Pre-implantation genetic screening (PGS) can evaluate the status of an embryo with regard to its chromosomal makeup. An abnormality in an embryo's chromosomal configuration may cause a specific syndrome to occur in the offspring or may cause the pregnancy to miscarry. PGS is accomplished as part of the in vitro fertilization (IVF) process, commonly used to treat infertile couples. But, in this case, the embryos are tested for the presence or absence of specific chromosomal abnormalities prior to transfer into the uterus (IVF-PGS).
There was a great deal of enthusiasm for PGS when it was first developed. Based on the original technology employed, it had not lived up to expectations and, in fact, led to lower overall IVF success rates. Today, using advanced technology, PGS is likely to live up to its potential.
According to guidelines from the American Society for Reproductive Medicine based on the old technology using Day 3 biopsies and fluorescence in situ hybridization (FISH) which at best could evaluate only 12 of the chromosomes:
But today’s new technology including Day 5 biopsy, comparative genomic hybridization (CGH) able to evaluate all chromosomes and better freezing techniques utilizing vitrification hold promise for realizing the full potential benefit of PGS, making PGS a reasonable option for all the above clinical indications.
For almost three decades, infertile couples have taken advantage of in vitro fertilization (IVF) to help create their families. Now scientists have the ability to create probes to find a chromosomal problem in as little as a single cell. This technology has the potential for doctors to select embryos free of that specific chromosomal problem in order to create healthy babies or to select the sex of the embryos being transferred for family balancing.
If a couple has an increased risk for aneuploidy, all they used to be able to do to prevent the birth of an affected baby was prenatal diagnosis in the already pregnant woman with amniocentesis or chorionic villus sampling (CVS). These procedures can detect the presence of the abnormal chromosome in the fetus, but if present, the only alternative to having an abnormal child is to abort the pregnancy. Now for those who would not consider pregnancy termination, PGS may be an acceptable alternative. With IVF/PGS, embryos can be screened in the laboratory for a specific chromosomal problem and only embryos thought not to be affected with the condition in question are transferred into the mother.
The initial part of the IVF cycle is carried out in the same way as for infertility and consists of five basic steps:
The most common PGS protocol used today is to biopsy the embryo on the fifth day (trophectoderm-precursor of the placenta biopsy) after the egg has been fertilized. Our embryologist removes a few cells from each multi-celled embryo (> 100 cells). The biopsied cells, containing the chromosomes representing that embryo, are specially prepared and couriered to the genetics laboratory.
RPMG uses comparative genomic hybridization (CGH) for chromosome screening of embryos, including for sex selection. CGH is a technique that involves amplifying the DNA and uses many thousands of probes to check all 23 chromosome pairs. As long as an intact nucleus is biopsied, it is virtually error-free, whereas with the older technique, fluorescence in-situ hybridization (FISH), many errors could occur because FISH relies on binding of a single probe to each chromosome, and there are potential cell fixation artifacts, overlapping signals, and a subjective microscopic analysis is required. FISH also cannot analyze all chromosomes. It takes 24-48 hours to obtain the results from CGH.
Because of the time it takes to do CGH, this most often requires freezing of the embryos by vitrification and later transfer in a frozen embryo cycle. This technique should make the chance of a healthy live birth from a single embryo transfer of a known chromosomally normal embryo very high while minimizing the chance of twins.
Considering that the determination of the well-being of an embryo in a Day 5 biopsy is being made on the basis of the evaluating the chromosomes in just a few cells of a >100 cell embryo and the results are being interpreted very rapidly, the estimated misdiagnosis rate using CGH for aneuploidy is remarkably low (< 0.01%).
A misdiagnosis may occur if the cells removed are not representative of the major cell line in that embryo. In other words, not all the cells in an early embryo are identical. The medical term for this is mosaicism. Also CGH is not able to discern an embryo with extra copies of all chromosomes (polyploidy), nor is it able to discern a balanced translocation. Another obvious concern is the possibility of injury to an embryo during the biopsy procedure which potentially could lead to lower success rates in PGS cases, but this is less likely with the Day 5 biopsy than with the Day 3. Other concerns include unanswered long-term health consequences of IVF-PGS for the mothers and resulting children, as well as the risk of multiple pregnancies posing additional potential risks to the mother and offspring.
The alternative to IVF-PGS is for a couple to achieve a pregnancy naturally, or through conventional fertility treatment, and to rely on prenatal diagnosis through chorionic villus sampling (CVS) or amniocentesis using similar molecular diagnostic techniques. With these techniques, more material can be sampled from a pregnancy and more time taken for interpretation. Misdiagnosis may also occur, but less frequently than with PGS. However, the only options for the couple at this time are either giving birth to a child with the defect, or termination of the pregnancy.