Pre-Implantation Genetic Diagnosis (PGD) as Both a Diagnostic

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					Pre-Implantation Genetic Diagnosis (PGD) as Both a Diagnostic
and Therapeutic Tool in Assisted Reproductive Technology (ART)
Lawrence Werlin, M.D.

IVF success rates are dependent on a variety of factors, including
the age of the oocyte, embryo quality, and endometrial lining
receptivity. Recently, we have begun to look directly at the
embryo from a genetic standpoint evaluating its chromosomal
make-up in an effort to improve IVF success.

PGD allows us to evaluate the chromosomal make-up of an
embryo, or to screen for a specific single gene defect, such as
cystic fibrosis, before placing the embryo into the uterine cavity.
Previously, chorionic villa sampling, or amniocentesis were the
established methods used to evaluate the abnormalities.
Unfortunately, these tests are only performed after pregnancy
has been achieved.

The Genesis Network for Reproductive Health, funded by an
ongoing educational grant from Organon Inc., has conducted
the first IRB approved, randomized, prospective study evaluating
the effectiveness of PGD in three high-risk groups of patients at
greater risk for genetically abnormal (aneuploidy) embryos. The
three high-risk groups include:

          1.        Recurrent Pregnancy Loss (RPL)
          2.        Advanced Maternal Age (AMA)
          3.        Repeated Failed Cycles (FC)

The data was published in Fertility and Sterility in August of
2003. Initially, it was clear that PGD offered no benefit in the FC
group. It appeared that the trend may be beneficial in the RPL
and AMA groups, however the numbers were small.

Subsequently, the study has been expanded and continued in
an effort to better evaluate the RPL and AMA groups to reach
statistical significance.

A total of 76 patients were enrolled from August 1, 2001 through
April 1, 2004. All patients were randomized into either controls
or PGD. All underwent stimulation protocols using Follistim and
Antagon (Organon, West Orange, NJ). At the appropriate time,
Pregnyl (hCG) 10,000 IU (Organon) was administered.
Approximately 34-36 hours after hCG administration, ultrasound
guided oocyte retrieval was performed. Intracytoplasmic sperm
injection was performed on all mature oocytes.

In the PGD group, embryo biopsy and blastomere fixation were
done on day 3 post retrieval on all 6-8 cell embryos, with only
one cell biopsied per embryo in most cases. Slides were sent to
Reprogenetics for fluorescence in situ hybridization analysis for
chromosomes 13, 15, 16, 17, 18, 21, 22, X and Y. Results were
received on day 4 post retrieval. Embryo transfer (ET) of only the
chromosomally normal embryos was done on day 5 post
retrieval. In the control group, ET was performed on day 3 or 5
post retrieval based on physician preference. In both the PGD
and control groups, corticosteroids, low-dose aspirin (80-81 mg),
and progestational supplementation were used. Serum B-hCG
levels were obtained 12 days after ET. Pregnancy was confirmed
by demonstrating at least two appropriate consecutively rising
B-hCG levels.

 65     ART RESOURCE DIRECTORY            2006
Pre-Implantation Genetic Diagnosis (PGD) as Both a Diagnostic
and Therapeutic Tool in Assisted Reproductive Technology (ART)
Lawrence Werlin, M.D.

Overall, in both groups, 68% of embryos biopsied were          Dr. Lawrence Werlin, a nationally noted specialist in reproductive
abnormal. Approximately 23% of the women had no                endocrinology and infertility, is the founder and Medical
embryo transfer due to all embryos being abnormal.             Director of Coastal Fertility Medical Center, and co-founder of
                                                               GENESIS Network for Reproductive Health
In the RPL/PGD group, 45.5% achieved pregnancy with            Contact information:
an implantation rate of 21%, as compared to 41.2%              Coastal Fertility Medical Center
pregnancy rate with an implantation rate of 14% in             4900 Barranca Parkway, Suite 103
controls. In the AMA/PGD group, 30% achieved                   Irvine, CA 92604
pregnancy with an implantation rate of 10%, as                 Phone: 949-726-0600
compared to 17.6% pregnancy rate with an implantation          Fax: 949-726-0601
rate of 11% in controls. In conclusion, a number of findings   Email:
were evident:
           1. It was re-confirmed that in both groups of       INCIID member profile:
           patients, PGD may be beneficial, since there is     member.php?cust_id=10278
           a tendency toward higher pregnancy and
           implantation rates.
           2. PGD confirms that aneuploidy is a common
           cause of RPL.
           3. In view of the large numbers of abnormal
           embryos in each group, couples may consider
           alternative options earlier, such as donor
           oocytes, donor embryos, and/or adoption.

Though PGD appears to be a beneficial tool, there are
various caveats to be considered. Although relatively
small, the risks include:
           1. False-positive results
           2. False-negative results
           3. Arrested development of the embryo

Also, at the present time, the greatest limitation of PGD is
that we can only safely look at 9 to 10 specific
chromosomes, previously mentioned above, for
aneuploidy. These chromosomes make up approximately
85% of all aneuploidies that occur. The remaining 14
chromosomes are not screened. Newer technologies such
as Comparative Genomic Hybridization (CGH), will allow
us to screen all 23 chromosomes.

Finally, there is obvious concern that ethical standards
must be applied to the use of PGD. Strict guidelines for
its uses must be established. Further discussion will
ensue to address these important issues.

                                                                          ART RESOURCE DIRECTORY               2006       66