PGD was born out of the need to screen embryos for genetic disorders. But, it was quickly adapted for embryo selection to improve IVF treatment outcomes by identifying chromosomally abnormal embryos. However, so far there have been no convincing demonstration that PGD improves pregnancy rates or reduces the chance of miscarriages.

A recent prospective randomized trial, considered a gold standard in medical research, demonstrated that PGD does not increase pregnancy rates or decreases abortions rates in patients over 35 years of age.

Proponents of PGD argue that that authors of the above trial arrived to their conclusion because of their general incompetence.

Listening to the arguments on both sides, American Society for Reproductive Medicine (ASRM) has issued a report discouraging several specific applications of PGD:

“ASRM Practice Committee to conclude that the available evidence does not support the use of PGD to improve live-birth rates in patients with advanced maternal age, previous implantation failure, recurrent pregnancy loss, or to reduce miscarriage rate in patients with recurrent pregnancy loss related to aneuploidy at this time.”

Nevertheless, the ASRM left the door for further research wide open:

“The use of preimplantation genetic screening for chromosomal problems may one day become an essential component of infertility therapy, but for now, available evidence does not support its effectiveness and common usage” Said Steven J. Ory, MD, President of ASRM”

It has to be mentioned that several retrospective studies suggest that PGD both improves implantation rates and decreases the rates of abortion. Retrospective studies, however, are much less reliable and often do not withstand the test of time.

Types of PGD:

There are several types of PGD testing. However, regardless of the specific type of analysis, PGD always involves an in vitro fertilization cycle and an embryo biopsy, during which one or some times more cells are removed.

Once cells are removed they could be used for:

- testing for single gene disorders
- chromosomal abnormalities
- gender selection

On this site, unless I specify otherwise, I will only discuss PGD for chromosomal abnormalities and gender selection using FISH (Fluorescent in Situ Hybridization).

Testing for single gene disorders is an entirely different field and I will just mention that benefits of PGD for single gene disorders are not in doubts.

PGD indications:

Miscarriages 

An application of PGD in patients with a history of prior miscarriage and particularly habitual miscarriages is based on the notion that about half of all miscarriages are due to chromosomal errors in the embryos. It follows that identification and exclusion those chromosomally abnormal embryos from transfer will decrease the chance of the miscarriage.

In spite of the fact that clinical miscarriage is a traumatic event, all large epidemiological data indicate that it is a good prognostic factor for subsequent pregnancy resulting in a healthy baby. This is because if you were pregnant, regardless of the fact that the pregnancy has stopped, you and your male partner are proven fertile.

In fact you are so fertile that, if you had 3 prior miscarriages, the chance that your next pregnancy would result in a live born baby is about 75% without any intervention. This is about as high as cumulative pregnancy rate of 2 IVF cycles!

The chance of a successful subsequent pregnancy, without any treatment, after three previous unexplained miscarriages varies from about 54% (!) in a 45 year old woman to about 90% in a 20 year old woman. A 30 year old woman with two previous unexplained miscarriages has about an 84% chance of a successful subsequent pregnancy, whereas for a woman of the same age with five previous unexplained miscarriages the success rate drops to about 71%.

As harsh as it may sound, it is normal to have a miscarriage. In fact it is estimated that about 70% of all pregnancies in the general population end up in miscarriage, which means about 3 miscarriages for every live born.

Most pregnancy losses (about 50% of all miscarriages) are pre-clinical, which means that a woman would be unaware that she was pregnant unless she had a pregnancy test.

If the reason for your miscarriage is chromosomal error, whether you pregnancy loss is pre-clinical or clinical is a random event.

For example, if an embryo was missing chromosome 11, the pregnancy would stop before you notice it. However, if a fetus is missing chromosome 16, the pregnancy would usually result in a miscarriage that you would be aware of.  

In their own turn, chromosomal errors are not patient specific (unless one of the prospective parents is a carrier of a specific chromosomal error): in the same couple one miscarriage may be cased an error of chromosome 18 and the next one by an error of chromosome 22, while the third one may not be caused by chromosomal errors at all.

Thus, which women will have a viable pregnancy next month, which one will have a clinical miscarriage, and which one would lose the pregnancy without even knowing - is in the vast majority of cases a random event.   

The random nature of the vast majority of miscarriages makes it very difficult to determine the true value of any treatment, including PGD; if you were to have a PGD cycle that resulted in a baby, you will never know if this is because, regardless or in spite of PGD. 

If you are 36 or younger, the chances that your miscarriage was not caused by chromosomal errors is higher and you are even less likely to benefit from PGD, even if there is a benefit. 

Furthermore, generally, the more miscarriages you have had the less likely they are caused by chromosomal errors.

In any case, because non-chromosomal reasons for a miscarriage are usually covered by insurance, it makes sense to rule them out first.

In conclusion, given high chance of term pregnancy in cases of prior miscarriages without any intervention, PGD should probably not be considered as a first treatment option.

Habitual miscarriages in patients with translocations.

Studies estimate that a small proportion of patients (6% -10%) with habitual abortions have chromosomal problems.

There are some evidences that PGD can fascilitate achieving a pregnancy in such couples. 

However, strong epidemiological data strongly suggest that patients with translocations have exactly the same chance of a viable pregnancy as those who do not have a translocation without any treatment. Their chance to have a chromosomally abnormal offspring is only 0.4%, which is too low to warrant an intervention with IVF and PGD.

Increase pregnancy rate in patients over 36 years old.

The rational for this indication is essentially the same as for miscarriages. There are no scientific data showing that PGD increases the chance of pregnancy in such cases.

Why does PGD not increase pregnancy rate and does not reduce miscarriages?

No one knows the exact answer, but it is most likely due to eliminating some good embryos through diagnostic errors, mosaicism, damage to the embryo and individual embryo culture.

Diagnostic errors 

PGD for more than 3 chromosomes is not very accurate with one study reporting a 40% error rate using probes for 5 chromosomes. This means that 40% of good embryos could have been discarded due to the errors where an embryo appears to have a missing or extra chromosome, where they are in fact normal. This would reduce a patient's chances to get pregnant.

Most centers report smaller rates of false positive results. Yet, it would be true for every PGD laboratory that each additional chromosome included into the testing increases the chance of error thereby decreasing the chance of pregnancy. This is mainly because each chromosomal probe requires unique optimal conditions for FISH and this is not achievable when they are applied simultaneously. Also, increasing the number of probes results in more artifacts which may look like a real signal, while they are not.

Some industry insiders, including myself, believe that the maximum number of chromosomes that can be used for testing on a single cell without significant loss of embryos to diagnostic errors is not more than three.

The accuracy of the diagnosis could be greatly improved by taking one more cell from the embryo. In fact, an accurate diagnosis in all other diagnostic testing (such as amniocentesis or CVS) requires scoring at least 100 cells! However, taking two cells would further reduce embryo viability, creating a catch 22.

This problem can be overcome by performing the biopsy on day 5 when the embryo becomes a blastocyst so that several cells can be safely removed for analysis. But high level of mosaicism seen at that stage makes the accuracy of the diagnosis very questionable.

Embryo Mosaicism

Embryo mosaicism refers to differences in chromosomal content between the cells in the same embryo. For example one cell can have a normal number of chromosomes, while another abnormal.  

As a result, the cell taken from an embryo for analysis may not be representative of the embryo and lead to diagnosis of a normal embryo as abnormal and vice versa. Embryo mosaicism is a sort of a non-technical error leading to misdiagnosis.

The true prevalence of this phenomenon is not known. It seems to be patient-specific and, as would be expected, much more common in poor quality embryos.

Damage to the embryo

Damage to the embryo usually refers to the gross mishaps where it is partially or completely physically destroyed. Those cases are rare. It is much more common that damage cannot be seen at the time of the biopsy, but just a mere fact of extra manipulations with an embryo, exposing it to the biopsy media, extra light, laser heat, etc reduces its developmental potential.  

Even if the biopsy was nearly perfect, removal of a cell which is required for PGD always affects embryo viability to some, albeit small, extent. 

It is important to understand that "reduction in embryo viability" only refers to the "average" embryo. It means that fewer embryos will be able to implant following PGD than without it. However, once biopsied embryo has implanted, it will have no "memory" or deficiencies related to the the biopsy and associated loss of cell or two.

Individual embryo culture after biopsy

There are some evidences that embryos produce growth factors that can facilitate their development. Therefore, they are usually cultured in groups in small droplets to maximize the impact of those putative growth factors.  

At the same time, once biopsy is completed an embryo is returned to the culture media, it will be cultured in individual droplets with an assigned number while the analysis results are pending, usually until blastocyst stage.  

Extended individual embryo culture can be avoided with Same Day PGD.

CHOOSING THE PLACE FOR PGD

Besides general considerations, such as reputable physician, embryologist and good pregnancy rates, consider the following factors:  

Strongly prefer that program which has an embryologist performing embryo biopsy and fixation on site while avoiding those programs which hire an embryologist for PGD on an as needed basis.

Embryo micromanipulation is an extremely delicate manual technique. It requires a lot of training to minimize trauma to the embryo. But even a well trained embryologist will go through an adjustment period getting used to the equipment and setups, that are different in every laboratory. At the very least this increases the duration of biopsy that by itself may affect embryos viability. This may also lead to an increased rate of embryo damage and fixation mishaps.

Prefer the place where slides are not sent out for diagnosis, but processed locally.

Local processing (under the same roof) creates an opportunity for the same day embryo transfer, which is particularly important in those cases when a patient has few embryos. Additionally, if there is no result, an embryo can promptly be biopsied again.