The older definition of repeated pregnancy loss (RPL), or what some call habitual abortion (HAB), was three or more pregnancy losses in the first trimester. At Arizona Center for Fertility Studies, we think that this is absurd, and feel strongly that no woman should have to go through more than two pregnancy losses before having a complete evaluation to determine the cause. Unfortunately, far too often, the best advice for women with repeated pregnancy loss is "to keep trying". At Arizona Center for Fertility Studies, we do not know a single woman who wants this advice. The loss of a baby, no matter how early in the pregnancy, is, on some level, the loss of a child; and thus, has all the emotional and physical feelings associated with it. Repeated pregnancy losses only compounds these feelings and can lead to increasing stress, anger, frustration, a feeling of loneliness and despair, emptiness and a feeling of a lack of self-worth and failure. You can "not count on luck" that the next pregnancy will be okay when there is a sophisticated work-up and successful treatments available.
One in every five pregnancies will result in pregnancy loss. Although, the odds of losing a pregnancy are 20% with each additional attempt, the chances of losing two or more pregnancies in a row drops to 5%; and, that is the group of woman that should be evaluated for repeated pregnancy loss. The evaluation should be complete and involve the following four categories:
Chromosome testing would include testing both partners to see if they are carriers for the same lethal chromosome abnormality that would result in repeated miscarriages. The chance that both partners are carriers for the same chromosome abnormality is low at 2-6%. Although most clinics will recommend chromosome testing as part of the work-up; since the yield is so low of finding anything and the tests cost about $600-800 for each partner, Arizona Center for Fertility Studies recommends that rather than testing the parents, that on the 2nd loss, to test the products of conception by doing a in-office D&C. That has two advantages. It will tell you the chromosome make-up of the pregnancy, letting you know if the chromosomes were normal or not; and if abnormal, whether it was due to a spontaneous chromosome abnormality that was incompatible with life or due to an abnormal carrier state of the parents. This is very important because recommending a work-up for RPL is based on having two or more pregnancy losses that cannot be explained. Since up to 20% of woman can lose a pregnancy, if the 2nd loss is due to a spontaneous chromosome abnormality, then you only have one loss that cannot be explained and generally a work-up and treatment is not recommended. If the 2nd loss showed that the chromosomes were normal, then a complete work-up should be initiated. It is important to know that 60-70% of all pregnancy loss is due to a spontaneous chromosome abnormality, not a carrier state, that is incompatible with life and is a random event that cannot be prevented under normal circumstances. Because of this fact, Arizona Center for Fertility Studies does not recommend doing chromosome testing on the first miscarriage unless the couple wants to know the reason why the pregnancy was lost, even though they understand that 60-70% of the time it will be due to a spontaneous chromosome abnormality and not a carrier state of the parents. However, if this is your 2nd loss, then Arizona Center for Fertility Studies feels strongly that you should be given the option of doing chromosome testing on the products of conception (POC) because the results can be very helpful in giving the couple an explanation of why they may have lost the pregnancy and whether or not a work-up should be started or should they just try again.
If there are 2 or more miscarriages due to the same or different spontaneous chromosome abnormalities, then the options would include continuing to attempt pregnancy, "hoping" that the next one will be normal, consider the use of donor eggs, or doing IVF (In-Vitro Fertilization) with PGD/PGS to determine the chromosome make-up of each embryo and only transferring the normal ones.
Alloimmune testing would do histocompatibility testing to see if the couple's genetic molecular make-up was similar. Normally, when a woman conceives, the pregnancy is recognized as a foreign object in her body and the immune system makes antibodies against the pregnancy to attempt to destroy it. This is very similar to what happens if bacteria or a virus invades the body. This is a needed mechanism to occur to fight off infection but not very practical when trying to get pregnant. However, in the case of a pregnancy, the immune system has the unique ability to make a second set of antibodies, known as blocking antibodies, that "sit" on the pregnancy sites and protect it from the first set of antibodies that would normally attack and destroy the pregnancy. The ability of the immune system to make these blocking antibodies is triggered by the fact that the pregnancy is different "than oneself" because it has different genetic material from the father. On the other hand, if the parents are genetically similar or histocompatible, than the immune system will not recognize the pregnancy as different than oneself and not make the blocking antibodies, thus, allowing the first set of antibodies to attack and destroy the pregnancy.
This was a very common theory in the 1990's and the treatment was to do immune therapy. In this process you would get your partner's white blood cells by drawing his blood and separating out the white blood cells and injecting a large dose of them into the woman. Since the couple were not identical, just histocompatible, the woman's system would recognize the large dose of white cells as different than oneself and trigger the immune system to make the blocking antibodies that would subsequently protect the next pregnancy from miscarrying. In theory, this made a lot of sense and numerous couples with a history of repeated pregnancy loss did immune therapy. However, after about 7-8 years, when the data was looked at, immune therapy was shown not to make a statistical difference in improving pregnancy outcomes for these couples; and hence, the testing and treatment is no longer recommended. Although, there are a few clinics that still advocate this treatment, it is no longer the standard of care for repeated pregnancy loss, and Arizona Center for Fertility Studies does not recommend it. Similar data showed that intravenous gammaglobulin (IVIG) showed no statistical improvement in preventing pregnancy loss and is also not recommended by Arizona Center for Fertility Studies.
Autoimmune testing is evaluating the woman to see if she is making microclots, by a number of different mechanisms, that can interfere with the blood flow to the early pregnancy and subsequently cause a miscarriage. Once all the other causes of pregnancy loss have been ruled out, this is the most common thinking for the etiology of repeated pregnancy loss. Testing would include anything that could trigger the women's own system to increase micro-damage and microclotting. The most common mechanism is that antibodies are made against the blood vessel walls and damage the walls. Once a blood vessel wall is damaged, platelets that are floating around in the blood stream, come out of solution and because of their inherent stickiness, stick to the area of damage and begin the healing process. Once platelets are out of solution, they trigger the clotting factors to come out of solution, thus forming a clot that attaches to the injured blood vessel wall and continues the healing process. These micro-injuries and micro-clots to the blood vessel walls are of no consequence to the major blood vessels of the body; but, in the smaller tiny blood vessels of an early developing pregnancy, they can block off blood flow to the early pregnancy and cause a woman to lose the pregnancy between ovulation and her period; or between 6-8 weeks, when there is an increased demand for blood flow to carry nutrients to the baby.
Testing would include antiphospholipid antibodies which are antibodies against the fatty portion of the blood vessel wall that can attack the wall and trigger the micro-damage and micro-clotting as part of the healing process; fasting homocysteine levels, an amino acid found in the blood, that if elevated, can also increase the risk of micro-clotting (and is treated with high doses of folic acid); prothrombin and Protein S and C deficiency that can also increase micro-clotting, normally these proteins are natural inhibitors of clotting but with a deficiency can increase the clotting cascade leading to a increase in the formation of micro-clots; and Factor V Leiden mutation, causing activated protein C (APC) which prevents clots from growing too large, to be unable to inactivate one of the important clotting factors, factor V, normally, resulting in increase risks of micro-clots.
Treatment of this category is aimed at prevention of the micro-damage and micro-clotting. This includes the use of low dose prednisone to decrease the antibody response against the blood vessel wall and to decrease or avoid damage to the wall, baby aspirin to decrease the stickiness of the platelets and low dose heparin to stop the clotting mechanism from making a micro-clot. All of these medications must be started before the woman conceives. Therefore, Arizona Center for Fertility Studies recommends that a couple use some means of birth control until the entire work-up is completed and treatment is started. Starting treatment after the fact, when a woman learns she is pregnant, is of little to no value. By the time most woman find out they are pregnant, they are already 3-4 weeks along and the micro-damage and micro-clotting has already occurred.
Non-immune testing would include everything that is not related to the above three categories and consists of the following tests: sonohysterogram to rule out any uterine pathology, like polyps or fibroids which can increase the risk of pregnancy loss; prolactin and thyroid levels, that if elevated, are associated with pregnancy loss, endometrial biopsy to make sure that the lining of the uterus is prepared properly for implantation and is supportive of an ongoing pregnancy; semen analysis to rule out white cells or bacteria in the semen that have also been associated with increase pregnancy loss; general cervical cultures; mycoplasma culture, a less commonly recognized bacteria that can bind with the embryo causing a mycoplasma-embryo complex that white blood cells attack leading to an increase chance of miscarriage; and antisperm antibodies, where antibodies against the paternal contribution to the embryo attack the early pregnancy and lead to an increase risk of pregnancy loss.
As you can see, there is a sophisticated work-up for pregnancy loss, that in the majority of the cases, will identify the cause(s) of why a woman is continuing to lose her pregnancies. Treatment is also very sophisticated and is aimed at correcting any of the non-immune problems; and if they are all normal, then treating the autoimmune problems with low dose prednisone, low dose heparin and baby aspirin. Complications from low dose prednisone are rare and the dose of heparin is so low that it will not change normal bleeding times. These are carefully monitored throughout the treatment regimen with bleeding times which are kept in the normal range; and, if you were to cut yourself, you would clot and stop bleeding in the normal fashion. The low dose heparin, injected right under our skin, only interferes with clotting at a microscopic level. All medications are started prior to attempting pregnancy and continued until the end of the 12th week of pregnancy when the pregnancy blood vessels are large enough and are not affected by the micro-clotting. At that point, heparin is discontinued, you taper off prednisone over the next three weeks and baby aspirin is continued until 34 weeks of pregnancy. None of these medications have any adverse risks to the pregnancy or the baby.
Also, at Arizona Center for Fertility Studies, we have found additional benefits to reducing the risks of pregnancy loss by adding 200 mg of natural progesterone, in the form of sub-lingual lozenges twice a day; and, the use of low dose injectable fertility medication, mainly human menopausal gonadotrophin (HMG). It has been our continued experience that HMG may "make better eggs", a "better hormonal environment for pregnancy to occur in" or "treat something that we do not know how to test for in 2009"; and, therefore, always include them as part of our protocol for repeated pregnancy loss; along with the prednisone, heparin and baby aspirin. What Arizona Center for Fertility Studies calls its 5-arm treatment protocol for repeated pregnancy loss. Clomid, on the other hand, is never used and may even be detrimental and increase the risk of pregnancy loss by interfering with the lining of the uterus. Even if the entire work-up is normal and nothing can be identified as to the cause of pregnancy loss, the couple is still given the option to do the complete treatment protocol of baby aspirin, prednisone, heparin, progesterone and HMG. Arizona Center for Fertility Studies believes that the autoimmune tests may come "in" and "out" of the normal range and thus random testing may overlook an abnormal value. By being proactive rather than reactive and doing the full treatment protocol, it will statistically improve your outcome. The statistics at Arizona Center for Fertility Studies show a significant improvement in pregnancy loss when the above protocol is implemented prior to conceiving and followed through the 12th week of pregnancy. It is our strong recommendation, that if a couple has lost 2 or more pregnancies in the first trimester, that they use some means of birth control until the complete work-up is finished and treatment is started. By not doing this, one cannot expect the outcome to be different.
As a last option, donor eggs or a gestational carrier can be considered. Interestingly, the more genetically different the embryo is to the uterus the greater the chances that you will not miscarry. Just the opposite of what you would think. These are viable choices that have to be considered when everything else has been unsuccessful including continued loss in the face of correcting anything that is found to be wrong and use of the 5-arm treatment protocol.
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