PGD for miscarriage
Preimplantation genetic diagnosis or PGD is a method used to identify genetic and chromosomal abnormalities in embryos. There are many potential applications for PGD in the field of reproductive medicine. One of the most exciting uses for PGD is the ability to decrease the rate of miscarriage.
Miscarriage due to chromosome abnormalities
The vast majority of miscarriages are due to abnormalities in the number of chromosomes contained in the embryo. Many of these are currently detectable by PGD. The biologic process by which embryos receive their chromosomes is complex. Prior to ovulation, an egg has two extra sets of chromosomes. At the time of ovulation, one set of chromosomes is pushed out of the egg into a tiny cell called the first polar body. In an IVF cycle, this occurs when a woman takes the hCG trigger injection. At the time of fertilization, the second extra set of chromosomes is pushed out into the second polar body. This second extra set of chromosomes is essentially replaced by the chromosomes contained in the sperm. When fertilization is completed, therefore, the egg should have contributed one set of 23 chromosomes and the sperm should have contributed one set of 23 chromosomes. Thus, an embryo that contains 23 pairs of chromosomes, for a total of 46, is considered normal or euploid.
Unfortunately, during this complicated process, occasionally an embryo will lose or gain one or more chromosomes. These embryos are abnormal and are called aneuploid. Certain chromosomes seem to be more prone to gain or loss. So for example, embryos with extra copies of chromosomes 13, 18 or 21 occur much more commonly than embryos with extra chromosomes 1, 2 or 3.
If an embryo contains an extra or missing chromosome, there are only three possible outcomes for that embryo. Most of these aneuploid, abnormal embryos will never implant into the uterus and produce a pregnancy. If the abnormal embryo does implant, the majority will be lost during the early portion of the pregnancy. This is the most common cause of miscarriage in human beings. If an abnormal embryo does not miscarry, the baby born will have birth defects. One of the most well known birth defects is when an extra copy of chromosome 21 is contained in the embryo. These babies are born with a disorder called Down’s syndrome.
As women age, the percentage of embryos with chromosomal abnormalities increases. This is the primary reason why older women have lower fertility rates, higher miscarriage rates and higher rates of birth defects.
Currently, there is no known method to prevent embryos from developing these chromosome abnormalities. PGD can be used, however, to detect embryos with these abnormalities before they are placed into the uterus.
In order to perform PGD on the embryo, cells containing DNA must be removed. Commonly, the polar bodies can be removed and once an embryo has divided into 8 cells, one of these cells or blastomeres can be removed. These techniques are known as polar body biopsy and blastomere biopsy.
The PGD method most commonly used to detect the number of chromosomes in an embryo is called FISH or flourescent in-situ hybridization. Chromosomes are essentially highly compact structures containing DNA. The DNA is composed of two helical strands that “complement” each other. A chemical base on one strand of DNA matches up to its complementary pair on the other strand. Thus, the strands stick together. A short strand of DNA can be synthesized that will recognize a specific sequence of DNA on a chromosome and bind to it. The short stretch of DNA is called a probe or molecular probe.
The probe will have another structure attached to it called a flourophore. The flourophore will glow a certain color when exposed to a certain wavelength of light. Thus, when a probe finds and attaches to the DNA in a chromosome, the chromosome can be seen by looking for the glowing light.
Each chromosome tested will be given a different color. So if chromosome #21 is red, it will be possible to count the number of red signals and determine the number of chromosomes.
PGD for miscarriage
PGD can therefore be used to detect the number of chromosomes in an embryo. Since not all chromosome abnormalities occur equally, PGD testing can be directed towards finding those chromosome abnormalities that most commonly result in miscarriage.
Most commercially available probe panels used in PGD are capable of analyzing 5 to 9 chromosomes. A recent study showed that using a 5-chromosome PGD panel, that about 30% of potential miscarriages would be detected. Using 9 chromosomes, PGD would detect about 70-75% of miscarriages.
A 2008 study looking at PGD and miscarriage published in the medical journal Fertility and Sterility found that using a 9 chromosome panel would decrease the risk of miscarriage by about 50%.
In clinical studies, reductions in miscarriage risk have been seen. For example, in our PGD program, a certain group of couples going through IVF without PGD had a miscarriage occur 15% of the time. Couples who had PGD with their IVF cycle miscarried 8% of the time. PGD was able to reduce the miscarriage rate by about 50%.
The couples who are at highest risk for chromosome abnormalities and miscarriages include those in whom the female is older. In fact, the older the female, the higher the rate of abnormalities found and the higher the miscarriage rate. Others at high risk include couples who have had recurrent miscarriage.
PGD for recurrent miscarriage
In 4-5% of couples with recurrent miscarriage, either the male or female has a structural abnormality involving two of their chromosomes known as a translocation. A translocation involves breakage of two chromosomes with the pieces going to the other chromosome. For example, a 13:21 translocation means that a small bit of chromosome 13 is attached to chromosome 21 and a small piece of chromosome 21 is attached to chromosome 13. The individual who carries a translocation may be completely unaffected because the total amount of DNA is normal. This is called a balanced translocation.
However, if a translocation carrier tries to reproduce, the embryos produced may have too much or too little DNA. This is called an unbalanced translocation and will lead to miscarriage.
PGD can be used to detect translocations in embryos by a different method called whole chromosome painting. The concept is similar to FISH analysis but instead of marking a small part of a chromosome, the probe used will recognize the entire chromosome. This enables analysis of the structure of the chromosome and determination of whether embryos have unbalanced translocations.
In studies of couples with recurrent miscarriage that have a translocation, the risk of miscarriage was reduced by over 90%.