Can Folate Help Prevent Congenital Heart Defects?

Can Folate Help Prevent Congenital Heart Defects?

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:

June 14, 2025

Table of Contents

    Can Folate Help Prevent Congenital Heart Defects?

    Supplementing with folate (vitamin B9) is imperative for women planning to become pregnant or who are already in their first trimester of pregnancy. Folate has been shown to prevent a wide range of birth defects, including neural tube and congenital heart defects.1


    Folate is best known for its role in synthesizing and repairing DNA2 and re-methylation of homocysteine to produce methionine. For this reason, the requirement for folate and the risk of deficiency are highest during pregnancy, lactation, and fetal development.


    This article will discuss the importance of folate in fetal development, namely in preventing congenital heart defects. We will also explain the risk factors in developing heart defects and how the MTHFR genetic mutation may play a role in this.

    Who is at Risk for Heart Defects?

    Congenital heart defect (CHD) is the most common3 of all birth defects, comprising 28% of all major congenital anomalies4.


    Risk factors5 include:

    • Advanced age of the parents.
    • Febrile illness in the mother during pregnancy.
    • History of previous abortions/stillbirths.
    • A lack of multivitamins and folate in the diet.


    Congenital heart disease has also been linked to genetic variations,6 including Mendelian mutations, copy number variants (CNVs), translocations, and single nucleotide polymorphisms (SNPs). Risk factors for CHD are usually linked to problems with specific anatomical structures of the cardiovascular system - such as the outflow tract, ventricular septum, and atrial septum. A complex pattern of functional interactions between genomic variation and environmental exposures7 modulate critical biological systems during heart development.


    The folate pathway is governed by MTHFR (5,10-methylenetetrahydrofolate reductase) enzymes encoded by the MTHFR gene, and some researchers believe that MTHFR polymorphisms may alter enzymatic activities8 involved in CHD development. Maternal MTHFR polymorphisms were found to be involved in the occurrence of CHD and Down Syndrome9 in the Indian population when controlling for periconceptional folic acid supplementation.


    However, a small meta-analysis found no substantial evidence10 of increased CHD risk in individuals with MTHFR 677CT and TT genotypes.

    Folate’s Effects on Fetal Development

    Folate is required for many enzymatic reactions, the production of amino acids, and the metabolism of various nutrients. Folate plays a significant role in nucleic acid synthesis and cell division, which occurs rapidly during fetal development. Folate plays a vital role in cardiovascular development as it is required for methylation, nucleotide synthesis, and maintaining healthy homocysteine levels.


    Increased folate intake is required for the growth of the uterus and the placenta, as well as for the increase of blood volume and the development of the fetus during pregnancy.


    Folic acid deficiency can arise from multiple causes,11 including inadequate dietary intake, malabsorption due to intestinal disorders or certain drugs, vitamin B-12 deficiency, alcoholism, pregnancy, and hemolytic anemia. The MTHFR genetic mutation may also result in folate deficiency due to the lack of the enzyme required for metabolizing folate.


    Low folate12 status means that methionine cannot be synthesized, resulting in hyperhomocysteinemia. High homocysteine is an independent risk factor13 for congenital heart disease; together with S-adenosyl homocysteine and methionine, it is one of the most important biomarkers14 in predicting congenital abnormalities.


    Folate deficiency15 may lead to DNA breaks and impaired repair, chromosomal and genomic instability, and increased mutations. Maternal folate depletion may increase the prevalence of intrauterine growth retardation16 and pre‐term delivery.


    Deficiency has also been associated with abnormalities in both mothers (anemia, peripheral neuropathy) and fetuses (congenital abnormalities17). 

    Can Folate Supplementation Help Prevent Heart Defects?

    Folate supplementation in pregnant women or a higher maternal folate status has been shown to be protective against other adverse birth outcomes such as congenital heart defects. Infants and children with congenital heart defects often have impaired folate metabolism,18 resulting in low folate, higher homocysteine, or low vitamin B12.


    Experimental evidence available from randomized controlled trials (RCTs) in humans has proven that folate supplementation19 can prevent many neural tube defects.


    A study involving zebrafish embryos found that too little or too much folic acid - combined with an MTHFR mutation - resulted in edema of the pericardium and cardiac defects20 just three days after fertilization. The researchers concluded that a precise dosage of folic acid is crucial for proper embryonic development, as it has a dose-dependent effect on the cardiovascular system.


    A Chinese study found that the earlier folic acid is taken before pregnancy and the longer supplementation continues, the lower the risk of CHDs21. Similarly, a Netherlands study found that periconceptional folic acid supplements reduced the prevalence of CHD22 by approximately 20%. Other studies have shown a similar association in which the risk of having CHDs in offspring was decreased by 60-25% in mothers who took multivitamins23 or folic acid24 during the first trimester of pregnancy.

    What if You Have an MTHFR Gene Mutation?

    Although folic acid is the standard form of supplementation recommended by doctors, it is unsuitable for mothers with an MTHFR mutation.


    Folic acid must be converted to L-5-Methyltetrahydrofolate (L-methylfolate)—the predominant form of folate in the body—to be used in biological processes. An MTHFR mutation impairs the body’s ability to methylate synthetic folic acid into a usable form, which can result in low folate status. Mutations in the MTHFR gene have been associated with congenital heart disease25 due to the crucial role folate plays in cardiovascular development.


    Folate is the natural form of the nutrient, while folic acid is the synthetic form, often used in supplements and fortified foods.


    The European Journal of Obstetrics & Gynecology and Reproductive Biology has noted that taking folic acid during preconception and pregnancy may pose certain health risks. These risks can be avoided by supplementing with methylfolate (5-MTHF)26 rather than folic acid.


    Unlike folic acid, methylfolate does not need to be activated by the MTHFR enzyme. It is immediately available to mother and fetus and does not accumulate in the blood (which unmetabolized folic acid can).


    Calcium L-methylfolate (L-5-MTHF-Ca) is shown to be the most active form of folate in plasma circulation. It is found to be absorbed faster and utilized more quickly in the body than folic acid, even in those with MTHFR defects.

    Final Thoughts

    Supplementing the correct folate form before conception and during pregnancy is crucial. Folate is not only required for the healthy development of the fetus and maintenance of the mother’s health but it has been shown to play a major role in reducing the incidence of congenital heart defects.


    Methyl-Life® offers a complete range of methylfolate supplements made with Magnafolate® PRO, a form of L-5-MTHF (calcium L-methylfolate). Magnafolate® PRO has been clinically tested as the world’s purest methylfolate.27


    This form of methylfolate bypasses the MTHFR block, making it an effective supplement for mothers with MTHFR. Taking the correct form of folate before conception and during pregnancy can significantly improve the chances of a successful pregnancy.


    Methyl-Life’s® comprehensive range includes supplements suitable for pregnancy and preconception.


    The exclusive “Pregnancy Bundle” includes three top-rated products that assist with optimal methylation: the Chewable Methylated Multi, L-Methylfolate 2.5mg, and Hydroxocobalamin (B12). Each product provides the essential nutrients required by the body during fetal development.

    Product Recommendations

    MTHFR Supplement: Methylfolate + B12 Chewable Multivitamin - Methyl-Life® Supplements

    MTHFR Supplement: Methylfolate + B12 Chewable Multivitamin
    (1)

    $97.00

    References

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      https://pmc.ncbi.nlm.nih.gov/articles/PMC6837928/

    2. Advances in Nutrition | An International Review Journal

      https://advances.nutrition.org/

    3. Shaad Abqari, Akash Gupta, Tabassum Shahab, MU Rabbani, S Manazir Ali, Uzma Firdaus; "Profile and risk factors for congenital heart defects: A study in a tertiary care hospital"; Annals of pediatric cardiology; 2016 Sep-Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007929/

    4. Helen Dolk, Maria Loane, Ester Garne, European Surveillance of Congenital Anomalies (EUROCAT) Working Group; "Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005"; Circulation; 2011 Mar

      https://pubmed.ncbi.nlm.nih.gov/21321151/

    5. Shaad Abqari, Akash Gupta, Tabassum Shahab, MU Rabbani, S Manazir Ali, Uzma Firdaus; "Profile and risk factors for congenital heart defects: A study in a tertiary care hospital"; Annals of pediatric cardiology; 2016 Sep-Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007929/

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    8. Ambreen Asim, Sarita Agarwal, Deepika Delsa Dean; "Maternal Risk Factors Triggering Congenital Heart Defects in Down Syndrome: A Case-Control Study"; Pediatric reports; 2022 Feb

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8950734/

    9. Ambreen Asim, Sarita Agarwal, Deepika Delsa Dean; "Maternal Risk Factors Triggering Congenital Heart Defects in Down Syndrome: A Case-Control Study"; Pediatric reports; 2022 Feb

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8950734/

    10. I.M. van Beynum , M. den Heijer , H.J. Blom , L. Kapusta; "The MTHFR 677C→T polymorphism and the risk of congenital heart defects: a literature review and meta-analysis"; QJM: An International Journal of Medicine; 2007 Dec

      https://academic.oup.com/qjmed/article-abstract/100/12/743/1545683?redirectedFrom=fulltext

    11. Kashif M. Khan, Ishwarlal Jialal; "Folic Acid Deficiency"; StatPearls [Internet]; 2023 Jun

      https://www.ncbi.nlm.nih.gov/books/NBK535377/

    12. Xuhui Han, Bingqi Wang, Dongxu Jin, Kuang Liu, Hongjie Wang, Liangbiao Chen, Yao Zu; "Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish"; Biology (Basel); 2021 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773176/

    13. Thomas G. Deloughery, Adam Evans, Abbas Sadeghi, Jeffrey McWilliams, W. David Henner, Lloyd M. Taylor, Richard D. Press; "Common Mutation in Methylenetetrahydrofolate Reductase: Correlation With Homocysteine Metabolism and Late-Onset Vascular Disease"; Circulation; 1996 Dec

      https://www.ahajournals.org/doi/10.1161/01.CIR.94.12.3074

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      https://academic.oup.com/qjmed/article/100/12/743/1545683

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    17. 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://pubmed.ncbi.nlm.nih.gov/22102928/

    18. Rima Obeid, Wolfgang Holzgreve, Klaus Pietrzik; "Folate supplementation for prevention of congenital heart defects and low birth weight: an update"; Cardiovascular diagnosis and therapy; 2019 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837928/

    19. Rima Obeid, Wolfgang Holzgreve, Klaus Pietrzik; "Folate supplementation for prevention of congenital heart defects and low birth weight: an update"; Cardiovascular diagnosis and therapy; 2019 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837928/

    20. Xuhui Han, Bingqi Wang, Dongxu Jin, Kuang Liu, Hongjie Wang, Liangbiao Chen, Yao Zu; "Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish"; Biology (Basel); 2021 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773176/

    21. Xiaohong Li, Shengli Li, Dezhi Mu, Zhen Liu, Yanli Li, Yuan Lin, Xinlin Chen, Fengzhi You, Nana Li, Kui Deng, Ying Deng, Yanping Wang, Jun Zhu; "The association between periconceptional folic acid supplementation and congenital heart defects: A case–control study in China"; Preventive Medicine; 2013 Jun

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    24. K S Scanlon, C Ferencz, C A Loffredo, P D Wilson, A Correa-Villaseñor, M J Khoury, W C Willett; "Preconceptional folate intake and malformations of the cardiac outflow tract. Baltimore-Washington Infant Study Group"; Epidemiology; 1998 Jan

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    25. Xuhui Han, Bingqi Wang, Dongxu Jin, Kuang Liu, Hongjie Wang, Liangbiao Chen, Yao Zu; "Precise Dose of Folic Acid Supplementation Is Essential for Embryonic Heart Development in Zebrafish"; Biology (Basel); 2021 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773176/

    26. 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

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    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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