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«Recurrent Miscarriage and Failed IVF Ti rA en vg or. W Miscarriage is the commonest complication of pregnancy. Approximately 15% of all pregnancies ...»

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Female Health Fact Sheet

Recurrent Miscarriage and Failed IVF








Miscarriage is the commonest complication of pregnancy. Approximately 15% of all pregnancies end in

a miscarriage and 25% of women who become pregnant will experience at least one miscarriage.

Recurrent miscarriage is usually defined as the loss of three or more consecutive pregnancies, and

fortunately only 1% of couples fall into this group.

If we include women who have experienced two miscarriages in the definition of recurrent miscarriage, the scale of the problem increases considerably and 3% to 5% of couples will be affected by this problem.

The difference between sporadic and recurrent miscarriage is important. It helps us to predict the chance of a successful pregnancy in the future, and the likelihood of there being a recurring cause for the loss of the pregnancy. A woman who has suffered a single sporadic miscarriage has an 80% chance and a woman with three consecutive miscarriages a 60% chance of her next pregnancy being successful.

One in six pregnancies in women under the age of 30 will end with a miscarriage. For women between the age of 30 and 40 the number increases to one on five and over the age of 40 to one in four. One in two hundred couples will experience two or more consecutive miscarriages. Many of these miscarriages are the result of Mother Nature's quality assurance system preventing abnormal fetal development continuing where there are chromosome abnormities which would prevent survival of the baby if born. Probably the most common cause of any pregnancy loss is a chromosome abnormality in the conception. The contribution of the inappropriate number of chromosomes usually comes from the egg. Best estimates are today that only about one half the eggs a woman makes in her reproductive lifetime are capable of a successful pregnancy. Most of these chromosomally abnormal eggs are never identified as pregnancies. Either they do not divide to produce an embryo or fetus, or the conception is lost very soon after implantation of the early embryo. A woman is a few days late for her menstrual period and thinks nothing of it. However in cases of repeated serial miscarriage the cause is pathological where something is wrong with the mother’s physiology. The same causes have now been proven to exist in many cases of repeated failed assisted conception treatment cycles. These are broadly described as immunological causes, where the either the mother or the fathers immune system incorrectly identifies the fetal cells as interlopers and attacks them in the same way as a viral, bacterial or parasitic interloper. There is a certain overall or background risk to pregnancy loss. The risk increases with age. Below is a table published in Fertility and Sterility.

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Many syndromes associated with recurrent fetal loss include anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects (Bick RL; Madden J; Heller KB; Toofanian A (1998) ) There are five categories of immune problems that can cause recurrent miscarriage and failed IVF cycles. Category 1 is the least severe, while Category 5 is the most severe. Without treatment, a woman with Category 1 problems can experience recurrent miscarriage, which may activate other categories of immune problems from Category 2, 3, 4 or 5.

2 All cells of the body have on their surfaces proteins or peptides called HLA (human leukocyte antigens). These are depicted in the figure below. These antigens serve as an early warning system that identifies foreign invaders - such as germs, viruses or cancer cells-that get into our bodies. With the new captured information, these cells signal the immune system to make antibodies (IgM, IgG and IgA) against the invader.

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A pregnancy must also be recognised as a foreign being (father puts HLA antigens on the placenta that are different from those of the mother).

When this applies, the mother makes an antibody called a blocking antibody that attaches to the placenta and effectively cloakes the pregnancy from the mothers immune system. The antibody she makes in this circumstance does not kill; it protects the baby and makes the placental cells grow faster.

When the father's HLA antigens placed on the placenta are too similar to the mother's HLA antigens, she does not make the antibody. In this circumstance the baby is not protected, the placental cells are not stimulated to grow and the baby dies. She interprets the pregnancy as "altered self" (i.e., a cancer cell). Therefore, when the cells of the baby die, she activates other immune problems from Category 2, 3, 4 or 5 where the natural killer cells that she was born with are now misinterpreting the baby as a cancer. This occurs in couples sharing DQ alpha HLA antigens.

This serves to alert the mother to react to the baby as a baby, not as an infection. Which results in blocking antibody production This initiates antibody production (gamma globulins) that destroys the bacteria or virus and remains in the body as a memory if the invader returns.

The HLA antigens on the placenta cells made by the father are called HLA-G. When the couple shares DQ alpha antigens in common, the G molecule put on the placental cells by the father is too similar to the G molecule that the woman's father put on her placenta to sustain her in her mother's uterus.

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1. Inadequate blocking antibody formation.

2. Ineffective camouflage of placenta.

3. Placental cells fail to grow and divide.

4. Death of placental cells.

5. Activation of category 2, 3, 4 and 5 immune problems.

HLA-G: Message sent from father to stimulate blocking antibody.

Blocking Antibody: Protects and stimulates the growth of placental cells.

Placental Cell Death: Consequences of low blocking antibody.

Whilst it has been known for a considerable time that a woman's blood becomes thicker in pregnancy, it has only recently been established that thisprocess is more pronounced in some women compared with others. If blood clots occur in the blood vessels of the placenta the blood flow to the baby is decreased and this can lead to either miscarriage or, if the pregnancy proceeds, to the birth of a baby that is smaller than he or she ought to be.

Repeated miscarriages, IVF failures, endometriosis and anything that causes tissue injury can lead to the formation of antibodies to phospholipids. These are called antiphospholipid antibodies.

Phospholipids are important molecules in the membranes of all cells, and antibodies to these important molecules can derange cell function, cause inflammation and can cause blood to clot too quickly.

Many patients with autoimmune diseases also have tissue injury and make antiphospholipid antibodies.

This is how antiphospholipid antibodies were discovered. Certain patients with lupus made antibodies that caused their blood to clot too quickly. This antibody is now called the "lupus anticoagulant antibody." When the test for this antibody is positive, most people think they have lupus. However, the majority of patients with this antibody have produced it because of infertility, IVF failures or recurrent miscarriage, not because they have lupus or other autoimmune diseases.

Today, 22% of women with recurrent miscarriage have antiphospholipid antibodies. The incidence of this problem increases in women by 15% with each pregnancy that is lost. It is a significant consequence of infertility, implantation failures and recurrent miscarriage.

4 Antiphospholipid antibodies, the two most important of which are the lupus anticoagulant and the anticardiolipin antibodies, cause blood to clot more easily. Women with a history of recurrent miscarriage who have persistently positive tests for either lupus anticoagulant and/or anticardiolipin antibodies are said to have the Primary Antiphospholipid Syndrome (PAPS). It has been shown in a recent large treatment trial conducted at St Mary’s Hospital London, that 15% of women with a history of recurrent miscarriage have PAPS. In pregnancies in which no drug treatment is given, women with PAPS have a 90% miscarriage rate. The trail also found that women with PAPS have a 40% chance of a successful pregnancy when they are treated with aspirin alone but a 70% chance when treated with aspirin blood thinning drugs. Subsequent studies have confirmed this high live birth rate with aspirin and blood thinning drugs and as a result this has become, both nationally and internationally, the established treatment for recurrent miscarriage sufferers with PAPS.

There are six different phospholipid molecules that have very important functions in cell membranes and intracellular organelles. The phospholipid molecules are

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Cell death or cell injury can lead to the production of antibodies to all or any one of these molecules.

These antibodies disrupt cell functions and increase the clotting speed of blood. This can cause major problems in the first few weeks of pregnancy.

As shown in the diagram, Serine and Ethanolamine are phospholipids that serve as glue molecules in allowing the placenta to be securely attached to the uterus during implantation. They also allow the cytotrophoblast to change into a new cell, the syncytiotrophoblast, which begins to feed the baby by transporting nutrition from the mother's blood into the baby.

Antibodies to these phospholipids prevent secure attachment or often totally prevent attachment. In addition, antibodies to these phospholipids prevent the cytophoblast from forming into the syncytiotrophoblast, which is needed to develop the fetus.

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Feeds the baby. Pregnancy loss or implantation failure.

Produces ß-hCG and progesterone.

Grows throughout pregnancy.

The three major gene mutations that lead to Inherited Thrombophilias are:

 Factor V Leiden mutation.

 Factor II (Prothrombin) G20210 gene mutation.

 Methylene-tetrahydrofolate reductase (MTHFR) mutation, leading to hyperhomocytseinemia.

The most common cause of APC resistance arises from the point (one DNA based-pair) mutation at the cleavage site of factor V, called factor V Leiden. It is the most common of the Inherited Thrombophilias, with a prevalence of 10% in the Caucasian population. The mutation has been discovered in 60% of patients who have clot formation during pregnancy, and is also a major cause of blood clots associated with oral contraceptive use. The Prothrombin (factor II) gene mutation has been shown to occur in 7.8% of women who experienced fetal loss due to a clotting disorder. Factor II is one of the major factors in the human clotting pathway. Homocysteine is normally present in low levels in the bloodstream. It is derived from dietary methionine, an amino acid. A gene mutation for the enzyme methylene-tetrahydrofolate reductase (MTHFR), will lead to build up of homocysteine in the bloodstream. This condition, called hyperhomocytseinemia, results in blood clot formation and hardening of the arteries, even in childhood. Nutritional lack of vitamins B6, B12 and folic acid aggravate the problem. Women who have the homozygous form of the MTHFR gene mutation (both of her alleles having the mutation) are more than a two-fold increased risk for a miscarriage.

Although there are numerous risk factors for venous thromboembolic disease, the term thrombophilia refers only to those familial or acquired disorders of the hemostatic system that result in an increased risk of thrombosis.

The inherited thrombophilias include  Antithrombin III deficiency,  Resistance to activated protein C (factor V Leiden),  Protein C and protein S deficiencies,  Prothrombin gene mutation,  The MTHFR gene mutation, as well as some  Rare forms of dysfibrinogenaemia.

In contrast, antiphospholipid syndrome is the only genuine acquired thrombophilic state and this acquired syndrome is far more common in women with recurrent pregnancy losses and implantation failures than the inherited thrombophilias.

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 Recurrent pregnancy losses,  Infertility,  Know implantation failures,  IVF failures,  Thromboembolic disease at a young age  Positive family history Antiphospholipid antibodies (aPL) are a family of autoantibodies with specificity for negatively charged phospholipids, or more accurately for their complex to phospholipid binding proteins. Their presence is associated with arterial/venous thrombosis and recurrent pregnancy losses. These clinical manifestations with the persistence of aPL are recognised as antiphospholipid syndrome (APS), one of the most common acquired thrombophilia. Beta 2-glycoprotein I (beta 2GPI) bears the epitope(s) for anticardiolipin antibodies (aCL) on its molecule, and lupus anticoagulant activity depends on the presence of beta 2GPI or prothrombin. Thus, phospholipid binding proteins may have some crucial roles in the pathophysiology of thrombotic events in APS. It has been hypothesized that aPL bind to cells and induce procoagulant activity via phospholipid binding proteins.

Category 3 immune problems occur in 22% of women with recurrent pregnancy losses and nearly 50% of women with infertility and IVF failures. Women with this problem make antibodies to DNA, or DNA breakdown products in the embryo or in the pregnancy. These antibodies form first in the blood as IgM. As the problem gets worse they appear as IgG and live in the lymphatic system and lymph nodes. With more losses they form IgA antibodies which have their home and action in the organs including the uterus. These antibodies can be against pure double stranded DNA (ds DNA), single stranded DNA (ss DNA), or smaller molecules called polynucleotides and histones that make up the single strands.

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Histone  Antinuclear Antibody (ANA) positive, speckled pattern.

 Autoantibody to DNA leads to inflammation in the placenta.

 Autoimmune disease screening in the woman is negative The test is reported as a titer and a pattern. Any titer above 1:40 is significant. The titers can get into the thousands such as 1:2,500. This simply means that the test is positive when the blood serum is diluted many times.

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