MTHFR and Pregnancy Success

MTHFR and Pregnancy Success

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:

March 25, 2025

Table of Contents

    MTHFR and Pregnancy Success

    Recent research has shown that an MTHFR mutation may increase the risk of complications during pregnancy. It’s also been suggested that MTHFR may explain why some women have recurrent miscarriages.


    While more research is pending, this information will no doubt have many women with MTHFR wondering if they can have a successful pregnancy.


    The MTHFR gene codes the enzyme required for metabolizing folate. While most people with MTHFR can obtain enough folate from their diet to make up for this impaired metabolism, the body’s needs for folate are much greater during pregnancy. As a result, women with an MTHFR polymorphism may be at a higher risk of complications or birth defects due to lack of folate.


    Folate is crucial for proper DNA synthesis and repair, control of gene expression, and many other biological processes of fundamental importance for cell division and embryo development.


    Impaired folate metabolism can also lead to elevated levels of homocysteine, which has been linked to recurrent miscarriage1. It’s for this reason that women who have had multiple miscarriages are often advised to undergo testing for folate levels or hyperhomocysteinemia.


    The good news is that yes, it is possible to have a successful pregnancy with an MTHFR mutation. It’s just a matter of taking the right nutrients.


    This article will explain the risks associated with different MTHFR variants during pregnancy, how these risks can be minimized, and the most effective folate supplements that pregnant mothers can take.

    How Can You Have a Successful Pregnancy with MTHFR?

    Folate is crucial to fetal development2, which is why taking the correct form of folate prior to conception and during pregnancy can significantly improve your chances of a successful pregnancy.


    Folic acid supplements are often prescribed by doctors, and also used in fortified foods and many prenatal multivitamins. However, the MTHFR mutation impairs the body’s ability to methylate3 the synthetic folic acid into a usable form. This mutation may also interfere with nutrient status of other B vitamins, including B12.


    The solution is to source a prenatal vitamin that contains methylated folate, referred to as 5-MTHF or 5-methyl-tetra-hydro-folate. A methylated B12 should also be included.

    Can an MTHFR Mutation Cause Infertility?

    Several studies have suggested that MTHFR genetic mutations may be associated with male infertility because of its effect on spermatogenesis; however, results are largely inconsistent. MTHFR appears not to affect female fertility: one study showed that the C677T mutation was found in 49.2% of fertile women, and in 58.5% of infertile women4, which the study authors conclude was not statistically significant.


    A meta-analysis5 of 37 studies found that the MTHFR C677T mutation was a risk factor for male infertility in patients with azoospermia (no sperm in the ejaculate) and oligoasthenoteratozoospermia (low number of sperm). This was especially high in Asian men.


    Another meta-analysis in 20156 also suggested that the MTHFR 677C>T polymorphism is associated with an enhanced risk of male infertility, with the authors suggesting that this may be due to a deficiency in folate and vitamin B12.

    Recurrent Miscarriage with MTHFR

    Recurrent miscarriage is most often defined as three or more consecutive spontaneous fetal losses7.


    A 1997 study showed that a homozygous MTHFR gene mutation increased the risk of miscarriage more than three-fold8. More recently, a significant association was seen between MTHFR C677T polymorphism and the number of miscarriages, with study authors concluding that the higher the number of miscarriages, the higher the presence of the MTHFR mutation9.


    A 2019 study found that the 1298AC and 677CT/1298AC (composite heterozygous) genotypes were both risk factors for unexplained recurrent pregnancy loss. The risk was highest in women with two mutations of A1298C and C677T10, with the incidence increasing six-fold. The authors suggested that supplementation with “folic acid and other corresponding measures” would be necessary to reduce the risk of pregnancy loss.

    The Role the MTHFR Gene Plays in Pregnancy

    A mutation of the MTHFR gene affects the body’s ability to process folate, which is especially problematic during pregnancy.


    Folate is absolutely crucial for the proper DNA replication11 involved in a baby’s development. It is an essential factor for the growing placental tissue, acts as a substrate for the metabolism of several amino acids, and is required for the transmethylation pathway. MTHFR also plays a part in the control of gene expression by DNA12 methylation during the first trimester of pregnancy.


    Folate deficiencies can lead to health issues for both mother and the fetus. Mothers are at a higher risk of anemia or peripheral neuropathy13, while the fetus is more likely to suffer congenital abnormalities.


    It has been noted that many studies suggest hyperhomocysteinemia, homozygous MTHFR gene mutations, and folate deficiency14 to be likely risk factors for recurrent miscarriage, fetal death, blood clotting disorders in pregnancy, neural tube defects, and congenital cardiac issues, along with many other placental diseases.


    Reduced MTHFR enzyme activity decreases the conversion of homocysteine into methionine, resulting in higher levels of homocysteine in the blood.


    Hyperhomocysteinaemia can be caused by enzyme deficiencies related to MTHFR15 and a subsequent lack of cofactors required for methionine metabolism (vitamins B6, B12, and folic acid).

    How an MTHFR Mutation Affects Developing Embryos

    Folate deficiency has been associated with a higher risk of folate-dependent functions16 required for DNA synthesis and repair, control of gene expression, and many other biological processes involved in cell division and embryo development.


    MTHFR mutations are associated with an increased risk of aneuploid pregnancy. This study17 found that parental MTHFR genotypes had a higher risk of aneuploid embryos (embryos with too many or too few chromosomes), indicating that MTHFR may affect rates of chromosome abnormality.


    Another study involving women with and without MTHFR polymorphisms showed that 94.7% of the women18 in the MTHFR group had pregnancies with chromosomal abnormalities.


    Abnormal folate metabolism in MTHFR mutations can lead to improper DNA methylation, resulting in abnormal gene expression and DNA strand breaks. Studies in mice affected by MTHFR showed growth defects and the appearance of congenital malformations19 through several generations.

    What About MTHFR Variants?

    Some research suggests that different variants have different effects on pregnancy. The activity of the MTHFR enzyme20 is reduced by 35% in people who are 677CT carriers (heterozygosity) and by 70% among 677TT carriers (homozygosity).


    Homozygosity for C677T is associated with elevated homocysteine2122 in women with a history of early or late recurrent miscarriage.


    In another study, the 1298C allele was found to be significantly higher23 in miscarriages involving fetal chromosomal aneuploidy than the 1298AA genotype. There was no association between miscarriage with fetal chromosomal aneuploidy and other polymorphisms. This study also suggested that 1298AC polymorphism may be an independent risk factor for miscarriage with chromosomal abnormalities.

    Numerous studies have reported associations of MTHFR polymorphisms with an array of conditions including autism and fetal neural tube defects.


    MTHFR polymorphisms that disrupt folate metabolism may increase the risk of neural tube defects. However, study results are mixed.  Significant 5-MTHF deficiency24 has  been associated with metabolic defects, specific mitochondrial disorders, and cerebral problems.


    Congenital malformations among babies born to parents with MTHFR mutations include neural tube defects (NTD), cleft lip or cleft palate25, and congenital heart defects. In this study, the most common malformations26 were NTD (25.3%) and cardiac anomalies (25.3%). Around 90% of babies with NTDs in the study included patients with reduced MTHFR activity.


    However, some researchers have noted given the high prevalence of the MTHFR polymorphisms and the low frequency of neural tube defects, they suggested that the polymorphisms alone27 were unlikely to have a significant role in causing neural tube defects.


    While there may be some increased risk of neural tube defects in those with the homozygous 677C>T variant, the exact level of risk is still uncertain. Folate supplementation may be more important: population-level fortification with folate led to a significant drop in neural tube defects28 by about 70%.

    Prevention Through Supplementation

    Folate is crucial for pregnancy success. This nutrient is especially important during the first few weeks of a fetus' development, which is often before a woman discovers she’s pregnant.


    Folate deficiency has been associated with greater risk of infertility, miscarriage, development abnormalities, and other negative pregnancy outcomes.


    Numerous studies show a strong link between an impaired folate cycle, and consequently altered metabolic pathways, and the ability to conceive and carry a pregnancy to term. However, those with MTHFR polymorphisms C677T and A1298C and who suffered repeated miscarriages improved the chances of pregnancy to term29 by supplementing with 5-MTF.


    Folate-containing multivitamin supplements have also been shown to reduce the risk of NTD recurrence30 in women with a previously affected pregnancy. Supplements containing vitamin B12, a co-factor in folate one-carbon metabolism, may further reduce the frequency of NTDs31.


    It is recommended that folic acid be avoided by couples experiencing infertility. However, 5-MTHF bypasses the MTHFR block and is therefore an effective treatment32. It also avoids potential adverse effects of the Unmetabolized Folic Acid (UMFA) syndrome, which has its own adverse effects.


    Women who are trying to conceive should look for a prenatal supplement containing methylated folate.


    One of the best methylfolate supplements for those with MTHFR mutations is Methyl-Life® Methylated Multivitamin. The Methyl-Life® range has been created by a team of natural health experts and contains the purest, most stable, and most potent of four of the world’s industry-leading patented L-Methylfolates. It is also suitable for vegans and those with cardiovascular risks.

    Possible Fetal Development Disorders

    • Icon Behavioral disorders (e.g, autism)
    • Icon Neural tube defects
    • Icon Metabolic defects
    • Icon Mitochondrial disorders
    • Icon Congenital heart defects
    • Icon Cleft palate/cleft lip

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    References

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936988/

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

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    6. Mancheng Gong, Wenjing Dong, Tingyu He, Zhirong Shi, Guiying Huang, Rui Ren, Sichong Huang, Shaopeng Qiu, Runqiang Yuan; "MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies"; PLoS One; 2015 Mar

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    7. Philippe Merviel, Rosalie Cabry, Emmanuelle Lourdel, Segolene Lanta, Carole Amant, Henri Copin, Moncef Benkhalifa; "Comparison of two preventive treatments for patients with recurrent miscarriages carrying a C677T methylenetetrahydrofolate reductase mutation: 5-year experience"; Journal of International Medical Research; 2017 Jan

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    9. Anil Kumar Sah, Nisha Shrestha, Pratikshya Joshi, Renu Lakha, Sweta Shrestha, Laxmi Sharma, Avinash Chandra, Neetu Singh, Yuvraj KC, Bhola Rijal; "Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss"; BMC Research Notes; 2018 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887178/

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

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    13. 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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    15. ​Lab Tests Online; "MTHFR Mutation"; Lab Tests Online; 2021 Nov

      https://labtestsonline.org/tests/mthfr-mutation

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      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262611/

    17. 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

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

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

    19. Nisha Padmanabhan, Dongxin Jia, Colleen Geary-Joo, Xuchu Wu, Anne C Ferguson-Smith, Ernest Fung, Mark C Bieda, Floyd F Snyder, Roy A Gravel, James C Cross, Erica D Watson; "Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects On Development"; Cell; 2014 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844871/

    20. Philippe Merviel, Rosalie Cabry, Emmanuelle Lourdel, Segolene Lanta, Carole Amant, Henri Copin, Moncef Benkhalifa; "Comparison of two preventive treatments for patients with recurrent miscarriages carrying a C677T methylenetetrahydrofolate reductase mutation: 5-year experience"; Journal of International Medical Research; 2017 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805189/

    21. Mami Hiraoka, Yasuo Kagawa; "Genetic polymorphisms and folate status"; Congenital anomalies; 2017 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601299/

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      https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.1999.01319.x

    23. Shin Young Kim, So Yeon Park, Ji Won Choi, Do Jin Kim, Shin Yeong Lee, Ji Hyae Lim, Jung Yeol Han, Hyun Mee Ryu, Min Hyoung Kim; "Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy"; American journal of reproductive immunology; 2011 Oct

      https://pubmed.ncbi.nlm.nih.gov/21410812/

    24. Belén Pérez-Dueñas, Aida Ormazábal, Claudio Toma, Barbara Torrico, Bru Cormand, Mercedes Serrano, Cristina Sierra, Elisa De Grandis, Merce Pineda Marfa, Angels García-Cazorla, Jaime Campistol, Juan M Pascual, Rafael Artuch; "Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects"; Archives of neurology.; 2011 May

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    25. Xinjuan Pan, Ping Wang, Xinjuan Yin, Xiaozhuan Liu, Di Li, Xing Li, Yongchao Wang, Hongle Li, Zengli Yu; "Association between Maternal MTHFR Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in Offspring, A Meta-Analysis Based on 15 Case-Control Studies"; International Journal of Fertility & Sterility; 2015 Feb

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355933/

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

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

    27. --

      https://www.racgp.org.au/download/Documents/AFP/2016/April/AFP-Professional-Long.pdf

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      https://pubmed.ncbi.nlm.nih.gov/1677062/

    29. Edouard J Servy, Laetitia Jacquesson-Fournols, Marc Cohen, Yves J R Menezo; "MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series"; Journal of Assisted Reproduction and Genetics; 2018 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086798/

    30. Sarah G Obican, Richard H Finnell, James L Mills, Gary M Shaw, Anthony R Scialli; "Folic acid in early pregnancy: a public health success story"; FASEB journal : official publication of the Federation of American Societies for Experimental Biology; 2010 Nov

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    31. N D Greene, A J Copp; "Inositol prevents folate-resistant neural tube defects in the mouse"; Nature medicine; 1997 Jan

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    32. Edouard J Servy, Laetitia Jacquesson-Fournols, Marc Cohen, Yves J R Menezo; "MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series"; Journal of Assisted Reproduction and Genetics; 2018 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086798/

    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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