UAB Preimplantation Genetic Diagnosis Program
ABSTRACT: For a select group of couples, preimplantation genetic analysis helps reduce the number of infants born with severe neurologic disorders or birth defects, resulting in an improved quality of life for those children, as well as their families.
CME OBJECTIVE: Readers will be more aware of the benefits, risks, limitations, and indications for preimplantation genetic diagnosis.
Michael P. Steinkampf, MD, no conflicts of interest
According to the March of Dimes, about 5% of babies — 1 of 28 — are born with birth defects every year in the United States, accruing health-care costs of roughly $8 billion annually. More importantly, families pay a high price, as well, as parents at risk for genetic disorders face difficult medical, moral, and financial decisions about the possibility of terminating a pregnancy.
"Until recently, parents' only recourse for reducing the risk of having a child affected by a genetic disorder was prenatal testing during a subsequent pregnancy, with the possible termination of the affected fetus," says Michael P. Steinkampf, MD, director of the UAB Division of Reproductive Endocrinology and Infertility and the UAB In Vitro Fertilization (IVF) Clinic. "Preimplantation genetic diagnosis (PGD) offers at-risk couples an alternative to pregnancy termination. Analyzing a single cell from an IVF embryo and testing for the disorder provides these parents the opportunity to know that any pregnancy they achieve should be unaffected," he says.
Each year in Alabama, an estimated 87,500 pregnancies occur, resulting in approximately 62,000 live births. Annually, about 2000 patients are seen at UAB for prenatal genetic counseling and diagnosis, and roughly 225 patients (preconceptional and pediatric) are examined with disorders amenable to preimplantation diagnosis. Of these patients, approximately 50 have undergone prenatal diagnostic studies, and on average, 20 pregnancies a year are terminated because of an affected fetus, reports Steinkampf.
At-risk Couples
PGD is recommended for patients with unexplained infertility, recurrent miscarriages, unsuccessful IVF cycles, single gene disorders, advanced maternal age, or male-factor infertility, where the most likely cause is a chromosome abnormality. "Since preimplantation diagnosis is performed before a pregnancy has begun, it may be more acceptable to couples who have either had an affected child or a previous termination of pregnancy or who have objections to termination of pregnancy," he suggests.
Disorders for which preimplantation diagnosis is used include:
- X-linked disorders, such as hemophilia and Duchenne muscular dystrophy
- Single-gene disorders, as in cystic fibrosis
- Structural chromosomal abnormalities (translocations)
- Abnormal chromosomal numbers, as occur in Down syndrome (aneuploidy)
Down syndrome is the most commonly occurring chromosomal abnormality, affecting 1 of every 800 to 1000 live births. "Chromosome abnormalities occur more often as the age of the mother increases and is one of the most important reasons why fertility declines with increasing age. Although 80% of children born with Down syndrome are born to women younger than 35 years, the incidence of all chromosomal anomalies, including Down syndrome, increases with age," says Steinkampf.
Experienced Team
The PGD program at UAB — the only one in the state — incorporates a highly experienced, multidisciplinary team of board-certified geneticists and clinicians, as well as dedicated scientists, embryologists, genetic counselors, and nurses. In addition to Steinkampf, the clinical and research faculty of the UAB preimplantation program includes perinatologist and clinical geneticist Joseph R. Biggio, MD; geneticists Paula C. Cosper, PhD, and Maria D. Descartes, MD; pediatric neurologists Alan K. Percy, MD, and Leon S. Dure, MD; and pediatric pulmonologist Raymond K. Lyrene, MD.
Currently, Mark R. Hughes, MD, PhD, nationally known geneticist and director of Wayne State University Diagnostic Development Laboratories in Detroit, Michigan, is performing prenatal genetic analyses for UAB's IVF/PGD programs.
Expanding Technology
"PGD is possible because of the advances made in IVF, where multiple oocytes are matured and retrieved by ultrasound-directed follicle aspiration," says Steinkampf. The oocyte is inseminated, then grown in culture until the 6- to 8-cell stage. One or two cells of the developing pre-embryo are removed and biopsied. Genetic testing is performed using fluorescent in situ hybridization (FISH) or polymerase chain reaction, depending on the disorder. Unaffected embryos are then transferred to the uterus in hopes of initiating a pregnancy with a child free from the at-risk disease.
"FISH allows us to count the number of specific chromosomes. Generally, the chromosomes more commonly involved in such abnormalities are chromosome 21, chromosome 18, or the number of X and Y chromosomes. The technique also is used to evaluate specific chromosome structural rearrangements, or translocations," Stein-kampf says. "When an individual carries a balanced translocation, their children are at risk of having an unbalanced translocation, resulting in either extra or missing pieces of the involved chromosomes."
Program Procedure
Following referral, couples undergo genetic counseling. "If eligible couples opt for PGD, we proceed with ovulation induction, egg retrieval, and fertilization," says Steinkampf.
On postfertilization day 3, a single cell is removed from each preimplantation embryo using micromanipulation techniques. The biopsied cells are sent via air courier to Hughes' laboratory, where the diagnostic analysis is performed within 24 to 36 hours and the embryos returned to UAB.
On postfertilization day 5, unaffected embryos of single-gene disorders are transferred to the uterus. For sex-linked disorders, which generally affect only male embryos, the embryos are tested, and only female embryos are transferred into the uterus. In some cases, unaffected "carrier" embryos may be transferred into the uterus. "By only transferring pre-embryos without specific chromosomal defects, the total number transferred can be reduced, which in turn, reduces the risk of a multiple pregnancy," says Steinkampf.
Patients are then followed in the IVF clinic, located in The Kirklin Clinic®, to determine if pregnancy ensues; pregnant patients are released to their obstetrician's care at 10-weeks gestation.
Steinkampf notes that, although diagnostic accuracy is high (approximately 95%), results are not absolute. "For this reason, couples are encouraged to undergo prenatal testing (amniocentesis or chorionic villus sampling) to confirm the preimplantation diagnosis result," he advises.
Making PGD Possible
IVF treatment involves ovarian stimulation with ultrasound and hormonal monitoring, sonographically guided egg retrieval, and embryo transfer. "At this time, most insurance carriers do not routinely cover this procedure, although reimbursement for drugs and monitoring sometimes is available," says Steinkampf. "We feel that initial patient recruitment will be compromised if patients are required to pay large out-of-pocket charges for this new clinical initiative. Therefore, the first 15 couples who participate in UAB's preimplantation diagnosis program will receive IVF treatment at a reduced charge.
"The UAB PGD program provides a highly visible, unique clinical service that reinforces UAB's position as a national center for human genetics," concludes Steinkampf.
To facilitate referrals to the new PGD program prior to, not during, pregnancy, UAB is developing educational brochures and programs for at-risk patients and area physicians, specifically obstetrician-gynecologists, pediatricians, and family practitioners. Educational materials may be obtained by calling Vicki Noles at 205.934.1030.
For more information
Dr. Michael Steinkampf
1.800.UAB.MIST
mist@uabmc.edu
UAB Insight, Winter 2003