Advertisement

Archives of Gynecology and Obstetrics

, Volume 300, Issue 3, pp 777–782 | Cite as

Hereditary thrombophilia genetic variants in recurrent pregnancy loss

  • Najmeh Ahangari
  • Mohammad Doosti
  • Nezhat Mousavifar
  • Matin Attaran
  • Sima Shahrokhzadeh
  • Sara Memarpour
  • Ehsan Ghayoor KarimianiEmail author
Gynecologic Endocrinology and Reproductive Medicine
  • 53 Downloads

Abstract

Background

The relationship between thrombophilia genes and recurrent pregnancy loss has been discussed. The aim of this study was to investigate the association between of MTHFR C677T, A1298C, F2G20210A, and F5 G1691A genetic variants among Iranian women with recurrent miscarriage.

Methods

A total of 245 women with two or more recurrent pregnancy loss, with mean age years were enrolled in the study. To compare genotypes, we have selected 250 healthy women without history of miscarriage as control group. Genomic DNA of participants was evaluated using polymerase chain reaction followed by Sanger sequencing to determine the genotype frequency.

Results

The mean age were 32.16 ± (21–42) and 31.81 ± (19–40) for case and control groups respectively. MTHFR C677T and A1298C mutant alleles were found to be significantly more prevalent in patients than control. However, F2G20210A and F5 G1691A genetic variants showed no significance.

Conclusion

The allele frequencies for the assessed genotypes in this study are consistent with the data obtained for other countries. We observed significant susceptible effects of MTHFR C677T, and A1298C among participants. According to the relatively high prevalence of these variants, we recommend genetic testing for women with RPL before therapeutic decisions.

Keywords

Thrombophilia Variants MTHFR Recurrent pregnancy loss 

Notes

Author contributions

NA: experiments, data analysis, writing manuscript. MD: bioinformatics. NM: clinical examination and gynecology. MA: clinical examination and gynecology. SS: experiments. SM: writing manuscript. EGK: genetic counseling, manuscript revision.

Funding

This study was supported by Next Generation Genetic Polyclinic.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Hatasaka HH (1994) Recurrent miscarriage: epidemiologic factors, definitions, and incidence. Clin Obstet Gynecol 37(3):625–634CrossRefGoogle Scholar
  2. 2.
    RPL EGGo, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE guideline: recurrent pregnancy loss. Oxford University Press, Oxford, 2018.Google Scholar
  3. 3.
    Clifford K, Rai R, Watson H, Regan L (1994) Pregnancy: an informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 9(7):1328–1332CrossRefGoogle Scholar
  4. 4.
    Brenner B (1999) Inherited thrombophilia and pregnancy loss. Thromb Haemost 82(02):634–640Google Scholar
  5. 5.
    Coumans A, Huijgens P, Jakobs C, Schats R, De Vries J, Van Pampus M et al (1999) Haemostatic and metabolic abnormalities in women with unexplained recurrent abortion. Hum Reprod 14(1):211–214CrossRefGoogle Scholar
  6. 6.
    Sarto A, Rocha M, Martinez M, Sergio RP (2000) Hypofibrinolysis and other hemostatic defects in women with antecedents of early reproductive failure. Medicina. 60(4):441–447Google Scholar
  7. 7.
    Grandone E, Colaizzo D, Bue AL, Checola MG, Cittadini E, Margaglione M (2001) Inherited thrombophilia and in vitro fertilization implantation failure. Fertil Steril 76(1):201–202CrossRefGoogle Scholar
  8. 8.
    Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE et al (2000) Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Obstet Gynecol Surv 55(5):265–266CrossRefGoogle Scholar
  9. 9.
    Foka Z, Lambropoulos A, Saravelos H, Karas G, Karavida A, Agorastos T et al (2000) Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod 15(2):458–462CrossRefGoogle Scholar
  10. 10.
    Finan RR, Tamim H, Ameen G, Sharida HE, Rashid M, Almawi WY (2002) Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population. Am J Hematol 71(4):300–305CrossRefGoogle Scholar
  11. 11.
    Buchholz T, Thaler CJ (2003) Inherited thrombophilia: impact on human reproduction. Am J Reprod Immunol 50(1):20–32CrossRefGoogle Scholar
  12. 12.
    Tranquilli AL, Giannubilo SR, Dell’Uomo B, Grandone E (2004) Adverse pregnancy outcomes are associated with multiple maternal thrombophilic factors. Euro J Obst Gynecol Reprod Biol. 117(2):144–147CrossRefGoogle Scholar
  13. 13.
    Molen EVD, Verbruggen B, Novakova I, Eskes T, Monnens L, Blom H (2000) Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy. BJOG. 107(6)6:785–791.CrossRefGoogle Scholar
  14. 14.
    Coulam CB, Jeyendran R, Fishel LA, Roussev R (2006) Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online. 12(3):322–327CrossRefGoogle Scholar
  15. 15.
    Lockwood C, Wendel G (2011) Practice bulletin no 124: inherited thrombophilias in pregnancy. Obst Gynecol. 118(3):730–740CrossRefGoogle Scholar
  16. 16.
    Inbal A, Carp H (2007) Defects in coagulation factor leading to recurrent pregnancy loss. In: Carp H (ed) Recurrent pregnancy loss. Causes controversies and treatment. Informa Healthcare, UK, pp 127–139CrossRefGoogle Scholar
  17. 17.
    Medicine PCotASfR. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertility and sterility. 2012;98(5):1103–1111.CrossRefGoogle Scholar
  18. 18.
    Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT (2004) Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 164(5):558–563CrossRefGoogle Scholar
  19. 19.
    Brenner B (2000) Inherited thrombophilia and fetal loss. Curr Opin Hematol 7(5):290–295CrossRefGoogle Scholar
  20. 20.
    Carp H, Salomon O, Seidman D, Dardik R, Rosenberg N, Inbal A (2002) Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod 17(6):1633–1637CrossRefGoogle Scholar
  21. 21.
    No G-tG. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. 2011.Google Scholar
  22. 22.
    Van den Boogaard E, Hermens R, Franssen A, Doornbos J, Kremer J, Van Der Veen F et al (2013) Recurrent miscarriage: do professionals adhere to their guidelines. Hum Reprod 28(11):2898–2904CrossRefGoogle Scholar
  23. 23.
    Kutteh WH, Triplett DA (2006) Thrombophilias and recurrent pregnancy loss. Semin Reprod Med 24(1):54–66CrossRefGoogle Scholar
  24. 24.
    Azem F, Many A, Yovel I, Amit A, Lessing JB, Kupferminc MJ (2004) Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod 19(2):368–370CrossRefGoogle Scholar
  25. 25.
    Bedaiwy MA, Falcone T, Mohamed MS, Aleem AA, Sharma RK, Worley SE et al (2004) Differential growth of human embryos in vitro: role of reactive oxygen species. Fertil Steril 82(3):593–600CrossRefGoogle Scholar
  26. 26.
    Ebisch I, Thomas C, Peters W, Braat D, Steegers-Theunissen R (2006) The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 13(2):163–174CrossRefGoogle Scholar
  27. 27.
    Unfried G, Griesmacher A, Weismüller W, Nagele F, Huber JC, Tempfer CB (2002) The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol 99(4):614–619Google Scholar
  28. 28.
    Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R (2006) Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss? Am J Reprod Immunol 56(4):230–236CrossRefGoogle Scholar
  29. 29.
    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):986–990CrossRefGoogle Scholar
  30. 30.
    Incebiyik A, Hilali NG, Camuzcuoglu A, Camuzcuoglu H, Akbas H, Kilic A et al (2014) Prevalence of thromogenic gene mutations in women with recurrent miscarriage: a retrospective study of 1,507 patients. Obst Gynecol Sci. 57(6):513–517CrossRefGoogle Scholar
  31. 31.
    Jeddi-Tehrani M, Torabi R, Zarnani AH, Mohammadzadeh A, Arefi S, Zeraati H et al (2011) Analysis of plasminogen activator inhibitor-1, integrin beta3, beta fibrinogen, and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss. Am J Reprod Immunol 66(2):149–156CrossRefGoogle Scholar
  32. 32.
    Svensson PJ, Dahlback B (1994) Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 330(8):517–522CrossRefGoogle Scholar
  33. 33.
    Rosendaal F, Koster T, Vandenbroucke J, Reitsma P (1995) High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]. Blood 85(6):1504–1508Google Scholar
  34. 34.
    Bare S, Poka R, Balogh I, Ajzner E (2000) Factor V Leiden as a risk factor for miscarriage and reduced fertility. Aust N Z J Obstet Gynaecol 40(2):186–190CrossRefGoogle Scholar
  35. 35.
    Rafiee NM, Rassi H, Godarzvand M (2016) Molecular analysis of G202010A mutation in factor II of blood coagulation and its relationship with polymorphism rs5030737 of MBL gene in recurrent pregnancy loss. Int J Adv Biotechnol Res. 8:359–367Google Scholar
  36. 36.
    Gawish G (2015) The prevalence of inherited thrombophilic polymorphisms in Saudi females with recurrent pregnancy loss confirmed using different screening protocols of PCR. J Mol Genet Med. 9(156):1747Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Modern Sciences and Technologies, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  2. 2.Department of Modern Sciences and Technology, School of MedicineMashhad University of Medical SciencesMashhadIran
  3. 3.Department of Obstetrics and Gynecology, School of MedicineMashhad University of Medical SciencesMashhadIran
  4. 4.Department of Physiology, Faculty of MedicineMashhad University of Medical SciencesMashhadIran
  5. 5.Molecular and Clinical Sciences InstituteSt. George’s University of LondonLondonUK
  6. 6.Innovative Medical Research Center, Mashhad BranchIslamic Azad UniversityMashhadIran

Personalised recommendations