Monday, 24 September, 2007

Recurrent Miscarriage - The Immunologic Causes

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. 
Alloimmune, in which the immune system attacks tissues considered foreign. 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 re-exposure. This is mediated by lymphocytes which produce highly specific antibodies that bind to the foreign molecules to further elicit (amplify) an immune response. 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 20% 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. 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.
There are 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 been modified over the years. 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 we 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) 
& the lupus anticoagulant test (positive in 1-2% of the general population, 10% of women with recurrent pregnancy loss) We do not routinely order specific anti-phospholipid antibody tests since ourmy management is not altered by the results. Some research centers may order these tests to determine experimental treatment protocols.
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 1)Low dose aspirin (75-81 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 of prostacyclin. 
2)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. 
We avoid this approach completely.3)Low molecular weight Heparin (2750 IU s/c per day in the first trimester after fetal viability is seen on ultrasound, continued through to the second trimester). Typically the aPTT test is used to monitor LMW heparin dosing but these test results are abnormal in APS so cannot be used. We generally go by the platelet count (If less than 100,000, we give LMWH on every second or third day). Use of LMW 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. We have treated over 300 patients using this approach over the last 10 years. 4)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. I believe that it is important for this treatment to be administered in a research facility until it is better understood.
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 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 on
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 such as 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. 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 1)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 . 2)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 techniques.

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