Stephen R. Wells MD

If you are reading this, then you probably have been diagnosed with a common gene mutation that is thought to be responsible for multiple miscarriages. This is a complex discussion and is incomplete. A thorough discussion would be about 40 pages long. My goal is to help give you a basic understanding as it relates to pregnancy.

 

WHAT IS MTHFR?

MTHFR (5,10-methylenetetrahydrofolate reductase – what a mouthful…) is a specific gene found on a specific chromosome within every cell in every person The MTHFR gene produces an enzyme responsible for a multi-step process that converts the amino acid homocysteine to another amino acid, methionine. Specifically, MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.  5-methyltetrahydrofolate is ultimately converted to methionine to make proteins and other important compounds. When the MTHFR enzyme “malfunctions” the process gets backed up, so that homocysteine (considered to be somewhat of a toxic amino acid) levels increase.  Elevated homocysteine can cause inflammation in blood vessels and increases the risk of microscopic clot formation.

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WHAT IS A MTHFR MUTATION?

An abnormal change in gene structure, called a mutation, of the MTHFR gene can cause a disruption of the MTHFR enzyme’s normal function of breaking down homocysteine.

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The two common MTHFR gene mutations occur at specific locations called “positions” along the gene. The one we generally test for is located at position 677. At this location, one amino acid base pair is different, in that Cytosine is replaced by Thymine. This mutation is thus called C677T. Another mutation we test for occurs at position 1298. At this location, Adenine is replaced by Cytosine and is therefore called A1298C.

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MTHFR mutations are common. The mutations can be “heterozygous” meaning they occur only on one strand or “allele” of the chromosome, orthey can be “homozygous”, occurring on both alleles. The frequency of a heterozygous C677T mutation is common, occurring in about 35% of the population. The homozygous C677T mutation is about 5-10% of the population. A mutation in A1298T is more common but is generally less problematic. The homozygous variety of A1298T occurs in 9% of the population. Another mutation involves both the C677T and the A1298T alleles. This is a “compound heterozygous” condition that occurs in approximately 17% of the population.

Okay, enough of MTHFR Science 101.

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HOW DOES MTHFR AFFECT PREGNANCY?

If the MTHFR gene is malfunctioning, homocysteine can build up and cause problems, both in the cardiovascular system, but also with pregnancy. At this time, we’ll confine this discussion to the impact on pregnancy.

Some MTHFR mutations are more serious than others as far as their ability to cause problems during pregnancy. Specifically, women who have multiple pregnancy losses are more likely to have a MTHFR gene mutation.

The association of MTHFR and recurrent pregnancy loss is under great debate. Some clinicians and researchers feel that the mutations can cause blood clots between the developing placenta and uterine wall, in an area called  “low flow maternal-placental interface”, thus preventing transport of vital nutrition to the developing fetus. This usually occurs early in pregnancy when the embryo or fetus is most vulnerable.

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It is unlikely that the exact mechanism of how MTHFR affects pregnancy loss will be worked out in the near future. As a result, women and clinicians need to understand that there is no set “standard of care” protocol for dealing with recurrent miscarriage in the presence of a MTHFR mutation.

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WHAT THERAPY IS AVAILABLE FOR WOMEN WITH MTHFR MUTATIONS?

Two scenarios that I feel benefit from therapy include the homozygous C677T mutation, and what is termed “compound heterozygote” mutation: heterozygous for both C677T and A1298T.

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In these situations I feel administering daily injections of anti-clotting medicines Heparin or Lovenox give the best hope for women with a history recurrent pregnancy loss. The desired effect is to prevent clot formation between the developing placenta and uterine wall. Since the condition seems to affect pregnancies early, it makes sense to begin treatment early and continue well past the first trimester. Less clear is how long to continue treatment. Additional treatments are daily administration of aspirin in low doses (St. Joseph’s chewable 81mg aspirin or generic).

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Previously, to supplement Lovenox and aspirin in treating women with this condition, we recommended extra folic acid during the earliest part of pregnancy, since the MTHFR condition tends to interfere with folate production incompletely. Again, Folate is important in reducing Homocysteine levels, which protects against clot formation. This benefit, however, has been less well studied. Currently, there are products available that “skip ahead”, providing folate that is biologically active, not needing the conversion via the MTHFR enzyme. We recommend L-5methyltetrahydrofolate or L-5 methylfolate via a prescription strength prenatal vitamin, or L-5methlytetrahydrofolate (L-5-MTHF, L-5 methylfolate) obtained OTC or through a host of different companies.  But look for pure ones, not blends containing R-5-methylfolate.

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Again, there is no concrete evidence based standard to guide us. I will typically be more conservative and treat with Lovenox for longer in a woman’s first successfully treated pregnancy, and then may discontinue the treatment somewhat earlier in subsequent pregnancies. Again, this tends to be a first to early second trimester phenomenon.

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