Journal of Assisted Reproduction and Genetics

, Volume 36, Issue 7, pp 1315–1328 | Cite as

Polymorphisms of methalenetetrahydrofolate reductase in recurrent pregnancy loss: an overview of systematic reviews and meta-analyses

  • Boran Du
  • Xiangjun Shi
  • Chenghong YinEmail author
  • Xin FengEmail author



The aim is to summarize and evaluate current systematic reviews and meta-analyses on MTHFR polymorphisms in recurrent pregnancy loss (RPL).


We searched Pubmed and Embase databases and selected in form of PICOS (participants, interventions, comparisons, outcomes, and study design). Our methodology was registered on PROSPERO (CRD42017042762). Systematic reviews and meta-analyses containing primary studies were extracted for meta-analyses, along with their OR and 95%CI. We assessed the quality of the included studies using AMSTAR and OQAQ criteria.


Eleven systematic reviews and meta-analyses were identified. C677T was significantly related to RPL overall in Allele (OR, 95%CI 1.43, 1.29–1.60), Recessive (OR, 95%CI 1.66, 1.42–1.95), and Homozygous (OR, 95%CI 2.08, 1.66–2.61). There was no correlation observed between A1298C and RPL, except for in Heterozygous (OR, 95%CI 1.62, 1.17–2.25).


We identified a difference in the association between MTHFR C677T polymorphism and RPL, especially in Asian population. No significant correlation was found between A1298C and RPL.


Recurrent pregnancy loss (RPL) Methalenetetrahydrofolate reductase (MTHFR) Polymorphism C677T A1298C Systematic review and meta-analysis 


Funding information

This research is supported by Beijing Obstetrics and Gynecology Hospital, Capital Medical University (FCYY201819). The authors are highly grateful to the support of Department of Pharmacy of Peking Union Medical College Hospital.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Page JM, Silver RM. Genetic causes of recurrent pregnancy loss. J Clin Obstet Gynecol. 2016;59(3):498–508. Scholar
  2. 2.
    Pritchard AM, Hendrix PW, Paidas MJ. Hereditary thrombophilia and recurrent pregnancy loss. J Clin Obstet Gynecol. 2016;59(3):487–97. Scholar
  3. 3.
    Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. J Obstet Gynecol. 2000;95(4):519–24.Google Scholar
  4. 4.
    Moll S, Varga EA. Homocysteine and MTHFR mutations. J Circulation. 2015;132(1):e6–9. Scholar
  5. 5.
    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg (London, England). 2010;8(5):336–41. Scholar
  6. 6.
    Jr Faggion CM. Critical appraisal of AMSTAR: challenges, limitations, and potential solutions from the perspective of an assessor. J BMC Med Res Methodol 2015;15:63. doi:
  7. 7.
    Delaney A, Bagshaw SM, Ferland A, Laupland K, Manns B, Doig C. The quality of reports of critical care meta-analyses in the Cochrane database of systematic reviews: an independent appraisal. J Crit Care Med. 2007;35(2):589–94. Scholar
  8. 8.
    Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. J Gene. 2013;514(2):105–11.CrossRefGoogle Scholar
  9. 9.
    Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis. J Arch Gynecol Obstet. 2016;293(2):283–90.CrossRefGoogle Scholar
  10. 10.
    Nair RR, Khanna A, Singh R, Singh K. Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. J Fertil Steril. 2013;99(5):1311–8e4.CrossRefGoogle Scholar
  11. 11.
    Nelen WLDM, Blom HJ, Steegers EAP, Den Heijer M, Eskes TKAB. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. J Fert Steril. 2000;74(6):1196–9.CrossRefGoogle Scholar
  12. 12.
    Rai V. Methylenetetrahydrofolate reductase gene A1298C polymorphism and susceptibility to recurrent pregnancy loss: a meta-analysis. J Cell Mol Biol. 2014;60(2):27–34.Google Scholar
  13. 13.
    Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. J Fertil Steril. 2006;86(6):1716–22.CrossRefGoogle Scholar
  14. 14.
    Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. J Genet Test Mol Biomarkers. 2012;16(7):806–11.CrossRefGoogle Scholar
  15. 15.
    Yang Y, Luo Y, Yuan J, Tang Y, Xiong L, Xu MM, et al. Association between maternal, fetal and paternal MTHFR gene C677T and A1298C polymorphisms and risk of recurrent pregnancy loss: a comprehensive evaluation. J Arch Gynecol Obstet. 2016;293(6):1197–211.CrossRefGoogle Scholar
  16. 16.
    Simcox LE, Ormesher L, Tower C, Greer IA. Thrombophilia and pregnancy complications. J Int J Mol Sci. 2015;16(12):28418–28.CrossRefGoogle Scholar
  17. 17.
    Clement A, Cornet D, Cohen M, Jacquesson L, Amar E, Clement P, et al. Impact of MTHFR iso form C667T on fertility through sperm DNA fragmentation index (DFI) and sperm nucleus decondensation (SDI). J Hum Reprod. 2017;32:i149–i50.Google Scholar
  18. 18.
    Bogdanova N, Markoff A. Hereditary thrombophilic risk factors for recurrent pregnancy loss. J Community Genet. 2010;1(2):47–53.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cohen H. Inherited thrombophilia and pregnancy loss-epidemiology. J Thromb Res. 2005;115(SUPPL):13–7.Google Scholar
  20. 20.
    Moll S. Thrombophilias - practical implications and testing caveats. J J Thromb Thrombolysis. 2006;21(1):7–15.CrossRefGoogle Scholar
  21. 21.
    Rambaldi MP, Mecacci F, Paidas MJ. Evaluation and management of recurrent pregnancy loss. J Placenta. 2011;32:5278.Google Scholar
  22. 22.
    Ray JG, Laskin CA. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. J Placenta. 1999;20(7):519–29.CrossRefGoogle Scholar
  23. 23.
    Yamada H, Sata F, Saijo Y, Kishi R, Minakami H. Genetic factors in fetal growth restriction and miscarriage. J Semin Thromb Hemost. 2005;31(3):334–45.CrossRefGoogle Scholar
  24. 24.
    Chen J, Chen L, Zhu LH, Zhang ST, Wu YL. Association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with preterm delivery and placental abruption: a systematic review and meta-analysis. J Acta Obstet Gynecol Scand. 2016;95(2):157–65. 12789 / (c) 2015 Nordic Federation of Societies of Obstetrics and Gynecology.CrossRefGoogle Scholar
  25. 25.
    Di Nisio M, Rutjes AWS, Ferrante N, Tiboni GM, Cuccurullo F, Porreca E. Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. J Blood. 2011;118(10):2670–8.CrossRefGoogle Scholar
  26. 26.
    Wiwanitkit V. Roles of methylenetetrahydrofolate reductase C677T polymorphism in repeated pregnancy loss. J Clin Appl Thromb/Hemost. 2005;11(3):343–5.CrossRefGoogle Scholar
  27. 27.
    Parveen F, Tuteja M, Agrawal S. Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among north Indian women. J Arch Gynecol Obstet. 2013;288(5):1171–7. Scholar
  28. 28.
    Rai V. Methylenetetrahydrofolate reductase C677T polymorphism and recurrent pregnancy loss risk in Asian population: a meta-analysis. J Indian J Clin Biochem. 2016;31(4):402–13.CrossRefGoogle Scholar
  29. 29.
    Naderi N, House JD. Recent developments in folate nutrition. Adv Food Nutr Res. 2018;83:195–213. Scholar
  30. 30.
    Quere I, Mercier E, Bellet H, Janbon C, Mares P, Gris JC. Vitamin supplementation and pregnancy outcome in women with recurrent early pregnancy loss and hyperhomocysteinemia. J Fertil Steril. 2001;75(4):823–5.CrossRefGoogle Scholar
  31. 31.
    Serman L, Dodig D. Impact of DNA methylation on trophoblast function. Clin Epigenetics. 2011;3:7. Scholar
  32. 32.
    Branco MR, King M, Perez-Garcia V, Bogutz AB, Caley M, Fineberg E, et al. Maternal DNA methylation regulates early trophoblast development. Dev Cell. 2016;36(2):152–63. Scholar
  33. 33.
    Koukoura O, Sifakis S, Spandidos DA. DNA methylation in the human placenta and fetal growth (review). Mol Med Rep. 2012;5(4):883–9. Scholar
  34. 34.
    Ozdemir O, Yenicesu GI, Silan F, Koksal B, Atik S, Ozen F, et al. Recurrent pregnancy loss and its relation to combined parental thrombophilic gene mutations. J Genet Test Mol Biomarkers. 2012;16(4):279–86. Scholar
  35. 35.
    Kumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab. 2017;14:78. Scholar
  36. 36.
    Imbard A, Benoist JF, Esse R, Gupta S, Lebon S, de Vriese AS, et al. High homocysteine induces betaine depletion. Biosci Rep. 2015;35(4).
  37. 37.
    Hiraoka M, Kagawa Y. Genetic polymorphisms and folate status. Congenit Anom. 2017;57(5):142–9. Scholar
  38. 38.
    Skovierova H, Vidomanova E, Mahmood S, Sopkova J, Drgova A, Cervenova T, et al. The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci. 2016;17(10).
  39. 39.
    Dutra CG, Fraga LR, Nacul AP, Passos EP, Goncalves RO, Nunes OL, et al. Lack of association between thrombophilic gene variants and recurrent pregnancy loss. J Hum Fertil (Camb). 2014;17(2):99–105. Scholar
  40. 40.
    Enciso M, Sarasa J, Xanthopoulou L, Bristow S, Bowles M, Fragouli E, et al. Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy. Hum Genet. 2016;135(5):555–68. Scholar
  41. 41.
    Servy EJ, Jacquesson-Fournols L, Cohen M, Menezo YJR. MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series. J Assist Reprod Genet. 2018.
  42. 42.
    Cornet D, Cohen M, Clement A, Amar E, Fournols L, Clement P, et al. Association between the MTHFR-C677T isoform and structure of sperm DNA. J Assist Reprod Genet. 2017;34(10):1283–8. Scholar
  43. 43.
    Lo CK, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers’ to authors’ assessments. J BMC Med Res Methodol. 2014;14:45. Scholar
  44. 44.
    Xu Y, Ban Y, Ran L, Yu Y, Zhai S, Sun Z, et al. Relationship between unexplained recurrent pregnancy loss and 5,10-methylenetetrahydrofolate reductase polymorphisms. Fertil Steril. 2019.
  45. 45.
    Govindaiah V, Naushad SM, Prabhakara K, Krishna PC, Radha Rama Devi A. Association of parental hyperhomocysteinemia and C677T methylene tetrahydrofolate reductase (MTHFR) polymorphism with recurrent pregnancy loss. Clin Biochem. 2009;42(4–5):380–6. Scholar
  46. 46.
    Evaluation and treatment of recurrent pregnancy loss: a committee opinion. J Fertil Steril. 2012;98(5):1103–11. doi:

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Beijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijingChina
  2. 2.School of Pharmaceutical ScienceTsinghua UniversityBeijingChina

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