Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in preeclampsia

BACKGROUND: The association between thrombophilic variants (Leiden mutation of the factor V gene, G20210A mutation of the prothrombin gene and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene) with preeclampsia was investigated in a north-eastern Italian population. METHODS: Fifty-eight preeclamptic (PE) women and 74 normal pregnancies were evaluated. Genotypes were determined by polymerase chain reaction. RESULTS: The frequency of heterozygous carriers of the factor V Leiden was similar between PE women (5.2%) compared to the control subjects (4.1%; p 0.76). Also the frequencies of G20210A and C677T mutations were similar between PE and control subjects. CONCLUSIONS: In this population, we found no difference in the prevalence of genetic risk factors for thrombosis in women with preeclampsia compared with control subjects.     

Third trimester nonrecurrent fetal loss is associated with factor V Leiden and prothrombin gene mutations.

OBJECTIVE: To determine the role of factor V Leiden and prothrombin gene mutation in the pathogenesis of unexplained second and third trimester nonrecurrent fetal loss. MATERIALS AND METHODS: One hundred and fourteen women with unexplained nonrecurrent late fetal loss made up the study group, and 106 normal pregnant women with a history of delivery of at least one healthy fetus and no history of late fetal loss made up the control group. The study group was further divided into two subgroups: second (n = 36) and third (n = 78) trimester fetal loss. All women were tested for factor V Leiden and G20210A prothrombin gene mutations. RESULTS: Twenty-one (18.4%) of the women in the study group and seven (6.6%) of the women in the control group were heterozygous carriers of factor V Leiden mutation (OR = 3.19). Eleven (9.6%) of the women in the study group and three (2.8%) of the women in the control group were heterozygous carriers of prothrombin gene mutation (OR = 3.66). In assessing with regard to trimesters, 18 (23%) factor V Leiden and 10 (12.8%) prothrombin gene mutations were present in the group of third trimester fetal loss (OR = 4.24 and OR = 5.04, respectively). Three (8.3%) factor V Leiden and one (2.7%) prothrombin gene mutation were detected in women with second trimester fetal loss (OR = 1.28 and OR = 0.40, respectively). CONCLUSION: Factor V Leiden and prothrombin gene mutations were associated with third trimester nonrecurrent fetal loss. These mutations should be screened in women with third trimester but not second trimester unexplained nonrecurrent late fetal loss.     

Ethnic differences in the association of factor V Leiden mutation and the C677T methylenetetrahydrofolate reductase gene polymorphism with preeclampsia

OBJECTIVE: This case-control study evaluates the association of the factor V Leiden mutation with preeclampsia and potential synergistic effects of the MTHFR-677T and factor V Leiden mutations with regard to disease risk in two different ethnic populations. STUDY DESIGN: 198 women and their 143 newborns from Germany/Croatia and Indonesia with normal pregnancy or preeclampsia participated in the study. The factor V Leiden mutation was determined by direct sequencing and the MTHFR genotype by a PCR-based RFLP method. RESULTS: The factor V Leiden mutation is rare in Indonesians. In Germans/Croatians, the frequency of the mutation was significantly increased in mothers with preeclampsia compared to controls. No disease association was found for combined factor V Leiden/MTHFR-677T genotypes on the maternal and fetal level. CONCLUSIONS: Our results underline the need for a clear distinction of ethnicity in association studies of functional gene polymorphisms. They further support the concept of preeclampsia as a complex disease with variable contributions of disease genes in different ethnic groups.     

Factor V Leiden and prothrombin 20210 G-A mutations in controls and in patients with thromboembolic events during pregnancy or the puerperium

Factor V Leiden and prothrombin 20210 G-A mutations are independent risk factors for venous thrombosis. We studied the frequency of these mutations in 35 patients who had thromboembolic events during pregnancy and puerperium, and in 32 women who had a history of uncomplicated pregnancy, delivered either vaginally or by cesarean section, and did not have a past history of thromboembolism. Factor V Leiden mutation was present in 7 patients (20%) in the study group. Of these 7 patients, 1 was homozygote, whereas the remaining 6 were heterozygote for the mutation. Prothrombin 20210 G-A mutation was present in 2 patients (5.7%) in the study group. In the control group none of the 32 patients was positive for the factor V Leiden and prothrombin 20210 G-A mutations. Our findings indicate that the factor V Leiden mutation is an important risk factor for thromboembolic disease during pregnancy or puerperium.     

Prevalence of antiphospholipid antibodies, factor V G1691A (Leiden) and prothrombin G20210A mutations in early and late recurrent pregnancy loss

OBJECTIVE: We assessed the prevalence of inherited (FV-Leiden and PRT G20210A), and acquired (anti-PL antibodies) risk factors among habitual aborters in Tunisia. STUDY DESIGN: We studied prospectively 146 patients with > or =3 consecutive early, late, or early-late recurrent pregnancy losses, together with 99 age-matched controls. Anticardiolipin antibodies (ACL), lupus anticoagulant (LA), and APC resistance (APCR) were detected by ELISA, dilute Russell Viper Venom Time (dRVVT), and coagulation tests, respectively, and FV-Leiden and PRT G20210A genotypes were assessed by PCR. RESULTS: Anti-PL antibody frequencies were 45 and 9% among patients and controls, respectively (P < 0.001), with positive LA only (P = 0.004), or combined elevated ACL-positive LA being consistently higher (P < 0.001) among patients than controls. FV-Leiden (20.54% versus 6.06%), but not PRT G20210A (2.74% versus 4.04%) was significantly higher in patients versus controls. Among LA-positive cases higher prevalence of G/A (14/146 versus 1/99) and A/A genotypes (4/146 versus 0/99) were seen, and among ACL-positive cases higher prevalence of G/A (10/146 versus 0/99) and A/A genotypes (2/146 versus 0/99) were recorded. CONCLUSIONS: Anti-PL antibodies and FV-Leiden, but not PRT G20210A, are associated with recurrent idiopathic pregnancy losses in Tunisian women.     

The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation

Objective To observe the effect of thrombophylaxis on pregnancy in women with a history of unexplained recurrent pregnancy loss also carrying the factor V Leiden mutation.
Methods Between 1 January and 31 December 1996, activated protein C (APC) resistance and factor V Leiden mutation were prospectively measured in 56 nonpregnant women, with a history of two or more unexplained recurrent pregnancy losses. During the same study period, seven women carrying the factor V Leiden mutation conceived, and were subsequently followed throughout their pregnancy. Subcutaneous low molecular weight heparin (LMWH, enoxaparin, 40 mg/day) and oral low dose aspirin (100 mg/day) were administered throughout the pregnancies, starting at early first trimester. Ultrasound and Doppler umbilical and fetal middle cerebral arterial flow studies were performed in the second and third trimesters, and the course and outcome of the pregnancies were documented.
Results Activated protein C resistance and factor V Leiden were found in 20 (36%) and 12 (21%) women of the study, respectively. Five of the seven pregnancies occuring progressed uneventfully to term with normal fetal growth, normal Doppler flow studies and uneventful neonatal outcome. Two of the seven women had early missed abortions.
Conclusions Thrombophylaxis, beginning in early pregnancy, in women with unexplained recurrent pregnancy loss associated with factor V Leiden mutation, seems to be safe and allow normal fetal development and good neonatal outcome. To prove the efficacy of thrombophylaxis by LMWH and low dose aspirin in this setting prospective controlled studies seem to be justified.     

A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction

OBJECTIVE: The purpose of this study was to conduct a systematic review of the literature of studies that examined the association between factor V Leiden and/or prothrombin gene variant and intrauterine growth restriction. STUDY DESIGN: This systematic review of studies assesses the association between factor V Leiden and/or prothrombin gene variant and intrauterine growth restriction. RESULTS: Ten case-control studies fulfilled the selection criteria for inclusion in the meta-analysis. There was a significant association between factor V Leiden and intrauterine growth restriction (odds ratio, 2.7; 95% CI, 1.3-5.5) and prothrombin gene variant and intrauterine growth restriction (odds ratio, 2.5; 95% CI, 1.3-5.0). Five cohort studies were identified in the systematic review; 3 studies were prospective (2 full publications), and 2 studies were retrospective (1 full publication). Combining the 2 full publication prospective studies yields a summary relative risk of 0.99 (95% CI, 0.5-1.9). CONCLUSION: This meta-analysis of case-control studies suggests that the factor V Leiden and prothrombin gene variant both confer an increased risk of giving birth to an intrauterine growth restricted infant, although this may be driven by small, poor-quality studies that demonstrated extreme associations. Large well-conducted prospective cohort studies are required to determine definitively whether an association between thrombophilia and intrauterine growth restriction is present.     

Absence of Factor V Leiden,thrombomodulin and prothrombin gene variants in Black South African women with pre-eclampsia and eclampsia

It has been suggested that gene aberrations may contribute to vascular endothelial dysfunction of pre-eclampsia in Caucasian and Japanese women. This study was undertaken to examine the association between pre-eclampsia in Black Zulu speaking South African women and the Factor 5 Leiden mutation. 100 patients with pre-eclampsia comprised the study group. The control group comprised 110 normotensive pregnant women of the same population group. Genotyping was performed to detect the G or A allele at residue 506 of the Factor V gene, and the C or T allele at residue 455 of the thrombomodulin gene. Our findings demonstrate that these particularly genetic loci are of little use in disease association studies for pre-eclampsia in homogenous Zulu speaking Africans.     

Homozygous factor V Leiden mutation in a woman with multiple adverse pregnancy outcomes

We report a case with one intrauterine fetal death (IUFD) at 32 weeks of gestation, one premature delivery at the same week, and one abortion of unknown etiology at 12 weeks of gestation. We discuss that the presence of homozygosity for Factor V Leiden may be associated with placental insufficiency in this woman. Application of anticoagulant therapy may have been beneficial in her current pregnancy. Received: 1 February 2000 / Accepted: 9 May 2000     

Screening for pre-eclampsia in a low-risk population at 24 weeks: uterine artery Doppler flow velocimetry and genetic variants of factor V, prothrombin and methylenetetrahydrofolate reductase

AIM: Pre-eclampsia is one of the major causes of maternal and fetal morbidity and mortality. The aim of this study was to evaluate the clinical usefulness of screening of genetic thrombophilic mutations and uterine artery Doppler flow velocimetry at 24 weeks of gestation in the prediction of pre-eclampsia in low risk pregnant women. METHODS: We performed the genetic analysis for Leiden mutation of factor V gene (FV), G20210A mutation of the prothrombin gene (PT) and C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene in 103 women that had already attended routine ultrasonography scanner at 24 weeks at our Department. RESULTS: The frequency of heterozygous carriers of the Leiden FV was 17.4% in women with pre-eclampsia and abnormal artery Doppler flow velocimetry compared with 3.12% in patients with normal pregnancies. This difference was statistically significant (P<0.05). The frequency of mutation G20210A of PT gene was 1.5% vs 4.3% between women with normal pregnancies and with pre-eclampsia. This difference is not statistically significant. The frequency of homozygous patients for the C677T mutation of MTHFR gene among patients with pre-eclampsia was 21.7% and in the control group was 10.3%, but this difference is not statistically significant. No thrombophilic genes variants were found in women with pre-eclampsia and normal uterine artery Doppler flow velocimetry. CONCLUSION: We demonstrated the important association between FV Leiden mutation, abnormal uterine artery Doppler flow velocimetry at 24 weeks and pre-eclampsia in our low-risk population.     

Factor V Leiden G1691A and factor II G20210A point mutations and pregnancy in North-West of Iran

Purpose  

The roles of several hereditary predispositions for venous thromboembolism have been evaluated in women with habitual abortion. We studied the prevalence of FV Leiden G1691A and FII G20210A mutations in women with habitual abortion and healthy controls.     

Genetic susceptibility to preeclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation

OBJECTIVE: The purpose of this study was to evaluate the association between preeclampsia and 3 relatively common mutations that are important in the development of vascular disease and thrombosis; these are similar to conditions observed in pregnancies complicated by preeclampsia. STUDY DESIGN: Deoxyribonucleic acid was extracted from whole blood or cheek swabs of 281 patients with preeclampsia and 360 control subjects (all white). Control subjects consisted of women who had undergone at least 2 term pregnancies unaffected by preeclampsia. Mutation frequencies among patients with preeclampsia and control subjects were compared by standard chi2 analysis, with P <.05 considered significant. RESULTS: Thirty-three of 281 women with preeclampsia (11.7%) and 22 of 193 women with severe preeclampsia (11.4%) were homozygous for cytosine-to-thymine substitution at nucleotide 677 in the gene for methyltetrahydrofolate reductase (MTHFR), versus 41 of 360 control subjects (11.4%; difference not significant). Forty of 258 women with preeclampsia (15.5%) and 22 of 175 women with severe preeclampsia (12.6%) were heterozygous for the insertion of 68 bases at position 844 in the gene for cystathionine beta-synthase (CBS), versus 58 of 332 control subjects (17.5%). Fifteen of 250 women with preeclampsia (6.0%) and 11 of 169 with severe preeclampsia (6.5%) were heterozygous for the Leiden mutation (glycine-to-alanine substitution at nucleotide 1691) in the gene for factor V (F5), versus 12 of 253 control subjects (4.7%; difference not significant). CONCLUSION: In this white population a missense mutation of MTHFR, an insertion mutation of CBS, and a missense mutation of F5 were not found to be associated with an increased risk for preeclampsia, either independently or in combination.     

Maternal carriership of factor V Leiden associated with pathological uterine artery Doppler measurements during pregnancy

To determine whether increased vascular resistance in the uterine artery is associated with carriership of factor V Leiden, a retrospective study was undertaken of 231 pregnant women who were monitored with Doppler velocimetry of the uterine arteries. These women had been part of a prospective study of 2480 pregnant women in whom factor V Leiden had been analysed. When compared with non-carriers of factor V Leiden, carriers had a tendency towards an increased proportion of pathological Doppler measurements, including a significant increase in bilateral uterine artery notches (7/33 vs 16/198, relative risk 3.1; 95% CI 1.2–8.1). This suggests an increased vascular resistance in the uteroplacental circulation among carriers of factor V Leiden.     

Use of selective factor V Leiden screening in pregnancy to identify candidates for anticoagulants

OBJECTIVE: To improve identification of gravidas at risk for thrombosis. Venous thromboembolic complications are a major cause of maternal mortality during pregnancy. Factor V Leiden, which causes activated protein C resistance, is the most prevalent thrombophilia in white populations. However, selective screening for factor V Leiden has not been evaluated previously for identifying women who might benefit from anticoagulant prophylaxis during pregnancy. METHODS: We constructed a risk score based on major risk factors such as overweight, family history of thrombosis, previous thrombosis, cesarean delivery, and preeclampsia. A cohort of 2384 women with known factor V Leiden status was studied. Using the risk score and its distribution, we explored possible strategies of doing selective testing for factor V Leiden and their consequences. RESULTS: During the postpartum period, but not antepartum, there is a possibility of identifying women at similar risk as those with a history of thrombosis. Women with a risk score of 2 (4% of women, 0.2% risk of thrombosis) would be screened for factor V Leiden, and those with a resulting risk score of at least 3 (ie, 1.2% risk of thrombosis) would be treated for 6 weeks. Theoretically, for every 83 women treated at this risk level, one thrombotic episode might be prevented. CONCLUSION: By using a risk score, a subgroup of women who could benefit from selective factor V Leiden screening were identified postpartum.     

The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus

OBJECTIVE: We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. METHODS: Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. RESULTS: One hundred thirty-four FVL mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0-2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.08%, 95% confidence interval 0.02-0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P = .04), adjusted odds ratio 2.4 (95% confidence interval 1.0-5.2, P = .05). CONCLUSION: Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated. LEVEL OF EVIDENCE: II-2.     

Pregnancy outcome in women with factor V Leiden and recurrent miscarriage

We compared the outcome of 25 untreated pregnancies among women with recurrent miscarriage (RM) at <12 weeks' gestation who were heterozygous for factor V Leiden with women with unexplained RM. The livebirth rate was lower among pregnancies in carriers of factor V Leiden (12/25; 48%) compared with pregnancies in women with unexplained RM (175/307; 57%), but the difference did not reach statistical significance. The best possible treatment regimen to improve livebirth rate in this group of women needs to be assessed in the form of a randomised controlled trial.