Skip to main content

Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation

Abstract

Purpose

Numerous studies have investigated the associations between methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss (RPL); however, the results remain controversial. The aim of this study is to drive a more precise estimation of association between MTHFR gene polymorphisms and risk of RPL.

Methods

We searched PubMed, EMBASE, Cochrane library, Web of Science and China Knowledge Resource Integrated Database for papers on MTHFR gene C677T and A1298C polymorphisms and RPL risk. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of association in the homozygous model, heterozygous model, dominant model, recessive model and an additive model. The software STATA (Version 13.0) was used for statistical analysis.

Results

Overall, 57 articles were included in the final meta-analysis. In maternal group the MTHFR C677T polymorphism showed pooled odds ratios for the homozygous comparison [OR = 2.285, 95 % CI (1.702, 3.067)] and the MTHFR A1298C polymorphism showed pooled odds ratios for recessive model [OR = 1.594, 95 % CI (1.136, 2.238)]. In fetal group the MTHFR C677T polymorphism showed pooled odds ratios for dominant model [OR = 1.037, 95 % CI (0.567, 1.894)] and the MTHFR A1298C polymorphism showed pooled odds ratios for dominant model [OR = 1.495, 95 % CI (1.102, 2.026)].

Conclusions

In summary, the results of our meta-analysis indicate that maternal and paternal MTHFR gene C677T and A1298C polymorphisms are associated with RPL. We also observed a significant association between fetal MTHFR A1298C polymorphism and RPL but not C677T.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Saravelos SH, Regan L (2014) Unexplained recurrent pregnancy loss. Obstet Gynecol Clin North Am 41(1):157–166. doi:10.1016/j.ogc.2013.10.008

    Article  PubMed  Google Scholar 

  2. 2.

    von Eye Corleta H (2010) It is time to respect the American Society for Reproductive Medicine definition of recurrent pregnancy loss. Fertil Steril 94(4):e61. doi:10.1016/j.fertnstert.2010.06.020

    Article  Google Scholar 

  3. 3.

    Alijotas-Reig J, Garrido-Gimenez C (2013) Current concepts and new trends in the diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv 68(6):445–466. doi:10.1097/OGX.0b013e31828aca19

    Article  PubMed  Google Scholar 

  4. 4.

    Mete Ural U, Bayoglu Tekin Y, Balik G, Kir Sahin F, Colak S (2014) Could platelet distribution width be a predictive marker for unexplained recurrent miscarriage? Arch Gynecol Obstet 290(2):233–236. doi:10.1007/s00404-014-3192-x

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Rai R, Regan L (2006) Recurrent miscarriage. Lancet 368(9535):601–611. doi:10.1016/s0140-6736(06)69204-0

    Article  PubMed  Google Scholar 

  6. 6.

    Steegers-Theunissen RP, Boers GH, Blom HJ, Trijbels FJ, Eskes TK (1992) Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet 339(8801):1122–1123

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK (2000) Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 74(6):1196–1199

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, Steegers-Theunissen RP, Eskes TK (1993) Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 60(5):820–825

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22(4):195–201

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Liew SC, Gupta ED (2015) Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Gene 58(1):1–10. doi:10.1016/j.ejmg.2014.10.004

    Article  Google Scholar 

  11. 11.

    Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 7(4):551

    CAS  PubMed  Google Scholar 

  12. 12.

    Wu X, Yang K, Tang X, Sa Y, Zhou R, Liu J, Luo Y, Tang W (2015) Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for preeclampsia: a meta-analysis. J Assist Reprod Genet. doi:10.1007/s10815-014-0408-8

    Google Scholar 

  13. 13.

    Ni W, Li H, Wu A, Zhang P, Yang H, Yang X, Huang X, Jiang L (2015) Lack of association between genetic polymorphisms in three folate-related enzyme genes and male infertility in the Chinese population. J Assist Reprod Genet 32(3):369–374. doi:10.1007/s10815-014-0423-9

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Salimi S, Saravani M, Yaghmaei M, Fazlali Z, Mokhtari M, Naghavi A, Farajian-Mashhadi F (2014) The early-onset preeclampsia is associated with MTHFR and FVL polymorphisms. Arch Gynecol Obstet. doi:10.1007/s00404-014-3561-5

    PubMed  Google Scholar 

  15. 15.

    Wu CY, Yang M, Lin M, Li LP, Wen XZ (2013) MTHFR C677T polymorphism was an ethnicity-dependent risk factor for cervical cancer development: evidence based on a meta-analysis. Arch Gynecol Obstet 288(3):595–605. doi:10.1007/s00404-013-2721-3

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Camprubi C, Pladevall M, Grossmann M, Garrido N, Pons MC, Blanco J (2013) Lack of association of MTHFR rs1801133 polymorphism and CTCFL mutations with sperm methylation errors in infertile patients. J Assist Reprod Genet 30(9):1125–1131. doi:10.1007/s10815-013-0013-2

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Nelen WL, Blom HJ, Thomas CM, Steegers EA, Boers GH, Eskes TK (1998) Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr 128(8):1336–1341

    CAS  PubMed  Google Scholar 

  18. 18.

    Kim NK, Choi YK, Kang MS, Choi DH, Cha SH, An MO, Lee S, Jeung M, Ko JJ, Oh D (2006) Influence of combined methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase enhancer region (TSER) polymorphisms to plasma homocysteine levels in Korean patients with recurrent spontaneous abortion. Thromb Res 117(6):653–658. doi:10.1016/j.thromres.2005.05.025

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Biswas A, Choudhry P, Mittal A, Meena A, Ranjan R, Choudhry VP, Saxena R (2008) Recurrent abortions in Asian Indians: no role of factor V Leiden Hong Kong/Cambridge mutation and MTHFR polymorphism. Clin Appl Thromb Hemost Off J Int Acad Clin Appl Thromb Hemost 14(1):102–104. doi:10.1177/1076029607303774

    CAS  Article  Google Scholar 

  20. 20.

    Hotoleanu C, Chouky E (2012) Hyperhomocysteinemia and methylenetetrahydrofolate reductase polymorphism in a patient with coronary artery disease and repetitive miscarriages. Roman J Intern Med Revue roumaine de medecine interne 50(4):313–316

    Google Scholar 

  21. 21.

    Nadir Y, Hoffman R, Brenner B (2007) Association of homocysteine, vitamin B12, folic acid, and MTHFR C677T in patients with a thrombotic event or recurrent fetal loss. Ann Hematol 86(1):35–40. doi:10.1007/s00277-006-0194-1

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A, Agorastos T, Zournatzi V, Makris PE, Bontis J, Kotsis A (2000) Factor V leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Human Reprod (Oxford, England) 15(2):458–462

    CAS  Article  Google Scholar 

  23. 23.

    Ren A, Wang J (2006) Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril 86(6):1716–1722. doi:10.1016/j.fertnstert.2006.05.052

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y (2012) Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Gene Test Mol Biomark 16(7):806–811. doi:10.1089/gtmb.2011.0318

    CAS  Article  Google Scholar 

  25. 25.

    Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, Zheng Q, Fu L, Du J (2013) Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene 514(2):105–111. doi:10.1016/j.gene.2012.10.091

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Rai V (2014) Methylenetetrahydrofolate reductase gene A1298C polymorphism and susceptibility to recurrent pregnancy loss: a meta-analysis. Cellular and molecular biology (Noisy-le-Grand, France) 60 (2):27–34

  27. 27.

    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283(15):2008–2012

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Chen H, Yang X, Lu M (2015) Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. Arch Gynecol Obstet. doi:10.1007/s00404-015-3894-8

    Google Scholar 

  29. 29.

    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. doi:10.1002/sim.1186

    Article  PubMed  Google Scholar 

  30. 30.

    Jackson D, White IR, Riley RD (2012) Quantifying the impact of between-study heterogeneity in multivariate meta-analyses. Stat Med 31(29):3805–3820. doi:10.1002/sim.5453

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    CAS  PubMed  Google Scholar 

  33. 33.

    Salanti G, Amountza G, Ntzani EE, Ioannidis JP (2005) Hardy-Weinberg equilibrium in genetic association studies: an empirical evaluation of reporting, deviations, and power. Eur J Hum Genet 13(7):840–848. doi:10.1038/sj.ejhg.5201410

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Wang LH, Wang LM, Zhou N (2015) 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with polycystic ovary syndrome in Chinese patients: a meta-analysis. Arch Gynecol Obstet 292(3):683–686. doi:10.1007/s00404-015-3678-1

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295(6):676–680. doi:10.1001/jama.295.6.676

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Grandone E, Margaglione M, Colaizzo D, d’Addedda M, D’Andrea G, Pavone G, Di Minno G (1998) Methylene tetrahydrofolate reductase (MTHFR) 677T– > C mutation and unexplained early pregnancy loss. Thromb Haemost 79(5):1056–1057

    CAS  PubMed  Google Scholar 

  37. 37.

    Holmes ZR, Regan L, Chilcott I, Cohen H (1999) The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol 105(1):98–101

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Lissak A, Sharon A, Fruchter O, Kassel A, Sanderovitz J, Abramovici H (1999) Polymorphism for mutation of cytosine to thymine at location 677 in the methylenetetrahydrofolate reductase gene is associated with recurrent early fetal loss. Am J Obstet Gynecol 181(1):126–130

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Murphy RP, Donoghue C, Nallen RJ, D’Mello M, Regan C, Whitehead AS, Fitzgerald DJ (2000) Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 20(1):266–270

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Pihusch R, Buchholz T, Lohse P, Rubsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ (2001) Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. American journal of reproductive immunology (New York, NY: 1989) 46(2):124–131

  41. 41.

    Unfried G, Griesmacher A, Weismuller W, Nagele F, Huber JC, Tempfer CB (2002) The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol 99(4):614–619

    CAS  PubMed  Google Scholar 

  42. 42.

    Wang YW, Li F, Li YP, Xue MZ, Yu XW, Li XC et al (2002) The study on the relationship between the methylenetetrahydofolate reductase 677C > T mutation and unexplained recurrent pregnancy loss. Chin J Prac Gynecol Obstet 05:37–39 (in Chinese)

    Google Scholar 

  43. 43.

    Hohlagschwandtner M, Unfried G, Heinze G, Huber JC, Nagele F, Tempfer C (2003) Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil Steril 79(5):1141–1148

    Article  PubMed  Google Scholar 

  44. 44.

    Kumar KS, Govindaiah V, Naushad SE, Devi RR, Jyothy A (2003) Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss. J Obstet Gynaecol J Inst Obstet Gynaecol 23(1):55–58

    CAS  Article  Google Scholar 

  45. 45.

    Makino A, Nakanishi T, Sugiura-Ogasawara M, Ozaki Y, Suzumori N, Suzumori K (2004) No association of C677T methylenetetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss. American journal of reproductive immunology (New York, NY: 1989) 52 (1):60–66. doi:10.1111/j.1600-0897.2004.00187.x

  46. 46.

    Li XM, Zhang YZ, Xu YX, Jiang S (2004) Study on the relationship of MTHFR polymorphisms with unexplained recurrent spontaneous abortion. Chin J Med Genet 01:43–46 (in Chinese)

    Google Scholar 

  47. 47.

    Wang XP, Lin QD, Ma ZW, Zhao AM (2004) C677T and A1298C mutation of the methylenetetrahydrofolate reductase gene in unexplained recurrent spontaneous abortion. Chin J Obstet Gyneco 04:25–28 (in Chinese)

    Google Scholar 

  48. 48.

    Couto E, Barini R, Zaccaria R, Annicchino-Bizzacchi JM, Passini Junior R, Pereira BG, Silva JC, Pinto e Silva JL (2005) Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia? Sao Paulo Med J 123(1):15–20

    Article  PubMed  Google Scholar 

  49. 49.

    Kobashi G, Kato EH, Morikawa M, Shimada S, Ohta K, Fujimoto S, Minakami H, Yamada H (2005) MTHFR C677T Polymorphism and factor V Leiden mutation are not associated with recurrent spontaneous abortion of unexplained etiology in Japanese women. Semin Thromb Hemost 31(3):266–271. doi:10.1055/s-2005-872430

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Parle-McDermott A, Pangilinan F, Mills JL, Signore CC, Molloy AM, Cotter A, Conley M, Cox C, Kirke PN, Scott JM, Brody LC (2005) A polymorphism in the MTHFD1 gene increases a mother’s risk of having an unexplained second trimester pregnancy loss. Mol Hum Reprod 11(7):477–480. doi:10.1093/molehr/gah204

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Guan LX, Du XY, Wang JX, Gao L, Wang RL, Li HB et al (2005) Association of genetic polymorphisms in plasminogen activator inhibitor-1 gene and 5, 10-methylenete2trahydrofolate reductase gene with recurrent early spontaneous abortion. Chin J Med Genet 03:330–333 (in Chinese)

    Google Scholar 

  52. 52.

    Song LY, Qi QH, She DX, Zhang HY, Chen SQ, Li JY (2005) Relationship between genetic polymorphism of homocysteine metabolism enzyme and unexplained repeated spontaneous abortion. Chin J Perinat Med 03:160–164 (in Chinese)

    Google Scholar 

  53. 53.

    Wang XP, Lin QD, Ma ZW (2005) The C677T and A1298C mutation of them ethylenetetrahydrofolate reductase gene in recurrent spontaneous abortion with anticardiolipin antibody positive. Prog Obstet Gynecol 06:476–479 (in Chinese)

    Google Scholar 

  54. 54.

    Mtiraoui N, Zammiti W, Ghazouani L, Braham NJ, Saidi S, Finan RR, Almawi WY, Mahjoub T (2006) Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction 131(2):395–401. doi:10.1530/rep.1.00815

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Dong SQ, Du XY, Liu XY (2006) Relationship between MTHFR gene polymorphisms and unexplained abortion. J Prac Obstet Gynecol 08:500–501 (in Chinese)

    Google Scholar 

  56. 56.

    Dong SQ, Du XY, Guan LX, Wang JX, Li HB (2006) Relationship between f olate level of red cell and MTHFR polymorphisms with unexplained recurrent spontaneous abortion. Chin J Perinat Med 05:315–319 (In Chinese)

    Google Scholar 

  57. 57.

    Callejon G, Mayor-Olea A, Jimenez AJ, Gaitan MJ, Palomares AR, Martinez F, Ruiz M, Reyes-Engel A (2007) Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss. Human Reprod (Oxford, England) 22(12):3249–3254. doi:10.1093/humrep/dem337

    CAS  Article  Google Scholar 

  58. 58.

    D’Uva M, Di Micco P, Strina I, Alviggi C, Iannuzzo M, Ranieri A, Mollo A, De Placido G (2007) Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from Southern Italy: a preliminary report. Thromb J 5:10–16. doi:10.1186/1477-9560-5-10

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Sotiriadis A, Vartholomatos G, Pavlou M, Kolaitis N, Dova L, Stefos T, Paraskevaidis E, Kalantaridou SN (2007) Combined thrombophilic mutations in women with unexplained recurrent miscarriage. Am J Reprod Immunol (New York, NY: 1989) 57(2):133–141. doi:10.1111/j.1600-0897.2006.00454.x

    CAS  Article  Google Scholar 

  60. 60.

    Cardona H, Cardona-Maya W, Gomez JG, Castaneda S, Gomez JM, Bedoya G, Alvarez L, Torres JD, Tobon LI, Cadavid A (2008) Relationship between methylenetetrahydrofolate reductase polymorphism and homocysteine levels in women with recurrent pregnancy loss: a nutrigenetic perspective. Nutr Hosp 23(3):277–282

    CAS  PubMed  Google Scholar 

  61. 61.

    Toth B, Vocke F, Rogenhofer N, Friese K, Thaler CJ, Lohse P (2008) Paternal thrombophilic gene mutations are not associated with recurrent miscarriage. Am J Reprod Immunol 60(4):325–332. doi:10.1111/j.1600-0897.2008.00630.x

    Article  PubMed  Google Scholar 

  62. 62.

    Vettriselvi V, Vijayalakshmi K, Paul SF, Venkatachalam P (2008) ACE and MTHFR gene polymorphisms in unexplained recurrent pregnancy loss. The journal of obstetrics and gynaecology research 34(3):301–306. doi:10.1111/j.1447-0756.2008.00792.x

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Zhong H, Zhu Y, Liu J, Jiao H, Peng L, Chen Y et al (2008) Study on correlation between MTHFR polymorphisms and repeated spontaneous abortion. In: The Genetics Society of Chinese Eighth Conference and seminar. Chongqing, China, p 2 (in Chinese)

  64. 64.

    Bae J, Choi DH, Kang MS, Cha SH, Oh D, Kim NK (2009) Effect of methylenetetrahydrofolate reductase and thymidylate synthase enhancer region polymorphisms on the risk of idiopathic recurrent spontaneous abortion in a Korean population. Fertil Steril 91(4 Suppl):1560–1562. doi:10.1016/j.fertnstert.2008.09.060

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Ciacci C, Tortora R, Scudiero O, Di Fiore R, Salvatore F, Castaldo G (2009) Early pregnancy loss in celiac women: the role of genetic markers of thrombophilia. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver 41(10):717–720. doi:10.1016/j.dld.2009.02.050

    CAS  Google Scholar 

  66. 66.

    Govindaiah V, Naushad SM, Prabhakara K, Krishna PC, Radha Rama Devi A (2009) Association of parental hyperhomocysteinemia and C677T Methylene tetrahydrofolate reductase (MTHFR) polymorphism with recurrent pregnancy loss. Clin Biochem 42(4–5):380–386. doi:10.1016/j.clinbiochem.2008.12.003

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Mukhopadhyay R, Saraswathy KN, Ghosh PK (2009) MTHFR C677T and factor V Leiden in recurrent pregnancy loss: a study among an endogamous group in North India. Genet Test Mol Biomark 13(6):861–865. doi:10.1089/gtmb.2009.0063

    CAS  Article  Google Scholar 

  68. 68.

    Rodriguez-Guillen Mdel R, Torres-Sanchez L, Chen J, Galvan-Portillo M, Blanco-Munoz J, Anaya MA, Silva-Zolezzi I, Hernandez-Valero MA, Lopez-Carrillo L (2009) Maternal MTHFR polymorphisms and risk of spontaneous abortion. Salud Publica Mex 51(1):19–25

    PubMed  Google Scholar 

  69. 69.

    Ma SF, Zheng ML (2008) The relation of MTHFRC677T gene polymorphism to recurrent abortion. Health Med Res Pract 5:1–5 (in Chinese)

    Google Scholar 

  70. 70.

    Wang SM, Shi XY, Shen R, Wang QX, Chen SQ, Zhang WY (2009) The role of fo latemetabolism re lated enzymes gene polymorphisms on recurrent early spontaneous abortion. Chin J Genet Genom 03:12–13 (in Chinese)

    CAS  Google Scholar 

  71. 71.

    Zhang JY, Zuo WJ, Wu GH, Sun HT (2009) Association between MTHFR gene C677T polymorphism and habitual abortion. J Jilin Univ (Medicine Edition) 04:698–701 (in Chinese)

    Google Scholar 

  72. 72.

    Zhong HJ, Liu JH, Zhu YS, Peng L, Dang J, Lu H et al. (2010) Study on correlation between MTHFR polymorphisms and repeated spontaneous abortion. Ningxia Med J (08):675–676+674 (in Chinese)

  73. 73.

    Kim SY, Park SY, Choi JW, Kim do J, Lee SY, Lim JH, Han JY, Ryu HM, Kim MH (2011) Association between MTHFR 1298A > C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy. American journal of reproductive immunology (New York, NY: 1989) 66 (4):252–258. doi:10.1111/j.1600-0897.2011.00996.x

  74. 74.

    Park CW, Han AR, Kwak-Kim J, Park SY, Han JY, Koong MK, Song IO, Yang KM (2011) The role of methylenetetrahydrofolate reductase C677T polymorphism on the peripheral blood natural killer cell proportion in women with unexplained recurrent miscarriages. Clin Exp Reprod Med 38(3):168–173. doi:10.5653/cerm.2011.38.3.168

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Settin A, Elshazli R, Salama A, ElBaz R (2011) Methylenetetrahydrofolate reductase gene polymorphisms in Egyptian women with unexplained recurrent pregnancy loss. Genet Test Mol Biomark 15(12):887–892. doi:10.1089/gtmb.2011.0049

    CAS  Article  Google Scholar 

  76. 76.

    Wang SM, Jia YF, Yang DT, Qiu Y, Yu JC, Lv XM et al (2011) Correlation between MTHFR gene C677T polymorphism and unexplained recurrent spontaneous abortion. Matern Child Health Care China (09):1385–1387 (in Chinese)

  77. 77.

    Nair RR, Khanna A, Singh K (2012) MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reproductive sciences (Thousand Oaks, Calif) 19 (2):210–215. doi:10.1177/1933719111417888

  78. 78.

    Zonouzi AP, Chaparzadeh N, Estiar MA, Sadaghiani MM, Farzadi L, Ghasemzadeh A, Sakhinia M, Sakhinia E (2012) Methylenetetrahydrofolate Reductase C677T and A1298C Mutations in Women with Recurrent Spontaneous Abortions in the Northwest of Iran. ISRN Obstetrics & Gynecology: 1–6. doi:10.5402/2012/945486

  79. 79.

    Han HK, Shen H, Wang YB, Yu WD. (2012) Methylenetetrahydrofolate reductase gene C677T polymorphism Hyperhomocysteinemia is associated with recurrent spontaneous abortion. Reproduction & Contraception (07):486–489+477 (in Chinese)

  80. 80.

    Yin L, Lv YG (2012) Analysis of the correlation between methylenetetrahydrofolate reductase gene polymorphism and spontaneous abortion. Jilin Medical Journal 21:4520–4521 (in Chinese)

    Google Scholar 

  81. 81.

    Creus M, Deulofeu R, Penarrubia J, Carmona F, Balasch J (2013) Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain. Clin Chem Lab Med CCLM/FESCC 51(3):693–699. doi:10.1515/cclm-2012-0452

    CAS  Google Scholar 

  82. 82.

    Parveen F, Tuteja M, Agrawal S (2013) Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Arch Gynecol Obstet 288(5):1171–1177. doi:10.1007/s00404-013-2877-x

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Puri M, Kaur L, Walia GK, Mukhopadhhyay R, Sachdeva MP, Trivedi SS, Ghosh PK, Saraswathy KN (2013) MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women. J Perinat Med 41(5):549–554. doi:10.1515/jpm-2012-0252

    CAS  PubMed  Google Scholar 

  84. 84.

    Chen HL, Chen CB, Lu YQ, Tang LY, Li Y (2013) Unexplained recurrent spontaneous abortion and methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphism. Chin J Birth Health Hered (06):29–30+36 (in Chinese)

  85. 85.

    Cao Y, Zhang Z, Zheng Y, Yuan W, Wang J, Liang H, Chen J, Du J, Shen Y (2014) The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes. Genes Nutr 9(3):1–8. doi:10.1007/s12263-014-0402-x

    Article  Google Scholar 

  86. 86.

    Yousefian E, Taghi Kardi M, Allahveisi A (2014) Methylenetetrahydrofolate reductase C677T and A1298C polymorphism in iranian women with idiopathic recurrent pregnancy losses. Iran Red Crescent Med J 16(7):e16763. doi:10.5812/ircmj.16763

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Hubacek JA, Rynekrova J, Kasparova D, Adamkova V, Holmes MV, Fait T (2015) Association of MTHFR genetic variants C677T and A1298C on predisposition to spontaneous abortion in Slavonic population. Clin Chim Acta 440:104–107. doi:10.1016/j.cca.2014.11.018

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Zetterberg H, Regland B, Palmer M, Ricksten A, Palmqvist L, Rymo L, Arvanitis DA, Spandidos DA, Blennow K (2002) Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Human Genet EJHG 10(2):113–118. doi:10.1038/sj.ejhg.5200767

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Bae J, Shin SJ, Cha SH, Choi DH, Lee S, Kim NK (2007) Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) in spontaneously aborted embryos. Fertil Steril 87(2):351–355. doi:10.1016/j.fertnstert.2006.06.027

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Ozdemir O, Yenicesu GI, Silan F, Koksal B, Atik S, Ozen F, Gol M, Cetin A (2012) Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. Genet Test Mol Biomark 16(4):279–286. doi:10.1089/gtmb.2011.0191

    CAS  Article  Google Scholar 

  91. 91.

    Nair RR, Khanna A, Singh R, Singh K (2013) 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 99(5):1311–1318.e1314. doi:10.1016/j.fertnstert.2012.12.027

  92. 92.

    Isotalo PA, Wells GA, Donnelly JG (2000) Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutations. Am J Hum Genet 67(4):986–990. doi:10.1086/303082

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Jivraj S, Rai R, Underwood J, Regan L (2006) Genetic thrombophilic mutations among couples with recurrent miscarriage. Human Reprod (Oxford, England) 21(5):1161–1165. doi:10.1093/humrep/dei466

    CAS  Article  Google Scholar 

  94. 94.

    Park HM, Shin SJ, Choi DH, Oh D, Lee S, Kim NK (2008) Association between folate metabolism-related gene polymorphisms and methylation of p16(INK4A) and hMLH1 genes in spontaneously aborted embryos with normal chromosomal integrity. Fertil Steril 90(5):1605–1610. doi:10.1016/j.fertnstert.2007.09.046

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Coulam CB, Jeyendran RS, Fishel LA, Roussev R (2006) Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. American journal of reproductive immunology (New York, NY : 1989) 55 (5):360-368. doi:10.1111/j.1600-0897.2006.00376.x

  96. 96.

    Yenicesu GI, Cetin M, Ozdemir O, Cetin A, Ozen F, Yenicesu C, Yildiz C, Kocak N (2010) A prospective case-control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss. Am J Reprod Immunol (New York, NY: 1989) 63(2):126–136. doi:10.1111/j.1600-0897.2009.00770.x

    Article  Google Scholar 

  97. 97.

    Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106(23):9362–9367. doi:10.1073/pnas.0903103106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Ioannidis JP (2003) Genetic associations: false or true? Trends in molecular medicine 9(4):135–138

    Article  PubMed  Google Scholar 

  99. 99.

    Yiyenoglu OB, Ugur MG, Ozcan HC, Can G, Ozturk E, Balat O, Erel O (2014) Assessment of oxidative stress markers in recurrent pregnancy loss: a prospective study. Arch Gynecol Obstet 289(6):1337–1340. doi:10.1007/s00404-013-3113-4

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Hayashi Y, Sasaki H, Suzuki S, Nishiyama T, Kitaori T, Mizutani E, Suzumori N, Sugiura-Ogasawara M (2013) Genotyping analyses for polymorphisms of ANXA5 gene in patients with recurrent pregnancy loss. Fertil Steril 100(4):1018–1024. doi:10.1016/j.fertnstert.2013.06.020

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Sergi C, Al Jishi T, Walker M (2015) Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet 291(3):671–679. doi:10.1007/s00404-014-3443-x

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Suryanarayana V, Rao L, Kanakavalli M, Padmalatha V, Deenadayal M, Singh L (2006) Recurrent early pregnancy loss and endothelial nitric oxide synthase gene polymorphisms. Arch Gynecol Obstet 274(2):119–124. doi:10.1007/s00404-005-0107-x

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Gurbuz B, Yalti S, Ozden S, Ficicioglu C (2004) High basal estradiol level and FSH/LH ratio in unexplained recurrent pregnancy loss. Arch Gynecol Obstet 270(1):37–39. doi:10.1007/s00404-003-0490-0

    CAS  Article  PubMed  Google Scholar 

  104. 104.

    Sehirali S, Inal MM, Yildirim Y, Balim Z, Kosova B, Karamizrak T, Sanci M, Topcuoglu N, Tinar S (2005) Prothrombin G20210A mutation in cases with recurrent miscarriage: a study of the mediterranean population. Arch Gynecol Obstet 273(3):170–173. doi:10.1007/s00404-005-0061-7

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Dominguez LJ, Galioto A, Pineo A, Ferlisi A, Ciaccio M, Putignano E, Belvedere M, Costanza G, Barbagallo M (2010) Age, homocysteine, and oxidative stress: relation to hypertension and type 2 diabetes mellitus. J Am Coll Nutr 29(1):1–6

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Zhang H, Tao X, Wu J (2014) Association of homocysteine, vitamin B12, and folate with bone mineral density in postmenopausal women: a meta-analysis. Arch Gynecol Obstet 289(5):1003–1009. doi:10.1007/s00404-013-3075-6

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Habibzadeh N, Schorah CJ, Smithells RW (1986) The effects of maternal folic acid and vitamin C nutrition in early pregnancy on reproductive performance in the guinea-pig. Br J Nutr 55(1):23–35

    CAS  Article  PubMed  Google Scholar 

  108. 108.

    Gaskins AJ, Rich-Edwards JW, Hauser R, Williams PL, Gillman MW, Ginsburg ES, Missmer SA, Chavarro JE (2014) Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Obstet Gynecol 124(1):23–31. doi:10.1097/aog.0000000000000343

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Zhao Y, Hao L, Zhang L, Tian Y, Cao Y, Xia H, Deng Y, Wang T, Yu M, Li Z (2009) Plasma folate status and dietary folate intake among Chinese women of childbearing age. Matern Child Nutr 5(2):104–116. doi:10.1111/j.1740-8709.2008.00172.x

    Article  PubMed  Google Scholar 

  110. 110.

    Control CfD (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports/Centers for Disease Control 41 (Rr-14):1–7

  111. 111.

    Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, Gilfix BM, Rosenblatt DS, Gravel RA, Forbes P, Rozen R (1999) Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet 84(2):151–157

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hao Liu.

Ethics declarations

Conflict of interest

The author(s) declare that they have no competing interests.

The authors have no support or funding to report.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Luo, Y., Yuan, J. et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. Arch Gynecol Obstet 293, 1197–1211 (2016). https://doi.org/10.1007/s00404-015-3944-2

Download citation

Keywords

  • MTHFR
  • C677T
  • A1298C
  • Polymorphisms
  • Recurrent pregnancy loss
  • Meta-analysis