PGD: The Next Step in Pregnancy Enhancement and Disease Prevention or the Search for the Holy Grail of Infertility Treatment by Carlene W. Elsner, M.D., Z. Peter Nagy, M.D., Ph.D, and Amy E. Jones, M.S.


PGD:  The Next Step in Pregnancy Enhancement and Disease Prevention or the Search for the Holy Grail of Infertility Treatment

Carlene W. Elsner, M.D., Z. Peter Nagy, M.D., Ph.D, and Amy E. Jones, M.S.


Preimplantion Genetic Diagnosis (PGD) makes it possible to detect genetic abnormalities in the embryo prior to embryo transfer. This technology offers huge potential for improvement in outcomes of IVF treatment, including improved pregnancy rates, reduced miscarriage rates, and avoidance of an ever expanding list of genetic abnormalities. With each passing year, more can be learned about an embryo and its ultimate development potential from a single cell.



Before PGD was available, chromosomal abnormalities in the conceptus could not be detected until the pregnancy was already established. Prenatal diagnosis of chromosomal abnormalities in the fetus prior to birth has been in use for many years. It is currently recommended for all pregnant women over the age of 35, because the risk of maternal age related genetic abnormalities begins to rise at this age. Fetal cells are obtained for culture either by chorionic villus sampling or amniocentesis. These procedures are typically performed in the late 1st trimester or in the early 2nd trimester of pregnancy. A relatively large number of fetal cells can be safely obtained at this time and tested to determine a full karyotype (testing of all 23 chromosome pairs) of the fetus as well as detection of single gene defects and translocations is possible. If an abnormality is detected, abortion can then be performed to terminate the pregnancy and avoid the birth of an abnormal child. However, couples who want children, find the concept of abortion emotionally difficult if not ethically impossible.

With PGD, there is the possibility to detect many, but not all, genetic abnormalities in the embryo before the pregnancy is established. This helps to avoid the need for many therapeutic abortions and reduces the risk of maternal age related miscarriage in older women. As a woman ages, the likelihood of becoming pregnant in any given cycle declines and the miscarriage rate rises. Every time a pregnancy is terminated or miscarried, the woman loses 3-6 months of precious time needed to complete her family plans. Older women cannot afford that lost time. By age 40, at least 50% of a woman’s embryos will be chromosomally abnormal (Munne et al.). With the use of PGD, abnormal embryos are eliminated from the group of embryos selected for replacement into the uterus or cryopreservation, so these pregnancies are never established. Clearly, PGD is a giant step forward in our ability to help women have healthy babies.

PGD can also be used to detect many genetic diseases that are a result of single gene defects occurring in some families. In these families, the risk of having an abnormal child is not related to maternal age, but to which genes are inherited from the mother and father. Usually, in these cases, both parents have one normal gene and one abnormal recessive gene. Each parent is healthy. For the disease to occur, the child must inherit the abnormal gene from both parents. PGD can detect which embryos have the disease (two abnormal genes), which are normal (two normal genes), and which are carriers (one normal and one abnormal gene) like the parents. This information can be used in the selection of which embryos to replace in the mother’s uterus and which are appropriate for cryopreservation. PGD offers the potential of eliminating these diseases altogether.

In addition to women with known genetic diseases in the family and older women at risk for maternal age related genetic abnormalities, there are two other groups who may benefit from PGD. Seventy percent of embryos may be abnormal in women under 35 who have a history of repeated unexplained miscarriage (Simon et al.). A similar percentage of abnormal embryos (70% has also been reported in a group of women with multiple failed IVF cycles (Pehlivan et al.). PGD should be discussed with both of these groups of women before additional IVF treatments are performed, so that the best embryos can be selected for transfer.



The development of microtechnology that makes it possible to test for chromosomes or single genes in a single cell has made PGD a reality. Testing can be performed either on the 1st and 2nd polar bodies of the egg or on a single cell extracted from the embryo at the 6-8 cell stage (day 3 of embryonic life) or on the embryo at the blastocyst stage (day 5 of embryonic life).

Polar body biopsy involves the analysis of genetic material extruded from the egg during meiosis. The 1stpolar body is formed with maturation of the egg, and the 2nd is formed during the process of fertilization. Both of these structures contain chromosomes that have been excluded from the embryo during its formation and, therefore, may be analyzed without risking damage to the embryo itself. Then, the chromosomal makeup of the egg may be determined by inference.

Embryo biopsy involves the removal of a single cell from an embryo after fertilization at the 6-8 cell stage of development, just after compaction (the process by which the cells of the embryo attach to one another) has occurred. Biopsy can be done at this time without damage to the embryo because one single cell can be removed through a small opening created in the zona pellucida without fear that the rest of the embryo might escape through the opening. Analysis of this cell can then give information on not only the maternal, but also the paternal genetic contribution to the embryo. Blastocyst biopsy is a possible alternative to day 3 embryo biopsy. It is not used very widely because it is technically more challenging and also because it may not always provide an interpretable result. Both polar body biopsy and embryo biopsy are in current usage.



Two techniques are available to test the genetic material (DNA) obtained in the biopsy. They cannot both be done on the same sample obtained from a single cell, so a choice must be made. Fluorescent in situ hybridization (FISH) is used to test for an abnormal number of chromosomes within the embryonic cell. Polymerase chain reaction (PCR) technology can detect an abnormality within a single gene on a chromosome pair, but PCR does not test for extra or absent chromosomes as does FISH. Some diseases are caused by aneuploidy (extra or absent chromosomes) and others are caused by single gene defects.

 A normal human cell contains 23 chromosome pairs. Fluorescent in situ hybridization (FISH) is used to test for aneuploidy. It involves attaching color coded fluorescent tags to chromosome pairs from a single cell removed from an embryo and fixed on a slide. When examined microscopically, two fluorescent signals indicate the normal diploid state. Three signals indicate trisomy, and one signal, monosomy for the particular chromosome studied. Currently, in our laboratory, testing is available for 9 chromosomes, X, Y, 13, 15, 16, 17, 18, 21, and 22. This technology detects Down’s syndrome (trisomy 21), Turner’s syndrome (45XO), Klinefelter’s syndrome (47XXY), and a myriad of other abnormalities involving extra or absent chromosomes.

When the abnormality to be detected is limited to a single abnormal gene on a single chromosomal pair, polymerase chain reaction (PCR) technology is used to amplify segments of DNA to make possible the detection of defects using the minute amount of DNA in a single cell. Some of these abnormal genes contain extra copies of a 3 base sequence (triplet repeat) that make them bigger than the normal gene, i.e. Fragile X. The number of these repeated sequences is variable, so each abnormality is unique. Other abnormal genes may have a portion of the gene deleted, i.e. cystic fibrosis. Therefore each test must be tailored to fit the couple and the exact abnormality to be detected. The test sample DNA from the embryo is then run along with DNA from each parent to detect the presence or absence of the defective gene. This technology is used for the detection of

normal, carrier, and affected embryos for diseases like Tay Sach’s disease, cystic fibrosis, Duchenne’s muscular dystrophy, Fragile X and an ever expanding list of diseases caused by single gene defects. Genetic matching (HLA typing) can be combined with PCR in families with children with Fanconi’s anemia to detect embryos that are both normal and an HLA match for the affected child so, after the birth of the normal child, stem cells from the normal child can be used to save the life of the sick child.

In both of these techniques, embryos are biopsied on day 3. The cell removed is then tested. Testing can be very time consuming and may require up to two days to complete. Normal embryos are replaced in the woman’s uterus on the afternoon of day 4 or the morning of day 5. If a pregnancy is established, chorionic villus sampling or amniocentesis is still recommended because it is not possible to detect all chromosomal abnormalities with current technology.



Microarray technology currently under development offers the opportunity to test for all 23 chromosome pairs at once. Additionally, it provides the possibility to screen the complete genetic information of the embryo, facilitating the prevention of genetically inheritable diseases. This exciting new technology is not yet sensitive enough for use with the minute amounts of DNA in a single cell, but research continues in this area. When microarray technology can be adapted for use in single cells, it may represent the next major breakthrough in PGD.


Carlene W. Elsner, M.D. is a reproductive endocrinologist at Reproductive Biology  Associates in Atlanta Georgia.
Phone: 404-843-3064 or Toll Free 1-888-RBA-4IVF




Z. Peter Nagy, M.D., Ph.D. is the scientific and laboratory director and Amy E. Jones M.S. is the laboratory supervisor at Reproductive Biology Associates.



Munne, S., Alikani, M., Tomkin, G., Grifo, J., and Cohen, J.. Embryo morphology, developmental rates, and maternal age are correlated with chromosomal abnormalities. Fertil. Steril. 64[2], 382-391. 1995.


Pehlivan, T., Rubio, C., Rodrigo, L., Romero, J., Remohi, J., Simon, C., and Pellicier, A..Impact of preimplantion genetic diagnosis on IVF outcome in implantation failure patients. Reprod. Bio. Online. 6[2], 232-237. 2003.


Rubio, C., Simon, C., Vidal, F., Rodrigo, L., Pehlivan T., Remohi, J., and Pellicer, A.. Chromosomal abnormalities and embryo development in recurrent miscarriage couples.

Hum. Reprod. 18[1], 182-188. 2003.    


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