Indications for PGD

Indications for PGD/PGS

• Recurrent Miscarriage
• Unsuccessful IVF Cycles (>2)
• Unexplained Infertility
• Advanced Maternal Age
• Male Factor Infertility
• History of Chromosomally Abnormal Child or Pregnancy
• Chromosomal translocations
• Family history of structural chromosomal condition
• Family history of X-linked disease
• Inherited genetic disorders
• Reduce genetic risk factors
• Single gene disorders
• Late on-set disorders
• Inherited predisposition to cancer
• HLA matching

PGD is indicated for couples with a high risk of transmitting an inherited condition

Generally, couples having already undergone several abortions usually oppose to prenatal diagnosis followed by selective termination of pregnancy. Some infertile couples choose PGD because they are carriers of an inherited condition. Pre-implantation diagnosis can be easily combined with their IVF treatment.

The main indications for PGD are:

• Single gene disorders (monogenic disorders), such as autosomal recessive, autosomal dominant or X-linked disorders), or;
• Chromosomal structural aberrations (such as a balanced translocation).

PGS is indicated for couples wishing to improve their chances of IVF success.

In this case, the couple's embryos are screened for chromosome aneuploidies (Pre-implantation Genetic Screening - PGS) to increase the chances of an ongoing pregnancy.

The main indications for PGS are:

• Advanced maternal age
• History of recurrent miscarriages
• Repeated unsuccessful implantations
• Patients with obstructive or non-obstructive azoospermia

PGD is available at EmBIO for a large number of single-gene diseases. The most frequently diagnosed autosomal recessive disorders are cystic fibrosis, b-thalassemia, sickle cell disease and spinal muscular atrophy type 1. The most common diseases are myotonic dystrophy, Huntington's disease and Charcot-Marie-Tooth disease type 1A.

Most PGD cycles for X-linked diseases are performed for fragile X syndrome, haemophilia A and Duchenne muscular dystrophy. Less frequently, PGD is performed for mitochondrial disorders or two indications simultaneously.

Regarding chromosomal abnormalities, PGD is mainly carried out for reciprocal and Robertsonian translocations, and few cases for other abnormalities such as chromosomal inversions or deletions.

Aneuploidy screening - PGS is probably the most frequent indication for preimplantation diagnosis, mainly suggested to couples undergoing IVF with an advanced maternal age and for patients with repetitive IVF failure.

A fourth group of PGD indications concerns HLA typing of the embryo, so that the child born out of this treatment could be a cord-blood stem cell donor for a sick sibling. The HLA matching can be combined with the diagnosis for single-gene diseases such as Fanconi anaemia or Beta-thalassemia in those cases where the ill sibling is affected with this disease, or be performed on its own for cases such as children with leukaemia.

Another option is the non-disclosure PGD for Huntington's disease. It is applied when the patients do not wish to know their carrier status but wish to have children free of the disease.

PGD may also diagnose late-onset diseases and cancer predisposition.

Although preimplantation genetic diagnosis is often regarded as an early form of prenatal diagnosis, some of the widely accepted indications for PGD would not be acceptable for prenatal diagnosis.

Recurrent Miscarriage & Infertility

PGD dramatically improves the chance of a successful IVF pregnancy in couples where prior IVF failures have remained unexplained. It has been estimated that over half of all IVF failures cannot be explained in reference to an apparent problem of embryo "quality". Generally, embryos are given "good" marks when they demonstrate an appropriate number of cell divisions at a given time in their growth cycle, when the individual cells of the embryo appear to have a uniform size and when there is absence of cellular "fragments" that may or may not represent problems in the growth progress of the embryo.

Recent advances, however, have shown that even embryos receiving the highest ratings from scientists based on their "normal" or "excellent" appearance under the microscope may in fact be highly abnormal and totally incapable of ever producing a pregnancy. This discovery was brought about with the use of preimplantation genetic diagnosis (PGD. PGD has offered scientists the chance to examine far beyond the superficial appearance of an embryo. We are now able to examine the most important internal genetic code of the embryo as well. Some embryos that appear on the surface to be of the highest quality may carry a genetic code that makes them poor choices for attempting to establish a healthy pregnancy. Other embryos that might have been classified as less than optimal based on their appearance may in fact be of the finest quality and have 10 or 20 more chances of producing a healthy pregnancy than those that would have been selected without the use of PGD. And this is the most precious reliable information to patients who have previously failed IVF.

PGD is helpful for patients with unexplained infertility, recurrent miscarriages, unsuccessful IVF cycles, advanced maternal age, or male factor infertility. In those cases, the most likely cause is a chromosome abnormality.

Chromosome abnormalities include aneuploidy and structural abnormalities. Aneuploidy is the most common chromosomal abnormality. Aneuploidy can occur in both eggs and sperm. Structural abnormalities include translocations, inversions, and deletions. Structural chromosome abnormalities can also be present in eggs and sperm. The transmission of a chromosome abnormality to an embryo can result in a low implantation rate, miscarriage or the birth of a baby with a genetic disorder. Using Fluorescence In Situ Hybridization (FISH), the scientists in our PGD laboratory can identify the absence of these specific genetic disorders in each normal developing embryo. As a result, only those embryos free of genetic disease will be transferred to the patient’s uterus so as to increase the chance of conception and ultimately a healthy baby.

Unsuccessful IVF Cycles (>2)

In vitro fertilization (IVF) frequently enables couples with infertility to achieve successful pregnancies. Some couples, even after numerous IVF attempts, are unable to achieve conception. Some cases of IVF failure are due to the transfer of embryos with chromosome abnormalities. PGD for aneuploidy minimizes the likelihood of a chromosomal abnormality in a future pregnancy and increases the chance of achieving an ongoing successful pregnancy.

Unexplained Infertility

The most probable cause of unexplained infertility or history of habitual miscarriage is a chromosome abnormality. The male or female partner may be a carrier of a translocation or be an aneuploid mosaic.

Advanced Maternal Age

Women of advanced maternal age (≥ 37) are at a higher risk of producing aneuploid embryos, resulting in implantation failure, a higher risk of miscarriage or the birth of a child with a chromosome abnormality (e.g. Down Syndrome). This is due to the fact that as years go by, the chromosomes within the woman's eggs are less likely to divide properly, resulting in cells with too many or too few chromosomes. Aneuploidy is believed to be a major reason for the decrease of fertility with age. Several studies have determined that approximately 70% of embryos from women of advanced maternal age may be aneuploid. For women aged 37 years and older undergoing IVF, PGD for aneuploidy significantly improves pregnancy rates, reduces miscarriage rates, and decreases the chances of a chromosomally abnormal pregnancy if six or more embryos of good quality are available for analysis.

Male Factor Infertility

Approximately one-half of all infertility is caused by sperm abnormalities. Many sperm disorders are due to a chromosome abnormality such as aneuploidy or a structural chromosome abnormality.Men carrying a balanced translocation chromosome are at risk of producing sperm with a structural chromosome abnormality. Several studies have determined that approximately 3-8% of sperm from normal, fertile men are aneuploid and 27-74% of sperm from men with severe infertility are aneuploid. Couples with infertility due to male factor, should consider chromosome analysis on the males sperm prior to IVF.

History of chromosomally abnormal child / pregnancy / structural chromosomal condition

For patients with a previous child or pregnancy with a chromosomal abnormality, PGD can reduce the risk of certain abnormalities in the patient’s next pregnancy. This may be an attractive alternative to CVS or amniocentesis for some people, as they may be able to avoid termination of an abnormal pregnancy.

Family history of X-linked disease

A category of monogenic diseases has an X-linked inheritance. Most couples at risk for an X-linked condition are identified by review of the family history or the birth of an affected child. X-linked conditions are caused by a change, or mutation, in a gene on the X chromosome and typically affect males only. This is because males have only one X chromosome, inherited from their mother, while they get a Y chromosome from their father. Since a male has only one X chromosome, if it has a mutated gene he will develop the disorder. It is this type of inheritance that causes disorders such as Duchenne Muscular Dystrophy, Hemophilia, Fragile X, Daltonism (colour blindness) etc.

Females are usually not affected because they have two X chromosomes. Females with one normal X chromosome and one mutated X chromosome generally do not have symptoms of the disease because of the presence of the normal gene. These females are referred to as “carriers” and are at risk for passing on the gene mutation to their children. If that child is a girl who inherits the gene, she also will be a carrier. Once the sex of the embryo is determined, female embryos, which would not be at risk for a sex-linked disorder, would be transferred (gender selection).

Inherited Genetic Disorders

Couples at high risk of transmitting an inherited disease to their offspring, have the option of undergoing prenatal diagnosis to allow the detection of the genetic disorder in fetus. However, if the analysis reveals a genetically affected fetus the only options available to couples are to have a child with a genetic disease or to terminate the affected pregnancy. This is a difficult and often traumatic decision, especially in advanced pregnancies.

Preimplantation genetic diagnosis (PGD) has been introduced as an alternative to prenatal diagnosis, to increase the options available for couples who have a known genetically transmittable disease, providing reassurance and a reduced anxiety associated with reproduction. PGD can be considered as a very early form of prenatal diagnosis. Its intended goal is to diagnose a specific genetic disease on oocytes or embryos before a clinical pregnancy has been established, by selecting and transferring to the uterus only embryos resulted unaffected after mutation analysis. Consequently, PGD may spare the couple decisions regarding possible pregnancy termination, ensuring a pregnancy free of the disease under consideration.

PGD usually requires that the couple undergoes an in vitro fertilization (IVF) treatment. This involves hormonal treatments that allow the collection of multiple eggs from the mother. The eggs are then fertilized using the father’s sperm and the resulting embryos are transferred to an incubator. After three days the embryos usually consist of a tiny ball of eight cells, known as blastomeres. To test the blastomere, an opening is made in the covering of the embryo. One or two blastomeres are then removed (biopsied) from each embryo and subjected to genetic testing. If a blastomere is found to be unaffected by the inherited disease then the embryo that has been removed will also be unaffected. Embryos found to be healthy can be transferred to the womb, ultimately producing unaffected babies.

Do you have a family history of a genetic condition you wish to prevent from being inherited to your children?

Contact EmBIO's PGD experts with complete discretion!

Dr Thanos Paraschos,
trained by the Father of PGD,
Lord Professor Robert Winston