Factor V Leiden G1691A, Prothrombin G20210A, and MTHFR C677T Mutations among Sudanese Women with Recurrent Pregnancy Loss

Asaad Ma. Babker, Sarah Elsiddig Dafallah, Khalid Abdelsamea Mohamedahmed, Rabab Hassan Elshaikh, Rania Saad Suliman,Qubaa Ahmed Elzubair, Sanaa Efatih Hussein, Salaheldein G Elzaki

For citation: Babker AMa, Sarah Dafallah SE, Mohamedahmed KA, Elshaikh RH, Suliman RS, Elzubair QA, Hussein SE, Elzaki SG. Factor V Leiden G1691A, Prothrombin G20210A, and MTHFR C677T mutations among Sudanese Women with Recurrent Pregnancy Loss.. International Journal of Biomedicine. 2024;14(1):59-65. doi:10.21103/Article14(1)_OA8
Originally published March 1, 2024


Background: Various factors, such as genetic causes, anatomic abnormalities of the uterus, infectious diseases, coagulative disorders, and endocrinological and immunological diseases, might influence recurrent pregnancy loss (RLP). This study aimed to evaluate the prevalence and frequency of the FII G20210A, FVL G1691A, and MTHFR C677T polymorphisms in Sudanese women with RPL.
Methods and Results: This descriptive cross-sectional study involved 100 women with a history of 3 or more RPLs (the case group) and 94 healthy multiparous women without pregnancy complications (the control group). DNA was extracted from peripheral blood samples. The study of the FII G20210A, FVL G1691A, and MTHFR C677T polymorphisms was performed by PCR and RFLP analysis.
For the FII G20210A, the genotype distribution in the case group and control group was as follows: GG=97.0%, GA=3.0%, AA=0% and GG=94.0%, GA=0%, AA=0%, respectively. In the case group, the allelic distribution was as follows: G=98.5%, A=1.5%. In the control group, the A allele was absent, and the frequency of the G allele was 100%. For the MTHFR C677T, the genotypic and allelic frequencies in the case group were 97%, 3%, and 0%, respectively, for the CC, CT, and TT genotypes, and 98.5% and 1.5%, respectively, for the C and T alleles. In the control group, the genotype distribution was as follows: CC-100% CT-0%, TT-0%; the T allele was absent, and the frequency of the C allele was 100%. For the FVL G1691A, the genotype distribution in the case group and control group was as follows: GG=92.0%, GA=8.0%, AA=0% and GG=93.6%, GA=6.4%, AA=0%, respectively. For G and A alleles, the frequencies were 96.0% and 4.0%, respectively, for the case group, and 96.8% and 3.2%, respectively, for the control group. Our analysis did not reveal a significant positive association between the MTHFR C677T, FII G20210A, and FVL G1691A polymorphisms and the risk of RPL across the dominant model, multiplicative model, and a comparison of the frequencies of the heterozygous and homozygous dominant genotypes. 
Conclusion: The research findings suggest that the MTHFR C677T, FVL G1691A, and FII G20210A variants do not significantly contribute to the increased susceptibility to RPL in this specific population of Sudanese women. Continued scientific inquiry is crucial for developing more nuanced and personalized strategies for the diagnosis and prevention of RPL, ultimately improving women's reproductive health.

recurrent pregnancy loss• Factor V Leiden•methylenetetrahydrofolate reductase• prothrombin• Sudanese women
  1. Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009 Spring;2(2):76-83. PMID: 19609401; PMCID: PMC2709325.
  2. von Eye Corleta H. It is time to respect the American Society for Reproductive Medicine definition of recurrent pregnancy loss. Fertil Steril. 2010 Sep;94(4):e61. doi: 10.1016/j.fertnstert.2010.06.020. Epub 2010 Jul 15. PMID: 20633877.
  3. van den Boogaard E, Kaandorp SP, Franssen MT, Mol BW, Leschot NJ, Wouters CH, van der Veen F, Korevaar JC, Goddijn M. Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status? Hum Reprod. 2010 Jun;25(6):1411-4. doi: 10.1093/humrep/deq089. Epub 2010 Apr 10. PMID: 20382970.
  4. Ahmed HKF, Elggourish AGA, Abdullah SE, Babker AMA, Alfeel AH, Abbas AOI, Mohamedahmed KA, Elzaki SG. Association of Plasminogen Activator Inhibitor-1 4G/5G and Angiotensin-Converting Enzyme I/D Polymorphisms with Recurrent Pregnancy Loss in Sudanese Women: A Case-Control study. International Journal of Biomedicine. 2023;13(1):127-133. doi:10.21103/Article13(1)_OA18
  5. Babker AMa, Ahmed IAM, Ismail M, Hassan FM, Osman AL, Kandakurti PK, et al. Lack of Association between Factor V Leiden G1691A, Prothrombin G20210A, MTHFC677T Mutations, and Early Recurrent Pregnancy Loss in a Group of Sudanese Women. Open Access Maced J Med Sci. 2020 Aug 15; 8(B):553-557.
  6. Grimstad F, Krieg S. Immunogenetic contributions to recurrent pregnancy loss. J Assist Reprod Genet. 2016 Jul;33(7):833-47. doi: 10.1007/s10815-016-0720-6. Epub 2016 May 12. PMID: 27169601; PMCID: PMC4930783.
  7. Li TC, Makris M, Tomsu M, Tuckerman E, Laird S. Recurrent miscarriage: aetiology, management and prognosis. Hum Reprod Update. 2002 Sep-Oct;8(5):463-81. doi: 10.1093/humupd/8.5.463. PMID: 12398226.
  8. Babker AM, Gameel FE. Methylenetetrahydrofolate reductase c677t polymorphism in Sudanese women with recurrent spontaneous abortions. Kuwait Medical Journal. 2016;48(2):100–104.
  9. McNamee K, Dawood F, Farquharson R. Recurrent miscarriage and thrombophilia: an update. Curr Opin Obstet Gynecol. 2012 Aug;24(4):229-34. doi: 10.1097/GCO.0b013e32835585dc. PMID: 22729089.
  10. Padda J, Khalid K, Mohan A, Pokhriyal S, Batra N, Hitawala G, Cooper AC, Jean-Charles G. Factor V Leiden G1691A and Prothrombin Gene G20210A Mutations on Pregnancy Outcome. Cureus. 2021 Aug 15;13(8):e17185. doi: 10.7759/cureus.17185. PMID: 34540419; PMCID: PMC8439407.
  11. Bloomenthal D, von Dadelszen P, Liston R, Magee L, Tsang P. The effect of factor V Leiden carriage on maternal and fetal health. CMAJ. 2002 Jul 9;167(1):48-54. PMID: 12137081; PMCID: PMC116643.
  12. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1004-8. doi: 10.1073/pnas.90.3.1004. PMID: 8430067; PMCID: PMC45799.
  13. Reznikoff-Etiévan MF, Cayol V, Carbonne B, Robert A, Coulet F, Milliez J. Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage. BJOG. 2001 Dec;108(12):1251-4. doi: 10.1111/j.1471-0528.2001.00298.x. PMID: 11843387.
  14. Bradley LA, Palomaki GE, Bienstock J, Varga E, Scott JA. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med. 2012 Jan;14(1):39-50. doi: 10.1038/gim.0b013e31822e575b. Epub 2011 Sep 13. PMID: 22237430.
  15. Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011 Jan;13(1):1-16. doi: 10.1097/GIM.0b013e3181faa0f2. PMID: 21116184.
  16. Lindqvist PG, Svensson PJ, Marsaál K, Grennert L, Luterkort M, Dahlbäck B. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost. 1999 Apr;81(4):532-7. PMID: 10235434.
  17. Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med. 1994 Feb 24;330(8):517-22. doi: 10.1056/NEJM199402243300801. PMID: 8302317.
  18. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995 Mar 15;85(6):1504-8. PMID: 7888671.
  19. Settin A, Alkasem R, Ali E, ElBaz R, Mashaley AM. Factor V Leiden and prothrombin gene mutations in Egyptian cases with unexplained recurrent pregnancy loss. Hematology. 2011 Jan;16(1):59-63. doi: 10.1179/102453311X12902908411959. PMID: 21269570.
  20. Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med. 2004 Mar 8;164(5):558-63. doi: 10.1001/archinte.164.5.558. PMID: 15006834.
  21. Raziel A, Kornberg Y, Friedler S, Schachter M, Sela BA, Ron-El R. Hypercoagulable thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss. Am J Reprod Immunol. 2001 Feb;45(2):65-71. doi: 10.1111/j.8755-8920.2001.450201.x. PMID: 11216876.
  22. Rai R, Tuddenham E, Backos M, Jivraj S, El'Gaddal S, Choy S, Cork B, Regan L. Thromboelastography, whole-blood haemostasis and recurrent miscarriage. Hum Reprod. 2003 Dec;18(12):2540-3. doi: 10.1093/humrep/deg494. PMID: 14645169.
  23. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. 2009 Aug;102(2):360-70. doi: 10.1160/TH09-01-0013. PMID: 19652888.
  24. Babker AM, Gameel FE. Molecular Characterization of Prothrombin G20210A gene Mutations In pregnant Sudanese women with spontaneous recurrent abortions. Rawal Medical Journal. 2015 Apr 1;40(2):207-9.
  25. Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol. 2004 Aug;191(2):412-24. doi: 10.1016/j.ajog.2004.03.001. PMID: 15343215.
  26. Mtiraoui N, Zammiti W, Ghazouani L, Braham NJ, Saidi S, Finan RR, Almawi WY, Mahjoub T. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction. 2006 Feb;131(2):395-401. doi: 10.1530/rep.1.00815. PMID: 16452733.
  27. Unfried G, Griesmacher A, Weismüller W, Nagele F, Huber JC, Tempfer CB. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol. 2002 Apr;99(4):614-9. doi: 10.1016/s0029-7844(01)01789-6. PMID: 12039122.
  28. Poursadegh Zonouzi A, Chaparzadeh N, Asghari Estiar M, Mehrzad Sadaghiani M, Farzadi L, Ghasemzadeh A, Sakhinia M, Sakhinia E. Methylenetetrahydrofolate Reductase C677T and A1298C Mutations in Women with Recurrent Spontaneous Abortions in the Northwest of Iran. ISRN Obstet Gynecol. 2012;2012:945486. doi: 10.5402/2012/945486. Epub 2012 Nov 14. PMID: 23209927; PMCID: PMC3504415.
  29. Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet. 1996 Jan;58(1):35-41. PMID: 8554066; PMCID: PMC1914961.
  30. van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998 May;62(5):1044-51. doi: 10.1086/301825. PMID: 9545395; PMCID: PMC1377082.
  31. Kupeli E, Verdi H, Simsek A, Atac FB, Eyuboglu FO. Genetic mutations in Turkish population with pulmonary embolism and deep venous thrombosis. Clin Appl Thromb Hemost. 2011 Nov-Dec;17(6):E87-94. doi: 10.1177/1076029610385224. Epub 2010 Nov 15. PMID: 21078611.
  32. Ekim M, Ekim H, Yılmaz YK. The prevalence of Factor V Leiden, prothrombin G20210A, MTHFR C677T and MTHFR A1298C mutations in healthy Turkish population. Hippokratia. 2015 Oct-Dec;19(4):309-13. PMID: 27688694; PMCID: PMC5033140.
  33. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003 Mar 15;361(9361):901-8. doi: 10.1016/S0140-6736(03)12771-7. PMID: 12648968.
  34. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994 May 5;369(6475):64-7. doi: 10.1038/369064a0. PMID: 8164741.
  35. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111-3. doi: 10.1038/ng0595-111. PMID: 7647779.
  36. Serrano F, Lima ML, Lopes C, Almeida JP, Branco J. Factor V Leiden and prothrombin G20210A in Portuguese women with recurrent miscarriage: is it worthwhile to investigate? Arch Gynecol Obstet. 2011 Nov;284(5):1127-32. doi: 10.1007/s00404-010-1834-1. Epub 2011 Jan 23. PMID: 21259017.
  37. Ahmed NA, Adam I, Elzaki SEG, Awooda HA, Hamdan HZ. Factor-V Leiden G1691A and prothrombin G20210A polymorphisms in Sudanese women with preeclampsia, a case -control study. BMC Med Genet. 2019 Jan 5;20(1):2. doi: 10.1186/s12881-018-0737-z. PMID: 30611230; PMCID: PMC6321713.
  38. Roqué H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost. 2004 Feb;91(2):290-5. doi: 10.1160/TH03-09-0596. PMID: 14961156.
  39. Clark P, Walker ID, Govan L, Wu O, Greer IA. The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes. Br J Haematol. 2008 Jan;140(2):236-40. doi: 10.1111/j.1365-2141.2007.06902.x. Epub 2007 Nov 19. PMID: 18028481.
  40. Cardona H, Castañeda SA, Cardona Maya W, Alvarez L, Gómez J, Gómez J, Torres J, Tobón L, Bedoya G, Cadavid AP. Lack of Association between Recurrent Pregnancy Loss and Inherited Thrombophilia in a Group of Colombian Patients. Thrombosis. 2012;2012:367823. doi: 10.1155/2012/367823. Epub 2012 Apr 11. PMID: 22577540; PMCID: PMC3345256.
  41. Abu-Asab NS, Ayesh SK, Ateeq RO, Nassar SM, El-Sharif WA. Association of inherited thrombophilia with recurrent pregnancy loss in palestinian women. Obstet Gynecol Int. 2011;2011:689684. doi: 10.1155/2011/689684. Epub 2011 Jun 14. PMID: 21765836; PMCID: PMC3135069.
  42. Abdelsalam T, Karkour T, Elbordiny M, Shalaby D, Abouzeid ZS. Thrombophilia gene mutations in relation to recurrent miscarriage. Int J Reprod Contracept Obstet Gynecol 2018; 7:796-800.
  43. Al-Achkar W, Wafa A, Ammar S, Moassass F, Jarjour RA. Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women. Reprod Sci. 2017 Sep;24(9):1275-1279. doi: 10.1177/1933719116682874. Epub 2016 Dec 21. PMID: 28814189.
  44. Eldeen F, Badawy A, AlSel A, Fawzy MS. Factor V Leiden G1691A and Prothrombin G20210A mutations are associated with repeated spontaneous miscarriage in Northern area of Saudi Arabia. Genet. Mol. Res. 2017;16(4): gmr16039810.
  45. Alfeel AH. 2016. Association of Factor V-leiden and Prothrombin G20210A Mutations wth Deep Venous Thrombosis in Patients attending Khartoum Hospitals, Khartoum State, Sudan (2013-2016). Doctoral dissertation, University of Gezira; 2016.
  46. Awad-Elkareem A, Elzaki SG, Khalid H, Abdallah MS, Adam I. A low rate of factor V Leiden mutation among Sudanese women with deep venous thrombosis during pregnancy and puerperium. J Obstet Gynaecol. 2017 Oct;37(7):963-964. doi: 10.1080/01443615.2017.1306033. Epub 2017 Apr 11. PMID: 28395587.

Download Article
Received January 2, 2024.
Accepted February 11, 2024.
©2024 International Medical Research and Development Corporation.