Is enoxaparin necessary to prevent adverse pregnancy outcomes in ethylenetetrahydrofolate reductase polymorphism positive recurrent pregnancy loss cases?

The association between methylenetetrahydrofolate reductase polymorphism and recurrent pregnancy loss is still under debate. Moreover, the use of enoxaparin to prevent adverse pregnancy outcomes is controversial in these patients. We aimed to analyse the effect of enoxaparin on pregnancy outcomes in recurrent pregnancy loss with only methylenetetrahydrofolate reductase gene polymorphism. A total of 339 pregnant women with recurrent pregnancy loss and methylenetetrahydrofolate reductase gene polymorphism between June 2017 and March 2019 were included. Patients were divided into two groups: enoxaparin plus folic acid (n=165) and folic acid group (n=174). Then, these groups were divided into subgroups: MTHFR A1298C homozygous (n=52), MTHFR A1298C heterozygous (n=141), MTHFR C677T homozygous (n=56) and MTHFR C677T heterozygous (n=90). Pregnancy outcomes were recorded and compared between two main group, and also between subgroups. There was no significant difference between enoxaparin plus folic acid group and only folic acid group according to delivery week (p=0.287), birthweight (p=0.677), miscarriage (p=0.372), stillbirth (p=0.585), live birth (p=0.246), preterm birth (p=0.700), anomaly (p=0.883), preeclampsia (p=0.656), intrauterine growth restriction (p=0.764), neonatal intensive care unit admission (p=0.820), APGAR 1st minutes

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1. Practice committee of the American Society for reproductive medicine. Evaluation and treatment of recurrent pregnancy loss: A committee opinion. Fertil Steril. 2012;98:1103-11.

2. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril. 1996;66:24-9.

3. Kovalevsky G, Gracia CR, Berlin JA, et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med. 2004;164:558-63.

4. Wu X, Zhao L, Zhu H, et al. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: A meta-analysis. Genetic testing and molecular biomarkers. 2012;16:806-11.

5. Dikmen M. Molecular biology of methylenetetrahydrofolate reductase (MTHFR) enzyme and its association with diseases. Med J Kocatepe. 2004;5:9-16.

6. Goddijin-Wessel TA, Wouters MG, van de Molen EF, et al. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet. 1992;339: 1122-3.

7. Cao Y, Xu J, Zhang Z, et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a metaanalysis. Gene. 2013;514:105-11.

8. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril. 2006;86:1716-22.

9. Fawzy M, Shokeir T, El-Tatongy M, et al. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebocontrolled study. Arch Gynecol Obstet. 2008;278:33-8.

10. Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA trial. J Rheumatol. 2009;36:279-87.

11. de Jong PG, Kaandorp S, Di Nisio M, et al. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inhe¬rited thrombophilia. Cochrane Database Syst Rev 2014(7):CD004734. DOI:10.1002/14651858.CD004734.pub4.

12. Di Renzo GC, Roura LC, European association of perinatal medicine-study group on preterm birth. Guidelines for the management of spontaneous preterm labor. J Perinat Med. 2006;34:359-66.

13. Dundar B, Dincgez Cakmak B, Turker UA. Risk factors triggering the development of preeclampsia in pregnant women with isolated gestational proteinuria and perinatal outcomes. Med Bull Haseki. 2019;57:255-61.

14. Dincgez Cakmak B, Turker UA, Temur M, et al. Pregnancy outcomes of antibody negative and untreated subclinical hypothyroidism. J Obstetric Gynaecol Res. 2019:45:810-6.

15. Royal college of obstetricians and gynaecologists. The investigation and treatment of couples with recurrent first trimester and second trimester miscarriage. London: RCOG, 2011.

16. Silver RM, Zhao Y, Spong CY, et al. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 2010;115:14-20.

17. Kocher O, Cirovic C, Malynn E, et al. Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients. Am J Clin Pathol. 2007;127:68-75.

18. Sottilotta G, Oriana V, Latella C, et al. Genetic prothrombotic risk factors in women with unexplained pregnancy loss. Thromb Res. 2006;117:681-4. 19. Rey E, Kahn SR, David M, et al. Thrombophilic disorders and fetal loss: a metaanalysis. Lancet. 2003;361:901-8.

20. Güven ESG, Güven S, İslamoğlu GA, et al. Tekrarlayan gebelik kayıplarında güncel algoritma. Hacettepe Tıp Dergisi. 2006;37:117-23.

21. Rosenquist TH, Ratashak SA, Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci. 1996;93:15227-32.

22. Nelen W, Blom H, Steegers E, et al. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril. 2000;74:1196-9.

23. Meegdes BHLM, Ingenhoes R, Peeters LLH, et al. Early pregnancy wastage: Relationship between chorionic vascularization and embryonic development. Fertil Steril. 1988;49:216-20.

24. Zetterberg H, Regland B, PalmeÂr M, et al. Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Euro J Human Genet. 2002;10:113-8.

25. Rodríguez-Guillén MR, Torres-Sánchez L, Chen J, et al. Maternal MTHFR polymorphisms and risk of spontaneous abortion. Salud Publica Mex. 2009;51:19-25.

26. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydro-folate reductase. Nat Genet. 1995;10:111-3.

27. Girelli D, Friso S, Trabetti E, et al. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine and folate in subjects from Northern Italy with or without angiographically decumented severe coronary atherosclerosic disease. Blood. 1998;91:4158-63.

28. Lissak A, Sharon A, Fruchter O, et al. Polymorphism for mutation of cytosine to thymine at location 677 in the methylenetetrahydrofolate reductase gene is associated with recurrent early fetal loss. Am J Obstet Gynecol. 1999;181:126-30.

29. Coulo E, Barini R, Zaccaria R, et al. Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate redutase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia? Sao Paulo Med J. 2005;123:15-20.

30. Altomare I, Adler A, Aledort L. The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature. Thromb J. 2007;5:17.

31. van der Put NMJ, GabreeÈls F, Stevens EMB, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62:1044-51.

32. Weisberg I, Tran P, Christensen B, et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64:169-72.

33. Malinow MR, Nieto FJ, Kruger WD, et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler Thromb Vasc Biol. 1997;17:1157-62.

34. Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost. 2005;11:1-13.

35. Merviel P, Cabry R, Lourdel E, et al. Comparison of two preventive treatments for patients with recurrent miscarriages carrying a C677T methylenetetrahydrofolate reductase mutation: 5-year experience. J Int Med Res. 2017;45:1720-30.

36. Yuksel H, Kayatas S, Boza AT, et al. Low molecular weight heparin use in unexplained recurrent miscarriage. Pak J Med Sci. 2014;30:1232-7.

37. Cetin O, Karaman E, Cim N, et al. The impact of low molecular weight heparin on obstetric outcomes among unexplained recurrent miscarriages complicated with methylenetetrahydrofolate reductase gene polymorphism. Ginekologia Polska. 2017;88,5:260-5.

38. Gris JC, Chauleur C, Faillie JL, et al. Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial. Thromb Haemost. 2010;104:771-9.

39. de Vries JIP, van Pampus MG, Hague WM, et al. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost. 2012;10:64-72.

40. Badawy AM, Khiary M, Sherif LS, et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol. 2008;28:280-4.