Association of Inherited Thrombophilia with Recurrent Pregnancy Loss in A Population of Lebanese Women: A Case Control Study

Document Type : Short Communication

Authors

1 Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Tripoli, Lebanon

2 Department of Medical Laboratory Sciences, Faculty of Health, Saint Holy Family University, Batroun, Lebanon

Abstract

Recurrent pregnancy loss (RPL) complication is a challenge of reproductive medicine due to its often unknown etiology.
A case-control study was carried out between June 2019 and April 2020 to examine the correlation between RPL
and inherited thrombophilia (IT), namely mutations in factor V Leiden (FVL G1691A), prothrombin (FII G20210A),
and methylenetetrahydrofolate reductase (MTHFR C677T). A total of 120 Lebanese women with RPL was studied
and compared, for the frequency of these mutations, to 100 healthy reproductive Lebanese women. The association
between the zygosity status of the three tested mutations, the existence of more than one prothrombotic single nucleotide polymorphisms (SNPs), and the increased risk of RPL were examined using Chi-square or two-tailed fisher exact test, and the student t test. The predictive factors of RPL were analyzed using a multiple logistic regression model.
P<0.05 was considered to be statistically significant. Our results showed statistically significant higher frequencies
of FVL G1691A and FII G20210A mutations among the cases with RPL compared to the control group. Thus, RPL is
associated with FVL G1691A and FII G20210A mutations. These mutations seem to increase the risk of RPL in the
Lebanese women. Therefore, we suggest thrombophilia screening and adequate genetic counseling for women with
RPL and at high-risk to plan for primary prevention, avoiding thromboembolic or obstetric accidents, and reducing
the associated morbidity and mortality among Lebanese women.

Keywords


  1. ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018; (2): hoy004.
  2. Patil R, Ghosh K, Vora S, Shetty S. Inherited and acquired thrombophilia in Indian women experiencing unexplained recurrent pregnancy loss. Blood Cells Mol Dis. 2015; 55(3): 200-205.
  3. Kaiser J, Branch DW. Recurrent pregnancy loss: generally accepted causes and their management. Clin Obstet Gynecol. 2016; 59(3): 464-473.
  4. Neamatzadeh H, Ramazani V, Kalantar SM, Ebrahimi M, Sheikhha MH. Serum immune reactivity against β2-Glycoprotein-I and anti-neutrophil cytoplasmic auto-antibodies by ELI-P-Complex Screening Technology in recurrent miscarriage. Minerva Ginecol. 2016; 68(3): 243-249.
  5. López-Jiménez JJ, Porras-Dorantes Á, Juárez-Vázquez CI, García-Ortiz JE, Fuentes-Chávez CA, Lara-Navarro IJ, et al. Molecular thrombophilic profile in Mexican patients with idiopathic recurrent pregnancy loss. Genet Mol Res. 2016; 15(4): 15048728.
  6. Pritchard AM, Hendrix PW, Paidas MJ. Hereditary thrombophilia and Rrecurrent pregnancy loss. Clin Obstet Gynecol. 2016; 59(3): 487-497.
  7. Dautaj A, Krasi G, Bushati V, Precone V, Gheza M, Fioretti F, et al. Hereditary thrombophilia. Acta Biomed. 2019; 90(10-S): 44-46.
  8. Croles FN, Nasserinejad K, Duvekot JJ, Kruip MJ, Meijer K, Leebeek FW. Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian metaanalysis. BMJ. 2017; 359: j4452.
  9. Lino FL, Traina É, Barreto JA, Moron AF, Mattar R. Thrombophilic mutations and polymorphisms, alone or in combination, and recurrent spontaneous abortion. Clin Appl Thromb Hemost. 2015; 21(4): 365-372.
  10. Almawi WY, Finan RR, Tamim H, Daccache JL, Irani-Hakime N. Differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene among the Lebanese population. Am J Hematol. 2004; 76(1): 85-87.
  11. Zahed LF, Rayes RF, Mahfouz RA, Taher AT, Maarouf HH, Nassar AH. Prevalence of factor V Leiden, prothrombin and methylene tetrahydrofolate reductase mutations in women with adverse pregnancy outcomes in Lebanon. Am J Obstet Gynecol. 2006; 195(4): 1114-1118.
  12. Jarjour RA, Ammar S, Majdalawi R. Frequency of three prothrombotic polymorphisms among Syrian population: factor V G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase C677T. Ann Hum Biol. 2017; 44(1): 70-73.
  13. Attili R, Hussein A, Odeh H, Hejaz H. Prevalence of thrombophilia in palestine and the association of thrombophilic gene polymorphisms with recurrent pregnancy loss. Res J Obstet Gynecol. 2019; 12: 6-10.
  14. Al-Zoubi N, Alrabadi N, Kheirallah K, Alqudah A. Prevalence and multiplicity of thrombophilia genetic polymorphisms of FV, MTHFR, FII, and PAI-I: A cross-sectional study on a healthy Jordanian population. Int J Gen Med. 2021; 14: 5323-5332.
  15. 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; 19(4): 309-313.
  16. Gao H, Tao FB. Prothrombin G20210A mutation is associated with recurrent pregnancy loss: a systematic review and meta-analysis update. Thromb Res. 2015; 135(2): 339-346.
  17. Barut MU, Bozkurt M, Kahraman M, Yildirim E, Imirzalioglu N, Kubar A, et al. Thrombophilia and recurrent pregnancy loss: The enigma continues. Med Sci Monit. 2018; 24: 4288-4294.
  18. Sergi C, Al Jishi T, Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Arch Gynecol Obstet. 2015; 291(3): 671-679.
  19. Ziakas PD, Poulou LS, Pavlou M, Zintzaras E. Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk. Eur J Obstet Gynecol Reprod Biol. 2015; 191: 106-111.
  20. Turki RF, Assidi M, Banni HA, Zahed HA, Karim S, Schulten HJ, et al. Associations of recurrent miscarriages with chromosomal abnormalities, thrombophilia allelic polymorphisms and/or consanguinity in Saudi Arabia. BMC Med Genet. 2016; 17 Suppl 1:69.
  21. Kamali M, Hantoushzadeh S, Borna S, Neamatzadeh H, Mazaheri M, Noori-Shadkam M, et al. Association between thrombophilic genes Ppolymorphisms and recurrent pregnancy loss susceptibility in the iranian population: a systematic review and meta-analysis. Iran Biomed J. 2018; 22(2): 78-89.
  22. Yengel I, Yorulmaz T, Api M. Association between FVL G1691A, FII G20210A, and MTHFR C677T and A1298C polymorphisms and Turkish women with recurrent pregnancy loss. Med Glas (Zenica). 2020; 17(1): 129-135.
  23. Ahangari N, Doosti M, Mousavifar N, Attaran M, Shahrokhzadeh S, Memarpour S, et al. Hereditary thrombophilia genetic variants in recurrent pregnancy loss. Arch Gynecol Obstet. 2019; 300(3): 777-782.
  24. Liu X, Chen Y, Ye C, Xing D, Wu R, Li F, et al. Hereditary thrombophilia and recurrent pregnancy loss: a systematic review and meta-analysis. Hum Reprod. 2021; 36(5): 1213-1229.
  25. Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A, Agorastos T, et al. Factor V leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod. 2000; 15(2): 458-462.
  26. 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(6): 590-595.
  27. Tiwari D, Bose PD, Das S, Das CR, Datta R, Bose S. MTHFR (C677T) polymorphism and PR (PROGINS) mutation as genetic factors for preterm delivery, fetal death and low birth weight: A Northeast Indian population based study. Meta Gene. 2015; 3: 31-42.
  28. Akdemir Y, Ayvaci H, Uludogan M. Effect of multiple thrombophilic gene mutations on uterine artery blood flow in nonpregnant recurrent pregnancy loss patients: are we searching enough? J Matern Fetal Neonatal Med. 2020; 33(14): 2466-2472.