The Part MTHFR Plays in Infertility and Miscarriages

The Part MTHFR Plays in Infertility and Miscarriages

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

May 25, 2025

Table of Contents

    The Part MTHFR Plays in Infertility and Miscarriages

    Infertility and miscarriage are devastating for both men and women. There are a wide range of reasons that infertility and miscarriages occur, but they often remain unexplained.


    Previously, research has suggested that at least half of miscarriages may be due to genetic abnormalities in the embryo,1 particularly chromosomal abnormalities.


    However, scientists have now detected that male and female infertility factors may include hormones, diet, and parental genetics.2 In particular, the MTHFR gene has emerged as a possible influence on male infertility3 and an increased risk of miscarriage.4


    Understanding the MTHFR gene and how it affects your fertility is essential for anyone trying to have children. It’s especially important for women as it may affect their ability to get pregnant, the pregnancy itself, or the future child’s health.


    This article will give an overview of the links between MTHFR, infertility, and miscarriage as well as whether having an MTHFR mutation can affect your chances of starting a family or not. We will also discuss possible health issues that can arise during pregnancy and the perinatal period and your options for minimizing these issues.

    How Does MTHFR Affect Female Fertility and Pregnancy?

    Folate is crucial for the healthy growth and development of the fetus,5 particularly in proper DNA replication. Demands for folate increase during pregnancy.


    For this reason, women who are considering starting a family are generally recommended to take folic acid.


    However, a mutation on the MTHFR gene can impair the body’s ability to carry out the methylation process, which is crucial for converting folic acid into folate. This process is also required for the breakdown of homocysteine to methionine.


    Deficiencies of folate and high levels of homocysteine can lead to health issues for both fertility and pregnancy,6 including Neural Tube Defects (NTD) and pregnancy loss.


    Maternal homocysteine has an independent effect on placenta-mediated pregnancy complications.7 Elevated maternal homocysteine has been implicated in complications including preeclampsia, placental abruption, intrauterine growth restriction (IUGR), and miscarriage. These complications are all linked to abnormal placental vasculature. High levels of homocysteine have also been linked to poor fertility due to low ovulation. This appears to occur in women both with and without polycystic ovarian syndrome.8


    Methylation is involved in the growth and development of important tissues required for a healthy pregnancy, including the endometrium. It’s also involved in proper ovulation.


    Healthy endometrium is essential for the successful implantation of the fertilized egg, so impairment of the methylation process may also affect the early stages of pregnancy.9

    How Does MTHFR Affect Male Fertility?

    Several studies have indicated that the MTHFR genetic mutations may be associated with male infertility.


    A meta-analysis of 37 studies showed that the MTHFR C677T mutation was a risk factor10 for both azoospermia (when there are no sperm in the ejaculate) and for oligoasthenoteratozoospermia (low sperm count).


    These conditions are especially noted in Asian men and can contribute significantly to poor male fertility. It was also found that men who were homozygous for 677TT11 were affected to a greater extent than heterozygous patients (C677T).


    The MTHFR A1298C mutation appeared not to be related to male infertility.


    MTHFR mutations affect the vital functions of folate-related enzymes. Homocysteine disrupts the synthesis of methionine, which in turn impacts negatively on protein synthesis and methylation. DNA repair can also be affected. A significant link between the incidence of methylation errors, defective sperm development,12 and the impact on embryonic development has now been well established.

    Possible Pregnancy Issues

    Early pregnancy loss (EPL)


    EPL rate is shown to increase with the degree of MTHFR polymorphism complexity. Pregnancy loss also appears to be significantly higher in patients with the C677T polymorphism compared to A1298C.


    Neural tube defects


    Neural tube defects include any congenital disability of the brain, spine, and/or spinal cord. They can result in nerve damage, learning disabilities, paralysis, and death. The C677T gene13 is particularly associated with an increased risk of NTD.


    Repeated miscarriage


    The 1298AC and C677T/1298AC14 genotypes appear to be risk factors for unexplained repeated pregnancy loss. Pregnancy loss also appears to be highest in women with two mutations (homozygous) of either A1298C or C677T.


    Intrauterine growth retardation (IUGR)


    IUGR occurs when the fetus does not grow as expected. The C677T polymorphism15 is associated with an increased risk of IUGR and placental abruption in the global population, especially in Caucasians and Africans.


    Preeclampsia (high blood pressure during pregnancy)


    The C677T genotype16 is associated with increased risk for PE, especially in Asians and Caucasians.


    Ablation placenta (partial or complete separation of the placenta from the inner wall of the uterus before delivery)


    While some studies have linked C677T17 with increased risk for placenta ablation, others have not.


    Fetal aneuploidies (presence or absence of one or more chromosomes)


    MTHFR is shown to be one of the few known human genes that can modulate rates of chromosome abnormality,18 in which either the number or structure of chromosomes are altered. For this reason, there is a correlation of C677T19 with Down syndrome and neural tube defects in the fetus.

    Possible Perinatal Issues

    Preterm delivery (babies born alive before 37 weeks of pregnancy)


    The C677T polymorphism20 may increase the risk of premature delivery, while the A1298C may reduce the risk.


    Congenital abnormalities


    A wide range of structural or functional abnormalities of prenatal origin with significant medical, social or cosmetic consequences, usually requiring medical intervention (e.g., cleft lip, spina bifida). The C677T type21 is a risk factor for congenital heart defects.


    Stillbirth/pregnancy loss


    A meta-analysis of the A1298C polymorphism in both repeat pregnancy loss and in miscarriage suggested that A1298C22 can increase the risk for pregnancy loss.

    What Options Do You Have?

    Many of the adverse pregnancy and perinatal outcomes associated with MTHFR stem from the body’s inability to process and use folate.


    Homocysteine-methionine and MTHFR-related biochemical pathways are required for an enormous range of biological processes23 during pregnancy, including the synthesis of various nucleotides and DNA methylation.


    Those with the MTHFR polymorphism - especially C677T - have very low activity of the MTHFR enzyme. This reduces their ability to convert folic acid into a usable form and can lead to the accumulation of the toxic amino acid homocysteine.

    Lifestyle recommendations

    Those with MTHFR are advised to avoid foods and supplements containing synthetic folic acid. This includes fortified foods.


    Instead, they should choose foods that contain natural forms of folate. Folate-rich foods include:

    • Dark, leafy greens
    • Fresh fruits and raw juices
    • Nuts
    • Beans
    • Peas
    • Seafood
    • Eggs
    • Dairy products
    • Meat
    • Poultry
    • Grains


    Other foods that support healthy methylation include asparagus, avocado, broccoli, and legumes.

    Supplementation

    Taking the bioavailable form of folate is the most effective way to provide adequate amounts of this nutrient. One study compared women who used a prenatal supplement that contained L-methylfolate with women who took folic acid. The L-methylfolate supplement resulted in significantly higher hemoglobin levels at the end of the second trimester and at delivery, including a lower incidence of anemia and adverse outcomes.24


    Supplementation with folic acid has also been linked to adverse health issues, including masking vitamin B12 deficiency. In offspring,25 folic acid may increase the risk of insulin resistance, certain cancers, depression, cognitive impairment, as well as reduced size.


    Unlike folic acid, methylfolate is already converted to its usable form. It can bypass an MTHFR polymorphism26 and cross the blood-brain barrier for immediate use in the body.


    Supplementing methylfolate is crucial, both before and after conception, especially for women with the C677T mutation. C677T has been associated with an increased risk of NTD in numerous studies; however, methylfolate has been shown to increase plasma folate more effectively than folic acid27 in women with the homozygous or wild-type C667T.


    The Methyl-Life® product range including our Methylated Multivitamin, B-Methylated II, and Methylfolate 2.5 supplements are well suited to those with an MTHFR mutation who are considering starting a family.


    These best-selling products are formulated with Magnafolate® PRO, a proprietary form of methylfolate shown to be more pure and stable than the other L-Methylfolates available on the health supplement market today.

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    References

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      https://www.sciencedirect.com/science/article/pii/S0925443912001494

    2. Thejaswini Venkatesh, Padmanaban S Suresh, Rie Tsutsumi; "New insights into the genetic basis of infertility"; The application of clinical genetics; 2014 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259396/

    3. Shelley M Vanderhout, Matineh Rastegar Panah, Bibiana Garcia-Bailo, Patricia Grace-Farfaglia, Konrad Samsel, Judith Dockray, Keith Jarvi, Ahmed El-Sohemy; "Nutrition, genetic variation and male fertility"; Translational andrology and urology; 2021 Mar

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

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    5. 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

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      https://www.hindawi.com/journals/bmri/2021/6652231/

    7. Shazia H. Chaudhry, Monica Taljaard, Amanda J. MacFarlane, Laura M. Gaudet, Graeme N. Smith, Marc Rodger, Ruth Rennicks White, Mark C. Walker, Shi Wu Wen; "The role of maternal homocysteine concentration in placenta-mediated complications: findings from the Ottawa and Kingston birth cohort"; Open access; 2019 Feb

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    8. Kara A. Michels, Jean Wactawski-Wende, James L. Mills, Karen C. Schliep, Audrey J. Gaskins, Edwina H. Yeung, Keewan Kim, Torie C. Plowden, Lindsey A. Sjaarda, Ellen N. Chaljub, Sunni L. Mumford; "Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women"; Human Reproduction, Vol. 32, Iss. 8; 2017 Aug

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    9. Shuntaro IKEDA, Hiroyuki KOYAMA, Miki SUGIMOTO, Shinichi KUME; "Roles of One-carbon Metabolism in Preimplantation Period"; Journal of Reproduction and Development; 2012

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    10. Kang Liu, Ruizhe Zhao, Min Shen, Jiaxin Ye, Xiao Li, Yuan Huang, Lixin Hua, Zengjun Wang, Jie Li; "Role of genetic mutations in folate-related enzyme genes on Male Infertility"; Open Access; 2015 Nov

      https://www.nature.com/articles/srep15548

    11. Dominique Cornet, Marc Cohen, Arthur Clement, Edouard Amar, Laetitia Fournols, Patrice Clement, Paul Neveux, Yves Ménézo; "Association between the MTHFR-C677T isoform and structure of sperm DNA"; Journal of assisted reproduction and genetics; 2017 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633564/#CR5

    12. Ozlem Tunc, Kelton Tremellen; "Oxidative DNA damage impairs global sperm DNA methylation in infertile men"; Journal of Assisted Reproduction and Genetics; 2009 Oct

      https://link.springer.com/article/10.1007%2Fs10815-009-9346-2

    13. Peadar N Kirke, James L Mills, Anne M Molloy, Lawrence C Brody, Valerie B O'Leary, Leslie Daly, Sharon Murray, Mary Conley, Philip D Mayne, Owen Smith, John M Scott; "Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study"; BMJ : British medical journal / British Medical Association; 2004 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC437144/

    14. Yajuan Xu, Yanjie Ban, Limin Ran, Yanru Yu, Shanshan Zhai, Zongzong Sun, Jingzhe Zhang, Miao Zhang, Teng Hong, Rui Liu, Lidan Ren, Lulu Hu; "Relationship between unexplained recurrent pregnancy loss and 5,10-methylenetetrahydrofolate reductase) polymorphisms"; Fertility and sterility; 2019 Mar

      https://pubmed.ncbi.nlm.nih.gov/30660395/

    15. 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/

    16. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429450/

    17. Cande V Ananth, Morgan R Peltier, Celeste De Marco, Denise Elsasser, Darios Getahun, Rima Rozen, John C Smulian, for the New Jersey-Placental Abruption Study Investigators; "Associations Between Two Polymorphisms in the Methylenetetrahydrofolate Reductase Gene and Placental Abruption"; American journal of obstetrics and gynecology; 2008 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2084064/

    18. María Enciso, Jonás Sarasa, Leoni Xanthopoulou, Sara Bristow, Megan Bowles, Elpida Fragouli, Joy Delhanty, Dagan Wells; "Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy"; Human Genetics; 2016 Apr

      https://link.springer.com/article/10.1007/s00439-016-1652-z

    19. Agnieszka Seremak-Mrozikiewicz; "[The significance of folate metabolism in complications of pregnant women]"; Ginekologia polska; 2013 May

      https://pubmed.ncbi.nlm.nih.gov/23819405/

    20. Yanrong Nan, Hongmei Li; "MTHFR genetic polymorphism increases the risk of preterm delivery"; International journal of clinical and experimental pathology; 2015 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525976/

    21. Ingrid M. van Beynum, Livia Kapusta, Martin den Heijer, Sita H.H.M. Vermeulen, Margreet Kouwenberg, Otto Daniëls, Henk J. Blom; "Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation"; European Heart Journal; 2006 Mar

      https://academic.oup.com/eurheartj/article/27/8/981/438946

    22. Rohini R Nair, Anuradha Khanna, Rajender Singh, Kiran Singh; "Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis"; Fertility and sterility; 2013 Apr

      https://pubmed.ncbi.nlm.nih.gov/23357458/

    23. Patrick J Stover; "One-Carbon Metabolism–Genome Interactions in Folate-Associated Pathologies"; The Journal of nutrition; 2009 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777484/

    24. Susan Bentley, Amy Hermes, Diane Phillips, Yahya A Daoud, Sylvia Hanna; "Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis"; Clinical therapeutics; 2011 Feb

      https://pubmed.ncbi.nlm.nih.gov/21440300/

    25. Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak, Irena Mlinarič-Raščan; "Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate"; Journal of clinical medicine; 2020 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

    26. Maša Vidmar Golja, Alenka Šmid, Nataša Karas Kuželički, Jurij Trontelj, Ksenija Geršak, Irena Mlinarič-Raščan; "Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate"; Journal of clinical medicine; 2020 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564482/

    27. R Prinz-Langenohl, S Brämswig, O Tobolski, YM Smulders, DEC Smith, PM Finglas, K Pietrzik; "[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase"; British Journal of Pharmacology; 2009 Dec

      https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2009.00492.x

    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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