Colorado has had live births from CGH-normal embryos.

#4 Choice4

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Posted 17 September 2008 - 04:27 PM

Dr
Please what is metaphase CGH, and how does it work, can you do it for a fresh transfer, and is it day 3 or day 5. is this different from the normal pgd testng 13 chromosomes.
Please i need to know so I can decide before transfer

#5 Geoffrey Sher, MD

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Posted 17 September 2008 - 05:19 PM

We have todate had about 100 CGH births using metapahse CGH. I cannot describe mCGH  here or compare it to aCGH. But indeed it is possible to do mCGH  in fresh cycles but this would require immediate access to onsight testing of egg polar body DNA rather than embryo DNA...but this is usually neither a necessary or even an advisable aproach. Staggered IVF is usually preferable. When mCGH or aCGH is applied to embryo (blastomere) biopsies, the embryos must of necessity be frozen and replaced in a later cycle (i.e. St-IVF).

GS

___________________________________________________________________

1.Staggered In Vitro Fertilization (St-IVF): Rational Expectations

Geoffrey Sher MD
Levent Keskintepe PhD

Our reported IVF results following egg biopsy, our unique experience in the performance of CGH, and our preliminary and growing experience with St-IVF, suggest a 55-65% chance of a live birth following the transfer of up to two “competent” blastocysts to a “receptive” uterus.
GS & LK

A. Introduction
The ability of an embryo (the “seed”), upon reaching a “receptive uterine environment (the “soil”) to successfully implant and develop into a healthy baby (the “plant”), is no different than what takes place in a regular agricultural setting. In simple terms, it is determined by establishing an ideal “seed/soil relationship”. It follows that it is no more possible to achieve a viable healthy pregnancy when a “competent” embryo (one that upon reaching a “receptive” is 50-60% likely to develop into a viable pregnancy) is transferred to a “non-receptive” uterus that when an “incompetent” embryo is transferred to a “receptive uterus”.
Throughout human reproduction, the establishment of an ideal “seed-soil” relationship is pivotal, since both embryo “competency” as well as uterine receptivity is indispensable to the development of a healthy baby. It is however an undeniable fact that reproductive failure (i.e. failed implantation, miscarriages and major birth anomalies) are far more likely to be due to embryo “incompetence” (70-75%) than to a lack of uterine receptivity (25-30%).
Successful treatment of reproductive failure demands full prior identification and treatment of those factors that adversely influence both embryo “competence” as well as uterine receptivity (i.e., thickness of the uterine lining, immunologic modalities, anatomical integrity of the uterus as well as infective and biochemical factors).
While advances both in methods and drugs used for ovarian stimulation, as well as improvements in embryo culture techniques, have undoubtedly had a positive influence, IVF success rates have lagged and even stagnated over the last 10 years. This is largely due to an inability to reliably identify and selectively transfer only “competent” embryos to the uterus. Even in young women, an embryo that “looks good” under a microscope is not necessarily “competent”. At best it has a 25% chance of implanting. Furthermore this statistic shrinks drastically with advancing age beyond 35 years. Even the use of preimplantation genetic diagnosis (PGD) using fluorescence in-situ hybridization (FISH) to identify chromosomes, does not significantly improve this capability. As a result, many IVF specialists still transfer multiple embryos at a time, in the hope that this will increase the odds that at least one “competent” embryo will reach the uterus and produce a pregnancy. The problem is that while this improves the chance of a pregnancy occurring, it also markedly increases the risk of multiple pregnancies.
The relatively unregulated IVF setting in the United States has provided a safety net for those wishing to transfer multiple embryos and this in turn has led to a virtual explosion in the incidence of multiple births in this country. The enormous financial cost associated with the short and long term prematurity related consequences of IVF multiple births represents one of the main reasons why health insurance providers in this country are reluctant to cover the procedure.

B. What methods are currently in use to differentiate between “competent” and “incompetent” embryos.

The following methods currently employed in IVF clinics across the world to evaluate embryo quality all, to a lesser or greater degree, fail to differentiate reliably between “competent” and “incompetent” embryos”.

o Microscopic Embryo Grading Systems: These evaluate and grade embryos based upon structural appearance (morphology). They are all unreliable. Even those embryos that appear to be morphologically normal are much more likely to be “incompetent” than “competent”. Furthermore, the older the woman who produces the eggs, the less reliable morphologic embryo grading becomes. For example, a morphologically normal embryo derived through fertilization of an egg taken from the ovary of a 30 year old woman might, on average have about a 25% chance of propagating a pregnancy, while a morphologically comparable embryo derived from the egg of a 45 year old, is 7-10 times less likely to do so.
o Prolonged embryo culture to the Blastocyst: This approach relies on the fact that by extending the embryo culture process, many poorer quality embryos will be culled out. Thus embryos that survive to the blastocysts stage are more likely to be “competent”. This approach, while helpful, is far from perfect because many “incompetent” embryos in fact will progress to the blastocyst stage.
o Preimplantation genetic diagnosis (PGD): Here, one or two cells (blastomeres) is/are microsurgically removed from the embryo on day 3 post-fertilization. The blastomere(s) are thereupon stained to reveal specific chromosomes, using a method known as fluorescence in situ hybridization (FISH). However since PGD/FISH only targets some (i.e. 8-12) of 23 chromosome pairs, it is unable to reliably differentiate between “competent” and “incompetent embryos. In fact an embryo that tests normal with FISH still has at least a 47% chance of having chromosome irregularities that involve those chromosome pairs that could not be evaluated by FISH. Accordingly PGD/FISH is of questionable value in selecting the best embryos for transfer.
o Egg/ Embryo Competency testing (ECT): ECT is a new method by which DNA derived from the first polar body (PB-1 of a mature egg and/or from a blastomere removed from day 3 embryos is tested using comparative genomic hybridization (“CGH”). CGH accurately identifies all the chromosomes in a cell and is thus >80% accurate in evaluating egg/embryo “competence”.

C. What makes one embryo “competent” and another, “incompetent?
It is mostly (but not exclusively) the chromosomal configuration of the embryo that determines its “competence”. The number of chromosomes in a cell is referred to as its ploidy. A cell with a normal number of chromosomes is euploid while one with an irregular chromosome number is aneuploid. It appears that it is the ploidy of the mature egg (rather than the sperm) that determines the post-fertilization chromosome configuration of the embryo. The embryo’s ploidy, in turn determines its “competence”.
We recently reported (Fertility and Sterility, May, 2007) on a two phase study involving the performance of CGH on a fragment of nuclear material (the first polar body or PB-1) discharged from the egg during the chromosomal rearrangement that takes place following the hCG trigger. The PB-1 has a chromosomal make up which is a mirror image of the chromosomes in the egg’s nucleus. Several hours following fertilization, PB-1 divides and a second polar body (i.e. PB-2) appears alongside it. PB biopsy involves removal of PB-1 and/or PB-2 from immediately below the outer envelopment (zona pellucida) of the pre or post-fertilized egg. This is achieved without damaging the egg itself.
Our study (referred to above) was performed on eggs extracted from women aged 25-42 years who underwent ovarian stimulation with fertility agents. Phase 1 involved performance of PB-1 and PB-2 egg biopsies before and after fertilization, and subsequently, on blastomeres removed from the corresponding day 3 embryos. Phase 2 involved a second study involving 35 women where we selectively transferred up to 2 embryos derived from eggs that previously had tested chromosomally normal following PB-1, CGH. The study produced the following, hitherto unknown information:

o It is definitively the chromosomal make-up of the egg, rather than the sperm, that is the main determinant of an embryo’s “competence”.
o Even in young women, >60% of all mature eggs are likely to be aneuploid and thus incapable of propagating “competent” embryos.
o The incidence of egg aneuploidy increases progressively with advancing age such that by the mid-forties it is probably above 90%.
o Eggs that have an abnormal number of chromosomes (i.e. aneuploid) will , upon fertilization always propagate aneuploid, “incompetent” embryos. Such embryos will either fail to attach to the uterine lining, attach and then subsequently miscarry, or produce chromosomal birth defects such as Trisomy 21 (Down’s syndrome).
o Approximately 85% of eggs that have a normal number of chromosomes (i.e euploid) fertilized with normal sperm subsequently result in euploid, “competent” embryos.
o In the absence of male infertility and untreated immunologic implantation dysfunction, the transfer of 1-2 euploid, (CGH-tested) embryos to a receptive uterine environment that is free of immunologic, anatomical and biochemical impediments, has better than a 60% chance of resulting in a live birth.
o Appropriately cultured embryos that fail to progress to the blastocyst stage are in fact almost always aneuploid and thus “incompetent”. This finding all but dispels the erroneous contention that embryos might be better off being transferred to the uterus prior to reaching the blastocyst stage.
o Most early miscarriages and many birth defects (e.g Down’s syndrome) are attributable to embryo aneuploidy. It follows that by only transferring euploid, “competent” embryos, will this risk be significantly reduced.

D. What is Staggered- In Vitro Fertilization (St-IVF)?
St-IVF is a new and improved IVF process that is capable of improving IVF success, reducing the risk of miscarriages, minimizing the risk of chromosomal birth defects such as Down’s syndrome, and reducing the incidence of multiple births. St-IVF involves dividing the IVF cycle up into 2 segments. The first segment involves ovarian stimulation and egg retrieval while the second comprises the embryo transfer (that can be performed weeks, months or even years later). . The purpose of dividing up the cycle into two parts is to allow the genetics laboratory sufficient time to complete CGH on one or more of the embryo’s cells (i.e. blastomeres) that were surgically removed from the embryo, 3 days following fertilization by intracytoplasmic sperm injection (ICSI).

First Segment:

• Ovarian stimulation, ultrasound and hormonal monitoring, egg retrieval is conducted in preparation for ICSI…performed 4-6 hours later.  

• Two possible approaches taken to obtain a DNA specimen for CGH analysis: a) Immediately following ER a PB-1 is removed or, b) 3 days  following  ER a single blastomere is/are removed (blastomere biopsy) from embryo(s) that have reached a 6-9 cell stage. Blastomere DNA is then processed in preparation for CGH analysis which is a highly complex process that takes a week or longer to complete.

• All fertilized eggs and embryos remain in culture for up to six days Those that develop into healthy expanded blastocysts (the most advanced state of pre-implantation development) are vitrified (i.e ultra-rapid freezing-see below) and then cryobanked. The remainders are discarded.

• Fully developed blastocysts derived from embryos that are determined through CGH to have all twenty three pairs (46) chromosomes intact, are retained in the vitrified state (i.e. cryostored), while those derived from chromosomally abnormal, day 3 embryos, are discarded.

• The patient is subsequently informed of the CGH test results and a date is set for the transfer of up to two euploid embryos.

Second Segment:

• Patients who have at least one “competent” embryo in cryostorage return for clinical assessment, ultrasound and hormonal monitoring in preparation for the embryo transfer.

• The “competent” vitrified blastocyst(s) selected for transfer is/are warmed (thawed) and, provided of course, that at least one “competent” blastocyst survives, is/are duly transferred under ultrasound guidance.

E. What is Ultrarapid Embryo Freezing (vitrification)?
Cryopreservation of human embryos has been a routine procedure since the early 1980s. Conventional cryopreservation which is still being used by most IVF centers, involves slowly reducing the embryo’s temperature until it freezes. This unfortunately results in ice crystal formation inside blastomeres, damaging them and reducing embryo “competency”. The relatively recent introduction of ultra-rapid freezing or vitrification has changed all this. This innovative technology, whereby the embryo is frozen within the blink of an eyelid, is so rapid that there is no time for intracellular crystallization and its resulting cell damage, to occur. The conventional slow freezing method leads to the death of up to 30% of blastocysts so frozen. In contrast with vitrification, less than 10% are lost. The survival rate is likely even higher for “competent” blastocysts.

F. Does a “competent”, (CGH-“normal”) embryo invariably produce a baby?
Unfortunately this is not the case. St-IVF with ECT, while potentially representing a major advance in the IVF arena, is not a panacea. First, an embryo, diagnosed to be euploid through single blastomere CGH, is not always, “competent”. Second, a “competent” embryo might not attach because of poorly understood uterine receptivity issues and, Third, there is a wide variation in technical expertise when it comes to the performance of embryo transfer, a rate-limiting factor in IVF.


G. What is “Mosaicism”? Mosaicism is the term used to describe an embryo that contains both euploid and aneuploid blastomeres. With ECT, using CGH, we only examine a single extracted cell (blastomere) removed from a 6-9 cell day 3 embryo. We cannot possibly examine all the blastomeres. Following fertilization, the cells of the early embryo along with their accompanying chromosomes, replicate repeatedly. During this process things can, and indeed do, go wrong about 20% of the time with regard to chromosomal arrangement resulting in one or more of the embryo’s blastomeres becoming aneuploid.. When an embryo rather than the egg is biopsied we only perform CGH on one of 6-9 existing blastomeres of the day 3 embryo, we will in about 20% of cases erroneously deem an embryo to be “euploid” throughout when in fact it might not be. However, in either the short or the long term, aneuploidy involving even one blastomere of a 3 day embryo (i.e mosaicism) will inevitably prove to be lethal. Accordingly an embryo that was initially regarded through single blastomere CGH analysis to be “competent” may in fact be “incompetent”. The explanation for this is as follows: With repeated cell division, one aneuploid blastomere out of 6-9 (in the day 3 embryo) will ultimately translate into such a high percentage of the overall total number of blastomeres in the embryo being aneuploid that the remaining normal euploid cells are incapable of insuring proper function and survival. The lethality associated with “incompetence” of an early day 3 embryos manifests as :
Mosaicism is a common finding in advanced embryos or blastocysts (the 100+ cell morula or blastocyst stage) and when it does occur, unlike the result of mosaicism in a day 3 embryo, it is not necessarily prejudicial to its function and/or its survival. The reason is that in such cases the ratio of aneuploid versus euploid component cells is so small, that the impact on overall functionality is usually negligible.

H. When should we biopsy the embryo versus the egg for CGH?
The advantage of performing CGH on the embryo, rather than the egg lies in the fact that the findings reflect the contribution made by both egg and sperm. The disadvantage is that in about 20% of cases chromosomal irregularities (aneuploidy) can occur with post-fertilization cell replication. In such cases there might be 1 or more chromosomally abnormal (i.e. aneuploid) cells amongst normal ones in the same embryo. We call this “mosaicism”. Such “mosaic” early embryos are almost certainly unable to produce a normal baby. nevertheless, the concern expressed by some patients and physicians (albeit unwarranted ) that in some cases such embryos  might   “autocorrect”  and go on to produce a viable, chromosomally normal  pregnancy has cast an undeserved aura of suspicion on the use single cell embryo biopsy for IVF embryo selection.
Notably, it is the egg (and not the sperm) that determines the embryo’s  chromosomal integrity in 90% of cases. Against this background (with a few notable exceptions) absent of sperm dysfunction, we do St-IVF starting with  CGH on the egg and  subsequently when CGH results are in, we selectively  transfer up to 2  blastocysts derived from chromosomally normal eggs. In cases of severe male infertility where the fertilizing sperm is more likely top be abnormal and contribute substantially to the chromosomal integrity of the embryo, we preferentially perform CGH on a cell (blastomere) extracted from the day 3 embryo.  
When CGH is performed on one of 6-9 blastomeres of the day 3 embryo, we will in about 15% of cases erroneously deem an embryo to be “euploid” throughout when in fact it might not be. However, in either the short or the long term, aneuploidy involving even one blastomere of a 3 day embryo (i.e mosaicism) will inevitably prove to be lethal. Accordingly an embryo that was initially regarded through single blastomere CGH analysis to be “competent” may in fact be “incompetent”. The explanation for this is as follows: With repeated cell division, one aneuploid blastomere out of 6-9 (in the day 3 embryo) will ultimately translate into such a high percentage of the overall total number of blastomeres in the embryo being aneuploid that the remaining normal euploid cells are incapable of insuring proper function and survival. The lethality associated with  “incompetence” of an early day 3 embryos manifests as :

o Arrested division (cleavage): In such cases, the embryo stops dividing and fails to reach the advanced (blastocyst) stage of development over the next 2-3 days in culture.
o Unexpanded blastocyst: A fully “competent” blastocyst has a fluid filled blastocele in its center. When we vitrify the blastocyst it often collapses and needs to re-expand upon warming/thawing. Failure to re-expand is an indication of “incompetence” of the blastocyst.
o Failure of a blastocyst to survive the freeze/thaw (vitrification/warming): Upon freezing (vitrification) the cellular content of the blastocyst “contracts”. Upon thawing the viable, competent blastocyst will rapidly re-expand to its full pre-frozen state. Failure to do so indicates “incompetence” and such embryos are not eligible for transfer to the uterus. Since failure of a blastocyst to survive the freeze/thaw process is a last minute discovery, it often proves to be highly bewildering and most distressing to the patient, and her partner as well as the treating physician who by this time were all fully anticipating that the embryo transfer would proceed.
o Preclinical and clinical miscarriage: An “incompetent”, expanded blastocyst that survives vitrification/warming and is transferred in its expanded state to the uterus, will usually fail to gain proper attachment to the uterine lining. In such cases, the pregnancy hormone (hCG) may either be undetectable in urine or blood (i.e. a negative pregnancy test), be temporarily present without there being subsequent ultrasound evidence of a pregnancy (i.e. a chemical pregnancy) or may attach long enough to result in a detectable pregnancy by ultrasound only to abort spontaneously a few days/ weeks later (i.e. miscarriage).

I. How Does Uterine Receptivity influence the Outcome of St-IVF?
As stated at the beginning of this presentation, when it comes to human reproduction we are dealing with a “seed-soil” relationship. It is important to recognize that given our current state of knowledge, it is not possible to diagnose and treat all causes of decreased uterine receptivity. Often elusive factors, such as: a) dysfunctional immunologic implantation; b) anatomical pathologic endometrial factors c) genetic and poorly understood molecular factors, all too often contribute to failure of a St-IVF procedure.

J. The Role of Technical Expertise with Embryo transfer, in the Outcome of St-IVF?
Embryo transfer is a critical rate limiting step in IVF. However the level of expertise in performing this important procedure varies widely. It is difficult to standardize a procedure that combines dexterity and skill, with know how. Alarmingly, there are still IVF practitioners who routinely perform ET without using ultrasound guidance to make certain that the embryo(s) is/are deposited in the uterus with precision. (In some cases, where the uterine cavity cannot be adequately visualized, the experienced physician can get by doing the embryo transfer by feel, but this represents the exception rather than the rule.)

J. Conclusion:
St-IVF represents an important advance in the ART arena. We believe that for the following reasons St-IVF could re-fashion the entire IVF panorama in the years to come.

o St-IVF produces about a 60% viable pregnancy rate per embryo transfer. This is approximately double the national average
o With St-IVF the implantation potential of each “euploid” embryo is markedly increased to > 50% (more than double the usual rate) per “competent” blastocyst transferred
o St-IVF markedly can reduce the risk of commonly occurring miscarriages and birth defects such as Down’s Syndrome that are due to embryo aneuploidy.
o St-IVF markedly reduces the incidence of IVF high order multiple births by making it possible to transfer up to two competent embryos for a remarkably high success rate


NOTE:  PGD by way of FISH and CGH can be wrong.
1. With Fluorescence in-situ hybridization: Preimplantation genetic diagnosis (PGD) of numerical chromosome abnormalities significantly reduces spontaneous abortions and may increase pregnancy rates in women of advanced maternal age undergoing in vitro fertilization. However, the technique has an error rate of around 10% and trisomy 21 conceptions have occurred after normal PGD/FISH.
2. With Comparative genomic Hybridization: While the transfer of blastocysts derived from fertilization of  CGH” normal” eggs/embryos minimizes the occurrence of aneuploidy related birth defects such as Down’s syndrome, it does not definitively preclude their occurrence.

We strongly recommended that Prenatal Genetic Diagnosis, including (but not necessarily limed to) 1st trimester chorionic villus sampling (CVS) and/or2nd trimester amniocentesis be carried out in all cases where pregnancy occurs following the transfer of “CGH-normal” embryos.

_____________________________________________________

2.CGH IN IVF:ADDITIONAL CONSIDERATIONS:

Geoffrey Sher MD



1. Subjectivity of CGH results: As far as I know, CGH reporting is definitely NOT subjective.
a. We have compared FISH and CGH results and they match in >95% of the chromosomal aneuploidies.
b. We have performed CGH linearly on pre-fertilized oocytes (PB-1) and then   post-fertilization (on PB-2, and blastomeres)  and the karyotype perpetuated throughout in 98% of cases.
This should NOT be confused with “inconclusive” results which only occur when the DNA signal cannot be picked up at all.

2. Auto-correction of embryo aneuploidy:. Here are a few thoughts to ponder on
a. Although advanced embryos (blastocysts) and early concepti appear to be able to overcome mitotic aneuploidy , this only occurs when a small percentage of their cells are aneuploid. When such aneuploidy occurs in 1/6-9 cells of the day 3 embryo it inevitably   translates 20% or more of cells in the advanced embryo or conceptus being aneuploid, and this would be lethal.
b. Remember, such a supposition would apply equally to FISH karyotyped embryos. As you are aware, embryo selection based on FISH karyotyping  has been done for >20 years in IVF. This would negate the value of karyotyping across the board…quite an indictment.
c. I recently met with and spoke with a few leaders in the field of reproductive genetics Santiago Munne, and Jacques Cohen and Simon Fishel in the last 2 weeks. We discussed this matter . Their opinion matches mine. They absolutely agree that a Day 3 PGD diagnosis of aneuploidy (meiotic or mitotic) means the embryo is flawed and should not be transferred.
d. Besides, who would be bold enough to advise the transfer of a dyskaryotic embryo?

3. The incidence of aneuploidy increases with age. While the exact incidence is not known, experience suggests that the age-related incidence of aneuploidy is probably about: 60-70% in women under 35Y; 70%-80% at 35Y-40Y; 80-90” between 40Y-43Y and > 90% thereafter.
4. The incidence of aneuploidy and is also subject to influence by the ovarian environment. That is why, PCOS women, older women,  and poor responders have higher rates of aneuploidy. The latter (older women and poor responders) also produce fewer eggs and thus fewer embryos, so there are less available to test. Accordingly in such cases there will be a high percentage of women who end up with no euploid embryos at all.
5. PGD by way of FISH and CGH can be wrong.
1. With Fluorescence in-situ hybridization: Preimplantation genetic diagnosis (PGD) of numerical chromosome abnormalities significantly reduces spontaneous abortions and may increase pregnancy rates in women of advanced maternal age undergoing in vitro fertilization. However, the technique has an error rate of around 10% and trisomy 21 conceptions have occurred after normal PGD/FISH.
2. With Comparative genomic Hybridization: While the transfer of blastocysts derived from fertilization of  CGH” normal” eggs/embryos minimizes the occurrence of aneuploidy related birth defects such as Down’s syndrome, it does not definitively preclude their occurrence.

We strongly recommended that Prenatal Genetic Diagnosis, including (but not necessarily limed to) 1st trimester chorionic villus sampling (CVS) and/or2nd trimester amniocentesis be carried out in all cases where pregnancy occurs following the transfer of “CGH-normal” embryos.


As you may know, there is  currently a great debate raging surrounding the controversy that embryo PGD could be harmful to an embryo and reduce its viability . This debate which is rampant in the UK and will undoubtedly soon be propagated in the U.S is part of a “smoking mirrors”  campaign aimed at turning public opinion against PGD in general. It is different than the one we confronted regarding whether gonadotropin therapy causes ovarian cancer, in the late 80’s. Whether position is right or wrong is not the issue. The fact is that It is likely to be   to escalate and be used by those in the medical field who oppose any change, regardless of merit, if it threatens  their comfort level. Against this background, and given the fact that in >90% of non-male infertility cases it is the egg, rather than the sperm that determines embryo ploidy (“competence”), Simon Fishel and his group at CARE-UK ( who use ore CGH lab) have decided that in all non-male infertility cases they will rather  do egg (PB-1)-CGH, than cleaved embryo (blastomere)-CGH , reserving the latter for MF infertility cases. They are willing to accept that by doing this they will miss a small percentage of aneuploidies that result from sperm contribution in non-male factor cases but for the lowing reasons, they feel that it would be “safer” for them (politically) to go this route:
 Oocyte PB-1 biopsy does not remove embryo’s cells and this removes criticism that PGD done later could be traumatic to the normal embryo
 Switching to PB-1 biopsy COMLETELY eliminates, ANY possibility of auto-correction (see #1 above) since this is absolutely impossible in cases of meiotic aneuploidy.
 It would be easier for patients to accept oocyte ‘incompetence” as being an inevitable cause of embryo “incompetence” because that removes and suspicion of laboratory causes.

We all need to discuss whether we wish to go the e route as CARE! However, in doing so we must consider following draw-backs:
 We would need to perform many more biopsies to do St0-IVF, since currently we only biopsy those MII’s that make it to 6-9 cells by day 3. This will raise cost.
 We would miss identifying and excluding about 20% OF embryos that become aneuploid because of sperm contribution or mitotic aneuploidy.

Finally, I again wish to emphasize that CGH is NOT a panacea.
 It does not promote a greater yield of “competent” embryos per IVF cycle. It only identifies them. It does not improve IVF success per egg retrieval.  Rather by improving baby rate per embryo that is transferred, and reduces the risk of multiple births, miscarriages and birth defects. As such, it does improve the “efficiency” of IVF.
 CGH should not be used across the board. Rather it is indicated :
i. When there are numerous embryos and you want to select one or 2 or ET
ii. For diagnostic reasons in cases of MF infertility (requiring both PB-1 and blastomere biopsy); unexplained infertility; recurrent unexplained IVF failure; RPL, differentiating between plantation and embryo/competency as the cause of IVF failure
iii. To stockpile embryos in poor responders and older women
iv. For egg freezing (Fertility Preservation).
v. Donor egg banking
vi. To stockpile CGH normal embryos in women whose biological clock is running out.
Sure,  it is tough to confront patients who produce good looking blasts only to nd that none are “competent”. Sometimes we ignore the fact that following conventional IVFMANY +ve betas” end as chemical pregnancies. This occurs in about 25% of cases in women <35Y, and >45% in women over 40Y. Levent went back and computed what percentage of +ve betas progressed to euploid pregnancies and in doing so found that it was the same the percentage per patient that have a healthy pregnancy after a CGH-selective ET,

The barriers to the entry of widespread ST-IVF with CGH are formidable. The above constraints and limitations of application, make it unlikely that IVF-CGH will readily grab hold in ART. No one likes to confront patients with bad news, at least 40% of the time. As with the  resistance we have encountered to implantation  immunology testing and selective immunotherapy i, where most RE’s prefer to tell patients with what they want to hear, rather than with what they need to know, CGH, will be slow to be accepted and will be criticized by those that  find it hard to compete. They will provoke a critical backlash. BUT therein also lies a huge opportunity for us at SIRM to differentiate from the competition. Patients are not gullible! While some will buy the disinformation fed to them by competitors, like with immunology, they will in the final analysis come to us and we will benefit.

Array CGH (aCGH) is on its way. While aCGH will not likely improve the efficacy of CGH it will definitely speed up the process enabling fresh rather than Staggered-IVF (using PB-1 biopsy) to be used in cases so indicated, allow for gender selection and permit improved prenatal genetic diagnosis. However, aCGH is more expensive and unfortunately still lacks necessary sensitivity and specificity. We remain hopeful as reliability improves and cost comes down, that ultimately conventional CGH with aCGH. Presently what is out there now is “smoking mirrors”.

So in summary, the real benefit of IVF-CGH lies in the ability to reduce multiples, virtually eliminate aneuploidy-related miscarriages and birth defects and its use as a diagnostic tool that helps decide when it is time to stop or move on to OD/GS/adoption. Rather than its application to IVF, the real future for CGH lies in egg freezing (Fertility Preservation and donor egg banking).