MTHFR Polymorphism Testing – The Evidence Isn’t There
Learning Objectives and CME/Disclosure Information
This activity is intended for healthcare providers delivering care to women and their families.
After completing this activity, the participant should be better able to:
1. Discuss which biologic reactions rely on MTHFR 2. Recall current evidence regarding the clinical utility of screening patients for polymorphic MTHFR variants
Estimated time to complete activity: 0.25 hours
Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project
Disclosure of Conflicts of Interest
Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.
The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.
Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.
Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.
Method of Participation and Request for Credit
Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Dec 31 2017 through Jan 25 2023, participants must read the learning objectives and faculty disclosures and study the educational activity.
If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.
For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.
Joint Accreditation Statement
In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physician Continuing Medical Education
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Continuing Nursing Education
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5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and is therefore critical to reactions and processes involving folate
MTHFR converts the amino acid homocysteine to methionine
MTHFR and consequent folate status impacts pathways involving DNA methylation and gene regulation
Two polymorphic variants are known to decrease enzyme activity
677C>T (“thermolabile” variant – enzyme less active at higher temperatures)
Commonly, a C is at position 677 that codes for an alanine
T at position 677 leads to a valine substitution
1298A>C is also common but does not cause increased homocysteine levels in heterozygous or homozygous individuals
Combined heterozygosity of 1298A>C and 677C>T results in an outcome like 677C>T homozygous individuals
677C>T is common and found throughout the world
10 – 15% of North American Caucasians are homozygous
> 25% of Hispanics are homozygous with the highest allele frequencies
6% in individuals of African descent are homozygous
20 to 40% of Caucasians or Hispanics in the US are heterozygotes (one allele)
Reduced MTHFR activity, especially when folate levels are low, is a risk factor for hyperhomocysteinemia
Hyperhomocysteinemia has been weakly associated with venous thrombosis and coronary artery disease
Other factors can elevate homocysteine levels (e.g. deficiencies of folate, vitamins B6 and B12)
Hyperhomocysteinemia may be mild to moderate in individuals who are homozygotes for MTHFR polymorphisms with limited clinical significance
Is MTHFR genotype status related to disease?
Until recently, it was thought that MTHFR deficiency, by causing elevated homocysteine levels, led to an increased risk of venous thrombosis, coronary heart disease, recurrent pregnancy loss and adverse pregnancy outcomes
More recent analysis has found no evidence for consistent associations or causation
Furthermore, there is no association with MTHFR variants and mortality
Homocysteinemia should not be confused with homocystinuria, a rare genetic disease usually seen in childhood, which presents with extremely high homocysteine levels and is associated with severe, early onset vascular disease and venous thromboembolism
There is no evidence that it is dangerous to vaccinate children with MTHFR mutations nor is testing of children for this reason indicated
Is there clinical utility to clinical testing for MTHFR variants?
MTHFR is only one factor in hyperhomocysteinemia
Fortification of cereals has led to higher folate levels and therefore reduced homocysteine levels
Due to gene-nutrient interaction, previous associations between MTHFR variants and disease may no longer be relevant
For example, the association between 677C>T and venous thromboembolism is no longer seen in the US
Lowering homocysteine levels through vitamin supplementation does not reduce the risk of blood clots or cardiovascular disease
MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia, recurrent pregnancy loss, or for at-risk family members.
Testing for MTHFR mutations in not recommended for recurrent pregnancy loss, as only antiphospholipid syndrome has shown consistent associations
MTHFR variants in isolation do not confer additional risk for thrombosis in either pregnant or nonpregnant women and therefore testing for MTHFR variants or fasting homocysteine levels in not recommended for the work up of venous thromboembolism
There is lack of association between heterozygosity or homozygosity for 677C>T and any negative pregnancy outcomes
ASRM and NSGC
Testing for MTHFR variants for recurrent pregnancy loss is not recommended
MTHFR polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss or for at-risk family members
Do not adjust preventative folic acid supplementation dose for NTDs based on MTHFR results
Due to lack of clinical utility and available data, treating hyperhomocysteinemia in patients with cardiovascular disease or VTE is not recommended, nor is vitamin supplementation for primary prevention of cardiovascular disease recommended
Joint Statement on Expanded Carrier Screening (ACOG/ACMG/NSGC/PQF/SMFM)
It may be preferable not to include variants on expanded prenatal genetic carrier panels that have high allele frequencies and low penetrance of a phenotype such as MTHFR
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Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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