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Pre-Implantation Genetic Diagnosis (PGD)
Pre-implantation Genetic Diagnosis (PGD), is a state-of-the-art procedure used in conjunction with in vitro fertilization (IVF Treatments).
PGD, also known as also known as Embryo Screening, is generally recommended to detect numerical or structural anomalies in the genetic structure of embryos, as well as conditions caused by single gene defects. When embryos are affected by certain chromosomal or genetic conditions, these can prevent implantation to the uterine lining, lead to pregnancy loss, or result in the birth of a child with physical problems and/or mental retardation.
PGD can help prevent adverse outcomes by identifying affected embryos as they are developing in the laboratory and before they are transferred to the womb during the IVF treatment cycle.
PRE-IMPLANTATION GENETIC DIAGNOSIS (PGD) FOR ANEUPLOIDY:
Normal human cells (i.e. embryonic cells) contain 46 chromosomes in 23 pairs. We receive 23 chromosomes from each parent. The first 22 pairs of chromosomes are the same for men and women. The 23rd pair determines our sex. A female has two "X" chromosomes, whereas a male has an "X" and a "Y."
As such, the woman can only pass an X to her child in her egg. The man passes either the X or the Y in the sperm, therefore determining the sex of the child. If an error occurs, and the egg or sperm has an extra or missing chromosome, the embryo created by that egg or sperm will have an extra or a missing chromosome resulting in a condition called aneuploidy. Having an extra chromosome is known as trisomy (tri = three of a given chromosome) and having a chromosome missing is known as monosomy (mono = one of the chromosome).
When aneuploidy involves the larger chromosomes, the embryo may not attach to the wall of the uterus or may stop developing soon after attaching and miscarry. However, if the aneuploidy involves chromosomes such as the 13, 18, 21, X or Y, the pregnancy may still carry on until birth, even though the pregnancy has a chromosomal disorder. The most common of these is an extra number 21, known as Down syndrome or trisomy 21 (three 21 chromosomes). Other common aneuploidies are Klinefelter syndrome (XXY), trisomy 13, and trisomy 18.
The features of the chromosome condition depend upon which chromosome is extra or missing, but can include physical differences and mental retardation.
ANEUPLOIDY AND MATERNAL AGE:
As a woman advances in age, the chance of aneuploidy in her pregnancies increases because her eggs are as old as she is. Females have all of their eggs in the foetal stage, and as a result, they are born with all the eggs they will have in their lifetime. In males, sperm is made every 65-75 days; therefore, the sperm is not as old as the man. Based on this, the theory regarding aneuploidy risk and advancing maternal age is that, over time, the chromosomes in the egg are less likely to divide properly, which results in the egg having an extra or missing chromosome. Therefore, the risk of aneuploidy increases with maternal age.
The purpose of preimplantation genetic diagnosis for aneuploidy, therefore, is to select for transfer only chromosomally normal embryos so as to achieve more pregnancies, reduce the number of pregnancy losses, and reduce the number of affected offspring.
HOW IS PGD PERFORMED?
Two procedures are currently available in order to do PGD of embryos. The PGD team of doctors, geneticists and embryologists will decide which procedure to use.
Polar Body Biopsy: The maturing egg produces two small cells, called the polar bodies, which degenerate after fertilization. The chromosomal content of these cells allows us to infer the chromosomal content of the egg. In order to test the polar body, an opening is made in the covering of the egg and the polar body is carefully removed. The polar body is then analysed while the egg is kept in culture in an incubator. Analysis of polar bodies provides information only from the mother. Chromosome abnormalities that may occur after fertilization, when the sperm meets the egg, will not be detected via Polar body biopsy.
Embryo Biopsy or Blastomere Biopsy: To test an embryo, a blastomere or embryonic cell is removed via a microscopic opening ade in the covering of the embryo during its third day of development (5 to 8-cell stage). The embryo is then kept in culture in an incubator while the cell is analysed by PGD.
THE PGD ANALYSIS:
The biopsied cells are analysed using a technique called FLUORESCENCE IN-SITU HYBRIDIZATION OR FISH. This technique uses probes, small pieces of DNA that are a match for the chromosomes we want to analyse, to count the chromosomes present. Each probe is labelled with a different fluorescent dye. These fluorescent probes are applied to the biopsied cell and attach to the chromosomes. Under a fluorescent microscope, the number of chromosomes of each type (colour) can then be counted. The geneticist, therefore, can distinguish normal cells from cells with aneuploidy. Testing of the cells destroys them because they must be glued to a glass slide and repeatedly heated and cooled. As such, one cannot use them for another purpose or return them to the embryo. This analysis causes no extra inconvenience to the patient as it is accomplished in one day. The picture displays various chromosomes during FISH analysis.
ADVANTAGES OF PGD
1. Reduction in the Chance of Having a Child with Aneuploidy:
According to current figures, the chance for a woman delivering a baby with aneuploidy is on average 1% if she is 35-39 years of age and ~3.5% if she is 40-45. PGD does lower the chance of having an affected baby. However, we are unable to test all of the chromosomes at present. We therefore recommend that prenatal testing be performed in the resultant pregnancy via chorionic villous sampling or amniocentesis in order to confirm our diagnosis from PGD and to rule out other aneuploidies for which we do not test.
2. Increased Embryo Implantation Rate:
It is well known that the pregnancy rate after IVF decreases dramatically with maternal age. Aneuploid embryos have much lower survival rates than normal embryos, and half of them (the ones missing a chromosome) seldom implant. It appears likely that the decrease in pregnancy rates with maternal age is mostly caused by a corresponding increase in the number of aneuploid embryos. By performing PGD for aneuploidy and transferring only chromosomally normal embryos, we might be able to increase the pregnancy rates noticeably.
3. Reduction in Pregnancy Losses:
In women 35 and older, approximately 35% of pregnancies are miscarried. Aneuploidy accounts for 50%, or more of these losses. By transferring only chromosomally normal embryos, the number of pregnancies going to term should increase. Recent studies have detected a significant reduction in pregnancy losses after PGD, from 23% to 9%. The increase in implantation rate and the significant decrease in pregnancy loss rate resulted in a significant increase in ongoing pregnancies and delivered babies.
ISSUES ASSOCIATED WITH PGD
1. The Risk of Embryo Biopsy:
While PGD is a relatively new procedure in IVF, the micromanipulation techniques required to perform it have been in use for many years. The risk of accidental damage to an embryo during removal of the cell(s) in the hands of an experienced embryologist is very low, and it is currently calculated at less than 1.0% Other Assisted Reproduction procedures such as Intracytoplasmic Sperm Injection (ICSI), Fragment Removal and Assisted Hatching are all performed by making microsurgical openings in the covering of the egg or embryo and none have been found to have other than mostly positive effects on implantation and viable pregnancy rates.
2. Removal of Cells from the Embryo
No part of the future fetus will be affected because one or two cells are removed from an embryo approximately two days after fertilization. At this developmental stage all cells in an embryo remain totipotent (until about the fourth day). These cells have not differentiated yet, meaning that each cell by itself can grow into a whole and perfect fetus.
The biopsy procedure merely delays continued cell division for a few hours, after which the embryo reaches the same number of cells as before and continues its normal development. It is possible that embryo biopsy may lower embryo implantation rates slightly, while selection of chromosomally normal embryos via PGD may increase them. Therefore, the balance between potential biopsy damage and beneficial effects of PGD seems to be positive.
The accuracy of PGD for aneuploidy is approximately 90%. This means that the error rate is 10%. Within this chance of misdiagnosis, there is a false negative rate, a false positive rate, the chance for no result and the chance for mosaicism. A mosaicism is defined as the embryo having cells with different chromosome make-up.
Typically, all cells of the embryo have the same chromosomal make-up as they originate from the same fertilized egg. However, it is possible for cells of the same embryo to have differing numbers of chromosomes.
When the cell analysed has a different chromosomal complement than all the others in the embryo a misdiagnosis occurs. Due to the chance of misdiagnosis as well as the presence of aneuploidies, for which testing is not available, we recommend prenatal testing as stated earlier.
SUMMARY OF REASONS TO CONSIDER PGD
1. Recurrent miscarriage
2. 2 unsuccessful IVF cycles
3. Family history of structural chromosomal condition
4. Unexplained Infertility
5. Advanced Maternal Age
6. Family history of X-linked disease
7. Severe Male Factor Infertility
8. Single-gene defects
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