Immunologic causes of recurrent pregnancy loss are poorly understood.
The theories proposed by authorities in this field appear to be
constantly evolving and most of the theories that have been proposed
to date have been proven to be either incorrect or largely incomplete.
Two major categories of immunologic causes of recurrent
pregnancy loss are
- autoimmune, in which the woman's immune system attacks her
own organs and tissues, and
- alloimmune, in which the immune system attacks tissues considered
The immune system is designed to protect oneself against
infectious organisms and their toxins. The system identifies,
immobilizes and eliminates "invaders." The two major
mechanisms of surveillance are
- nonadaptive immunity, in which cells respond nonspecifically
to foreign molecules or material via either phagocytosis and lysis
(by macrophages), lysozyme secretion (by lachrymal cells) or cell
lysis (by natural killer cells). This type of response does not
adapt and so its efficiency is not improved with further exposure
- adaptive immunity, in which action against specific foreign
molecules (antigens) is enhanced by reexposure. This is mediated
by lymphocytes which produce highly specific antibodies that bind
to the foreign molecules to further elicit (amplify) an immune
The immune system is constantly operational (turned on) since
it must synthesize an enormous catalog of different antibodies
and cell surface receptors to deal with the wealth of foreign
material that it is presented with.
An important feature of the immune system is its ability to distinguish
foreign (unwanted) material from its own (desired) self. If this
ability to distinguish non-self from self fails, then the system
produces an immune response against itself (or its own tissues).
This is called "autoimmune" disease.
Autoimmune disease or dysfunction may play a role in up
to 10% of recurrent pregnancy loss. Phospholipids are molecular
building blocks that help to make up a large portion of the walls
around the cells of the body, including placental cells. Anti-phospholipid
syndrome (APS) is the autoimmune dysfunction that is classically
associated with recurrent pregnancy loss.
APS is associated with pregnancy loss in any trimester, placental
thrombosis (blood clots), and small placentae. The interruption
of the circulation to the fetus via these blood clots is a possible
reason for the fetal losses.
Identifying the mechanism behind the fetal losses would allow
specific treatment to be developed. Clotting mechanisms are difficult
to understand without a background in this area (this paragraph
is included for completeness sake). Thrombosis may be caused by
a relative deficiency in prostacyclin production within the cells
that line the blood vessels (endothelial cells) since prostacyclin
is a potent vasodilator and inhibitor of platelet aggregation.
Thrombosis may also be caused by a relative insufficiency of the
active form of the endogenous anticoagulant protein C, which normally
degrades certain clotting factors to limit thrombosis, since phospholipids
are required to activate protein C. At this time, the mechanism
of thrombosis and fetal loss with APS is largely unknown.
Establishing the diagnosis of APS is important since most of the
treatment options involve considerable expense and some added
risk. Antiphospholipid antibodies are a large varied group of
immunoglobulins directed against several different negatively
charged cell surface phospholipids. Many of these phospholipids
have been identified, with the best known being cardiolipin. Tests
for APS can be divided into coagulation based tests and tests
that detect the presence of the antibodies directly.
A group of phospholipid dependent coagulation tests are available
(such as the kaolin clotting time, the plasma clotting time, dilute
Russell viper venom time, and activated partial thromboplastin
time) and serve as popular screening tests for antiphospholipid
antibodies. Each of these coagulation tests relies on the activation
of a "prothrombin activator complex" to allow for clot
formation. Antiphospholipid antibodies block this activation to
delay clot formation, such that in the presence of these antibodies
there will be a prolongation of the time required for clotting
and an abnormal result for these coagulation tests.
Other causes for an abnormal coagulation test do exist and should
be ruled out if an abnormal result is found. The ways to exclude
the other causes for abnormality include
- diluting the test plasma with a control plasma containing
normal concentrations of the necessary clotting factors and then
rerunning the assay to determine if the test results normalize
- reversing the anticoagulant effect of the antibodies by adding
a surplus of phospholipid (such as contained in the cell wall
fragments resulting from freeze thawing platelets)
These manipulations are not always run if the test ordered is
abnormal (especially if a simple aPTT is ordered) but most labs
are equipped to run these additional tests if requested by the
There are a several available sensitive and specific assays for
anti-cardiolipin antibodies, one of which should be obtained when
there is a history of recurrent pregnancy loss. The classic assay
for anti-cardiolipin antibodies is the Loizou ELISA, which has
generally been modified over the years. At this time, the physician
ordering any of the anti-cardiolipin antibody tests should become
familiar with the particular assay used and its reference ranges
since this information is necessary to interpret the results.
When the units of measurement are GPL (IgG phospholipid units)
and MPL (IgM phospholipid units) the results are not necessarily
the same as when the units of measurement are IU (international
units). When GPL and MPL units are used the cutoffs of normal
are usually about 30 and 11, respectively. It is often easiest
if the lab reports the sample results in terms of "multiples
of the median" with interpretation being negative if less
than 2, low positive if 2-3, positive if greater than 3. Results
that are negative or low positive are generally considered clinically
irrelevant and do not require treatment.
There are commercial assays for some of the other phospholipids
such as phosphatidyl-serine, phosphatidyl-inositol, phosphatidyl-ethanolamine,
phosphatidly-choline and phosphatidyl-glycerol. Rather than testing
for each phospholipid individually, the more cost efficient test
is one that detects a panel (usually all) of these phospholipids
(such as an "antiphospholipid antibody package"). If
the panel is positive then more specific detection of specific
phospholipids can be considered. Clinically, it is not necessary
to test for each of these specific antibodies since the treatment
is the same for any of them. Specific testing is most appropriate
in a research setting.
To summarize, all couples with recurrent pregnancy loss should
be screened for APS. The tests that I routinely order include
- one of the coagulation tests (aPTT) that relies on the activation
of the "prothrombin activator complex" and which will
be appropriately diluted with normal plasma when abnormal,
- the anti-cardiolipin antibody test (positive in 2-3% of the
general population, 7-45% of women with recurrent pregnancy loss-
depending on what level is considered abnormal), and
- the lupus anticoagulant test (positive in 1-2% of the general
population, 10% of women with recurrent pregnancy loss)
- I do not routinely order specific anti-phospholipid antibody
tests since my management is not altered by the results. Some
research centers may order these tests to determine experimental
APS is classically defined as a triad of recurrent pregnancy loss,
thrombosis and autoimmune thrombocytopenia (decreased platelet
concentration). For those couples with recurrent pregnancy loss,
the positive finding (on 2 separate occasions) of either an appropriately
performed coagulation based test or a direct antibody test is
generally all that is required to propose treatment.
Without treatment, couples with APS have a poor chance of carrying
a fetus to term. The worst prognosis appears to occur when there
is a prior fetal loss and high anti-cardiolipin antibodies. Treatment
options for APS include
- low dose aspirin (81 mg per day) starting prior to pregnancy.
Rationale for this treatment is based on the theory that a relative
decrease in prostacyclin is the cause for thrombosis. Aspirin
at these low doses has the effect of increasing the prostacyclin
to thromboxane (its natural competitor) ratio to enhance the effect
- prednisone (30-60 mg per day) to suppress the immune system.
This corticosteroid can have several potentially serious complications.
When given during pregnancy for this indication, prednisone has
been associated with preterm premature rupture of the fetal membranes,
preterm delivery and pregnancy induced hypertension. This medication
should only be given by physicians experienced in its use for
this indication and typically in a research setting.
- heparin (15,000 units per day in the first trimester after
fetal viability is seen on ultrasound, 20,000 units per day starting
in the second trimester). Typically the aPTT test is used to monitor
heparin dosing but these test results are abnormal in APS so cannot
be used. Use of heparin is based on the theory that decreased
levels of activated protein C may be responsible for the thrombosis
seen, and acts as an anti-coagulant. There appears to be small
risk for serious morbidity with the use of heparin, however, until
there is much more experience with this medication I believe it
is prudent to administer this treatment in a research facility
with considerable experience in its use.
- Immunoglobulin (Ig) therapy, with intravenous injections of
Igs, has been used for several decades in the treatment of immunodeficiency
conditions and more recently in the treatment of autoimmune disorders.
The mechanism of action is not known, the dosing is not standardized
for recurrent pregnancy loss, and this treatment is very expensive.
On the other hand, early experience with this treatment has been
very encouraging. I believe that it is important that this treatment
should be administered in a research facility until it is better
Alloimmune dysfunction resulting in recurrent pregnancy
loss has also been proposed. Allogeneic antigens are molecular
structures that occur in different members of the same species
and have the ability to elicit an immune response. Normally, a
person will reject dissimilar (non-self) tissues or structures
from the body using the immune system. In pregnancy, the placenta
and growing embryo are not entirely "self" but rather
are a result of both the maternal and paternal genetic heritages
(referred to as a semi-allograft). The placenta (and pregnancy)
has a "privileged" relationship with the pregnant woman
that allows for it to escape rejection. The mechanism for this
privilege is not known.
There have been several interesting and complex theories attempting
to describe how the normal pregnancy achieves its privileged status
in the maternal uterus. Thus far, none of these theories has been
generally accepted and proven. Some of the theories are based
- increased sharing of HLA types (genes encoding antigens that
distinguish and mark tissue as "self") within the maternal
and paternal chromosomes. With increased sharing the placenta
may not trigger the production of special blocking antibodies
which confer privilege
- decreased numbers of blocking factors that normally allow
the placenta to be retained as a privileged site, either due to
increased HLA sharing or other factors
- decreased numbers of natural suppresser cells in the uterus,
which may control the activity of the natural killer cells and
allow for placental survival within the uterus
The diagnosis of alloimmune recurrent pregnancy loss is one of
exclusion. That is, when all other tests have been performed and
the findings have come back normal then some of those with "unexplained"
losses are thought to fall into this category.
Several physicians refuse to treat alloimmune recurrent pregnancy
loss since there are no direct diagnostic tests, treatment options
are expensive and their benefits are largely unproven, and treatment
options potentially involve risk. I think that it is prudent to
limit treatment to a research facility with expertise in these
therapies. Having said this, I can honestly recall from my own
experience several couples with no abnormal findings in their
testing who decided to undergo this "experimental" treatment
and surprisingly went on to deliver at term. It does appear that
this treatment can be beneficial in some subsets of patients,
its just not clear how to predict which patients will benefit.
Also, you must consider that there is reportedly up to a 60-70%
chance of carrying a pregnancy to term even after 3 spontaneous
abortions without treatment.
The two main treatment options include
- unified leukocyte (white blood cell, WBC) immunization with
paternal or donor blood cells, using 200-300 million mononuclear
cells from the isolated buffy coat of blood, once the woman is
pregnant and prior to 6 weeks gestation on one occasion only
- immunoglobulin (Ig) therapy, with intravenous injections of
Igs. The mechanism of action is not known, the dosing is not standardized
for recurrent pregnancy loss, and this treatment is very expensive.
With treatment, viable pregnancy rates of 70-80% have been reported
in uncontrolled studies. In my experience, better candidates for
this treatment are couples who have no other treatment options
available and are willing to commit themselves to the time, energy
(especially emotional) and money required to pursue experimental