Dr. Fernandez-Shaw, who has more than 20 years of experience in Assisted Reproduction, directs the Assisted Reproduction Unit at URH Garcia del Real. She has several publications and conferences on the specialty, especially on endometriosis, ovarian stimulation protocols, multiple pregnancy prevention, blastocyst embryo transfer and the impact of Assisted Reproduction techniques on the health of the children born from them. In this article he explains what preimplantation genetic diagnosis consists of and what controversies it involves.
Preimplantation Genetic Diagnosis (PGD) is a technique developed in the 1990s to evaluate the chromosomal condition of embryos before transferring them to the maternal uterus. There are many published studies on PGD.
While there is no doubt about its usefulness in the case of severe hereditary diseases, there is controversy when it is used in cases of implantation failure, advanced maternal age or repeated miscarriages. Some studies find an improvement in the results of in vitro fertilization and others do not.
What does preimplantation genetic diagnosis consist of?
To carry out a preimplantation genetic diagnosis (PGD), the woman must undergo a cycle of In Vitro Fertilization (IVF). This consists of stimulating the woman’s ovaries to produce several eggs, inseminate them with sperm and obtain embryos.
To perform PGD it is necessary to extract (biopsy) a cell from each embryo on its third day of development (they usually have about 8 cells), or extract a larger number if the extraction occurs on the fifth day of development (blastocyst stage).
The biopsy consists of making a small hole in the zona pellucida of the embryo (membrane that surrounds it) in order to access the cells. This can be done with a laser, mechanically or with tyrodes acid (which “digests” the zona pellucida). Depending on the day of the biopsy and the technique used, the embryos can be transferred fresh (in that same IVF cycle), or the embryos will have to be frozen, wait for the results and transfer the embryos without alterations in a subsequent cycle of thawing and cryotransfer.
Preimplantation genetic diagnosis for monogenic diseases
PGD is indicated when there are monogenic diseases, to avoid transmitting to the offspring a particular disease that one or both parents have. For example, Duchenne muscular dystrophy, Marfan syndrome, Fragile X syndrome, hereditary cancer syndromes, hemophilia A and B. That is, “serious hereditary diseases of early onset and not susceptible to postnatal treatment or for the detection of other alterations that may compromise the viability of the pre-embryo”. Other hereditary diseases that do not fall under this definition require special permission from the National Commission on Assisted Human Reproduction (CNRHA), which is the advisory body in charge of authorizing PGD cycles on a case-by-case basis.
It is estimated that there are more than 6000 monogenic diseases. Individually they tend to be rare, but as a whole they are a serious medical problem because many of them also cause significant disorders to those who suffer from them. Today, PGD can be applied for any monogenic disease for which the causative gene is known.
Preimplantation genetic diagnosis for aneuploidy screening (or PGS)
PGS is performed to see if the chromosomes of the embryo are in the correct number, or if there is too much or too little genetic material. The objective is to avoid transferring embryos to the uterus that will not result in pregnancy or that will produce miscarriages. Nowadays, the most frequent cases in which this test is recommended are repeated miscarriages, advanced maternal age, previous IVF cycles without pregnancy, or knowledge of a possible chromosomal alteration in the eggs or sperm.
Controversies about preimplantation genetic diagnosis
- It is not possible to biopsy all embryos: for PGD only embryos of good morphological quality can be biopsied; that is to say, not all embryos obtained after IVF can be biopsied since it is common that not all of them are of good quality. This decision can exclude from PGD embryos that are not of good morphological quality, but which could nevertheless, although with a low probability, give rise to pregnancy.
- Decrease in the probability of implantation; PGD makes it necessary to remove one or more cells from the embryo in order to diagnose them. The manipulation of embryos with any of the techniques used can result in morphologically good quality and chromosomally normal embryos not resulting in pregnancy due to the damage caused by the biopsy.
- Embryos without diagnosis. Sometimes there may be a technical problem when performing PGD making it impossible to have a reliable diagnosis of the embryo. In these cases embryos are discarded without knowing whether or not they are chromosomally normal.
- False positives and negatives. In PGD a few cells of the embryo are analyzed, but not the embryo as a whole. It has been demonstrated that chromosomally normal and abnormal cells can co-exist in embryos within the same embryo, so there are cases in which an embryo is diagnosed as healthy when it has abnormal cells and vice versa. It has also been described that the human embryo is capable of leaving abnormal cells out of its development, giving rise to a healthy pregnancy.
Several authors argue that PGS increases the probability of pregnancy by embryo transfer, and decreases the time to achieve pregnancy, since it performs a pre-selection of the embryos before their transfer to the uterus. However, to date, it has not been demonstrated that PGS increases the probability of having a child at home per patient or per IVF cycle started. In the last registry of the Spanish Fertility Society, in 2015, less than half (41%) of the PGS cycles started reached an embryo transfer. It is possible that the transfer was not performed because all the embryos were abnormal, but it is also possible that embryos were discarded for the transfer due to the problems described above. Embryos that, without such analysis, could have given rise to a healthy pregnancy.
Although PGD is a widely used technique in Assisted Reproduction, the cases that could benefit from it, especially PGS, must be carefully evaluated, since it is an expensive and invasive technique, and not all patients will improve their pregnancy rate with it.