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Recurrent Pregnancy Loss -
The Benefits of PGD
Preimplantation Genetic
Diagnosis (PGD) may significantly improve the risk of miscarriage / recurrent
pregnancy loss in patients who have had 2 or more first trimester pregnancy
losses or have lost a pregnancy due to a chromosomal abnormality. PGD can also
decrease the increased risk of miscarriage due to maternal age over 37. Saint
Barnabas is a world leader in the PGD technique and research and has a proven
success rate.
Preimplantation
genetic diagnosis (PGD) is a new test that can detect genetic abnormalities in
embryos before they are implanted into a mother’s womb to prevent the
conception of an abnormal pregnancy or child. PGD may be a reasonable option
for many patients with recurrent first-trimester miscarriage or a history of a
chromosomally abnormal pregnancy. The test can be used to detect aneuploidy.
Aneuploidy is a condition where there are an abnormal number of
chromosomes. Chromosomes are the structures inside a cell that carry our
genetic material. Each embryo
should contain 46 chromosomes in each of its cells, 23 from the mother and 23
from the father. When an embryo
has an abnormal number of chromosomes, the embryo may not be able to implant
in the uterus, or it may implant and miscarry, or it may develop birth
defects. Down’s syndrome, for
example, is a type of aneuploidy caused when an extra chromosome number 21 is
present. Aneuploidy causes 50% to
70% of first-trimester miscarriages. PGD
can significantly reduce the risk of miscarriage and aneuploidy by detecting
abnormal numbers of chromosomes in embryos prior to replacement into the
mother’s womb.
The
Institute for Reproductive Medicine and Science at Saint Barnabas Medical
Center in Livingston, New Jersey, is one of the few centers with significant
experience in this technique, and this article reviews the experiences and
results there. This article examines the indications, benefits, and
limitations of PGD, and demonstrates why it should be considered for women
with recurrent miscarriage.
PGD
TECHNIQUE
As
PGD requires the creation of embryos in the laboratory, patients must undergo
in vitro fertilization (IVF). This involves ovarian stimulation of multiple
egg development using injectable fertility drugs called gonadotropins (Gonal-f,
Follistim, Repronex, Pergonal, etc). While the patient is under sedation or
anesthesia, the eggs are retrieved by placing a needle through the vaginal
wall and into the ovary under ultrasonographic guidance. The eggs are then
inseminated with the partner’s sperm in the laboratory. Once fertilization
occurs, the embryos are allowed to grow and divide in the laboratory for 3
days, when the embryos should reach the 6- to 8-cell stage. At this point in
development, each cell in the embryo is the same, so that analyzing the
chromosomes of a single cell should provide information about the chromosomes
analyzed for all the cells in the embryo.
An
embryo biopsy is performed by creating an opening in the zona pellucida –the
“shell” around the embryo - using mechanical means, diluted acid solution,
or a laser. A single blastomere or cell is removed through this opening using
gentle suction and a micropipette. The biopsy is undertaken using a special
microscope with delicate micromanipulators. The cell is then attached to a
glass slide, and the embryo is returned to an incubator to await the results
of the biopsy.
The diagnosis of aneuploidy uses fluorescence in-situ hybridization
(FISH). This technique uses small
pieces of DNA attached to fluorescent labels or tags.
The tags bind to specific chromosomes in the cell. Once the chromosomes
are labelled, the signals are read under a fluorescent microscope so that the
number and type of chromosomes present in that cell can be determined. Under
the fluorescent microscope the tags look like brightly colored light signals.
Each type of chromosome is labeled with a different color, allowing the
embryologist to count the number and type of chromosomes present in that cell.
The analysis takes approximately 1 day to complete. Embryos found to be
normal are then transferred to the patient’s uterus on day 4 or 5 after egg
retrieval. Due to the small size of the embryonic cell and the limited
window of time in which to obtain a diagnosis, only eight of the 24 types of
chromosomes can be analyzed. The chromosomes most commonly analyzed are 13,
15, 16, 18, 21, 22, X, and Y (ie, the chromosomes thought to be responsible
for most first trimester miscarriages).
results
The
use of PGD to detect aneuploidy can reduce a woman’s chance of having a
miscarriage. In a group of patients undergoing IVF, there was a significant
decrease in the rate of miscarriages in the group that underwent PGD for
aneuploidy compared with the group that underwent IVF without PGD (9% versus
23%, respectively), along with a subsequent higher ongoing pregnancy and
delivery rate in the PGD group.
The rate of chromosomally abnormal pregnancies is also significantly
reduced by PGD. In addition, PGD for aneuploidy in patients undergoing IVF may
improve the chance of pregnancy by increasing embryo implantation rates (the
chance that a single embryo will become a pregnancy) . It is thought that PGD
improves the process of selecting embryos for transfer, allowing embryologists
to choose embryos most likely to result in a normal pregnancy. By improving
embryo selection and reducing the number of embryos transferred, PGD can also
help to decrease the frequency of high-order multiple births after IVF.
risks
and limitations
The
risks of PGD include the possibility that the embryo will be damaged during
the biopsy procedure. The current risk of embryo damage at the Saint Barnabas
is 0.9%, and depends on the experience and skill of the technician performing
the biopsy. The damage appears to
cause the embryo to stop developing, but does not appear to increase the rate
of birth defects.
Because PGD for aneuploidy is currently limited to eight of the 24
types of chromosomes, an embryo that is deemed normal by PGD could have an
abnormality in one of the 16 remaining types of chromosomes that were not
analyzed by PGD. In addition, because the analysis is performed using FISH,
the only abnormalities that can be detected are those of chromosome number.
Therefore, other types of abnormalities (ie, chromosome rearrangements, small
abnormalities) may not be detected as they would be with karyotyping,
chorionic villus sampling (CVS), or amniocentesis. As only a single cell is
analyzed, mosaicism cannot be detected. A mosaic embryo does not have the same
chromosomal component for all cells, so that a single cell does not reflect
the karyotype of the entire embryo. Because of these limitations, the error
rate for the chromosomes analyzed (including mosaics and
false-positive/false-negative results) is approximately 7% at Saint Barnabas,
while the error rate for CVS and amniocentesis is typically less than 1%.
Thus, PGD cannot be considered a substitute for prenatal diagnosis.
While a patient may not want to undergo CVS or amniocentesis for other
reasons, she should not decline this testing just because PGD was done.
PGD is not equivalent to CVS or amniocentesis and cannot be used as a
substitute. At this time, it is
recommended that patients at high risk for chromosomal abnormalities undergo
CVS or amniocentesis even if PGD has been performed.
Recurrent
First-trimester Pregnancy Loss
Recurrent
pregnancy loss (defined as three or more miscarriages in a row) affects
approximately 1% of the US population. The evaluation of these patients should
first rule out genetic, anatomic, endocrine, and immunologic causes for
recurrent miscarriage. Many doctors will also test for genetic blood clotting
disorders, although this remains controversial. The medical evaluation
recurrent miscarriage should be individualized, but typically includes a
physical examination; pelvic ultrasonography, hysterosalpingography, or saline
hysterosonography to evaluate the uterus; complete blood cell count; testing
for thyrotropin, antithyroid antibodies, prolactin, lupus anticoagulant,
anticardiolipin, and antiphosphatidylserine antibodies; karyotyping
(chromosomal analysis) of both partners; and possibly an endometrial biopsy
(biopsy of the lining of the uterus) and screening for genetic blood clotting
disorders.
Approximately 5% to 8% of couples with a history of recurrent pregnancy
loss have an abnormal karyotype, usually a balanced translocation. A balanced
translocation is a rearrangement of chromosomes in an otherwise normal person
that markedly increases that persons risk of producing abnormal eggs or sperm,
leading to an increased risk for miscarriage and birth defects.
PGD can be performed for couples with a balanced translocation,
allowing them to implant only chromosomally balanced embryos, thus reducing
their risk of miscarriage. The use of PGD for translocations is technically
more complicated than for aneuploidy. Patients with a translocation should be
referred to a genetics counselor to review their options. A referral for PGD
at a center with experience in this type of analysis can then be made if the
couple desires it.
Even after undergoing a complete work-up, many couples have no
identifiable cause for their miscarriages, and therefore no standard treatment
options. Without treatment, couples with recurrent miscarriage have a 55% to
70% chance of a successful live birth, depending on how many miscarriages they
have had and whether they have any previous normal full-term pregnancies.
Thus, expectant management with close follow-up (no treatment or intervention)
is a reasonable option for these patients. For couples desiring a more
aggressive approach, PGD may be offered for significant reduction (by more
than 50%) of the risk of first-trimester miscarriage due to an abnormal number
of chromosomes.
History
of Chromosomally Abnormal Child or Pregnancy
For
patients with a previous child or pregnancy with a chromosomal abnormality,
PGD can reduce the risk of certain abnormalities in the patient’s next
pregnancy. This may be an attractive alternative to CVS or amniocentesis for
some people, as they may be able to avoid termination of an abnormal
pregnancy.
Advanced
Maternal Age
As
a woman ages, her risk for both miscarriage and aneuploid pregnancy increases
markedly. For women aged 37 years and older undergoing IVF, the author’s
center has demonstrated that PGD for aneuploidy significantly improves
pregnancy rates, reduces miscarriage rates, and decreases the chance of a
chromosomally abnormal pregnancy if six or more embryos of good quality are
available for analysis.
CONCLUSION
The
availability of PGD for aneuploidy is increasing quickly at IVF centers around
the country. Saint Barnabas is a world leader in
the PGD technique and research and has a proven success rate. To
undergo PGD, patients must conceive via IVF. PGD should be considered as
a reasonable option for patients who have a history of repeated
first-trimester miscarriages that are due to a chromosomal abnormality or are
unexplained. The use of PGD can significantly reduce the risk of
miscarriage in these patients. PGD can also decrease the increased risk of
miscarriage due to maternal age over 37. If
a patient wants to consider PGD she should have a consultation with our
genetics counselor for a more extensive discussion of the procedure and its
limitations. While PGD can have significant benefits, it is a limited
genetic test, and is not a substitute for CVS or amniocentesis.
For
further information about preimplantation
genetic diagnosis - PGD, please
contact the Institute for Reproductive Medicine and Science at (973) 322-8286.
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