Biopsy services for Preimplantation Genetic Diagnosis (PGD) are available through the Center for Reproductive Biology of Indiana, LLC.

Pre-implantation Genetic Diagnosis (PGD) Pregnancy Rates at CRBI

* At least one normal embryo available for transfer

As far as PGD is concerned, the advent of blastocyst culture provides two additional days before transfer during which individual embryos can be analyzed and diagnosed. At the 8-cell stage, the pre-embryo’s cells are genetically identical and theoretically, each cell could give rise to a complete organism. Each cell contains the identical genetic information so analysis of any one of the cells provides a genetic picture of the embryo, while leaving enough intact cells for the embryo to safely continue its development. Two extra days in culture before transfer provides the opportunity to remove (biopsy) one to two cells for PGD, and express-ship the biopsied cell(s) to a specialty lab that performs the actual genetic testing. The reference lab reports the information to the patient and physician before the embryo transfer scheduled on day 5 of culture.

Why is embryonic selection beneficial?
For patients with genetic diseases, selection of embryos most likely to implant and develop into a healthy child becomes extremely important. Historically, the microscopic appearance of the embryo was the only criteria available to the physician and patient for selection of “healthy” embryos for transfer. Unfortunately, there is no correlation between embryonic appearance and genetic health. Perfect-appearing embryos can carry chromosomal abnormalities and “unattractive” embryos can be genetically normal. The advent of PGD gave physicians and their patients with genetic disease an effective diagnostic tool for embryo selection before transfer. With pre-implantation genetic diagnosis to select for unaffected embryos before a pregnancy is initiated, prospective parents are able to begin a pregnancy, knowing that their baby will be unaffected by the disease that they carry.

It is well established that fertility declines with age while the miscarriage rate and chromosomal abnormalities detected in pregnancy increase with maternal age. At least part of this decline in fertility and increase in miscarriage rate in the older patient may be due to the increased incidence of embryos with aneuploidy (abnormalities in chromosome number) (Gianaroli et al., 1999; Munne et al., 1993, 1995, 1996, 1998, 1999). For older IVF patients, PGD can determine whether gross abnormalities in chromosome number or composition exist (aneuploidy testing). Over 90 percent of embryos produced by women over the age of forty carry chromosomal abnormalities (Munne et al., 1995). Without PGD, embryos can only be assessed by their appearance under the microscope. Unfortunately, embryos that look textbook-perfect may have genetic abnormalities, while others that appear “unattractive” may be genetically normal. Younger women who suffer from recurrent spontaneous abortion may also benefit from PGD because genetic defects in the embryo are often the cause of recurrent pregnancy losses. The ability to detect these abnormalities and choose embryos with a normal number of chromosomes to initiate a pregnancy can provide new hope for a successful pregnancy and birth.

Why is embryonic selection beneficial?

For patients with genetic diseases, selection of embryos most likely to implant and develop into a healthy child becomes extremely important. Historically, the microscopic appearance of the embryo was the only criteria available to the physician and patient for selection of “healthy” embryos for transfer. Unfortunately, there is no correlation between embryonic appearance and genetic health. Perfect-appearing embryos can carry chromosomal abnormalities and “unattractive” embryos can be genetically normal. The advent of PGD gave physicians and their patients with genetic disease an effective diagnostic tool for embryo selection before transfer. With pre-implantation genetic diagnosis to select for unaffected embryos before a pregnancy is initiated, prospective parents are able to begin a pregnancy, knowing that their baby will be unaffected by the disease that they carry.

It is well established that fertility declines with age while the miscarriage rate and chromosomal abnormalities detected in pregnancy increase with maternal age. At least part of this decline in fertility and increase in miscarriage rate in the older patient may be due to the increased incidence of embryos with aneuploidy (abnormalities in chromosome number) (Gianaroli et al., 1999; Munne et al., 1993, 1995, 1996, 1998, 1999). For older IVF patients, PGD can determine whether gross abnormalities in chromosome number or composition exist (aneuploidy testing). Over 90 percent of embryos produced by women over the age of forty carry chromosomal abnormalities (Munne et al., 1995). Without PGD, embryos can only be assessed by their appearance under the microscope. Unfortunately, embryos that look textbook-perfect may have genetic abnormalities, while others that appear “unattractive” may be genetically normal. Younger women who suffer from recurrent spontaneous abortion may also benefit from PGD because genetic defects in the embryo are often the cause of recurrent pregnancy losses. The ability to detect these abnormalities and choose embryos with a normal number of chromosomes to initiate a pregnancy can provide new hope for a successful pregnancy and birth.

What is the Center for Reproductive Biology’s role in providing PGD?

The Center for Reproductive Biology of Indiana has invested in it’s laboratory by ensuring that state-of-the-art embryo biopsy micromanipulation equipment and highly qualified staff are available to perform your embryo biopsy procedures. CRBI staff have performed other “traditional” micromanipulation techniques (ICSI and assisted hatching) since these techniques became available. Progression to embryo biopsy services is a natural extension of these capabilities. Embryo biopsy is currently being performed on-site at CRBI so that there is no need to hire “traveling embryologists” from PGD centers to biopsy embryos. With our own trained biopsy technicians onsite, delayed flights or overcommitted biopsy technicians from other programs are not a concern for our patients. Biopsied specimens are then shipped overnight by medical couriers to either Genesis Genetics or Genzyme Genetics, depending on the type of genetic analysis required. Patients can have their IVF performed here at CRBI with the doctors they know and trust, yet benefit from the genetic expertise of world-renowned experts for genetic analysis of their embryos.

Our Collaborating PGD Centers:

For single gene defects: Dr. Marcus Hughes of Genesis Genetics Institute-PGD Group, Detroit, Michigan.
Dr. Hughes specializes in detection of single-gene defects. His research program is responsible for the first unaffected pregnancies using PGD for cystic fibrosis (Ao et al., 1996) and sickle cell anemia (Xu et al., 1999). Currently, his lab has developed and tested over 120 different probes to detect various genetic diseases. His lab, in collaboration with national and international IVF labs, has been able to detect numerous novel mutations/deletions (Kristjansson et al., 1994; Snabes et al., 1994; Verlinsky et al., 1994; Van der Veyver et al., 1994; Harper et al., 1999). As more genetic defects that cause disease are identified, more diseases will be amenable to pre-pregnancy detection by PGD. Dr. Hughes, as part of his PGD program, provides genetic counseling to Clarian Reproductive Biology Laboratory patients prior to PGD. Ongoing ultrasound monitoring of the pregnancy is recommended for all PGD patients. Patients may choose to have traditional CVS (chorionic villus sampling ,what does this stand for?) and amniocentesis testing performed to further assure themselves that their child is unaffected by the genetic disease they carry.

For FISH analysis: Genzyme Genetics, a part of Genzyme Corporation, a global leader in biotechnology products and services.
Our staff biopsy patients’ embryos onsite at our lab, then biopsied samples are shipped to Genzyme Genetics for analysis. FISH analysis is used to detect abnormalities in chromosome number. For example, FISH is used to detect triplicates of chromosome 21, an abnormal number of chromosomes resulting in Down Syndrome.

Clinical indications for which PGD can be used include, but are not limited to:

• Single-gene defects (Duchenne muscular dystropy, sickle cell anemia, Tay-Sachs disease, Huntington’s chorea, cystic fibrosis. plus over 100 other genetic diseases caused by single-gene defects)
• Aneuploidy testing for advanced maternal age and recurrent pregnancy losses (duplicated or missing chromosomes
• Gender identification (XX or XY chromosome detection) is used for the purpose of identifying embryos carrying sex-linked diseases

Is PGD an experimental treatment?

The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART), published a joint Practice Committee Report on Preimplantation Genetic Diagnosis in which they recommend PGD as a viable alternative to post-conception diagnosis and pregnancy termination. In their words, “PGD should be regarded as an established technique with specific and expanding applications for standard clinical practice.”

What does PGD cost and does insurance cover these costs?

Fees for PGD include fees to CRBI for biopsy and shipping and fees to the genetics testing lab used for your case. In total, these fees add approximately $4,000 to standard IVF costs that are on average $10,000, for a total of $14,000. Your actual costs will vary depending on any special services you may or may not need for your treatment. Some insurance plans may cover PGD, particularly for known single-gene defects, but this is still relatively rare. However, as the use of IVF and PGD becomes more common, pressure for insurance coverage will likely increase.

Want to know more about PGD?

American Society for Reproductive Medicine and Society for Assisted Reproductive Technology, A Practice Committee Report: Preimplantation Genetic Diagnosis (June 2001). Report available on line at www.ASRM.org.

Reference Articles (PGD for Aneuploidy)

Gianaroli L, Magli C, Ferraretti AP, Munné S (1999). Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: identification of the categories for which it should be proposed. Fertility and Sterility, 72, 837-844.

Grifo JA, Tang YX, Munné S, Alikani M, Cohen J, Rosenwaks Z (1994). Healthy deliveries from biopsied human embryos. Human Reproduction, 9, 912-916.

Hardy K, Martin KL, Leese HJ, Winston RML, Handyside AH (1990). Human preimplantation development in vitro is not adversely affected by biopsy at the 8-cell stage. Human Reproduction, 5,6, 708-714.

Hill DL, (2004). Ten years of preimplantation genetic diagnosis-aneuploidy screening: Review of a multicenter report. Fertility and Sterility, Aug 82(2):300-1.

Munné S, Lee A, Rosenwaks Z, Grifo J, Cohen J (1993). Diagnosis of major chromosome aneuploidies in human preimplantation embryos. Human Reproduction, 8, 2185-2191.

Munné S, Alikani M, Tomkin G, Grifo J, Cohen J (1995). Embryo morphology, developmental rates and maternal age are correlated with chromosome abnormalities. Fertility and Sterility, 64, 382-391.

Munné S, Weier U (1996). Simultaneous enumeration of chromosomes 13, 18, 21, X and Y in interphase cells for preimplantation genetic diagnosis of aneuploidy. Cytogenetics and Cell Genetics, 75, 263-270.

Munné S, Magli C, Bahçe M, Fung J, Legator M, Morrison L, Cohen J, Gianaroli L (1998). Preimplantation diagnosis of the aneuploidies most commonly found in spontaneous abortions and live births: XY, 13, 14, 15, 16, 18, 21, 22. Prenatal Diagnosis, 18, 1459-1466.

Munné S, Magli C, Cohen J, Morton P, Sadowy S, Gianaroli L, Tucker M, Márquez C, Sable D, Ferraretti AP, Massey JB, Scott R (1999). Positive outcome after preimplantation diagnosis of aneuploidy in human embryos. Human Reproduction 2191-2199.

Werlin L, Rodi I, DeCherney A, Marello E, Hill David and Munne, S. 2003. Preimplantation genetic diagnosis as both a therapeutic and diagnostic tool in assisted reproductive technology. Fertility and Sterility, Vol 80. No 2. 467-468.

Reference Articles (PGD for single gene defects)
Ao A, Ray P, Harper J, Lesko J, Paraschos T, Atkinson G, Soussis I, Taylor D, Handyside A, Hughes M, Winston RM (1996). Clinical experience with preimplantation genetic diagnosis of cystic fibrosis (delta F508). Prenat Diagn 16(2):137-42

Kristjansson K, Chong SS, Van den Veyver IB, Subramanian S, Snabes MC, Hughes MR (1994). Preimplantation single cell analyses of dystrophin gene deletions using whole genome amplification. Nat Genet 1994:6(1):19-23.

Ray, PF, Harper JC, Ao A, Taylor DM, Winston RM, Hughes M, Handyside AH (1999). Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan Syndrome using specific diagnosis. Prenat Diagn 19(13):1237-41.

Snabes MC, Chong SS, Subramanian SB, Kristjansson K, DiSepio D, Hughes MR (1994). Preimplantation single-cell analysis of multiple genetic loci by whole-genome amplification. Proc. Natl. Acad Sci USA 21:91(13):6181-5.

Van den Veyver IB, Chong SS, Kristjansson K, Snabes MC, Moise KJ Jr, Hughes MR (1994). Molecular analysis of human platelet antigen system 1 antigen on single cells can be applied to preimplantation genetic diagnosis for prevention of alloimmune thrombocytopenia. Am J Obstet Gynecol 170(3):807-12.

Verlinsky Y, Handyside A, Grifo J, Munne S, Cohen J, Liebers I, Levinson G, Arnheim N, Hughes M, Delhanty J, et al. (1994). Preimplantation diagnosis of genetic and chromosomal disorders. J. Assist Reprod Genet 11(5):236-43.

Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z (1999). First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. JAMA 281(18):1701-6.