Prospective Evaluation of the Risk Conferred by Factor V Leiden and Thermolabile Methylenetetrahydrofolate Reductase Polymorphisms in Pregnancy

Abstract

Abstract-Factor V (FV) Leiden and thermolabile methylenetetrahydrofolate reductase (MTHFR) are 2 common polymorphisms that have been implicated in vascular thrombosis. We determined whether these mutations predicted an adverse outcome in pregnancy. Second, we looked for an interaction between these 2 mutations in patients with recurrent fetal loss or thrombosis in pregnancy. Primigravid subjects at their booking visit to the National Maternity Hospital (Holles Street, Dublin, Ireland) were screened for the polymorphisms. Thermolabile MTHFR and FV Leiden genotypes were detected by either restriction fragment length polymorphism or heteroduplex capillary chromatography. The carrier frequency of FV Leiden in the screened primigravid population was 2.7% (allele frequency 1.36%), all being heterozygous for the mutation. This value was lower than expected from previous studies in European populations. Forty-nine percent of the screened population (289 of 584) were heterozygous for thermolabile MTHFR, and 10.6% were homozygous (62 of 584). The frequency of the 2 polymorphisms was no higher in those who subsequently developed preeclampsia (nϭ12) or intrauterine growth retardation (nϭ9), and none of the screened population developed thrombosis. However, the frequency of FV Leiden was higher in patients who subsequently miscarried after the first trimester of pregnancy (allele frequency of 5.5%, Pϭ0.0356). Among those positive for FV Leiden, 3 of 27 miscarried, compared with 24 of 572 of FV Leiden-negative patients (11% versus 4.2%). No interaction was found between the 2 mutations in the control or patient populations. In patients with a prior history of venous thrombosis, the carrier rate of FV Leiden was increased (4 of 33, allele frequency of 7.6%, Pϭ0.0115). In contrast, the carrier frequency for thermolabile MTHFR was no higher, and there was no interaction between the 2 mutations. Neither mutation occurred at a significantly higher frequency in patients with a prior history of recurrent fetal loss. In conclusion, FV Leiden is a risk factor for thrombosis in pregnancy and possibly for second-trimester miscarriage independent of thermolabile MTHFR. However, prospective analysis suggests that the risk conferred by FV Leiden is low in a primigravid population. The thermolabile MTHFR genotype was not implicated in any adverse outcome. Key Words: factor V Leiden polymorphism Ⅲ thermolabile methylenetetrahydrofolate reductase polymorphism Ⅲ pregnancy Ⅲ venous thrombosis Ⅲ recurrent fetal loss Ⅲ genetic risk factors

Association of anticardiolipin antibody and C677T in methylenetetrahydrofolate reductase mutation in women with recurrent spontaneous abortions: a new path to thrombophilia?

“…Some authors agree that C677T, as a cause of hyperhomocysteinemia, could lead to RSA, 17,22 but others do not. 36,37 Homozygous C677T was detected in twelve women from Group 1 and in nine from Group 2. This difference was not significant.…”

Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to pre-eclampsia

“…Among the 40 eligible articles, four studies were excluded because the genotype distribution in the control population deviated significantly from the HWE. [14][15][16][17] There were four overlapping casecontrol studies in two publications, [18][19][20][21] and we chose the most recent studies. 19,20 Thus, 34 reports were eligible.…”

Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)

“…Systematic reviews are limited by the underlying published studies, the majority of which are retrospective giving an estimate of the magnitude of the increased risk of pregnancy complications which is not reliable and based on the relative risk instead of the absolute risk. Therefore, the expert panel chose to base their evaluation on the results of cohort studies performed in relatives of patients with a particular thrombophilic defect [24][25][26][27][28][29][30][31][32][33]. The overall absolute risk of VTE or obstetric complications is generally low; therefore, there is no clear indication for performing mass screening for thrombophilia.…”