MTHFR and Miscarriage

MTHFR C677T mutation causes a 6.3 fold increase in early miscarriage risk

Methylene tetrahydrofolate reductase (MTHFR C677T) and factor V Leiden were investigated in 84 women with two or more miscarriages and in 80 age and ethnicity matched healthy controls. Both MTHFR C677T and Factor V Leiden were not found to be significantly more prevalent in patients than controls as a whole. However, MTHFR C677T showed significant association with early pregnancy loss (odds ratio = 6.3).

MTHFR 677TT and 1298AC mutation increases miscarriage risk by 400% and 450%, respectively

Carriers of MTHFR 677TT and 1298AC genotypes respectively showed an increased risk of miscarriage (odds ratio 677TT vs. CC/CT=5.0, and odds ratio 1298 AC vs. AA=5.5). CONCLUSIONS: Our results support the role of MTHFR polymorphisms as a risk factor for miscarriage, regardless of dietary intake of B vitamins. 

MTHFR 677T mutation in the father causes recurrent miscarriage odds to increase 130%

Maternal (odds ratio: 4.486) and paternal (odds ratio: 6.92) hyperhomocysteinemia, paternal age (OR: 1.16), paternal MTHFR 677T allele (OR: 2.30) and DNA damage were found to increase the risk for repeat miscarriage. DNA damage showed positive correlation with plasma homocysteine and MTHFR 677T allele. Parental hyperhomocysteinemia, paternal age, paternal C677T MTHFR polymorphism and DNA damage are risk factors for repeat miscarriage. DNA damage showed positive correlation with plasma homocysteine and MTHFR 677T allele.

Only homozygous 677 and 1298 and 1793G>A are associated with repeat miscarriage

The aim of this study was to evaluate the frequency of MTHFR polymorphisms (677C>T, 1298A>C, and 1793G>A) in women with recurrent miscarriages. We have analyzed 104 Polish women with a history of 3 or more unexplained recurrent miscarriages in the first pregnancy trimester (6-13 gestation week). The control group consisted of 169 women without obstetrical complication, any history of miscarriage and with at least one live birth in anamnesis. RESULTS: For MTHFR 1793G>A polymorphism we have observed significant overrepresentation of heterozygotic GA genotypes in repeat miscarriage group (Odds ratio = 4.21). For 677C>T and 1298A>C we have shown lack of significant association with repeat miscarriage. Nevertheless, such significant association was observed if more than one mutated MTHFR variant was present in one patient.

Only homozygous and multiple gene mutations are associated with recurrent miscarriage

A total of 150 women with a history of two or more recurrent miscarriages and 20 fertile control women with no history of pregnancy losses had buccal swabs taken for DNA analyses of 10 gene mutations [factor V G1691A, factor V H1299R (R2), factor V Y1702C, factor II prothrombin G20210A, factor XIII V34L, beta-fibrinogen -455G>A, PAI-1 4G/5G, HPA1 a/b (L33P), MTHFR C677T, MTHFR A1298C]. The prevalence of these mutations was compared between women experiencing recurrent miscarriage and controls. RESULTS: No differences in the frequency of specific gene mutations were detected when women with recurrent miscarriage were compared with control women. However, the prevalence of homozygous mutations and total gene mutations among patients with recurrent miscarriage was significantly higher than among controls. Homozygous mutations were found in 59% of women with a history of recurrent pregnancy loss contrasted to 10% of control women. More than three gene mutations among the 10 genes studied were observed in 68% of women with recurrent miscarriage and 21% of controls.


Only C677T and triple+ mutations are associated with recurrent miscarriage

C677T and A1298C mutation of MTHFR was tested in 148 cases with recurrent miscarriage and 82 normal controls. RESULTS: (1) The distribution frequencies of C667T associated 3 genotypes between the recurrent miscarriage and control group showed statistically significant difference. The frequencies of C677T genotypes were: CC (33.3%), CT (53.1%), TT (13.6%) in recurrent miscarriage group and CC (52.4%), CT (51.5%), TT (6.1%) in control group, respectively. And the frequency of CC genotype in recurrent miscarriage group was decreased significantly, while the frequency of T allele in URSA was increased. (2) The prevalence of the MTHFR A1298C associated 3 genotypes and A/C alleles in the recurrent miscarriage group did not differ significantly from the control. (3) According to the linkage analysis of C677T and A1298C, 8 linkage genotypes were found, and the frequency of 677CC/1298AA in URSA was significantly lower compared with the control, the linkage of 677 (CT + TT)/1298CC was only observed in recurrent miscarriage group.


Neither C677T or A1298C MTHFR polymorphisms are associated with embryo quality or miscarriage

MTHFR C677T and A1298C polymorphism genotyping was performed on 374 subjects for this study, representing 197 couples undergoing IVF. Analyses were used to assess whether these polymorphisms are associated with embryo quality or with ongoing pregnancy or miscarriage rates. RESULTS: The C677T and A1298C variants, either alone or in combination, did not associate with embryo quality or short-term pregnancy outcome. CONCLUSIONS: The common polymorphisms in MTHFR are not associated with embryo quality or with short-term pregnancy outcomes. Therefore, in our population in which women receive adequate folic acid, MTHFR genotypes are not informative in explaining IVF failure.


MTHFR C677T not associated with recurrent miscarriage

 The main objective of this research was to investigate the association between the C677T polymorphism of the MTHFR gene as a genetic risk factor for idiopathic recurrent miscarriage. Molecular analysis was performed in 80 DNA samples from 30 patients with recurrent miscarriage and among 50 healthy control subjects. 677T MTHFR allele frequencies for group with recurrent miscarriage and the control group were 35% and 33%, respectively and 677C MTHFR allele frequencies were 65% and 67%, respectively. There was no significant difference in allele frequency between these two groups. The data presented in this study fail to support the relationship between MTHFR C677T polymorphism and risk in women with recurrent miscarriage.

Elevated homocysteine is the only type of thrombophilia which causes first trimester miscarriages

In 2005, a review of the literature from the previous 10 years revealed that only 3 types of thrombophilia may be related to recurrent miscarriage: elevated homocysteine levels (caused by MTHFR mutation or lifestyle factors), factor V Leiden or APC resistance (associated with second trimester loss), and antiphospholipid antibodies (associated with second trimester loss).

MTHFR 1298AC/CC increases risk of miscarriage with fetal aneuploidy by 293%

The frequencies of MTHFR 1298AC and combined 1298AC/CC genotypes were higher in miscarriage with fetal chromosomal aneuploidy than in controls. The 1298C allele frequency was also significantly higher in miscarriage with fetal chromosomal aneuploidy than in controls. Moreover, the 1298C allele frequency was higher in miscarriage with fetal chromosomal aneuploidy than in miscarriage with normal fetal karyotype. The combined 1298AC/CC genotype was significantly associated with the risk of miscarriage with fetal chromosomal aneuploidy compared with that of the 1298AA genotype (adjusted odds ratio = 2.93). There was no association between miscarriage with fetal chromosomal aneuploidy and other polymorphisms. Conclusions: Our findings indicate that MTHFR 1298A>C polymorphism may be an independent risk factor for miscarriage with fetal chromosomal aneuploidy.

MTHFR + Low dietary folate associated with miscarriage, developmental delay and birth defects

MTHFR +/+ and +/- female mice were fed a control or folic acid-deficient diet for 6 weeks, then mated with MTHFR +/- males. RESULTS: Maternal MTHFR and folate deficiencies resulted in increased developmental delays and smaller embryos. We also observed a low frequency of a variety of embryonic defects in the experimental groups, such as neural tube, heart looping, and turning defects; these results mimic the low incidence and multifactorial nature of these anomalies in humans. Folate-deficient mice also had increased embryonic losses and severe placental defects, including placental abruption and disturbed patterning of placental layers. CONCLUSIONS: Our study provides biological evidence linking maternal MTHFR and dietary folate deficiencies to adverse pregnancy outcomes in mice. It underscores the importance of folate not only in reducing the incidence of early embryonic defects, but also in the prevention of developmental delays and placental abnormalities that may increase susceptibility to other defects and to reproductive complications.


Excess dietary folic acid is associated with delayed embryonic development and birth defects

MTHFR +/+ or +/- pregnant mice on a control diet or folic acid-supplemented diet (20-fold higher than the recommended intake) were examined for embryonic loss, delay, and defects. RESULTS: Plasma homocysteine levels were not affected by diet. The folic acid diet was associated with embryonic delay and growth retardation, and may confer susceptibility to embryonic defects. The folic acid diet did not adversely affect placental development. Embryos from the folic acid diet MTHFR +/+ group were delayed and the folic acid diet was associated with thinner ventricular walls in embryonic hearts. There was a significant interaction between maternal MTHFR deficiency and a high folate diet for several developmental outcomes. CONCLUSIONS: Our study suggests that high folate intake may have adverse effects on fetal mouse development and that maternal MTHFR deficiency may improve or rescue some of the adverse outcomes. These findings underscore the need for additional studies on the potential negative impact of high folate intake during pregnancy.

Other topics covered under Thrombophilia and Miscarriage:

Factor V Leiden and Miscarriage

Hormones and Thrombophilia

Insulin Resistance and Thrombophilia

Reducing Hypercoagulation