Title: Thrombophilia Gene Mutations in Relation to Recurrent Miscarriage
Authors: Dina, Medhat Shalaby, Tawfik, Abdel Salam Tawfik, Tarek, Abdel Zaher Karkour, Magdy Mamdouh Elbordiny, Zaid ,Samy Abou Zaid
DOI: http://dx.doi.org/10.18535/jmscr/v4i4.24
The present study was undertaken to investigate the prevalence of thrombophilia- associated gene mutations (factor V Leiden,prothrombin gene G20210A and methylene-tetrahydrofolate reductase MTHFR C677T) in relation to recurrent miscarriage. Two hundred pregnant women divided into two groups were included in the study. Group I included 100 women with history of ≥ 3 unexplained consecutive pregnancy losses and group II included 100 age-matched controls with no history of recurrent miscarriage. Blood samples were collected from all pregnant women enrolled in the study for DNA extraction and genotype analysis based on polymerase chain reaction and reverse hybridization. Factor V Leiden and prothrombin gene mutations did not differ significantly between groups, whereas, MTHFR C677T mutations and combined thrombophilias (Factor V Leiden and MTHFR C667T) were significantly increased in group I compared to controls. Moreover, the total prevalence of gene mutations was significantly increased in group I (61%) compared to controls (21%). Homozygosity and heterozygosity did not differ significantly between groups , however , in group I, heterozygotes were significantly increased compared to homozygotes for each of the three gene mutations studied. Keywords: Recurrent miscarriage, thrombophilia, factor V Leiden, prothrombin gene G20210A, methylene- tetrahydrofolate reductase. 1. A.J.Wilcox, C.R.Weinberg, J.F.O' Connor, et al,Incidence of early loss of pregnancy.N Engl J Med, 319(4),pp.189-194, 2000 2. O.B.Christian, R.Steffensen, H.S. Nielsen and K.Varming, Multi-factorial etiology of recurrent miscarriage and its scientific and clinical implications.Gynecol Obstet Invest ,66,pp.257-267, 2008. 3. J.E.Warren, R.M.Silver.Genetics of pregnancy loss.Clin Obstet Gynecol, 51,pp.84-95,2008. 4. M.A.Rodger, M.Paidas, C. Mclin-tock, et al, Inherited thrombophilia and pregnancy complications re-visited. Obstet Gynecol,112, pp.320,2008 5. J.M.Said, J.R.Higgins, E.K.Moses, et al, Inherited thrombophilia polymorphisms in pregnancy outcomes in nulliparous women. Obstet Gynecol,115,pp.5, 2010 6. L.Robertson,O .Wu,P. Langhorne, et al.Thrombophilia in pregnancy; a systematic review.Br J Haematol, 132,pp.171,2006. 7. M.J.Kupfermine.Thrombophilia and pregnancy.Reprod Biol Endocrinol,1,pp.111,2003. 8. D.Dizon-Townson, C. Miller, B.Sibai, et al.The relationship of factor V Leiden mutation and pregnancy outcomes for mother and fetus.Obstet Gynecol,106,pp.517-524,2005. 9. R.M.Silver,Y.Zhao, C.Y. Spong, et al. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol,115, pp.14,2010. 10. M.D.McColl, J.Ellison, F.Reid, et al.Prothrombin 20210G-A, MTHFR C667T mutations in women with venous thromboembolism associated with pregnancy.BJOG,107,pp.565,2000. 11. B.T.Zhu.On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis. Histol Histopathol,17,pp.1283-1291,2002. 12. R.P.Murphy,C. Donoghue, R.J. Nalten, et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylene tetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vas Biol, 20,pp.266,2000. 13. C.H.J.Lockwood, K.A.Bauer, L.K.Leung, S.M.Ramin, et al. Inherited thrombophilias in pregnancy.Up To Date , Dec,2015 14. L.Robertson, O.Wu,P. Langhorne, et al.Thrombophilia in pregnancy: a systemic review.Br J Haematol ,132,pp.171,2006. 15. S.Bouvier,E.Cochery-Nouvellon, G.Lavigne-Lissalde, et al. Comparative incidence of pregnancy outcomes in thrombophilia positive women from NOH-APS observational study. Blood,123,pp.414,2014. 16. M.J.Kupfermine.Thrombophilia and pregnancy.Reprod Biol Endocrinol, 1,pp.111,2003 17. A.Rozano-Gorelick, E. Papadakis, B.Brenner. Combined thrombophilia and obstetric complications.Open Athero Thromb J, 2,pp.38-41, 2009. 18. G.Sarig, G.Vidergor, B. Brenner. Assessment and masnagement of high risk pregnancies in women with thrombophilia. Blood Rev,23 (4),pp. 143-147,2009 19. I.A.Greer.The challenge of thrombophilia in maternal-fetal medicine.N Engl J Med ,342,pp.424,2000. 20. M.A.Rodger, M.T.Betancourt, P.Clark, et al.The association of factor V Leiden and prothrombin gene mutation and placenta mediated pregnancy complications: a systemic review and meta analysis of prospective cohort studies. PLOS Med,7(6), pp.e1000292, 2010. 21. H.Roque, M.J.Paidas, E.F. Funai, et al.Maternal thrombophilias are not associated with early pregnancy loss.Thromb Haemost , 91,pp.290,2004. 22. P.Clark, I.D.Walker,L.Govan , et al.The GOAL study: a prospective examination of the impact of factor V Leiden and ABO blood groups on haemorrhagic and thrombotic pregnancy outcomes. Br J Haematol, 140,pp.236,2008. 23. F.E.Preston, F.R.Rosendaal, I.D.Walker, et al.Increased fetal loss in women with heritable thrombop-hiliaL. Lancet ,348,pp.913,1996. 24. U.Kjellberg, M.Van Rooijen, K. Bremme,M.Hellgren.Factor V Leiden mutation and pregnancy related complications. Am J Obstet Gynecol, 203,pp.469-468,2010. 25. S.Bouvier,E.Cochery-Nouvellon, G.Lavigne-Lissalde, et al. Comparative incidence of pregnancy outcomes in thrombo-philia positive women from NOH-APS observational study. Blood,123,pp.414,2014. 26. P.Di Mico,M.D'Uva.Recurrent pregnancy loss and thrombophilia.Open Atherosclerosis &Thrombosis J,2,pp.33-35,2009. 27. A.Lissak, A.Sharon, O.Fruchter, A.Kassel, et al. Polymorphism for mutation of cytosine to thymine location 677 in the methylene-tetrahydrofolate reductase gene is associated with recurrent early pregnancy loss. Am J Obstet Gynecol, 181,pp.126-130,1999. 28. M.G.Wouters,G.H.Boers, H.J. Blom, F.J.Trijbels, C.M.Thomas, et al.Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss.Fertil Steril,60,pp.820-825,1993. 29. A.Makino, T.Nakanishi, M.Sugiura-Ogasawara ,Y.Ozaki, N.Suzumori, K.Suzumori. No association of C667T methylene-tetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss.Am J Reprod Immunol ,52,pp.60-66,2004. 30. A.Ren, J.Wang. MTHFR C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis.Fertil Steril,86,pp.1716,2006. 31. M.Aksoy,I.Tek,H.Karabulut,B.Berker,F.Soylemez.The role of thrombophilia related to factor V and factor II G20210A mutations in recurrent abortions. J Pak Med Assoc ,55,pp.104-108,2005. 32. A.Raziel,Y.Kornberg,S.Friedler, et al.Hypercoaguble thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss.Am J Reprod Immunol,45,pp.65-71,2001. 33. C.B.Coulam,R.S.Jeyendran,A.L.Fishel,R.Roussev.Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage .Am J Reprod Immunol,55,pp.360-380,2006. 34. H.Mandel,B.Brenner,M.Berant.Co-existence of hereditary homocysteinemia and factor V Leiden-effect on thrombosis.N Engl J Med,348,pp.763-768,1996. 35. E.Couto,M.L.Nomura,R.BariniJ.L.Pinto.Silva.Pregnancy associated venous thromboembolism in combined heterozygous factor V Leiden and prothrombin G20210A mutations.Sao Paulo Med J,123(6):pp.286-288,2005. 36. R.B.Zotz, A.Gerhtardt, R.E.Scharf.Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol,16,pp.243,2003. 37. American College of Obstetricians and Gynaecologists Women Health Care Physicians. ACOG Practice Bulletin no 138:Inherited thrombophilias in pregnancy.Obstet Gynecol,122,pp.706-717,2013Abstract
References