What is the MTHFR gene?
Methylenetetrahydrofolate reductase (MTHFR) gene is the gene responsible for making the enzyme, also called methylenetetrahydrofolate reductase. This enzyme is necessary for a chemical reaction, involving B vitamins like folic acid, that converts the amino acid homocysteine to another amino acid, methionine. If this enzymatic reaction is impaired or diminished (due to a gene mutation), levels of homocysteine can build up in the blood. Homocysteine levels can also increase with normal MTHFR gene activity if the diet is deficiency in folic acid.
At least 40 mutations in the MTHFR gene has been identified however only 2 genes are commonly implicated in homocysteine-related health problems: C677T and A1298C. A person can inherit one or two copies of the gene mutation. It is called “heterozygous” if you inherit one mutation or “homozygous” if you inherit two. The more MTHFR gene mutations a person has, the more likely they will have high homocysteine levels.
How are mutations in the MTHFR gene implicated in infertility?
Initially cardiologist observed a link between elevated homocysteine and blood clots; some infertility doctors have hypothesized that elevated homocysteine can also cause blood clots between the placenta and uterine wall, thus impairing nutrient and blood flow to the developing fetus. In addition, elevated homocysteine has been more frequently observed in women with certain pregnancy complications, such a pre-eclampsia (elevated blood pressure), problems with the attachment of the placenta, recurrent pregnancy loss and low-birth-weight babies. Women with elevated homocysteine have a higher rate of having babies with neural tube defects (problems with the development of the brain and nervous system). However, it is important to note that there are many factors that play a role in determining the risks associated with these complex disorders.
Controversies in testing
To demonstrate how controversial MTHFR testing/treatment is a quick perusal of the web will demonstrate that many reproductive endocrinologist do not routinely test for MTHFR mutations. However interspersed in websites with skeptical opinions on the validity of MTHFR testing for pregnancy complications you will find some OBGYNS such as Dr. Stephan Wells of Walnut Creek, CA recommending MTHFR mutation testing for all women with recurrent pregnancy loss. His website also recommends high dose folic acid, low dose aspirin and also daily heparin (lovenox) injections, with the latter he claims “may be the only hope for women with a history of recurrent pregnancy loss.”
Not all doctors evaluating infertility or recurrent pregnancy loss, test for MTHFR gene mutations. This is because there is conflicting evidence about the relation between MTHFR mutations and pregnancy complications and losses. In fact, a recent meta-analysis of all MTHFR studies found that there was not an association between MTHFR mutations and pregnancy complications and losses. Another reason why a physician might not order the MTHFR test is because theoretically speaking, MTHFR gene mutations should only cause complications in pregnancy if homocysteine levels are elevated. Therefore many physicians may order a fasting homocysteine (which is also a cheaper test than directly testing MTHFR gene status). Testing for a homocysteine level is less controversial since it indicates potential B vitamin deficiency regardless of MTHFR status.
High doses of folic acid with a B complex can help reduce homocysteine levels and provide important nutrients and cofactors for DNA synthesis and the development of a healthy fetus. (I like Thorne’s Methyl-Guard Plus which includes a methylated form of folate which would not require MTHF enzyme activity for processing; and I have no financial affiliations with Thorne). Folic acid can also be found in dark leafy green vegetables, such as spinach and broccoli, oranges and legumes, such as peas and dried beans. All women of a childbearing age should be taking a prenatal vitamin with folic acid; additional folic acid and B vitamins should be recommended based on clinical history and laboratory testing (which should included a fasting homocysteine).
Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000; 151: 862–877.
Bos MJ, Heijer M, Willems H, Blom H, Gerrits W, Cattaneo M, Eichinger S, Rosendaal F. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a first randomized, placebo-controlled, double-blind trial. Blood. 2004
Higdon J, Drake VJ, Shane B. Folic acid. Linus Pauling Institute Accessed on 9-26-11 athttp://lpi.oregonstate.edu/infocenter/vitamins/fa/
Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb. 2002; 32: 51–58
Ray JG, Laskin CA. Folic acid and homocysteine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta. 1999; 20: 519–529.
Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000;71(5 Suppl):1295S-1303S.
Wells S. MTHFR and Recurrent Pregnancy Loss. Accessed on 9-26-11 at http://www.stephenwellsmd.com/mthfr.htm