5, 10-methylenetetrahydrofolate reductase gene mutation and reproductive outcome: how much do we know? A case series in Indian population


  • Pooja Nadkarni Singh Nimaaya Women’s Center for Health, Surat, Gujarat, India
  • Mridula Raghav Nimaaya Women’s Center for Health, Surat, Gujarat, India
  • Prabhkar Singh Nimaaya Women’s Center for Health, Surat, Gujarat, India
  • Vanita Viradiya Nimaaya Women’s Center for Health, Surat, Gujarat, India




MTHFR gene mutation, RPL, Recurrent IVF failures, Surrogacy, MTHFR c.677C>T, MTHFR c.1298A>C


Recurrent pregnancy loss (RPL) defined as loss of two or more pregnancies is one of the reasons why couples visit an ART clinic. 2-5% of RPL cases show an abnormal parental karyotype. Folic acid is an essential B vitamin involved in processes of fundamental importance for cell division and embryo development. Folic acid deficiency can have effect on many processes involved in oocyte development, acquisition of endometrial receptivity, embryo implantation and also in the maintenance of pregnancy. The 5, 10-methylenetetrahydrofolate reductase (MTHFR) enzyme plays an important role in folate metabolism. The most investigated MTHFR gene mutations are single nucleotide polymorphisms (SNPs) at the mRNA positions 677 (rs1801133) and 1298 (rs1801131). MTHFR gene mutations are found less in Asian population and hence have not been studied or evaluated much. We presented a case series of 3 different cases of MTHFR gene mutation variants that were managed at our ART center. Testing for MTHFR gene mutation after 3 early pregnancy failures/missed abortions, PGT-A and surrogacy being our proposed interventions.


Gupta N, Gupta G, Chakrabarti S, Thangaraj K, Singh L, Chakravarty B. Mutation analysis of mthfr gene in indian women with unexplained recurrent miscarriages; folic acid supplementation improves pregnancy outcomes. Am J Stem Cell. 2019;14.

Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet.1998;62(5):1258-60.

Tamura T, Picciano MF. Folate and human reproduction. Am J Clin Nutr. 2006;83(5):993-1016.

Wagner CL. Biochemical role of folate in cellular metabolism. Folate in health and disease. In: Bailey LB, eds. New York, NY: Marcel Dekker; 1995: 23-42.

Obican SG, Finnell RH, Mills JL, Shaw GM, Scialli AR. Folic acid in early pregnancy: a public health success story. Faseb J 2010;24(11):4167-74.

Kim KC, Friso S, Choi SW. (2009). DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging. J Nutr Biochem. 2009;20(12):917-26.

Gmyrek GB, Sozanski R, Jerzak M, Chrobak A, Wickiewicz D, Skupnik A, et al. Evaluation of monocyte 24 chemotactic protein-1 levels in peripheral blood of infertile women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2005;122(2):199-205.

Thaler CD, Epel D. Nitric oxide in oocyte maturation, ovulation, fertilization, cleavage and implantation: a little dab'll do ya. Curr Pharm Des. 2003;9(5):399-409.

Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005;11(2):162-77.

Forges T, Monnier-Barbarino P, Alberto JM, Gueant-Rodriguez RM, Daval JL, Gueant JL. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007;13(3):225-38.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-3.

Yamada K, Strahler JR, Andrews PC, Matthews RG. Regulation of human methylenetetrahydrofolate reductase by phosphorylation. Proc Natl Acad Sci U S A. 2005;102(30):10454-9.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111-3.

Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93(1):7-9.

Malinow MR, Nieto FJ, Kruger WD, Duell PB, Hess DL, Gluckman RA, et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17(6):1157-62.

Put NMJ, Gabreels F, Stevens EM, Smeitink JAM, Trijbels FJM, Eskes et al. A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044-51.

Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169-72.

Chango A, Boisson F, Barbe F, Quilliot D, Droesch S, Pfister M, et al. The effect of 677C-->T and 1298A-->C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr. 2000;83(6):593-6.

Nelen WL, Bulten J, Steegers EA, Blom HJ, Hanselaar AG, Eskes TK. Maternal homocysteine and chorionic vascularization in recurrent early pregnancy loss. Hum Reprod. 2000;15(4):954-60.

Nair RR, Khanna A, Singh K. MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci. 2012;19(2):210-5.

Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, et al. (2013). Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene. 2013;514(2):105-11.

Kim SY, Park SY, Choi JW, Kim J, Lee SY, Lim JH, et al. Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy. Am J Reprod Immunol. 2011;66(4):252-8.

James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr. 1999;70(4):495-501.

Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, et al. (2000). Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet. 2000;67(3):623-30.

Hassold TJ, Burrage LC, Chan ER, Judis LM, Schwartz S, James SJ, et al. Maternal folate polymorphisms and the etiology of human nondisjunction. Am J Hum Genet. 2001;69(2):434-9.

Enciso M, Sarasa J, Xanthopoulou L. Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy. Hum Genet. 2016;135:555-68.

Laanpere M, Altmae S, Kaart T, Stavreus-Evers A, Nilsson TK, Salumets A. Folate-metabolizing gene variants and pregnancy outcome of IVF. Reprod Biomed Online. 2011;22(6):603-14.

Soldo V, Cutura N, Zamurovic M. Defect of methylenetetrahydrofolate reductase in a patient with ten habitual miscarriages: a case report. Clin Exp Obstet Gynecol. 2012;39(4):556-8.






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