The Part MTHFR Plays in Infertility and Miscarriages

The Part MTHFR Plays in Infertility and Miscarriages

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Jamie Hope - Methyl-Life® Founder

Edited By:

Jamie Hope - Methyl-Life® Founder
Last updated:

How does MTHFR affect fertility?

Folate is essential for DNA, RNA, and protein synthesis, for balancing homocysteine, and for supplying methyl groups involved in methylation. Because these processes are central to cell division and the turning ‘on’ and ‘off’ of genes, folate metabolism directly affects fertility and reproductive health, including assisted reproduction.1

How Does MTHFR Affect Female Fertility and Pregnancy?

Folate is especially critical for reproduction as it plays a key role in follicle development and fetal development, when cells divide rapidly.2

The enzyme MTHFR is required for converting folate into its active form. Genetic variations in the MTHFR gene impair this process, potentially leading to low folate levels.

The most studied MTHFR variants are C677T and A1298C. Evidence suggests the C677T variant may be linked with fewer oocytes, reduced oocyte maturation, lower fertilization rates, and higher miscarriage rates.3

How does MTHFR affect male fertility?

MTHFR C677T has been associated with poorer semen quality, including abnormal morphology, oligo-asthenospermia (low sperm count and low motility), and altered DNA structure. Supplementation with methylfolate may improve semen parameters which is important for healthy embryo development.4

MTHFR and fertility

Healthy blood vessels and folate levels are essential for fertility and pregnancy. High homocysteine - which is common in those with MTHFR variants - can have a negative impact on both conception and pregnancy.5


A 2024 study found that women with the C677T homozygous and A1298C wild-type variants had the lowest MTHFR enzyme activity and significantly lower oocyte maturation rates, as well as poorer embryo quality. These findings suggest that MTHFR mutations may impair early reproductive processes such as DNA replication, methylation, and gene expression during maturation of ovarian follicles.6

Possible pregnancy issues

During pregnancy, the demand for folate significantly increases five-to-10 fold due to its critical role in rapid cell division to support the growth and development of the fetus and maternal tissue, as well as DNA and RNA synthesis, and amino acid metabolism.7,8

Multiple clinical studies have indicated that fetal malformations may be linked to MTHFR and folate levels, and can then affect the fetus in early pregnancy.9 Researchers have also emphasized that mutations of the MTHFR gene may be involved in the occurrence and development of neural tube defects and/or fetal malformations.10

A 2022 analysis found that low folate levels and MTHFR are associated with a higher risk of fetal malformations in the early stages of pregnancy, particularly structural and chromosomal abnormalities.11

Possible perinatal issues

Beyond pregnancy complications, MTHFR variants have been linked to adverse perinatal outcomes such as intrauterine growth restriction, preeclampsia, preterm labor, placental abruption, and stillbirth.12

Low folate levels may also contribute to maternal mood disorders, including antenatal and postpartum depression.13

A 2022 meta-analysis of 19 case-control studies confirmed a significant link between MTHFR C677T and neural tube defects (NTD), especially spina bifida.14 Previous research has indicated that low folate may play a role in around 80% of NTD cases.15

Researchers estimate that up to half of birth defects could be prevented by improving folate levels before conception.16

MTHFR and miscarriages

Multiple studies indicate that impaired MTHFR activity increases risk of early pregnancy loss.

A 2018 study found that the severity of MTHFR variants correlated with risk of miscarriage, and that risk was significantly higher in patients with MTHFR C677T.17

A 2021 meta-analysis also suggested that MTHFR C677T (single mutation) and 677TT and MTHFR 1298CC genotypes (both double mutations) were both associated with unexplained recurrent pregnancy loss. The researchers suggested that MTHFR impaired folate metabolism and methylation pathways, which are critical for DNA synthesis and normal fetal development, were the cause.18

A 2017 study found that couples with recurrent miscarriage and unresponsiveness to high-dose folic acid, achieved pregnancies after supplementing with methylfolate. This suggested that methylfolate may support better pregnancy outcomes than folic acid.19

MTHFR and IVF

A 2022 study involving 1,173 women undergoing their first IVF embryo transplant found that the MTHFR 677TT (double mutation) reduces enzyme activity, leading to impaired folate metabolism, higher homocysteine, and potentially poorer oocyte and embryo quality. Those with MTHFR 677TT had significantly reduced numbers of transferable embryos and cumulative live birth rates.

MTHFR and PCOS (polycystic ovarian syndrome)

A 2025 study found that elevated homocysteine and MTHFR variants C677T and A1298C are significantly associated with PCOS and adverse reproductive outcomes, especially recurrent pregnancy loss. Women with PCOS were also more likely to have MTHFR C677T and A1298C variants (double mutation) than women who didn’t have PCOS. Researchers suggested that MTHFR may affect fertility and pregnancy by increasing homocysteine levels.20

MTHFR and preeclampsia

A 2015 meta-analysis found that women with the MTHFR C677T variant had a 1.4-fold higher risk of preeclampsia. Although the mechanism is unclear, researchers suggest that impaired endothelial function and impaired folate metabolism may contribute.21

Testing for MTHFR while pregnant

Testing for MTHFR during pregnancy is not a standard medical practice and is not recommended by the American College of Medical Genetics and Genomics.22 However, some fertility clinics may test for MTHFR SNPs and homocysteine in patients with recurrent miscarriage or unexplained infertility.23

Treatment options and lifestyle recommendations for MTHFR-related fertility issues

Pregnant women are generally advised to take 400 mcg of folic acid daily, starting at least one month before conception and ideally continuing throughout the entire pregnancy. 

However, researchers and many health practitioners emphasize that folic acid is not suitable for pregnant women with MTHFR due to their inability to process it. Unmetabolized folic acid can mask B12 deficiency and anemia, and can also accumulate in the bloodstream as unmetabolized folic acid (UMFA), which may pose risks to the health of both mother and baby.24

Methylfolate is consistently recommended as an alternative to folic acid. It is the active form of folate and immediately available for use upon ingestion, and bypasses the MTHFR mutation. Several studies have shown that methyfolate is effective in reducing homocysteine, improving fertility, preventing neural tube defects, and reducing symptoms of depression.25

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  • Bioactive L-Methylfolate 3 Mg & Methylated B12
  • Great for Bypassing MTHFR Mutations
  • 3rd-Party Tested for Purity, Potency & Safety
  • 90 Vegan, Non-GMO, Chewable Mint Tablets

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Frequently Asked Questions about MTHFR and fertility

Is it hard to get pregnant with MTHFR?

Research suggests that women with a MTHFR mutation may find it more difficult to get pregnant, especially if they have high homocysteine and/or low folate levels. This may be because folate supports healthy DNA/RNA synthesis, reproductive function, oocyte quality, as well as healthy blood vessels.

Is MTHFR related to miscarriage?

Studies suggest that certain MTHFR mutations may increase the risk of miscarriage. Miscarriage is shown to be significantly higher in patients with MTHFR C677T compared to those with MTHFR A1298C.26

How to avoid miscarriage with MTHFR?

If you have been diagnosed with MTHFR and are planning to start a family, it’s highly recommended that you talk to a health practitioner. They may recommend that you supplement with methylfolate, the active form of folate that bypasses the MTHFR mutation and improves folate levels. Folate is critical for healthy reproductive function, fertility, and pregnancy.

What prenatal should I take if I have MTHFR?

If you have MTHFR, look for a prenatal that contains methylfolate rather than folic acid. Research suggests that folic acid is not suitable for those with MTHFR mutations as it cannot be processed properly, while methylfolate is not affected by MTHFR and is absorbed immediately. Folate is critical for healthy pregnancy and preventing neural tube defects.

Can I have a baby with MTHFR?

Yes, you can have a baby with MTHFR. However, it is recommended that you supplement with methylfolate rather than folic acid, as methylfolate is what your body needs during pregnancy.

How do you treat MTHFR infertility?

If you have MTHFR and you are struggling with infertility, it’s first of all very important that you talk to a qualified health practitioner about your health and possible options. Once they have assessed you, they may recommend that you take methylfolate, the active form of folate required for healthy reproductive function and fertility.

References

  1. Konstantinos Sfakianoudis, Athanasios Zikopoulos, Sokratis Grigoriadis, Nikolaos Seretis, Evangelos Maziotis, George Anifandis, Paraskevi Xystra, Charilaos Kostoulas, Urania Giougli, Konstantinos Pantos, Mara Simopoulou, Ioannis Georgiou; "The Role of One-Carbon Metabolism and Methyl Donors in Medically Assisted Reproduction: A Narrative Review of the Literature"; International journal of molecular sciences; 2024 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11084717/

  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. Yong-Jie Lu, Qin Li, Li-Xue Chen, Tian Tian, Jia Kang, Yong-Xiu Hao, Jian-Suo Zhou, Yuan-Yuan Wang, Li-Ying Yan, Rong Li, Liang Chang, Jie Qiao; "Association between maternal MTHFR C677T/A1298C combination polymorphisms and IVF/ICSI outcomes: a retrospective cohort study"; Human reproduction open; 2022 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9749479/

  4. Laetitia Jacquesson-Fournols, Edouard J Servy, Brian Dale, Arthur Clement, Yves JR Menezo; "MTHFR Testing in ART Should be Compulsory for both Male and Female Patients Including Oocyte Donation Programs"; Journal of Gynecology and Women’s Health; 2017 Oct

    https://www.laboclement.com/sites/default/files/publications/jgwh._mthfr_testing.pdf

  5. Henk J Blom, Yvo Smulders; "Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects"; Journal of inherited metabolic disease; 2011 Feb

    https://pubmed.ncbi.nlm.nih.gov/20814827/

  6. Yong-Jie Lu, Qin Li, Li-Xue Chen, Tian Tian, Jia Kang, Yong-Xiu Hao, Jian-Suo Zhou, Yuan-Yuan Wang, Li-Ying Yan, Rong Li, Liang Chang, Jie Qiao; "Association between maternal MTHFR C677T/A1298C combination polymorphisms and IVF/ICSI outcomes: a retrospective cohort study"; Human reproduction open; 2022 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9749479/

  7. James A Greenberg, Stacey J Bell, Yong Guan, Yan-hong Yu; "Folic Acid Supplementation and Pregnancy: More Than Just Neural Tube Defect Prevention"; Reviews in obstetrics & gynecology; 2011 Summer

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3218540

  8. 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/

  9. Vandana Kamath, Mary Purna Chacko, Richard Kirubakaran, Mariano Mascarenhas, Mohan S Kamath; "Single nucleotide polymorphism array versus karyotype for prenatal diagnosis in fetuses with abnormal ultrasound: A systematic review and meta-analysis"; European journal of obstetrics, gynecology, and reproductive biology; 2022 Apr

    https://pubmed.ncbi.nlm.nih.gov/35245714/

  10. Juan Carlos Fernández-Macías, Angeles Catalina Ochoa-Martínez, Anette Aylin Pérez-López, Amairani Lizbeth Pérez-López, Ignacio Neri-Maldonado, Iris Gabriela Piña-López, Iván Nelinho Pérez-Maldonado; "The interplay between exposure to PAHs and MTHFR C677T polymorphism on cardiovascular risk biomarkers in Mexican women"; Environmental science and pollution research international; 2022 Jul

    https://pubmed.ncbi.nlm.nih.gov/35192163/

  11. Hong Zhang, Juan Pan, Haoyu Jiang, Xiaobo Xiong, Lu Huang, Xin Liu, Wei Xin Wangzi, Lida Chen; "A study on the correlation between MTHFR and folic acid combined with trace elements for the prevention of fetal malformations in the first trimester of pregnancy"; Medicine (Baltimore); 2023 Nov

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10627646/

  12. Mert Turgal, Fatma Gumruk, Ergun Karaagaoglu, Mehmet Sinan Beksac; "Methylenetetrahydrofolate Reductase Polymorphisms and Pregnancy Outcome"; Geburtshilfe und Frauenheilkunde; 2018 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6138472/

  13. Emily Morris, Catriona Hippman, Arianne Albert, Caitlin Slomp, Angela Inglis, Prescilla Carrion, Rolan Batallones, Heather Andrighetti, Colin Ross, Roger Dyer, William Honer, Jehannine Austin; "A prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk womenA prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk women"; PLoS One; 2020 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7735580/

  14. Razieh Sadat Tabatabaei, Neda Fatahi-Meibodi, Bahare Meibodi, Atiyeh Javaheri, Hajar Abbasi, Amaneh Hadadan, Reza Bahrami, Seyed Reza Mirjalili, Mojgan Karimi-Zarchi, Hossein Neamatzadeh; "Association of Fetal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects: A Systematic Review and Update Meta-Analysis"; Fetal and Pediatric Pathology; 2020 Jun

    https://www.tandfonline.com/doi/full/10.1080/15513815.2020.1775734

  15. Nicholas J Wald; "Folic acid and neural tube defects: Discovery, debate and the need for policy change"; Journal of medical screening; 2022 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9381685/

  16. 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://pmc.ncbi.nlm.nih.gov/articles/PMC11435031/

  17. Mert Turgal, Fatma Gumruk, Ergun Karaagaoglu, Mehmet Sinan Beksac; "Methylenetetrahydrofolate Reductase Polymorphisms and Pregnancy Outcome"; Geburtshilfe und Frauenheilkunde; 2018 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6138472/

  18. Genzhu Wang, Zhaohui Lin, Xiaoying Wang, Qiang Sun, Zhikun Xun, Baiqian Xing, Zhongdong Li; "The association between 5, 10 – methylenetetrahydrofolate reductase and the risk of unexplained recurrent pregnancy loss in China"; Medicine (Baltimore); 2021 Apr

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8084099/

  19. E. Servy, Y. Menezo; "The Methylene Tetrahydrofolate Reductase (MTHFR) isoform challenge. High doses of folic acid are not a suitable option compared to 5 Methyltetrahydrofolate treatment"; openaccesstext.com; 2017

    https://api.semanticscholar.org/CorpusID:49331042

  20. Elene Asanidze, Zurab R Tsetskhladze, Jenaro Kristesashvili, Marina Pirtskhalava, Manana Urjumelashvili, Shorena Tchiokadze, Malkhaz Vakhania, Nino Parunashvili, Aleksandre Asanidze; "The Relationship between Homocysteine Levels, MTHFR C677T and A1298C Polymorphism, and Pregnancy Outcomes in Georgian Women with Polycystic Ovary Syndrome: A Case-Control Study"; International journal of fertility & sterility; 2025 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11744196/

  21. Xiaoming Wu, Kunxian Yang, Xiaodan Tang, Yalian Sa, Ruoyu Zhou, Jing Liu, Ying Luo, Wenru Tang; "Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for preeclampsia: a meta-analysis"; Journal of assisted reproduction and genetics; 2015 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC4429450/

  22. Laura Dean; "Methylenetetrahydrofolate Reductase Deficiency"; Medical Genetics Summaries [Internet]; 2024 Nov

    https://www.ncbi.nlm.nih.gov/books/NBK66131/

  23. Arthur Clément, Edouard Amar, Charles Brami, Patrice Clément, Silvia Alvarez, Laetitia Jacquesson-Fournols, Céline Davy, Marc Lalau-Keraly, Yves Menezo; "MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients"; Biomolecules; 2022 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9405832/

  24. Ali M Fardous, Ahmad R Heydari; "Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review"; Nutrients; 2023 Nov

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10648405/

  25. Enrico Ferrazzi, Giulia Tiso, Daniela Di Martino; "Folic acid versus 5- methyl tetrahydrofolate supplementation in pregnancy"; European journal of obstetrics, gynecology, and reproductive biology; 2020 Oct

    https://pubmed.ncbi.nlm.nih.gov/32868164/

  26. Mert Turgal, Fatma Gumruk, Ergun Karaagaoglu, Mehmet Sinan Beksac; "Methylenetetrahydrofolate Reductase Polymorphisms and Pregnancy Outcome"; Geburtshilfe und Frauenheilkunde; 2018 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6138472/

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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