Case of the Month June 2006

Recurrent Pregnancy Loss

Anne Bode MD, Patricia Canfield MD



Answer: B Correct.

This patient has a mutation in the enzyme methylenetetrahydrofolate reductase (MTHFR). This is a very common genetic mutation with approximately 44% of the population being heterozygous and 12% being homozygous for the mutation. MTHFR is crucial in the biochemical pathway that converts the amino acid homocysteine into methionine. In order for this pathway to properly function, vitamins B12, B6 and folic acid are required as co-factors. (See figure below.)


MTHFR converts 5,10, Methylene-tetrahydrofolate into 5-Methyl-tetrahydrofolate, which in turn lends a methyl group to homocysteine in order to create methionine. If MTHFR does not function properly homocysteine does not acquire the methyl group needed to become methionine and an excess of homocysteine accumulates.

This patient had a homozygous mutation which replaced cytosine with thymine at the 677 position in the gene for MTHFR. This mutation is commonly denoted as C677T. The mutated gene does not cause the enzyme to become completely defunct, but rather reduces the efficacy of the enzyme. A homozygous mutation will cause the enzyme to work at approximately 35% to 50% of normal. This mutation is known to be “thermolabile” meaning that the enzymatic activity begins to decrease when the temperature reaches 37 C.

A second genetic mutation that affects MTHFR is the A1298C mutation which replaces adenine with cytosine. Homozygotes for this mutation do not have higher serum homocysteine levels unless there is also a heterozygous mutation for C677T. The enzyme activity is slightly decreased, but not enough to cause a build-up of homocysteine.

The reduction in MTHFR activity subsequently results in an increased amount of homocysteine. Homocysteine has been found to be a risk factor in a number of medical conditions including thrombosis, coronary artery disease, miscarriage, and neural tube defects. The exact mechanism by which these complications occur is currently unknown, however, some literature suggests that increased levels of homocysteine are toxic to vascular endothelial cells. Under normal circumstances, vascular endothelium is thromboresistant. When injury to the endothelial cells occurs, vWF is released, platelets are activated and the coagulation cascade is initiated resulting in thrombosis, infarction, acute coronary events and perhaps fetal loss.

It has been shown that by providing high levels of the cofactors required in the pathway (folate, B12, and B6) the decreased enzymatic activity can be compensated for and homocysteine levels will be decreased. Therefore, this patient should increase her intake of these vitamins in order to treat her genetic disorder. A low-dose aspirin every day has also been given to these patients along with the B vitamins in order to reduce the risk of a miscarriage caused by placental infarction. This is necessary only when the level of homocysteine continues to be elevated after treatment with B6, B12 and folate. Heparin has not been found to be necessary in these patients (Answer A). Heparin is a common treatment for pregnancy loss due to anti-phospholipid syndrome and systemic lupus erythematosus. There is no reason to advise against pregnancy in this woman (Answer D). Pregnancy is advised against if there is a serious risk to the mother’s life. Therapeutic intervention is usually not necessary in patients with a history of one miscarriage because this is considered statistically “normal”.


  1. Hultdin J. High homocysteine levels in elderly [editorial]! Rondel 2003; 14. URL:
  2. Bailey L and Gregory J. (1999) Polymorphisms of Methylenetetrahydrofolate Reductase and Other Enzymes: Metabolic Significance, Risks and Impact on Folate Requirements. Journal of Nutrition. 1999;129:919-922.
  3. Botto L., Yang Q. (2000) 5,10-Methylenetetrahydrofolate reductase Gene Variants and Congenital Anomalies: A HuGE Review. American Journal of Epidemiology. 2000;151:862-877.
  4. Moll, Stephen. FVL. Thrombophilia Support Page. 2004. December 12, 2005.
  5. MTHFR. Evanston Northwestern Healthcare Division of Maternal Fetal Medicine. 11/13/2003. December 12, 2005.