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

Department of Clinical Pharmacology, Royal College of Surgeons in Ireland.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 02/2000; 20(1):266-70. DOI: 10.1161/01.ATV.20.1.266
Source: PubMed


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 (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 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%, P=0. 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.

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    • "Genotype and allele frequencies, HWE and NOS scale information are presented in Table S2 and Table S3. Of the total 114 studies, 20 different studies [27], [35], [40], [45], [73], [79], [85], [87], [94], [96], [105], [107], [109], [110], [115], [116], [122], [129], [135] showed significant deviations from HWE (18 studies concerned C677T and two studies concerned A1298C). Thirteen studies only reported combined genotypes (CC+CT, CT+TT, AC+CC), thus HWE could not be evaluated (12 studies concerned C677T [29], [41], [49], [51], [67], [69], [71], [77], [100], [101], [114], [119] and one study concerned A1298C [119]). "
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    ABSTRACT: Several epidemiological studies have investigated the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with hypertension (H) or hypertension in pregnancy (HIP). However, the results were controversial. We therefore performed a comprehensive meta-analysis to provide empirical evidences on the associations. The English and Chinese databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, cumulative meta-analysis and assessment of publication bias were performed in our study. A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism. Overall, the C677T polymorphism was significantly associated with H and HIP (H & HIP: OR = 1.26, 95% CI = 1.17-1.34; H: OR = 1.36, 95% CI = 1.20-1.53; HIP: OR = 1.21, 95% CI = 1.08-1.32). Stratified analysis by ethnicity revealed a significant association among East Asians and Caucasians, but not among Latinos, Black Africans, and Indians and Sri Lankans. In the stratified analyses according to source of controls, genotyping method, sample size and study quality, significant associations were observed in all the subgroups, with the exception of population based subgroup in H studies and large sample size and "others" genotyping method subgroups in HIP studies. For the A1298C polymorphism, no significant association was observed either in overall or subgroup analysis under all genetic models. This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "In line with the aforementioned considerations, the estimates from populationbased prospective cohort studies of pregnant women with heterozygous FV Leiden showed only a modest increase in the absolute risk of VTE during pregnancy. In a Swedish prospective study enrolling 270 pregnant women carriers of FV Leiden, three women developed VTE during pregnancy (1%) [39], while two subsequent prospective cohort studies did not observe VTE during pregnancy among 16 and 134 pregnant women carriers of FV Leiden, respectively [45] [46]. The lower absolute risk observed in population-based studies compared to family studies is possibly due to co-segregation of unknown thrombophilias in affected families and therefore, women with thrombophilia and a positive family history should be considered at higher risk than those with a negative family history (Table 2). "
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    ABSTRACT: Venous thromboembolism (VTE) is a leading cause of maternal mortality and morbidity during pregnancy in developed countries. The incidence of VTE per pregnancy-year increases about 4-fold during pregnancy and at least 14-fold during the puerperium. Risk factors include a personal history of VTE, presence of inherited or acquired thrombophilia, a family history of VTE and general medical conditions, such as immobilisation, overweight, varicose veins, some haematological diseases and inflammatory disorders. VTE is considered potentially preventable with the prophylactic administration of anticoagulants, but there are no high quality randomized clinical trials that compared different strategies of thromboprophylaxis in pregnant women. Balancing the absolute risk of VTE against the risks of exposure to anticoagulants, this review provides advice regarding which women may benefit from thromboprophylaxis during and after pregnancy.
    Full-text · Article · Feb 2012 · Thrombosis Research
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    • "Dudding et al examined both factor V Leiden and prothrombin gene mutation and concluded that neither mutation was associated with the development of either pre-eclampsia or fetal growth restriction (Dudding et al. 2008). Another study examined factor V Leiden and MTHFR 677 and found no significant increase in the risk of adverse pregnancy outcomes although the small sample size (n=584) and low prevalence of factor V Leiden (2.7%) meant that this cohort was underpowered to detect a significant difference (Murphy et al. 2000). Three studies investigated factor V Leiden, prothrombin gene mutation and also the MTHFR 677 polymorphism (Salomon et al. 2004; Karakantza et al. 2008; Said et al. 2010a). "

    Full-text · Chapter · Nov 2011
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