MTHFR and Recurrent Miscarriages - What's the Story?

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In looking for information about treatment of recurrent miscarriages, you will probably come across mentions of various unproven treatments. Researchers have many theories about the causes of recurrent miscarriages but relatively few have treatments that are solidly grounded in conclusive evidence.

In the meantime, doctors often test for and treat potential causes of recurrent miscarriages that they feel have a solid theoretical base and for which they feel the potential treatment is unlikely to cause harm even if it does not help.

The practice of testing for MTHFR gene mutations falls into this category. Let's take a look at what MTHFR is and why some doctors feel it relates to miscarriages.

Current Status of MTHFR 

Researchers have looked at MTHFR gene mutations as being a possible factor in recurrent miscarriages with quite mixed results. Some studies find that MTHFR gene variations increase the risk of miscarriages while others find no link.

Right now, some doctors test for MTHFR in patients with history of miscarriage and offer aggressive treatment to everyone with MTHFR gene mutations. Others do not ever test for MTHFR variants. There is currently no official recommendation and no conclusive evidence about the value of testing for MTHFR gene mutations, so practice varies widely.

Background of MTHFR and Miscarriage

MTHFR stands for methylenetetrahydrofolate reductase. This is an enzyme that is involved in amino acid metabolism in the body.

Common mutations in the MTHFR gene can affect how a person's body processes homocysteine, an amino acid found in the blood.

People with MTHFR gene mutations may have elevated levels of homocysteine, although not everyone with an MTHFR gene mutation is affected. (Note that elevated homocysteine is considered a potential risk factor for miscarriages independently and can be caused by other factors beside MTHFR mutations.) People with MTHFR gene mutations can have a decreased ability to metabolize folic acid and other B vitamins, also.

Over the years, dozens of common and rare mutations in the MTHFR gene have been identified. Among the more common are mutations called C677T and A1298C, with the former often called the more problematic of the two. A person can be either heterozygous or homozygous for either or both of these MTHFR gene mutations (heterozygous would mean a person had one copy of the mutation and homozygous means that the person has two copies of the mutation).

MTHFR gene mutations are fairly common; nearly half the population of the United States may be at least heterozygous for an MTHFR gene mutation.


In the camp that favors MTHFR genes as a possible miscarriage risk factor, the theory often centers around the idea that because MTHFR mutations can cause elevated homocysteine, which increases risk of blood clots, an MTHFR gene mutation should be treated as a hereditary thrombophilia.

Many doctors believe that hereditary thrombophilias, such as Factor V Leiden, may increase the risk of miscarriage by creating tiny blood clots that block nutrient flow to the placenta and so they include MTHFR gene mutations in this category.

However, hereditary thrombophilias are not universally accepted as a cause of recurrent miscarriages -- the only thrombophilia disorder with a widely accepted treatment is antiphospholipid syndrome.

Doctors who follow the theory of MTHFR variations as a thrombophilia disorder may prescribe anti-clotting therapy such as heparin and low dose "baby" aspirin to reduce the risk of blood clots. Others may recommend high doses of folic acid and possibly other B vitamins with the idea that this will reduce homocysteine levels and eliminate any added risk on that front.

In doctors who believe in treatment of women with MTHFR gene variations, some believe in treating women who are heterozygous as well as homozygous, whereas others only treat women who are homozygous.


Other doctors do not test for MTHFR gene mutations at all because the link is far from conclusively proven, but they choose to test homocysteine instead and recommend therapies for women with high homocysteine levels.

Still other doctors (and probably the majority fall in this category) do not test for either MTHFR or homocysteine because neither has a formally recommended treatment that is solidly shown to reduce the risk of miscarriage.

Where It Stands

With all of this in mind, MTHFR gene mutations definitely fall in the category of being an unproven cause of recurrent miscarriages. Researchers are uncovering new information all the time, and certain MTHFR gene mutations may ultimately be proven to play a role in miscarriages or the link may be ultimately ruled out.

The research is increasingly pointing to high levels of homocysteine, or hyperhomocysteinemia, as being the more likely factor involved in miscarriages -- and many researchers feel that this will ultimately explain the past studies that have found an association between MTHFR gene variants and likelihood of miscarriages. Homocysteine can also be elevated for other reasons beside MTHFR gene mutations. Further research will hopefully clarify the link between homocysteine levels and miscarriage as well as what treatment works best for this condition.

In the meantime, if your doctor treats for MTHFR or homocysteine, be sure to direct any concerns you have about the the treatment to him or her.

Similarly, if your doctor does not test for MTHFR gene mutations, the reason is probably because of the lack of conclusive evidence about the value of doing so. But if you are concerned, it doesn't hurt to bring the matter up and hear your doctor's reasons behind his opinion.


Dilley, A. C. Benito, W.C. Hooper, H. Austin, C. Miller, M. El-Jamil, S. Cottrell, J. Benson, B.L. Evatt, A. Patterson-Bamett, D. Eller, and C. Philipp, "Mutations in the factor V, prothrombin and MTHFR genes are not risk factors for recurrent fetal loss." Journal of Maternal Fetal Neonatal Medicine Mar 2002. Accessed 26 Mar 2008.

Johns Hopkins University, "5,10-@METHYLENETETRAHYDROFOLATE REDUCTASE; MTHFR." Online Mendelian Inheritance in Man 2008. Accessed 26 Mar 2008.

Komura, Steven, "Methylenetetrahydrofolate reductase (MTHFR) mutation assay for determination of thermolabile MTHFR C677T and MTHFR A1298C mutations." Clinical Laboratories of Hawaii. Accessed 26 Mar 2008.

Murphy, Michelle, "Homocysteine: biomarker or cause of adverse pregnancy outcome?Biomarkers in Medicine June 2007. Accessed 26 Mar 2008.

Unfried, Gertrud, Andrea Griesmacher, Wolfgang Weismüller, Fritz Nagele, Johannes C. Huber, and Clemens B. Tempfer, "The C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene and Idiopathic Recurrent Miscarriage." Obstetrics & Gynecology 2002. Accessed 7 Dec 2009.

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