Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial

Azita Hekmatdoost, Farhad Vahid, Zahra Yari, Mohammadreza Sadeghi, Hassan Eini-Zinab, Niknam Lakpour, Soheila Arefi, Azita Hekmatdoost, Farhad Vahid, Zahra Yari, Mohammadreza Sadeghi, Hassan Eini-Zinab, Niknam Lakpour, Soheila Arefi

Abstract

Purpose: To determine whether 5-methylenetetrahydrofolate (MTHF) is more effective than folic acid supplementation in treatment of recurrent abortion in different MTHFR gene C677T and A1298C polymorphisms.

Methods: A randomized, double blind, placebo-controlled trial conducted April 2011-September 2014 in recurrent abortion clinics in Tehran, Iran. The participants were women with three or more idiopathic recurrent abortion, aged 20 to 45 years. Two hundred and twenty eligible women who consented to participate were randomly assigned to receive either folic acid or 5-MTHF according to the stratified blocked randomization by age and the number of previous abortions. Participants took daily 1 mg 5-methylentetrahydrofolate or 1 mg folic acid from at least 8 weeks before conception to the 20th week of the pregnancy. The primary outcome was ongoing pregnancy rate at 20th week of pregnancy, and the secondary outcomes were serum folate and homocysteine at the baseline, after 8 weeks, and at the gestational age of 4, 8, 12, and 20 weeks, MTHFR gene C677T and A1298C polymorphisms.

Results: There was no significant difference in abortion rate between two groups. Serum folate increased significantly in both groups over time; these changes were significantly higher in the group receiving 5-MTHF than the group receiving folic acid (value = 2.39, p<00.1) and the result was the same by considering the time (value = 1.24, p<0.01). Plasma tHcys decreased significantly in both groups over time; however these changes were not significantly different between the groups (value = 0.01, p = 0.47).

Conclusion: The results do not support any beneficial effect of 5-MTHF vs. folate supplementation in women with recurrent abortion with any MTHFR C677T and/or A1298C polymorphism.

Trial registration: ClinicalTrials.gov NCT01976676.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT Flow Diagram of Trial…
Fig 1. CONSORT Flow Diagram of Trial Participants.
Fig 2. Serum folate concentration in folic…
Fig 2. Serum folate concentration in folic acid and MTHFR groups over time.
Fig 3. Serum tHcys concentration in folic…
Fig 3. Serum tHcys concentration in folic acid and MTHFR groups over time.
Fig 4. Serum folate concentration in folic…
Fig 4. Serum folate concentration in folic acid and MTHFR groups in different MTHFR polymorphisms over time.
Fig 5. Serum tHcys concentration in folic…
Fig 5. Serum tHcys concentration in folic acid and MTHFR groups in different MTHFR polymorphisms over time.

References

    1. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000;71(5 Suppl):1295S–303S. Epub 2000/05/09. .
    1. Steegers-Theunissen RP, Boers GH, Blom HJ, Trijbels FJ, Eskes TK. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet. 1992;339(8801):1122–3. Epub 1992/05/02. .
    1. Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr. 2000;71(4):962–8. Epub 2000/03/25. .
    1. Brouwer IA, van Dusseldorp M, Thomas CM, Duran M, Hautvast JG, Eskes TK, et al. Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am J Clin Nutr. 1999;69(1):99–104. Epub 1999/01/30. .
    1. Gindler J, Li Z, Berry RJ, Zheng J, Correa A, Sun X, et al. Folic acid supplements during pregnancy and risk of miscarriage. Lancet. 2001;358(9284):796–800. Epub 2001/09/21. .
    1. George L, Mills JL, Johansson AL, Nordmark A, Olander B, Granath F, et al. Plasma folate levels and risk of spontaneous abortion. JAMA. 2002;288(15):1867–73. Epub 2002/10/17. doi: joc20985 [pii]. .
    1. Bergen NE, Jaddoe VW, Timmermans S, Hofman A, Lindemans J, Russcher H, et al. Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG: an international journal of obstetrics and gynaecology. 2012;119(6):739–51. Epub 2012/04/12. 10.1111/j.1471-0528.2012.03321.x .
    1. Byrne J. Periconceptional folic acid prevents miscarriage in Irish families with neural tube defects. Irish journal of medical science. 2011;180(1):59–62. Epub 2010/11/06. 10.1007/s11845-010-0629-5 .
    1. Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, et al. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril. 1993;60(5):820–5. Epub 1993/11/01. .
    1. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Thomas CM, Eskes TK. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet Gynecol. 2000;95(4):519–24. Epub 2000/03/22. .
    1. Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, et al. Preconception folate and vitamin B(6) status and clinical spontaneous abortion in Chinese women. Obstet Gynecol. 2002;100(1):107–13. Epub 2002/07/09. .
    1. Yamada T, Morikawa M, Yamada T, Kishi R, Sengoku K, Endo T, et al. First-trimester serum folate levels and subsequent risk of abortion and preterm birth among Japanese women with singleton pregnancies. Archives of gynecology and obstetrics. 2013;287(1):9–14. Epub 2012/08/10. 10.1007/s00404-012-2501-5 .
    1. Zhang X, Li J, Gu Y, Zhao Y, Wang Z, Jia G. A pilot study on environmental and behavioral factors related to missed abortion. Environmental health and preventive medicine. 2011;16(4):273–8. Epub 2011/03/25. 10.1007/s12199-010-0196-4 ; PubMed Central PMCID: PMCPmc3117210.
    1. Charles DH, Ness AR, Campbell D, Smith GD, Whitley E, Hall MH. Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review. Paediatric and perinatal epidemiology. 2005;19(2):112–24. Epub 2005/03/25. 10.1111/j.1365-3016.2005.00633.x .
    1. Chiaffarino F, Ascone GB, Bortolus R, Mastroia-Covo P, Ricci E, Cipriani S, et al. [Effects of folic acid supplementation on pregnancy outcomes: a review of randomized clinical trials]. Minerva ginecologica. 2010;62(4):293–301. Epub 2010/09/10. .
    1. Furness D, Fenech M, Dekker G, Khong TY, Roberts C, Hague W. Folate, vitamin B12, vitamin B6 and homocysteine: impact on pregnancy outcome. Maternal & child nutrition. 2013;9(2):155–66. Epub 2011/10/26. 10.1111/j.1740-8709.2011.00364.x .
    1. Kim MW, Ahn KH, Ryu KJ, Hong SC, Lee JS, Nava-Ocampo AA, et al. Preventive effects of folic acid supplementation on adverse maternal and fetal outcomes. PLoS One. 2014;9(5):e97273 Epub 2014/05/21. 10.1371/journal.pone.0097273 ; PubMed Central PMCID: PMCPmc4026223.
    1. Shi H, Yang S, Liu Y, Huang P, Lin N, Sun X, et al. Study on Environmental Causes and SNPs of MTHFR, MS and CBS Genes Related to Congenital Heart Disease. PLoS One. 2015;10(6):e0128646 Epub 2015/06/04. 10.1371/journal.pone.0128646 PONE-D-14-52335 [pii].
    1. Nelen WL, Blom HJ, Thomas CM, Steegers EA, Boers GH, Eskes TK. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr. 1998;128(8):1336–41. Epub 1998/08/04. .
    1. Tempfer CB, Kurz C, Bentz EK, Unfried G, Walch K, Czizek U, et al. A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril. 2006;86(1):145–8. Epub 2006/05/24. 10.1016/j.fertnstert.2005.12.035 .
    1. Quere I, Mercier E, Bellet H, Janbon C, Mares P, Gris JC. Vitamin supplementation and pregnancy outcome in women with recurrent early pregnancy loss and hyperhomocysteinemia. Fertil Steril. 2001;75(4):823–5. Epub 2001/04/05. .
    1. Zetterberg H, Zafiropoulos A, Spandidos DA, Rymo L, Blennow K. Gene-gene interaction between fetal MTHFR 677C>T and transcobalamin 776C>G polymorphisms in human spontaneous abortion. Hum Reprod. 2003;18(9):1948–50. Epub 2003/08/19. .
    1. Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006;84(1):156–61. Epub 2006/07/11. doi: 84/1/156 [pii]. .
    1. Obeid R, Holzgreve W, Pietrzik K. Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? J Perinat Med. 2013;41(5):469–83. Epub 2013/03/14. 10.1515/jpm-2012-0256 /j/jpme.ahead-of-print/jpm-2012-0256/jpm-2012-0256.xml [pii]. .
    1. Ray JG, Laskin CA. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review. Placenta. 1999;20(7):519–29. Epub 1999/08/24. 10.1053/plac.1999.0417 .
    1. Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K. Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr. 2004;79(3):473–8. Epub 2004/02/27. .
    1. Fohr IP, Prinz-Langenohl R, Bronstrup A, Bohlmann AM, Nau H, Berthold HK, et al. 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr. 2002;75(2):275–82. Epub 2002/01/30. .
    1. Prinz-Langenohl R, Bramswig S, Tobolski O, Smulders YM, Smith DE, Finglas PM, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C—>T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009;158(8):2014–21. Epub 2009/11/18. doi: BPH492 [pii] 10.1111/j.1476-5381.2009.00492.x
    1. Kirke PN, Mills JL, Molloy AM, Brody LC, O'Leary VB, Daly L, et al. Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ. 2004;328(7455):1535–6. Epub 2004/05/25. 10.1136/ [pii].
    1. Nair RR, Khanna A, Singh R, Singh K. Association of maternal and fetal MTHFR A1298C polymorphism with the risk of pregnancy loss: a study of an Indian population and a meta-analysis. Fertil Steril. 2013;99(5):1311–8 e4. Epub 2013/01/30. doi: S0015-0282(12)02536-8 [pii] 10.1016/j.fertnstert.2012.12.027 .
    1. Cao Y, Xu J, Zhang Z, Huang X, Zhang A, Wang J, et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis. Gene. 2013;514(2):105–11. Epub 2012/12/04. doi: S0378-1119(12)01396-0 [pii] 10.1016/j.gene.2012.10.091 .
    1. Creus M, Deulofeu R, Penarrubia J, Carmona F, Balasch J. Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain. Clin Chem Lab Med. 2013;51(3):693–9. Epub 2012/10/26. 10.1515/cclm-2012-0452 /j/cclm.ahead-of-print/cclm-2012-0452/cclm-2012-0452.xml [pii]. .
    1. Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y. Association between the MTHFR C677T polymorphism and recurrent pregnancy loss: a meta-analysis. Genet Test Mol Biomarkers. 2012;16(7):806–11. Epub 2012/02/09. 10.1089/gtmb.2011.0318 .
    1. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril. 2006;86(6):1716–22. Epub 2006/11/01. doi: S0015-0282(06)03070-6 [pii] 10.1016/j.fertnstert.2006.05.052 .
    1. Rothenberg SP, da Costa MP, Sequeira JM, Cracco J, Roberts JL, Weedon J, et al. Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect. N Engl J Med. 2004;350(2):134–42. Epub 2004/01/09. 10.1056/NEJMoa031145350/2/134 [pii]. .
    1. Molloy AM, Quadros EV, Sequeira JM, Troendle JF, Scott JM, Kirke PN, et al. Lack of association between folate-receptor autoantibodies and neural-tube defects. N Engl J Med. 2009;361(2):152–60. Epub 2009/07/10. doi: 361/2/152 [pii] 10.1056/NEJMoa0803783

Source: PubMed

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