Recurrent Pregnancy Loss
Peri (Around)-Implantation
What is peri-implantation pregnancy loss?
Peri-implantation
pregnancy loss presents clinically as unexplained
infertility and/or preclinical, occult or chemical
pregnancy loss. There are usually no pregnancy
symptoms, but a blood test reveals small amounts of
the pregnancy hormone hCG in the mother’s blood. In
a classic study by Wilcox in 1988, 22% of
pregnancies diagnosed by a positive blood pregnancy
test were lost around the time of expected menses.
What are the causes of recurrent peri-implantation
pregnancy loss?
Difficulties in completing the
implantation process can be the result of an embryo
not capable of m implanting or a uterus not capable
of responding to the invading embryo. Problems with
the embryo can be contributed by either the sperm of
the egg and consist of abnormal chromososmes, genes
or DNA. Problems within the uterus that prevent
completion of implantation after initial attachment
involve interference with the processes of (1)
invasion of the embryo into the lining of the
uterus, (2) the ability of the embryo to not be
rejected by the maternal immune system, and (3) the
ability of the embryo to induce its own blood supply
to receive nutrient for further growth and
development.
1. The migration of the embryo into the uterine
lining is accomplished by proliferation of the
invading cells of the embryo and the ability of
these cells to digest a path through the uterine
tissue.
a. Proliferation of the invading cells is
stimulated by proteins called growth factors
secreted by cells within the uterine lining.
b.
Digestion of the path through the uterine tissues is
accomplished by the same enzymes that are involved
in dissolving clots (fibrinolysis). Thus, defects in
production of growth factors or fibrinolysis result
in peri-implantation pregnancy loss. Once the embryo
has migrated into the uterus, two events need to
occur to ensure success of pregnancy. The embryo
must not be rejected by the maternal immune cells
and the embryo must induce its own blood supply to
get enough nutrients to continue to grow.
2. Since
the embryo contains proteins contributed by the
father, they will be foreign to the mother.
Therefore, the mother must adapt her immune response
so as to not reject or destroy the pregnancy. At the
same time the maternal immune system has to
“tolerate” the paternal contribution to the
pregnancy, it must maintain anti-infectious immune
responsiveness to protect both the mother and the
embryo. Pregnancy has, thus, been thought of as a
state of immunologic tolerance. This tolerance is
induces by signals from the embryo to maternal
immune cells. Such signals include secretion of a
protein called soluble HLA G. Deficiencies in
induction in tolerance can lead to pregnancy loss.
Thus, immunologic causes for peri-implantation
pregnancy loss include inadequate embryonic
signaling for tolerance or inappropriate response of
the maternal immune cells to proper embryonic
signaling.
3. Peri-implantation pregnancy loss can
result from lack of establishment of blood supply to
the pregnancy so that insufficient nutrients are
available to support further growth of the embryo.
From studies of cancer cells, we know that groups of
cells can grow to a size of approximately 3 mm
nourished by diffusion alone. But to exceed the 3mm
size, the cells must recruit host blood vessels to
provide nourishment for growth. The pregnancy
reaches a size of 3 mm approximately 2 week after
fertilization. If blood vessels are not induced, the
pregnancy does not continue to grow. Lack of
recruitment of blood vessels results from a defect
in a process called angiogenesis. Angiogenesis is
the formation of new blood vessels from preexisting
vessels and is induced by proteins called cytokines.
If cytokines do not stimulate angiogenesis so that
the pregnancy can have its own blood supply, peri-implantation
pregnancy loss will ensue.
How can we determine the cause of recurrent peri-implantation pregnancy losses?
Peri-implantation
losses can occur as a result of a problem within the
embryo or within the uterine environment in which
the embryo is implanting. Problems within the embryo
can be contributed by the egg or the sperm. Markers
of risk factors contributed by the egg are found
with the day 3 concentrations of:
- Follicle
Stimulating Hormone (FSH), estradiol - FSH and
estradiol levels present in blood on day 3 of a
menstrual cycle are markers of ovarian reserve.
Elevated FSH levels would predict low ovarian
reserve. In general, the low ovarian reserve is
associated with an increased risk of chromosomal
abnormalities within the eggs.
- Inhibin B - Inhibin-B is secreted by granulosa cells and
controls FSH secretion from the pituitary gland. It
is,therefore, a more direct measurement of assessing
ovarian reserve that FSH. In general, the low
ovarian reserve is associated with an increased risk
of chromosomal abnormalities within the eggs.
Problems within the sperm not diagnosed by the
standard parameters of semen analysis can be
detected by:
- Sperm DNA Integrity assay (SDIa) -
Results of recent research indicate that sperm
quality influences not only rates of fertilization
of eggs but also subsequent embryo development and
implantation. The markers of sperm quality used to
predict implantation potential are not the
parameters included in the standard semen analysis
(sperm concentration, motility or morphology), but
rather the results of the Sperm DNA Integrity assay
(SDIa) that measures DNA damage in sperm reported as
DNA fragmentation index (DFI).
Problems within the uterus that prevent
completion of implantation after initial attachment
involve interference with the processes of (1)
invasion of the embryo into the lining of the
uterus, (2) the ability of the embryo to not be
rejected by the maternal immune system, and (3) the
ability of the embryo to induce its own blood supply
to receive nutrient for further growth and
development.
1. Migration of the embryo into the
uterine lining is accomplished by proliferation of
the embryo’s cells which is stimulated by proteins
called growth factors. A source of the growth
factors is the immune cells. Abnormalities in the
numbers or functions of the immune cells can be
predicted by the following tests:
- Antiphospholipid
Antibody (APA) Panel - Antiphospholipd antibodies have
been shown to inhibit invasion of embryonic (trophoblastic)
cells
- Antinuclear Antibody (ANA) Panel - Antinuclear
antibodies have also been shown to be embryotoxic
- Antithyroid Antibody (ATA) Panel - Antithyroid
antibodies are a marker of activated T cells in the
lining of the uterus. Activated T cells have been
shown to cause chemical pregnancy losses
- Reproductive Immunophenotype (RIP) - measures
circulating levels of NK cells. Elevation of
circulating NK cells are associated with
implantation failure
- Natural Killer cell Activity
(NKa) assay - measures killing activity with NK cells.
Elevated NK killing activity (greater than 10%) has
been associated with implantation failure
- Embryotoxicity Assay (ETA) - measures circulating
substances that impair preimplantation embryos
In addition to proliferation of embryonic cells,
invasion of the embryo into the ling of the uterus
requires digestion of a path through the uterine
tissues. This digestion involves enzymes that are
responsible to dissolving blood clots after they are
formed. Tests available to look for defects in this
process of dissolving blood clots called
finbrinolysis are included in the
- Thrombophilia
Panel - Included in the Thrombophilia Panel is the
gene for Plasminogen Activator Inhibitor (PAI) which
can detect the most common cause of defective
fibrinolysis contributed by an increase in
plasminogen activator inhibitor (PAI 1)
concentrations.
2. The embryo must signal the mother’s immune
cells not to reject it since it expresses proteins
from the father and therefore foreign to the mother.
Such signals include secretion of a protein called
soluble HLA G. HLA G turns off the “attack” by NK
and T cells. Abnormalities in HLA G signaling can
result in lack of this immunologic tolerance. These
abnormalities can be transmitted genetically by
either the father or the mother. To detect gene
mutations, cells from both the father and mother can
be tested for:
- HLA G Testing - The most frequent HLA
G gene mutation found in couples experiencing
recurrent pregnancy loss is HLA G-725C/G.
3. To continue to grow and develop, the embryo
once implanted in the lining of the uterus must
induce its own blood supply through a process known
as angiogenesis. A test that can predict
interference with angiogenesis is
- Antiphophospholipid Antibodies - Antiphospholipid
antibodies interfere with angiogenesis and are
present in 80% of women experiencing recurrent
per-implantation pregnancy loss.
How can we treat recurrent peri-implantation
pregnancy loss?
Treatment of recurrent
pre-implantation pregnancy loss is dependent on the
cause. If the cause of the loss lies within the
embryo itself, the options for treatment include:
- Donor sperm , egg or embryo
- Preimplantation
genetic diagnosis
If the cause of recurrent peri-implantation
pregnancy loss is the result of inappropriate
uterine response to the embryo, the treatment
options include:
- Intravenous
Immunoglobulin - Intravenous immunoglobulin (IVIg) is
the only medication that has been shown in randomized
placebo controlled trials to be effective in the
treatment of implantation failure. Overall, the
pregnancy rate per cycle in women with a history of
previous implantation failure after IVF/ET who are
treated with IVIg is 50% and live birth rate is 70%. The usual dosage for implantation failure is 40mg
prior to embryo transfer and 40mg after the first
positive pregnancy test. In some instances it may be
necessary to repeat IVIg infusions every three to
four weeks until the end of the first trimester of
pregnancy.
- Intralipid - Evidence from both animal and human
studies suggest that intralipid administered
intravenously may enhance implantation. Intralipid
is a 20% intravenous fat emulsion used routinely as
a source of fat and calories for patients requiring
parental nutrition. It is composed of 10% soybean
oil, 1.2% egg yolk phospholipids, 2.25% gylcerine
and water. Intralipid stimulated the immune system
to remove “danger signals” that can lead to
pregnancy loss. The appeal of Intralipid lies in the
fact that it is relatively inexpensive and is not a
blood product.
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