Impact of 677C > T Mutation of the 5,10- Methylenetetrahydrofolate Reductase on IVF Outcome: Is Screening Necessary for All Infertile Women? Roberto Marci, 1 Franco Lisi, 2 Ilaria Soave, 1 Giuseppe Lo Monte, 1 Alfredo Patella, 1 Donatella Caserta, 3 and Massimo Moscarini 3 Aim: Polymorphisms of genes connected to folate metabolism may alter the beneficial effect of folic acid on the methyl group cycle. The most common variation is the 677C > T polymorphism of the gene of the 5,10-methy- lentetrahydrofolate reductase (MTHFR). The aim of this study is to investigate of what influence, if any, does MTHFR 677C > T mutation have on female fertility and on the in vitro fertilization (IVF) outcome. Patients and Methods: Data of 273 patients were retrospectively analyzed. The study group (group A) consisted of 103 women, homozygous for the MTHFR 677C > T mutant genotype. The control group (group B) consisted of 170 patients without the mutation. Results: A longer stimulation duration was found in group A and the total amount of recombinant follicle-stimulating hormone (r-FSH) needed was appreciably higher. The fertilization rate was significantly higher in group B, although the implantation rate and clinical pregnancies were similar in both groups. Conclusions: Alteration of inherited thrombophilic factors is connected with early pregnancy loss and IVF implantation failure. Our study showed an abortion rate higher, but not statistically significant, in group A. Based on these findings, our study suggests that MTHFR 677C > T mutation does not affect the IVF outcome and patients without thrombophilic risk factors undergoing an IVF cycle should not all be screened for thrombophilic disorders. Introduction F olate is an important vitamin B that is involved in several physiological and pathological processes, includ- ing reproduction (Tamura and Picciano, 2006). It is a funda- mental cofactor for amino acid metabolism, for purine and pyrimidine synthesis and for proteins, lipids, and nucleic acid methylation. Deficiency of folic acid could alter these cellular pathways and lead to accumulation of homocysteine, a thiol- containing amino acid, originated from the metabolism of methionin ( Jacques et al., 2001). Thus folates, acting as methyl donors, allow homocysteine to be remethylated to methionine (Lucock, 2000). Several genes are involved in folate absorption and me- tabolism, and polymorphisms of these genes may alter the beneficial effect of folic acid on the methyl group cycle (Nar- ayanan et al., 2004). The most common variation is the 677C > T polimorphism of the gene of the 5,10-methylente- trahydrofolate reductase (MTHFR) (Frosst et al., 1995). This enzyme is physiologically involved in the remethylation process of homocysteine to methionine and is the precursor of the ultimate methyl donor S-adenosylmethionine, which is involved in hundreds of biologic transmethylation reactions (Yamada et al., 2005). This mutation consists of an alanine-to- valine substitution at amino acid position 222, resulting in a thermolabile enzyme with only 30% of the wild-type activity (Frosst et al., 1995) that could lead to accumulation of homo- cysteine and to aberrant methylation reactions. Folate deficiency and increased homocysteine levels appear to have a high impact on female reproductive functions. Re- lated possible alterations are reduced cell division (Gmyrek et al., 2005), abnormal methylation reactions (Forges et al., 2007), altered nitric oxide metabolism (Thaler and Epel, 2003), increased oxidative stress (Agarwal et al., 2005), and apoptosis (Hussein, 2005). Severe folate deficiency before conception and during gestation could impair oocyte development, fol- liculogenesis, endometrial receptivity, implantation process, and fetal development. In addition, a recent study showed how multivitamin supplements, including folate, decrease the risk of anovulatory infertility (Chavarro et al., 2007). 1 Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy. 2 CERMER, Centro Ricerca Medicina della Riproduzione, Clinica Villa Mafalda, Rome, Italy. 3 Department of Woman Health and Territory’s Medicine, University of Rome Sapienza, S. Andrea Hospital, Rome, Italy. GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 16, Number 9, 2012 ª Mary Ann Liebert, Inc. Pp. 1011–1014 DOI: 10.1089/gtmb.2012.0087 1011