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Preimplantation Genetic Diagnosis - PGD and IVF
Does PGD, or PGS for chromosomal tests of embryos (aneuploidy testing) improve in vitro fertilization success for infertile couples?

Advanced Fertility Center of Chicago
Gurnee & Crystal Lake, Illinois

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What is PGD?

• Preimplantation genetic diagnosis involves testing done on in vitro fertilization IVF embryos prior to transferring them to the mother's uterus. The testing is done either to check for a specific genetic abnormality (such as a disease like cystic fibrosis), or it can be done to determine if the embryos are chromosomally normal (also called aneuploidy screening).

• PGD is done by removing 1 or 2 cells usually at about the 8-cell stage (day 3 after fertilization). A hole is made in the shell of the embryo, and then a pipette is used to suck the cell(s) away from their neighbors - removing them from the embryo so that testing can be done. This process is called embryo biopsy or blastomere biopsy. Some programs biopsy the polar bodies of the egg, rather than the cells from the early embryo.

• Specialized techniques are then used to either check for the genetic disease in question, or to investigate for overall chromosomal normality.

• The testing can generally be completed in 1 day. Therefore, embryos can be tested on day 3 after fertilization and transferred back to the wife on day 4 or 5 after the results are back.

• The first report of PGD in humans with pregnancy resulting was published in 1990 - major improvements in these technologies have occurred since then.

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Who might benefit from PGD?

In general, there are 4 major groups of patients that might be offered PGD (other indications could be considered as well)

1. Patients with inherited genetic diseases (rare)

2. Patients that are carriers of chromosomal translocations that have suffered recurrent miscarriages (rare)

3. Patients that are having IVF with advanced female age - 38 or older (common)

4. Patients of any age with repeated IVF failure - usually defined as 3 or more failed attempts

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Does PGD help?

The answer, at this time, may depend on the reason that PGD is being done:
 

PGD for inherited genetic diseases:

This is a rare situation in which a couple knows that they carry a gene that would put their child at risk for having a serious medical condition. In such a scenario, PGD can clearly benefit the couple. For example, if husband and wife are both carriers of a recessive disease (such as cystic fibrosis), their child (conceived naturally) would have a 25% chance of having this terrible disease. By having IVF and PGD, they can have "normal" embryos transferred so that (if the IVF is successful) their child should not have cystic fibrosis.

PGD for patients that are carriers of chromosomal translocations:

This is another rare situation in which a couple knows that one of them has a chromosomal arrangement called a balanced translocation. When someone (the husband or the wife) has a balanced chromosomal translocation they are normal - until they try to have a child. When their chromosomes join with those of their partner in the fertilized egg they make a high percentage of chromosomally abnormal embryos. These embryos are at very high risk for miscarriage or could result in the birth of a child with birth defects. This is another situation where PGD can help. By having IVF and PGD, they can have chromosomally normal embryos transferred (if there are any) - greatly reducing their risk for miscarriage and birth defects.

PGD for aneuploidy screening (PGS) - checking the chromosomes (because they are having IVF and the wife is 38 or older, or because of multiple previous IVF failures)

• Background: Human eggs are often chromosomally abnormal - and the percentage of eggs with a chromosomal abnormality increases with increasing female age. In general, it seems that about 25-40% of human embryos have some type of chromosomal abnormality. This increases to about 50% and higher as women approach or exceed age 40.
• Theory: By testing the chromosomes of the embryos available for transfer, we can discard all embryos with abnormal chromosomal arrangements and pick the embryo(s) for transfer to the wife's uterus from those demonstrating normal chromosomes. This is fascinating technology, and the theory is logical as well. However, the data from studies on pregnancy outcomes after PGD testing of chromosomal normality does not appear to show any clear benefit at this time. PGD for aneuploidy is often referred to as preimplantation genetic screening, or PGS (instead of diagnosis).

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What is the data showing with PGD for aneuploidy screening?

• Miscarriage rates are lower after PGD in some, but not all studies
• There is no proof that pregnancy rates or live birth rates are better with PGD. In fact they appear to be lower with PGD from damage to the biopsied embryos (see studies below on this page)
• There is no proof that we are able to transfer fewer embryos and get the same live birth success rate by using PGD
• Sometimes PGD gives false results, such as:
   
  • The embryo is truly chromosomally abnormal but PGD says it is normal
  • The embryo is truly chromosomally normal but PGD says it is abnormal
  • False results are seen for about 5-15% of embryos (this issue is actually fairly complicated)

Controlled randomized studies of PGD for aneuploidy vs. no PGD

New PGS study published in July 2007 in the New England Journal of Medicine, July 5, 2007;357(1):9-17.

In vitro fertilization with preimplantation genetic screening

Authors:    Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, Vogel NE, Arts EG, de Vries JW, Bossuyt PM, Buys CH, Heineman MJ, Repping S, van der Veen F.

IVF Centers:    Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

• This study was done in multiple IVF centers
• 408 couples were randomly assigned to 3 IVF cycles with or without PGD (206 couples had PGD and 202 did not have PGD)
• 836 total cycles of IVF (434 cycles with and 402 cycles without preimplantation genetic screening)
• The ongoing pregnancy rate (12 weeks of pregnancy) was 25% in the PGD group, which was significantly lower than the ongoing pregnancy rate of 37% in the no PGD group
• The PGD group also had a significantly lower live birth rate of 24% compared to a live birth rate of 35% in the group that did not have PGD
• They concluded that preimplantation genetic screening did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of advanced maternal age
• This is the biggest and best scientific study that has been published thus far that was designed to determine if PGD for aneuploidy screening increases or decreases IVF success rates for couples with a female partner over 35 years old

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• A small study presented as a poster (Poster # 322) at American Society for Reproductive Medicine annual meeting in October 2004 looked at whether PGD can improve IVF success.
• The study was done by J. Stevens, Wale, Surrey, Schoolcraft and Gardner from the Colorado Center for Reproductive Medicine.
• Title of the study: "Is aneuploidy screening for patients aged 35 or older beneficial?"
• The study results showed that the group of patients having PGD showed:
  • The same percentage rate of embryos developing to blastocysts by day 5
  • Lower rates for pregnancy
  • Lower rates for ongoing pregnancy
  • Lower rates of implantation per embryo
  • Lower rates of miscarriages
• However, this study was small, and therefore none of the differences between the 2 groups were statistically different
• Data from this study are shown in the table below

• This was an excellent study, and larger controlled randomized trials of PGS for aneuploidy are needed to determine whether it improves (or reduces) the chances for a healthy live birth outcome for infertile couples having IVF treatment.
• It is important to consider that regardless of the outcome of a few studies, further research is needed from multiple IVF centers. What works (or doesn't) in one center might show a different result in another center.

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• A prospective randomized controlled trial of PGD for aneuploidy was published in the December 2004 issue of the medical journal - "Human Reproduction".
• The study was done by C. Staessen, Platteau, Van Assche, Michiels, Tournaye, Camus, Devroey, Liebaers and Van Steirteghem from the Center for Reproductive Medicine and the Center for Medical Genetics, University Hospital, Dutch-speaking Brussels Free University, Brussels, Belgium.
• Title of the study: "Comparison of blastocyst transfer with or without PGD for aneuploidy screening in couples with advanced maternal age: A prospective randomized controlled trial"
• 400 couples having IVF with a wife 37 years old or older were randomly assigned to 2 groups:
  • IVF and ICSI without PGD
  • IVF and ICSI with PGD on the day 3 embryos
  • Embryos were transferred on day 5 at the morula or blastocyst stage for both groups (PGD results were available by day 5)
• The study results showed:
  • Lower initial pregnancy rates per egg retrieval with fertilized eggs in the group having PGD (20.9% vs. 28.7%)
  • Lower ongoing pregnancy rates per egg retrieval with fertilized eggs in the group having PGD (15.8% vs. 21.3%)
  • Very high rate of having no embryos at all for transfer in the in the group having PGD (41.7% vs. 11.0%)
  • Higher rates of implantation per embryo transferred in the group having PGD (but a lot less embryos were transferred in that group)
  • No difference in the miscarriage rate with or without PGD
• The authors concluded that:
  • PGD for aneuploidy did not improve IVF outcome for couples with a female partner 37 or older when there are no restrictions on the number of embryos that can be transferred (they transferred an average of 2.8 in the group without PGD and 2.0 in the PGD group)
  • They speculated that PGD might be advantageous when there are strict regulations on the number of embryos that can be transferred (such as no more than 1 or no more than 2 embryos)
• In my opinion, the bottom line for couples with infertility is the chance for a healthy live birth from the treatment, and to a lesser extent the financial costs involved.
  • Chances for a healthy live birth appear to be better without PGD (ongoing pregnancy rate without PGD = 21.3%, vs. 15.8% with PGD).
  • IVF without PGD is also much less costly than IVF with PGD (at least in the US)
• Data from this study are shown in the table below
  • I have taken the liberty to reorganize the data from the publication in order to make it easier to understand
     

• 58 patients had fertilized eggs but no embryo transfer in the PGD group, compared to only 15 patients with fertilized eggs and no transfer in the group without PGD. Patients with PGD were about 3.9 times as likely to have no embryo transfer as compared to couples without PGD. Three categories for no embryo transfer were listed:
  • No embryos were suitable for biopsy (9 of the 58 cases with no transfer in the PGD group)
  • No embryos were chromosomally normal after the PGD results were back (38 of the 58 cases with no transfer in the PGD group)
  • No morula or blastocyst was available for transfer on day 5 (11 of the 58 cases with no transfer in the PGD group)
  • It is very possible that the embryo biopsy process in PGD weakens the embryo and lowers chances for a live birth when those biopsied embryos are transferred.

   

• This was an excellent study with good numbers of patients assigned randomly to the control and the PGD groups. Additional large controlled randomized trials of PGD for aneuploidy are needed to further investigate whether PGD for aneuploidy improves, or reduces, the chances for a healthy live birth for infertile couples having IVF treatment.

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The 3 studies detailed above are a good start. However, it is important to consider that regardless of the outcome of these studies, more studies on PGD for aneuploidy screening are needed. The studies on PGD and IVF should be from multiple in vitro fertilization programs. Also, as PGD techniques continue to evolve and improve, pregnancy and live birth rates after PGD might increase.

What are some of the additional problems and concerns with PGD at this time?

• The embryos are traumatized with PGD. The question remains unanswered as to how often they can "recover enough from the beating" to retain viability. It seems that many embryos do not recover completely. If some embryos did not suffer lethal damage from the PGD biopsy process, then we should expect that identifying and transferring to the wife only chromosomally normal embryos would result in higher embryo implantation rates, higher clinical pregnancy rates, and higher live birth rates - as compared to what is seen in otherwise similar cases that did not have PGD. However, thus far, studies do not clearly support that being the case (see above). Said another way, too many normal, strong embryos are weakened to the point of being non-viable by the embryo biopsy procedure.
• As with any new technique and technology, there is a "learning curve". Some technicians will be more proficient at the biopsy procedure. Some labs will also be more proficient at the diagnostic component after the cells are removed - giving a higher percentage of accurate results. Therefore, there will potentially be large differences between centers performing these techniques, and possibly even between different technicians within the same center.
• It is expensive to do PGD - costs in the US are usually between $2000 and $4000 - in addition to the usual IVF related fees
• About half of the chromosomal abnormalities in human preimplantation embryos are problems with the chromosome count - for example a missing or an extra chromosome. The other half of the abnormalities are "mosaics". This means that the chromosome testing revealed that there are 2 (sometimes more) different chromosomal patterns found in cells in the embryo. For example, one cell can show normal results while a second cell tested shows evidence of a doubling of the normal number of chromosomes. Other combinations of normal and abnormal chromosome numbers are also fairly common. There is some evidence that mosaics can "repair" themselves, and/or possibly designate abnormal cells preferentially to the placenta instead of to the fetus. More research is needed in this area.
  • So if we only test 1 cell from an 8-cell embryo and it is normal, are the other 7 cells also normal? We can't know. It can still be useful to know whether that one cell is normal or abnormal, however, we know that about half of all embryos are mosaic.

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If so many embryos have abnormal chromosomes, what is the risk for having a chromosomally abnormal baby for couples that do not have PGD with their IVF?

• In humans, there is a natural selection process that prevents implantation of abnormal embryos
• The large majority of chromosomally abnormal embryos will arrest in early development and not survive long enough to implant in the wife's uterus
• Some will implant and result in early miscarriages
• An extremely small number could continue further into pregnancy and could go on to a live birth of a chromosomally abnormal baby - if not detected during the pregnancy by non-invasive screening tests such as blood and ultrasound (more invasive testing such as chorionic villus sampling (CVS) would discover these abnormalities by about 10-12 weeks of pregnancy, or amniocentesis by 18-20 weeks)
• In the general population, the risk for a live birth with a chromosomal abnormality is about:
   

The overall risk for a chromosomally abnormal live birth does not appear to be increased by having IVF or IVF with ICSI (intracytoplasmic sperm injection)

What else can be done to help couples to have a successful IVF outcome with a normal, healthy baby?

• Grading of embryo quality in the IVF lab can help pick the chromosomally normal embryos for transfer. Embryos that are "graded" on the higher end of the scale have lower rates of chromosomal abnormalities as compared to those embryos that have lower grades.
• Embryos that make normal looking blastocysts on day 5 have lower rates of chromosomal abnormalities as compared to those embryos that do not make blastocysts. Therefore, some clinics are using blastocyst culture and transfer in order to be able to select embryos with higher implantation potential and lower rates of chromosomal abnormalities as compared to transferring embryos back on day 2 or day 3.

In summary regarding PGD for aneuploidy screening

• A very significant percentage of embryos are chromosomally abnormal
• PGS or PGD technology exists that allows us to biopsy IVF embryos on day 3 of development and test chromosomal normality of 1 or 2 cells from each embryo
• Test results can be back in one day - and then embryo(s) can be selected for transfer
• More large prospective randomized trials (see studies discussed above) of PGD for aneuploidy vs. no PGD are very much needed. Prospective randomized trials are the best type of study to properly determine whether there is a real benefit for our patients from this procedure. These studies should preferably be done at multiple high-quality IVF centers.

The published studies on success rates and pregnancy outcomes after PGD for aneuploidy thus far (generally) show:

• No improvement in clinical pregnancy rates with PGD - it appears at this time that PGD actually results in lower pregnancy rates
• No improvement in  live birth rates with PGD - it appears at this time that PGD actually results in lower live birth rates
• Questionable improvement in implantation rates with PGD - possibility of actually having lower rates - fewer embryos are transferred after PGD in some cases
  • "Implantation rate" is the percentage of transferred embryos that implant in the uterus and are seen with early pregnancy ultrasound
• Some studies are showing a somewhat lower rate of miscarriage after PGD, other studies are not showing any difference (see details of studies discussed above)

Other issues of concern:

• The test results are not always correct
  • Sometimes the embryo has abnormal chromosomes, but PGD testing shows a normal result
  • Sometimes the embryo has normal chromosomes, but PGD testing shows an abnormal result
  • Therefore, some chromosomally normal embryos will be discarded, and some chromosomally abnormal embryos will be transferred after PGD
• PGD is expensive (about $2000 to $4000 in the US, in addition to all other IVF charges)
• I believe that there is a lot of confusion created by the aggressive "marketing" of PGD that is done by some fertility centers and/or PGD labs. Marketing brochures, "patient education" videos, etc. are telling consumers of infertility services that PGD can improve pregnancy rates, reduce multiple birth rates, reduce the risk of miscarriage, and reduce the risk of having a baby with a chromosomal abnormality. Patients are understandably confused when the theoretical benefits of PGD are crafted into slick marketing brochures at centers that make a substantial profit on PGD for chromosomal testing.
• I believe that the business of PGD has pushed ahead of science and good medical practice at some centers.

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Having considered all of the above, we are not currently offering PGD for aneuploidy screening at our center.

We will offer it when (and if):

• It has been proven (in well-controlled and published studies) to benefit our patients with higher implantation rates or higher live birth rates (or both)
• The technique has been improved so that it is more accurate (less mistakes in diagnosing chromosomally normal vs. abnormal embryos)
• The cost is low enough to justify the amount of benefit that our patients would derive from the procedure

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The technology exists to investigate chromosomal normality in IVF embryos. However, that does not mean we should necessarily employ that technology - unless it clearly benefits our patients.

In my opinion, PGD for aneuploidy screening has been implemented (by some IVF centers) before proof of benefit for the infertile couples. We should have proof of higher implantation and live birth rates from well-designed, large, prospective randomized trials  before aneuploidy screening is routinely offered to IVF patients.

This might be another example of incredible technology seeking a real world indication...

In all fields of medicine we must try our best to help our patients - and "first do no harm".

Page author:  Richard Sherbahn, MD