MTHFR and Pregnancy Success

MTHFR and Pregnancy Success

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Dr. Nare Simonyan - PhD Pharmaceutical Science

Edited By:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Last updated:

How the MTHFR Mutation Affects Pregnancy

Women with certain MTHFR genetic variants who are planning a pregnancy may have questions about miscarriage, preeclampsia, and birth defects. Some research has reported associations between common MTHFR mutations, folate status, homocysteine, and adverse pregnancy outcomes. It’s important to note that these findings are often linked to folate deficiency, which can be prevented.1


Folate (vitamin B9) is essential during early pregnancy because it is involved in DNA synthesis, cell division, and methylation reactions in rapidly dividing tissues. Adequate folate before conception and in early pregnancy lowers the risk of neural tube defects affecting the baby’s brain and spinal cord.2


The MTHFR gene encodes the methylenetetrahydrofolate reductase enzyme, which converts 5,10‑methylenetetrahydrofolate to 5‑methyltetrahydrofolate (5‑MTHF), the main circulating form of folate used in the body. Certain MTHFR mutations reduce enzyme activity, which can lower 5‑MTHF availability and lead to increased homocysteine.

In pregnancy, low folate levels and elevated homocysteine have been linked to a higher risk of neural tube defects and other complications.3

The Role of the MTHFR Gene in Pregnancy

The MTHFR gene provides instructions for the production of the MTHFR enzyme, which has a key role in converting folate to its biologically active form, 5-methyltetrahydrofolate (methylfolate). Methylfolate is one of the body’s primary methyl donors, required for the chemical reactions in DNA/RNA synthesis and methylation. These processes are vital for healthy fetal development.


Mutations in the MTHFR gene can impair the production of the MTHFR enzyme. Depending on the severity of the mutation, this means the body cannot metabolize folic acid properly. Common variants such as C677T can reduce MTHFR activity by around 35-70%.4

As a result, those with certain MTHFR genotypes typically have lower serum folate levels.


Low folate levels during pregnancy can alter DNA synthesis and repair and reduce methylation capacity in rapidly dividing embryonic tissues, which has been linked to neural tube defects and other congenital abnormalities. Folate is also required for the conversion of homocysteine to methionine, and high homocysteine (hyperhomocysteinemia) is also linked to pregnancy complications and poor outcomes.5

How an MTHFR Mutation Affects Developing Embryos

MTHFR gene mutations (specifically C677T) are linked to a higher risk of neural tube defects (NTDs) because they impair folate metabolism. Folate is essential for the closure of the neural tube which occurs within the first 28 days of pregnancy (embryogenesis). 

Neural tube defects (NTDs) are complex congenital malformations such as anencephaly, spina bifida, and encephalocele, which are caused by the failure of the neural tube to close. This is closely linked to folate deficiency, although other factors may also be involved. 

DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Folate deficiency can also result in DNA hypomethylation and other errors, increasing the risk of genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration.6 These have been linked to NTDs. 

Possible Fetal Development Disorders

Maternal folate levels have important impacts on fetal development. Fetal development disorders and neonatal risk linked to MTHFR mutations may include:

  • Neural Tube Defects (NTDs)
    Higher risk among those with the MTHFR C677T mutation as typical MTHFR enzymatic activity in carriers of the TT and CT genotypes is reduced by around 70% and 35%, respectively.7

  • Congenital Heart Defects
    Some research has shown that the MTHFR C677T variant is associated with the risk of congenital heart defects.8

  • Intrauterine Growth Restriction (IUGR)
    The MTHFR C677T mutation may increase risk of IUGR and placental abruption.9

  • Developmental delay
    Animal studies suggest that the MTHFR C677T variant (which mimics human 677TT) is associated with an increased risk of developmental delays.10

How Can You Have a Successful Pregnancy with MTHFR?

Women who are pregnant or planning pregnancy are often advised to take folic acid. Folic acid is the synthetic form of folate most commonly used in prenatal supplements, and has been shown to prevent up to 70% of neural tube defects.11


However, folic acid is not always suitable for women with MTHFR mutations. While research suggests that folic acid still increases folate levels, the conversion from folic acid to methylfolate may be less efficient, especially at higher doses. Supplementing with methylfolate (5‑MTHF) provides folate in its bioactive form and bypasses the MTHFR enzyme step.12


Methylfolate is biologically suitable as an alternative supplemental form to folic acid because it is directly usable by cells, and effectively improves folate biomarkers in women of reproductive age. It does not lead to unmetabolized folic acid in the circulation, has no defined tolerable upper intake level, and does not mask vitamin B12 deficiency, which are key advantages over folic acid.13


A 2024 study in pregnant women found that methylfolate was as effective as folic acid at maintaining serum and erythrocyte folate concentrations during pregnancy. In addition, it did not result in circulating levels of unmetabolized folic acid.14


A 2024 study on hypertensive disorders during pregnancy found that methylfolate increased endothelial BH4 (a cofactor for endothelial nitric oxide synthase in vascular cells) and also reduced oxidative stress and improved nitric oxide synthase activity, while folic acid did not. Methylfolate also prevented and treated hypertension in mice and reduced fetal growth restriction when given from mid‑gestation onwards.15

Other studies have shown that methylfolate supplementation restores folate levels in women more quickly and consistently than folic acid due to its higher bioavailability.16


However, despite the potential value of 5-MTHF as an alternative to folic acid, clinical studies regarding its efficacy and dosage are still limited. Only folic acid has clinical trial evidence for preventing neural tube defects, so it is still most commonly recommended by clinicians.17


The FDA and the European Food Standards Agency have approved products containing a 5-MTHF calcium salt and a 5-MTHF glucosamine salt for use in pregnancy.

MTHFR and Pregnancy Success

Key takeaways

  • Icon Common MTHFR variants can lead to low folate levels and high homocysteine, which is linked to higher risks of neural tube defects and some adverse pregnancy outcomes.
  • Icon For people with MTHFR variants, a prenatal with methylfolate plus other key B vitamins can help support healthy pregnancy outcomes.
  • Icon Currently, folic acid is the only form of folate supported by clinical studies for preventing neural tube defects, but methylfolate is the biologically active alternative that bypasses MTHFR.

Product Recommendations

MTHFR Supplements: L-Methylfolate, Vitamin B12 Supplement, Multivitamin & Magnesium

MTHFR Supplements: L-Methylfolate, Vitamin B12 Supplement, Multivitamin & Magnesium

$125.00

  • Fully Bioactive L-Methylfolate & Vitamin B12 Supplement
  • Cofactors Supporting Methylation, Cognition & Wellbeing
  • Superior-Absorbing Magnesium, Proven in Human Study
  • 3rd-Party Tested for Purity & Safety, Non-GMO, Gluten-Free

Frequently Asked Questions about MTHFR and Pregnancy Success

How to have a successful pregnancy with MTHFR?

Although the MTHFR genetic mutation has been associated with certain pregnancy complications, it does not mean you cannot have a successful pregnancy. Many of the complications associated with MTHFR are due to folate deficiency and high homocysteine. Improving your folate levels with biologically active folate (methylfolate) along with other B vitamins can support healthy fetal development and maternal wellbeing.

Can MTHFR affect pregnancy?

A MTHFR mutation may affect pregnancy if it leads to folate deficiency. Folate is critical to the health and development of a fetus, and deficiency is common in people with MTHFR mutations as the body is unable to properly metabolize folic acid. However, supplementing with active folate (methylfolate) and other B vitamins during pregnancy and preconception can help support healthy pregnancy outcomes.

Can you take prenatals with MTHFR?

Yes, but research suggests that pregnant women with MTHFR should take a prenatal that contains methylfolate rather than folic acid. People with MTHFR cannot properly convert folic acid to the active form required for many of the processes that contribute to fetal development. Only methylfolate can be used by the body without further conversion.

What to take during pregnancy if you have MTHFR?

Everyone is different, so it’s best to discuss your own personal needs with your healthcare professional. However, general recommendations for pregnant women with MTHFR mutations are to supplement with bioactive methylfolate and other active B vitamins, as these help support the development of the fetus.

Can MTHFR cause recurrent pregnancy loss?

Some research has shown that the MTHFR mutations C677T and A1298C are associated with recurrent pregnancy loss. This is usually a result of high homocysteine, and women with these mutations are advised to supplement with methylfolate and vitamin B12, as well as appropriate physical exercise.

References

  1. Benkhalifa Mustapha, Lahimer Marwa, Bahri Hatem, Zidi Wiem, Beaumont Marion, Chougar Taous, Cabry Rosalie, Benkhalifa Moncef; "Assessment of Genetic Polymorphism’s of MTHFR, Homocysteine, MTRR, and Leiden Factors in Infertile Women with Recurrent Pregnancy Loss"; BioMedical Journal of Scientific & Technical Research; 2025 May

    https://biomedres.us/pdfs/BJSTR.MS.ID.009667.pdf

  2. Fikadu Seyoum Tola; "The concept of folic acid supplementation and its role in prevention of neural tube defect among pregnant women: PRISMA"; Medicine (Baltimore); 2024 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11081602/

  3. Priyanka Thakur, Anuja Bhalerao; "High Homocysteine Levels During Pregnancy and Its Association With Placenta-Mediated Complications: A Scoping Review"; Cureus; 2023 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10034471/

  4. Nitish Kumar Singh, Sarita Choudhary, Sangeeta Rai, Abhay Kumar Yadav, Royana Singh; "Association between the MTHFR (rs1801133) gene variation and serum trace elements levels (Copper and Zinc) in individuals diagnosed with neural tube defects"; Clinica Chimica Acta; 2024 Apr

    https://www.sciencedirect.com/science/article/abs/pii/S0009898124021089

  5. Priyanka Thakur, Anuja Bhalerao; "High Homocysteine Levels During Pregnancy and Its Association With Placenta-Mediated Complications: A Scoping Review"; Cureus; 2023 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10034471/

  6. Xiuwei Wang, Jialu Yu, Jianhua Wang; "Neural Tube Defects and Folate Deficiency: Is DNA Repair Defective?"; International journal of molecular sciences; 2023 Jan

    https://pubmed.ncbi.nlm.nih.gov/36768542/

  7. Nitish Kumar Singh, Sarita Choudhary, Sangeeta Rai, Abhay Kumar Yadav, Royana Singh; "Association between the MTHFR (rs1801133) gene variation and serum trace elements levels (Copper and Zinc) in individuals diagnosed with neural tube defects"; Clinica Chimica Acta; 2024 Apr

    https://www.sciencedirect.com/science/article/abs/pii/S0009898124021089

  8. Nora N. Esmaiel, Engy A. Ashaat, Ghada M. Al-Ettribi, Alaaeldin Fayez, Sonia A. Alsaiedi, Mona O. El Ruby; "Association between MTHFR C677T variant and risk for congenital heart defects in Egyptian children: a case–control study including meta-analysis based on 147 cases and 143 controls"; Egyptian Journal of Medical Human Genetics; 2023 Apr

    https://link.springer.com/article/10.1186/s43042-023-00408-y

  9. Reza Bahrami, David A Schwartz, Fatemeh Asadian, Mojgan Karimi-Zarchi, Seyed Alireza Dastgheib, Razieh Sadat Tabatabaie, Bahare Meibodi, Hossein Neamatzadeh; "Association of MTHFR 677C>T polymorphism with IUGR and placental abruption risk: A systematic review and meta-analysis"; European journal of obstetrics, gynecology, and reproductive biology; 2021 Jan

    https://pubmed.ncbi.nlm.nih.gov/33212322/

  10. Karen E. Christensen, Marie-Lou Faquette, Vafa Keser, Alaina M. Reagan, Aaron T. Gebert, Teodoro Bottiglieri, Gareth R. Howell, Rima Rozen; "Low Dietary Folate Increases Developmental Delays in the Litters of Mthfr677TT Mice"; Nutrients; 2025

    https://www.mdpi.com/2072-6643/17/15/2536

  11. Viswanathan M, Urrutia RP, Hudson KN, et al.; "Folic Acid Supplementation to Prevent Neural Tube Defects: A Limited Systematic Review Update for the U.S. Preventive Services Task Force [Internet]."; Rockville (MD): Agency for Healthcare Research and Quality (US); 2023 Aug

    https://www.ncbi.nlm.nih.gov/books/NBK593617/

  12. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative medicine; 2022 Jul

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836

  13. Yasmin Dickinson, Ruth Boehni, Rima Obeid, Jean-Pierre Knapp, Rudolf Moser, Adam J. Lewandowski, Gillian Douglas, Paul Leeson, Keith M. Channon, Surawee Chuaiphichai; "Novel Role of 5-Methyl-(6S)-Tetrahydrofolate in Mediating Endothelial Cell Tetrahydrobiopterin in Pregnancy and Implications for Gestational Hypertension"; Hypertension; 2024 Jul

    https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.22838

  14. Kelsey M Cochrane, Rajavel Elango, Angela M Devlin, Chantal Mayer, Jennifer A Hutcheon, Crystal D Karakochuk; "Supplementation with (6 S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada"; The British journal of nutrition; 2024 Jan

    https://pubmed.ncbi.nlm.nih.gov/37649241/

  15. Yasmin Dickinson, Ruth Boehni, Rima Obeid, Jean-Pierre Knapp, Rudolf Moser, Adam J. Lewandowski, Gillian Douglas, Paul Leeson, Keith M. Channon, Surawee Chuaiphichai; "Novel Role of 5-Methyl-(6S)-Tetrahydrofolate in Mediating Endothelial Cell Tetrahydrobiopterin in Pregnancy and Implications for Gestational Hypertension"; Hypertension; 2024 Jul

    https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.124.22838

  16. Steven W. Bailey, June E. Ayling; "The pharmacokinetic advantage of 5-methyltetrahydrofolate for minimization of the risk for birth defects"; Scientific Reports; 2018 Mar

    https://www.nature.com/articles/s41598-018-22191-2

  17. María de Lourdes Samaniego-Vaesken, Carmen Morais-Moreno, Alejandra Carretero-Krug, Ana María Puga, Ana María Montero-Bravo, Teresa Partearroyo, Varela-Moreiras Gregorio; "Supplementation with Folic Acid or 5-Methyltetrahydrofolate and Prevention of Neural Tube Defects: An Evidence-Based Narrative Review"; Nutrients; 2024 Sep

    https://pubmed.ncbi.nlm.nih.gov/39339754/

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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