$5000

Recurrent Miscarriage

Recurrent Miscarriage or Recurrent Pregnancy Loss

Of all the problems we confront, both as physicians as well as patients, RPL is arguably the most troubling, frustrating and confusing to address. Firstly, there are many causes of RPL and it is not always easy to identify the specific cause of the problem. Next, the definition of the problem (Le. two or more pregnancy losses), itself creates problems for the patient. It is as if the first and second miscarriages do not count and the patient should not be taken seriously until she (and her partner), have suffered two or more losses. Anyone who has had to deal with this problem, knows how emotionally devastating the loss of a desired pregnancy can be. Therefore, to be told that you do not have a problem until you have suffered two or more losses, can be quite overwhelming. This is not to imply that an expensive "mega work-up" has to be initiated with the first loss. However, the history should be taken to try to determine if there may be cause for concern and it is my opinion that an initial treatment strategy should be contemplated even after the first unwanted miscarriage.

Causes of Pregnancy Loss:

There are many possible causes of this problem. In order to effectively treat this condition, every effort should be made to try to identify the specific etiology. That said, in about 40%+ of cases, even after the work - up, the specific cause cannot be pinpointed. The following is a clinical approach and I shall discuss the causes, in this section:

a) Chromosomal: Approximately 50 %of miscarriages occur due to chromosomal defects.
Chromosomally healthy individuals have 46 chromosomes -- 22 pairs of autosomes and
1 pair of sex chromosomes (XX =female; XV =male). This chromosomal make-up results from meiotic divisions in both the sperm and egg, such that under normal circumstances, the egg and sperm, each containing 23 chromosomes (haploid), and will unite to form a single organism, with 46 chromosomes (diploid). Therefore, any errors in cell division, so called non-disjunction errors, can result in an egg with for example 24 chromosomes, rather than 23. Therefore, when a sperm enters, the 23 chromosomes contained therein, result in a new organism, which now contains 47 chromosomes, rather than 46. This embryo will be far less likely to come to term and the result will be a miscarriage, on the basis of a chromosomal abnormality. Now, there are NUMEROUS different chromosomal abnormalities and to cover all of them is beyond the scope of this piece. Suffice it to say, however, chromosomal abnormalities are a frequent cause of miscarriage. There are several different ways to approach such a problem. The first is to take a family history to determine if there are any family members who may have a chromosomal abnormality, such as Down's syndrome (trisomy 21), or Turner's syndrome (45 XO). If it is determined that there is a strong family history of chromosomal problems, the services of a trained genetic counselor should be used, to develop a family tree to identify these problems with greater clarity and therefore, help to counsel the patients.A Karyotype is frequently ordered in the work-up of patients with RPL. This would be a blood test on both the female and male partners. This will provide information on their genetic make-up. A normal make has a 46XY chromosomal pattern and the female has a 46 XX pattern. Any deviation from this, represents an abnormality and a possible explanation for the miscarriages. The problem with Karyotype analyses, is that the test is rather expensive, is low yield (not very likely to show problems) and will miss so-called point mutations (small genetic defects within the structure of the chromosome, which may be incompatible with life). However, it remains an important screening test that should be undertaken relatively early in the work-up.The Karyotype may identify translocation disorders (where a piece of one chromosome is not located at the site it is supposed to be), or inversion problems (a segment of the chromosome is turned upside down). When this occurs, the person may be completely normal because there is balance and the abnormality is balanced by another chromosome, thereby cancelling the defect. However, when passed on to the offspring, imbalance occurs and this will inevitably result in a miscarriage. This diagnosis is important because using IVF with PGD (pre-implantation genetic diagnosis), the defect can be diagnosed and only those embryos that are normal will be replaced.Another reason to perform a karyotype analysis in the context of RPL, relates to male patients with severe oligospermia (very low sperm count). Not infrequently, these patients may be found to have a Ychromosome microdeletion defects. Depending on what the defect is determined to be, it may be necessary to use donor sperm. The key issue is that even if it is not possible to correct the problem, helping the couple to understand their situation, can go a long way to helping them through this most difficult time in their lives.

b) Structural Anomalies:
The embryological development of the vagina and uterus is quite complex. It involves the fusion of two hollow tube like structures in the midline. These "tubes" come together and then there is a recession of the segment in the midline that connects the structures. Any defect in this process can result in a variety of midline fusion defects.Examples of this include a uterine septum or a complete double system (uterine didelphys). The central piece invariably has a very poor blood supply. Therefore, if the embryo implants upon this area, or immediately adjacent to it, it is likely to miscarry relatively early on.Fibroid tumors are another example of a structural lesion which can distort the uterine cavity and architecture. Here again, the blood flow dynamics can be significantly impeded and implantation of the embryo upon or immediately adjacent to these lesions, can be suboptimal and result in an early miscarriage.Other examples of structural abnormalities within the uterine cavity include polyps, adhesions (Asherman's syndrome - due to prior surgeries or infection). In all cases of suspected structural anomalies, the defects are identified by one of several uterine imaging techniques. These include hysterosalpingogram, hysteroscopy, fluid ultrasound or MRI with contrast. Each has advantages and disadvantages. The best is arguably a hysteroscopy because it allows direct visualization, as well as the ability to treat any lesions then and there. Surgical correction of the uterine cavity should not be undertaken lightly because the surgery itself can cause scar tissue formation. Therefore, the benefits of the procedure should outweigh the risks of the procedure.Hysteroscopic procedures can be quite effective at restoring normal or near normal anatomy of the uterine cavity. In cases of extremely severe structural abnormalities, not amenable to surgical correction, the option of gestational surrogacy can be discussed with the patient.

c} Immunological:
This is a very complex but important cause of RPL. While a complete summary of immune is beyond the scope of this piece, consider the following concept. Take a kidney or heart from any individual and transplant it into another person. There is a strong (even overwhelming) likelihood that the transplanted organ will not survive the transplant, because the host's immune system recognizes the tissue as foreign and rejection occurs. {This is the reason that patients who receive transplants, are treated with relatively high dose steroids, so as to diminish rejection and give greater chances for the transplanted tissue to survive}. Now consider this within the context of reproduction. In this instance, we are not talking about a single transplanted organ, but instead an entire organism. Such an organism, generates from an individual (partner or husband), who is quite different to the host. It therefore should not be surprising that the host's immune system would mount a rejection type of chemical reaction in an effort to reject the embryo. The immediate question that should arise is "how do any of us come to exist if this is the case?” The answer to this question lies in a concept we refer to as tolerance. Immediately upon initiating a pregnancy, through a series of highly complex chemical/immune reactions, i.e. through a chemical dialogue, the host's immune system is "taking surveillance" of the embryo and making a decision whether or not to accept/tolerate this foreign tissue and allow implantation to take place.Hopefully the embryo and the mother's immune system will reach a "negotiated settlement", tolerance will occur and successful implantation will take place. However, in a relatively significant group of patients who present with RPL, these aforementioned mechanisms do not work properly and rather than successful implantation, there is rejection of the pregnancy.Fortunately, tests can be performed in an effort to determine if there is an underlying immune issue. It would be misleading to suggest that these problems can be clearly identified in all cases. However, it would be equally disingenuous for a physician to say they "do not believe in immune problems". As part of the work-up of immune disorders, blood samples should be tested for Natural Killer Cells, Antiphospholipid antibodies, antithyriod antibodies, Reproductive Immunophenotype (RIP). If abnormalities are discovered in these tests, immune-modulation treatment can be considered and the patient may need to take a combination of anticoagulation meds (heparin or lovenox), steroids, other agents like intra-lipid or IVIg. The point being is that there are treatments that can be instituted to favor successful implantation. In cases of intractable non-responsive immune disorders, gestational surrogacy may need to be considered. Again, this summary of immune issues is not meant to be comprehensive or exhaustive. This is a very complex area and if you are found to have this problem, as the basis for your RPL, a comprehensive discussion needs to be undertaken with a Reproductive Specialist who has knowledge and experience dealing with these kinds of problems.

d) Thrombophilias:
The word thrombophilia means tendency toward blood clot formation. As it turns out, the ability of our blood to flow through our vessels (a vitally important bodily function), results from a balance between clotting mechanisms on the one hand, and anticlotting mechanisms on the other. Pregnancy in all individuals, Is a condition which 'tilts the balance' so to speak, in favor of clotting. I have heard a reputable authority on this topic make the statement that it is surprising that during pregnancy, the person 'does not become one large clot'. Now we each have an underlying genetic predisposition toward clot formation. Some people are more prone to develop clots and others less prone. It stands to reason, that the person with a greater genetic predisposition toward clot formation, will be more likely to form clots when pregnant, than the person with a lower genetic predisposition toward clot formation. Through a series of blood tests, we can determine if a patient has thrombophilic tendencies and may benefit from the addition of aspirin or heparin/lovenox.Thrombophilias are inherited or acquired conditions, which predispose an individual to thromboembolism (blood clots). This is due to an imbalance between certain blood clotting factors and anti-clotting proteins in the blood. As many as one in five people in the United States is a carrier of a type of thrombophilia. There is limited information in medicine today regarding the testing and treatment criteria of thrombophilias, but studies are emerging.Although most women with thrombophilias have healthy pregnancies, thrombophilias can contribute to a number of pregnancy complications. These include recurrent first trimester pregnancy losses, second or third trimester stillbirths, placental abruption (when the placenta separates from the uterine wall before delivery), preeclampsia less than 37 weeks gestation (high blood pressure and presence of protein in the urine) and poor fetal growth. Several of these problems are believed to result from blood clots in placental blood vessels that lead to changes in the placenta and reduced blood flow to the fetus. As yet, no proven cause and effect relationship has been shown to exist between thrombophilias and failed embryo implantation, poor IVF outcome or very early pregnancy losses (chemical pregnancy).As already mentioned, pregnant women in general are more likely than non pregnant women to develop venous thromboembolism (VTE), or development of a blood clot in a vein. This is due to the normal pregnancy-related changes in the blood clotting system in order to limit blood loss during labor and delivery. Pregnant women with a thrombophilia are at a higher risk of developing VTE. Studies suggest that more than half of pregnant women who develop a VTE have an underlying thrombophilia disorder.Women with a personal or family history of blood clots, pulmonary embolism (blood clot in the lung), strokes, low platelet counts, a history of pregnancy complications including stillbirth, preterm preeclampsia, placental abruption, recurrent pregnancy loss or poor fetal growth due to undetermined causes should be considered for testing.The heritable thrombophilias are a group of genetic disorders of coagulation that result in an increased risk of thrombosis (clotting). Successful pregnancy requires the creation of the early placental circulation, the lifeline of nutrients, oxygenation and removal of wastes for the developing fetus. Thrombosis of the placental vessels in the setting of a genetic condition that predisposes to increased clot formation may result in serious problems for a pregnancy. These include first and second trimester miscarriages, growth restriction, preeclampsia and intrauterine fetal death in the third trimester. This review will discuss the role of three of the genetic thrombophilias; the Factor V Leiden mutation, the Prothrombin Gene Mutation and the MTHFR mutation, and discuss their possible role in recurrent miscarriages.Factor V Leiden: Two Vitamin K-dependent clotting proteins, named Protein C and Protein 5 are located on blood platelets, and are therefore part of the normal coagulation mechanism. These proteins inactivate additional clotting factors, Factor V and Factor VIII, resulting in decreased clot formation, which is part of the body's protective mechanism against excessive clot formation. A resistance to the activated form of Protein C due to a genetic mutation in Factor V, with subsequent amino acid change, is termed the Factor V Leiden mutation. This mutation is the most common genetic thrombophilia, with a prevalence of 3-5% of Caucasian women being heterozygous carriers. In addition to problems in pregnancy, this condition is felt to be the leading cause of clot formation in women who take oral contraceptive pills. This condition is found in approximately 60% of women with gestational (pregnancy-related) thrombosis. In addition, the factor V Leiden mutation has been demonstrated in between 15-30% of women with recurrent early miscarriages.

Thrombophilic Status	Relative Risk of Venous Thrombosis
Normal	1
Oral contraceptive (OCP) use	4
Factor V Leiden, heterozygous	5 to 7
Factor V Leiden, heterozygous + OCP	30 to 35
Factor V Leiden, homozygous	80
Factor V Leiden, homozygous + OCP	??? > 100
Prothrombin Gene Mutation, heterozygous	3
Prothrombin Gene Mutation, homozygous	??? Also possible risk of arterial thrombosis
Prothrombin Gene Mutation, heterozygous + OCP	16
Protein C deficiency, heterozygous	7
Protein C deficiency, homozygous	Severe thrombosis at birth
Protein S deficiency, heterozygous	6
Protein S deficiency, homozygous	Severe thrombosis at birth
Antithrombin deficiency, heterozygous	5
Antithrombin deficiency, homozygous	Thought to be lethal prior to birth
Hyperhomocysteinemia	2 to 4
Hyperhomocysteinemia combined with Factor V Leiden, heterozygous	20

*The terms heterozygous (hetero-different) and homozygous (homo-same) are terms used in genetics. The human genome contains to copies of the information. If the copies are the same, they are homozygous; if the copies are different, they are heterozygous. For example, take a protein called A. The normal genome would code for the protein as AA. This is homozygous for the normal protein. If there is a variation of the protein called a, there are two possible ways to get the a. The genome could be Aa, which is called heterozygous or the genome could be aa, which is called homozygous.

Prothrombin (Factor II) 20210 Gene Mutation: Prothrombin is another clotting protein that is critical in the body's formation and dissolution of clots. An amino acid change in this gene is associated with elevated levels of Prothrombin and subsequent increased clot formation in both the venous and arterial systems. Heteroygotes (one normal copy, one abnormal copy) for this gene has been identified in 2% of normal individuals and in 6% of individuals with Deep Venous Thrombosis (DVT). Several research studies have shown correlation between this condition and recurrent miscarriages. One study demonstrated that in women with recurrent miscarriages, the incidence of this mutation was approximately 8%, vs. 4% in controls. Hyperhomocystinemia/MTHFR: Homocysteine is an amino acid that may accumulate in the body under certain conditions and cause enhanced clot formation via stimulated increase of certain clotting factors and stimulation of toxic free radicals. The metabolism of homocysteine is controlled by Folic Acid and Vitamin B-12, and dietary deficiencies of these substances may therefore contribute to enhanced levels of homocysteine in the blood (Hyperhomocystinemia). Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the metabolism of homocysteine, and deficiency of this enzyme may likewise cause enhanced accumulation of this amino acid. Two amino acid mutations in MTHFR, the C677T and the A1298C mutations, contribute to the potential for accumulation of homocysteine. The risks for elevated homocysteine are predominantly with the homozygous (two copies) state of each of these mutations, with the A1298 overall being less severe than the C677T mutation. Homozygosity for the C677T mutation can be found in up to 15% of otherwise normal individuals. Compound heterozygotes (one copy of each), may have similar risks as the homozygous C677T individuals. These mutations are extremely common, with approximately 20% of the general population heterozygous for one of the MTHFR variants. In addition to recurrent miscarriages, homozygous and compound heterozygous individuals are at risk for venous and arterial thrombosis, preeclampsia, placental abruption, decreased folate levels and fetal neural tube defects. Although some data is conflicting, studies with homozygous MTHFR and elevated homocysteine levels have demonstrated an approximate doubling of risk for spontaneous miscarriages. In addition, additional studies suggest that in women with at least two miscarriages, the incidence of MTHFR is 2-3 x that of women without history of miscarriages.Combined Thrombophilic Defects: Combinations of genetic thrombophilias result in an increased risk of thrombosis and miscarriage, as well as other adverse pregnancy events. Certain combinations, such as the combination of Factor V Leiden and homozygous MTHFR, may be particularly severe. One study showed that the risk of still births in women with combined defects was 14 times that of controls without these mutations. Later pregnancy complications, including early onset preeclampsia, growth restriction and abruption are also dramatically increased in these individuals.

Treatment of Thrombophilias:

Heparin: Although conclusive data on its efficacy remains controversial, anti-thrombotic treatment with the blood thinner heparin. A low molecular weight form of heparin, enoxaprin (Lovenox), is also available. These agents are especially important in the setting of combined thrombophilias and in women with a history of prior thrombosis. It is believed that heparin may help to reduce the possibility of clot formation in the placental vessels, and therefore decrease the chance of miscarriage. A typical regimen would consist of heparin administered as a subcutaneous injection of 5000 units twice daily. Lovenox, at a dose of 40 mg subcutaneously once daily has also been show to be effective, and allows for a once daily dosing. One study with Lovenox demonstrated a 75% live birth rate in women with thrombophilias vs. 20% in untreated women.

Aspirin: The use of low-dose baby aspirin (80mg) for the prevention of recurrent pregnancy loss in women has been extensively studied. The mechanism for aspirin's effectiveness is believed to be an improvement in microcirculation due to aspirin's effect on prostaglandins, chemical substances that have numerous effects throughout the human body. It is felt that aspirin improves circulation by facilitating a prostaglandin profile that encourages improved placental blood flow through vessel dilation and inhibition of platelet aggregation (clumping) and adhesion (stickiness). Most studies of thrombophilias have incorporated aspirin with an anti-thrombotic such as heparin or Lovenox, with improved live births shown with this combination. In two prospective studies in women with recurrent miscarriages and the Antiphospholipid Syndrome, an antibody-associated acquired thrombophilias, live birth rates were 70-80% for the combination vs. 40% with aspirin alone. While large controlled studies with the genetic thrombophilias have not been performed, several studies have shown a similar live birth rate when aspirin is used in combination with an anti-thrombotic such as heparin or Lovenox.Additional Therapy: Since folic acid intake may also lower homocysteine levels, a minimum of 1mg of folic acid should be part of the regimen in women with positive MTHFR. Some authorities suggest even higher doses of folic acid, up to 4 mg, although limited data is available on the efficacy of this dosing in the prevention of miscarriages. Additionally, B-12 and B-6 supplementation, both co-factors in folic acid metabolism, should be offered as well, with some authorities recommending up to 1000 mcg of Vitamin B-12 and 200 mg of Vitamin B-6. Folic acid at a dose of 1 mg is contained in most prenatal vitamins, and has been shown to be effective in the prevention of neural tube defects such as spina bifida. As such, folic acid intake should be considered part of good nutritional intake for a healthy pregnancy in all women.Genetic thrombophilias may playa significant role in the devastating problem of recurrent pregnancy loss. Appropriate diagnosis is critical in the process, to identify those individuals who require specific treatment. In our center, we believe that liberal use these treatment modalities are crucial to maximize early placental circulation, to decrease miscarriages, and to foster a healthy pregnancy and a healthy newborn. Patients with the inherited type of these disorders may benefit from genetic evaluation because of the possibility of passing these genes on to the offspring. In certain types of thrombophilias testing of family members may be necessary due to the inherited characteristic of these disorders and some patients may need life-long prophylaxis. A thorough consultation with the reproductive endocrinologist and geneticist is of utmost importance in the testing and treatment of these disorders.e) Infection: This should not be overlooked as a cause of RPL. In the 80's and 90's a lot of attention was paid to organisms such as urea plasma or mycoplasma as a cause of RPL. In truth the vagina is a veritable minefield of microorganisms. Any of them, if present in high enough concentrations can impair successful reproduction. These could include beta hemolytic streptococcus, e-coli (especially in those who practice anal intercourse), chlamydia, a variety of yeast species or trichomonas. The uterine cervix is supposed to create a barrier to the ascent of organisms from the lower genital tract into the upper tact. Sometimes, the bacterial load can be so extensive as to overcome the natural barriers. An early pregnancy does not have a sufficiently developed immune system to effectively deal with these microorganisms, and the result can be RPL. If suspected, cervical cultures should be taken and appropriate antibiotic therapy instituted if deemed appropriate. Any patient who has had a past history of significant pelvic infection or IUD use, or a therapeutic termination of pregnancy with complications, should be evaluated to determine if infection could be at the root of this problem.f) Hormonal: The early pregnancy is highly dependent on hormonal support to establish the implantation. In general, in particular with those going through ART procedures such as IVF, there is more than sufficient hormonal support. However, these levels should be closely monitored and replacement therapy instituted if necessary. For this patients who experience RPL despite treatment with ART, hormonal reasons are not likely to be the underlying cause of the problem.Summary & Conclusion: This piece is intended to help those suffering through this very difficult and frustrating problem, to get a better understanding of the areas of concern, as well as those places where efforts should be used to try to determine the cause(s) of the problem. Anyone who has experienced recurrent pregnancy losses can attest to the enormous toll this can take on their lives. As mentioned already, despite all best efforts, it is not always possible to pinpoint the exact reason(s) for the recurrent losses. However, if we are able to identify the cause(s) of the problems, it will be far more likely that therapeutic interventions will be successful. The good news is that there are efficacious treatments for most problems we encounter in clinical practice. If all else fails, or if it determined that therapy is unlikely to result in a successful outcome, consideration should be given to gestational surrogacy as an effective alternative to establish the family and realize dreams.