Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 8, pp 1437–1442 | Cite as

Prevalent genotypes of methylenetetrahydrofolate reductase (MTHFR) in recurrent miscarriage and recurrent implantation failure

  • Yuanchang Zhu
  • Tonghua Wu
  • Lijun Ye
  • Guangui Li
  • Yong Zeng
  • Yaou ZhangEmail author



To evaluate the association of two common methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with recurrent miscarriage (RM) and repeated implantation failure (RIF)


The study comprised of 521 patients, with a history of RM (n = 370) or RIF (n = 151). One hundred forty-four women with fallopian tube blockages who had successfully conceived after the first in vitro fertilization embryo transfer treatment served as the control group. The MTHFR alleles, genotypes, and haplotypes were assessed in different groups.


There was no difference in allele frequency and distribution of MTHFR polymorphisms between case and control patients. The 1298AA genotype was represented in a higher frequency, and 1298AC genotype was significantly lower in subfertile group when compared to the control group. A significant relationship was found between the 1298AC genotype and the RIF subgroup. The haplotype 677CC/1298AA was overrepresented in the RM subgroup (> 2 times) and haplotype 677CC/1298AC was underrepresented in the RIF subgroup (P < 0.05). Nevertheless, these two haplotypes were not connected to fertilization and embryo cleavage rates.


Our findings indicate that the MTHFR gene polymorphism might play a role in the etiology of patients with RM or RIF. No adverse effects of different MTHFR haplotypes on embryo development were detected. Further studies on the biological role are needed to better understand the susceptibility to pregnancy complications.


MTHFR Polymorphism Genotype Repeated implantation failure Recurrent miscarriage 



methylenetetrahydrofolate reductase


recurrent miscarriage


repeated implantation failure


in vitro fertilization


embryo transfers



We are very grateful to all participants in this study and we thank all the clinical staff. We also thank all the members of the Zhang and Zeng group for their interesting discussions, helpful suggestions, and technical support.

Authors’ contributions

YOZ and YZ: supervised and supported the study. YCZ: designed and wrote the manuscript. GGL: revised the manuscript. THW: data collection. LJY: PCR assay. All authors read and approved the final manuscript.


This study was supported by the National Natural Science Foundation of China (No. 31371315, 2014; No. 81601279, 2016) and International Cooperation Grant of Shenzhen (No. GJHZ20140416153718941, 2014).

Compliance with ethical standards

Ethics approval and consent to participate

The research project met our ethics criteria and was approved and performed strictly according to the protocols. Informed consent was obtained from all couples prior to the study.

Consent for publication

The ethical committee reviewed the manuscript and consent for publication.

Competing interests

The authors declare that they have no conflicts of interest.


  1. 1.
    Practice Committee of the American Society for Reproductive, M. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98:1103–11.CrossRefGoogle Scholar
  2. 2.
    Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368:601–11.CrossRefPubMedGoogle Scholar
  3. 3.
    Stephenson M, Kutteh W. Evaluation and management of recurrent early pregnancy loss. Clin Obstet Gynecol. 2007;50:132–45.CrossRefPubMedGoogle Scholar
  4. 4.
    Tang AW, Quenby S. Recent thoughts on management and prevention of recurrent early pregnancy loss. Curr Opin Obstet Gynecol. 2010;22:446–51.CrossRefPubMedGoogle Scholar
  5. 5.
    Simon A, Laufer N. Repeated implantation failure: clinical approach. Fertil Steril. 2012;97:1039–43.CrossRefPubMedGoogle Scholar
  6. 6.
    Ghosh S, Chattopadhyay R, Goswami S, Ganesh A, Chaudhury K, Chakravarty B. Recurrent implantation success in consecutive embryo transfer cycles: a unique case report. Syst Biol Reprod Med. 2013;59:285–6.CrossRefPubMedGoogle Scholar
  7. 7.
    RoyChoudhury S, Singh A, Gupta NJ, Srivastava S, Joshi MV, Chakravarty B, et al. Repeated implantation failure versus repeated implantation success: discrimination at a metabolomic level. Hum Reprod. 2016;31:1265–74.CrossRefPubMedGoogle Scholar
  8. 8.
    Obican SG, Finnell RH, Mills JL, Shaw GM, Scialli AR. Folic acid in early pregnancy: a public health success story. FASEB J. 2010;24:4167–74.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yang B, Liu Y, Li Y, Fan S, Zhi X, Lu X, et al. Geographical distribution of MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in China: findings from 15357 adults of Han nationality. PLoS One. 2013;8:e57917.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Abd El-Aziz TA, Mohamed RH. Influence of MTHFR C677T gene polymorphism in the development of cardiovascular disease in Egyptian patients with rheumatoid arthritis. Gene. 2017;610:127–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Zappacosta B, Graziano M, Persichilli S, Di Castelnuovo A, Mastroiacovo P, Iacoviello L. 5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle-southern Italian adults. Cell Biochem Funct. 2014;32:1–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Fatini C, Conti L, Turillazzi V, Sticchi E, Romagnuolo I, Milanini MN, et al. Unexplained infertility: association with inherited thrombophilia. Thromb Res. 2012;129:e185–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Ge J, Wang J, Zhang F, Diao B, Song ZF, Shan LL, et al. Correlation between MTHFR gene methylation and pre-eclampsia, and its clinical significance. Genet Mol Res. 2015;14:8021–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Azem F, Many A, Ben Ami I, Yovel I, Amit A, Lessing JB, et al. Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod. 2004;19:368–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Skeith L, Carrier M, Kaaja R, Martinelli I, Petroff D, Schleussner E, et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood. 2016;127:1650–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Christiansen OB, Nielsen HS, Kolte AM. Future directions of failed implantation and recurrent miscarriage research. Reprod BioMed Online. 2006;13:71–83.CrossRefPubMedGoogle Scholar
  17. 17.
    Celik O, Unlu C, Otlu B, Celik N, Caliskan E. Laparoscopic endometrioma resection increases peri-implantation endometrial HOXA-10 and HOXA-11 mRNA expression. Fertil Steril. 2015;104:356–65.CrossRefPubMedGoogle Scholar
  18. 18.
    Vannuccini S, Clifton VL, Fraser IS, Taylor HS, Critchley H, Giudice LC, et al. Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome. Hum Reprod Update. 2016;22:104–15.CrossRefPubMedGoogle Scholar
  19. 19.
    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. Gene. 2013;514:105–11.CrossRefPubMedGoogle Scholar
  20. 20.
    Yang Y, Luo Y, Yuan J, Tang Y, Xiong L, Xu M, 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. 2016;293:1197–211.CrossRefPubMedGoogle Scholar
  21. 21.
    Holmes ZR, Regan L, Chilcott I, Cohen H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol. 1999;105:98–101.CrossRefPubMedGoogle Scholar
  22. 22.
    Barbosa PR, Stabler SP, Machado AL, Braga RC, Hirata RD, Hirata MH, et al. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur J Clin Nutr. 2008;62:1010–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Chatzidimitriou M, Chatzidimitriou D, Mavridou M, Anetakis C, Chatzopoulou F, Lialiaris T, et al. Thrombophilic gene polymorphisms and recurrent pregnancy loss in Greek women. Int J Lab Hematol. 2017;39:590–5.CrossRefPubMedGoogle Scholar
  24. 24.
    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;135:555–68.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yuanchang Zhu
    • 1
    • 2
  • Tonghua Wu
    • 3
  • Lijun Ye
    • 3
  • Guangui Li
    • 3
  • Yong Zeng
    • 3
  • Yaou Zhang
    • 2
    Email author
  1. 1.School of Life SciencesTsinghua UniversityBeijingChina
  2. 2.Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at ShenzhenTsinghua UniversityShenzhenChina
  3. 3.Shenzhen Key Laboratory for Reproductive Immunology of Preimplantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility CenterShenzhen Zhongshan Urology HospitalShenzhenChina

Personalised recommendations