Causes of Miscarriage
Unfortunately, miscarriage is a common problem. About half the women in the U.S. will have at least one miscarriage at some point during their reproductive lives. Even worse, about 5% of women will experience two miscarriages and 1% will have three or miscarriages. These women are said to have recurrent miscarriage or recurrent pregnancy loss. Extensive diagnostic testing is performed in couples having recurrent miscarriage but about half the time, no specific underlying cause is found. In this article, we explores some common and uncommon known causes of miscarriage.
- Embryo Chromosomal Abnormalities
- Parental Chromosomal Abnormalities
- Genetic mutations
- Immune Causes of Miscarriage
- Uterine Abnormalities and Miscarriage
- Progesterone Deficiency and Miscarriage
- Environmental Causes of Miscarriage
- Listeria infection and miscarriage
The vast majority of miscarriages are caused by abnormalities in the number of chromosomes contained in the embryo. Human beings normally have 23 pairs of chromosomes (a total of 46) Very often embryos will have too many or too few chromosomes. These abnormalities are called aneuploidies. The older a woman is when she becomes pregnant, the greater the chance for aneuploidy and the greater the risk for miscarriage.
Sometimes, when evaluating a woman for the cause of miscarriages, the physician may attempt to obtain fetal or placental tissue for chromosome analysis. In the past, a procedure called a D&C (Dilation and Curretage) was performed to obtain the fetal tissue. However, a D&C will obtain both the fetal cells (wanted) and the mother’s uterus cells (unwanted). A newer, more accurate method for obtaining fetal cells is to use a hysteroscope to direct the physician to where the fetal cells are. This is called fetoscopy or embryoscopy.
The tissue obtained would be sent to a laboratory which would try to grow the cells in the tissue and then evaluate them for chromosome abnormality. This process is known as karyotyping. Unfortunately, this method had several problems. Sometimes the cells wouldn’t grow so a chromosome analysis couldn’t be performed. In other instances, the chromosome analysis results would be that of a normal female. When this happens, it is impossible to determine if the result is from the fetal cells or the cells of the mother’s uterus. If the mother’s cells get analyzed by mistake, it is called maternal cell contamination or MCC.
More recently, a new type of analysis has begun replacing the standard karyotype. This new analysis to perform a chromosome analysis is called a microarray. Microarrays do not depend on growing cells so a result can be obtained almost 100% of the time. It is also possible to determine whether the results are from the fetus or mother so maternal cell contamination can be ruled out.
When a chromosome analysis is performed, about 70-80% of the miscarriages will be found to have aneuploidy as the cause.
The actual percentage may be even higher. Because of maternal cell contamination, the laboratory can’t tell the difference. When the time comes to evaluate the chromosomes, the result will appear to be results from a female with a normal number of chromosomes. However, it is impossible to determine if this was from the fetus or from the mother.
Many times, doctors or other health professionals will tell a woman that this means the miscarriage was not caused by a chromosomal abnormality. This is incorrect. In fact, when more sophisticated means are used to obtain and analyze the fetal tissue, such as microarray, it has been proven that most of the time when the result reads “normal female” it really is just missing the fetal abnormality and is looking at the mom’s chromosomes instead.
Treatment of miscarriages due to fetal chromosomal abnormalities
There is no treatment that will prevent embryos from having chromosome abnormalities. The older a woman gets, the higher the chances that an embryo will have an abnormal number of chromosomes. This is why women have a higher miscarriage rate as they get older.
However, using a technology known as preimplantation genetic screening also known as PGS or CCS, we can now identify embryos with chromosomal abnormalities during an In vitro Fertilization cycle. By avoiding those embryos that have abnormalities, couples can reduce their risk for a miscarriage caused by chromosomal abnormality.
Otherwise, there is no way to treat a pregnancy that already has been established if the embryo has an abnormal number of chromosomes. This is an extremely important point! If an embryo is abnormal, then no amount of bed rest or progesterone or medications or herbal supplements is going to affect the outcome. Not all embryos with chromosomal abnormalities will miscarry. Some can go on to be live born babies. These babies however, will be born with birth defects such as Down’s syndrome or other syndromes depending on which chromosomes are extra or missing.
Less commonly, the male or female parent may have a different type of abnormality in their own chromosomes that causes miscarriage in a fetus. This type of chromosome abnormality is called a translocation abnormality.
Translocations occur when a portion of two different chromosomes, for example chromosomes number 13 and 21, have “swapped” positions with each other. The result (from our example) is that a little piece of chromosome 13 is now on chromosome 21 and a little piece of 21 is now on chromosome 13.
This can occur in the chromosomes of the egg or the sperm.
When fertilization occurs in these couples, a few different possible outcomes may occur:
- The embryo may be completely normal
- The embryo may end up with a balanced amount of chromosome material and end up like the parent, essentially, a carrier of the problem
- The embryo may end up with an unbalanced amount of chromosomal material. These embryos, like the aneuploidies will be miscarried.
These abnormalities can be detected with a fetal karyotype analysis unless the amount of swapped information is very small. These micro translocations (also called telomeric translocations) will be missed by standard karyotype techniques. It is therefore important for couples who have recurrent miscarriage to undergo a high resolution chromosome analysis to look for very subtle abnormalities.
Maintenance of pregnancy is an extremely complicated process. It is is likely that hundreds of different genes are involved – each one to a small extent. Because of this complexity, it has been difficult to isolate individual genes or gene mutations that are responsible for miscarriage.
Recently, researchers using new bioinformatics techniques, have identified a gene responsible for recurrent miscarriage called FOXD1. They were able to show that women who had certain variants in this gene were ten times more likely to suffer from recurrent miscarriage than those without the variants. FOXD1 acts as a sort of master controller for other genes that are involved in creating the blood vessels necessary to “feed” the placenta oxygen and nutrients and for fine tuning the balance between a mother’s immune system and the placenta. FOXD1 is now referred to as the miscarriage gene.
Testing for FOXD1 is a blood test. There are some ideas for possible treatment but no studies which show benefit yet.
As in the case of embryos with aneuploidies, embryos with unbalanced translocations cannot be fixed. They can be prevented if the affected parent’s gametes (sperm or eggs) are not used. This is an indication for egg donation or sperm donation.
Women can have disorders that make it more like to have problems with blood clotting. Blood clotting can be an important cause of miscarriage since the growth and development of the embryo is highly dependent on obtaining oxygen and nutrients from the mother’s blood supply.
Some of the more common causes for increased blood clotting risk are genetic mutations that a woman is born with. For several years now, we have been performing testing for the presence of these mutations:
- Factor 5 Leiden Mutation
- Factor 2 (Prothrombin) Mutation
- Variants in the Methyl tetra hydrofolate reductase (MTHFR) gene
Thrombophilias can also result from deficiency or excess amounts of the factors in the blood that control the balance between bleeding and clotting. These include:
- Protein C Deficiency
- Protein S Deficiency
- Antithrombin III Deficiency
- Folate Deficiency
- Plasminogen activator inhibitor
Treatment of miscarriage caused by thrombophilias
In some cases, treatment for these problems entails the use of anti-coagulant medications, that is, medications that lower the risk of blood clotting. Unfortunately, there still isn’t a lot of data about the best way to give the medications so you end up with a fair amount of variability from physician to physician. For example, should the medication be started before pregnancy or only after a pregnancy has been diagnosed? How long should the treatment continue? what is the ideal dose? Until further studies are performed, we can only guess as to the correct answers.
Some problems, like hyperhomocysteinemia, may be treated with high dose supplementation of a B vitamin called folic acid. This technique has proven to be successful with other problems caused by hyperhomocysteinemia.
Problems with a woman’s immune system make up a much smaller proportion of the causes of miscarriage. There are several types of problems:
Autoimmune causes of miscarriage
Normally a person’s immune system functions to “fight off” foreign invaders like bacteria and viruses and rid the body of abnormal cells such as cancer. Occasionally, however, the immune system may malfunction causing it to attack and destroy a persons own normal body tissues or cells. In medicine, there are many examples of diseases causes by this autoimmunity: Rheumatoid arthritis, Lupus, and asthma are just a few examples.
Evidence for autoimmunity has been detected as a possible cause of miscarriage. Overall immune problems as a cause for miscarriage are infrequent but autoimmunity makes up the largest proportion of immune mediated miscarriages. Tests performed to detect an autoimmune problem are blood tests that look at the levels of various antibodies. These antibodies are present in all individuals. They are though to represent a problem is the levels are significantly higher than that seen in the general population. It is not known whether these antibodies are directly involved with the loss of the pregnancy or whether they are just a marker for a woman who has an “autoimmune problem”.
The most common type of autoantibodies thought to be involved with miscarriage are known as Anti-phospholipid antibodies:
- Anti-cardiolipin antibodies – There are three subclasses: IgG, IgA and IgM. Unfortunately, many of the “abnormal” results that we get can be falsely positive. For example, the IgG subclass is elevated in 6.5% of general population and in 10.6% of women with completely normal pregnancies. The IgM subclass is elevated in 9.4% of the general population and 17% of women with completely normal pregnancies. To further complicate matters, the levels of these antibodies can fluctuate and so it is recommended that a positive test be repeated in six weeks to determine if the elevated antibody levels are persistent.
- Lupus anticoagulants – These are a group of antibodies that are commonly identified in individuals with the disease Lupus. Many women can have evidence for the presence of lupus anticoagulants without actually having the full blown disease. Accurate measurement of this group of antibodies is difficult since there is no direct test. Typically, a woman first has a screening test. The test is based on the fact that when lupus anticoagulants are present, a standard test to look at blood clotting activity called aPTT (activated partial thromboplastin time) becomes abnormal. However, this screening test alone is inadequate to establish the presence of a lupus anticoagulant because many affected patients, especially pregnant women, have normal aPTT’s and sometimes women with an abnormal test have a different type of problem. Thus, additional tests are needed both to establish and exclude the presence of a lupus anticoagulant. Other tests that aid in the recognition and confirmation of lupus anticoagulants include tests for the dilute Russell viper venom time (dRVVT, the hexagonal lipid neutralization test, and testing for alpha-2 glycoprotein I.
Treatment of miscarriages caused by anti-phospholipid antibodies: Anticoagulation
As in the case with thrombophilias, women with recurrent miscarriage and evidence for anti phospholipid antibodies are treated with anticoagulant medications such as Lovenox and baby aspirin. There are two theories as to why this might work.
There is some evidence that anti phospholipid antibodies increase blood clotting risk. Anticoagulants decrease blood clotting risk. Other data point to the possibility that anti-phospholipid antibodies actually interfere with the cells of the developing placenta known as trophoblastic cells. Medications like Lovenox may prevent the antibodies from interfering.
Another type of autoantibody that may be a cause for miscarriage are antibodies which attack the thyroid gland. These are known as anti-thyroid antibodies. Little is known about this class of antibodies. Several studies have suggested that elevated levels are associated with a higher risk of miscarriage. Treatment with thyroid hormone (Synthroid) has been suggested as a way to reduce the risk.
Alloimmune causes of miscarriage
It was once thought that some causes of miscarriage could be explained by immunologic “rejection” of the fetus as an allograft. An allograft is when an organ or tissue is transplanted from one individual to another of the same species. If you think about it, an embryo is part allograft since it contains material (called antigens) that comes from the father and is thus foreign to the mother. It is thought that the mother must have the ability to suppress her immune system so it will not automatically reject this “transplant” as foreign. This is called immune tolerance. If the mother fails to achieve immune tolerance then the fetus will be rejected (aborted). It was thought that immune tolerance was brought about by the mother first recognizing the foreign father’s antigens, then producing “blocking antibodies” which would “coat” the fetal cells and protect them from damage from the mother’s immune “killer” cells.
Treatment of miscarriages due to Alloimmune factors: Paternal Leukocyte Immunization
In the past, a few researchers thought that injecting white blood cells from the father would make it easier for the mother to produce blocking antibodies and reduce the risk of miscarriage. This treatment became known as Paternal Leukocyte Immunization. Unfortunately, we now know that this treatment does not work and in some cases, actually increases the risk for miscarriage. Because it was ineffective and due to safety concerns, in the United States, this therapy was halted by the Food and Drug Administration.
Nonspecific immune causes of miscarriage
In addition to antibodies, the immune system is composed of more than 30 types of white blood cells. A few of these cells have been studied to determine their role in causing miscarriage. They include T lymphocytes and natural killer (NK) cells. The cells can be differentiated by the presence or absence of specific markers on the surface of the cells. These markers are written as abbreviations followed by a (+) or (-) to indicate their presence or absence.
For example, there is a special class of Natural killer (NK) cells (CD3-, CD16-, CD56+).
Natural killer (NK) cells are the main type of lymphocyte in the uterine lining at the time of implantation and during early pregnancy. Uterine NK cells are different from those circulating in peripheral blood. The function of uterine NK cells in pregnancy is still largely unknown. Tests to measure NK cells in the blood may not give useful information on uterine NK cells. Use of powerful therapies to reduce levels of NK cells in women with infertility or recurrent miscarriage is unjustified and is associated with known side effects to mother and fetus.
A woman can be born with or develop abnormalities of her uterus. Some of these abnormalities have been strongly associated with an increased risk of miscarriage. Others have only weak evidence associating them with miscarriage.
Congenital abnormalities (problems a woman is born with):
- Uterine septum
- Bicornuate uterus
- Unicornuate uterus
- Uterus didelphus
- Various combinations of the above
- Intrauterine adhesions (Asherman’s syndrome)
- Uterine fibroids
- Uterine polyps
- Uterine infections
Treatment of miscarriages due to uterine abnormalities
Treatment of uterine abnormalities is usually surgical. When possible, hysteroscopy is used. Hysteroscopy is the passage of a fiberoptic telescope into the uterine cavity. Through operative channels in the telescope, instruments can be introduced to allow the surgeon to cut, vaporize or remove abnormalities.
In some cases, however, surgical repair must be performed through an open surgery going through the abdominal wall.
After ovulation, the ovaries produce large amounts of the hormone progesterone. Progesterone has an important role. It prepares the uterine lining for implantation of the embryo and maintains the uterine lining afterward. In experiments in primates, if the ovaries are removed soon after the establishment of a pregnancy, it will lead to miscarriage. This forms the basis of the presumption that progesterone production by the ovaries is important for the maintenance of the pregnancy and prevention of miscarriage.
Progesterone levels are difficult to measure accurately, however. There have never been any studies that have been able to accurately correlate progesterone levels with miscarriage risk. Most physicians believe that progesterone supplementation is low in risk so it is often given to women as a treatment to prevent miscarriage. In reality, it may be of limited benefit.
Environmental causes of miscarriage
Several factors have been associated with an increased risk of miscarriage. Tobacco, alcohol and caffeine use by a woman or even her partner increase miscarriage risk. Several herbal remedies can also trigger an abortion. Mercury in the diet, mostly from certain types of seafood, have been associated with miscarriage and birth defects. Even chlorine compounds in the drinking water are thought to play a role.