Dr Natalie Burger - What is Recurrent Pregnancy Loss?
Recurrent Miscarriage: Causes & Treatment with our Fertility Experts
Recurrent pregnancy loss is defined by the American
Society of Reproductive Medicine as two or more
pregnancy losses that occur before the 28th
week of pregnancy. In the United States,
approximately 25% of all pregnancies are lost at
some point during gestation. Only 5% of women
experience two or more pregnancy losses and less
than 1% of women experience three or more pregnancy
losses. Although this condition can be very
frustrating and emotionally challenging, the
overwhelming majority of patients with recurrent
pregnancy loss eventually will successfully deliver
a healthy child.
There are many causes of recurrent pregnancy loss. The major
categories are listed in the table below and each will be discussed
in greater detail in this section of our website.
CAUSE
OCCURRENCE (%)
Anatomic
22%.
Genetic
3%.
Infectious
6%.
Hematolgic or
immunologic 25%.
Hormonal
20%.
Unknown
40%.
As you can see from the table, these numbers total more than 100%,
indicating that some patients have multiple causes for their
miscarriages. Unfortunately, following the completion of a thorough
evaluation for recurrent pregnancy loss, 40% of couples with
recurrent pregnancy loss will still not have a definitive diagnosis
for their problem.
As women age, their risk of spontaneous miscarriage increases. At
age 20, the risk ranges from 9 to 17%; it rises to 20% in women by
age 35, 40% at age 40, and 80% in women 45 and over. Most
specialists believe that this age-related increase is most likely
due to chromosomal abnormalities within the egg.
All healthy pregnancies attach to and grow within the uterine
cavity. Unfortunately, some women are born with a uterus that not
been formed normally. It appears that approximately 5% of fertile
women have uterine anomalies. In other words, despite their
abnormally shaped uterus, they were still able to successfully
conceive and deliver a child. On the other hand, approximately 15%
of patients with recurrent pregnancy loss have an abnormal uterus.
When a woman is a fetus developing in her mother's uterus, she
initially has two separate uteruses ("uteri"), each originating near
the corresponding kidney. As the female fetus develops, these two
early uteruses migrate towards each other and eventually fuse. In
the normal situation, the wall between the two separate uteruses
reabsorbs, resulting in a normal, single, triangular shaped uterine
cavity. Anatomical abnormalities result when this sequence of
events does not occur or fails to occur completely.
The most common uterine abnormality is the septate uterus. In a
large study from Yale, 85% of patients with a septate uterus either
failed to conceive or miscarried repeatedly. Following repair of
this abnormality, 88% of patients went on to deliver successfully
while only 12% continued to have difficulty – either they failed to
conceive or they continued to miscarry. Other uterine abnormalities
include the bicornuate uterus (2 separate uterine cavities sharing a
single cervix), the unicornuate uterus (a situation where only one
of the fetal uteri develops), or a complete uterine duplication (2
uterine cavities, each with its own cervix). These are far less
common and surgical correction does not appear to improve the
prognosis in these patients.
Another uterine abnormality that can interfere with successful
conception is the presence of scar tissue within the uterine
cavity. This typically results following a D&C if too much uterine
lining tissue is removed – the walls of the uterus can subsequently
stick together, making the cavity small and irregular. Additional
anatomic abnormalities that are associated with recurrent pregnancy
loss include uterine fibroids or
endometrial polyps. Fibroids are
benign tumors caused by an overgrowth of uterine muscular
tissue. They can occur inside the uterine cavity, in the muscular
wall of the uterus, or on the outside of the uterus. Polyps are an
overgrowth of glandular tissue within the uterus. Either of these
conditions can cause abnormal uterine bleeding or they may be
asymptomatic. Fibroids may also cause a significant increase in
menstrual cramps, pelvic pressure, or pelvic pain.
Genetic abnormalities are one of the most common causes of recurrent
pregnancy loss. It is thought that the more severe the embryonic
genetic abnormality, the earlier the pregnancy is lost. Studies
have shown that 60% of normal appearing day three embryos from
35-year-old women are chromosomally abnormal. This percentage rises
to 90% in 40-year-old women. These abnormalities usually result
from problems within the egg – either the egg's chromosomes are
abnormal or the structure responsible for chromosome separation as
each cell divides is abnormal. Research suggests that, although
problems in the sperm can lead to chromosomal abnormalities as well,
this occurs much less frequently. Typically, if sperm are not
chromosomally normal, either they fail to fertilize the egg or the
fertilized egg fails to divide, resulting in loss of the pregnancy.
Despite the fact that genetic abnormalities in miscarried embryos
are common, genetic abnormalities in parents are very rare. Even
when patients have lost several pregnancies that were known to be
chromosomally abnormal, only 2% to 3% of patients or their partners
turn out to have a genetic abnormality themselves. Genetic
translocations (where parts of two different chromosomes change
places) represent the most common parental cause of genetic
abnormalities.
Although many studies suggest that infections such as gonorrhea,
chlamydia, mycoplasma, and ureaplasma are associated with recurrent
pregnancy loss, this still remains somewhat controversial.
Regardless, a thorough evaluation of recurrent pregnancy loss
includes the performance of cervical cultures designed to detect the
presence of these conditions. Regardless of the culture results,
each member of the couple is subsequently treated with antibiotics
for at least 10-14 days, as cervical cultures have been demonstrated
to be accurate less than 70% of the time.
When a pregnancy attaches to the uterine wall, it gets nourishment
and oxygen from the mother by way of the placenta. This circulatory
connection is critical to the survival and growth of the baby. Some
miscarriages are caused by blood clots that form in the small
vessels of the placenta, as these clots prevent the transfer of
either nutrition or oxygen to the fetus. These clots may be caused
by abnormalities in the normal blood clotting mechanism.
This category of miscarriage is referred to as "hematologic or
immunologic", and consists of three basic causes. The first is
antiphospholipid antibody syndrome (APAS). APAS has been reported
to occur in 3%-15% of women with recurrent pregnancy loss. Although
many blood tests can detect the presence of APAS, the only test that
has been demonstrated to correlate with recurrent pregnancy loss is
the anti-cardiolipin antibody test. This simple blood test
effectively confirms the presence or absence of APAS.
The second major hematolgic cause of recurrent pregnancy loss is
lupus anticoagulant. While this condition unfortunately shares the
same name as the chronic disease commonly referred to as "lupus",
the two conditions have little in common with each other. Like APAS,
lupus anticoagulant is a disorder in which blood clots occur within
the small vessels of the placenta. As with APAS, a simple blood
test can detect the presence of lupus anticoagulant.
The final category of hematologic causes of recurrent pregnancy loss
is a group of disorders called thrombophilias. This category
includes such conditions as deficiencies of factor V Leiden, protein
C, protein S, and methyl-tetrahydrofolate reductase (MTHFR). It
remains controversial as to whether thrombophilias cause recurrent
pregnancy loss and, in fact, the American Society for Reproductive
Medicine in their August, 2008 practice committee report, stated
that there is no evidence that it is beneficial to either diagnosis
or treat these conditions. Therefore, many fertility specialists no
longer test patients with recurrent pregnancy loss for
thrombophilias.
The evidence supporting a hormonal cause of recurrent pregnancy loss
is also somewhat limited. This condition, called "luteal phase
inadequacy", is thought to result from inadequate progesterone
production, leading to a disorder in which the development of the
uterine lining is not synchronized with the development of the
embryo. Therefore when the embryo tries to attach to the uterine
wall, an unstable attachment may occur which may lead to
miscarriage. This condition is classically diagnosed by performing
an endometrial biopsy – a procedure where a small piece of uterine
tissue is removed and subsequently evaluated under a microscope.
This test is somewhat uncomfortable and, as even normal women can
occasionally have an abnormal biopsy, the biopsy should actually be
performed twice (preferably in consecutive cycles) in order to
confirm the presence of the abnormality. If luteal phase inadequacy
is diagnosed, it is treated with either progesterone or Clomid. Due
to the discomfort caused by the biopsy, many fertility specialists
will initiate treatment without a repeat biopsy. Other hormonal
etiologies that have been associated with luteal phase inadequacy
include thyroid disease and hyperprolactinemia.
The basic diagnostic testing for recurrent pregnancy loss includes:
Evaluation of
parental chromosomes ("karyotype"). This test is performed by
analyzing a blood sample obtained from each parent.
Cervical cultures,
which are performed on the woman to rule out the presence of an
infection.
Hysterosalpingogram
(HSG), which is an X Ray in which dye is injected through the
vagina into the uterus to evaluate the shape and contour of the
uterine cavity.
A blood test for
lupus anticoagulant (aPTTT as well as a confirmatory test).
A blood test for
anticardiolipin antibodies.
Other tests, such as testing for insulin resistance, lupus,
anti-thyroid antibodies, or endo-toxins have been determined by the
American Society for Reproductive Medicine to be of no proven
benefit.
The treatment of anatomic defects consists of surgical correction.
In the case of uterine fibroids, endometrial polyps, intrauterine
adhesions, or a uterine septum, this can usually be performed on an
outpatient basis by passing a telescope through the vagina into the
uterus (hysteroscopy). As discussed above, the unicornuate uterus
and bicornuate uterus are not corrected, as studies show that
pregnancy rates do not improve following surgical correction.
Treatment of genetic abnormalities may include the use of either
donor oocytes or donor sperm, in order to replace the gametes of the
affected parent when one of the parents has a genetic abnormality
that would likely be passed on to the child.
Infections are treated with the appropriate antibiotics.
The treatment for hematologic causes usually includes baby aspirin.
For those cases that are more severe, additional anticoagulation
with heparin or Lovenox may be recommended.
Hormonal disorders are treated with progesterone, bromocriptine, or
thyroid hormone to correct the actual hormonal deficiency.
Treatment for the largest category of patients, those with an
unknown cause for their miscarriages, consists of empiric therapy
with either in vitro fertilization with pre-implantation genetic
screening (PGS) of the embryos, or the use of donor gametes. PGS is
a technique in which a single cell can be removed from an embryo and
then tested genetically to evaluate its chromosomes. Until recently,
the technology to test all 24 chromosomes (numbers 1-22 plus X and
Y) has not been clinically available. Therefore our laboratories
tested only the 9 chromosomes that are most commonly abnormal.
Thanks to significant advances in technology, we are now able to
test not only all embryonic chromosomes, but we can also frequently
determine, when an embryo is chromosomally abnormal, whether the
abnormality came from the egg or from the sperm. The accuracy of
this new technology exceeds 95%, allowing our physicians and
embryologists to select the embryo(s) for transfer that are thought
to be chromosomally normal, significantly lessening the risk of a
chromosomally abnormal pregnancy that would more than likely
miscarry.
Lifestyle alterations may also benefit many couples with recurrent
pregnancy loss. Without question, all couples attempting to
conceive should completely eliminate the use of nicotine –
regardless of the source. All women should take folic acid
supplementation. They should also reduce their caffeine and alcohol
intake, although the exact levels of caffeine and alcohol that are
appropriate remain somewhat controversial. Moderate exercise (less
than four hours of cardiovascular exercise per week) is also
recommended, as are weight and diet control.
The following table illustrates the likelihood of a successful
pregnancy based on maternal age and the number of prior pregnancy
losses.
NUMBER
OF PRIOR
LOSSES
PATIENT AGE
2
3
4
5
20
92
90
88
85
25
89
86
82
79
30
84
87
76
71
35
77
73
68
62
40
69
64
58
52
45
60
54
48
42
Brigham S, Conlon C,
Farquharson R., Human Reproduction 1999; 14:2868
As shown in this table,
the likelihood of a successful pregnancy remains very high, even
when a patient has already had up to five prior miscarriages. As
one can see, a 30-year-old woman who has had five previous
miscarriages still has a 71% likelihood that her next pregnancy will
be healthy.
In summary, there are
many causes of recurrent pregnancy loss. The evaluation of this
condition frequently leads to a definitive diagnosis, and effective
treatments are available. Even patients in whom no diagnosis can be
determined have an overwhelming likelihood of eventually having a
successful pregnancy.
