Recurrent Miscarriage

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Carl A. Laskin, MD, FRCPC
Summer 2008

At least 15% of all pregnancies will miscarry. A study performed several years ago indicated that miscarriage may actually affect a third of all pregnancies. These losses usually occur very early in the pregnancy, and indeed, many women are unaware that they are even pregnant at the time of the loss. Regardless of the timing, before a pregnancy loss can be diagnosed, appropriate laboratory testing must be undertaken to confirm that the woman was actually pregnant, as being late for a period is not sufficient evidence that a miscarriage has occurred. Pregnancy must be confirmed by a blood test, so that if a pregnancy loss occurs, an accurate history can be documented and appropriate investigations undertaken. Losses later in pregnancy are a different matter, as the diagnosis of pregnancy is not in doubt and the cause of a late loss is likely very different from that of an early pregnancy loss.

In this article, I will discuss the problem of early recurrent pregnancy loss or miscarriage, review the possible reasons for the losses, and summarize the investigations and approaches to management. Before proceeding, it is important for anyone with the problem of recurrent miscarriage to appreciate that every patient is different. It would be inappropriate to draw conclusions regarding your specific case after reading this article: I strongly recommend discussing your situation with your physician.

Early pregnancy loss

After fertilization, the start of a pregnancy is the implantation of the embryo within the wall of the womb or uterus. The fetal heart can be seen on ultrasound between 4 and 6 weeks of pregnancy as the embryo continues to develop. The placenta develops during the first trimester, and is fully functional by the end of that time. Most pregnancy losses occur during the first trimester and may be due to a problem at any one of these stages of development.

Chemical Pregnancy.

This is the earliest form of pregnancy loss. Although fertilization may have taken place, the pregnancy does not proceed, as there was likely an abnormality within the fertilized egg. Unless a pregnancy test was performed, the woman may be unaware that she was even pregnant.

Embryonic Loss.

After fertilization and maturation, implantation must occur. The embryo or blastocyst must actually dig into or invade the wall of the uterus. To maintain the pregnancy, the blastocyst must be genetically normal and the implantation site must have an adequate blood supply. Genetic abnormalities can occur at any time during the growth of the embryo up to and beyond the blastocyst phase. Accidents in cell division may lead to genetic abnormalities that are incompatible with life. Under these circumstances, the pregnancy terminates. Embryonic losses are the most common type of pregnancy loss. The incidence of these genetic losses increases with maternal age owing to a breakdown in genetic material within the woman’s egg. Hence the older a woman becomes, the more likely it is that she will have an early pregnancy loss. Of course, genetic losses may also occur owing to a genetic abnormality in either the male or female partner. Some of these abnormalities are incompatible with life, and lead to a miscarriage. Some will be associated with a genetic disorder in the baby, while others may be harmless.

The establishment of an adequate blood supply at the implantation site in the wall of the uterus is critical. Implantations can take place anywhere in the uterus, including, unfortunately, locations with limited blood supply. This can occur in a uterus with an anatomical abnormality such as a septum. A septum is a piece of uterine tissue with a limited blood supply that hangs down from the top of the uterus. It is like a piece of scar tissue that has been present in the woman from the time of her own birth. If the embryo implants in a septum, it will continue to grow until it outgrows the blood supply contained within the septal tissue. At that point the pregnancy will miscarry.

Hormonal loss.

Implantation requires an appropriate hormonal environment.  Adequate amounts of progesterone must be produced after ovulation in the luteal  phase of the menstrual cycle. Failure to produce sufficient progesterone can  result in an early pregnancy loss.

Investigation of early pregnancy loss

Based upon the above discussion, a strategy for investigation of recurrent pregnancy loss can be devised. The first question, however, is when should investigations begin? There is some debate as to whether investigations should be initiated after three or only two early pregnancy losses. Although many obstetricians do not advise any investigation before three pregnancy losses, the American College of Obstetricians and Gynecologists has now recommended that women with two or more consecutive early pregnancy losses should be evaluated. The controversy exists because of the strong probability of a successful pregnancy after two losses with no intervention. Many physicians, however, believe that intervention is justified after two losses and that investigations should be undertaken.

In 1987 our group established the TERM Programme (Treatment and Evaluation of Recurrent Miscarriage). Our position on the above controversy is that investigation is warranted after two consecutive early pregnancy losses.

Evaluation of a woman with recurrent pregnancy loss should initially be along conventional lines, reserving any experimental studies for situations where no cause can be found. The first series of investigations addresses the possible causes discussed above: anatomical, genetic, and hormonal causes of recurrent miscarriage must be ruled out.

Anatomical Evaluation.

An ultrasound or x-ray assesses the uterine cavity for anatomical abnormalities within the uterus such as a septum, abnormal shape, polyp, or an impinging fibroid which alters the shape of the uterus. In addition these may also help detect a bicornuate uterus where the uterus is essentially divided into two separate horns. This latter abnormality is more often associated with later pregnancy losses. Newer techniques such as 3D ultrasound are becoming increasingly helpful in identifying anatomical abnormalities. Once the abnormality has been detected, the woman must then be evaluated to determine if it can be corrected surgically.

Genetic Investigations.

A genetic abnormality may occur in the embryo during cell division. This common cause of early pregnancy loss is best determined through an examination of the tissue from the miscarried pregnancy. Unfortunately this is often not possible, as the tissue must contain live cells. Fresh tissue must be collected in a sterile container and taken to the lab immediately. The timing of the collection and the absence of contamination makes this part of the investigation difficult, which is why we often cannot establish a genetic cause for the loss. Nonetheless, where possible, it is very helpful to attempt to collect the tissue for a possible genetic diagnosis.

A genetic abnormality can also arise if one or both of the parents have a chromosomal abnormality. This is detected by performing an analysis on both partners. This blood test may detect abnormalities that can lead to miscarriage.

Genetic counseling should be undertaken in anyone found to have a chromosomal defect.

Hormonal Studies.

There is much controversy regarding the occurrence and the significance of hormonal causes of recurrent miscarriage. If the woman’s menstrual cycles are regular, then studies can be undertaken to evaluate hormonal responses. A timed endometrial biopsy from the inner lining of the uterus is the standard investigation. The cells of the endometrium show specific growth patterns at various stages of the menstrual cycle. The biopsy determines if the luteal phase of the cycle is appropriately established under progesterone influence. If not, then it is hypothesized that implantation will be impaired and the pregnancy lost. The problem with this evaluation is that there is often a lack of agreement among pathologists in grading the biopsied tissue. Therefore, the reliability of the diagnosis is frequently called into question. Furthermore, there are many who doubt the significance of a luteal phase defect and who feel that it is not associated with pregnancy loss.

Experimental investigations

Approximately 60% of early miscarriages remain unexplained because results for all of the above investigations are normal. Under these circumstances, it may be appropriate to look for the presence of autoimmune abnormalities or clotting defects. Over the past several years, research has determined that abnormalities in the clotting system are associated with recurrent miscarriage. These abnormalities may be the result of autoantibodies or inherited defects in the clotting system.

Antiphospholipid Antibodies. These are proteins produced by the immune system that are directed against certain normal tissues or biochemical reactions. The antibodies may be harmless or they may interfere with the proper functioning of the clotting system and increase the chance of developing clots in either veins or arteries. In some individuals, excessive clotting in the blood vessels never occurs until they have problems with placental blood flow in a pregnancy. Under these circumstances, the blood supply in the placenta will be interrupted due to clotting and this leads to a decrease in blood flow to the developing fetus. As a result the fetus grows more slowly and is smaller than expected (this is called intrauterine growth restriction) and in severe cases, this may lead to late pregnancy loss. The placenta may also be under-developed and have numerous clots and areas of dead tissue. Antiphospholipid antibodies are difficult to measure and the testing can be unreliable. Once detected, the test should be repeated and confirmed at least eight to twelve weeks later.

Circulating Anticoagulants. These are antibodies that interfere with the clotting system directly. They are measured and confirmed by a panel of tests. Circulating anticoagulants may actually be antiphospholipid antibodies. It is important to look for both antiphospholipid antibodies and the circulating anticoagulant when evaluating recurrent miscarriage as they can occur independently.

Thrombophilias. Thrombophilias are a group of coagulation defects that are usually inherited. Since they are genetic abnormalities, their measurement is reliable in contrast to antiphospholipid antibodies whose levels may fluctuate over time. If a thrombophilia is present, the woman may have had abnormal clotting in the veins of the leg or in an artery (resulting in a stroke) prior to becoming pregnant. It is also possible that the clotting defect only becomes evident during pregnancy, when it causes diminished placental function and eventual pregnancy loss.

Thrombophilias, anti-phospholipid antibodies and circulating anticoagulants may be associated with both early and later pregnancy losses. Initial studies implied that these clotting defects were only seen in later pregnancy losses. More recent studies, however, have supported the view that the abnormalities can be associated with either early or late pregnancy losses.

Experimental Treatments

Much has been published on the treatment of recurrent pregnancy loss in women with antiphospholipid antibodies or a thrombophilia. Such pregnancies may be treated with aspirin with or without additional heparin. This protocol is still experimental although it is used with increasing frequency.

Indications for laboratory testing for antiphospholipid antibodies, circulating anticoagulants, and thrombophilias

Tests for coagulation defects and antibodies should only be undertaken upon completion of a conventional evaluation. It is far easier to draw a tube of blood and test for the presence of the antibody or coagulation defect than it is to perform an endometrial biopsy. However, the conventional tests that detect anatomic, hormonal and genetic abnormalities have stood the test of time in contrast to the coagulation tests that are relatively new and remain experimental. At present the newer tests have no predictive value so there is no rationale for performing a coagulation screen to predict pregnancy outcome. These tests should only be carried out if there is a history of recurrent pregnancy loss.

Summary

Early pregnancy loss continues to be a frustrating problem for both patient and physician because the majority of cases remain unexplained. Appropriate investigations should start with a conventional approach ruling out anatomic, genetic and hormonal causes. If an underlying cause is identified, treatment is directed at correcting the problem before another pregnancy is attempted. If no genetic, anatomic or hormonal abnormalities are detected, experimental investigations for anti-phospholipid antibodies, circulating anticoagulants and thrombophilias should then be undertaken. If one or more of the coagulation or immune abnormalities is present, then the woman may be treated during the next pregnancy using an experimental protocol of aspirin with or without heparin. Both physician and patient must approach the problem of recurrent miscarriage methodically, exercising patience while investigations are underway. The problem may be frustrating, but a haphazard or erratic investigative plan will only add to the frustration and often lead to inappropriate and ineffective treatment.

About the author

Carl Laskin, MD, FRCSC is an expert in Reproductive Immunology and autoimmune diseases in pregnancy and is the Director of Canada’s largest program devoted to the study and treatment of “unexplained,” recurrent miscarriage, the T.E.R.M. Programme at LifeQuest Centre for Reproductive Medicine in Toronto.