MTHFR Mutations and Recurrent Miscarriages

Why Some Scientists Doubt an Association Exists

MTHFR mutation and miscarriage
Laguna Design Photo Library/Getty Images

Over the past several decades, increasing focus has been placed on the MTHFR genetic mutation and its association with a host of health conditions. Some of these proposed links are strongly supported, but others are speculative at best.

In recent years, a handful of scientists have suggested that the mutation could explain why certain women have recurrent miscarriages. While the theory is far from conclusive, it does highlight the role that genetics may play in otherwise unexplained pregnancy loss.

Explaining the MTHFR Mutation

The MTHFR mutation is an anomaly, or "mistake," in a person's genetic code that interferes with the body's ability to produce the MTHFR enzyme. This enzyme is needed to change folate into its active form in the body.

Once activated, folate enables the transformation of an amino acid called homocysteine into a different amino acid, methionine. Both of these amino acids play critical biological roles. Methionine is involved in a multitude of functions including:

  • Gene expression
  • Metabolism of B vitamins
  • Production of proteins
  • Regulation of fat metabolism and immune function

When the MTHFR enzyme doesn't work correctly or is not made at all, a variety of health problems can ensue. While most people with the mutation never know they have it, those with a more severe variant may encounter the following conditions:

Homocystinuria

This rare genetic condition is characterized by homocysteine spilling into the urine as a result of markedly high levels of homocysteine in the blood (called hyperhomocysteinemia.)

Children born with homocystinuria often experience abnormal blood clotting, movement disorders, feeding difficulties, and learning disabilities.

This condition can also cause eye problems, skeletal abnormalities, and psychiatric disturbances.

Hyperhomocysteinemia

One version of the MTHFR mutation, C677T, can cause hyperhomocysteinemia and has been implicated in recurrent miscarriages and cardiovascular disease. But not all researchers and doctors are convinced of the role it plays in pregnancy loss, if any.

While some studies have shown higher levels of homocysteine in women with preeclampsia (high blood pressure during pregnancy), placental abruption, and other pregnancy loss, others have seen no relationship between pregnancy outcome and the MTHFR mutation. Some experts believe elevated homocysteine could be a result rather than a cause of miscarriage.

Neural Tube Defects

Both anencephaly, a birth defect characterized by missing or incompletely formed parts of the brain or skull, and spina bifida, the incomplete formation of bone around the spinal cord, have been linked to the MTHFR mutation.

Remember the role played by the MTHFR enzyme in activating folate? Scientists suspect that when folate is not converted to its active form, the resulting lower blood levels of folate may cause impaired formation of the brain, skull, and spinal cord during pregnancy.

Other Health Problems

Medical evidence has linked the MTHFR mutation to hypertension, glaucoma, psychiatric disorders, age-related hearing loss, and certain types of cancer. Most studies have been largely mixed, however, with associations found in some studies but not others.

The most severe problems tend to occur in people who have inherited the MTHFR mutation from both parents (referred to as homozygosity). Those who inherit the mutation from only one parent (heterozygosity) may have few issues, if any.

The MTHFR mutation is fairly common: an estimated 20% to 40% of the U.S. population is at least heterozygous for this genetic defect. Although statistics vary by study, it appears to be most prevalent among Hispanics and Whites.

MTHFR and Miscarriage Risk

Because the current evidence is inconclusive, many scientists challenge the notion that miscarriages and the MTHFR mutation are somehow linked. Those who support the hypothesis do so based on the increased incidence of miscarriage among women with the MTHFR C677T variant.

One Italian study conducted in 2018 found no association between the C677T mutation and recurrent pregnancy loss. However, a 2019 study in China came to the opposite conclusion: those with recurrent pregnancy loss were more likely to have the C677T mutation and/or another variant known as A1298C (it's possible to carry both mutations.)

In addition, a 2019 review of studies involving over 7500 Canadian patients found an increase in placenta-related complications among patients with hyperhomocysteinemia.

Those who support the link between the MTHFR mutation and pregnancy loss have suggested that homocysteinemia may cause the formation of tiny blood clots which block the flow of nutrition to the placenta, essentially starving the fetus and triggering a spontaneous abortion.

Although how the mutation causes miscarriage is still unclear, many women with recurrent pregnancy loss do test positive for the MTHFR mutation. Because of this, some doctors have endorsed the use of anti-clotting drugs such as enoxaparin and low-dose aspirin to improve pregnancy outcomes.

Others recommend high doses of folic acid and other B vitamins, which have been shown to lower blood levels of homocysteine. This is not common practice among OB/GYNs, however, nor is routine testing for the MTHFR mutation.

A Word From Verywell

The debate continues as to the impact of the MTHFR mutation on pregnancy. A 2013 advisement from the American College of Obstetricians and Gynecologists stated that current evidence regarding the issue is either "limited" or "inconsistent" and advised against using an MTHFR genetic analysis or fasting homocysteine test as part of a routine prenatal exam.

If you have had several miscarriages or if pregnancy loss runs in your family, you may want to discuss the possibility of being tested for the MTHFR mutation with your OB/GYN or other healthcare provider.

Was this page helpful?
Article Sources
Verywell Family uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. U.S. National Library of Medicine. MTHFR gene. Updated August 18, 2020.

  2. Levin BL, Varga E. Mthfr: addressing genetic counseling dilemmas using evidence-based literature. Journal of Genetic Counseling. 2016;25(5):901-911. doi:10.1007/s10897-016-9956-7

  3. Huemer M, Mulder-Bleile R, Burda P, et al. Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (Mthfr) deficiency. J Inherit Metab Dis. 2016;39(1):115-124. doi:10.1007/s10545-015-9860-6

  4. Dell’Edera D, L’Episcopia A, Simone F, Lupo MG, Epifania AA, Allegretti A. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. Biomedical Reports. 2018;8(2):172-175. doi:10.3892/br.2018.1039

  5. Chaudhry SH, Taljaard M, MacFarlane AJ, et al. The role of maternal homocysteine concentration in placenta-mediated complications: findings from the Ottawa and Kingston birth cohort. BMC Pregnancy Childbirth. 2019;19(1):75. doi:10.1186/s12884-019-2219-5

  6. Merviel P, Cabry R, Lourdel E, Lanta S, Amant C, Copin H, and Benkhalifa M. Comparison of two preventive treatments for patients with recurrent miscarriages carrying a C677T methylenetetrahydrofolate reductase mutation: 5-year experience. J Int Med Res. 2017;45(6):1720-1730. doi:10.1177%2F0300060516675111

  7. American College of Obstetricians and Gynecologists Women's Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2013 Sep;122(3):706-17. doi:10.1097/01.AOG.0000433981.36184.4e. PMID:23963422.

Additional Reading