What are PGD and PGS?

Pre-Implantation Genetic Diagnosis (PGD) and Pre-Implantation Genetic Screening (PGS) are two diagnostic tools which play a role within the field of in vitro fertilization (IVF).  They are often referred to interchangeably, but they refer to different types of analyses. Both tests involve removing a few cells from an embryo via “embryo biopsy” and analyzing them for DNA/chromosomal normalcy in the lab. This is nowadays typically done at the blastocyst stage. The biopsied blastocysts are vitrified, and then healthy embryos are transferred in a future frozen embryo transfer cycle (FET) to allow for genetic/chromosomal diagnosis to take place. The blastocyst stage is ideal, for at this point, the embryo is least likely to be affected by the removal of a few trophoblast cells (from the trophectoderm) and able to provide very accurate results.

The main advantage of these techniques is that they help couples identify embryos carrying a genetic disease or a chromosome abnormality, thus dramatically increasing the odds of a healthy pregnancy (well documented for PGD, not yet unequivocally demonstrated for PGS). Both procedures can also give information on sex of the embryo. Recently, more rapid, reliable, and inexpensive techniques have become readily available to the average IVF patient. Indeed, NGS or next generation sequencing, is nowadays the recommended method for testing as it can detect mosaicism with good sensitivity.

What is the difference between PGD and PGS? And who is a candidate for PGD or PGS?

 PGD is used for the detection of embryos with a known risk for a genetic disorder.  The most frequently diagnosed genetic autosomal recessive diseases (monogenic) are cystic fibrosis, Beta-thalassemia, sickle cell disease and spinal muscular atrophy type 1. The most common dominant diseases are myotonic dystrophy, Huntington’s disease and Charcot–Marie–Tooth disease; and in the case of the X-linked diseases, most of the cycles are performed for fragile X syndrome, hemophilia A and Duchenne muscular dystrophy. In some cases, breast cancer risk can also be identified. Identification of carrier status can and should be performed by all couples with a simple blood test that examines over 200 genetic conditions. PGD is performed in individuals with a known family history of a genetically linked disease, or when a carrier status is detected in both members of a couple.

PGS, on the other hand is used to identify embryos at risk of chromosomal anomalies (aneuploidy, i.e., Down and Turner syndrome, and others), that are associated with advanced maternal age. As many as half of all embryos from women in their mid-30s, and over 75% from women in their 40s, may be aneuploid.  PGS is typically offered to: 1. women over 35 years; 2. women who have suffered from recurrent pregnancy loss; 3. women who have repeatedly failed IVF treatment.

Are PGD and PGS safe?

To date, studies have been published indicating that  biopsies performed at the blastocyst stage by trained embryologists have no negative effects on the embryo or its ability to produce a healthy pregnancy.  Because of this, as well as the continually falling cost of analysis and the increased pregnancy rates with PGS, embryo biopsy and analysis are becoming a more frequent addition to IVF for all age groups at many practices.

Limitations of PGS: diagnosis and incidence of mosaicism in the biopsied material

Embryonic mosaicism is defined as the presence of karyotypically (chromosomally) different cell lines in an embryo. It is considered a major limitation for the routine application of PGS for aneuploidy testing.  There is a tremendous variability on the reported incidence of mosaicism in preimplantation embryos between 4 and 90%. However, these data are in sharp contrast with what is known from clinical pregnancies, where true fetal mosaicism is observed in less than 0.5% of cases. The clinical consequences of mosaic aneuploidies may depend on many variables, including which chromosome is involved, when the error occurs (at what stage of development) and thus what percentage of the embryo is aneuploid, and where it is located within the embryo (trophectoderm -future placenta- or inner cell mass -future fetus).

 What happens after the FET with “normal” embryos?

If you are fortunate to have chromosomally normal embryos (euploid) after PGS, then an FET is estimated to achieve a 50-70% chance of success. This means that approximately one third of euploid embryos still do not implant, and that is unexplained so far. So, you should not expect 100% pregnancy rate! Nothing is, as we all well know.

This failure could be due to several factors: 1-presence of other undiagnosed embryonic problems (i.e., high degree of mosaicism, or other non-chromosomal anomalies of mitochondrial/energetic/metabolic origin); 2- could be a subjacent endometrial problem; 3- inadequate transfer technique; and 4- eventually one must ponder the impact of the invasive biopsy and freezing process, maybe leading to sublethal cellular damage.

So, is PGS worth it? The testing itself can add to the IVF cost. In my opinion it really depends on the clinical situation, affordability, and if you have enough embryos so that the risk of doing the biopsy feels manageable, but again, these are all debatable points as of today.

In summary, PGD and PGS have evolved into very successful techniques for selecting healthy embryos prior to transferring them to the mother in high risk cases. While it is generally accepted that the benefits of these techniques outweigh any shortcomings, it is always important to consult with a well-informed healthcare provider regarding each case before proceeding. At Sher Fertility Institute New York we will provide you with guidance on a one-to-one basis.