Recurrent Pregnancy Loss
Pre (Before)-Implantation
What are the causes of recurrent
pre-implantation pregnancy losses?
An embryo may not implant either because there is
something wrong with the embryo itself that it can’t
implant, or there is something in the uterine
environment that doesn’t allow a normal embryo to
implant.
- Problems with the embryo
The most common abnormality found in
pre-implantation embryos is an abnormal chromosome
complement. Data from preimplantation genetic
diagnosis suggest that 30% to 90% of in vitro
fertilized eggs depending on maternal age are
chromosomally abnormal. Furthermore, it has been
estimated that 75% of karyotypically normal
pre-implantation embryos fail to implant. Other than
chromosomal abnormalities, problems with the
pregnancies can include abnormal genes or abnormal
DNA contributing to their losses. While mutations in
HLA G genes have been associated with
post-implantation recurrent pregnancy loss,
secretion of soluble HLA G protein by
pre-implantation embryos has been used to predict
implantation potential of in vitro fertilized eggs
before embryo transfer into the uterus. Fragmented
DNA from the sperm has also been associated with
poor embryo quality and implantation failure.
- Problems within the uterus
Problems within the uterine environment that
inhibits the embryo from implanting have been
classified as anatomic, hormonal and immunologic.
a. Anatomic abnormalities are lesions inside the
uterus that mechanically inhibit implantation. These
anatomic abnormalities act like an intrauterine
device to prevent implantation of the embryo and
include:
- Endometrial polyps-- benign outgrowths of the
uterine lining that protrude into the uterine
cavity)
- Submucous fibroids – benign tumors of the uterine
wall that protrude into the uterine cavity
- Uterine synechia - scarring or adhesions inside the
uterine cavity
b. Hormonal responses of the lining of the uterus to
both estrogen and progesterone are necessary for the
uterus to be receptive to the embryo. Mutations in
some of the genes encoding for the progesterone
receptor have been associated with recurrent
implantation failure. c. Immunologic mechanisms involved in implantation
are being identified.
The uterus as well as the embryo has to be made
amenable (receptive) to implantation. Uterine
receptivity requires continuous interactions between
the embryo and the mother. These interactions are
communicated through proteins known as cytokines.
Cytokines are secreted by the cells within the
uterine lining including the immune cells. During
the pre-implantation period preparation of the
uterine lining for implantation involves stimulation
expression of adhesion systems that hold the embryo
to the uterus. If the immune cells don’t send proper
signals through secretion of appropriate cytokines
to the embryo or if these cells don’t respond to
signals from the embryo, then adhesion and thus
subsequent implantation will not occur.
How can we determine the cause of recurrent
pre-implantation pregnancy losses?
Establishing the correct diagnosis is an important
component in treating couples
with reproductive failure. Pre-implantation
pregnancy loss occurs after fertilization and prior
to implantation . Thus it can be the consequence of
problems within the egg or the sperm that gives rise
to an embryo that it can’t implant or problems
within uterine lining that don’t allow an otherwise
normal embryo to implant.
Problems within the egg can manifest clinically as
diminished ovarian reserve or premature ovarian
failure. Diagnostic tests useful in identifying
individuals at greater risk for diminished ovarian
reserve or premature ovarian failure include:
- Follicle Stimulating Hormone (FSH), estradiol and
inhibin B-- Ovarian Reserve describes the ovary's
capacity to respond to gonadotropin stimulation by
producing a sufficient number of good quality eggs
capable of generating normal embryos. Inhibin-B
serum concentration provides a new measure of
ovarian reserve to accompany the measurement of day
3 Follicle Stimulating Hormone (FSH) and Estradiol
(E2) concentrations. Since Inhibin-B is secreted by
granulosa cells and controls FSH secretion from the
pituitary gland, it is a more direct measurement of
assessing follicular function than FSH. Inhibin B
serum concentrations drawn on day 3 have also been
shown to predict response of ovaries to gonadotropin
stimulation in IVF cycles. Women who had less than
45 pg/ml Inhibin-B on cycle day 3 had a 70%
reduction in pregnancy rate than women with day 3
Inhibin concentrations greater than 45pg/ml.
- Antiovarian Antibodies (AOA)-- Anti-Ovarian
Antibodies (AOA) have been reported in women with
premature ovarian failure, low ovarian reserve and
unexplained infertility. Among women with
infertility, those with evidence of ovarian
autoimmunity appear to have poorer in vitro
fertilization (IVF) treatment outcomes than women
without antiovarian antibodies. Both reduced
responsiveness to gonadotropin stimulation and
reduced pregnancy rates are observed in women with
ovarian antibodies. Women with antiovarian
antibodies are less likely to become pregnant after
IVF/ET than women without antiovarian antibodies.
The predictive value of a positive antiovarian
antibody for poor pregnancy outcome after IVF/ET is
82%.
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. In humans,
these paternal effects have been shown to affect
rates of embryo cleavage, blastocyst formation and
implantation. The markers of sperm quality used to
predict pregnancy outcome 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) and high DNA staining (HDS).
- Y chromosome microdeletion assay -- Microdeletions
in the Y chromosome is a genetic condition that
results in no or very low sperm counts. Estimates
report that one out of five or 20% of men with no or
very low sperm counts have one or more
microdeletions. It is important to identify
individuals who have Y chromosome deletions because
these deletions are transmissible by
intracytoplasmic sperm injection.
Problems within the uterine environment in that
result in failure of implantation of an embryo
giving appropriate signals have been classified as
anatomic, hormonal and immunologic. Anatomic abnormalities of the uterus can be
diagnosed by:
- Hysterosonography (ultrasound evaluation of the
uterus after fluid is injected) or
- Hysterosalpingography (x-ray with instillation of
dye into the uterus and fallopian tubes) or
- Hysteroscopy (telescopic evaluation of the uterine
cavity)
Hormonal response of the uterus can be diagnosed
with the aid of the ultrasound:
- Transvaginal ultrasound examination of the lining
of the uterus around the time of ovulation
- Color Doppler flow studies to evaluate blood flow
to the lining of the uterus
Immunologic malfunction can be diagnosed with
immunologic testing. Such tests include:
- Antiphospholipid Antibody (APA) Panel-Antiphospholipd
antibodies have been shown to kill pre-implantation
embryos
- Antinuclear Antibody (ANA) Panel-Antinuclear
antibodies have also been shown to be embryotoxic
- Antithyroid Antibody (ATA) Panel-Antithyroid
antibodies have no direct effect on pre-implantation
embryos, but are a marker of activated T cells in
the lining of the uterus
- 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 kill preimplantation embryos
- Immunoglobulin (Ig) Panel-Elevated levels of
immunoglobulin, particularly immunoglobulin M, have
been associated with implantation failure. Also the
immunoglobulin panel will detect deficiencies in IgA
which can be a contraindication to the use of IVIg
if anti IgA antibodies are present.
How can we treat recurrent pre-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
Treatment of problems within the uterine environment
vary with the cause. Anatomic abnormalities are
removed surgically. Hormonal therapy is usually
prescribed with assisted reproductive technology
procedures. Immunologic problems are treated with
immunotherapy. Treatments that have been shown to be
effective for treatment of recurrent
pre-implantation pregnancy loss include:
- Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIg) is the only
medication that has bee shown in randomized placebo
controlled trials to be effective in the treatment
of implantation failure. IVIg was shown to benefit
those women experiencing implantation failure after
IVF/ET who were good embryo producers (fertilized at
least 50% of eggs retrieved and generated at least 3
embryos for transfer). Implantation rates increased
from 7% with placebo to 18% with IVIg in one
randomized trial and from 9% to 40% in another
randomized trial. IVIg is usually administered at
least 6 to 7 days prior to embryo transfer. 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. 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%.
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.
- Phosphodiesterase Inhibitors
The phosphodiesterases are responsible for enzymatic
degradation of molecules within the cells involved
in generating energy for the cell to function. They
have anti-inflammatory effects. Two
phosphodiesterase inhibitors—Sildenfil (Viagra) and
Pentoxiphylline (Trental) have been shown to
increase blood flow to the uterus. Viagra in the
form of vaginal suppositories given in the dosage of
25 mg four times a day has been shown to increase
uterine blood flow as well as thickness of the
uterine lining. Significant improvement of the
thickness of the uterine lining in about 70% of
women treated. Successful pregnancy resulted in 42%
of women who had previously experienced repeated IVF
failures and who responded to the Viagra. Similar
results were obtained when Trental was used in 400mg
twice a day doses alone with vitamin E to treat
women experiencing implantation failure associated
with thin endometrium and elevated uterine NK cells.
Animal studies have demonstrated that pentoxifylline
prevents miscarriages in abortion-prone mice.
Efficacy of pentoxifylline for treatment of
recurrent pregnancy loss in human beings remains to
be established.
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