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Fruit of the Womb
Fruit of the Womb

Recurrent Early Pregnancy Loss - 7 - Immunologic and Hematologic Causes

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Our blood clotting system helps prevent us from bleeding and also may potentiate an immune response since it is ‘activated’ by tissue damage. Blood clotting (coagulation or thrombosis) and the breaking down of blood clots (fibrinolysis or thrombolysis) are processes that go on continuously within our bodies. There is a delicate balance between the coagulation system and the fibrinolytic system and many factors can shift that balance in one direction or the other with resulting complications, respectively, of either too many (or persistent) clots (deep venous thrombosis; arterial thrombosis; pulmonary emboli; strokes; heart attacks) or excessive bleeding. Nowhere is that balance challenged more than at the site of implantation of the embryo in the uterus and the subsequent development of the placenta, a site where there is invasion of the mother’s tissues by fetal cells, interaction between fetal tissues and the maternal immune defenses, invasion and remodeling of maternal blood vessels, and proliferation of new blood vessels.

Normal pregnancy is considered by many to be a ‘hypercoagulable state.’ Many of our blood clotting factors are made in the liver and production of these is enhanced by estrogens, levels of which rise 100-1000-fold during pregnancy because of their production by the placenta. Although this would seem to place all pregnant women ‘at risk’ for blood clotting problems, few actually develop such complications (although this is still a major cause of morbidity and mortality for pregnant women). When such complications do arise, however, we have discovered that certain environmental, genetic, and acquired factors, working alone or in concert, may contribute to the imbalance. We have also come to suspect that some of these same factors may play a role in recurrent early pregnancy loss as well as later pregnancy complications such as small (growth restricted) babies, hypertensive disorders of pregnancy (preeclampsia; eclampsia; HELLP syndrome), intrauterine fetal demise, and early delivery, even if a woman has never had a problem related to clotting.

Perhaps the most common environmental influence associated with an increased tendency to ‘clot’ is smoking. I do not want to imply that smoking’s effects on the coagulation system is its sole contribution to pregnancy complications. Tobacco products have the potential to exert multiple deleterious effects on a pregnancy (and highly variable expression of those effects in different individuals). However, I have had several patients over the years that consulted me for repetitive miscarriages, had no other identifiable risk factors, and who only successfully carried a pregnancy after they were finally convinced to discontinue smoking. Although I do not want to dwell on ‘environmental factors’ in this post, certain prescription medications and over-the-counter ‘natural’ herbal preparations may also be culprits that need to be evaluated in the context of recurrent pregnancy loss.

The ‘genetic’ and ‘acquired’ factors have various mechanisms by which they effect the coagulation system, but the upshot is that those abnormalities which shift the balance in the directions of either increasing clot formation or diminishing fibrinolysis (the rate at which blood clots are broken down) have the greatest potential to cause pregnancy complications (although the contributions of these to early pregnancy loss is still highly controversial). Affectionately, these conditions have been termed ‘thrombophilias’ (= clot loving). Included among the common genetic abnormalities associated with an increased tendency to form or retain clots (and without going into detail about the specific mechanisms of action of any!) are gene mutations such as Factor V Leiden, prothrombin gene mutations, antithrombin III deficiency, methylenetetrahydrofolate reductase (MTHFR) deficiency (especially when associated with hyperhomocysteinemia which is also correlated with risk for neural tube and congenital heart defects), and deficiencies in Protein C and Protein S.

With regard to ‘acquired factors’ (perhaps also a misnomer because genetics also plays a role in the development of autoimmune conditions), in my last post we discussed a patient who had recurrent pregnancy losses and a ‘lupus anticoagulant.’ Lupus anticoagulants were named such because of their ability to prolong clotting in certain laboratory assays, but they are actually associated with a greater tendency to form blood clots in humans. They were first detected in patients who had systemic lupus erythematosus, but are now known to occur spontaneously in individuals who do not have lupus and may not cause any problems except difficulty carrying a pregnancy (as was the case with our patient). Lupus anticoagulants are only one of a host of autoantibodies (antibodies directed against ‘self’) classified as antiphospholipid antibodies. Others include anticardiolipin and antiphosphatidylserine antibodies among others.

As demonstrated by my patient with the lupus anticoagulant, the effects of antiphospholipid antibodies on different individuals is highly variable and probably dependent on other components of the person’s own genetic make up. In the most extreme cases, some individuals have severe and life-threatening problems related to these antibodies. Indeed, the triad of recurrent pregnancy losses or poor obstetrical outcomes (related to severe preeclampsia, intrauterine growth restriction; fetal deaths, and preterm delivery), recurrent episodes of venous and arterial thrombosis, and persistence of antiphospholipid antibodies has been termed the “antiphospholipid syndrome (APS).” In individuals with APS, successful pregnancy may not only be difficult to achieve, it could prove deadly, even with aggressive medical management.

In closing today’s post, I would be remiss in not mentioning another characteristic (and when dysfunctional, perhaps, an aberration) of the immune system that may be associated with recurrent early pregnancy loss. In fact, as I have alluded to previously, this may be the barrier which must be overcome to carry any pregnancy and also may be the most common cause of first pregnancy losses and, in some cases, consecutive miscarriages in many women who have no other identifiable ‘risk factors’ before they can successfully carry a pregnancy. It appears to be necessary that the maternal immune system recognizes the fetal tissues as ‘foreign’ (i.e., become ‘immunized’ to them) before it is able to generate a response that will nurture their growth (while maintaining certain boundaries).

It has been proposed (and is indeed the basis for some forms of empiric therapy) that the maternal immune response at times has difficulty properly recognizing the fetal tissues in this way. This may be more likely to occur if the fetal tissues are too similar to the maternal tissues. Indeed, some couples that share multiple ‘transplantation antigens’ seem to have the greatest hurdles to overcome in this regard. The reasons for this are unclear. Our immune system has both humoral (antibody) and cell-mediated components. It has been proposed that failure to elicit ‘blocking antibodies’ might be involved (and in some cases may be) under circumstances of recurrent early pregnancy loss. However, we also know that some women, who have a condition called ‘agammaglobulinemia’ and don’t make measurable levels of certain antibodies, may successfully achieve and carry a pregnancy. My own bias in this regard is that the important actors are components, perhaps, both nonspecific and specific, of the cellular immune system.

Well, we have come a long way in our discussion of factors that contribute to recurrent early pregnancy loss (and there are more we could mention!). But, I plan to conclude this series by devoting two more posts to this subject that will focus on the practical aspects of using the information we have presented to formulate plans for both evaluation and management of this problem. Thanks for hanging in there with me and I hope the thoughts will help those of you who have had their lives affected by this condition…
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