Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy

Factor V (FV) Leiden and thermolabile methylenetetrahydrofolate reductase ( MTHFR) are 2 common polymorphisms that have been implicated in vascular thr ombosis. We determined whether these mutations predicted an adverse outcome in pregnancy. Second, we looked for an interaction between these 2 mutatio ns in patients with recurrent fetal loss or thrombosis in pregnancy. Primig ravid subjects at their booking visit to the National Maternity Hospital (H olles Street, Dublin, Ireland) were screened for the polymorphisms. Thermol abile MTHFR and FV Leiden genotypes were detected by either restriction fra gment length polymorphism or heteroduplex capillary chromatography. The car rier frequency of FV Leiden in the screened primigravid population was 2.7% (allele frequency 1.36%), all being heterozygous for the mutation. This va lue was lower than expected from previous studies in European populations, Forty-nine percent of the screened population (289 of 584) were heterozygou s for thermolabile MTHFR, and 10.6% were homozygous (62 of 584). The freque ncy of the 2 polymorphisms was no higher in those who subsequently develope d preeclampsia (n=12) or intrauterine growth retardation (n=9), 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%, P=0.0356), Among those po sitive for FV Leiden, 3 of 27 miscarried, compared with 24 of 572 of FV Lei den-negative patients (11% versus 4.2%). No interaction was found between t he 2 mutations in the control or patient populations. In patients with a pr ior history of venous thrombosis, the carrier rate of FV Leiden was increas ed (4 of 33, allele frequency of 7.6%, P=0.0115), In contrast, the carrier frequency for thermolabile MTHFR was no higher, and there was no interactio n between the 3 mutations. Neither mutation occurred at a significantly hig her frequency in patients with a prior history of recurrent fetal loss. In conclusion, FV Leiden is a risk factor for thrombosis in pregnancy and poss ibly for second-trimester miscarriage independent of thermolabile MTHFR. Ho wever, prospective analysis suggests that the risk conferred by FV Leiden i s low in a primigravid population. The thermolabile MTHFR genotype was not implicated in any adverse outcome.