- Mohammad Reza Javan 1
- Bahareh Moghimian-Boroujeni 2
- Hossein Ayatollahi 3
- Amirali Ayatollahi 4
- Nafise Amini 4
- Elham Jafaei 4
- maryam sheikhi 4
- Narjes Soltani 4
1 Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization (IBTO), Tehran, Iran.
2 Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
3 MD, professor of hematopathology, Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
4 Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Background: Recurrent pregnancy loss (RPL) is the occurrence of three or more miscarriages before the 20th week of pregnancy. Thrombophilia factors are one of the main causes of RPL.
Methods: This retrospectively study was performed on women with more than two miscarriages. 620 patients’ documents with pregnancy loss were investigated. Based on number of pregnancy loss, the women divided to a control group with less than three miscarriages (212) and RPL group (180). Cytogenetics analysis and thrombophilia panel (MTHFR 677 C⁄T/ FV Leiden G1691A/Prothrombin G20210A (FII), ACE I/D, PAI1) were performed for all patients.
Result: In the analysis between Control and RPL groups, none of the studied polymorphisms (MTHFR 677 C⁄T /Factor V Leiden /Prothrombin G20210A/ ACE I/D/ PAI-1) showed a significant relationship (P-value ˃ 0.05). Cytogenetic analysis showed 2 numerical and 9 structural abnormalities among both groups. Statistical analysis indicated significant association between number of abortion and age (P value= 0.005, r =0.139). We even realized that there was significant relationship between polymorphism number and recurrent number of abortion (P value= 0.018, r = 0.6).
Conclusion: We showed that polymorphisms analysis for thrombophilia factors is more precious test than cytogenetics analysis for RPL detection due to frequency in pregnant woman. We even indicated that no association was found between thrombophilia polymorphisms in Control and RPL groups. This means that screening for Factor V Leiden, prothrombin G20210A, MTHFR C677T, ACE I/D and PAI-1 and cytogenetic analysis in patients with a history of RPL is not recommended.
- 1. 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):777-82. 2. Bigdeli R, Younesi MR, Panahnejad E, Asgary V, Heidarzadeh S, Mazaheri H, et al. Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population. Syst Biol Reprod Med. 2018;64(4):274-82. 3. Gianaroli L, Racowsky C, Geraedts J, Cedars M, Makrigiannakis A, Lobo R. Best practices of ASRM and ESHRE: a journey through reproductive medicine. Hum Reprod. 2012;27(12):3365-79. 4. Arias-Sosa LA, Acosta ID, Lucena-Quevedo E, Moreno-Ortiz H, Esteban-Pérez C, Forero-Castro M. Genetic and epigenetic variations associated with idiopathic recurrent pregnancy loss. J Assist Reprod Genet. 2018;35(3):355-66. 5. Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009;2(2):76-83. 6. Brenner B. Inherited thrombophilia and pregnancy loss. Thromb Haemost. 1999;82(2):634-40. 7. Sarto A, Rocha M, Martínez M, Sergio Pasqualini R. [Hypofibrinolysis and other hemostatic defects in women with antecedents of early reproductive failure]. Medicina (B Aires). 2000;60(4):441-7. 8. Coulam CB, Jeyendran RS, Fishel LA, Roussev R. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online. 2006;12(3):322-7. 9. Azem F, Many A, Ben Ami I, Yovel I, Amit A, Lessing JB, et al. Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod. 2004;19(2):368-70. 10. Bedaiwy MA, Falcone T, Mohamed MS, Aleem AA, Sharma RK, Worley SE, et al. Differential growth of human embryos in vitro: role of reactive oxygen species. Fertil Steril. 2004;82(3):593-600. 11. Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Hum Reprod Update. 2007;13(2):163-74. 12. Su MT, Lin SH, Chen YC, Kuo PL. Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss: a systematic review and meta-analysis. Thromb Haemost. 2013;109(1):8-15. 13. Soltani N, Mirzaei F, Ayatollahi H. Cytogenetic Study of Patients with Primary Amenorrhea in the Northeast of Iran. Iran J Pathol. 2021;16(1):57-61. 14. Yenicesu GI, Cetin M, Ozdemir O, Cetin A, Ozen F, Yenicesu C, et al. A prospective case-control study analyzes 12 thrombophilic gene mutations in Turkish couples with recurrent pregnancy loss. Am J Reprod Immunol. 2010;63(2):126-36. 15. Behjati R, Modarressi MH, Jeddi-Tehrani M, Dokoohaki P, Ghasemi J, Zarnani AH, et al. Thrombophilic mutations in Iranian patients with infertility and recurrent spontaneous abortion. Ann Hematol. 2006;85(4):268-71. 16. Zetterberg H, Regland B, Palmér M, Ricksten A, Palmqvist L, Rymo L, et al. Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Hum Genet. 2002;10(2):113-8. 17. Dissanayake VH, Sirisena ND, Weerasekera LY, Gammulla CG, Seneviratne HR, Jayasekara RW. Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women. J Obstet Gynaecol Res. 2012;38(9):1168-76. 18. Subrt I, Ulcova-Gallova Z, Bibkova K, Micanova Z, Hejnalova M, Cerna M, et al. Recurrent pregnancy loss and frequency of eight antiphospholipid antibodies and genetic thrombophilic factors in Czech women. Am J Reprod Immunol. 2008;59(3):193-200. 19. Hohlagschwandtner M, Unfried G, Heinze G, Huber JC, Nagele F, Tempfer C. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil Steril. 2003;79(5):1141-8. 20. Udry S, Aranda FM, Latino JO, de Larrañaga GF. Paternal factor V Leiden and recurrent pregnancy loss: a new concept behind fetal genetics? J Thromb Haemost. 2014;12(5):666-9. 21. Mohammadi MMA, Al-Halabi MG, Monem FMS. Prevalence of factor V Leiden mutation and its relation with recurrent spontaneous pregnancy loss in a group of Syrian women. 2007. 22. Sottilotta G, Oriana V, Latella C, Luise F, Piromalli A, Ramirez F, et al. Genetic prothrombotic risk factors in women with unexplained pregnancy loss. Thromb Res. 2006;117(6):681-4. 23. Mierla D, Szmal C, Neagos D, Cretu R, Stoian V, Jardan D. Association of Prothrombin (A20210G) and Factor V Leiden (A506G) with Recurrent Pregnancy Loss. Maedica (Bucur). 2012;7(3):222-6. 24. 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):1114-8. 25. Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol. 2001;97(5 Pt 1):753-9. 26. Carp H, Salomon O, Seidman D, Dardik R, Rosenberg N, Inbal A. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Human Reproduction. 2002;17(6):1633-7. 27. Pauer HU, Voigt-Tschirschwitz T, Hinney B, Burfeind P, Wolf C, Emons G, et al. Analyzes of three common thrombophilic gene mutations in German women with recurrent abortions. Acta Obstet Gynecol Scand. 2003;82(10):942-7. 28. Sotiriadis A, Vartholomatos G, Pavlou M, Kolaitis N, Dova L, Stefos T, et al. Combined thrombophilic mutations in women with unexplained recurrent miscarriage. Am J Reprod Immunol. 2007;57(2):133-41. 29. Parand A, Zolghadri J, Nezam M, Afrasiabi A, Haghpanah S, Karimi M. Inherited thrombophilia and recurrent pregnancy loss. Iran Red Crescent Med J. 2013;15(12):e13708. 30. Yalcintepe S, Ozdemir O, Hacivelioglu SO, Akurut C, Koc E, Uludag A, et al. Multiple Inherited Thrombophilic Gene Polymorphisms in Spontaneous Abortions in Turkish Population. Int J Mol Cell Med. 2015;4(2):120-7. 31. Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler CJ. Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod. 2003;18(11):2473-7. 32. Kim JJ, Choi YM, Lee SK, Yang KM, Paik EC, Jeong HJ, et al. The PAI‐1 4G/5G and ACE I/D Polymorphisms and Risk of Recurrent Pregnancy Loss: A Case–Control Study. American Journal of Reproductive Immunology. 2014;72(6):571-6. 33. Kurzawińska G, Barlik M, Drews K, Różycka A, Seremak-Mrozikiewicz A, Ożarowski M, et al. Coexistence of ACE (I/D) and PAI-1 (4G/5G) gene variants in recurrent miscarriage in Polish population. Ginekol Pol. 2016;87(4):271-6. 34. Nikitina TV, Sazhenova EA, Zhigalina DI, Tolmacheva EN, Sukhanova NN, Lebedev IN. Karyotype evaluation of repeated abortions in primary and secondary recurrent pregnancy loss. J Assist Reprod Genet. 2020;37(3):517-25. 35. Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. Bmj. 2000;320(7251):1708-12. 36. Smits MAJ, van Maarle M, Hamer G, Mastenbroek S, Goddijn M, van Wely M. Cytogenetic testing of pregnancy loss tissue: a meta-analysis. Reprod Biomed Online. 2020;40(6):867-79. 37. Awartani KA, Al Shabibi MS. Description of cytogenetic abnormalities and the pregnancy outcomes of couples with recurrent pregnancy loss in a tertiary-care center in Saudi Arabia. Saudi Med J. 2018;39(3):239-42. 38. Alibakhshi R, Nejati P, Hamani S, Mir-Ahadi N, Jalilian N. Cytogenetic Analysis of 570 Couples with Recurrent Pregnancy Loss: Reporting 11 Years of Experience. J Hum Reprod Sci. 2020;13(3):216-20.