Indications for PGD

Currently, PGD is primarily performed for the following:

Couples at high risk of transmitting a hereditary disease to their offspring. This disease can be a single-gene disorder (autosomal recessive, autosomal dominant, or X-linked disorder) or a structural chromosomal abnormality (such as a balanced translocation). Generally, these couples oppose prenatal diagnosis and subsequent selective termination of pregnancy for ethical or religious reasons, or because they have previously experienced multiple miscarriages. Additionally, there are infertile couples who are carriers of a hereditary disease and readily accept PGD in conjunction with their IVF treatment.

Couples undergoing IVF whose embryos are screened for chromosomal aneuploidies (PGS) have an increased chance of pregnancy. PGS is particularly recommended for women of advanced maternal age, those with a history of recurrent miscarriages or implantation failures, and for men with obstructive or non-obstructive azoospermia.

Today, PGD is available for a wide range of single-gene disorders. Common autosomal recessive disorders diagnosed with this method include cystic fibrosis, beta-thalassemia, sickle cell disease, and spinal muscular atrophy type 1. The most common autosomal dominant diseases are myotonic dystrophy, Huntington’s disease, and Charcot-Marie-Tooth disease type A1. For X-linked disorders, most diagnoses are for fragile X syndrome, hemophilia A, and Duchenne muscular dystrophy.

In very rare cases, some centers have reported performing PGD for mitochondrial disorders or for two conditions simultaneously. For chromosomal abnormalities, PGD is primarily used for reciprocal and Robertsonian translocations, with a smaller number of cases involving other abnormalities such as inversions or deletions. Aneuploidy screening is probably the most common reason for PGD and is primarily recommended for couples undergoing IVF due to advanced maternal age, as well as for patients with recurrent IVF failure.

The underlying principle is that since numerical chromosomal abnormalities cause a significant proportion of miscarriages and a large number of embryos are aneuploid, selective transfer of euploid embryos should increase the chances of successful IVF treatment. Various studies have shown that PGS increases implantation rates and reduces miscarriage rates, although more large randomized controlled trials are needed to evaluate the true impact of this technique in different scenarios.

Another group of critical PGD indications involves complex ethical dilemmas. For instance, determining the HLA type of an embryo to use the baby as a cord blood stem cell donor for a sick sibling. Verlinsky and colleagues reported the first case of this kind in 2001. Consequently, HLA typing has become a significant PGD application in five countries, including the United States, Italy, Turkey, Belgium, and Australia.

HLA matching can be combined with the diagnosis of monogenic diseases such as Fanconi anemia or beta-thalassemia, especially when siblings are affected. Alternatively, it can be performed alone for cases like children with leukemia. The primary ethical concern with these applications is the instrumentalization of the child, although some authors argue that ethics are not violated in this case, as the child is not only a donor but also a loved member of the family.

Another challenging aspect of PGD is performing the procedure without revealing the Huntington’s disease status to the patient. This scenario arises when patients do not wish to know their carrier status but still desire healthy offspring. This can place clinicians in a difficult position, such as when no embryos are available for transfer, necessitating a sham transfer to prevent the patient from suspecting that they are carriers and that the absence of embryos is due to all of them being affected by the disease.

The ESHRE Ethics Committee currently recommends the use of exclusion testing. The basis of exclusion testing is the investigation of linkage with polymorphic markers where the origin of the chromosome in the parents and two previous generations is determined. In this way, only embryos that do not carry the chromosome obtained from the affected grandparent are transferred, and therefore, there is no longer a need to identify the mutation. A newer application of PGD is for the diagnosis of late-onset diseases and cancer predisposition syndromes.

It can be argued that PGD is unethical for late-onset diseases as individuals remain healthy until the disease manifests, usually in their fourth decade of life. On the other hand, the high probability or certainty of developing certain disorders, along with their untreatable nature, can lead to a life filled with stress, anticipation of the first symptoms, and the expectation of an early death. While PGD is often considered an early form of prenatal diagnosis, the nature of the request for PGD is often distinct from that of prenatal diagnosis. Some cases widely accepted for PGD, as mentioned earlier, would not be acceptable for prenatal diagnosis.”