• Rationale and Comments

    MTHFR is responsible for the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Genetic variant C677T and A1286C have been associated with a mild decrease in enzymatic activity, which in the setting of reduced folate levels has been found to be a risk factor for hyperhomocysteinemia. Although hyperhomocysteinemia is a risk factor for cardiovascular disease and venous thrombosis, its cause is multifactorial and independent of the MTHFR genotype, even in homozygotic individuals. Despite earlier (mostly case control) studies that found an association between the MTHFR genotype and adverse outcomes, recent studies of more robust design have not replicated these findings. Due to the lack of evidence associating genotype independently with thrombosis, recurrent pregnancy loss, or other adverse pregnancy outcomes, MTHFR genotyping should not be ordered as part of a workup for thrombophilia.

    Sponsoring Organizations

    • Society for Maternal-Fetal Medicine


    • ACOG guidelines
    • American College of Medical Genetics and Genomics guidelines


    • Genetic
    • Hematologic
    • Obstetrical


    • Inherited thrombophilias in pregnancy. ACOG Practice Bulletin No. 197. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2018;132:e18-34.
    • Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6.
    • Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149:209-220.