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ORIGINAL RESEARCH |
From the Departments of Gynecologic Endocrinology and Reproductive Medicine, and Obstetrics and Gynecology, University of Vienna School of Medicine, Vienna, Austria, and Department of Laboratory Medicine, Hospital Kaiser Franz-Josef Spital, Vienna, Austria.
Address reprint requests to: Fritz Nagele, MD, University of Vienna School of Medicine, Department of Gynecologic Endocrinology and Reproductive Medicine, Waehringer Guertel 18-20, Vienna, A-1090, Austria; E-mail: fritz.nagele{at}akhwien.ac.at.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: In a case control study, we investigated 133 women with a history of three or more consecutive pregnancy losses before 20 weeks’ gestation and 74 healthy controls with at least two live births and no history of pregnancy loss. A DNA extraction and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the MTHFR C677T polymorphism. Serum homocysteine levels were assessed by a fluorescence polarization immunoassay.
RESULTS: The MTHFR allele frequencies in women with idiopathic recurrent miscarriage and controls were 34.6% and 21.6%, respectively, for the T allele (mutant) and 65.4% and 78.4%, respectively, for the C allele (wild type) (P = .007, odds ratio 1.9, 95% confidence interval 1.2, 3.1). The MTHFR genotype frequencies in women with idiopathic recurrent miscarriage and controls were: 17.3% (T/T), 34.6% (C/T), 48.1% (C/C) and 5.4% (T/T), 32.4% (C/T), 62.2% (C/C), respectively (P = .03, odds ratio 3.7, 95% confidence interval 1.2, 11.8 [T/T versus C/T and C/C]). Serum concentrations of homocysteine were significantly higher in carriers of a MTHFR mutant allele compared with women with no mutant allele (mean 7.4 ± 2.4 µmol/L [T/T + C/T] versus 6.5 ± 2.6 µmol/L [C/C], P = .05).
CONCLUSION: Carriage of the mutant allele of the MTHFR C677T polymorphism is associated with elevated serum levels of homocysteine and idiopathic recurrent miscarriage.
Hyperhomocysteinemia can result from genetic or nutrient-related disturbances in the trans-sulphuration and remethylation pathways of the homocysteine metabolism.1–4 The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetra-hydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate and the carbon donor for the remethylation of homocysteine to methionine. A polymorphism of the gene MTHFR results in the production of a less active, thermolabile isoform of MTHFR, thus decreasing the remethylation of homocysteine.5,6
The gene encoding MTHFR has been mapped to chromosomal region 1p36.3.7 A polymorphism of MTHFR (C677T) leads to an alanine to valine amino acid substitution within the predicted catalytic domain of MTHFR.8 The prevalence of this polymorphism varies widely according to ethnic origin and ranges from 23% to 37% in different European populations.9
Homozygosity for the thermolabile variant of MTHFR predisposes to the development of hyperhomocysteinemia.6,10 Mild hyperhomocysteinemia has been described as a risk factor for atherosclerosis,11 venous thrombosis,12 neural tube defects,13 placental abruption,14 and preeclampsia.15 Several studies reported on disturbances of the folate metabolism among women with recurrent miscarriages. Some authors,16–20 but not others21,22 observed increased frequencies of hyperhomocysteinemia, genetic vitamin deficiency, reduced enzyme activities, and decreased serum folate concentrations among women with recurrent miscarriage.
The exact mechanism linking hyperhomocysteinemia to miscarriage is unknown. Several hypotheses have been put forward, among them structural and neurologic effects on the fetus or increased thrombogenic potential with subsequent placental thrombosis.13,14,18 In a recent report, Nelen et al demonstrated elevated maternal plasma homocysteine concentrations to be associated with defective chorionic villous vascularization.23
We investigated the frequency of the C677T MTHFR polymorphism and serum concentrations of homocysteine in a Middle-European white population with a history of idiopathic recurrent miscarriage and a control population of women with no history of spontaneous miscarriage. The aim of this study was to assess the associations between the MTHFR C677T polymorphism, serum homocysteine concentrations, and idiopathic recurrent miscarriage.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The diagnosis of idiopathic recurrent miscarriage was made on the basis of a documented history of at least three spontaneous, consecutive miscarriages before 20 weeks’ gestation. Each woman underwent a diagnostic workup to rule out a verifiable cause of the recurrent miscarriages. Diagnostic procedures included hysteroscopy; paternal and maternal karyotyping; cervical cultures for chlamydia, ureaplasma, mycoplasma; a comprehensive hormonal status; and evaluation of antiphospholipid syndrome with immunoglobulins M and G anticardiolipin antibody assessment and lupus anticoagulant testing. According to the diagnostic work-up, the following reasons for exclusion have been identified: uterine abnormalities (n = 22), luteal phase defect (n = 16), hyperprolactinemia (n = 15), hyperandrogenemia (n = 19), genital infections (n = 11), maternal/ paternal balanced translocations (n = 6), antiphospholipid syndrome (n = 5), venous thrombosis (n = 6), and thyroid autoantibodies (n = 10). None of the women included in the study group were pregnant at the time of blood sampling. Among these women, primary recurrent miscarriage was defined as no history of a pregnancy carried beyond 20 weeks’ gestation. Secondary recurrent miscarriage was defined as a history of at least one pregnancy carried beyond 20 weeks’ gestation.
The control group consisted of 74 women with at least two live births and no history of miscarriage. Patients were recruited consecutively at our outpatient clinic for postmenopausal disorders between January 1996 and September 1999. Control subjects were not randomly selected. Seventy-four women agreed to participate and were included in the study. All control women were postmenopausal, to rule out possible future miscarriages after inclusion in the study. Written informed consent was obtained from participating women. To avoid confounding by ethnicity, only Middle-European white women were included in the study and control groups. To avoid confounding by genetic admixture, only women whose parents were of the same ethnicity were enrolled.
Blood was drawn from the antecubital vein. Serum samples were stored at -80C in aliquots to avoid possible interference with assay results due to repeated freezethaw cycles. The DNA was extracted using the QIA-GEN System (QIAamp DNA Blood Midi Kit, Qiagen GmbH, Hilden, Germany) and stored at 4C until analyzed. Using the polymerase chain reaction (PCR) strategy described by Frosst et al,8 PCR conditions comprised an initial denaturation step at 96C for 5 minutes, followed by 35 cycles of 93C for 1 minute, 55C for 1 minute, and 72C for 2 minutes, and a final extension step at 72C of 4 minutes. Oligonucleotide primers (forward 5'-TGAAGGAGAAGGTGTCTGCGGGA-3' and reverse 5'-AGGACGGTGCGGTGAGAGTG-3') were used to generate a 198 base pair product. With the use of a restriction fragment length polymorphism strategy, the PCR product was digested by Hinf I (New England Biolabs, Beverly, MA), separated on a 2% agarose gel, and stained with SYBR Green I (FMC, Bio Products Europe, Vallensbaek Strand, Denmark). The T substitution at nucleotide 677 creates a Hinf I restriction site with subsequent cleavage of the original 198 base pair PCR fragment into a 175 base pair fragment and a 23 base pair fragment. In the absence of the mutation, no cleavage is observed.
Serum levels of homocysteine were determined using a fluorescence polarization immunoassay (FPIA, Abbott, Laboratories, Abbott Park, IL). The assay measures total L-homocysteine. Intra- and interassay coefficients of variation were below 5%. Normal values for homocysteine serum levels ranged from 4.3 to 10 µmol/L.24
Differences in the MTHFR genotype and allele frequencies between the study and control groups were analyzed by 
2 test and Fisher exact test, respectively. The odds ratio (OR) was used as a measure of the strength of the association between allele and genotype frequencies and idiopathic recurrent miscarriage. All P values were two-tailed, and 95% confidence intervals (CIs) were calculated. Homocysteine serum levels are given as mean ± standard deviation. Comparisons between groups were made using Student t test. P values < .05 were considered statistically significant.
A calculation of the dependence of allele frequencies in our patient sample was performed by using the SPSS software (SPSS Inc., Chicago, IL) for Windows 10.0.1 (1999). Relations between the T and C alleles and idiopathic recurrent miscarriage were examined by Pearson’s product-moment-correlation coefficient for dichotomous variables, by Cramer’s V coefficient, and by the contingency coefficient. These coefficients are comparable with correlation coefficients and have values between -1 and 1 (interpretation: coefficients 0.1–0.3, weak effect; 0.3–0.5, medium effect; greater than 0.5, strong effect). All symmetric dependency measures revealed a weak but very significant connection between the distribution of the T and C allele frequencies and the occurrence of idiopathic recurrent miscarriage (Table 1
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RESULTS |
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). Median age at diagnosis of women with idiopathic recurrent miscarriage was 32 years (range 23–43). The median numbers of miscarriages and live births were 3.8 (range 3–9) and 0.3 (range 0–3), respectively. Seventy-three percent of women were primary aborters, 27% were secondary aborters. Seventy-four women were examined as controls (Table 2). Median age at time of blood sampling was 56 years (range 40–81). The median numbers of live births were 2.3 (range 2–5).
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. The observed genotype frequencies are in accordance with previously published genotype frequencies in a Dutch population with recurrent early pregnancy loss.19 We found that the allele frequencies as well as the distribution of genotypes were significantly different between the study and control groups. The MTHFR allele frequencies in women with idiopathic recurrent miscarriage and controls were 34.6% and 21.6%, respectively, for the T allele (mutant) and 65.4% and 78.4%, respectively, for the C allele (wild type) (P = .007, OR 1.9, 95% CI 1.2, 3.1). The MTHFR genotype frequencies in women with idiopathic recurrent miscarriage and controls were 17.3% (T/T), 34.6% (C/T), 48.1% (C/C) and 5.4% (T/T), 32.4% (C/T), 62.2% (C/C), respectively. Genotype comparisons were made for T/T versus C/T and C/C. (P = .03, OR 3.7, 95% CI 1.2, 11.8).
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Serum concentrations of homocysteine were significantly higher among carriers of a MTHFR mutant allele compared with women with no mutant allele (mean 7.4 ± 2.4 µmol/L [T/T ± C/T] versus 6.5 ± 2.6 µmol/L [C/C], P = .05) (Figure 1).
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The regulation of homocysteine metabolism is complex and is dependent on multiple vitamin cofactors, including folate, pyridoxine, and vitamin B12.10 Vitamin cofactor deficiencies and enzyme deficiencies are the leading causes of hyperhomocysteinemia. Folate status plays a crucial role in regulation of homocysteine levels in individuals homozygous for the C677T MTHFR polymorphism. Moderate elevations of homocysteine levels caused by suboptimal intake of folic acid can be corrected by folic acid supplements in individuals with vascular disease and thermolabile MTHFR.10,25 It has been hypothesized that the region in the MTHFR gene relating to the common mutation is involved in folate binding and that the enzyme may be stabilized in the presence of folate.26 Therefore, the combination of the genetic defect and inadequate folate intake may cause elevated homocysteine and subsequently increase the risk of idiopathic recurrent miscarriage. The differences between the homocysteine levels in our study group were small but statistically significantly different. The clinical relevance of this finding remains open to discussion.
Our results are in accordance with the largest previously reported data set, published by Nelen et al, who reported an increased prevalence of the C677T mutation in a cohort of Dutch women with a history of unexplained recurrent pregnancy loss.19 They found a threefold increased risk (OR 3.3, 95% CI 1.3, 10.1) for recurrent miscarriage in women homozygous for the MTHFR T/T genotype (genotype frequencies: 16% in the study group, 5% in the control group). A recent meta-analysis summarized ten studies reporting on the risk of recurrent pregnancy loss and elevated homocysteine concentrations or homozygosity for the MTHFR C677T polymorphism. Of six studies, only one found the MTHFR T/T genotype to be a significant risk factor for idiopathic recurrent miscarriage. The remaining five studies gave nonsignificant ORs. However, the pooled estimate for the MTHFR T/T genotype was significant with an OR of 1.4 (95% CI 1.0, 2.0).27
In summary, our results and the previously reported data support the notion of hyperhomocysteinemia with or without a genetic contribution by MTHFR C677T as a significant risk factor of recurrent miscarriage. It has to be recognized, however, that both hyperhomocysteinemia and the MTHFR C677T polymorphism are neither necessary nor sufficient for the development of idiopathic recurrent miscarriage. It is reasonable to speculate that disturbances in the folate metabolism act as cofactors in a multifactorial disease process.
Besides genetic diversity, ethnic variation also needs to be considered in an evaluation of the genetic background of idiopathic recurrent miscarriage. The manner in which ethnic variation can influence the interpretation of association studies has been clearly demonstrated.28 Thus, we made efforts to reduce error in the interpretation of our results by only considering Middle-European white women. Another concern relates to the selection of a proper control group. Various other studies investigating women with recurrent miscarriage used age-matched controls to compare genotype frequencies. An age-matched control group may influence the results of association studies dealing with the risk of miscarriage in a significant way. If at least some women in the control group will suffer one or more miscarriages in their remaining reproductive life (ie, long after the study has been completed), the clinical characteristics of the control group would have changed significantly in retrospect. This fact may severely bias the results toward masking a possible biologic effect of the variable studied. Thus, we made efforts to reduce this bias in the interpretation of our results by only considering postmenopausal women because this strategy does rule out future miscarriages among control women.
Of note, Wouters et al found over 20% of women with idiopathic recurrent miscarriage to harbor elevated homocysteine concentrations.16 From a clinical perspective, it seems reasonable to advise women with a history of idiopathic recurrent miscarriage to consume folic acid throughout their pregnancies. In a recent report, however, Gindler et al29 published a retrospective cohort study of folic acid supplements during pregnancy and risk of spontaneous miscarriage in a Chinese population. They found no benefit for daily consumption of 400 µg of folic acid before and during early pregnancy.29 Whether the results of this study are valid for women with recurrent miscarriage is unknown.
In summary, the C677T MTHFR polymorphism is associated with elevated serum concentrations of homocysteine as well as idiopathic recurrent miscarriage in a Middle-European white population. Our data add to the growing body of evidence that folate metabolism disturbances are a genuine etiologic factor of idiopathic recurrent miscarriages.
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Footnotes |
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Received August 23, 2001. Received in revised form November 19, 2001. Accepted November 29, 2001.
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REFERENCES |
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2. Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 1985;37:1–31.[Medline]
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11. Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, et al. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk for cardiovascular disease. Am J Hum Gen 1996;58: 35–41.[Medline]
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14. Steegers-Theunissen RP, Boers GH, Blom HJ, Trijbels FJ, Eskes TK. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet 1992;339: 1122–3.[Medline]
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16. 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;60:820–5.[Medline]
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