What is this jumble of letters and what does it
have to do with pregnancy?
At first glance MTHFR may look like an abbreviation for an expletive, but in reality it is an acronym for an enzyme called methylenetetrahydrofolate reductase. This enzyme converts folic acid into a form that the body can use (5-methyltetrahydrofolate) to carry out a number of important bodily processes such as building and repairing DNA and building red blood cells.[i],[ii],[iii] MTHFR also helps regulate a chemical called homocysteine. i,ii Too much homocysteine in the blood has been linked to health conditions such as heart disease and abnormal blood clotting.[iv]
Every human inherits two MTHFR genes—one from mom and one from dad. These genes are responsible for the creation and performance of the MTHFR enzyme.[v] This is where the wrinkle in the ointment arises: not every MTHFR gene is created equal. Individuals can receive one or two mutated copies of the MTHFR gene. This means that the DNA in these genes varies from the norm. They are also referred to as genetic variants. Having MTHFR gene mutations can affect the body’s ability to metabolize folic acid and homocysteine. ii The two most commonly studied mutations are C667T and A1298C.v Having more than one mutated copy of the MTHFR gene can result in a more significant decrease in the function of the MTHFR enzyme and possibly affect homocysteine and folate status.ii
Implications for pregnancy
Now that you have a mini genetics lesson under your belt, you’re probably wondering what the implications of an MTHFR mutation are for your pregnancy.
Congenital heart defects
Recent studies have found a linkage between the C667T MTHFR mutation in mothers and congenital heart defects in their offspring.[vi],[vii],[viii] However, one study discusses that these heart defects seem to occur when the mother has low folate levels, high homocysteine levels, and the presence of C667T MTHFR mutations.vi
One study examined data from 20 different studies regarding the MTHFR mutation status of mothers and the presence of Down Syndrome (DS) in their offspring. It linked C667T mutations with an increased risk for DS.[ix] Another study examined the findings of 28 studies investigating the linkage of maternal MTHFR status and DS in offspring. It also suggested an increased risk for DS in offspring of mothers with C667T MTHFR variants.ii Neither study found an association between maternal A1298C MTHFR variants and the presence of DS in offspring.
Recurrent pregnancy loss
Studies suggest an association between maternal MTHFR gene mutations and recurrent pregnancy loss (RPL).[x],[xi],[xii] One study suggests that elevated homocysteine is a better indicator of risk for RPL than the presence of maternal MTHFR variants.x Another study found an increased risk for RPL if the mother had two MTHFR genetic variants.xi A third study analyzed the data of 57 studies and found that the presence of C667T and A1298C MTHFR variants in both parents increased the risk for RPL.xii Aspirin at 12 weeks can help with this, discuss your options with your OBGYN.
Neural tube defects
Neural tube defects (NTDs) are defects of the brain, spine, or spinal cord. The two most common NTDs are spina bifida and anencephaly.xvi Spina bifida occurs when the spinal column fails to completely form. The spinal cord sometimes protrudes through an open hole in the spinal column. Typically there is nerve damage which can cause paralysis of the legs and lack of sensation below the waist. Anencephaly occurs when the brain and skull do not completely develop. This typically leads to babies being born stillborn or dying shortly after birth.[xiii]
Studies show an increased risk for NTDs in the offspring of women with C667T MTHFR variants.ix,[xiv],[xv],[xvi] Low folate levels are a risk factor for infant NTDs, and the presence of MTHFR mutations puts women at risk for lower folate levels than normal.[xvii],[xviii] However, having an MTHFR genetic mutation does not necessarily mean that you will have low folate levels. Proper folate supplementation and a diet rich in folic acid/folate can effectively increase folate levels for adequate NTD prevention.[xix] For example, C667T MTHFR variants are common in women in southern Italy, but the incidence of infant NTDs is not high in that region. It has been suggested that the Mediterranean diet consumed by the women in that region leads to adequate folate intake which offsets the risk for NTDs.xiv
It is 100% possible that you have an MTHFR genetic mutation, and it has absolutely no effect on your pregnancy! While studies exist which show an association between MTHFR genetic variations and the conditions discussed above, there are also studies which show no linkage whatsoever.[xx] The existing evidence is conflicting, and health professionals have differing opinions on the impact MTHFR mutations have on pregnancy-related complications.v,ix
Should you get tested?
Genetic testing for MTHFR is not routinely recommended.v If you are interested in finding out if you have an MTHFR genetic mutation(s), talk to your doctor. Health practitioners often look at homocysteine levels rather than testing for MTHFR mutations.[xxi],[xxii] If homocysteine levels are high, there are simple treatments which can typically bring them down—including supplementation with vitamin B6, B12, and/or folate/folic acid.iv,xxi MTHFR mutations in the absence of elevated homocysteine levels do not typically require treatment, therefore testing for them can be unnecessary.xxi If deemed necessary, a simple blood test can reveal your results.xxii However this is test not always covered by insurance.
What should I do if I have MTHFR?
Ensuring optimal folate and homocysteine levels is key (generally studies suggest low folate and high homocysteine are associated with complications).x,ix Optimal folate levels are achieved by consuming the vitamin–which can be done with a combination of food and vitamin supplementation. The Centers for Disease Control and Prevention (CDC) recommends all women of childbearing age consume 400 micrograms (mcg) of folic acid daily in addition to eating foods rich in folate or fortified with folic acid.[xxiii] This requirement can increase when pregnant. Folic acid is the synthetic version of folate and can be found in supplements and fortified foods such as cereal, bread, flour, cornmeal, pasta, and rice.iii Foods naturally rich in folate include eggs, beets, broccoli, avocado, bananas, beef liver, asparagus, Brussel sprouts, dark leafy greens, citrus fruits, and legumes (including beans, peas, and lentils).iii,[xxiv]
It is controversial whether individuals with MTHFR should supplement with methylfolate–a vitamin which is easier for those with MTHFR mutations to absorb–versus folic acid.iii,ix One study found that methylfolate supplementation was as effective as folic acid supplementation in increasing folate levels and reducing homocysteine levels.[xxv] The CDC also recommends higher intake of folate (4,000 mcg per day) for women who have previously had a child with a neural tube defect.xxiii You should always seek the guidance of a doctor when deciding how much folate to consume daily during pregnancy. Homocysteine regulation is typically achieved by ensuring adequate intake of B vitamins (including folate), however there are other factors that can affect homocysteine levels, and you should work with your doctor to ensure you are receiving the appropriate treatment. iv,xxi
The bottom line
Even if you have been diagnosed with an MTHFR genetic variation you can have a perfectly healthy baby. Find an OB/GYN that you like and communicate openly throughout your pregnancy—referring any questions to him or her. You and your doctor should be a team, working together to create a pregnancy plan that you both feel good about. It never hurts to consume foods naturally rich in folate–many of these foods are full of additional nutrients good for you and your baby during pregnancy. Last but not least, try to relax! Pregnancy can be a scary time but staying calm and enjoying this special time is good for you and your baby!
Written by: Stephanie Morrow, MSN, RN, CPN
[i] U.S. National Library of Medicine, Genetics Home Reference. MTHFR gene. Retrieved from
[ii] Wu, X., Wang, X., Chan, Y., Jia, S., Luo, Y., & Tang, W. (2013). Folate metabolism gene
polymorphisms MTHFR C677T and A1298C and risk for down syndrome offspring: A
meta-analysis. European Journal of Obstetrics & Gynecology & Reproductive Biology,
167(2), 154-159. doi:10.1016/j.ejogrb.2012.11.022
[iii] National Institutes of Health, Office of Dietary Supplements. (2018). Folate: Fact sheet for
consumers. Retrieved from https://ods.od.nih.gov/factsheets/Folate-Consumer/
[iv] Varga, E. A., Sturm, A. C., & Moll, S. (2005). Homocysteine and MTHFR mutations: Relation
to thrombosis and coronary artery disease. Circulation, 111(19), 289-293. Doi:
[v] U.S. Department of Health and Human Services, National Institutes of Health. MTHFR Gene
Variant. Retrieved from https://rarediseases.info.nih.gov/diseases/10953/mthfr-gene-
[vi] Elizabeth, K.E., Praveen, S. L., Preethi, N. R., Jissa, V. T., & Pillai, M. R. (2017). Folate,
vitamin B12, homocysteine and polymorphisms in folate metabolizing genes in children
with congenital heart disease and their mothers. European Journal of Clinical Nutrition,
71(12), 1437-1441. doi: 10.1038/ejcn.2017.135
[vii] Guo, Q., Wang, H., Tie, L., Li, T., Xiao, H., Long, J., & Liao, S. (2017). Parental genetic
variants, MTHFR 677C>T and MTRR 66A>G, associated differently with fetal congenital heart defect. BioMed Research International, 2017, 1-7. doi:10.1155/2017/3043476
[viii] Wang, L., Yang, B., Zhou, S., Gao, H., Wang, F., Zhou, J., . . . Wang, Y. (2018). Risk factors
and methylenetetrahydrofolate reductase gene in congenital heart disease. Journal of Thoracic Disease, 10(1), 441-447. doi:10.21037/jtd.2017.12.08
[ix] Zhang, Y., He, X., Xiong, X., Chuan, J., Zhong, L., Chen, G., & Yu, D. (2019). The
association between maternal methylenetetrahydrofolate reductase C677T and A1298C
polymorphism and birth defects and adverse pregnancy outcomes. Prenatal
Diagnosis, 39(1), 3-9. doi:10.1002/pd.539
[x] Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK (2000). Hyperhomocysteinemia
and recurrent early pregnancy loss: a meta-analysis. Fertility and Sterility, 74(6):1196–
[xi] Xu, Y., Ban, Y., Ran, L., Yu, Y., Zhai, S., Sun, Z., . . . Hu, L. (2019). Relationship between
unexplained recurrent pregnancy loss and 5,10-methylenetetrahydrofolate reductase)
polymorphisms. Fertility & Sterility, 111(3), 597-603.
[xii] Yang, Y., Luo, Y., Yuan, J., Tang, Y., Xiong, L., Xu, M., . . . Liu, H. (2016). Association
between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms
and risk of recurrent pregnancy loss: A comprehensive evaluation. Archives of
Gynecology & Obstetrics, 293(6), 1197-1211. doi:10.1007/s00404-015-3944-2
[xiii] MedlinePlus. (2018). Neural tube defects. Retrieved from:
[xiv] Agodi, A., Barchitta, M., Valenti, G., Marzagalli, R., Frontini, V., & Marchese, A. E. (2011).
Increase in the prevalence of the MTHFR 677 TT polymorphism in women born since
1959: Potential implications for folate requirements. European Journal of Clinical
Nutrition, 65(12), 1302-1308. doi:10.1038/ejcn.2011.125
[xv] Nauman, N., Jalali, S., Shami, S., Rafiq, S., Große, G., Hilger, A. C., . . . Zhang, R. (2018).
Low maternal folate concentrations and maternal MTHFR C677T polymorphism are
associated with an increased risk for neural tube defects in offspring: A case-control
study among pakistani case and control mothers. Asia Pacific Journal of Clinical
Nutrition, 27(1), 253-260. doi:10.6133/apjcn.032017.10
[xvi] Yadav, U., Kumar, P., Yadav, S. K., Mishra, O. P., & Rai, V. (2015). Polymorphisms in folate
metabolism genes as maternal risk factor for neural tube defects: An updated meta-
analysis. Metabolic Brain Disease, 30(1), 7-24. doi: 10.1007/s11011-014-9575-7
[xvii] Colson, N., Naug, H., Nikbakht, E., Zhang, P., & McCormack, J. (2017). The impact of
MTHFR 677 C/T genotypes on folate status markers: A meta-analysis of folic acid
intervention studies. European Journal of Nutrition, 56(1), 247-260. doi:10.1007/s00394-
[xviii] Tsang, B. L., Devine, O. J., Cordero, A. M., Marchetta, C. M., Mulinare, J., Mersereau, P., . .
. Hamner, H. C. (2015). Assessing the association between the methylenetetrahydrofolate
reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: A
systematic review and meta-analysis of trials and observational studies. American
Journal of Clinical Nutrition, 101(6), 1286-1294. doi:10.3945/ajcn.114.099994
[xix] Stover, P. J., MacFarlane, A. J., & Field, M. S. (2015). Bringing clarity to the role of MTHFR
variants in neural tube defect prevention. American Journal of Clinical Nutrition, 101(6),
[xx] Dell’Edera, D., L’Episcopia, A., Simone, F., Lupa, M. G., Epifania, A. A., & Allegretti, A.
(2018). Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms
and susceptibility to recurrent pregnancy loss. Biomedical Reports, 8(2), 172-175. Doi:
[xxi] Eng, C. (2013). A genetic test you don’t need: Testing MTHFR is usually
unncessary. Retrieved from https://health.clevelandclinic.org/a-genetic-test-you-dont-need/
[xxii] MedlinePlus. (2019). MTHFR mutation test. Retrieved from https://medlineplus.gov/lab-
[xxiii] Centers for Disease Control and Prevention. (2018). Folic acid. Retrieved from
[xxiv] Link, R. (2018). 15 healthy foods that are high in folate (folic acid). Retrieved from
[xxv] Pietrzik, K., Bailey, L., Shane, B., Pietrzik, K., Bailey, L., & Shane, B. (2010). Folic acid and
L-5-methyltetrahydrofolate: Comparison of clinical pharmacokinetics and
pharmacodynamics. Clinical Pharmacokinetics, 49(8), 535-548. doi:10.2165/11532990-