Association between Methylenetetrahydrofolate Reductase Gene Polymorphism and the Risk of Unexplained Recurrent Spontaneous Abortion: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 MIMan-li ¹ , SONGYan-xin ¹ , AIHai-quan ² ,  LAXiao-lin ²

1. Luoyang Women and Children Medical Care Center, Luoyang 471000, China;
2. Department of Reproductive Medicine Center, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China;

Corresponding author：

LAXiao-lin, Email: xiaolinla@hotmail.com

Keywords：

Methylenetetrahydrofolate reductase; Gene polymorphism; Unexplained recurrent spontaneous abortion; Meta-analysis

DOI：

10.7507/1672-2531.20160139

Video：

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Objective To systematically review the association between C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene and the risk of unexplained recurrent spontaneous abortion (URSA). Methods We searched PubMed, EMbase, CBM, CNKI, VIP and WanFang Data from inception to May 2015 to collect case-control studies about the association between the MTHFR gene C677T and A1298C polymorphisms and the risk of URSA. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.0 and Stata 12.0 software. Results A total of 42 case-control studies involving 3 970 URSA patients and 5 297 controls were included. The results of meta-analysis showed that MTHFR C677T polymorphism was associated with the increased risk of URSA (T vs. C: OR=1.34, 95% CI 1.16 to1.54, P < 0.000 01; TT vs. TC+CC: OR=1.70, 95% CI 1.36 to 2.12, P < 0.000 01; TT+TC vs. CC: OR=1.34, 95% CI 1.11 to 1.62, P=0.002; TC vs. CC: OR=1.19, 95% CI 0.99 to 1.43, P=0.061; TT vs. CC: OR=1.95, 95% CI 1.48 to 2.56, P < 0.000 01). Subgroup analysis by ethnicity indicated that the MTHFR C677T polymorphism was associated with the increased risk of URSA in east Asians (T vs. C: OR=1.61, 95% CI 1.39 to 1.87, P < 0.000 01; TT vs. TC+CC: OR=2.05, 95% CI 1.54 to 2.71, P < 0.000 01; TT+TC vs. CC: OR=1.76, 95% CI 1.41 to 2.19, P < 0.000 01; TC vs. CC: OR=1.53, 95% CI 1.21 to 1.94, P < 0.000 01; TT vs. CC: OR=2.77, 95% CI 1.94 to 3.97, P < 0.000 01) but was not associated with the increased risk of URSA in Caucasians. The results of meta-analysis also showed that there was no significant association between the MTHFR A1298C polymorphism and the URSA in all population. Conclusion Current evidence indicates that significant association is found between MTHFR C677T mutation and URSA in east Asians but not in Caucasians. Further study indicates that women carrying TT or TC gene significantly increases the risk of URSA and TT mutant gene carriers have a higher URSA risk. There is no significant association between MTHFR A1298C mutation and URSA in all population. Due to the quantity and quality limitations of included studies, more high quality case-control or cohort studies are needed to verify the above conclusions.

Citation： MIMan-li, SONGYan-xin, AIHai-quan, LAXiao-lin. Association between Methylenetetrahydrofolate Reductase Gene Polymorphism and the Risk of Unexplained Recurrent Spontaneous Abortion: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2016, 16(8): 897-905. doi: 10.7507/1672-2531.20160139 Copy

1.	Stirrat GM. Recurrent miscarriage. Lancet, 1990, 336(8716):673-675.
2.	Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet, 2005, 272(2):95-108.
3.	Steegers-Theunissen RP, Boers GH, Blom HJ, et al. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet, 339(8801):1122-1123.
4.	Lissak A, Sharon A, Frnehters O, et al. Polymorphism for mutation of cytocine to thymine at location 677 in the methylenetetrahydrofolate reduetase gene is associate with recurrent early fetal loss. Am J Obstet Gynecol, 1999, 18l(1):126-130.
5.	刘宇岩, 杨博逸, 李永芳, 等. 5, 10-亚甲基四氢叶酸还原酶C677T基因多态性与原因不明复发性流产关联的Meta分析.中国全科医学, 2013, 16(31):2992-2997.
6.	曾宪涛, 刘慧, 陈曦, 等. Meta分析系列之四:观察性研究的质量评价工具.中国循证心血管医学杂志, 2012, 4(4):297-299.
7.	Bae J, Choi DH, Kang MS, et al. Effect of methylenetetrahydrofolate reductase and thymidylate synthase enhancer region polymorphisms on the risk of idiopathic recurrent spontaneous abortion in a Korean population. Fertil Steril, 2009, 91(4 Suppl):1560-1562.
8.	Ciacci C, Tortora R, Scudiero O, et al. Early pregnancy loss in celiac women:The role of genetic markers of thrombophilia. Dig Liver Dis, 2009, 41(10):717-720.
9.	Couto E, Barini R, Zaccaria R, et al. Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions:a new path to thrombophilia. Sao Paulo Med J, 2005, 123(1):15-20.
10.	Dilley A, Benito C, Hooper WC, et al. Mutations in the factor V, prothrombin and MTHFR genes are not risk factors for recurrent fetal loss. J Matern Fetal Neonatal Med, 2002, 11(3):176-182.
11.	Grandone E, Margaglione M, Colaizzo D, et al. Methylene tetrahydrofolate reductase (MTHFR) 677T>C mutation and unexplained early pregnancy loss. Thromb Haemost, 1998, 79(5): 1056-1057.
12.	Hohlagschwandtner M, Unfried G, Heinze G, et al. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil Steril, 2003, 79(5):1141-1148.
13.	Holmes ZR, Regan L, Chilcott I, et al. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol, 1999, 105(1):98-101.
14.	Kim SY, Park SY, Choi JW, et al. Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy. Am J Reprod Immunol, 2011, 66(4):252-258.
15.	Kobashi G, Kato EH, Morikawa M, et al. MTHFR C677T Polymorphism and factor V Leiden mutation are not associated with recurrent spontaneous abortion of unexplained etiology in Japanese women. Semin Thromb Hemost, 2005, 31(3):266-271.
16.	Kumar KS, Govindaiah V, Naushad SE, et al. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss. J Obstet Gynaecol, 2003, 23(1):55-58.
17.	Luo L, Chen Y, Wang L, et al. Polymorphisms of Genes Involved in the Folate Metabolic Pathway Impact the Occurrence of Unexplained Recurrent Pregnancy Loss. Reprod Sci, 2014, 22(7):845-851.
18.	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(1):126-130.
19.	Makino A, Nakanishi T, Sugiura-Ogasawara M, et al. No association of C677T methylenetetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss. Am J Reprod Immunol, 2004, 52(1):60-66.
20.	Mtiraoui N, Zammiti W, Ghazouani L, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction, 2006, 131(2):395-401.
21.	Murphy RP, Donoghue C, Nallen RJ, et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol, 2000, 20(1):266-270.
22.	Nair RR, Khanna A, Singh K. MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci, 2012, 19(2):210-215.
23.	Nelen WL, Steegers EA, Eskes TK, et al. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet, 1997, 350(9081): 861.
24.	Parle-McDermott A, Pangilinan F, Mills JL, et al. A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss. Mol Hum Reprod, 2005, 11(7):477-480.
25.	Pauer HU, Voigt-Tschirschwitz T, Hinney B, et al. Analyzes of three common thrombophilic gene mutations in German women with recurrent abortions. Acta Obstet Gynecol Scand, 2003, 82(10):942-947.
26.	Pihusch R, Buchholz T, Lohse P, et al. Thrombophilic gene mutations and recurrent spontaneous abortion:prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol, 2001, 46(2):124-131.
27.	Puri M, Kaur L, Walia GK, et al. MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women. J Perinat Med, 2013, 41(5):549-554.
28.	Settin A, Elshazli R, Salama A, et al. Methylenetetrahydrofolate reductase gene olymorphisms in Egyptian women with unexplained recurrent pregnancy loss. Genet Test Mol Biomarkers, 2011, 15(12): 887-892.
29.	Sotiriadis A, Vartholomatos G, Pavlou M, et al. Combined thrombophilic mutations in women with unexplained recurrent miscarriage. Am J Reprod Immunol, 2007, 57(2):133-141.
30.	Toth B, Vocke F, Rogenhofer N, et al. Paternal thrombophilic gene mutations are not associated with recurrent miscarriage. Am J Reprod Immunol, 2008, 60(4):325-332.
31.	Unfried G, Griesmacher A, Weismüller W, et al. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol, 2002, 99(4):614-619.
32.	Vanilla S, Dayanand CD, Kotur PF, et al. Evidence of Paternal N5, N10-Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District-A South West of India. Clin Diagn Res, 2015, 9(2):BC15-18.
33.	Vettriselvi V, Vijayalakshmi K, Paul SF, et al. ACE and MTHFR gene polymorphisms in unexplained recurrent pregnancy loss. J Obstet Gynaecol Res, 2008, 34(3):301-306.
34.	Wramsby ML, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril, 2000, 74(5):987-991.
35.	万加华, 刘肖曼, 张红岩, 等.反复性自然流产患者MTHFR基因的多态性研究.中国与遗传杂志, 2007, 15(7):9-10.
36.	宋绿茵, 戚潜辉, 余达贤, 等.同型半胱氨酸代谢相关酶基因多态性与习惯性流产关系的研究.中华围产医学杂, 2005, 8(3):160-164.
37.	徐俐, 刘肖曼, 张红岩, 等.亚甲基四氢叶酸还原酶、凝血因子V和凝血酶原基因多态性与原因不明复发性早期流产的关系.中华妇产科杂志, 2007, 42(3):180-183.
38.	李晓梅, 张友忠, 许燕雪, 等. MTHFR基因C677T位点多态性与不明原因重复性自然流产的相关性.中华医学遗传学杂志, 2004, 21(1):39-42.
39.	汪希鹏, 林其德, 马政文, 等.原因不明复发性流产患者血中亚甲基四氢叶酸还原酶基因C677T和A1298C位点突变的研究.中华妇产科杂志, 2004, 39(4):238-241.
40.	王亚文, 李芬, 李义平, 等.亚甲基四氢叶酸还原酶677C→T突变与不明原因反复流产相关性研究.中国实用妇科与产科志, 2002, 18(5):291-293.
41.	王苏梅, 贾颐舫, 杨丹形, 等. MTHFR基因C677T多态性与原因不明复发性自然流产的相关性.中国妇幼保健, 2011, 26(9):1385-1387.
42.	管立学, 杜欣莹, 王敬先, 等. PAI-1基因和MTHFR基因多态性与复发性早期自然流产的关系.中华医学遗传学杂志, 2005, 22(3): 330-333.
43.	胡晓东, 梁佩燕, 刁梁辉, 等.亚甲基四氢叶酸还原酶基因突变不明原因复发性流产的关系.中国优生与遗传杂志, 2014, 22(11):87-89.
44.	董素芹, 杜欣莹, 刘学云. MTHFR基因多态性与不明原因习惯性流产的相关性分析.实用妇产科杂志, 2006, 22(8):500-501.
45.	钟慧军, 刘军红, 朱永生, 等. MTHFR C677T基因多态性与复发性自然流产的相关性研究.宁夏医学杂志, 2010, 32(8):675-676.
46.	陈惠丽, 唐落韵, 陈春宝, 等.不明原因复发性流产与亚甲基四氢叶酸还原酶及甲硫氨酸合成酶还原酶基因多态性研究.中国优生与遗传杂志, 2013, 21(6):29-30.
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1. Stirrat GM. Recurrent miscarriage. Lancet, 1990, 336(8716):673-675.
2. Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet, 2005, 272(2):95-108.
3. Steegers-Theunissen RP, Boers GH, Blom HJ, et al. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet, 339(8801):1122-1123.
4. Lissak A, Sharon A, Frnehters O, et al. Polymorphism for mutation of cytocine to thymine at location 677 in the methylenetetrahydrofolate reduetase gene is associate with recurrent early fetal loss. Am J Obstet Gynecol, 1999, 18l(1):126-130.
5. 刘宇岩, 杨博逸, 李永芳, 等. 5, 10-亚甲基四氢叶酸还原酶C677T基因多态性与原因不明复发性流产关联的Meta分析.中国全科医学, 2013, 16(31):2992-2997.
6. 曾宪涛, 刘慧, 陈曦, 等. Meta分析系列之四:观察性研究的质量评价工具.中国循证心血管医学杂志, 2012, 4(4):297-299.
7. Bae J, Choi DH, Kang MS, et al. Effect of methylenetetrahydrofolate reductase and thymidylate synthase enhancer region polymorphisms on the risk of idiopathic recurrent spontaneous abortion in a Korean population. Fertil Steril, 2009, 91(4 Suppl):1560-1562.
8. Ciacci C, Tortora R, Scudiero O, et al. Early pregnancy loss in celiac women:The role of genetic markers of thrombophilia. Dig Liver Dis, 2009, 41(10):717-720.
9. Couto E, Barini R, Zaccaria R, et al. Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions:a new path to thrombophilia. Sao Paulo Med J, 2005, 123(1):15-20.
10. Dilley A, Benito C, Hooper WC, et al. Mutations in the factor V, prothrombin and MTHFR genes are not risk factors for recurrent fetal loss. J Matern Fetal Neonatal Med, 2002, 11(3):176-182.
11. Grandone E, Margaglione M, Colaizzo D, et al. Methylene tetrahydrofolate reductase (MTHFR) 677T>C mutation and unexplained early pregnancy loss. Thromb Haemost, 1998, 79(5): 1056-1057.
12. Hohlagschwandtner M, Unfried G, Heinze G, et al. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil Steril, 2003, 79(5):1141-1148.
13. Holmes ZR, Regan L, Chilcott I, et al. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol, 1999, 105(1):98-101.
14. Kim SY, Park SY, Choi JW, et al. Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy. Am J Reprod Immunol, 2011, 66(4):252-258.
15. Kobashi G, Kato EH, Morikawa M, et al. MTHFR C677T Polymorphism and factor V Leiden mutation are not associated with recurrent spontaneous abortion of unexplained etiology in Japanese women. Semin Thromb Hemost, 2005, 31(3):266-271.
16. Kumar KS, Govindaiah V, Naushad SE, et al. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss. J Obstet Gynaecol, 2003, 23(1):55-58.
17. Luo L, Chen Y, Wang L, et al. Polymorphisms of Genes Involved in the Folate Metabolic Pathway Impact the Occurrence of Unexplained Recurrent Pregnancy Loss. Reprod Sci, 2014, 22(7):845-851.
18. 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(1):126-130.
19. Makino A, Nakanishi T, Sugiura-Ogasawara M, et al. No association of C677T methylenetetrahydrofolate reductase and an endothelial nitric oxide synthase polymorphism with recurrent pregnancy loss. Am J Reprod Immunol, 2004, 52(1):60-66.
20. Mtiraoui N, Zammiti W, Ghazouani L, et al. Methylenetetrahydrofolate reductase C677T and A1298C polymorphism and changes in homocysteine concentrations in women with idiopathic recurrent pregnancy losses. Reproduction, 2006, 131(2):395-401.
21. Murphy RP, Donoghue C, Nallen RJ, et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol, 2000, 20(1):266-270.
22. Nair RR, Khanna A, Singh K. MTHFR C677T polymorphism and recurrent early pregnancy loss risk in north Indian population. Reprod Sci, 2012, 19(2):210-215.
23. Nelen WL, Steegers EA, Eskes TK, et al. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet, 1997, 350(9081): 861.
24. Parle-McDermott A, Pangilinan F, Mills JL, et al. A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss. Mol Hum Reprod, 2005, 11(7):477-480.
25. Pauer HU, Voigt-Tschirschwitz T, Hinney B, et al. Analyzes of three common thrombophilic gene mutations in German women with recurrent abortions. Acta Obstet Gynecol Scand, 2003, 82(10):942-947.
26. Pihusch R, Buchholz T, Lohse P, et al. Thrombophilic gene mutations and recurrent spontaneous abortion:prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol, 2001, 46(2):124-131.
27. Puri M, Kaur L, Walia GK, et al. MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women. J Perinat Med, 2013, 41(5):549-554.
28. Settin A, Elshazli R, Salama A, et al. Methylenetetrahydrofolate reductase gene olymorphisms in Egyptian women with unexplained recurrent pregnancy loss. Genet Test Mol Biomarkers, 2011, 15(12): 887-892.
29. Sotiriadis A, Vartholomatos G, Pavlou M, et al. Combined thrombophilic mutations in women with unexplained recurrent miscarriage. Am J Reprod Immunol, 2007, 57(2):133-141.
30. Toth B, Vocke F, Rogenhofer N, et al. Paternal thrombophilic gene mutations are not associated with recurrent miscarriage. Am J Reprod Immunol, 2008, 60(4):325-332.
31. Unfried G, Griesmacher A, Weismüller W, et al. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol, 2002, 99(4):614-619.
32. Vanilla S, Dayanand CD, Kotur PF, et al. Evidence of Paternal N5, N10-Methylenetetrahydrofolate Reductase (MTHFR) C677T Gene Polymorphism in Couples with Recurrent Spontaneous Abortions (RSAs) in Kolar District-A South West of India. Clin Diagn Res, 2015, 9(2):BC15-18.
33. Vettriselvi V, Vijayalakshmi K, Paul SF, et al. ACE and MTHFR gene polymorphisms in unexplained recurrent pregnancy loss. J Obstet Gynaecol Res, 2008, 34(3):301-306.
34. Wramsby ML, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril, 2000, 74(5):987-991.
35. 万加华, 刘肖曼, 张红岩, 等.反复性自然流产患者MTHFR基因的多态性研究.中国与遗传杂志, 2007, 15(7):9-10.
36. 宋绿茵, 戚潜辉, 余达贤, 等.同型半胱氨酸代谢相关酶基因多态性与习惯性流产关系的研究.中华围产医学杂, 2005, 8(3):160-164.
37. 徐俐, 刘肖曼, 张红岩, 等.亚甲基四氢叶酸还原酶、凝血因子V和凝血酶原基因多态性与原因不明复发性早期流产的关系.中华妇产科杂志, 2007, 42(3):180-183.
38. 李晓梅, 张友忠, 许燕雪, 等. MTHFR基因C677T位点多态性与不明原因重复性自然流产的相关性.中华医学遗传学杂志, 2004, 21(1):39-42.
39. 汪希鹏, 林其德, 马政文, 等.原因不明复发性流产患者血中亚甲基四氢叶酸还原酶基因C677T和A1298C位点突变的研究.中华妇产科杂志, 2004, 39(4):238-241.
40. 王亚文, 李芬, 李义平, 等.亚甲基四氢叶酸还原酶677C→T突变与不明原因反复流产相关性研究.中国实用妇科与产科志, 2002, 18(5):291-293.
41. 王苏梅, 贾颐舫, 杨丹形, 等. MTHFR基因C677T多态性与原因不明复发性自然流产的相关性.中国妇幼保健, 2011, 26(9):1385-1387.
42. 管立学, 杜欣莹, 王敬先, 等. PAI-1基因和MTHFR基因多态性与复发性早期自然流产的关系.中华医学遗传学杂志, 2005, 22(3): 330-333.
43. 胡晓东, 梁佩燕, 刁梁辉, 等.亚甲基四氢叶酸还原酶基因突变不明原因复发性流产的关系.中国优生与遗传杂志, 2014, 22(11):87-89.
44. 董素芹, 杜欣莹, 刘学云. MTHFR基因多态性与不明原因习惯性流产的相关性分析.实用妇产科杂志, 2006, 22(8):500-501.
45. 钟慧军, 刘军红, 朱永生, 等. MTHFR C677T基因多态性与复发性自然流产的相关性研究.宁夏医学杂志, 2010, 32(8):675-676.
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Chinese Journal of Evidence-Based Medicine

Association between Methylenetetrahydrofolate Reductase Gene Polymorphism and the Risk of Unexplained Recurrent Spontaneous Abortion: A Meta-analysis

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