MTHFR Mutations and Recurrent Miscarriages: Is There a Link?

There may be a link for certain populations, but it's not conclusive yet.

Doctor talking with patient in office
Hero Images/Getty Images

In looking for information about 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 scientifically proven.

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.

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 a history of miscarriage and offer aggressive treatment to everyone with MTHFR gene mutations. Others do not ever test for MTHFR variants. 

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.

In addition, people with MTHFR gene mutations can have a decreased ability to metabolize folic acid and other B vitamins. 

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).

It's important to understand that MTHFR gene mutations are fairly common—nearly half the population of the United States may be at least heterozygous for an MTHFR gene mutation.

The Debate: Is MTHFR A Miscarriage Risk Factor?

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 the risk of blood clots (albeit weakly), 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—it's a controversial topic. In fact, 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. However, there is no scientific evidence that treatment helps. 

To further add to the variability in the treatment of these mutations, some doctors 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 vast majority fall into 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.

The Big Picture on MTHFR Mutations

With all of this in mind, MTHFR gene mutations fall into the category of being an unproven cause of recurrent miscarriages. It may be that MTHFR mutations pose a risk for a certain population of women, like the Chinese population, according to a 2016 study in the Archives of Gynecology and Obstetrics

That being said, as the MTHFR story evolves, professional societies like the American College of Obstetricians and Gynecologists (ACOG) are making recommendations to guide doctors on whether or not they should be testing certain women.

In a 2013 Practice Bulletin in Obstetrics Gynecology, ACOG gives a level B recommendation (meaning based on limited or inconsistent scientific evidence) stating that MTHFR mutation analyses or fasting homocysteine levels are not recommended (due to the lack of association found between these tests and negative pregnancy outcomes).

A Word From Verywell

In the meantime, if your doctor treats you for a MTHFR mutation or homocysteine level, be sure to direct any concerns you have about 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.

Sources:

American College of Obstetricians and Gynecologists in Women's Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013 Sep;122(3):706-17.

Chen H, Yang X, Lu M.Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016 Feb;293(2):283-90.

Dilley, A. et al.Mutations in the factorV, prothrombin and MTHFR genes are not risk factors for recurrent fetal loss.J Matern Fetal Neonatal Med. 2002 Mar;11(3):176-82.

Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril. 2006 Dec;86(6):1716-22.

Unfried G, Griesmacher A, Weismüller W, Nagele F,  Huber JC, Tempfer CB. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol. 2002 Apr;99(4):614-9.

Continue Reading