P-912: Elevated Homocysteine levels in women with recurrent pregnancy loss (RPL) are associated with A1298C mutations of methylenetetrahydrofolate reductase (MTHFR) in the absence of C677T mutations

Abstract

Hyperhomocystenemia has emerged as a risk factor for arterial and venous thrombosis. Folic acid is an important factor in the metabolism of homocysteine. MTHFR is one of three enzymes that are responsible for the circulating form of folic acid. Recently, pregnancy complications such as RPL and fetal neural tube defects have been reported in association with hyperhomocysteinemia. Two frequent polymorphisms have been identified in the gene for MTHFR. The first, C677T, occurs in 10 to 15% of the white population and has been associated with hyperhomocysteinemia. The second, A1298C, is also found frequently but, to date, has not been associated with hyperhomocysteinemia. The purpose of this study was to identify the frequency of elevated homocysteine in a populataion of women with a history of RPL, and to determine the association with the mutations C677T and A1298C. Folate deficiency is also a common cause of hyperhomocysteinemia. Single-center, prospective study. Women with RPL were included in this study if they had at least two consecutive pregnancy losses by the same partner. All women had a complete evaluation including karyotypes, assessment of the uterine cavity, hormonal tests for TSH, prolactin, midluteal progesterone, fasting insulin and glucose, autoimmune tests for lupus anticoagulant and anticardiolipin antibodies, a thrombophilia panel, and cervical cultures. Homocysteine levels were determined by immunoassay on a fasting sample. Levels were considered abnormal if values were greater than 10.4 umol/L. All patients with elevated levels of homocysteine had blood drawn for DNA analysis of the MTHFR gene by PCR amplification followed by restriction analysis.The diaganostic sensitivity is > 99%. Thirty-six of two humdred and seven (17.4%) of women with RPL were found to have and elevated homocysteine. The following MTHFR polymorphisms were identified: MTHFR A1298C heterozygous 9/36 25.0%, MTHFR A1298C homozygous 3/36 8.3%, MTHFR C677T heterozygous 7/36 19.4%, MTHFR C677T/A1298C 8/36 22.2%, MTHFR wild type, normal 9/36 25.0% Elevated homocysteine is found frequently in women with RPL. This is probably an underestimate because virtually all of these women were taking prenatal vitamins with folate, vitamin B6, and vitamin B12 at the time of the assay. Approximately one-third of the women had hyperhomocysteinemia associated with the A1298C polymorphism in contrast to what is routinely reported in the literature. Another one-third of patients had polymorphisms at C677T or combinations of C677T and A1298C while one-third of women had no mutations identified. Fasting homocysteine is easy to test for and is easily treated with supplemental B vitamins (folate, B6, B12). When elevations of homocysteine are found associated with MTHFR mutations, women should be advised that they have an increased lifetime risk of thrombosis, that her parents and siblings should be screened, and that she should stay on lifelong B vitamin supplementation.