The medical community just loves its acronyms!
Although none of these tests are currently available in Singapore, they are routinely used in many other countries. Ever since we were told that it is possible to transport embryos out-of-country to have them tested with PGD, we've been thinking that this is something we would like to incorporate in our next step. Having long felt that they would be advantageous to us, I wanted to understand exactly what the differences and risks were in each.
What are the benefits of PGD?
PGD is the only way to know if the embryos are chromosomally normal, that is, that they have 23 matching pairs of chromosomes. If an embryo has a translocation, such as monosomy (deletion of 1 chromosome) or trisomy (addition of 1 chromosome) of one or more of the 23 pairs, it is considered aneuploid (abnormal).
Chromosomal abnormality is the highest cause of miscarriage, aneuplody (abnormal embryos) is thought to be the cause of up to 60% of natural and IVF miscarriages. Young women in their 20s may produce up to 20% chromosomally abnormal eggs in natural cycles, this rate goes up to 30%-100% with IVF or in older women. PGD reduces the incidence of miscarriage post IVF.
PGD reduces the rate of disability, because some trisomy conditions can survive to birth.
PGD improves the success rate of pregnancy to 50%, as opposed to 30% purely because the remaining embryos could survive the attrition, from Day 3 to Day 5.
Why might we need PGD?
In our particular case, I think we might need PGD because of multiple factors. First, we have had recurrent and unexplained IVF failure. Second, although I am not old in chronological age, I exhibit symptoms of Diminished Ovarian Reserve, which means that the remaining eggs may have a high percentage of chromosomal abnormalities.
Third, our embryos often fall apart between Day 2 and Day 5, with very high rates of attrition, again that suggests high chromosomal abnormalities. Lastly, in our last two rounds, we had a blastocyst with no visible fetal pole and a lousy, slow-growing 4-cell-at-Day-3 embryo that made it to a visibly normal blastocyst and was frozen.
The blastocyst which had no visible fetal pole might have implanted, but it would have been an empty sac and we would have miscarried. The slow-growing embryo was almost discarded and even though it looks normal on Day 5, without a PGD test, there is really no way to tell if it is actually chromosomally normal. What it does tell me is that my best quality (or chromosomally normal) embryos may not align with our fastest growing or even most visually pretty embryos.
What causes anueploidy?
Organisms that reproduce sexually have 23 pairs of chromosomes within each cell — one chromosome within each pair is inherited from each genetic parent. A process called meiosis creates gametes (eggs or sperm) that have only one chromosome set (i.e. 23 single chromosomes).
If the chromosome pairs fail to separate properly during cell division, your eggs or his sperm may end up with a second copy of one of these chromosomes. The resulting embryo will also have an entire copy of the extra chromosome.
The apparatus that spins or divides these chromosomes into daughter cells is known as the meiotic spindle. If your meiotic spindle is defective because of age, ovarian failure, environmental factors, or fertility conditions, you will produce a higher percentage of aneuploid eggs and therefore embryos.
Who is PGD for? / PGD is suitable for couples who have:
experienced recurrent IVF failure
experienced multiple miscarriage
poor quality embryos or eggs with a high propensity for chromosomal abnormalities
advanced ages (>35 for women, >40 for men) which increases the propensity for chromosomal abnormalities
used IVF to conceive, thus increasing the propensity for chromosomal abnormalities
used an unknown egg donor
pre-existing conditions such as PCOS (poly-cystic ovarian syndrome) or DOR (diminished ovarian reserve) which may affect the quality of eggs
had a number of abortions because of genetic conditions and abnormalities in the foetus
a family history of serious genetic, blood-transmitted conditions
a family history of genetic conditions that only affect one gender, typically male
already have a child with a serious genetic condition.
a preference for SET (single embryo transfer)
undergone IVF for gender selection
What is the difference between PGD and PGS?
The terms PGD and PGS are often used interchangeably – the "d" technically stands for diagnosis, the "s" for screening – but they are both types of preimplantation genetic testing.
PGD – preimplantation genetic diagnosis.
In the past, this was the "catch-all" used for any genetic testing of embryos. However, strictly speaking, it is testing for a known single gene defect or mutation, within the 23 balanced pairs. Single gene defects are such conditions as cystic fibrosis, hemophilia and Tay-Sachs.
The American Society of Reproductive Medicine says the term PGD applies when "one or both genetic parents carry a gene mutation or a balanced chromosomal rearrangement, and testing is performed to determine whether that specific mutation or an unbalanced chromosomal complement has been transmitted to the oocyte or embryo."
PGS – preimplantation genetic screening.
This is a newer term for screening embryos for the correct number of chromosomes and to look for any abnormalities in the chromosomes. It is also sometimes called aneuploidy screening (meaning chromosomal defects).
The ASRM says PGS presumes that the genetic parents are known to be chromosomally normal and their embryos are screened for aneuploidy. So I guess what we would be doing is correctly termed PGS.
What are the different PGD techniques?
FISH Methods — The FISH (Fluorescent In Situ Hybridization) test is an older test that typically only tests between 5 – 10 chromosomes, rather than all of the chromosomes. Thus, it is possible to pass testing with FISH method and still have some chromosomal abnormalities. These biopsies in the past have been typically done on day 3, and only biopsy a single cell.
This is a test for specific genetic defects and not for overall (23 chromosome pairs) competency. There is a school of thought that there is a higher likelihood of false positives on Day 3 because the embryo is less developed and that some defects on Day 3 may self-correct by Day 5.
The added concern with a day 3 biopsy is that some feel there is possibly a higher risk of damaging the embryo, since you are removing 1 cell out of 8. This is definitely a concern for me, since few of my embryos are even 8 cells on Day 3!
With the day 3 biopsy, the results are typically back in time for a fresh blastocyst transfer on day 5.
CCS – Comprehensive Chromosomal Screening. CCS is a form of PGS and screens all 23 pairs of human chromosomes rather than 5 pairs with FISH methods. It does not look for a specific type of genetic defect.
CCS is a group term, which comprises several techniques of evaluation — the most common methods are CGH (also known as array CGH or aCGH), SNP and qPCR.
PCR, sometimes called DNA amplification, is most often used for the diagnosis of single gene defects, including dominant and recessive disorders. CGH allows all 23 chromosomes to be examined and provides a more detailed picture of the entire length, as opposed to a sample of the chromosome. Array CGH or microarray CGH (mCGH) is an accelerated CGH protocol providing results within 24 hours. SNP is also a newer technique that examines all 23 chromosome pairs and can map the number of copy changes, translocations and inversion (flipped chromosome pairs).
CCS can be done on a Day 3 biopsy (again, only one, single cell is used) or on a Day 5 biopsy, which allows you to biopsy a few cells, giving them more material to analyse. Most research appears to suggest that a Day 3 and Day 5 biopsy are similar, just that the embryo may be better able to tolerate the Day 5 biopsy.
On Day 5, the embryo is 100-150 cells and the cells have separated into two types — cells that will form the fetus, known as the inner cell mass (ICM) and cells which will form the placenta (trophectoderm). They take a cell swab from the trophectoderm shell, which later forms the placenta. The thinking is that this is therefore less harmful for the embryo.
With a Day 5 biopsy, an FET transfer is typical. For patients who travel out-of-state or country to do these tests, it means two separate trips. There are only a few clinics that can do a Day 5 blastocyst biopsy in time for a fresh Day 6 transfer.
For a more technical discussion of PGS, CCS methodologies and comparisons of FISH and CCS, an informative article published in the March 2012 Journal of Assisted Reproduction and Genetics can be found at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348286/
What questions should you ask of your clinic and lab?
(1) Ask which lab is doing the PGD testing, as this is not always the same as the embriology lab. I didn't know this! If your clinic does not have an in-house lab, it is often not possible to do PGD and do a 5-day transfer.
(2) Does the clinic have licenses from the requisite authorities to carry out PGD testing? The licence allows the clinic to test for any condition or combination of conditions that a list of PGD conditions. Some clinics will have particular experience of testing only for some conditions.
What are the risks of PGD?
PGD is not always 100% accurate. You should still consider pre-natal testing even if you have done PGD.
Embryos may be damaged from removing cells for PGD testing, particularly with removing one cell out of an 8-cell Day 3 embryo
Embryos must be cultured to 5 days for a PGD 5 day testing and it is possible that none make it to 5 day, or to freeze. Hence, you run the risk of no transfer.
It may not be possible to do a fresh transfer with PGD testing, depending on how long the turnaround time is for PGD testing and results. You may also be charged freezing costs, even if the embryos are later found to be abnormal and discarded.
PGD improves the chances for implantation but it does not mean that implantation will take place. Just because embryos are chromosomally normal does not mean they will take or grow.
PGD reduces but does not remove the risk of miscarriage
What are the costs of PGD?
In the US, costs for PGD/PGS vary by clinic and type of testing, but the typical cost of CCS ranges from around $4000 – $8000USD for up to 6 or 8 embryos, and a top-up fee per additional embryo tested.
In Thailand, the cost also ranges by clinic but the typical cost of PGD is $3000SGD for up to 5 embryos, and $400SGD per additional embryo.
There is often an additional FET freezing fee for the transfer that is added to cost, although some clinics will waive the FET fee since they did not do a fresh transfer.
At some European clinics, there are some financial savings by batching embryos for testing (day 5 biopsy/vitrification and transfer in FET cycle). For example, where you may be charged $3100USD for up to 6 Day-5 tests in time for a fresh transfer, if you biopsy and freeze all the embryos, then test them as part of a larger batch, each embryo will cost $500USD. This benefits patients who are older and only likely to produce fewer viable embryos.
Why is PGD not available in Singapore?
There is no direct answer to this question.
PGD technology is available in Singapore but only to those who have known, blood-transmitted conditions such as thalysemia, or where both parents are blood carriers of the same genetic condition.
PGD allows for gender selection, which is illegal in Singapore.
Singapore follows the UK convention, where it is also illegal to utilise PGD for sex selection, but it is allowable to use PGD to avoid serious medical conditions. This is similar to Canada and Germany.
There are countries such as Switzerland, where the use of PGD is entirely banned.
In the US, France, South Africa, Malaysia and Thailand, PGD is not regulated, it is allowable for medical reasons, and to improve conditions of recurrent miscarraige or recurrent IVF failure and for gender selection.
Specific clinics in these countries may not practice gender selection. This is self-monitored, the fertility specialist is not allowed to reveal or allude to the gender of the foetus, until it is revealed to you by your obstetrician at a later date of pregnancy.
The state or insurance coverage of PGD as part of IVF differs between these countries.
Some genetic diseases only affect one sex rather than the other. Examples of these include Duchenne muscular dystrophy, which affects boys but not girls. (Girls may still be carriers of the gene, but will not suffer from it). In these cases, the embryo has to be tested to find out its sex and only embryos of the non-affected sex are transferred to the womb. Therefore, it can be quite difficult to seperate blood-transmitted diseases from sex selection.
