Immune Problems And Pregnancy Loss

Most people tend to think of infertility as the inability to become pregnant. It really is, however, the inability to have a baby. Thus, couples with recurrent pregnancy losses also have a fertility problem even though the woman is able to conceive.

There is now increasing evidence that abnormalities in the immune system affect a woman’s ability to carry a pregnancy to term and deliver a healthy baby. It is a rapidly developing area of reproductive medicine and all the facts are not yet in. Nonetheless, I wanted to give you an idea as to what I do know at this time. This pamphlet will be updated as more information becomes available.

Many years ago, it was recognized that women with Systemic Lupus frequently aborted pregnancies in the first trimester. It was discovered that these women had, in their blood, a substance that affected the tests that I use to measure the ability of the blood to clot. This substance prolonged certain coagulation tests. Women who had the substance in the blood stream, when tested, behaved as if they were taking an anti-coagulant such as Heparin. This substance, but because it was found initially in women who had Lupus, was named “the Lupus Anti-Coagulant”.

It is critically important to understand that the Lupus anti-coagulant (LAC) is not an anti-coagulant itself. It simply affects certain coagulation studies and, therefore, gives the appearance of being an anti-coagulant. In fact, it is undoubtedly a substance that promotes the formation of blood clots. We now know also that the Lupus anti-coagulant is an antibody.

Over the years other antibodies have been found that behave similarly to the Lupus anti-coagulant. The most well known of these is called anti-cardiolipin.

The antibodies that appear to play a major role in this problem are directed toward a group of substances on the platelets called “phospholipids”. When the antibodies attach to the phospholipids, the tendency of the platelets to clump together is increased. This is one of the initial steps in clot formation.

As a result, the name that is now used to describe this situation is “The Anti-Phospholipid Syndrome”.

It quickly became apparent that there were many women with various forms of pregnancy wastage who did not test positive for either the Lupus anti-coagulant or anti-cardiolipin. More recent studies have demonstrated that these women have defects in their immune system but there is no one single test that will detect this problem. Recent data from Scandinavia shows that a whole panel of tests are necessary and that women who have this problem will show one or more abnormalities but the pattern of the abnormalities will vary from one women to another.

There are two standard tests that have been used over the years to screen people for coagulation abnormalities and it is routine in many hospitals to run these tests on patients who are about to undergo surgery. These two tests are called the Prothrombin Time (PT) and the Activated Partial Thromboplastin Time (APTT). Initially, it was felt that to perform these two tests would serve as a useful screen to detect those people who might be at risk for one of these immune problems. We now recognize that they are usually not sensitive enough but another test (Russell Viper Venom Time) is a much more sensitive test and will pick up people that the PT and APTT might miss.

In case you are interested, many poisonous snakes have powerful anti-coagulants in their venom. Russell’s Viper is a poisonous snake and the venom from this snake is used as a coagulation test. It is a very sensitive test and will often show abnormalities where more routine tests will not.

The question for women who have problems with pregnancy wastage is how does this all impact upon her, what does this mean in terms of her health, and how can I detect and treat these problems so that she may have a successful pregnancy.

Our immune system is designed to fight off foreign invaders such as viruses and bacteria. It is also designed to get rid of dead cells, cancer cells and other substances within our body that do not belong there.

In many people (women are more commonly affected than men) the immune system becomes activated in an abnormal way and antibodies are formed against the person’s own tissues. Your body then literally begins to attack itself. There are many diseases where this is occurring and we call these diseases “autoimmune”. Common examples of autoimmune diseases include Diabetes, Lupus, Rheumatic Fever, Rheumatoid Arthritis, Psoriasis, Multiple Sclerosis, Hashimoto’s Thyroiditis, Myasthenia Gravis, and possibly Inflammatory Bowel Disease such as Ulcerative Colitis, Crohn’s Disease, etc.

The mechanism common to all these diseases is antibodies formed against your own normal, healthy tissue. Depending upon which antibodies are formed, various tissues will be attacked and, therefore, the type of disease and the symptoms it produces will vary greatly. However, the basic underlying mechanism appears to be the same.

Our body is held together with connective tissue and the principal connective tissue is collagen. When the autoimmune disease affects the connective tissue predominantly, blood vessels are also affected. We call these diseases “collagen vascular diseases”. Although certain types of autoimmune diseases such as juvenile onset diabetes appear to affect men and women equally, the collagen vascular diseases have a definite predilection for women. Lupus occurs nine times more frequently in women, most rheumatoid arthritis occurs in women, etc.

A very common problem in women who have various collagen vascular diseases is the formation of blood clots in the smaller blood vessels of the body. I currently believe that this is the mechanism whereby women who have abnormalities in their immune system are predisposed to pregnancy losses. I believe that blood clots form in the lining of the uterus under the placenta and interfere with the blood supply to the developing fetus. This interference with the blood supply then either kills the pregnancy or affects its ability to develop.

Women who have these types of autoimmune problems show different patterns of pregnancy wastage. Very commonly, these women have repetitive first trimester spontaneous abortions. The woman becomes pregnant but the pregnancy is lost by the time she gets to be 6 or 8 weeks pregnant. However, in other women, the pregnancy will survive but because of impaired blood flow to the placenta, the baby will not develop properly. The baby is not getting proper nourishment; this is termed “intrauterine growth retardation”. In other situations, the baby may die in the uterus later in pregnancy. However, we now recognize that these are all parts of the same underlying problem.

We believe that because these women have an autoimmune disorder, the blood clots form under the placenta and affect the growth and development of the pregnancy. The treatment then is to prevent these blood clots from forming and for this, I use small doses of aspirin which is a well recognized anti-coagulant.

One question I am frequently asked is why only a small dose of aspirin (a baby aspirin = 80 mg.). The reason is that the body has a defense mechanism for everything it does. To help your blood clot in the case of an injury, you have a coagulation system. To get rid of the clots or to prevent clots from forming abnormally, the body also has a very efficient anti-coagulation system. I want to prevent the clots from forming but I don’t want to eliminate the anti-coagulation system as well. It turns out that a small dose of aspirin will prevent the formation of the clots but will not affect the anti-coagulant system that is present in the walls of the blood vessels and it is this reason that the 80 mg. dose of aspirin is used.

Another common question I am asked is “if my test for the Lupus anti-coagulant is positive, why are you giving me an anti-coagulant in the form of aspirin?” The reason is that the problem is the presence of substances that make the blood clot. The term Lupus anti-coagulant is an unfortunate misnomer. The tests behave as if there were an anti-coagulant present but it is an artifact of the test - the problem really is an enhancement of the coagulation system and, therefore, an anti-coagulant must be used in therapy.

When women start to realize that they have a disorder of their immune system and they are also aware that other disease such as Lupus or rheumatoid arthritis also represent disorders of the immune system, increased anxiety immediately results. Everyone begins to worry that some horrible disease will occur later in life. Furthermore, when these women hear the term “Lupus”, they immediately assume that they either have the disease or that they will develop it at some future time.

At this time, the evidence suggests that for women with this problem, pregnancy wastage is the principal clinical manifestation of this type of underlying autoimmune problem. In other words, there does not appear to be any evidence that women who have this problem affecting their ability to have a baby will develop some other autoimmune disease later in life. However, this is still a new and relatively poorly understood phenomenon and all the data is not yet in.

Once tests have established that a woman has one of these autoimmune disorders, treatment with one baby aspirin a day is instituted. This treatment is maintained throughout the pregnancy until the woman reaches term. In fact, there is some evidence that the woman should keep on taking the baby aspirin even after she as delivered since this is a time of great risk for the formation of blood clots.

I am well aware of information that tells women not to take aspirin when they are pregnant. Without getting into a whole long discussion, there are several important points to keep in mind. First, I am not totally convinced that that prohibition is reasonable. Some of it is based more on theoretical grounds than on any actual clinical information. Secondly, they are talking about the routine use of aspirin in women who have no other problems. Here the aspirin is being used as a very definite medication for a very definite problem and, therefore, those other warnings do not apply. Lastly, the 80 mg. dose is far less than most women would take for a headache.

A woman who is receiving the baby aspirin therapy is then monitored very carefully throughout her pregnancy, principally by ultrasound. Ultrasound determinations throughout the pregnancy carefully assess the growth and development of the baby. If there is any evidence of intrauterine growth retardation, or if there is any evidence that the placenta is not receiving an adequate blood supply, additional therapies (usually heparin) can then be instituted. Using this approach, success rates of 80% have been reported.

The other drug that is often used to prevent blood clots is heparin. Some physicians favor the use of heparin over aspirin and others use both. It is not yet a fully resolved issue. Since most reports indicate a good result with aspirin, I still favor this drug as the initial therapy. Heparin (which must be given by injection twice a day) can always be initiated if the aspirin alone does not seem to be doing job properly.

Another problem I see arising is the indiscriminate use of anti-coagulant therapy in women with a history of miscarriage, much like we saw many years ago with DES. These drugs do have some risk and it is important to make sure there is a valid indication for their use. Women who have a documented anti-phospholipid syndrome with a history of pregnancy losses are candidates for these therapies. Women who repeated pregnancy losses are due to something else should not be treated with anti-coagulant therapy. Similarly, women who may test “positive” for the anti-phospholipid syndrome with abnormal blood tests but who do not have a history of pregnancy loss should also not be treated.

The real problem with this whole discussion is the controversy as to whether the anti-phospholipid syndrome really plays a role in recurrent abortion and whether aspirin therapy makes a difference. The medical literature is very divided. More recent data suggests that the anti-phospholipid syndrome is important in cases of Intra-Uterine Growth Retardation and “unexplained” fetal deaths but is not important in early pregnancy loss. This is an area of infertility that is still being hotly debated and the final answer is not in.

There is another area concerning immune problems and pregnancy loss that has received a great deal of press recently that I want to discuss. It involves couples where the problem is supposed to be that the man and woman are too similar to each other immunologically. Treatment consists of giving the woman injections of the man’s white blood cells to boost her immune response to a new pregnancy. Failure of the woman’s immune system to respond properly is supposed to be the reason for the repeated pregnancy losses.

This is a very controversial area of Reproductive Medicine. The theory has never been proven, the therapy has never been proven, and the long term consequences are unknown. An article in the journal “Human Reproduction” several years ago discussed this treatment and concluded that never in the history of medicine has a treatment with so little proof as to its effectiveness come into such wide use.

However, to be fair, there is some evidence that in women with recurrent abortion who have no evidence of any other cause and who have no evidence of auto-immune disease may show improved pregnancy rates using their husband’s white blood cells. More studies are needed.

An alternative therapy involves the use of high dose steroids (prednisone) to suppress the immune system. This therapy does appear to be of value in women where an abnormality can be proven.

In summary then, it is now becoming increasingly apparent that women with defects in their immune system ( by the formation of blood clots in the small vessels of the uterus ) may suffer pregnancy wastage either in the form of repeated spontaneous abortions, growth retardation or unexplained intrauterine fetal death. As I become increasingly aware of these problems and understand how to diagnose them properly, I am in a position to detect these abnormalities before they cause a problem with the pregnancy. The treatment is relatively simple and relatively risk free. With proper detection and therapy, it is now possible to offer women with these problems an excellent chance of a successful pregnancy with a live, healthy baby at the end.

Another therapy which is receiving a great deal of publicity recently is the use of Intra-Venous Immune Globulin (IVIG). This is very controversial, very much unproved, very expensive, and potentially dangerous. It takes about 150 pints of donated blood to make one dose of IVIG and the cost of processing the product is around $15,000. With that much blood involved, the risk of AIDS becomes a real possibility. I mention it here only to decry its use.

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