Introduction
Pregnancy loss, commonly referred to as miscarriage, is the most
common complication of pregnancy. Approximately 10-15% of all
first time pregnancies result in miscarriage. Recurrent pregnancy
loss, defined as 3 or more miscarriages, occurs in approximately
5% of couples attempting pregnancy. In the past, the specific
cause for recurrent pregnancy loss was unknown, however, now there
is a greater understanding of what factors may cause or contribute
to these losses with hope for a successful pregnancy following
appropriate treatment. Chemical pregnancies are those pregnancies
that only show with positive pregnancy tests, no clinical sign
of sac or heart beat. These are very early losses and may be due
to different causes from the clinical miscarriages. The unexplained
infertile patient may represent an earlier manifestation of a
chemical pregnancy.
Diagnosis
The most important part of treating couples with recurrent pregnancy
loss or reproductive dysfunction is determining the cause or diagnosis.
Causes of recurrent miscarriage include chromosomal defects, uterine
defects, hormone deficiencies and immunological factors. We conduct
a thorough evaluation of each couple who has experienced recurrent
pregnancy loss to determine the cause of the miscarriages and
plan an appropriate course of treatment based on our diagnosis.
Chromosomal Abnormalities
Chromosomal abnormalities can be caused by abnormalities in the
genetic structure of one or both parents. These abnormalities,
while not life threatening to the parents, can cause miscarriage
when passed on to the embryo. A chromosomal analysis can be done
of both partners to determine if abnormalities exist. This is
done by actually looking at the chromosomes in the blood cells
of both partners.
Other chromosomal abnormalities can occur when the normal chromosomes
of the parents do not split normally or do not match up correctly.
This type of abnormality will occur only in the growing embryo
and is not passed on to other pregnancies. If a miscarriage occurs
from this type of abnormality, the cells from the embryo can be
tested to confirm it.
Most chromosomal abnormalities are not treatable. Genetic counseling
can offer guidance to couples who have chromosomal abnormalities.
Based on the chances of passing the abnormalities on to their
children, the couples can then make informed decisions about their
fertility. They may elect to continue to try to conceive using
their own eggs and sperm, try using donor eggs/oocytes or donor
sperm, look into adoption, or remain childless.
Uterine Defects
Defects of the uterus can be caused by several factors. Some
women are born with defects in the structure of the uterus caused
by genetics or by exposure to certain chemicals while they were
still in the uterus of their mother. The most well known defect
caused by a chemical is that of diethylstilbesterol (DES). DES
is an estrogen-like compound that was used in the 1940’s until
the 1970’s to treat women who were threatening to miscarry. The
female offspring who were exposed to this medication were born
with defects in the uterus and cervix and had a higher risk of
developing a rare type of vaginal cancer; male offspring had a
higher risk of developing testicular cancer.
Other defects of the uterus can be caused by polyps (small growths
in lining of the uterus) or fibroids (tumors in the muscle wall
of the uterus) which can cause problems with implantation of the
embryo or development of the fetus.
Uterine defects can be diagnosed by hysterosalpingogram (HSG)
or hysteroscopy. Hysterosalpingogram is an x-ray during which
a dye is injected into the uterus. The contour of the inside of
the uterus and the progression of the dye through the tubes is
then documented with a series of x-rays (see Testing
and Diagnosis). Hysteroscopy is a procedure in which a an
instrument is inserted through the vagina and cervix and placed
into the uterus to visualize the inside of the uterine cavity.
Treatment options for uterine defects include surgery to remove
polyps or fibroids or to reshape the uterus General
Operative Procedures.
Hormone Deficiencies
Hormone deficiencies associated with very early miscarriage are
uncommon. The cause of a hormone deficiency is the inadequate
functioning of the corpus luteum (yellow body) on the ovary following
ovulation. The corpus luteum is responsible for producing progesterone
that is necessary to maintain the pregnancy. If this hormone is
not present in sufficient quantities, the pregnancy will be lost,
sometimes even before the woman knows she is pregnant.
Women who experience a luteal phase defect often have this type
of hormone deficiency. A luteal phase defect is also caused by
a lack of progesterone produced by the corpus luteum during the
menstrual cycle and can be detected by an endometrial biopsy and/or
a serum progesterone level during that phase of the cycle (after
ovulation).
Progesterone deficiency can be treated with the use of supplemental
progesterone given during the luteal phase of the menstrual cycle
and/or during the first trimester of pregnancy when an inadequate
corpus luteum is suspected. Supplemental progesterone is also
given during superovulation cycles such as with IVF/GIFT/ZIFT
to counteract the increased levels of estrogen produced by multiple
follicles. Progesterone supplementation is often maintained through
the first trimester of pregnancies achieved through assisted reproductive
technologies to ensure adequate levels are maintained until the
placenta is mature enough to take over.
In some women the endometrium (lining of the uterus) fails to
mature to an optimal thickness even though the composition is
normal. The optimal endometrial thickness is 8-13mm at the time
of the LH surge. We suspect that certain women may be deficient
in estrogen or may respond inadequately to the estrogen that is
required to build up the lining in the first half of the menstrual
cycle. A thin endometrial lining
leads to miscarriage. The treatment for this condition is superovulation
with or without additional estrogen supplementation Medications.
Immunologic Factors
One of the newest and most controversial issues associated with
recurrent pregnancy loss is that of an autoimmune response. The
theory is that disorders of reproduction (miscarriage, infertility)
produces an over-reaction of the immune system causing antibodies
to form. These antibodies then cause abnormal clotting to occur
leading to an interruption of blood flow to the placenta. As this
interruption in blood flow becomes more and more severe, the fetus
begins to starve for oxygen and nutrients and eventually dies.
This theory has not been wholly borne out, but the mechanism of
interruption in blood flow is still viable. Recently other primary
problems with blood clotting mechanisms have surfaced as contributing
factors of both infertility and recurrent miscarriage. These clotting
disorders acts similarly to those described above and cause pregnancy
loss at various stages in the pregnancy.
The most widely used treatment for immunologic/hematologic factors
of miscarriage is the administration of low-dose aspirin, heparin,
and steroids (see Section 6, Medications). These medications cause
a masking affect that can help prevent clot formation, leading
to less fibrin deposition in the placenta. (fibrin is the substance
we make to form a scab) While the benefits from this treatment
remain controversial, our experience leads us to believe that
many women receive benefit from this treatment and this is shown
by the dramatic increase in the number of pregnancies achieved
and delivered after we began using of this treatment more frequently.
In a small group of women with recurrent miscarriage, (<5%)
who fail to show a cause for their miscarriages, we have been
able to diagnose the onset of eosinophillia once they are pregnant.
We have noted that miscarriage occurred about two weeks after
the eosinophils showed up. We have been able to keep this group
of patients pregnant with pulsed steroids and serial blood smears
to follow the level of eosinophils. Eosinophils are a special
type of white blood cell that is supposed to increase in situations
such as asthma, allergies, parasites, or rejection of a transplanted
organ.
In a large group of women who were previously diagnosed with
“unexplained infertility” or “unexplained recurrent pregnancy
loss”, our work with area hematologists has shown an association
between pregnancy loss, infertility and certain coagulation/clotting
disorders. Empirical treatment for these coagulation disorders
has been offered to our patients through the use of aspirin, heparin,
and prednisone. While caution is indicated, we feel there are
great benefits associated with this treatment.
Biological Response Modifiers
The most cutting edge research is currently being done on “natural
killer cells” in the uterus. These natural killer cells produce
cell signals that can disrupt the conditions necessary for the
embryo to adequately implant in the uterus resulting in miscarriage.
If this condition exists, the current treatment option is IVIG
(intravenous immunoglobulin) therapy. Prior to IVIG, white blood
cell (WBC) immunizations were used to improve the outcomes of
women who experienced recurrent miscarriage. This approach eventually
spread to include treatment of the couple with unexplained infertility.
The concept of this treatment modality, not universally adopted
by the experts, has been debated for several years. A search of
the literature reveals articles that are both pro and con. My
experience in this field supports the treatment of immunological
factors that interfere with reproduction in both unexplained infertility
and recurrent pregnancy loss.
The blocking antibody model developed by Dr. Alan Beer has been
the most prominent theory and justification for doing WBC immunizations.
It is my belief that this theory is not a true description of
what occurs. It has recently been shown that elevated NK cells
in the circulating blood will normalize after WBC immunizations.
This effect has been duplicated in women who experience recurrent
miscarriage following the use of a low dose of a biological response
modifier in the form of Killed Staphylococcus Preparation (KSP).
It may be that WBC immunizations act as a biological response
modifier (BRM) causing a normalization of “natural killer” cells.
Encouraging research has been done with the use of biological
response modifiers. White cell immunization (PLI), a potential
biological response modifier, has been removed from general use
by the FDA and placed it under their umbrella of authority. This
makes it available for research institutions only. KSP, another
potential biological response modifier, is made in Japan, but
not licensed for use in the United States. For this reason we
have considered using a common biological response modifier (BRM)
in the form of killed yeast and yeast supernatant to see if clinical
outcomes improve. The desired result is a thicker endometrial
lining, reduction in peripheral natural killer activity, achievement
of a clinical pregnancy, and delivery of a viable infant. We are
currently offering this treatment option to select patients at
no charge.
My theory regarding the use of biological response modifiers
is based on the current knowledge of programmed cell death, or,
apotosis: Corticotropin-releasing hormone induces the uterine
cavity to produce molecular prongs in response to hormones. There
molecular prongs, called FAS
ligands, bind to a FAS receptor on mature white blood cells
and cause them to die. Immature white bloods cells, however, have
not acquired FAS receptors and, therefore, cannot be induced to
die. This inability to control the number of white blood cells
in the uterus may account for the elevation in natural killer
cells in the uterine cavity and in the peripheral blood of women
with recurrent pregnancy loss and unexplained infertility. Biological
response modifiers, such as PLI, KSP, or, IVIG, may induce these
immature white blood cells to acquire FAS receptors allowing apotosis/cell
death causing a decrease in natural killer cells in the peripheral
blood. If this theory is correct, the uterine cavity is capable
of making itself an immuno-privileged site.
