Preimplantation Genetic Diagnosis (PGD)
Studies
from many different IVF clinics have shown that even embryos with good
physical appearance or "morphology" can have chromosome problems. Even
in women younger than 35, at least one third of the embryos have
abnormal numbers of chromosomes. The number of embryos that have
abnormal chromosomes increases every year since eggs become older.
A technique called Preimplantation Genetic Diagnostics or PGD can select most of those embryos that are chromosomally normal so that
they are transferred to your uterus. This can improve the chance of
getting pregnant and carrying to term. And can reduce the chance of
having a baby with a condition like Down syndrome. It also may decrease
the chance of losing a pregnancy early.
Chromosomes are string-like structures found in the center of every
cell (the nucleus). Chromosomes contain genes that are made of DNA.
Therefore, out inherited information is housed on the chromosomes.
Normal human cells (embryo, fetus, baby or adult) contain 46
Chromosomes or 23 pairs. We receive 23 chromosomes from each parent.
The first 22 pairs of are the same for men and women and labeled
largest to smallest: 1 through 22. The 23 rd pair determines our sex.
To test for a chromosome abnormality such as Down syndrome, the
chromosomes are studied.
Spermatozoa or eggs that have extra or missing chromosomes will pass
this problem on to the embryo after fertilization. This situation is
known as aneuploidy. There can be extra (trisomy) or missing (monosomy)
chromosomes. Both conditions are a problem. If the aneuploidy involves
the larger chromosomes, the embryo may not attach to the wall of the
uterus or may stop developing soon after and miscarry. In some cases,
however, the aneuploidy may cause the fetus to be abnormal but carry to
birth. Down syndrome is an example of this, but there are several other
types. The features of the chromosome condition depend upon which
chromosome is extra or missing, but can include physical abnormalities
and mental retardation.
As a woman advances in age, the chance of aneuploidy in her pregnancies
increases. This association is due to the fact that a woman's eggs are
as old as she is. Females have all of their eggs from the fetal stage
on, therefore they are born with all the eggs they will have in their
lifetime. As such, the theory regarding aneuploidy risk and advancing
maternal age is that, over time, the chromosomes in the egg are less
likely to divide properly leading to the egg having an extra or missing
chromosome. The risk of conceiving an abnormal baby increases with
maternal age, but the frequency of aneuploidy in embryos is much higher
than at delivery. This difference in percentages of affected embryos
versus live born is due to the fact that a pregnancy with aneuploidy is
less likely to attach to the uterus or go to term. Most will not
implant or will be miscarried. The percentage of affected pregnancies
is reduced over the course of the pregnancy. The lack of implantation
and loss rate of aneuploidy embryos are believed to be the main reasons
why pregnancy rates decrease with advancing maternal age.
Aneuploid embryos are mostly indistinguishable morphologically and
developmentally from chromosomally normal ones, thus, without
genetically testing them, the embryologists doing your IVF procedure
cannot recognize them and may transfer chromosomally abnormal embryos
to you.
A technique called Preimplantation Genetic Diagnostics (PGD) has been
developed to test your embryos prior to the transfer of the embryos to
the uterus. This technique consists of the removal (biopsy) of one cell
of each embryo, followed by a very fast genetic analysis using a
technique called fluorescence in situ hybridization (FISH), and the
subsequent replacement of those embryos identified as normal. Normal
embryos have a higher chance of implanting, resulting in pregnancy and
not miscarrying, than abnormal embryos.
The cells to be analyzed are either polar bodies or
blastomeres. The ripening egg produces two small cells called polar
bodies that degenerate after fertilization. The chromosomal or genetic
content of these cells allows us to infer the chromosomal content of
the egg. If one is testing the polar body, an opening is made in the
zona pellucida, the covering of the egg, and the polar body is removed
via aspiration with a pipette, a very thin glass tube. The polar body
is then analyzed while the egg is placed in an incubator. By analyzing
polar bodies, we obtain information from only the mother.
Paternal
or sperm genetic information or chromosome abnormalities that may occur
after fertilization will not be detected. At least one third of
abnormalities occur during or after fertilization and are not found in
the egg. That is why we prefer to biopsy cells from the embryo. A
blastomere is a cell from an embryo. To obtain the blastomere, an
opening is made in the covering of the embryo during its third day of
development when the embryo has 6 to 10 cells. A blastomere is removed
by gentle suction. The embryo is placed in an incubator while the cell
is analyzed. Chromosomal disorders are tested by direct study of the
chromosomes.
Not all genes or chromosomes can be studied
by PGD and one cannot test for both genes and chromosomes from the
singles cell concurrently. Neither test is 100% accurate because we can
only biopsy a single cell from the embryo, thus follow-up prenatal
testing via chorionic villous sampling (CVS) or amniocentesis is highly
recommended.
An embryo undergoing blastomere (single cell) removal
in order to diagnose the genetic make-up of the embryo.
Most chromosomally abnormal embryos either do not implant or
spontaneously abort shortly after implantation. Thus, if only normal
embryos are replaced, which have higher chances of implanting and
reaching term, the probability of conceiving a healthy child may
increase if PGD is applied.
PGD
of aneuploidy has been proven to double implantation rates in several
studies, reduce the rate of pregnancy loss by half and increase
take-home baby rates. Unpublished data from Reprogenetics also indicate
a four-fold reduction in the frequency of chromosomally abnormal
conceptions after PGD. Data from other centers has not been so encouraging.
While PGD is a relatively new procedure in IVF, the micromanipulation
or biopsy techniques required to perform the procedure have been in use
for many years. The risk of accidental damage to an embryo during the
removal of the cell(s) is less than 1% in experienced fertility
centers. Additionally, no part of the future fetus will be lacking
because of the removal of a cell. There is no clear evidence that
biopsy of one cell is a problem for the developing embryo later on.
The
test may occasionally classify an abnormal embryo as normal. Very few
of such pregnancies have occurred. The reverse may happen, too - a
normal embryo that is tested may be classified as abnormal by mistake,
though the chance of this is also small. Again, due to the small chance
of misdiagnosis as well as the presence of conditions not tested for
via PGD, prenatal testing is still recommended.
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Women with a prior history of multiple miscarriage or aneuploid pregnancies:
Regardless of age, these patients could benefit from PGD. In all these
patients, higher implantation rates, reduced pregnancy loss and reduced
risk of chromosomally abnormal conceptions are expected after PGD. It
is not clear yet if patients with repeated IVF failure benefit from
PGD.
PGD is usually preformed in a very specialized genetics center. Your
IVF center will arrange for or perform the biopsy and process the cell
and then send it to Reprogenetics. Reprogenetics scientists developed
the first tests for PGD of aneuploidy, and therefore, are one of the
PGD centers with the most experience in this technique. For more
information regarding Reprogenetics, please check www.reprogenetics.com. If you are interested in PGD through Main Line Fertility, please email or call Tyl H. Taylor, MS at 610-526-8969.
As you might expect, this technology doesn't come cheaply. This
procedure may add close to $5,000 to the cost of IVF. Few insurance
policies cover the expense.
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