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Update on MTHFR, Thrombophilias & IVF

There has been confusion over the years about testing for clotting disorders in infertility patients, especially those undergoing IVF treatment. Routine testing for these disorders is not recommended as a part of the initial work up for infertility and prior to or during pregnancy. Unfortunately, there have been overutilization and overinterpretation of these tests (thrombophilia testing) in obstetrics and gynecology and infertility practices.

Thrombophilias are a group of disorders that increase the risk of clot formation in various parts of the body including the placenta. Additionally, we now know that they also result in an inflammatory reaction, which is believed to be the mechanism of poor pregnancy outcome. They can be associated with pregnancy related complications, recurrent first trimester pregnancy loss (RPL) and also clot formation in the legs, lungs and stroke. Some of the indications for testing include RPL, poor obstetrical outcome in a prior pregnancy, fetal demise and a strong family or a personal history of thromboembolic (clots) events.

The most well known and studied disorder in this group is anti-phospholipid syndrome (APS). Unfortunately, all other disorders in this group are screened and treated the same way APS has been approached over the years, which may be a problem because the severity and the relevancy may not be the same relating to obstetrical outcome. One of the most commonly screened and overtreated finding is the presence of the MTHFR gene mutation

MTHFR, which stands for methylenetetrahydrofolate reductase, is the enzyme closely involved in the metabolism of homocysteine. Elevated levels of homocysteine have been linked to increased risk of clot formation, pregnancy loss and complications. MTHFR gene mutations may result in elevated levels of homocysteine, although the gene defect needs to be at a severe level to cause such an elevation. The most common cause of elevated homocysteine level is folate deficiency. If homocyteine level is not elevated, testing for MTHFR is not clinically indicated or relevant.

The most common MTHFR mutation is C677T (heterozygote) which is not associated with elevated homocysteine levels and can be present in 40% of the general population. The less common is the homozygote type, which sometimes can be associated with elevated levels of homocyteine and observed in 10% of the general population. Therefore, testing for this common gene variation is not clinically useful, but measurement of homocysteine levels may be useful in some patients. The second type of gene mutation is A1298C which does not appear to be associated with any adverse pregnancy related complications, unless it is present along with C677T mutation AND elevated homocysteine levels.

A recent study published in the journal of Obstetrics and Gynecology concluded that the presence of MTHFR mutation is not associated with increased risk of complications during pregnancy. In fact, the presence of A1289C mutation was protective against pregnancy complications. The only genetic problem that increased the risk of complications in this study was prothrombin gene mutations.

Another commonly tested gene problem is Factor 5 Leiden (FVL) and its association with pregnancy complications. Majority of the studies did not find an association with pregnancy related complications, except one study that reported an increased risk of stillbirth. At this time, routine testing is not recommended for the general population, during pregnancy or for women undergoing IVF treatment. In cases of repeated IVF failures, testing is also not recommended. For patients with recurrent pregnancy loss, activated protein C resistance testing is recommended instead of testing for FVL because some these problems may be acquired and not related to the actual gene deletion.

Other thrombophilias commonly involved in RPL and adverse pregnancy outcomes include Protein C, Protein S and Thrombin III deficiency, APS and increased PAI-1 levels. If these disorders are confirmed by repeat testing, blood thinners (heparin or low molecular weight heparin along with baby aspirin) are used during the pregnancy and the postpartum period. It is recommended to seek a consultation with a reproductive endocrinology and infertility specialist for such disorders along with a hematology and rheumataolgy consultation in some cases.

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