Thrombophilia: Another Factor to Consider
in Cases of Recurrent Pregnancy Loss
Recurrent pregnancy loss exacts a devastating emotional toll on patients' lives. Each miscarriage brings with it a profound sense of loss and frustration. While hormonal, uterine, immune system, and chromosomal abnormalities are widely accepted as possible causes of repeat miscarriages, the latest studies point to a new area of investigation - inherited blood clotting factors.
When a patient has a tendency to form blood clots, the condition is called thrombophilia. Thrombophilia can be a life-threatening event if the clots restrict blood flow. Thrombophilia can be an inherited disorder, but can also be caused by external events such as surgery, obesity, pregnancy, use of oral contraceptives, antiphospholipid syndrome, or long periods of immobility. Physicians may suspect thrombophilia when patients have a blocked blood vessel at a young age or have a strong family history of clotting disorders (such as stroke, pulmonary embolism, or deep vein thrombosis). However, some patients with thrombophilia do not experience any symptoms. Or if they do have symptoms, the condition often goes undiagnosed because the tendency to make clots is subtle. Recent research suggests a possible correlation between inherited thrombophilia and recurrent fetal loss. Genetic markers for these clotting factors include factor V Leiden mutation and prothrombin G20210A mutation. These two mutations are the most common causes of inherited thrombophilia. These markers, as well as several others that have also been associated with recurrent miscarriage, can be detected through simple blood tests (see recommended testing).
Recent research indicates that patients who experience recurrent miscarriage may have one or more of these markers for thrombophilia. One study found that 19% of miscarriage patients (15 of 80) carried the factor V Leiden mutation compared to 4% of controls. Other indicators of thrombophilia (prothrombin mutation, activated protein C resistance, and antithrombin III deficiency) are also more prevalent among women experiencing frequent miscarriages [1,2]. Several other recent studies have reached similar conclusions. While more research is needed, this is a promising new area of investigation.
The PCOS Patient and Thrombophilia
Patients with polycystic ovarian syndrome have a significantly elevated risk of miscarriage. It used to be thought that high levels of serum luteinizing hormone (LH) associated with PCOS caused chromosomally abnormal eggs, leading to an increased risk of miscarriage. However, recent studies have disproved that theory. Some researchers have suggested that high androgen levels among patients with PCOS may contribute to high rates of miscarriage. While the exact cause remains unknown, clotting factor abnormalities associated with insulin resistance (PAI-1 level and activity) are important to consider. Elevated levels of insulin interfere with the normal clotting balance causing abnormal uterine blood flow. This could lead to placental insufficiency and miscarriage. Since this new data suggests an increased frequency of genetic thrombophilia in women with recurrent miscarriage, it seems especially prudent to test for clotting disorders in PCOS patients. (See testing information in next paragraph.)
Recommended Tests for Patients with Recurrent Miscarriage
Ongoing research has uncovered new clues about possible reasons for recurrent pregnancy loss. Because many of these conditions are easily treated, physicians owe it to their patients to conduct thorough evaluations. This is especially true considering these new findings. We recommend that in addition to the usual infertility panel (which would include testing for antiphospholipid antibodies, lupus anticoagulant, and anticardiolipin antibodies), patients with recurrent miscarriages should be tested for genetic markers of thrombophilia, including:
Abnormal results on any of these tests may indicate an increased risk of forming placental blood clots, deep vein thrombosis, and potentially fatal pulmonary embolism during pregnancy. Because of this, therapy should be strongly considered.
- PAI-1 levels and activity
- Antithrombin III
- Prothrombin II mutation
- Protein C activity
- Protein S activity
- Factor V Leiden
Treatment regimens used at Georgia Reproductive Specialists to manage thrombophilia may include heparin or Lovenox (low molecular weight heparin) injections, and baby aspirin or metformin (for insulin resistant patients with elevated PAI-1). These treatments are designed to improve blood flow in the follicle, optimize egg quality, and improve pregnancy outcomes. Treatment for the PCOS patient is summarized in an earlier article. All patients receiving treatment must be carefully monitored. Patients on heparin require monthly PTT, blood counts, and platelet levels. These patients should also consider dietary calcium supplementation.
Because inherited thrombophilia has been shown to be a major cause of recurrent miscarriage, patients with recurrent fetal loss should be evaluated for clotting disorders, even in the absence of clinical signs. This is especially true if the loss occurred after a heartbeat was detected. When lab results show a clotting disorder, appropriate treatment and follow-up should be initiated.
 Foka ZJ, et al. Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductatse C677T, are associated with recurrent miscarriages, Human Reproduction, 15:458-462, 2000.
 Blumenfeld Z, Brenner B. Thrombophilia-associated pregnancy wastage, Fertil Steril, 72:765-774, 1999.