Clinical Management of In Vitro Fertilization With Preimplantation Genetic Diagnosis

Ilan Tur-Kaspa, M.D.


Semin Reprod Med. 2012;30(4):309-322. 

In This Article

Special PGD Challenges for Clinical Management

Nondisclosure PGD

A center's clinical experience is particularly important for special PGD cases, such as nondisclosure PGD. Most potential carriers of late-onset autosomal dominant diseases, such as Huntington disease (HD) and amyotrophic lateral sclerosis (ALS), decide that knowing their actual status as a carrier or not is significantly detrimental to their well-being, and therefore, they elect not to be tested. At the same time, they wish to assure that their children will not carry the disease and have to go through similar emotional turmoil. Nondisclosure PGD, in which mutation results are not disclosed to the couple, can achieve these goals simultaneously.

The way nondisclosure PGD originated, with direct mutation testing, has raised several ethical concerns. The first and most important concern was the difficulty in assuring full nondisclosure, especially in some leading PGD centers in Europe.[125,126] The need for nondisclosure brought on other ethical concerns for fear that patients would guess their genetic status based on their treatment results. These included the possible use of fake transfers for patients who did not have unaffected embryos for transfer, collecting payment for PGD that was not necessary in 50% of the time (for noncarriers), as well as avoiding embryo cryopreservation so that patients will not be able to guess their genetic status based on how many embryos were available for it. The consensus is that performing "unnecessary IVF" for ~50% of the couples to maintain the nondisclosure cannot be avoided. Exclusion testing for nondisclosure PGD was suggested as a way to resolve some of these issues. It is based on a linkage analysis with polymorphic markers when parental and grandparental origins of the chromosomes can be established, and thus the genetic status of the potential carrier remains unknown both to the medical staff and to the patients. However, its main disadvantage is that it results in discarding also potentially unaffected embryos, decreasing the numbers of viable embryos available for transfer, and thus decreasing the patient's chance to conceive.

Tur-Kaspa and Najeemuddin[127] described a revised nondisclosure PGD protocol that we believe eliminates the ethical and practical dilemmas of the patients and of the medical staff. This protocol was approved by the institutional ethical board of IHR/RGI and was applied successfully in patient care. These are the main principles of this revised protocol:[127] (1) Direct mutation testing will be performed, but to maintain the nondisclosure, all medical and administrative staff in direct contact with the couple will not be aware of the genetic status of the patient. (2) General PGS will be added to decrease the risk of nonrelated fetal chromosomal abnormalities (thus the issue of payment for "unperformed PGD" will be avoided). (3) Because aneuploidy or embryo development may cause to have no embryos for transfer, regardless of the patients' genetic status, performing sham transfers will not be needed. (4) For the same reason, embryo cryopreservation will be performed when possible. (5) Because direct mutation testing will be performed, no unaffected embryos will be discarded. And (6), to avoid multiple pregnancies, the couple will decide in advance whether they wish for one or two (if possible) blastocysts to be transferred.

Patients with a family history of HD or ALS who underwent such nondisclosure IVF-PGD treatments successfully, delivered healthy children, and some have cryopreserved blastocysts. All patients and medical staff involved in their care were very comfortable with this protocol.[127] Although many different professionals were involved in the direct care of these couples, including collaboration with other national and international ART centers, ensuring nondivulgence of the carrier status of the patients was easy to maintain.

In summary, potential carriers of late-onset autosomal dominant diseases have the right not to know their genetic status. PGD can be performed effectively in selected centers while assuring nondisclosure for these couples.

PGD for HLA Typing

Another unique PGD procedure is PGD for HLA typing, which has generated an ongoing international controversy on the issue of "savior siblings." IVF with PGD for HLA typing is a well-established procedure to conceive with a child who may donate matched hematopoietic stem cell transplantation (HSCT) to an ill sibling.[128] HSCT from an HLA matched donor is the best therapeutic option for children with nonmalignant disorders such as genetic diseases affecting the hematopoietic and/or the immune system (e.g., thalassemia, Fanconi anemia, Wiskott-Aldrich syndrome, sickle-cell disease) or acquired diseases like aplastic anemia. HLA-matched transplant from biological siblings are preferred as donors because of the reduced risks of transplant-related complications as compared with unrelated donors.[129,130] It can also be offered for the treatment of malignant diseases like leukemia. Match-related HSCT for leukemic patients has less posttransplant mobility and mortality rates compare with unrelated matched transplants.[131,132] About 70% of patients do not have a match-related donor in their immediate and extended family. IVF with PGD can be used to select unaffected HLA-matched embryo for ET and to give birth to a healthy matched sibling that can donate cord blood or bone marrow to its affected brother or sister.[133–138]

Ethical concerns of the medial staff and the lack of availability of this technology in many countries have significantly limited its use. To assist families when PGD for HLA was not available locally, IHR and RGI have established clinical collaborations with >100 different centers worldwide to provide these advanced services. Other leading centers have done the same.[137,138] Recently, Bellavia et al[124] described a setup for an international collaboration when PGD for HLA is not permitted locally.

Families should be informed about this option of PGD for HLA sooner than later to allow them ample time to consider it, especially because women's age is a major factor in ART success. Because we have encountered several occasions when PGD for HLA was never discussed with families that may need it, Tur-Kaspa and Najeemuddin[139] recently proposed clinical guidelines on when to offer PGD for HLA typing to parents of a sick child: PGD for HLA should be offered to families when a related matched donor is not available, within weeks of the diagnosis (even for diseases with a good prognosis), and when HSCT is not urgent and clinically can be postponed by at least 9 to 12 months. Moreover, if PGD for HLA is not available locally or nationally, than collaboration with another center should be established to have this treatment available for the family.

In summary, conceiving with a healthy infant that is HLA matched to his sibling is a unique opportunity for parents to act independently to save their sick child with HSCT. Clinical guidelines will improve the care of children in need of matched HSCT. Once future advances lead to improved outcomes of unrelated transplants, this rationale should be revised.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.