PREIMPLANTATION GENETIC DIAGNOSIS FOR BRCA 1/2 CARRIERS
A
Assisted Embryo Hatching
a procedure in which a hole is made in the zona pellucida of the early embryo. The embryo may more easily “hatch” out of the zona through the hole prior to implantation.
Assisted Reproductive Technologies (ART)
a collective term which refers to a variety of medical procedures used to achieve pregnancy.
B
Blastocyst
the stage of development that the embryo is in when it enters the uterine cavity for implantation (typically 5-6 days after fertilization). It is comprised of two types of cells; an outer layer of cells called the trophoblast that will become the supporting tissue of the embryo such as the placenta and an inner layer referred to as the Inner Cell Mass, which will be multiply and contribute to the cells of the embryo.
Blastomere
a single cell from the developing 3-day embryo.
C
Cryopreservation
halting the embryo development before implantation through a freezing procedure.
Controlled Ovarian Hyperstimulation (COH)
the use of medications to stimulate growth and development of multiple ovarian follicles.
F
Follicle
a structure in the ovary that has nurtured the ripening egg and from which the egg is released or retrieved.
Follicle Stimulating Hormone (FSH)
a hormone produced by the pituitary gland that stimulates the ovary to ripen a follicle for ovulation.
Fluorescent in-situ hybridization (FISH)
a type of visualization used to determine the chromosome number and chromosomal mutation status of the embryo via PGD or PND.
G
Genetic counselor
a medical professional with specialized training in clinical genetics.
I
Intracytoplasmic Sperm Injection (ICSI)
an assisted fertilization technique in which a sperm is micro injected directly into the egg cytoplasm.
In Vitro Fertilization (IVF)
a procedure during which an egg is removed from a ripe follicle and fertilized by a sperm outside the human body.
L
Linkage Analysis
involves the study of BRCA1/2 inheritance patterns within a family and the identification of genetic markers that map near the gene. These genetic markers are physically linked to the gene.
M
Meiosis
this term describes cell division that occurs during the formation of the mature egg and sperm. During meiosis, the number of chromosomes (genes) is reduced so that the egg and sperm contribute only half of the parent’s genes to the embryo.
O
Ovarian Hyperstimulation Stimulation Syndrome (OHSS)
a medical complication of the stimulation procedures and medications in which stimulated follicles produce excess hormones and other factors which may lead to serious complications and may cause cancellation of a cycle and for a small number of women may result in death.
P
Polar body
a polar body is a small cell that is naturally released by the egg or oocyte during the process of meiosis. The first polar body is released by the oocyte near the time of ovulation. The second polar body is released by the oocyte, at the time of fertilization. The polar bodies do not contribute to the developing embryo, but are naturally discarded by the oocyte during the process of meiosis. Because the polar body contains one half of the possible genetic information of the mother, the genetic information of the oocyte can be inferred by the genetic testing of the polar body.
Polymerase chain reaction (PCR)
one of the most widely used laboratory techniques for visualizing genetic information and can be used for PGD or PND.
Preimplantation Genetic Diagnosis (PGD)
refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization to determine gene status.
Prenatal Diagnosis (PND)
testing for genetic mutations in a fetus during the first or second trimester of pregnancy.
A Visual Guide to BRCA and PGD:
The following graphic represents the different stages of the IVF, PGD, and PND procedures. The outer circle shows the order of the stages, an explanation and the approximate time span. The inner circle holds a visual representation of the procedure.
The "+" in the graphic refers to the procedure being successful; the "–" refers to the procedure being unsuccessful.
Benefits and Risks of PGD:
If you are considering using PGD, it is important to consider the benefits and the risks involved in the procedure.
Benefits
- Currently, PGD is the only procedure that can provide you with information about carrier status before pregnancy.
- When successful, PGD ensures that your child will not inherit the BRCA mutation, thus ending the intergenerational transmission of that particular BRCA mutation.
- If you choose PGD, you will have the option to obtain additional genetic information (chromosomal abnormalities) that may influence you child’s health.
Risks of Undesired Outcome
Each embryo has a 50% chance of inheriting a BRCA mutation, assuming one biological parent carries the mutation. When you undergo Assisted Reproductive Technology (ART) to create embryos, it is possible that all embryos will inherit a mutation, that none will inherit a mutation, or (most likely) that some will and some will not inherit a mutation. The misdiagnosis rate for PGD in general ranges from 1-10% (Offit et al, 2006; Sermon et al. 2004). Because there are limited data on PGD for dominant genetic single gene mutations, like BRCA 1/2, mathematical modeling is used to predict PGD misdiagnosis in these instances, and it has been calculated to be as high as 11% (Lewis et al. 2001). You may also want to consider the success rate of Assisted Reproductive Technology (ART) using non-donor eggs that result in live births. For the last reported year, 2007, ART success was 30%, and multiple factors can contribute to this success, including maternal age (CDC, 2010). Therefore, it is likely that multiple cycles of ovarian stimulation and egg removal must be performed to become pregnant with a child free of BRCA mutation. IVF can be physically, financially, and emotionally demanding, and you may be limited in the number of cycles you can pursue.
- IVF may not produce any viable embryos
- Embryos collected in a given cycle may not be free of mutation
- Potential need for multiple IVF cycles
- Rare chance that PGD would fail to detect the gene mutation
- Embryos free of mutation may not result in successful pregnancy
Health Risks to Woman and Child
Female Hormones
If you have a history of cancer in your family, you may be concerned about hormone use. While hormones are generally considered safe, there are limited data available about the risk of IVF hormones as they relate to women with BRCA mutations. Additionally, fertility hormones have been known to cause a condition known as Ovarian Hyperstimulation Syndrome (OHSS) in which the ovaries produce too many eggs and become enlarged. According to the World Health Organization, .6-14% of women will experience mild to moderate symptoms including abdominal bloating, nausea, and chest pain. Rare cases, if left undetected or untreated can result in death in .2-1% of all cases (Kol, 2003). Also, multiple embryo transfer physically taxes the woman’s body.
Embryo Conditions and Transfer
During the course of IVF, embryos are cultured outside the body in a Petri dish and exposed to growth factors that may influence the child’s health and cognitive abilities later in life (Wilkins-Haug, 2009). The risk of accidental damage to an embryo during removal of cells for PGD testing is .6% (Hardy, et al. 1990). To increase the chances for pregnancy, often more than one embryo will be implanted. Higher order pregnancies can pose significant health risks to the developing fetus including premature birth, low birth weight, and an increase in birth defects. To reduce the risk of complications associated with higher order pregnancies, the American Society for Reproductive Medicine recommends that no more than two embryos transferred per IVF attempt.
