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PGD and IVF - Preimplantation Genetic Diagnosis & In Vitro Fertilization, Pros and Cons About PGD and PGS

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What is PGD, or preimplantation genetic testing?

PGD, preimplantation genetic diagnosis, is the process of removing a cell from an in vitro fertilization embryo for genetic testing before transferring the embryo to the uterus.

The term PGD, preimplantation genetic diagnosis, is often loosely used to refer to any testing performed on an embryo prior to it being transferred to the uterus. However, the distinction should be made between the terms PGD and PGS.

  • PGD, preimplantation genetic diagnosis, involves removing a cell from an IVF embryo to test it for a specific genetic condition (cystic fibrosis, for example) before transferring the embryo to the uterus.
  • PGS, preimplantation genetic screening, is the proper term for testing for overall chromosomal normalcy in embryos. PGS is not looking for a specific disease diagnosis - it is screening the embryo for normal chromosome numbers.

History of PGD - PGS

IVF, in vitro fertilization, was first successfully used in 1978. It was not until years later that scientists began tinkering with the possibility for extracting one or more cells from the embryo to get information about the potential health of the child that might result following implantation of that embryo.

The first report of pre-implantation genetic testing in humans with a pregnancy resulting was published in 1990. Major improvements in these technologies have been developed since then. Both the embryo biopsy techniques as well as the genetics technologies used on cells removed from embryos have improved dramatically.

  • Much has been learned in the PGD/PGS field over the past 20 years - and much remains to be learned

Different stages of egg and embryo development can be biopsied

There are 3 basic stages at which eggs or embryos are biopsied at the present time.

  1. Polar body biopsy is performed at an early stage when the polar body of the egg is removed and can have its genetic material tested. A mature egg has one polar body and a fertilized egg has 2 polar bodies. Either the first polar body of the egg or the first and second polar bodies can removed for testing.
  • This technique does not involve involved taking anything from the embryo from the cells that would become part of the fetus or the placenta. However there is still potential for damaging the developmental potential of the resulting embryo with polar body biopsy.
  • There is some evidence that the polar bodies may help direct differentiation of the cells in the very early embryo. They may be involved in determination of which cells become precursors to the fetus (inner cell mass) and which cells become present precursors to the placenta (trophectoderm).
  1. Biopsy at the cleavage stage is done on day 3 of embryo development. At this point the embryo usually has 6 to 10 cells.
  • Removal of a portion of the zona pellucida (outer shell of embryo) is performed
  • Then 1 or 2 cells is pulled out of the embryo for subsequent testing
  • The day 3 cleavage stage biopsy technique has been shown in several studies to be detrimental to embryo development. Therefore, many IVF programs are moving away from it in recent years.
  1. The third type of PGD biopsy is called trophectoderm biopsy. It is performed at the blastocyst stage after the embryo has differentiated into an inner cell mass, a trophectoderm component and a fluid filled cavity.
  • With trophectoderm biopsy at the blastocyst stage a small hole is made in the shell of the embryo and several cells that are precursors to the placenta (trophectoderm) are removed for testing
  • This technique has shown promising results in some US IVF programs. It is now considered by many experts to be the biopsy procedure of choice for PGD and PGS testing.

Which are the best PGD clinics?

  • In general, the best clinics for PGD or PGS will be the clinics with the best IVF success rates.
  • It is critical to have an excellent culture system in order to get a maximal number of quality blastocysts for biopsy.
  • Also, the skills that lead to successful IVF are the same skills that facilitate blastocyst culture, embryo biopsy and blastocyst vitrification (freezing) and successful frozen-thawed embryo transfers.
  • Check the CDC and SART sites to find an IVF clinic in your area with a good volume of cases and high success rates. Then make sure that they have been doing trophectoderm biopsies.
  • Come to our clinic for IVF and PGS / PGD

Who might benefit from PGD?

In general, there are 5 main groups of patients that might utilize PGS or PGD (list is not exhaustive)

  1. Patients that are having IVF with advanced female age - 38 or older (common)
  2. Patients of any age with repeated IVF failure - usually defined as 3 or more failed attempts
  3. To screen for inherited genetic diseases
  4. Patients that are carriers of chromosomal translocations
  5. Patients that have had recurrent miscarriages
PGD / PGS and Age - aneuploidy screening (PGS) - checking the chromosomes
  • The most common reason that PGS is done in the US is for "advanced age".
  • This would often mean older than about 37 in many programs offering PGD.
  • The logic relates to the fact that women of advancing age have increased rates of chromosomally abnormal eggs - which after fertilization will become chromosomally abnormal embryos.

Human eggs are often chromosomally abnormal - and the percentage of eggs with a chromosomal abnormality increases with increasing female age. In general, about 50% of human embryos have some type of chromosomal abnormality. This increases to 80% and higher as women approach age 42.

In theory, by testing the chromosomes of the embryos available for transfer, we can discard embryos with abnormal chromosomal arrangements and pick the embryo(s) for transfer to the female partner's uterus from those with normal chromosomes.

There is controversy as to whether PGD testing of early embryos before transfer will increase the chance of a successful outcome. The logic works for offering chromosomal screening of the embryos prior to choosing the best ones for transfer back to the uterus. However, if the embryos are damaged significantly from the biopsy procedure, then we risk losing more than we gain from the test results.

What does the data show with PGD for aneuploidy screening?
  • Miscarriage rates are lower after PGS in most studies
  • The data on improvement in pregnancy and live birth rates are inconsistent
  • The data from older prospective randomized trials using day 3 biopsies and the older FISH technology (less reliable) shows lower live birth rates with PGS
  • Data from recent studies using trophectoderm biopsies combined with chromosomal analysis using advanced genetics technologies assessing all 23 chromosomes show very high IVF success rates.

There are currently 3 technologies that can be utilized for assessment of chromosomal normalcy in biopsied IVF embryos:

  1. Array Comparative Genomic Hybridization (aCGH)
  2. Single nucleotide polymorphism microarrays (SNP)
  3. Quantitative real time polymerase chain reaction(qPCR)

More about the new genetics technologies that assess all 23 chromosomes - array CGH, SNP and qPCR

PGD for inherited genetic diseases

This is an uncommon 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 the male partner and female partner 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 IVF is successful) their child should not have cystic fibrosis.

PGD for patients that are carriers of chromosomal translocations

This is a rare situation in which a couple knows that one of them has a chromosomal arrangement called a balanced translocation. When someone has a balanced chromosomal translocation they are normal - until they try to have a child.

When the chromosomes in their sperm or eggs join with those of their partner in the fertilized embryo, they have a high percentage of chromosomal abnormalities.

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 PGS can help. By having IVF aneuploidy screening of the embryos, they can have chromosomally normal embryos transferred. This greatly reduces their risk for miscarriage and birth defects.

What are some concerns with PGD?
  • The embryos could be traumatized by the biopsy procedure - particularly for day 3 embryo biopsies
  • There is some evidence that carefully performed trophectoderm biopsies done on day 5 and day 6 blastocysts might not weaken the embryo at all
  • As with any new technique and technology, there is a "learning curve"
    • Some technicians will be more proficient at the biopsy procedure
    • Some genetics labs will be more proficient at the diagnostic component after the cells are removed - giving a higher percentage of accurate results
    • Therefore, there could be large differences between centers performing these techniques, and even between technicians within the same IVF center
  • Mosaicism can complicate matters. An embryo is a mosaic if there are 2 (or more) different chromosomal patterns in cells of that embryo
    • There is evidence that mosaic embryos sometimes "self-repair", or possibly designate abnormal cells preferentially to the placenta instead of the fetus. More research on mosaicism is needed.
If so many embryos have abnormal chromosomes, what is the risk for having a chromosomally abnormal baby for couples that do not have PGS 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 female partner's uterus
  • Some will implant and result in early miscarriages
  • An extremely small percentage can continue further into pregnancy and could progress to a live birth of a chromosomally abnormal baby - if not detected during pregnancy.
  • Testing for this can be done in early pregnancy:
    • Non-invasive screening tests such as blood tests or ultrasound evaluation of the baby
    • Invasive testing in early pregnancy such as CVS or amniocentesis
      • CVS, chorionic villus sampling is done at about 11-12 weeks of pregnancy
      • Amniocentesis is done at about 16-18 weeks
In the general population, the risk for a live birth with a chromosomal abnormality is:
Female age
Risk of a live birth with any
chromosomal abnormality
25
1/476
30
1/385
35
1/164
40
1/51
45
1/15

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.

Women that are of advanced reproductive age (such as 38 and older) will sometimes have chromosomal abnormalities in a very high percentage of their remaining eggs.

Rather than having IVF with PGS using their eggs, many of these women will need to do IVF with egg donation in order to have a successful pregnancy.

Because egg donors are young (usually under 30) and chromosomally abnormal eggs are much less common in young women, PGS is generally not used with donor eggs.

In summary regarding PGD for aneuploidy screening
  • A high percentage of human embryos are chromosomally abnormal
  • PGS technology allows us to biopsy IVF embryos and test for chromosomal normality
  • Day 3 embryo biopsy and PGS using FISH technology reduces IVF success rates
  • There is recent evidence that trophectoderm biopsy and PGS using one of the newer genetics technologies (aCGH, SNP or qPCR) can improve IVF success rates
  • Prospective randomized trials of no PGS vs. PGS for aneuploidy using trophectoderm biopsy in conjunction with these new genetics technologies are needed

Cost of PGD and PGS

Another issue with PGS and PGD is cost. Over the years the cost has been dropping, but it is still expensive technology.

  • The biopsies and tests cost from about $4000-$9000 plus all other associated IVF costs
  • There will often need to be a frozen embryo transfer cycle done after PGD or PGS testing
  • There are costs associated with the embryo biopsy procedure itself and there are costs for the genetics laboratory performing the genetic studies on the cells.
  • IVF and PGD Costs - How much is PGD?
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