Thrombophilia gene mutations in relation to recurrent miscarriage
Keywords:Factor V leiden, MTHFR, Prothrombin gene mutation, Recurrent miscarriage, Thrombophilia
Background: Recurrent pregnancy loss is multifactorial involving clinical and biological risk factors. Evidence addressed the association of inherited thrombophilia with recurrent pregnancy loss and other serious pregnancy complications. However, the relation between thrombophilia associated gene mutations and adverse obstetric outcome is controversial and data in the literature are inconsistent. The aim of this study was 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.
Methods: Case control study conducted on 200 women recruited from Elshatby Maternity Hospital clinics. The cases group included 100 women with history of three or more unexplained consecutive pregnancy losses, while 100 healthy age matched women with no history of recurrent miscarriages served as controls. Blood samples were collected from all women enrolled in the study for DNA extraction and genotype analysis. Factor V, prothrombin and MTHFR gene mutations were assayed based on polymerase chain reaction (PCR) and reverse-hybridization.
Results: The prevalence of Factor V Leiden and prothrombin gene G20210A mutations did not differ significantly between cases and controls. However, MTHFR C667T mutations and the total prevalence of the three gene mutations were significantly increased in the patients group compared to controls (p=0.001, p=0.003 respectively). The prevalence of combined thrombophilia of Factor V Leiden and MTHFR C677T was significantly increased in the patients group compared to controls (p=0.032). Regarding homozygosity of each of the gene mutations, no homozygosity was detected in controls and heterozygotes were significantly increased in the patients group compared to homozygotes.
Conclusions: MTHFR mutations and the total prevalence of the three gene mutations were significantly increased in the patients group compared to controls. There was a significant increase in the prevalence of combined thrombophilia (Factor V Leiden and MTHFR C677T) in the patients group compared to controls without involvement of prothrombin gene.
Wilcox AJ, Weinberg CR, O'Connor JF. Incidence of early loss of pregnancy. N Engl J Med. 2000;319(4):189-94.
Christian OB, Steffensen R, Nielsen HS, Varming K. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol Obstet Invest. 2008;66:257-67
Kupferminc MJ. Thrombophilia and pregnancy. Reprod Biol Endocrinol. 2003;1:111.
Rodger MA, Paidas M, McLintock C. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112:320.
Greer IA. The challenge of thrombophilia in maternal-fetal medicine. N Engl J Med. 2000;342:424.
Yamada H, Kato EH, Kobashi G, Ebina Y. Recurrent pregnancy loss: etiology of thrombophilia. Semin Thromb Hemost. 2001;27(2):121- 9.
Said JM, Higgins JR, Moses EK. Inherited thrombophilia polymorphisms in pregnancy outcomes in nulliparous women. Obstet Gynecol. 2010;115:5.
Dizon-Townson D, Miller C, Sibai B. The relationship of factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol. 2005;106:517-24.
Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G. Comparative incidence of pregnancy outcomes in thrombophilia positive women from the NOH-APS observational study. Blood. 2014;123:414.
Di Mico P, D' Uva M. Recurrent pregnancy loss and thrombophilia. Open Atherosclerosis Thrombosis J. 2009;2:33-5.
Lissak A, Sharon A, Fruchter O, Kassel A. 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. 1999;181:126-30.
Makino A, Nakanishi T, Sugiura-Ogasawara M, Ozaki Y, Suzumori N, Suzumori K. No association of C677T methylenetetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss. Am J Reprod Immunol. 2004;52:60-6
Ren A, Wang J. MTHFR C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta analysis. Fertil Steril. 2006;86:1716.
Aksoy M, Tek I, Karabulut H, Berker B, Soylemez F. The role of thrombophilia related to Factor V and Factor II G20210A mutations in recurrent abortions. J Pak Med Assoc. 2005;55:104-8.
Raziel A, Kornberg Y, Friedler S. Hypercoagulable thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss. Am J Reprod Immunol. 2001;45:65-71.
Roque H, Paidas MJ, Funai EF. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost. 2004:91:290.
Clark P, Walker ID, Govan L. 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. 2008;140:236.
Rozano-Gorelick A, Papadakis E, Brenner B. Combined thrombophilia and obstetric complications. The Open Atherosclerosis Thrombosis J. 2009;2:38-41.
Coulam CB, Jeyendran RS, Fishel LA, Roussev R. Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol. 2006;55:360-8.
Sarig G, Vidergor G, Brenner B. Assessment and management of high risk pregnancies in women with thrombophilia. Blood Rev. 2009;23(4):143-7.
Couto E, Nomura ML, Barini R, Pinto Silva JL. Pregnancy associated venous thromboembolism in combined heterozygous factor V Leiden and prothrombin G20210A mutations. Sao Paulo Med J. 2005;123(6):286-8.
Lockwood CHJ, Bauer KA, Leung LK, Ramin SM,. Inherited thrombophilias in pregnancy. UpToDate. 2011. Available at http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?27/37/28241?source=HISTORY