Pre-Implantation Genetic Diagnoses

PGD is a relatively new procedure. Nevertheless, over 2,000 unaffected children have been born following PGD for various genetic defects in about 30 clinics worldwide. This section aims to answer the most frequently asked questions about PGD and explains the procedures involved when a patient undergoes this treatment.

For couples at risk of having children with an inherited disease, preimplantation genetic diagnosis (PGD) is a new approach to preventing the birth of affected children. Other methods of prenatal diagnosis such as amniocentesis or chorion villus sampling (CVS) involve taking samples from an established pregnancy. If the fetus is diagnosed as affected, couples then have to decide whether or not to terminate the pregnancy. Some couples may have several terminations trying for a healthy child. With PGD, In Vitro Fertilization (IVF) treatment is used to screen early embryos for the inherited defect causing the disease within a few days of conception. Couples can then choose to have only those embryos diagnosed as free of the disease replaced in the woman’s uterus knowing that any resulting pregnancy should be normal.

Dr. Asangla Ao, formerly of Hammersmith Hospital, London, UK, where the first baby was born after preimplantation diagnosis in 1989, leads the scientific side of the PGD team at the McGill Reproductive Centre.

FREQUENTLY ASKED QUESTIONS

Which inherited diseases can be screened by PGD at the McGill Reproductive Centre?

At present, we offer PGD for X-linked diseases, which only affect boys, eg, Duchenne muscular dystrophy (DMD), haemophilia A , adrenoleukodystrophy, Hunter's disease, by identifying the sex of embryos and transferring only female embryos. We also offer PGD for single gene defects such as cystic fibrosis (CF) - the common deletion (^F508), spinal muscular atrophy (SMA)and Myotonic Dystrophy (DM). We also perform Aneuploidy screening and chromosome translocations to detect abnormalities which may cause spontaneous abortions in early pregnancy. We can do PGD for all single gene defects where the specific mutation is identified and as long as we can develop a special genetic probe for the disease.

Do you need to undergo IVF? Why?

Yes. It is generally necessary to have IVF because the PGD procedure requires the testing of embryos at a very early stage of development before implantation in the womb. Initially, therefore, you need to make an appointment with Dr. Tan at the MRC to assess your suitability for IVF and PGD. This will involve taking a full medical and genetic history from you and your partner and a physical examination for the female partner. A transvaginal ultrasound scan is performed, some blood tests are done and a semen analysis arranged for the male partner. In addition, we ask one or both of you for a small blood sample for us to check the diagnostic tests we plan to use to screen your embryos.

For selected patients, IVM (In Vitro Maturation) can be offered for PGD instead of IVF. Your physician will explain why this approach may benefit you.

What does PGD involve?

In a average IVF cycle, between 10 and 15 eggs may be collected and about 5 or 6 embryos reach the stage where they can be biopsied. For PGD, one or two cells are removed or "biopsied" from each embryo by micromanipulation when the fertilized eggs have divided into approximately eight cells, which usually occurs early on the morning of the third day following fertilization. This allows the genetic material or DNA in these cells to be analysed for the genetic defect causing the inherited disease. Extensive studies with animal embryos have shown that at early stages of development, the cells are not yet in the process of forming specific parts of the placenta or fetus, and removal of some cells does not cause fetal or congenital abnormalities. Nevertheless, there are too few pregnancies following PGD to be sure there is absolutely no risk of abnormality or minor effects that may only appear later in childhood. For this reason, we ask your permission to allow a pediatrician to examine the babies at birth and to follow up their development during childhood.

Inherited defects are detected by amplifying a short fragment of the genetic material or DNA from the single cell over a millionfold by a process called the polymerase chain reaction (PCR) and testing the amplified DNA in various ways. Alternatively, the DNA in the nucleus of the cell is spread on a microscope slide and colour stained to identify the sex of each embryo (two X chromosomes in females: one X and one Y chromosome in males),or to identify embryos, which have inherited an abnormal number of chromosomes.

When the results are ready, you will be asked to come to the hospital and the results will be carefully explained to you. We will also let you know which embryos we consider have the best chance of implanting and establishing pregnancy.

It is then for you to decide which embryos you wish to be transferred. This is an important and sometimes difficult decision, which has to be taken in a short space of time on the day of transfer. We recommend therefore that you talk over the possible outcomes beforehand so that you have adequate time to think through all the issues.

Sometimes, because of the limit on the number of embryos transferred, there may be one or more good quality unaffected embryos remaining after transfer. You may decide that you want these embryos frozen (cryopreserved) for transfer in a later cycle. Indeed you may wish to have even those embryos diagnosed as affected cryopreserved in anticipation of effective treatment for the disease in the future.

However, at the moment there are very few data on live births from cryopreserved biopsied embryos. Therefore it has to be understood that the prognosis from these cases is poor. Alternatively, you may consider donating the embryos for research or ask for them to be discarded. If you donate the embryos for research they will be used to develop and improve methods of PGD or to study genetic defects in early human development.

How accurate is PGD?

Genetic analysis of single cells is technically demanding and prone to errors of various kinds. Also the early human embryo has a relatively high incidence of genetically abnormal cells which, is used for genetic analysis may on some occasions result in misdiagnosis. For these reasons, it is important for you to be aware that we cannot be 100% accurate with the diagnosis for each embryo. However, reagents are extensively tested beforehand and we do everything we can to minimize technical errors.

As PGD research is constantly evolving, please contact us for the most current list of available diagnoses.

A few misdiagnoses have been reported in the literature but each has involved a different genetic test and is not a reliable guide to the likely incidence in your case. Nevertheless, you should consider carefully the possibility of having a conventional prenatal diagnosis by CVS or amniocentesis if a pregnancy is established to confirm that the fetus is not affected.

What are the alternatives to PGD?

(1)”Trusting to luck”: Couples may not wish to undergo screening and simply to opt to achieve a pregnancy spontaneously in the hope that the resulting child will be unaffected.

(2) Prenatal diagnosis in a natural pregnancy: Amniocentesis involves removal of a sample of the fluid from around the fetus, which contains some fetal cells. This is normally performed between 14 and 17 weeks of pregnancy, and the results take between 2 to 3 weeks. There is about a 1% risk of miscarriage. Chorionic villus sampling (CVS) involves taking a small piece of placenta by needle, and can be performed at an earlier stage in pregnancy (between 10 to 13 weeks), and the results are usually available much sooner. However, the risk of miscarriage is slightly higher (at about 2%).

(3) Adoption

(4) Remain childless: Some couples may simply decide not to have children to avoid any risk.

(5) Donor gametes: Alternatively, you may wish to consider using donor gametes, the sperm or eggs of another person, so as not to transmit the faulty gene.

I believe PGD might be an option for me, but I do not live in Montreal. What can I do?

The McGill Reproductive Centre offers Transport PGD for patients who do not live in the Montreal area.

With whom can we discuss any problems?

In the initial consultation with your physician and the genetic counselor, you will be given an opportunity to discuss any queries you may have.

For further information about the PGD program, please send your questions to PGD@mcgillivf.com