When should patients with a personal or family history of thrombophilia, recurrent pregnancy loss, or cardiovascular disease, or those planning to become pregnant, be screened for the Methylenetetrahydrofolate Reductase (MTHFR) gene?

MTHFR Gene Screening: When to Test

MTHFR screening is generally NOT recommended for most patients with thrombophilia, recurrent pregnancy loss, or cardiovascular disease, as the clinical significance of MTHFR mutations remains controversial and current guidelines do not support routine testing.

Key Guideline Recommendations

MTHFR Testing is NOT Routinely Recommended

The available evidence indicates that MTHFR mutations have controversial clinical significance and are not included in standard thrombophilia screening panels recommended by major professional societies 1.

• The American College of Chest Physicians (2012) guidelines for VTE and pregnancy do not recommend screening for inherited thrombophilia in women with recurrent pregnancy loss 1
• The American College of Medical Genetics guidelines focus on Factor V Leiden and prothrombin mutations but do not establish clear indications for MTHFR testing 2, 3
• Random screening of the general population for thrombophilias, including MTHFR, is explicitly not recommended 2, 3

Limited Situations Where MTHFR Testing May Be Considered

Recurrent Pregnancy Loss Context

While guidelines advise against routine thrombophilia screening for pregnancy complications 1, some research suggests potential associations:

• Homozygous MTHFR C677T showed significant correlation with recurrent pregnancy loss in research studies 4
• Women with recurrent pregnancy loss had significantly higher frequencies of homozygous MTHFR C677T mutations compared to controls 4
• However, the 2012 ACCP guidelines specifically state: "For women with a history of pregnancy complications, we suggest not to screen for inherited thrombophilia" 1

Family History of Thrombosis

• Pregnant women with a family history of thrombosis may be screened for both genetic and nongenetic prothrombotic risk factors according to ACOG 1
• However, MTHFR is not specifically highlighted as a priority mutation in these recommendations 1

Important Clinical Caveats

Risks of Screening

Significant psychosocial and practical risks exist with thrombophilia screening 1:

• Job-related discrimination issues
• Potential denial of healthcare coverage
• Insurance implications for genetic testing
• Family member implications

Evidence Quality Issues

• The importance of MTHFR mutations is described as "controversial" in AHA guidelines 1
• Most high-quality guidelines focus on Factor V Leiden and prothrombin mutations rather than MTHFR 2, 3
• Research showing associations between MTHFR and recurrent pregnancy loss 5, 4, 6 has not translated into guideline-level recommendations for routine screening 1

What to Screen Instead

If thrombophilia screening is indicated, prioritize testing for 2, 3:

• Factor V Leiden mutation
• Prothrombin G20210A mutation
• Antiphospholipid antibodies (for recurrent pregnancy loss) 1
• Protein C, Protein S, and antithrombin deficiencies (in select cases)

Specific Indications for Thrombophilia Panel (Not MTHFR-Specific)

• Venous thrombosis under age 50 3
• Thrombosis in unusual sites (hepatic, mesenteric, cerebral veins) 3
• Recurrent venous thrombosis 3
• Strong family history of thrombotic disease 3
• Pregnant women or women on oral contraceptives who develop VTE 3

Bottom Line

Do not routinely screen for MTHFR mutations. The clinical utility remains unproven, guidelines do not support routine testing, and screening carries potential harms. Focus instead on established thrombophilias (Factor V Leiden, prothrombin mutation) when thrombophilia screening is clinically indicated based on personal or family history of thrombosis 2, 3.