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​Cihat Şen, ​Nicola Volpe

Cecilia Villalain, Daniel Rolnik, M. Mar Gil

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Methyl-tetrahydrofolate reductase defect in two habitual abortion patients

Feyzi Gökosmanoğlu, Hakan Cinemre, Cemil Bilir

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Methyl-tetrahydrofolate reductase defect in two habitual abortion patients. Perinatal Journal 2008;16(1):31-35

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Feyzi Gökosmanoğlu,
Hakan Cinemre,
Cemil Bilir

  1. Düzce Üniversitesi Tıp Fakültesi, İç Hastalıkları Anabilim Dalı- Düzce TR
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Conflicts of Interest

No conflicts declared.

Methyltetrahydrofolate reductase(MTHFR) defect is a result of a mutation in the encoding gene where thymidine is replaced by cytosine(C667T) Prevalence of the mutation varies in different societies. Resulting thermo labile MTFHR enzyme results in hyperhomocysteinemia which itself is a risk factor for thrombosis Elevated plasma homocysteine levels also can result in neural tub defects, fetal death, abruption placenta and placental infarctions
We report two siblings presented with habitual abortus and were found to have heterozygote MTHFR defect
We believe that even heterozygosis for MTHFR defect can cause spontaneous abortion alone or in combination with unknown factors This accompanying unknown factor might be heterozygote â fibrinogen 455 GA mutation that we found in both of our patients Studies about this mutation reported especially high incidence of ischemic stroke in these patients. Further studies are needed to confirm whether MTHFR defect combined with â fibrinogen455 GA mutation definitely increase risk of spontaneous abortion Folic acid supplementation and enoxaparin might be helpful, as in our patients, in the management of these patients.

MTHFR defect, recurrent pregnancy loss, treatment

Habitual abortus is defined as spontaneous termination of two or more successive pregnancies before 20th weeks of pregnancy. Determinations of etiologic and prognostic factors are among the most difficult situations in obstetrics. About 15-33% of the recurrent abortus cases are idiopathic. Efficient utero-plecental circulation, which can be effected from hemostasis disorders, is a prerequisite for continuation of a successful pregnancy. Thus, maternal thrombophilias (factor V Leiden mutation, MTHFR defect, Factor II mutations, protein C or S deficiencies) are also important disorders in obstetrics (1).
MTHFR is an essential enzyme for homocysteine metabolism. MTHFR and other gene mutations in homocysteine metabolism lead to hyperhomocysteinemia. In the MTHFR defect, mutation of C667T located in MTHFR gene results in replacement of alanine in the catalytic domain of MTHFR by valine. This change makes the enzyme thermo-labile. In turn, in vitro MTHFR activity decreases 70% and 35% in homozygote and heterozygote, respectively. On the other hand, plasma homocysteine levels in patients who are homozygous for C677T allele in crease moderately and this is significant especially during folate deficiency periods. Heterozygous allele carrying patients have mildly increased levels plasma of homocysteine(2,3).
The exact mechanism between hyperhomocyteinemia and preganancy loss is not known and several mechanisms like constitutional and neurologic effects on the fetus, increase in thrombogenic potential or thrombosis in the effected mother are proposed.
MTHFR is a cause for hyperhomocysteinemia accompanying decreased folate levels which might cause mental retardation, skeletal abnormalities, premature vascular disease or thrombosis. Hyperhomocysteinemia increases the risk of neural tube defect, fetal losses, abruptio placenta and placental infarction. Studies have shown borderline increases homozygous MTHFR defect in women with fetal losses and an increase in relative risk of fetal loss in women with this defect (4). It’s still not clear whether folate supplementation decrease fetal loss risk. MTHFR mutation is accepted as a risk factor in habitual abortus. Homozygote variant frequency have been reported to be elevated among women with three or more recurrent abortion in some studies while others couldn’t find a relationship between fetal loss and MTHFR mutations, and still others reported similar or lower MTHFR mutation prevalence between idiopathic fetal losses and controls (5,6,7,8). We found MTHFR defect in two sisters leading to habitual abortus and decided to report this as there were conflicting data regarding MTHFR defect in the literature.
The first case was a 30 y/o female who had 7 spontaneous abortions during the first trimester. Her sister, the second case, was 28 y/o woman who had 5 spontaneous abortions during the first trimester. The patients were consulted to our clinic for nonspecific complaints after being evaluated at the gynecology- obstetrics department of our university hospital. Both patients have normal physical examination findings including the vitals. Serum biochemistry, hormone levels and hemogam were unremarkable. Plasma homocysteine were measured as 15 umol/l (N: 5-12) in the fist patient and 16 umol/l in the second. Heterozygote carrier state for MTHFR C667T and â-fibrinogen-455 G-A mutations were found in both patients. They didn’t carry other thrombophilia producing defects like factor V G1691A,factor V H1299R, phrothrombin G20210A , factor XIII V34L, MTHFR A1298C, Apo B R3500Q, PAI-1, HPA`, ACE or Apo E. Both of our patients received po folic acid 5 mg/d and sc enoxaparin 4000 IU/ 0.4 mL /day until 1 day before delivery. Both pregnancies carried on without adverse events leading to delivery of two healthy babies. Deliveries were with ceserian section; first patient's delivery was performed at the 36th week with a birth weight of 3,140 g. Second patient's delivery was performed at the 38th week with a birth weight of 2,980 g.Patients have not received heparin and adviced to take low dose aspirin during nursery period. Oral anticoagulation was planned for the post-nursery period.
Fetal loss is a frequent clinical entity. 15% of the pregnancies terminate with spontaneous abortion while 0.5-1% of the couples experience recurrent fetal losses. Habitual abortus is defined as spontaneous termination of two or more successive pregnancies before 20th weeks of pregnancy(9) and is one of the most unknown areas in obstetrics. All fetal losses were in during the first trimester in both of our patients.
The most frequent cause of hereditary thrombophilias are factor V Leiden mutation and activated protein C resistance (APCR). Acquired or hereditary APCR have been proposed to be among the potential causes of placental circulatory failure. There are studies in the literature supporting a relationship between factor V Leiden and factor II G20210A mutations and recurrent fetal losses. These mutations are not only reported to be important risk factors for recurrent abortions but also for thrombosis, and arterial and venous thromboembolism in atherosclerotic young women (1,10,11) .
Wramsby et al., have found higher prevalence of factor V Leiden mutation among primary habitual abortus patients but couldn’t find a significant difference between factor II G20210A or MTHFR C677T mutation carriers and controls. They reported higher risk for primary habitual abortus patients compared to secondary ones (12). We found our patients to have MTHFR defect and carrier (heterozygote) state for â-fibrinogen-455 G-A mutation, but couldn’t find other etiologic factors for thrombophilia.
MTHFR is an important enzyme in folate metabolism. Mutation in this enzyme, the most common of which is C677T polymorphism, results in decrease in the activity of the enzyme. As a result, 5-methyl THF levels are decreased and 5,10-methyl THF as well as plasma homocysteine levels are increased (13,14). Increased homocysteine levels are reported to be a risk factor for thrombosis and it’s well understood that clinical results of this situation are widespread. Severe MTHFR defect, where hyperhomocyteinemia and homocycteinuria develop, might result in peripheral neuropathy, retardation development, hypotonia, stroke and thrombosis. On the other hand, mild MTHFR defect is pretty common in general population and accepted as a risk factor for arterial disorders (15).
Nelen et al., reported that MTHFR C677T mutation increase plasma homocysteine levels which in turn results in 2-3 times increase in the frequency of recurrent spontaneous abortion (16). Successive studies reported very much increase in plasma homocysteine levels in patients with MTHFR C677T homozygote TT variant that is significantly associated with recurrent spontaneous abortion. In contract, some studies reported C677T polymorphism was not a risk factor for fetal losses (17). Recent meta-analysis, also suggested no relationship between recurrent spontaneous abortion and C677T variant state (18).
Data on the effect of MTHFR gene mutations on idiopathic recurrent spontaneous abortion are still controversial. Some investigators report MTHFR mutations among risk factors for idiopathic fetal losses. Others reported high prevalence of homozygote variant state in recurrent spontaneous abortion but still others couldn’t find a relationship between MTHFR mutations and fetal loses and moreover reported similar or lower prevalence of MTHFR mutation among idiopathic pregnancy losses compared to controls (5,6,7,8). In our cases, both patients were found to have heterozygote MTHFR defect and both responded the treatment successfully. Thus we believe that even heterozygosis for MTHFR defect can cause spontaneous abortion alone or in combination with unknown factors. This accompanying unknown factor might be heterozygote â- fibrinogen-455 G-A mutation that we found in both of our patients. Studies about this mutation reported especially high incidence of ischemic stroke in these patients (19).
Some explanations for the mechanisms for the etiology of recurrent abortions have been proposed but not been explained clearly. One of them is MTHFR mutations. There are conflicts in the literature on this point. It may be other factors which can play a role on this problem. Folic acid supplementation and enoxaparin might be helpful, as in our patients, in the management of these patients.
1. FE Preston, FR Rosendaal et al. İncreased fetal loss in women with heritable thrombophilia. Lancet 1996; 348(5): 913-916.
2. Dekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs C, van Geijn HP. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol. 1995 Oct; 173(4): 1042-8
3. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May; 10(1): 111-3.
4. Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, Steegers-Theunissen RP, Eskes TK. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril. 1993 Nov; 60(5): 820-5.
5. Quere I, Bellet H, Hoffet M, Janbon C, Mares P, Gris JC. A woman with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevelance in 100 consecutive women with recurrent miscarriages. Fertil Steril 1998, 69:152-54.
6. Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A, Agorastos T, Zournatzi V, Makris PE, Bontis J, Kotsis A. Factor V leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod. 2000 Feb; 15(2): 458-62.
7. 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 Jul; 52(1): 60-6.
8. Holmes ZR, Regan L, Chilcott I, Cohen H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss. Br J Haematol. 1999 Apr; 105(1): 98-101.
9. Clark DA, Lea RG, Podor T, Daya S, Banwatt D, Harley C. Cytokines determining the success or failure of pregnancy. Ann NY Acad Sci 1991; 626: 524-536.
10. Brenner B, Mandel H, Lanir N, Younis J, Rothbart H, Ohel G, Blumenfeld Z. Activated protein C resistance can be associated with recurrent fetal loss. Br J Haematol 1997 Jun; 97(3): 551-554.
11. RF Franco et al. The 20210G A mutation in the 3' untranslatedregion of the prothrombin gene and the risk for arterial thrombotic disease. B J Haematol 1999; 104: 5054.
12. Wramsby ML, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril 2000 Nov; 74(5): 987-91.
13. Rosenblatt DS. Methylenetetrahydrofolate reductase. Clin Invest Med, 2001; 24: 56-59.
14. 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: 169-172.
 15. Rady PL, Tyring SK, Hundnall SD, et al. Methylenetetrahydrofolate reductase (MTHFR): The incidence of mutations C677T and A1298C in the Ashkenazi Jewish population. Am J Med Genet, 1999; 86: 380-384.
16. Nelen WL, Steegers EA, Eskes TK, Blom HJ. Genetic risk factor for unexplained recurrent early pregnancy loss.Lancet. 1997 Sep 20; 350(9081): 861.
17. Kobashi G, Kato EH, Morikawa M, Shimada S, Ohta K, Fujimoto S, Minakami H, Yamada H. 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 Jun; 31(3): 266-71.
18. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril. 2006 Dec; 86(6): 1716-22.
19. Dong QL, Zhang C.Association between the polymorphism of beta-fibrinogen gene -455G/A and ischemic stroke. 2004 Jun;21(3):274-6.