Evaluation of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations in patients with severe pregnancy complications in northern Finland

BACKGROUND: Thrombosis in placenta may lead to severe pregnancy complications. Most important inherited thrombophilias are factor V Leiden mutation, prothrombin mutation, and methylenetetrahydrofolate reductase mutation. The aim of our research was to evaluate the prevalence of inherited thrombophilias in severe pregnancy complications and in normal pregnancies. MATERIAL AND METHODS: The study subjects with severe preeclampsia, intrauterine growth restriction, placental abruption or fetal death were collected during the period 1999-2004 from Oulu University Hospital. We also collected during the same period voluntary parturients with normal pregnancy outcome as the control group. FVL, FII, and MTHFR gene mutations of the patients and controls were analyzed. RESULTS: We found a significant difference in the prevalence of FVL mutation between the groups. There were 9.5% FVL mutations in the study group compared to 1.8% in the control group; the observed difference between prevalences was 7.7% (95% CI 2.0-13.4). No statistical difference was found in the FII or MTHFR mutations between the groups. All FV and FII mutations were heterozygous and all the MTHFR mutations homozygous. CONCLUSION: Women with thrombophilia have a risk for severe pregnancy complications. Randomized controlled trials are needed to assess the influence of low-molecular-weight heparin in pregnant women with thrombophilia.     

Hemorragia intraventricular fetal por factor V Leiden

We present a case of fetal intraventricular hemorrhage diagnosed at week 28 of gestation. The cause was resistance to activated protein C due to factor V Leiden. We describe the maternal and fetal risk factors associated with intraventricular hemorrhage, as well as sonographic findings.     

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.     

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.     

First trimester cervical length is associated with mid-trimester loss

Objective: To study the value of the cervical length (CL) measurement at 11–14 weeks in predicting second trimester miscarriage occurring at 16–24 weeks.

Methods: Prospective study in routine obstetric population using transvaginal ultrasound examination to measure the length of the endocervical canal at 11–14 weeks.

Results: The study group consisted of 2836 singleton pregnancies. Eleven (0.0038%) women miscarried between 16 and 24 weeks whereas 2825 delivered after 34 weeks. CL was significantly shorter (Mann–Whitney U test, p?=?0.001), in women that had a second trimester miscarriage in comparison to those who delivered after 34 weeks (median CL 28?mm versus 32?mm, respectively). First trimester CL was predictive of a late miscarriage (OR?=?0.7093304, R^2?=?0.1211, AUC?=?0.7838, p?<?0.001). The detection rate was 63.64% for 20% screen positive rate.

Conclusions: First trimester endocervix is significantly shorter in women destined to miscarry between 16 and 24 weeks. In low risk singleton pregnancies, first trimester CL can be useful in predicting second trimester miscarriage.     

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.     

Genetic thrombophilic defects (Factor V Leiden, prothrombin G20210A, MTHFR C677T) in women with recurrent fetal loss

Maternal thrombophilia (inherited and acquired) has recently been identified as a major cause of thrombembolism, but it may also contribute to adverse pregnancy outcomes and recurrent pregnancy loss. To determine the association of specific inherited thrombophilias and recurrent fetal loss (RFL), three gene mutations (Factor V Leiden, prothrombin G20210A, MTHFR C677T) were investigated. The prevalence of the thrombophilic markers was compared in 156 women with history of fetal loss in different trimester of pregnancy and 80 matched controls. At least one thrombophilic defect was found in 28.2% of total study group women compared with 16.2% in controls (p=0.06; OR-2.02) and in 50% of women with RFL in third trimester (p=0.008; OR-5.15). Factor V Leiden was more common in the group of women with fetal loss in third trimester (37.5%) compared to the controls (6.2%) (p=0.002; OR-9.0). Presence of FVL was associated with a significant increased risk for RFL in second and third trimester (OR-6.25; P<0.001) and significant protection for RFL in first trimester (OR-0.16; P<0.001). Mutation prothrombin G20210A or MTHFR C677T was more common in group of women with fetal loss in first trimester compared to the controls (28.3% vs. 11.2% respectively; p=0.009; OR-3.11). The presence of either of these mutations was associated with no significant increased risk for RFL in first trimester (OR-2.5). Genetic thrombophilic defects are common in women with RFL and are associated with late fetal loss. This association is manifest by FVL rather than total number of defects involved.     

Mutations in the factor V,prothrombin and MTHFR genes are not risk factors for recurrent fetal loss

Objective: Recurrent fetal loss, defined as the occurrence of three or more consecutive spontaneous abortions regardless of previous live birth, is a condition that affects about 2% of all reproductive-aged women. The role of gene mutations in recurrent pregnancy loss is not fully understood. The present research examined the relationship between factor V Leiden, factor V HR2, prothrombin G20210A and MTHFR and recurrent fetal loss in a case-control study. Methods: Women aged 22-45 with a history of three or more fetal losses, being seen at a perinatal medicine clinic in New Jersey or Georgia, were eligible as cases. Overall, the study consisted of 60 women with three or more fetal losses and 92 women with at least one successful pregnancy. Results: Factor V HR2 and MTHFR were not related to recurrent fetal loss. The prothrombin G20210A mutation appeared to confer an elevation in risk but the association was based upon small numbers and was not statistically significant (OR 4.8, 95% CI 0.50-47.2). Cases were 90% less likely to have the factor V Leiden mutation than controls (OR 0.10, 95% CI 0.01-0.81). Conclusions: Our study did not demonstrate that women who are carriers of the factor V, prothrombin, or MTHFR mutations are at higher risk of recurrent fetal loss than women without these mutations. In regards to factor V Leiden, the prevalence in our cases (1.7%) was not statistically different from the known population prevalence of 5%. However, the high prevalence in our controls (14%) was unusual. Factor V Leiden may protect against bleeding in early pregnancy.     

Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage

Objective To determine whether there is an association between early recurrent miscarriage (before 10 weeks of pregnancy) and Factor V Leiden and G20210A prothrombin mutations.
Design A prospective study.
Setting Department of Gynaecology and Obstetrics, Saint Antoine Hospital, Paris, France.
Population Two groups of women: those with early unexplained recurrent miscarriage before 10 weeks of pregnancy (   n =260  ) and control healthy women without a previous history of thromboembolism (   n =240  ).
Methods Screening for defects in the protein C anticoagulant pathway was performed using the anticoagulant response to agkistrodon confortrix venom (ACV test). Protein C and Factor V Leiden mutation testing was performed for each low ACV level. Each sample was tested for the G20210A prothrombin mutation.
Results Factor V Leiden and G20210A mutations were found to be associated with early recurrent spontaneous miscarriage before 10 weeks of pregnancy, the odds ratios being 2.4 (95% CI 1–5) and 2.7 (95% CI 1–7), respectively. Similar results were found whether or not women had had a previous live birth.
Conclusions Early recurrent miscarriage before 10 weeks of pregnancy is significantly associated with Factor V or G20210A prothrombin mutations. These results indicate a possible role for anticoagulant prevention in these early miscarriages.     

M385T polymorphism in the factor V gene, but not Leiden mutation, is associated with placental abruption in Finnish women

This study determines whether genetic variability in the gene encoding factor V contributes to differences in susceptibility to placental abruption. Allele and genotype frequencies of three single nucleotide polymorphisms (SNPs) in the factor V gene leading to nonsynonymous changes (M385T in exon 8, and R485K and R506Q [Leiden mutation] in exon 10) were studied in 116 Caucasian women with placental abruption and 112 healthy controls. Single-point analysis was expanded to haplotype analysis and haplotype frequencies were estimated using an expectation-maximisation (EM) algorithm. Comparison of single-point allele and genotype distributions of SNPs in exon 8 and exon 10 of the factor V gene revealed statistically significant differences in M385T allele (P = 0.021) and genotype ( P = 0.013) frequencies between the patients and the control subjects. The C allele of SNP M385T was significantly less frequent among the patients (7%) vs. the control subjects (13%), at an odds ratio of 0.48 (95% CI 0.25-0.91). Allele and genotype differences between the patients and control subjects as regards R485K and Leiden mutation were not significant. In haplotype estimation analysis, there was a significantly lower frequency of haplotype T-R-R encoding the T385-R485-R506 variant in the group with placental abruption vs. the control group (P = 0.038) at an odds ratio of 0.519 (95% CI 0.272-0.987). We conclude that T385 is less frequent among the patient group than in the control group. The M385T variant in the factor V gene other than the Leiden mutation may play a role in disease susceptibility.     

Primary habitual abortions are associated with high frequency of factor V Leiden mutation

OBJECTIVE: To analyze the prevalence of the mutation G1691A in factor V gene (Leiden mutation), of mutation C677T in the methylenetetrahydrofolate reductase (MTHFR) gene, and of polymorphism in G20210A in the prothrombin gene in women with recurrent abortions; further, to identify a subgroup at higher risk of being carriers of these mutations. DESIGN: Prospective case control evaluation. SETTING: University clinic. PATIENT(S): Eighty-four women with 3 or more consecutive miscarriages were compared with 69 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Polymerase chain reactions were performed to identify the mutations G1691A in factor V and C677T in MTHFR genes and the polymorphism G20210A in the prothrombin gene. RESULT(S): In women with primary habitual abortions, 27.8% carried the Leiden mutation. No difference was observed in the prevalence of mutation C677T in the MTHFR gene or in polymorphism G20210A in the prothrombin gene. CONCLUSION(S): The Leiden mutation may play a considerable role for women having primary recurrent abortions.     

HELLP syndrome and factor V Leiden

The association of thrombophilia and obstetrical complications is documented and well consistent with the hypothesis of an insufficient placental perfusion due to fibrin deposition as a major underlying pathophysiological mechanism. Factor V Leiden is one of the most frequent thrombophilic mutations. A high prevalence of this mutation has recently been reported in a group of 21 German women with haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. In this respect, we studied the prevalence of factor V Leiden in 18 women who were consecutively diagnosed at our Department of Obstetrics and Gynaecology as having HELLP syndrome, between 1995 and 1999.Women were tested either at the time of diagnosis or months or years after delivery for coagulation parameters, protein C (PC), protein S (PS), antithrombin III, lupus-like anticoagulant, anticardiolipin antibodies (ACA), activated protein C (APC) resistance and detection of the G1691A mutation (factor V Leiden). In all women, the parameters studied were normal and in none of the investigated cases was the G1691A mutation found. HELLP being a severe form of preeclampsia, we think that the reported association between factor V Leiden and HELLP may reflect the well-known association with preeclampsia.     

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.     

Fetal loss associated with second trimester amniocentesis

Objective  

To evaluate the fetal loss rate associated with second trimester amniocentesis.